ELEXACAFTOR (VX-445) +TEZACAFTOR (VX-661) +IVACAFTOR (VX-770)

“TRIKAFTA” (in USA) “KAFTRIO” (in UK)

2018

2018 Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, Ramsey BW, Rowe SM, Sass LA, Tullis E, McKee CM, Moskowitz SM, Robertson S, Savage J, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Taylor-Cousar JL; VX16-445-001 Study Group. VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles N Engl J Med. 2018 Oct 25;379(17):1612-1620. doi: 10.1056/NEJMoa1807120. Epub 2018 Oct 18. [Pubmed]

Dominic Keating

VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and ivacaftor (VX-445-tezacaftor-ivacaftor). The authors evaluated the effects of VX-445-tezacaftor-ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV₁) from baseline.

Results. In vitro, VX-445-tezacaftor-ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV₁ of up to 13.8 points in the Phe508del-MF group (P<0.001). In patients in the Phe508del-Phe508del group, who were already receiving tezacaftor-ivacaftor, the addition of VX-445 resulted in an 11.0-point increase in the percentage of predicted FEV₁ (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire-Revised.

The authors concluded the use of VX-445-tezacaftor-ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients. (Clinical trials NCT03227471 ; and EudraCT number, 2017-000797-11)

Dominic T Keating is Respiratory Physician at the Alfred Hospital · Department of Allergy, Immunology & Respiratory Medicine (AIRmed) Australia, Melbourne

2019

Middleton PG, Mall MA, Drevinek P, Lands LC, McKone EF, Polineni D, Ramsay BW, Taylor0Cousar JL, Tullis E, Vermeulen F, marifwada G, Mosowski SM, Nair N, Savage J, Simard C, Tian S, Waltz D, Xuan F, Jain Rassha for the VX17-445-i102 Study Group. Elexacaftor-tezacaftor-iavacaftor for cystic fibrosis with a single The 508del allele. N Eng J Med 2019; 381:1809-19. [Pubmed]

Peter Middleton

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal- function mutation (Phe508del–minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.

The authors conducted a phase 3, randomised, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor–tezacaftor–ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del–minimal function geno- types. Patients were randomly assigned to receive elexacaftor–tezacaftor–ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4.

A total of 403 patients underwent randomisation and received at least one dose of active treatment or placebo. Elexacaftor–tezacaftor–ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire– Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per litre lower (P<0.001 for all comparisons). Elexacaftor– tezacaftor–ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor–tezacaftor–ivacaftor group.

Conclusion – Elexacaftor–tezacaftor–ivacaftor was efficacious in patients with cystic fibrosis with Phe508del–minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (VX17-445-102 ClinicalTrials.gov number, NCT03525444.)

Professor Peter Middleton is Clinical Professor of Respiratory and Sleep Medicine Westmead Hospital and CF Research Group, Ludwig Engel Centre for Respiratory Research, University of Sydney.

Heijerman HGM, McKone EF, Downey DG, Van Braeckel E, Rowe SM, Tullis E Mall MA, Welter JJ, Ramsey BW, McKee CM, Marigowda G, Moskowitz SM, Waltz D, Sosnay PR, Simard C, Ahluwalia N, Xuan F, Zhang Y, Taylor-Cousar JL, McCoy KS; VX17-445-103 Trial Group. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Collaborators (45). Lancet. 2019 Oct 30. pii: S0140-6736(19)32597-8. doi: 10.1016/S0140-6736(19)32597-8. [Epub ahead of print] Full copy available [Pubmed]

Harry Heijerman

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.

This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548.

Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor.

The authors concluded Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.

Dr Harry Heijerman is at the Department of Pulmonology, University Medical Center Utrecht, Utrecht, Netherlands.

Taylor-Cousar JL, Mall MA, Ramsey BW, McKone EF, Tullis E, Marigowda G, McKee CM, Waltz D, Moskowitz SM, Savage J, Xuan F, Rowe SM.Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles.ERJ Open Res. 2019 Jun 17;5(2). pii: 00082-2019. doi: 10.1183/23120541.00082-2019. eCollection 2019 Apr. [Pubmed] Free PMC Article

Jennifer Taylor-Cousar

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR) that result in diminished quantity and/or function of the CFTR anion channel. F508del-CFTR, the most common CF-causing mutation (found in ∼90% of patients), causes severe processing and trafficking defects, resulting in decreased CFTR quantity and function. CFTR modulators are medications that increase the amount of mature CFTR protein (correctors) or enhance channel function (potentiators) at the cell surface. Combinations of CFTR correctors and potentiators (i.e. lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous for F508del-CFTR and a minimal function mutation, i.e. a mutation that produces either no protein or protein that is unresponsive to currently approved CFTR modulators. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and function in vitro and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two F508del–CFTR alleles. Here, we present the rationale and design of four randomised phase 3 studies, and their open-label extensions, evaluating VX-659 (ECLIPSE) or VX-445 (AURORA) plus tezacaftor and ivacaftor in patients with one or two F508del–CFTR alleles.

Corresponding author Dr Steven Rowe, Gregory Flemming James Cystic Fibrosis Research Center, University of Alabama at Birmingham.A very comprehensive review of triple-combination CFTR modulators

Hoy SM. Elexacaftor/Ivacaftor/Tezacaftor: First Approval. Drugs. 2019 Nov 29. doi: 10.1007/s40265-019-01233-7. [Epub ahead of print]Author information.[Pubmed]
A fixed-dose combination tablet of the cystic fibrosis transmembrane conductance regulator (CFTR) corrector tezacaftor and the CFTR potentiator ivacaftor with the next-generation CFTR corrector elexacaftor (hereafter referred to as elexacaftor/ivacaftor/tezacaftor) [Trikafta™] has been developed by Vertex Pharmaceuticals Inc. to treat patients with the most common cystic fibrosis mutation (F508del). Its use has been associated with statistically significant and/or clinically meaningful improvements in lung function and respiratory-related quality of life compared with comparator regimens (placebo or ivacaftor/tezacaftor) in multinational phase II and III studies, and in October 2019 elexacaftor/ivacaftor/tezacaftor was approved by the US FDA for the treatment of cystic fibrosis in patients aged ≥ 12 years who have ≥ 1 F508del mutation in the CFTR gene. A regulatory assessment for elexacaftor/ivacaftor/tezacaftor as a treatment for cystic fibrosis is underway in the EU. This article summarises the milestones in the development of elexacaftor/ivacaftor/tezacaftor leading to this first approval for the treatment of cystic fibrosis in patients aged ≥ 12 years who have ≥ 1 F508del mutation in the CFTR gene.

Dr S M Hoy is at Springer Nature, Private Bag 65901, Mairangi Bay, Auckland

2020

New Drug Hailed as Major Breakthrough in Cystic Fibrosis. Am J Med Genet A. 2020 Jan;182(1):8-9. doi: 10.1002/ajmg.a.61420.[Pubmed] This is my summary as their is no abstract: No authors are listed for this neat account of the progress in the development of CFTR modulator therapy from the FDA approval of ivacaftor (VX-771) in January 2012 for patients with one copy of the G551D mutation, to Orkambi, the combination of lumacaftor (VX-809) and ivacaftor, for those with 2 copies of the F508del mutation in 2015, to another drug combination of tezacaftor (VX-661) and ivacaftor (Symdeko) in 2018 for those people with at least one F508del mutation.

In 2019 the combination drug Trikafta, combining elexacaftor (VX-445), ivacaftor (Kalydeco) and tezacaftor (VX-661), was approved for patients aged 12 years and over with at least one F508del – a group comprising some 90% of the CF population. Approval was based on two phase III clinical trials (Middleton et al, 2019; Heijerman et al, 2019). Sadly these drugs are very expensive and funding is and will remain a major problem.

Cuevas-Ocaña S, Laselva O, Avolio J, Nenna R. The era of CFTR modulators: improvements made and remaining challenges Breathe (Sheff). 2020 Jun;16(2):200016. doi: 10.1183/20734735.0016-2020. [Pubmed] PMC article.

Sara Cuevas-Ocaña

The entry into the clinic of CFTR modulators such as TRIKAFTA has significantly improved life for 90% CF patients carrying one or two F508del mutations but challenges remain for rare CFTR mutations and the management of lung infections.
This last decade has created historical moments for CF, primarily driven by the development of CFTR modulators. First for patients with gating mutations who benefited from Kalydeco, then for those patients with one F508del copy who could benefit from Orkambi, and most recently, patients with at least one F508del copy who can benefit from Trikafta. Despite heterogeneity in patient response, the majority of CF patients will be greatly impacted by using a CFTR modulator therapy, thus changing the trajectory of their life. Furthermore, it remains to be determined whether the next generation of modulators will be effective for individuals bearing rare mutations that are Orkambi resistant. However, it should not be forgotten that there still remains 10% of the CF population who do not have a targeted CFTR modulator treatment. In addition, even with these novel drug therapies, managing infections will continue to be a challenge, thus the CF community will need to adapt the standards for an improving, but ageing CF population.

Dr Sara Cuevas-Ocaña is a Research Fellow in the University of Nottingham Biodiscovery Institute, Nottingham, UK

– An excellent very readable summary of the present situation regarding the modulators including the key references

Elizabeth Marie Gavioli, Nerli Guardado, Farah Haniff, Nouran Deiab, Etty Vider. A current review of the safety of cystic fibrosis transmembrane conductance regulator modulators. J Clin Pharm Ther 2020 Dec 7.doi: 10.1111/jcpt.13329. Online ahead of print. [Pubmed]
What is known and objective: Treatment with cystic fibrosis transmembrane conductance regulator (CFTR) modulators has led to improved clinical outcomes and an increase in lifespans of cystic fibrosis (CF) patients. As CF patients continue to live longer, they are at risk for developing adverse drug reactions associated with polypharmacy and CFTR modulators.
Comment: The authors aim to describe safety concerns of the current combination CFTR modulators, based upon a literature review, including notable safety concerns and recommendations for drug-drug interactions.
What is new and conclusion: Cystic fibrosis transmembrane conductance regulator agents are generally well tolerated with low discontinuation rates when compared to placebo. Elevations in liver enzymes and drug-drug interactions are the most notable safety concerns. Additionally, lumacaftor/ivacaftor has shown more respiratory-related adverse events and drug-drug interactions compared to elexacaftor/tezacaftor/ivacaftor and tezacaftor/ivacaftor. Postmarketing studies are needed to determine long-term safety concerns.

Elizabeth Marie Gavioli is assistant professor of pharmacy practice at the Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Brooklyn, NY, USA.

DiMango E, Overdevest J, Keating C, Francis SF, Dansky D, Gudis D. Effect of highly effective modulator treatment on sinonasal symptoms in cysticfibrosis. J Cyst Fibros. 2020 Jul 18:S1569-1993(20)30794-3. doi: 10.1016/j.jcf.2020.07.002. Online ahead of print. [Pubmed]

Emily DiMango

Elexacaftor-tezacaftor-ivacaftor is a highly effective modulator for cystic fibrosis (CF) patients homozygous or heterozygous for F508del. Effects of the drug on sinonasal symptoms have not been studied Adult participants were prospectively evaluated at baseline and after three months of treatment using validated questionnaires assessing sinonasal symptoms (SNOT-22) and CF-related quality of life (CFQ-R).
Results: Forty-three participants completed the study; 23 were taking other CF transmembrane conductance (CFTR) modulators at the time of study participation. There was a significant improvement in mean SNOT-22 from 34.8 (29.4-40, 95% confidence interval) to 24.4 (19.9-29.0) (p = 0.000003) and in the Respiratory domain of the CFQR from 60.6 (57.1-64.1) to 83.3 (79.4-87.2) (p = 0.0000002), both achieving a minimal clinically important difference. Patients previously taking CFTR modulators experienced a greater benefit in sinonasal and respiratory symptoms

Conclusions: Elexacaftor-tezacaftor-ivacaftor is associated with significant improvement in sinonasal symptoms; previous use of CFTR modulators is associated with greater benefit

Dr Emily DiMango is Professor of Medicine at Columbia University Medical Center; Director, John Edsall-John Wood Asthma Center; Director, Adult Cystic Fibrosis Program

Onofrio Laselva, Claire Bartlett, Tarini N A Gunawardena, Hong Ouyang, Paul D W Eckford, Theo J Moraes, Christine E Bear, Tanja Gonska. Rescue of multiple class II CFTR mutations by elexacaftor+ tezacaftor+ivacaftor mediated in part by the dual activities of Elexacaftor as both corrector and potentiator. Eur Respir J 2020 Dec 10;2002774.doi: 10.1183/13993003.02774-2020. Online ahead of print.
Positive results in preclinical studies of the triple combination of elexacaftor, tezacaftor and ivacaftor, performed in airway epithelial cell cultures obtained from patients harboring F508del-CFTR, translated to impressive clinical outcomes for subjects carrying this mutation in clinical trials and approval of TRIKAFTA^TM Encouraged by this correlation, we were prompted to evaluate the effect of the elexacaftor, tezacaftor and ivacaftor triple combination on primary nasal epithelial cultures obtained from individuals with rare Class II cystic fibrosis causing mutations; G85E, M1101K and N1303K for which TRIKAFTA^TM is not approved. Cultures from individuals homozygous for M1101K responded better than cultures harboring G85E and N1303K after treatment with the triple combination with respect to improvement in regulated channel function and protein processing. A similar genotype specific effect of the triple combination was observed when the different mutations were expressed in HEK-293 cells, supporting the hypothesis that these modulators may act directly on the mutant proteins. Detailed studies in nasal cultures and HEK-293 cells showed that the corrector: elexacaftor, exhibited dual activity as both corrector and potentiator and suggested that the potentiator activity contributes to its pharmacological activity. These preclinical studies using nasal epithelial cultures identified mutation genotypes for which elexacaftor, tezacaftor and ivacaftor may produce clinical responses that are comparable to, or inferior to those observed for F508del-CFTR.

Onofrio Laselva is with the Programme in Molecular Medicine, Hospital for Sick Children, Toronto, Canada and the Department of Physiology University of Toronto

Scott A Kanner, Zunaira Shuja, Papiya Choudhury, Ananya Jain, Henry M Colecraft. Targeted deubiquitination rescues distinct trafficking-deficient ion channelopathies. Nat Methods 2020 Dec;17(12):1245-1253.doi: 10.1038/s41592-020-00992-6. Epub 2020 Nov 9. [Pubmed]

Scott Kanner

Impaired protein stability or trafficking underlies diverse ion channelopathies and represents an unexploited unifying principle for developing common treatments for otherwise dissimilar diseases. Ubiquitination limits ion channel surface density, but targeting this pathway for the purposes of basic study or therapy is challenging because of its prevalent role in proteostasis. We developed engineered deubiquitinases (enDUBs) that enable selective ubiquitin chain removal from target proteins to rescue the functional expression of disparate mutant ion channels that underlie long QT syndrome (LQT) and cystic fibrosis (CF). In an LQT type 1 (LQT1) cardiomyocyte model, enDUB treatment restored delayed rectifier potassium currents and normalized action potential duration. CF-targeted enDUBs synergistically rescued common (ΔF508) and pharmacotherapy-resistant (N1303K) CF mutations when combined with the US Food and Drug Administation (FDA)- approved drugs Orkambi (lumacaftor/ivacaftor) and Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor). Altogether, targeted deubiquitination via enDUBs provides a powerful protein stabilization method that not only corrects diverse diseases caused by impaired ion channel trafficking, but also introduces a new tool for deconstructing the ubiquitin code in situ

Scott A Kanner is on the Doctoral Program in Neurobiology and Behavior, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

Onofrio Laselva, Jacqueline McCormack, Claire Bartlett, Wan Ip, Tarini N A Gunawardena, Hong Ouyang, Paul D W Eckford, Tanja Gonska, Theo J Moraes, Christine E Bear. Preclinical Studies of a Rare CF-Causing Mutation in the Second Nucleotide Binding Domain (c.3700A>G) Show Robust Functional Rescue in Primary Nasal Cultures by Novel CFTR Modulators. J Pers Med 2020 Nov 5;10(4):209.doi: 10.3390/jpm10040209. Free PMC article [Pubmed]

Onofrio Laselva

The combination therapies ORKAMBI^TM and TRIKAFTA^TM are approved for people who have the F508del mutation on at least one allele. In this study we examine the effects of potentiator and corrector combinations on the rare mutation c.3700A>G. This mutation produces a cryptic splice site that deletes six amino acids in NBD2 (I1234-R1239del). Like F508del it causes protein misprocessing and reduced chloride channel function. We show that a novel cystic fibrosis transmembrane conductance regulator CFTR modulator triple combination (AC1, corrector, AC2-2, co-potentiator and AP2, potentiator), rescued I1234-R1239del-CFTR activity to WT-CFTR level in HEK293 cells. Moreover, we show that although the response to ORKAMBI was modest in nasal epithelial cells from two individuals homozygous for I1234-R1239del-CFTR, a substantial functional rescue was achieved with the novel triple combination. Interestingly, while both the novel CFTR triple combination and TRIKAFTA^TM treatment showed functional rescue in gene-edited I1234-R1239del-CFTR-expressing HBE cells and in nasal cells from two CF patients heterozygous for I1234-R1239del/W1282X, nasal cells homozygous for I1234-R1239del-CFTR showed no significant response to the TRIKAFTA^TMcombination. These data suggest a potential benefit of CFTR modulators on the functional rescue of I1234-R1239del -CFTR, which arises from the rare CF-causing mutation c.3700A>G, and highlight that patient tissues are crucial to our full understanding of functional rescue in rare CFTR mutations.

Onofrio Laselva at the Programme in Molecular Medicine, Hospital for Sick Children, Toronto, ON M5G 8X4, Canada and the Department of Physiology, University of Toronto, Toronto, ON M5G 8X4, Canada

Guido Veit

Guido Veit, Ariel Roldan, Mark A Hancock, Dillon F Da Fonte, Haijin Xu, Maytham Hussein, Saul Frenkiel, Elias Matouk, Tony Velkov, Gergely L Lukacs^.Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination. JCI Insight 2020 Sep 17;5(18):e139983.doi: 10.1172/jci.insight.139983. Free PMC article [Pubmed]
Based on its clinical benefits, Trikafta – the combination of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor), and the gating potentiator VX-770 (ivacaftor) – was FDA approved for treatment of patients with cystic fibrosis (CF) carrying deletion of phenylalanine at position 508 (F508del) of the CF transmembrane conductance regulator (CFTR) on at least 1 allele.
Neither the mechanism of action of VX-445 nor the susceptibility of rare CF folding mutants to Trikafta are known. Here, we show that, in human bronchial epithelial cells, VX-445 synergistically restores F508del-CFTR processing in combination with type I or II correctors that target the nucleotide binding domain 1 (NBD1) membrane spanning domains (MSDs) interface and NBD2, respectively, consistent with a type III corrector mechanism. This inference was supported by the VX-445 binding to and unfolding suppression of the isolated F508del-NBD1 of CFTR. The VX-661 plus VX-445 treatment restored F508del-CFTR chloride channel function in the presence of VX-770 to approximately 62% of WT CFTR in homozygous nasal epithelia. Substantial rescue of rare misprocessing mutations (S13F, R31C, G85E, E92K, V520F, M1101K, and N1303K), confined to MSD1, MSD2, NBD1, and NBD2 of CFTR, was also observed in airway epithelia, suggesting an allosteric correction mechanism and the possible application of Trikafta for patients with rare misfolding mutants of CFTR.

Dr Guido Veit is in the Department of Physiology and.²SPR-MS Facility, McGill University, Montréal, Quebec, Canada.

William Tindell, Amanda Su, Sarah M Oros^, Abner O Rayapati, Gopalkumar Rakesh. Trikafta and Psychopathology in Cystic Fibrosis: A Case Report. Psychosomatics Nov-Dec 2020;61(6):735-738.doi: 10.1016/j.psym.2020.06.021. Epub 2020 Jul 2. [Pubmed]

William Tindell

Abstract requested but not available.

Dr William Tindell is a resident in the Department of Psychiatry, University of Kentucky Medical Center, Lexington, KY

Nazan Çobanoğlu, Uğur Özçelik, Erkan Çakır, Tuğba Şişmanlar Eyüboğlu, Sevgi Pekcan, Güzin Cinel^.et al. Patients eligible for modulator drugs: Data from cystic fibrosis registry of Turkey. Pediatr Pulmonol 2020 Sep;55(9):2302-2306.doi: 10.1002/ppul.24854. Epub 2020 May 26.[Pubmed]

Nazan Cobanoglu

Background: A better understanding of cystic fibrosis transmembrane conductance regulator biology has led to the development of modulator drugs such as ivacaftor, lumacaftor-ivacaftor, tezacaftor-ivacaftor, and elexacaftor-tezacaftor-ivacaftor. This cross-sectional study evaluated cystic fibrosis (CF) patients eligible for modulator drugs.
Methods: Data for age and genetic mutations from the Cystic Fibrosis Registry of Turkey collected in 2018 were used to find out the number of patients who are eligible for modulator therapy.
Results: Of registered 1488 CF patients, genetic analysis was done for 1351. The numbers and percentages of patients and names of the drugs, that the patients are eligible for, are as follows: 122 (9.03%) for ivacaftor, 156 (11.54%) for lumacaftor-ivacaftor, 163 (11.23%) for tezacaftor-ivacaftor, and 57 (4.21%) for elexacaftor-tezacaftor-ivacaftor. Among 1351 genotyped patients total of 313 (23.16%) patients are eligible for currently licensed modulator therapies (55 patients were shared by ivacaftor and tezacaftor-ivacaftor, 108 patients were shared by lumacaftor-ivacaftor and tezacaftor-ivacaftor, and 22 patients were shared by tezacaftor-ivacaftor and elexacaftor-tezacaftor-ivacaftor groups).
Conclusions: The present study shows that approximately one-fourth of the registered CF patients in Turkey are eligible for modulator drugs. As, frequent mutations that CF patients have in Turkey are different from North American developing countries like Turkey is noteworthy and European CF patients, developing modulator drugs effective for those mutations is necessary. Furthermore, as modulator drugs are very expensive currently, financial support of the government in developing countries like Turkey is noteworthy

Prof. Dr Fatama Nazan Çobanoğlu is at the Division of Pediatric Pulmonology, Faculty of Medicine, Ankara University, Ankara, Turkey.

Shannon M Rotolo, Stephanie Duehlmeyer, Sarah M Slack, Hollyann R Jacobs, Brian Heckman.Testicular pain following initiation of elexacaftor/tezacaftor/ivacaftor in males with cystic fibrosis. J Cyst Fibros 2020 Sep;19(5):e39-e41.doi: 10.1016/j.jcf.2020.04.017.Epub 2020 May 27. [Pubmed]

Shannon Rotolo

There were no documented reports of testicular pain during clinical trials. In this case series, we discuss 7 males between 17 and 39 years of age who reported testicular pain or discomfort within the first two weeks of starting therapy. The precise mechanism of this side effect is unknown, but it may be related to restoration of CFTR function in the male reproductive tract. All patients experienced resolution of this side effect within a week after onset, regardless of the management, except for one. Further research is needed to determine short- and long-term impact of this drug on male fertility. Until more data is available, the authors recommend counselling patients on contraceptive options.

Shannon M Rotolo is Clinical Pharmacy Specialist at the University of Chicago Medicine, Department of Pharmacy, Chicago, IL

New Drug Hailed as Major Breakthrough in Cystic Fibrosis. Am J Med Genet A. 2020 Jan;182(1):8-9. doi: 10.1002/ajmg.a.61420.[Pubmed] My summary as their is no abstract: No authors are listed for this neat account of the progress in the development of CFTR modulator therapy from the FDA approval of ivacaftor (VX-771) in January 2012 for patients with one copy of the G551D mutation, to Orkambi, the combination of lumacaftor (VX-809) and ivacaftor, for those with 2 copies of the F508del mutation in 2015, to another drug combination of tezacaftor (VX-661) and ivacaftor (Symdeko) in 2018 for those people with at least one F508del mutation.

Giada Righetti, Monica Casale, Michele Tonelli, Nara Liessi, Paola Fossa, Nicoletta Pedemonte, Enrico Millo, Elena Cichero. New Insights into the Binding Features of F508del CFTR Potentiators: A Molecular Docking, Pharmacophore Mapping and QSAR Analysis Approach. Pharmaceuticals (Basel) 2020 Dec 4;13(12):E445.doi: 10.3390/ph13120445. [Pubmed]

Giada Righetti

Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. To combat this disease, many life-prolonging therapies are required and deeply investigated, including the development of the so-called cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as correctors and potentiators. Combination therapy with the two series of drugs led to the approval of several multi-drug effective treatments, such as Orkambi, and to the recent promising evaluation of the triple-combination Elexacaftor-Tezacaftor-Ivacaftor.
This scenario enlightened the effectiveness of the multi-drug approach to pave the way for the discovery of novel therapeutic agents to contrast CF. The recent X-crystallographic data about the human CFTR in complex with the well-known potentiator Ivacaftor (VX-770) opened the possibility to apply a computational study aimed to explore the key features involved in the potentiator binding.
Herein, we discussed molecular docking studies performed onto the chemotypes so far discussed in the literature as CFTR potentiator, reporting the most relevant interactions responsible for their mechanism of action, involving Van der Waals interactions and π-π stacking with F236, Y304, F305 and F312, as well as H-bonding F931, Y304, S308 and R933.
This kind of positioning will stabilize the effective potentiator at the CFTR channel. These data have been accompanied by pharmacophore analyses, which promoted the design of novel derivatives endowed with a main (hetero)aromatic core connected to proper substituents, featuring H-bonding moieties. A highly predictive quantitative-structure activity relationship (QSAR) model has been developed, giving a cross-validated r² (r²_cv) = 0.74, a non-cross validated r² (r²_ncv) = 0.90, root mean square error (RMSE) = 0.347, and a test set r² (r²_pred) = 0.86.

On the whole, the results are expected to gain useful information to guide the further development and optimization of new CFTR potentiators

Smyth RL. New drug treatments for cystic fibrosis. BMJ. 2020 Jan 20;368:m118. doi: 10.1136/bmj.m11 [Pubmed]

Rosiland Smyth

The present situation regarding the new CFTR modulators is neatly summarised by Prof. Ros Smyth in this BMJ article. As some readers may not have access to the full text, I have summarised some of the key points and added the key references –
Mutations that result in CFTR being expressed on the cell surface but incorrectly regulated, such as G551D, were the most straightforward targets. Ivacaftor, a potentiator, increases the time that the CFTR chloride channel remains open. In a phase III randomised placebo controlled trial, ivacaftor improved forced expiratory volume in one second (FEV₁) by 11% as well as respiratory symptoms and weight gain without substantial adverse effects (Ramsey et al 2011). The trial recruited 161 patients and was completed in 19 months despite the small pool of just 2000 people worldwide with the G551D mutation. Ivacaftor was licensed in Europe in 2012.
Ivacaftor is effective for only 4-5% of patients with cystic fibrosis. Many more patients have the F508del mutation, which causes misfolding of CFTR protein so that it remains trapped in the cell’s endoplasmic reticulum. Any CFTR that does reach the cell surface is unable to activate normally. Although potentiators can enhance activation at the cell surface, dealing with the trapped protein requires agents that correct the misfolding (correctors).
In 2015, a trial of Orkambi, a drug combining the corrector lumacaftor with the potentiator ivacaftor, showed improvements in weight gain and respiratory exacerbations among patients who were homozygous for F508del, but the modest 3% increase in FEV₁ relative to placebo was associated with transient dyspnoea and abnormal liver function (Wainwright et al, 2015)
Subsequent trials of a different corrector, tezacaftor, combined with ivacaftor showed similar improvements in FEV₁ to Orkambi but with fewer side effects (Taylor-Cousar et al, 2017; Rowe SM et al, 2017)
In 2018, tezacaftor-ivacaftor (Symkevi) was licensed in the US and Europe for patients with F508del (either homozygous or F508del plus an allele with another mutation associated with residual CFTR function), representing around 50% of patients worldwide (Davies JC et al, 2018; Keating D et al, 2018).
Although 90% of people with cystic fibrosis have at least one copy of the F508del mutation, around 30% also have other minimal function mutations that are unresponsive to current CFTR modulators. This led to the development of next generation correctors and trials of “triple therapy” combining two correctors and a potentiator.
In 2019, phase III trials of elexacaftor-ivacaftor-tezacaftor in patients with F508del reported greater than 10% improvements in FEV₁ compared with placebo and substantial reductions in respiratory exacerbations (Heijerman et al, 2019; Middleton et al, 2019).

– Ramsey BW, Davies J, McElvaney NG, et al., VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663-72. doi:10.1056/NEJMoa1105185 [Pubmed] –Wainwright CE, Elborn JS, Ramsey BW, et al., TRAFFIC Study Group, TRANSPORT Study Group. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med2015;373:2231.doi:10.1056/NEJMoa1409547 [Pubmed]
– Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med2017;377:2013-23. doi:10.1056/NEJMoa1709846 [Pubmed]
– Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med2017;377:2024-35. doi:10.1056/NEJMoa1709847 [Pubmed]
– Davies JC, Moskowitz SM, Brown C, et al., VX16-659-101 Study Group. VX-659-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med2018; 379:1599-611. doi:10.1056/NEJMoa1807119 pmid [Pubmed
– Keating D, Marigowda G, Burr L, et al., VX16-445-001 Study Group. VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med2018; 379:1612-20. doi:10.1056/NEJMoa1807120 pmidL [Pubmed]
– Heijerman HGM, McKone EF, Downey DG, et al., VX17-445-103 Trial Group. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet2019; 394:1940-8. doi:10.1016/S0140-6736(19)32597-8 [Pubmed]
– Middleton PG, Mall MA, Dřevínek P, et al., VX17-445-102 Study Group. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019; 381:1809-19. doi:10.1056/NEJMoa1908639 [Pubmed]

The authors concluded Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

Shteinberg M, Taylor-Cousar JL. Impact of CFTR modulator use on outcomes in people with severe cystic fibrosis lung disease. Eur Respir Rev. 2020 Mar 20;29(155). pii: 190112. doi: 10.1183/16000617.0112-2019. Print 2020 Mar 31. Free full text [Pubmed]

Michal Shteinberg

Drug compounds that augment the production and activity of the cystic fibrosis (CF) transmembrane regulator (CFTR) have revolutionised CF care. Many adults and some children with CF suffer advanced and severe lung disease or await lung transplantation. While the hope is that these drug compounds will prevent lung damage when started early in life, there is an ongoing need to care for people with advanced lung disease. The focus of this review is the accumulating data from clinical trials and case series regarding the benefits of CFTR modulator therapy in people with advanced pulmonary disease. We address the impact of treatment with ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor on lung function, pulmonary exacerbations, nutrition and quality of life. Adverse events of the different CFTR modulators, as well as the potential for drug-drug interactions, are discussed.

Dr Michal Shteinberg is heading the bronchiectasis and adult CF service in the Pulmonology institute and CF Center, Carmel medical Center, Haifa, Israel and a Clinical Assistant Professor in the Faculty of medicine at the Technion, Israel Institute of Technology.

Kevin W Southern, Jared Murphy, Ian P Sinha, Sarah J Nevitt^.Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev 2020 Dec 17;12:CD010966. doi: 10.1002/14651858.CD010966.pub3. [Pubmed]

Kevin Southern

Authors’ conclusions: There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer-term adult data when considering lumacaftor-ivacaftor. There is high-quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor-tezacaftor-ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function.

Prof. Kevin Southern is in the Department of Women’s and Children’s Health, University of Liverpool, Liverpool, UK.

– This is a useful up-to-date review and source of reference of these treatments with a full documentation of the various trials.

Sanja Stanojevic, Katarina Vukovojac, Jenna Sykes, Felix Ratjen, Elizabeth Tullis, Anne L Stephenson. Projecting the impact of delayed access to elexacaftor/tezacaftor/ivacaftor for people with Cystic Fibrosis. J Cyst Fibros 2020Aug 5;S1569-1993(20)308092.doi10.1016/j.jcf.2020.07.017.Online ahead of print [Pubmed]

Sanja Stanojevic

Therapies that target the underlying defect in Cystic Fibrosis (CF) will likely impact the future characteristics of the CF population and healthcare utilization. The objectives of this study were to estimate the potential impact of elexacaftor/tezacaftor/ivacaftor on morbidity and mortality, and the impact of delayed access
A microsimulation transition model was applied to Canadian CF Registry data to forecast lung disease severity, pulmonary exacerbations, deaths and transplants to 2030 under three scenarios: 1) no availability of elexacaftor/tezacaftor/ivacaftor, 2) availability in 2021 (‘early’) or 3) availability in 2025 (‘delayed’). Published Phase III data on treatment effects were used to estimate transition rates between disease severity states.
Results: Under specific assumptions regarding disease state and treatment effect applied to the Canadian CF population it is projected that by 2030, early introduction of elexacaftor/tezacaftor/ivacaftor is expected to reduce the number of individuals with severe lung disease by 60% (95% CI 55.3; 63.9), increase the number of individuals with mild lung disease by 18% (95%CI 18.2; 19.0) and reduce the number of pulmonary exacerbations by 19% (95%CI 18.9; 19.5). Earlier introduction of elexacaftor/tezacaftor/ivacaftor could reduce deaths by 15% (95% 13.2; 18.4) and improve the median age of survival by 9.2 years (7.5; 10.8) over a 10-year period. The expected benefits of therapy are cumulative, therefore delayed access to elexacaftor/tezacaftor/ivacaftor will result in preventable health care utilization and deaths.
Conclusions: Delayed access to elexacaftor/tezacaftor/ivacaftor will have a negative impact on lung health and survival in the CF population.

Dr Sanja Stanojevi is at Translational Medicine, Hospital for Sick Children, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Canada; Department of Community Health and Epidemiology, Dalhousie University, Halifax, Canada.

Dr Scott D Sagel is Professor Pediatrics and Pulmonary Medicine at the Department of Pediatrics, Children’s Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado

2021

Kate M O’Shea, Orla M O’Carroll, Catherine Carroll, Brenda Grogan, Anna Connolly, Lynda O’Shaughnessy, Trevor T Nicholson, Charles G Gallagher, Edward F McKone^.Efficacy of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease. Eur Respir J. 2021 Feb 25;57(2):2003079.doi: 10.1183/13993003.03079-2020. Print 2021 Feb. [Pubmed]

Kate O’Shea

No abstract but the following abstract form the article – This study shows that ELX/TEZ/IVA improves multiple outcome measures in a small cohort of 14 patients with advanced CF lung disease attending a single centre and that these improvements are similar to those seen in patients with milder disease.
Follow-up measurement dates varied with mean repeat FEV₁ at 26.4±4.2 days, mean BMI at 62±35 days and mean SwCl at 64±84 days after ELX/TEZ/IVA initiation. After treatment with ELX/TEX/IVA, FEV₁ improved (27.3±7.3% pred versus 36.3±16.5% pred; p<0.0001). BMI also improved (20.7±3.6 versus 22.1±3.4 kg·m⁻²; p<0.0001). Sweat chloride results were only available for 11 patients, mainly due to insufficient sweat volume despite multiple attempts, but also revealed significant improvement (104.9±15.04 versus 53.6±23.3 mmol·L⁻¹; p<0.0001). Infective exacerbations requiring hospitalisation reduced in frequency (0.28±0.17 exacerbations per month in 12 months prior versus 0.04±0.07 exacerbations per month during follow-up period of 4.9 months; p<0.001)
Most significant were the reduction in requirement for intravenous antibiotic therapy as well as improvements in lung function and sweat chloride. These results were seen in both patients exposed to previous modulator therapies and in those who were CFTR modulator-naïve. There were few significant adverse events. This therapy is expected to improve the disease trajectory for many CF patients with at least one Phe508del mutation and this expectation should also apply to those groups with more advanced disease.

Kate M O’Shea is studying at the School of Medicine, University College Dublin

Dr Orla M O’Carroll is a Respiratory Specialist Registrar in the Department of Respiratory medicine St Vincent’s University Hospital, Dublin

Kavita Dave, Rebecca Dobra, Sandra Scott, Clare Saunders, Jess Matthews, Nicholas J Simmonds, Jane C Davies.Entering the era of highly effective modulator therapies. Pediatr Pulmonol 2021 Feb;56 Suppl 1:S79-S89. doi: 10.1002/ppul.24968. [Pubmed]

Kavita Dave

Since the discovery of the gene responsible for cystic fibrosis (CF) in 1989, hopes have been pinned on a future with novel therapies tackling the basis of the disease rather than its symptoms. These have become a reality over the last decade with the development through to the clinic of CF transmembrane conductance regulator (CFTR) modulators. These are oral drugs which improve CFTR protein function through either increasing the time the channel pore is open (potentiators) or facilitating its trafficking through the cell to its location on the cell membrane (correctors). The first potentiator, ivacaftor, is now licensed and available clinically in many parts of the world. It is highly effective with impressive clinical impact in the lungs and gastrointestinal tract; longer-term data from patient registries show fewer exacerbations, a slower rate of lung function loss and reduced need for transplantation in patients receiving ivacaftor. However, as a single drug, it is suitable for only a small minority of patients. The commonest CFTR mutation, F508del, requires both correction and potentiation for clinical efficacy. Two dual-agent drugs (lumacaftor/ivacaftor and tezacaftor/ivacaftor) have progressed through to licensing, although their short term impact is more modest than that of ivacaftor; this is likely due to only partial correction of protein misfolding and trafficking. Most recently, triple compounds have been developed: two different corrector molecules (elexacaftor and tezacaftor) which, by addressing different regions in the misfolded F508del protein, more effectively improve trafficking. In addition to large improvements in clinical outcomes in people with two copies of F508del, the combination is sufficiently effective that it works in patients with only one copy of F508del and a second, nonmodulator responsive mutation. For the first time, we thus have a drug suitable for around 85% of people with CF. Even more gains are likely to be possible when these drugs can be used in younger children, although more sensitive outcome measures are needed for this age group. Special consideration is needed for people with very rare mutations; those with nonmodulatable mutation combinations will likely require gene or messenger RNA-based therapeutic approaches, many of which are being explored. Although this progress is hugely to be celebrated, we still have more work to do. The international collaboration between trials networks, pharma, patient organizations, registries, and people with CF is something we are all rightly proud of, but innovative trial design and implementation will be needed if we are to continue to build on this progress and further develop drugs for people with CF.

Dr Kavita Dave is the UK CF Trust Clinical Fellow at Departments of Cystic Fibrosis and Paediatric Respiratory Medicine, Royal Brompton & Harefield Foundation Trust, London, UK

Kelsey Leonhardt, Elizabeth B Autry, Robert J Kuhn, Mark A Wurth. CFTR modulator drug desensitization: preserving the hope of long term improvement. Pediatr Pulmonol. 2021 Apr 29.doi: 10.1002/ppul.25437. Online ahead of print. [Pubmed]

Kelsey Leonhardt

The development of modulator therapy has, for the first time, allowed direct targeting of the underlying cause of cystic fibrosis (CF), the cystic fibrosis transmembrane conductance regulator (CFTR). Patients treated with CFTR modulators have improvement in lung function and decreased rates of pulmonary exacerbations. In 2019, elexacaftor/tezacaftor/ivacaftor was approved for use in the United States, opening these therapies to 90% of patients with CF.

Intolerable adverse drug reactions (ADRs) to CFTR modulators results in discontinuation of therapy, which can be devastating to our patients. We describe our approach to two cases, not previously reported, of rash to elexacaftor/tezacaftor/ivacaftor in patients with a previous history of cutaneous adverse reactions to dual modulator therapy that had been addressed by desensitization. Case 1 was able to tolerate elexacaftor/tezacaftor/ivacaftor after desensitization to the triple combination therapy, while in case 2 tolerance was obtained by treating through the reaction. The loss of tolerance in these patients was unexpected, and may be a common finding in patients with history of cutaneous adverse reactions to these drugs. We hope reporting our experience, including our desensitization protocol, may benefit CF patients for whom these drug reactions may be limiting access to powerful disease altering therapies

Guido Veit, Christian Vaccarin, Gergely L Lukacs. Elexacaftor co-potentiates the activity of F508del and gating mutants of CFTR. J Cyst Fibros 2021 Mar 25;S1569-1993(21)00087-4.doi: 10.1016/j.jcf.2021.03.011.Online ahead of print. [Pubmed]

Guido Veit

Trikafta, the combination of elexacaftor (VX-445), tezacaftor (VX-661) and ivacaftor (VX-770), was approved for therapy of cystic fibrosis (CF) patients with at least one allele of the CFTR mutation F508del. While the corrector function of VX-445 is well established, here we investigated the putative potentiator activity of VX-445 alone and in combination with VX-770. Acute addition of VX-445 increased the VX-770-potentiated F508del- and G551D-CFTR current by ~24% and >70%, respectively, in human bronchial and nasal epithelia. Combinatorial profiling and cluster analysis of G551D- and G1244E-CFTR channel activation with potentiator pairs indicated a distinct VX-445 mechanism of action that is, at least, additive to previously identified potentiator classes, including the VX-770. Since VX-770 only partially normalizes the G551D-CFTR channel function and adult G551D patients still experience progressive loss of lung function, VX-445+VX-770 combination therapy could provide clinical benefit to CF patients with the G551D and other dual potentiator responsive mutants.

Dr Guido Veit is a Research Associate in the Department of Physiology, McGill University, Montréal, Canada. His main research interest: Epithelial biology with focus on the interplay between extracellular events (cytokines, extracellular matrix) and cellular responses (transmembrane proteins, signalling, transcriptional activation).

Zumi Mehta, Khalid M Kamal, Richard Miller, Jordan R Covvey, Vincent Giannetti. Adherence to cystic fibrosis transmembrane conductance regulator (CFTR) modulators: analysis of a national specialty pharmacy database, J Drug Assess. 2021 Apr 5;10(1):62-67.doi: 10.1080/21556660.2021.1912352. Free PMC article [Pubmed]

Zumi Mehta

Objective: To calculate the medication adherence in patients taking CFTR modulators using a national specialty pharmacy database.
Methods: This retrospective observational cohort study utilized de-identified specialty pharmacy data from September 2017 to August 2018 to assess medication adherence for three CFTR modulators: ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor & ivacaftor. The primary outcome was proportion of days covered (PDC) for each medication, with mean PDC values compared across age groups and insurance characteristics. All analyses were performed using the SAS 9.4 University Edition (SAS Institute, Cary, NC).
Results: A total of 2,548 patients were analyzed, including 1,289 (50.59%) patients on lumacaftor/ivacaftor, 784 (30.77%) on ivacaftor, and 475 (18.64%) on tezacaftor/ivacaftor & ivacaftor. The mean PDC value for all CFTR modulators was above 0.80. Tezacaftor/ivacaftor & ivacaftor had the highest overall PDC of 0.92, while PDC values for both lumacaftor/ivacaftor and ivacaftor were 0.84. Children/adolescents on lumacaftor/ivacaftor (p = 0.0001) and tezacaftor/ivacaftor & ivacaftor (p = 0.001) had significantly higher mean PDC values compared to adults but not for ivacaftor (p = 0.3744). No statistical differences were seen in PDC across insurance characteristics.
Conclusion: To the best of our knowledge, this is the first study to assess the adherence of three CFTR modulators using a large nationwide specialty database. With high acquisition costs of CFTR modulator therapies, there is a need to improve rates of adherence in patients with CF

Dr Zumi Mehta is graduate student in the Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA.

Frédéric Becq, Sandra Mirval, Thomas Carrez, Manuella Lévêque, Arnaud Billet, Christelle Coraux, Edouard Sage, Anne Cantereau. The rescue of F508del-CFTR by elexacaftor/tezacaftor/ivacaftor (Trikafta) in human airway epithelial cells is underestimated due to the presence of ivacaftor. Eur Respir J 2021 Jul 15;2100671.doi: 10.1183/13993003.00671-2021.Online ahead of print. [Pubmed]

Frederic Becq

Trikafta, currently the leading therapeutic in Cystic Fibrosis (CF), has demonstrated a real clinical benefit. This treatment is the triple combination therapy of two folding correctors elexacaftor/tezacaftor (VX445/VX661) plus the gating potentiator ivacaftor (VX770). In this study, our aim was to compare the properties of F508del-CFTR in cells treated with either lumacaftor (VX809), tezacaftor, elexacaftor, elexacaftor/tezacaftor with or without ivacaftor. We studied F508del-CFTR function, maturation and membrane localisation by Ussing chamber and whole-cell patch clamp recordings, Western blot and immunolocalization experiments. With human primary airway epithelial cells and the cell lines CFBE and BHK expressing F508del, we found that, whereas the combination elexacaftor/tezacaftor/ivacaftor was efficient in rescuing F508del-CFTR abnormal maturation, apical membrane location and function, the presence of ivacaftor limits these effects. The basal F508del-CFTR short-circuit current was significantly increased by elexacaftor/tezacaftor/ivacaftor and elexacaftor/tezacaftor compared to other correctors and non-treated cells, an effect dependent on ivacaftor and cAMP. These results suggest that the level of the basal F508del-CFTR current might be a marker for correction efficacy in CF cells. When cells were treated with ivacaftor combined to any correctors, the F508del-CFTR current was unresponsive to the subsequently acute addition of ivacaftor unlike the CFTR potentiators genistein and Cact-A1 which increased elexacaftor/tezacaftor/ivacaftor and elexacaftor/tezacaftor-corrected F508del-CFTR currents. These findings show that ivacaftor reduces the correction efficacy of Trikafta. Thus, combining elexacaftor/tezacaftor with a different potentiator might improve the therapeutic efficacy for treating CF patients

Professor Frédéric Becq is at the Laboratoire Signalisation et Transports Ioniques Membranaires, Université de Poitiers, France.

Jennifer L Taylor-Cousar, R Jain. Maternal and fetal outcomes following elexacaftor-tezacaftor-ivacaftor use during pregnancy and lactation. J Cyst Fibros. 2021 Mar 21;S1569-1993(21)00055-2.doi: 10.1016/j.jcf.2021.03.006.Online ahead of print. [Pubmed]

Jennifer Taylor-Cousar

There is currently no data in the literature regarding use of Elexacaftor-tezacaftor-ivacaftor (ETI) in pregnant women. Thus, the decision to continue therapy during pregnancy (with the associated unknown fetal impact) versus discontinuing therapy (with the known risk of maternal health decline) is challenging.
Methods: CF Center staff completed an anonymous questionnaire regarding pregnancy and infant outcomes for women who used ETI during pregnancy and/or lactation.
Results: Of 45 ETI-exposed pregnancies reported to date, complications in 2 mothers and in 3 infants (2 born to mothers with poorly controlled diabetes) were rated by clinicians as unknown (possible) or suspected relatedness to ETI use. Two women terminated unplanned pregnancies. Miscarriage rates were consistent with that known in the general U.S.
Population: Five of the six women who discontinued ETI out of concern for unknown foetal risk restarted because of clinical deterioration. No infant cataracts were reported though only two infants were formally evaluated.
Conclusions: In the context of the known increased rate of complications in women with CF and their infants, data from this retrospective survey is reassuring for women who choose to continue ETI during pregnancy. However, a large, multi-centre prospective study is needed to assess impact of use of ETI in pregnancy.

Dr Jennifer L Taylor-Cousar is in the Departments of Medicine and Pediatrics, National Jewish Health, 1400 Jackson Street; J318, Denver, CO 80206.

– Evidence accumulating that there seems to be no serious consequences of taking ETI during pregnancy.

Marika Comegna, Vito Terlizzi, Donatello Salvatore, Carmela Colangelo, Antonella Miriam Di Lullo, Immacolata Zollo, Giovanni Taccetti, Giuseppe Castaldo, Felice Amato. Elexacaftor-Tezacaftor-Ivacaftor Therapy for Cystic Fibrosis Patients with The F508del/Unknown Genotype. Antibiotics (Basel)2021 Jul 7;10(7):828.doi: 10.3390/antibiotics10070828. Free PMC article [Pubmed]

Marika Comegna

The new CFTR modulator combination, elexacaftor/tezacaftor/ivacaftor (Trikafta) was approved by the FDA in October 2019 for treatment of Cystic Fibrosis in patients 6 years of age or older who have at least one F508del mutation in one allele and a minimal-function or another F508del mutation in the other allele. However, there is a group of patients, in addition to those with rare mutations, in which despite the presence of a F508del in one allele, it was not possible to identify any mutation in the other allele. To date, these patients are excluded from treatment with Trikafta in Italy, where the CF patients carrying F508del/unknown represent about 1.3% (71 patients) of the overall Italian CF patients. In this paper we show that the Trikafta treatment of nasal epithelial cells, derived from F508del/Unknown patients, results in a significant rescue of CFTR activity. Based on our findings, we think that the F508del/Unknown patients considered in this study could obtain clinical benefits from Trikafta treatment, and we strongly suggest their eligibility for this type of treatment. This study, adding further evidence in the literature, once again confirms the validity of functional studies on nasal cells in the cystic fibrosis theratyping and personalized medicine

Dr Marika Comegna is in the Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Pansini, 5, 80131 Naples, Italy.

CEINGE-Advanced Biotechnologies, Via G. Salvatore, 486, 80145 Naples, Italy.

Edith T Zemanick, Jennifer L Taylor-Cousar, Jane Davies, Ronald L Gibson, Marcus A Mall, Edward F McKoneet al, A Phase 3 Open-Label Study of ELX/TEZ/IVA in Children 6 Through 11 Years of Age With CF and at Least One F508del Allele. Am J Respir Crit Care Med 2021 Mar 18. doi: 10.1164/rccm.202102-0509OC.Online ahead of print. [Pubmed]

Edith Zermanick

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients aged 12 years and older with cystic fibrosis and at least one F508del-CFTR allele, but has not been evaluated in children <12 years of age.
Objectives: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del-minimal function or F508del-F508del genotypes.
Methods: In this 24-week open-label Phase 3 study, children (N=66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours) while children weighing ≥30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours).
Measurements and main results: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most common reported adverse events (AEs) included cough, headache, and pyrexia; in most of the children who had AEs, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the ppFEV1 (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z-score increased over the 24-week treatment period compared to the pre-treatment baselineds, UK

Conclusions: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population.

Dr Edith T Zemanick is Associate Professor at the Colorado Anschutz Medical Campus and Children’s Hospital Colorado, Department of Pediatrics, Aurora, Colorado, United States

Cori L Daines, Wayne J Morgan The Future of Highly Effective Modulator Therapy in Cystic Fibrosis.. Am J Respir Crit Care Med 2021 Jun 15;203(12):1453-1455.doi: 10.1164/rccm.202104-0850ED. 33901406 Free PMC article [Pubmed]

Wayne J Morgan

Cori Daines

There is no abstract, but the Free PMC article is a clear commentary on the article of Zemanick ET et al, Am J Respir Crit Care Med 2021;203:1522-1532.(ABOVE)
The success of highly effective modulator therapy (HEMT) in cystic fibrosis (CF) now illustrates two areas of deficiency: the lack of HEMT for younger children and for approximately 10% of the CF population without a qualifying mutation………
At this point, the previous modulators IVA, lumacaftor/IVA, and TEZ/IVA have all been approved for younger ages than the original phase III qualifying studies (11, 12). IVA has recently been approved down to 4 months, whereas lumacaftor/IVA is approved to 2 years and TEZ/IVA is approved to 6 years (13–15). Longer-term data from these extensions show ongoing safety and efficacy even in the youngest patients (16, 17). Previous modulators have been shown to be safe, both in the short and long term, in young children. This knowledge should reaffirm the safety findings in the current study and should prove the appropriateness of moving ELX/TEZ/IVA to the 6- to 11-year-old age group. The CF community has been waiting for the results of this study and to have ELX/TEZ/IVA for children. The goal and expectation will be much better long-term outcomes for people living with CF.

Both authors are in the Department of Pediatrics University of Arizona Tucson, Arizona.
Cori L Daines is a professor of Pediatric Pulmonary Medicine
Wayne J Morgan is Professor of Pediatrics and Physiology Arizona Elks Foundation Chair for Statewide Pediatric Research and Program Director, Pediatric Pulmonary Fellowship Pediatric Pulmonary and Sleep Medicine

Julian Stashower, Patrick Carr, Virginia Miller, Barrett Zlotoff. Novel reaction to new cystic fibrosis medication Trikafta. Clin Case Rep 2021 May 4;9(5):e04116.doi: 10.1002/ccr3.4116.eCollection 2021 May. [Pubmed] Free PMC article

Legs of patient

Julian Stashower

The authors describe a novel case of an urticaria multiforme-type drug reaction to the new cystic fibrosis medication Trikafta (elexacaftor + tezacaftor + ivacaftor). Equipped with this information, clinicians may be more prepared to counsel and treat patients if they experience similar symptoms after beginning Trikafta

There are more images in the Free PMC article

Dr Julian Stashower is at the University of Virginia School of Medicine, Charlottesville USA

This is the first study assessing changes of airway inflammation on a day-to-day basis in CF patients receiving a newly administered CFTR-modulator therapy. It proves a decline of airway inflammation during ivacaftor-therapy.

Dr Jochen G Mainz is Professor at the Cystic Fibrosis Center, Brandenburg Medical School (MHB) University, Klinikum Westbrandenburg, Brandenburg an der Havel,, the CF-Center, Jena University Hospital, Jena and the Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus -Senftenberg, The Brandenburg Medical School Theodor Fontane and the University of Potsdam, Cottbus, Brandenburg an der Havel and Potsdam, Germany.

C Martin, E Burnet, A Ronayette-Preira, P de Carli, J Martin, L Delmas, B Prieur, P-R Burgel. Patient perspectives following initiation of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis and advanced lung disease. Respir Med Res. 2021 May 17;80:100829.doi: 10.1016/j.resmer.2021.100829.Online ahead of print. [Pubmed]
Backgound: Elexacaftor-tezacaftor-ivacaftor partially restores cystic fibrosis transmembrane conductance regulator function, and has been shown to induce significant clinical improvement in patients with at least one Phe508del allele. Yet little data exist on patient perspectives following elexacaftor-tezacaftor-ivacaftor initiation.
Methods: A mixed methods study was conducted using an online 13-item questionnaire (including 9 closed questions and 4 open questions), submitted from July 10^th to August 21^th2020 to French patients aged 12 years and older with advanced CF who were treated with elexacaftor-tezacaftor-ivacaftor. Their responses were summarized as numbers (%), and free-text items were analysed using a grounded theory approach.
Results: Of 245 patients who started elexacaftor-tezacaftor-ivacaftor in France, 101 (41%) participated. Median [IQR] age was 35 [28-41] years and duration of elexacaftor-tezacaftor-ivacaftor treatment was 4.3 [3.0-5.6] months. Patients generally reported a rapid impact on respiratory symptoms, sleep quality, general well-being and physical self-esteem, and a reduction in overall treatment burden. The majority of patients contrasted treatment burden, symptom severity, depression and a closed future marked by death or transplantation before elexacaftor-tezacaftor-ivacaftor, to renewed and unexpected physical strength, leading to greater self-confidence, autonomy and long-term planning, after treatment initiation. A small number of patients expressed concerns, mainly regarding changes in body representation and/or the fear of becoming dependent on the treatment.
Conclusion: After initiation of elexacaftor-tezacaftor-ivacaftor, CF patients with advanced disease reported rapid and positive physical, psychological and social effects, which translated into improved quality of life and the formulation of new life goals.

Dr C Martin is at the Université de Paris, Institut Cochin, Inserm U1016, Paris, France; Respiratory Medicine and National Reference Cystic Fibrosis Reference Center, Cochin Hospital, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; ERN-Lung CF network.

Frederic Becq

Professor Frédéric Becq is at the Laboratoire Signalisation et Transports Ioniques Membranaires, Université de Poitiers, France.

Marika Comegna

Dr Marika Comegna is in the Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Pansini, 5, 80131 Naples, Italy.

CEINGE-Advanced Biotechnologies, Via G. Salvatore, 486, 80145 Naples, Italy.

Scott D Sagel, Umer Khan, Sonya L Heltshe, John P Clancy, Drucy Borowitz, Daniel Gelfond, Scott H Donaldson, Antoinette Moran, Felix Ratjen, Jill M VanDalfsen, Steven M Rowe. Clinical Effectiveness of Lumacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR. A Clinical Trial. Ann Am Thorac Soc 2021 Jan;18(1):75-83.doi: 10.1513/AnnalsATS.202002-144OC. [Pubmed]

Scott Segal

To evaluate the effectiveness of LUM/IVA in children (6 yr or more) and adults (more than 18 yr) in a postapproval setting. A total of 193 patients initiated LUM/IVA, and 85% completed the study through 1 year. Baseline mean percent-predicted forced expiratory volume in 1 second (ppFEV₁) was 85 (standard deviation, 22.4) in this cohort. No statistically significant change in ppFEV₁ was observed from baseline to any of the follow-up time points, with a mean absolute change at 12 months of -0.3 (95% confidence interval [CI], -1.8 to 1.2). Body mass index improved from baseline to 12 months (mean change, 0.8 kg/m²; P < 0.001). Sweat chloride decreased from baseline to 1 month (mean change, -18.5 mmol/L; 95% CI, -20.7 to -16.3; P < 0.001), and these reductions were sustained through the study period. There were no significant changes in hospitalization rate for pulmonary exacerbations and Pseudomonas aeruginosa infection status with treatment.
Conclusions: In this real-world multicentre cohort of children and adults, LUM/IVA treatment was associated with significant improvements in growth and reductions in sweat chloride without statistically significant or clinically meaningful changes in lung function, hospitalization rates, or P. aeruginosa infection. (NCT02477319).

Dr Scott D Sagel is Professor Pediatrics and Pulmonary Medicine at the Department of Pediatrics, Children’s Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Eva Furstova, Tereza Dousova, Jakub Beranek, Malgorzata Libik, Libor Fila, Martin Modrak, Ondrej Cinek, Milan Macek Jr, Pavel Drevinek Response to elexacaftor/tezacaftor/ivacaftor in intestinal organoids derived from people with cystic fibrosis. J Cyst Fibros 2021 Aug 1;S1569-1993(21)01304-7.doi: 10.1016/j.jcf.2021.07.006.Online ahead of print.[Pubmed]

Eva Furstova

Superior efficacy of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) over tezacaftor/ivacaftor (TEZ/IVA) in people with cystic fibrosis (CF) and Phe508del/Phe508del genotype was shown in clinical trials. We utilized intestinal organoid approach to compare in vitro responses to these 2 CFTR modulator drug combinations and to check potential inter-individual variability in therapeutic response to the triple combination.

Organoids from 17 subjects with Phe508del/Phe508del were screened with forskolin induced swelling assay. Significantly larger swelling, when exposed to ELX/TEZ/IVA as compared to TEZ/IVA, was observed in 16 of them. However, 1 sample showed no additional effect of ELX. The finding of unique CFTR variants in this sample indicates that genetic traits other than CF-causing CFTR mutation are worth exploring as they may have an impact on the definitive modulator drug response.

Dr Eva Furstova is a medical doctor and PhD researcher in the Department of Paediatrics, 2nd Faculty of Meicine, Charles University and Motol University Hospital, Prague, Czech Republic; Department of Medical Microbiology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

Donatello Salvatore, Carmela Colangelo, Michele D’Andria, Giovanni Marsicovetere, Domenica Passarella. Elexacaftor/tezacaftor/ivacaftor as rescue therapy in a patient with the cystic fibrosis genotype F508DEL/ G1244E. Clin Case Rep 2021 Aug 25;9(8):e04713.doi: 10.1002/ccr3.4713.eCollection 2021 Aug. OPEN access for full case reports [Pubmed]

Donatello Salvatore

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane regulator (CFTR) modulator. It is known to be efficacious in stable patients with severe pneumopathy, but there are few data concerning its effectiveness during acute exacerbations. We here describe its use in a woman with CF and respiratory failure.
A 50-year old woman with severe CF who eventually went into respiratory failure. Our patient had an F/G genotype and had been previously treated with ivacaftor but, after an initial improvement, experienced rapid disease progression (as has been previously described in ivacaftor-treated adults with G mutations), possibly aggravated by Bcc colonization. During her subsequent hospitalization, she did not improve significantly until ETI was administered, and, as all her other treatments remained unchanged, this suggests it played a role in her recovery. Furthermore, her lung disease continued to improve after she was discharged: There was no recurrence of PEx, no need for antibiotics, and her lung function and ABG parameters improved.

Dr Donatello Salvatore is Director of the Cystic Fibrosis Centre – Hospital San Carlo Potenza Italy.

Oded Breuer, David Shoseyov, Shifra Koretz, Nadia Alyan, Joel Reiter, Malena Cohen-Cymberknoh, Isaiah Wexler, Eitan Kerem. Ethical dilemma: ELX/TEZ/IVA or Lung Transplantation in Cystic Fibrosis and End Stage Lung Disease? Chest 2021 Sep 7;S0012-3692(21)03846-0.doi: 10.1016/j.chest.2021.08.073.Online ahead of print. [Pubmed]

Oded Breuer

Cystic fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Novel, highly effective, modulator therapies correcting and potentiating CFTR function are changing the course of the disease. We present an ethical dilemma involving an 11-year-old child with CF and end stage lung disease. Shortly after starting treatment with Elexacaftor-Tezacaftor-Ivacaftor, the family received notification that a matched donor lung had been allocated. Clinical decision-making in this case is challenging as definitive data to medically support one treatment option over the other is limited. A survey of CF center team members was conducted for the purpose of this manuscript. Ethical principles that may guide us in these situations are discussed.

Overall, results of the survey present a lack of agreement as to the best approach in this situation. Physicians, when compared to other team members, are more likely to provide a specific recommendation vs. to present the information and let the family decide (odds ratio (95% confidence interval)=4.0 (1.2-12.8), p=0.021). A shared decision-making model, stressing our moral obligation as clinicians to respect autonomy by appreciating family values while offering to participate in the decision-making process and ensuring non-maleficence, is presented.
In summary, CFTR modulators affect the outcomes of CF disease and influence clinical decision-making. Current lack of data on long-term outcomes, in young patients with CF receiving effective modulator therapy, should not preclude CF team participation in decision-making. Shared decision-making which is focused on respecting autonomy is our preferred approach in these situations.

Donatello Salvatore, Angela Pepe, Vincenzo Carnovale, Fabio Majo, Rita Padoan^, Serena Quattrucci, Marco Salvatore, Domenica Taruscio, Annalisa Amato, Gianluca Ferrari, Giuseppe Campagna Elexacaftor/tezacaftor/ivacaftor for CFTR variants giving rise to diagnostic uncertainty: Personalised medicine or over-medicalisation? J Cyst Fibros 2021 Sep 25;S1569-1993(21)01416-8. doi: 10.1016/j.jcf.2021.09.011.Online ahead of print. [Pubmed]
In order to assess the real-world frequency of the three categories that may give rise to diagnostic uncertainty (mutations uncertainly interpreted as being pathogenic, mutations of unknown significance, and non CF-causing variants), we queried the Italian CF Registry (ICFR) and found that 113 (2.06%) of the 5,489 subjects registered and genotyped in 2018 had at least one such mutation: nine had four different mutations uncertainly interpreted as being pathogenic; three had two different mutations of unknown significance; and 101 had ten different non CF-causing variants.
These findings highlight an important question concerning the eligibility of subjects without a clearly diagnostic mutation for CFTR modulator treatment because the number of currently eligi- ble patients has greatly increased and the annual retail cost of ETI exceeds $300,000 per patient, which is much more expensive than the cost of other chronic CF treatments.
On the one hand, CF physicians often have to provide care for patients with rare CF genotypes in clinical practice, and so there is a need to test the potential efficacy of approved modulators in the treatment of rare CF-causing genotypes. On the other, although it is true that robust clinical trial data may be very difficult (if not impossible) to obtain, we wonder whether in vitro data alone are sufficient to justify the use of a very expensive treatment, especially in the case of patients with a diagnosis of CF based on genotypes containing non-CF-causing variants or variants whose clinical effect is doubtful or unknown.

The introduction of second tier CFTR-extended genetic analyses in new-born screening programmes without filtering for all known CF variants with full penetrance would inevitably increase the number of eligible subjects. A significant number of infants with so-called CF transmembrane conductance regulator-related metabolic syndrome (CRMS)/cystic fibrosis screen positive, inconclusive diagnosis (CFSPID) would be considered eligible for HEMT, and their parents would probably expect them to receive it only in the presence of mutations that were simply verifiable on a free- access website. However, the diagnosis of CF is and may remain inconclusive for a long time.
The wise use of economic resources is an important consideration when attempting to improve the access to treatment of patients who could really benefit from HEMT.

Dr Donatello Salvatore is at the Cystic Fibrosis Centre, San Carlo Hospital, Potenza, Italy; Italian Cystic Fibrosis Registry, Rome Italy.

Kevin J Scully, Peter Marchetti, Gregory S Sawicki, Ahmet Uluer, Manuela Cernadas, Rebecca E Cagnina, John C Kennedy, Melissa S Putman. The effect of elexacaftor/tezacaftor/ivacaftor (ETI) on glycemia in adults with cystic fibrosis. J Cyst Fibros 2021 Sep 13;S1569-1993(21)01377-1.doi: 10.1016/j.jcf.2021.09.001.Online ahead of print.[Pubmed]

Kevin Scully

The impact of elexacaftor-tezacaftor-ivacaftor (ETI) on glycemic control is currently unknown. Our objective was to investigate the effect of ETI initiation on glycemia in adults with CF using continuous glucose monitoring (CGM).
Methods: In this prospective observational study, 34 adults with CF and at least one F508del CFTR mutation wore CGM sensors for 14 days prior to starting ETI and again 3-12 months after ETI initiation. Hypoglycemia symptoms were queried at each visit, and most recent anthropometric measures and spirometry data were obtained by chart review.
Results: Twenty-three participants completed the study. Compared to baseline, average glucose (AG), standard deviation (SD), % time >200 mg/dL, and peak sensor glucose decreased with ETI treatment, and % time in target range 70-180 mg/dL increased. Improvements in glycemic parameters were most notable in individuals with CFRD. There was no significant change in CGM-measured or self-reported hypoglycemia before and after ETI initiation.
Conclusion: Initiation of ETI in adults with CF was associated with improvement CGM-derived measures of hyperglycemia and glycemic variability with no effect on hypoglycemia. The authors suggest further studies are needed to investigate underlying etiology of these changes and the long-term impact of ETI on glycemic control in patients with CF.

Dr Kevin J Scully is attending physician and clinical fellow in the Division of Endocrinology, Boston Children’s Hospital, 333 Longwood Avenue, 6th Floor, Boston, MA, 02115, United States; Harvard Medical School, Boston MA, United States.

Rosara Bass, Jefferson N Brownell, Virginia A Stallings. The Impact of Highly Effective CFTR Modulators on Growth and Nutrition Status. Nutrients 2021 Aug 24;13(9):2907. doi: 10.3390/nu13092907 free article [Pubmed]

Rosara Bass

Dysfunctional CFTR contributes to increased energy expenditure, exocrine pancreatic insufficiency causing impaired dietary macronutrient digestion and absorption, intestinal dysbiosis, and impaired bile acid homeostasis. Poor nutritional status as a result of these mechanisms is associated with decreased lung function, worse clinical outcomes, and ultimately, increased mortality. Nutritional interventions addressing these mechanisms, such as pancreatic enzyme-replacement therapy and enteral caloric supplementation, have improved nutritional status and, by association, clinical outcomes. In the last decade, the advent of medications targeting defective CFTR proteins has revolutionized the care of patients with CF by reducing the overall impact of CFTR dysfunction. Below, we summarize the effects of highly effective CFTR modulators on nutritional status overall as well as specific factors including bile acid metabolism, pancreatic function, energy expenditure, and intestinal dysbiosis. The authors suggest the future of CF nutrition care will require a paradigm shift away from focusing on methods addressing CFTR dysfunction such as excess calorie provision and toward an individualized, holistic approach in the context of specific mutations and CFTR-directed therapy.

Table 1 (from full paper available via PubMed) Summary of the effects of highly effective CFTR modulators on markers of growth, nutritional status and gastrointestinal health.

Outcome	Ivacaftor	ELEX-TEZ-IVA
Weight-Z	Increased	Increased
Height-Z	Increased in youth	To be determined
BMI-Z	Increased	Increased
Fat Mass	Increased	To be determined
Fat-Free Mass	Unchanged to increased	To be determined
Bile Acid Metabolism	Increased FGF-19 and decreased C4	To be determined
CF Liver Disease	To be determined, case reports of improved steatosis	To be determined
Exocrine Pancreatic Insufficiency	Increased fecal elastase at younger ages	To be determined
Bicarbonate Secretion	Decreased time to reach pH 5.5	To be determined
Energy Expenditure	Decreased	To be determined
GI Microbiome	Changes in intestinal flora and decreased calprotectin	To be determined

Dr Rosara Bass is attending physician with the Division of Gastroenterology, Hepatology and Nutrition at the Children’s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA.

– This is an excellent comprehensive review of the general effects of CFTR modulators on wide variety of factors relevant to nutrition

Ruth H Keogh, Rebecca Cosgriff, Eleni-Rosalina Andrinopoulou, Keith G Brownlee, Siobhán B Carr, Karla Diaz-Ordaz, Emily Granger, Nicholas P Jewell, Alex Lewin, Clemence Leyrat, Daniela K Schlüter, Maarten van Smeden, Rhonda D Szczesniak, Gary J Connett^. Projecting the impact of triple CFTR modulator therapy on intravenous antibiotic requirements in cystic fibrosis using patient registry data combined with treatment effects from randomised trials Thorax 2021 Sep 23;thoraxjnl-2020-216265.doi: 10.1136/thoraxjnl-2020-216265.Online ahead of print. [Pubmed]

Ruth Keogh

Background: Cystic fibrosis (CF) is a life-threatening genetic disease, affecting around 10 500 people in the UK. Precision medicines have been developed to treat specific CF-gene mutations. The newest, elexacaftor/tezacaftor/ivacaftor (ELEX/TEZ/IVA), has been found to be highly effective in randomised controlled trials (RCTs) and became available to a large proportion of UK CF patients in 2020. Understanding the potential health economic impacts of ELEX/TEZ/IVA is vital to planning service provision.
Methods: We combined observational UK CF Registry data with RCT results to project the impact of ELEX/TEZ/IVA on total days of intravenous (IV) antibiotic treatment at a population level. Registry data from 2015 to 2017 were used to develop prediction models for IV days over a 1-year period using several predictors, and to estimate 1-year population total IV days based on standards of care pre-ELEX/TEZ/IVA. We considered two approaches to imposing the impact of ELEX/TEZ/IVA on projected outcomes using effect estimates from RCTs: approach 1 based on effect estimates on FEV₁% and approach 2 based on effect estimates on exacerbation rate.
Results: ELEX/TEZ/IVA is expected to result in significant reductions in population-level requirements for IV antibiotics of 16.1% (~17 800 days) using approach 1 and 43.6% (~39 500 days) using approach 2. The two approaches require different assumptions. Increased understanding of the mechanisms through which ELEX/TEZ/IVA acts on these outcomes would enable further refinements to our projections.
Conclusions: This work contributes to increased understanding of the changing healthcare needs of people with CF and illustrates how Registry data can be used in combination with RCT evidence to estimate population-level treatment impacts.

Professor Ruth H Keogh is at the Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK

Lauryn A Benninger, Cesar Trillo, Jorge Lascano. CFTR modulator use in post lung transplant recipients. J Heart Lung Transplant 2021 Aug 26;S1053-2498(21)02482-7.doi: 10.1016/j.healun.2021.08.009. Online ahead of print. [Pubmed]

Lauryn Benninger

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapy has previously been contraindicated in solid organ transplant recipients. This was due to lack of data and concern for interactions with immunosuppressive drug regimens. However, in post-lung transplant recipients, CFTR modulators may improve extrapulmonary manifestations of cystic fibrosis without impacting graft function or immunosuppressive drug levels. Herein, we present our single center experience with the use of elexacaftor/tezacaftor/ivacaftor, Trikafta, in adult post-lung transplant recipients.

Dr Lauryn A Benninger is a pulmonologist in the Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida College of Medicine, Gainesville, Florida

Edith T Zemanick, Jennifer L Taylor-Cousar, Jane Davies, Ronald L Gibson, Marcus A Mall, Edward F McKone; McNally P; Ramsey BW; Rayment JH; Rowe SM; Tullis E; Ahluwalia N; Chu C; Ho T; Moskowitz SM; Noel S; Tian S; Waltz D; Weinstock TG; Xuan F; Wainwright CE; McColley SA. A Phase 3 Open-Label Study of ELX/TEZ/IVA in Children 6 Through 11 Years of Age With CF and at Least One F508del Allele.Am J Respir Crit Care Med 2021 Mar 18. doi: 10.1164/rccm.202102-0509OC.Online ahead of print.[Pubmed]

Edith Zermanick

Dr Edith T Zemanick is Associate Professor at the Colorado Anschutz Medical Campus and Children’s Hospital Colorado, Department of Pediatrics, Aurora, Colorado, United States

Peter J Barry, Marcus A Mall, Antonio Álvarez¹, Carla Colombo, Karin M de Winter-de Groot, Isabelle Fajac et al. VX18-445-104 Study Group Collaborators, Triple Therapy for Cystic Fibrosis Phe508del-Gating and -Residual Function Genotypes. N Engl J Med 2021 Aug 26;385(9):815-825.doi: 10.1056/NEJMoa2100665. [Pubmed]

Peter J Barry

Background: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508delallele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear.
Methods: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV₁) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group
Results: After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV₁ that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group.

Conclusions: Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del-gating or Phe508del-residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).

Dr Peter J Barry is at the Manchester University NHS Foundation Trust, Manchester, United Kingdom.

Rebecca H Goldberg, Natalie H Matthews, Alexandra C Hristov, Frank Wang^.Urticaria multiforme-like eruption due to a novel agent elexacaftor/tezacaftor/ivacaftor in a pediatric patient with cystic fibrosis. JAAD Case Rep. 2021 Oct 25;18:71-73.doi: 10.1016/j.jdcr.2021.10.018.eCollection 2021 Dec.Free article [Pubmed]

Rebecca Goldberg

Rebecca H Goldberg is at the University of Michigan Medical School, Ann Arbor, Michigan.

(Please note there is a free article with good quality images via PubMed)

Mahan Salehi, Mubashar Iqbal, Asha Dube, Amer AlJoudeh, Frank Edenborough.Delayed hepatic necrosis in a cystic fibrosis patient taking Elexacaftor/Tezacaftor/Ivacaftor (Kaftrio)Respir Med Case Rep 2021 Nov 10;34:101553.doi: 10.1016/j.rmcr.2021.101553. eCollection 2021 Free PMC article. [Pubmed]

Frank Edenborough

Mahan Salehi

The introduction of Cystic Fibrosis Trans Regulatory modulator (CFTRm) drugs has seen a transformation in Cystic Fibrosis (CF) treatment. This has led to a significant improvement in lung function and quality of life with the potential for a real impact on life expectancy. Transient mild to moderate hepatic transaminitis is a well-known side effect of CFTRm drugs, which often improves on cessation and may not recur following the re-institution of the drug. We describe a case of transaminitis developing nine months after the initiation of Kaftrio, which progressed to liver necrosis despite stopping Kaftrio and took many months to resolve. The patient had experienced significant improvement in lung function and overall health while on Kaftrio and deteriorated when it was stopped. He was keen to restart; however, Kaftrio was not reinstated due to the potential risk of acute liver failure.

Mahan Salehi an Academic Foundation Doctor at the Sheffield Teaching Hospitals, Adult Cystic Fibrosis Centre, Sheffield, UK.

Lo M Sosinski, Christian Martin H, Kerri A Neugebauer, Lydia-Ann J Ghuneim, Douglas V Guzior, Alicia Castillo-Bahena, Jenna Mielke, Ryan Thomas, Marc McClelland, Doug Conrad, Robert A Quinn. A restructuring of microbiome niche space is associated with Elexacaftor-Tezacaftor-Ivacaftor therapy in the cystic fibrosis lung J Cyst Fibros 2021 Nov 22;S1569-1993(21)02131-7.doi: 10.1016/j.jcf.2021.11.003.Online ahead of print. [Pubmed]

Lo Sosinski

Background: Elexacaftor-Tezacaftor-Ivacaftor (ETI) therapy is showing promising efficacy for treatment of cystic fibrosis (CF) and is becoming more widely available since recent FDA approval. However, little is known about how these drugs will affect lung infections, which are the leading cause of morbidity and mortality among people with CF (pwCF).
Methods: We analyzed sputum microbiome and metabolome data from pwCF (n=24) before and after ETI therapy using 16S rRNA gene sequencing and untargeted metabolomics.
Results: The sputum microbiome diversity, particularly its evenness, was increased (p=0.036) and the microbiome profiles were different between individuals before and after therapy (PERMANOVA F=1.92, p=0.044). Despite these changes, the microbiomes remained more similar within an individual than across the sampled population. No specific microbial taxa differed in relative abundance before and after therapy, but the collective log-ratio of classic CF pathogens to anaerobes significantly decreased (p=0.013). The sputum metabolome also showed changes associated with ETI (PERMANOVA F=4.22, p=0.002) and was characterized by greater variation across subjects while on treatment. Changes in the metabolome were driven by a decrease in peptides, amino acids, and metabolites from the kynurenine pathway, which were associated with a decrease in CF pathogens. Metabolism of the three small molecules that make up ETI was extensive, including previously uncharacterized structural modifications.
Conclusions: ETI therapy is associated with a changing microbiome and metabolome in airway mucus. This effect was stronger on sputum biochemistry, which may reflect changing niche space for microbial residency in lung mucus as the drug’s effects take hold.

Lo M Sosinski is a graduate student in the Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA

David P Nichols, Alex C Paynter, Sonya L Heltshe, Scott H Donaldson, Carla A Frederick, Steven D Freedman et al, PROMISE Study Group. Clinical Effectiveness of Elexacaftor/Tezacftor/Ivacaftor in People with Cystic Fibrosis Am J Respir Crit Care Med 2021 Nov 16.doi: 10.1164/rccm.202108-1986OC.Online ahead of print.[Pubmed]

David Nichols

Rationale: The cystic fibrosis (CF) modulator drug elexacaftor/tezacaftor/ivacaftor (ETI) proved highly effective in controlled clinical trials for individuals with ≥1 F508del allele, which occurs in at least 85% of people with CF (PwCF).
Objective: PROMISE is a post-approval study to understand the broad effects of ETI through 30 months clinical use in a more diverse US patient population with planned analyses after 6 months
Methods: Prospective, observational study in 487 PwCF age ≥12 years with ≥1 F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in ppFEV₁, sweat chloride concentration, body mass index, and self-reported respiratory symptoms.
Results: average age was 25.1 years. 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor while 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV₁ improved 9.76 percentage points (95% CI 8.76, 10.76) from baseline, CFQ-R Respiratory Domain score improved 20.4 points (95% CI 18.3, 22.5), and sweat chloride decreased -41.7 mmol/L (95% CI 43.8, 39.6). BMI also significantly increased. Changes were larger in those naïve to modulators but substantial in all groups, including those treated with ivacaftor at baseline.
Conclusions: ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naïve to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV₁ in the overall study population.

David P Nichols is in the University of Washington School of Medicine, 12353, Pediatrics, Seattle, Washington, United States.Seattle Children’s Hospital, 7274, Pediatric Pulmonology, Seattle, Washington, United States.

Michael Williamson, Michelle Casey, Claudie Gabillard-Lefort, Aram Alharbi, Yu Qing Jolene Teo, Noel G McElvaney, Emer Reeves.Current evidence on the effect of highly effective CFTR modulation on interleukin-8 in cystic fibrosis. Expert Rev Respir Med 2021 Nov 2.doi: 10.1080/17476348.2021.2001333.Online ahead of print.[Pubmed]

Introduction:Cystic fibrosis (CF) is a genetically inherited disease, with mortality and morbidity associated with respiratory disease. The inflammatory response in CF is characterized by excessive neutrophil influx to the airways, mainly due to the increased local production and retention of interleukin-8 (IL-8), a potent neutrophil chemoattractant.
Areas covered:: We discuss how the chemokine IL-8 more than any other dominates the inflammatory profile of the airways in CF lung disease. Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein resulting from specific CFTR mutations. This review covers current evidence on the impact of CFTR impairment on levels of IL-8 and outlines the influence of effective CFTR modulation on inflammation in CF with a focus on cytokine production. Review of the literature was carried out using the PUBMED database, Google Scholar and The Cochrane Library databases, using several appropriate generic terms.
Expert opinion:: Therapeutic interventions specifically targeting the defective CFTR protein have improved the outlook for CF. Accumulating studies on the effect of highly effective CFTR modulation on inflammation indicate an impact on IL-8 levels. Further studies are required to increase our knowledge of early onset innate inflammatory dysregulation and on anti-inflammatory mechanisms of CFTR modulators.

Michael Williamson is Consultant Respiratory Physician is at the Royal College of Surgeons in Ireland, Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland

Sivagurunathan Sutharsan, Edward F McKone, Damian G Downey, Jamie Duckers, Gordon MacGregor, Elizabeth Tullis, Eva Van Braeckel, Claire E Wainwright, Danie Watson, Neil Ahluwalia, Bote G Bruinsma, Christopher Harris, Anna P Lam, Yiyue Lou, Samuel M Moskowitz, Simon Tian, Jason Yuan, David Waltz, Marcus A Mall, VX18-445-109 study group. Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial. Lancet Respir Med 2021 Dec 20;S2213-2600(21)00454-9.doi: 10.1016/S2213-2600(21)00454-9. Online ahead of print [Pubmed]

Sivagurunathan-Sutharsan

Background:Elexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation.
Methods:We conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV₁ of 40-90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV₁, age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor’s study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV₁ up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972.
Findings:Between Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (-1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], p<0·0001), the mean percent predicted FEV₁ increased by 11·2 percentage points (95% CI 9·8 to 12·6) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·0 percentage points (-0·4 to 2·4) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 10·2 percentage points [8·2 to 12·1], p<0·0001), and the mean sweat chloride concentration decreased by 46·2 mmol/L (95% CI 43·7 to 48·7) in the elexacaftor plus tezacaftor plus ivacaftor group and by 3·4 mmol/L (1·0 to 5·8) in the tezacaftor plus ivacaftor group (least squares mean treatment difference -42·8 mmol/L [-46·2 to -39·3], nominal p<0·0001). Most participants (70 [80%] in the elexacaftor plus tezacaftor plus ivacaftor group and 74 [84%] in the tezacaftor plus ivacaftor group) had adverse events that were mild or moderate in severity; serious adverse events occurred in five (6%) of 87 participants in the elexacaftor plus tezacaftor plus ivacaftor group and 14 (16%) of 88 participants in the tezacaftor plus ivacaftor group. One (1%) participant in the elexacaftor plus tezacaftor plus ivacaftor group discontinued treatment due to an adverse event of anxiety and depression. Two (2%) participants in the tezacaftor plus ivacaftor group discontinued treatment due to adverse events of psychotic disorder (n=1) and obsessive-compulsive disorder (n=1).
Interpretation:The elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population.

Dr Sivagurunathan Sutharsan is in the Department of Pulmonary Medicine, Division of Cystic Fibrosis, University Medicine Essen-Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany.

2022

Jonathan Guo, Anna Garratt, Andrew Hill. Worldwide rates of diagnosis and effective treatment for cystic fibrosis. J Cyst Fibros 2022 Feb 3;S1569-1993(22)00031-5.doi: 10.1016/j.jcf.2022.01.009.Online ahead of print. [Pubmed]

Jonathan Guo

Background: Time has seen management for Cystic Fibrosis (CF) advance drastically, most recently in the development of the disease-modifying triple combination therapy ivacaftor/tezacaftor/elexacaftor. There is currently limited evidence regarding both the global epidemiology of CF and access to this transformative therapy – and therefore where needs are not being met. Therefore, this study aims to define gaps in access to CF treatment.

Methods: Patient data were extracted from established CF registries. Where these were not available, literature searches were conducted alongside an international survey of 51 CF experts to determine the diagnosed patient population. National CF prevalence estimates were combined with registry data on estimated population coverage, to extrapolate the total estimated number of undiagnosed patients. Estimates of ivacaftor/tezacaftor/elexacaftor treatment coverage were extracted from publicly available sales summaries and pricing data.

Results: 162,428 [144,606-186,620] people are estimated to be living with CF across 94 countries. Of these, an estimated 105,352 (65%) are diagnosed, with 19,516 (12%) receiving triple combination therapy. We estimated 57,076 patients with undiagnosed CF. Owing to a paucity of high-quality data, estimates of undiagnosed CF in low- and middle-income countries are highly uncertain. Patient registries were available in 45 countries, and used to identify 90% of the estimated diagnosed population.

Conclusions: A significant CF patient burden exists in countries where disease-modifying drugs are unavailable, and final figures are likely underestimates. This analysis shows the potential to improve rates of diagnosis and treatment for CF, so a higher percentage of patients receive the most effective triple combination treatment.

Dr Jonathan Guo is in the Faculty of Medicine, Imperial College London, United Kingdom

Clémence Martin, Martine Reynaud-Gaubert, Rebecca Hamidfar, Isabelle Durieu, Marlène Murris-Espin, Isabelle Danner-Boucher, Raphaël Chiron, Sylvie Leroy, Benoit Douvry, Dominique Grenet^. Laurent Mely, Sophie Ramel, Sylvie Montcouquiol, LydieLemonnier, Espérie Burnet, Jean-Louis Paillasseur, Jennifer Da Silva, Pierre-Régis Burgel^.Sustained effectiveness of elexacaftor-tezacaftor-ivacaftor in lung transplant candidates with cystic fibrosis. J Cyst Fibros. 2022 Feb 2;S1569-1993(22)00032-7.doi: 10.1016/j.jcf.2022.01.012.Online ahead of print [Pubmed]

Clemence Martin

Background: Elexacaftor-tezacaftor-ivacaftor induces rapid clinical improvement in patients with cystic fibrosis (CF) and advanced pulmonary disease, often leading to suspend the indication for lung transplantation. Yet no long-term data is available in lung transplant candidates.

Methods: Lung transplant candidates (defined as being waitlisted for lung transplantation or considered for listing within 3 months) who have initiated elexacaftor-tezacaftor-ivacaftor were identified in the French cohort of patients with CF and advanced pulmonary disease. Patients were prospectively followed to evaluate treatment safety and effectiveness from initiation to July 20th, 2021.
Results: Among the 331 patients with advanced CF pulmonary disease who initiated elexacaftor-tezacaftor-ivacaftor, 65 were lung transplant candidates (17 listed for transplantation, 48 considered for listing within 3 months). Median [IQR] follow-up time was 363 [329; 377] days. At the end of the follow-up period, two patients were transplanted five and 11 days following treatment initiation, two were listed for transplantation, and 61 no longer met transplantation criteria. Improvement in percent predicted forced expiratory volume in 1 s (ppFEV₁) at one month was +13.4% (95% confidence interval, 10.3%-16.5%; P < 0.0001) and remained stable thereafter. Treatment burden decreased substantially, with an 86% decrease in the need for intravenous antibiotics, 59% for oxygen therapy and 62% for non-invasive ventilation.

Conclusion: In lung transplant candidates eligible for elexacaftor-tezacaftor-ivacaftor, the rapid improvement following initiation of treatment persisted over one year with a reduction in treatment burden and lung transplantation could be safely deferred in most patients.

Clémence Martinis at the Université de Paris, Institut Cochin, InsermU1016, Paris, France; Respiratory Medicine and Cystic Fibrosis National Reference Center, Cochin Hospital, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; ERN-Lung CF network, Frankfurt, Germany.

Amanda L Stapleton, Adam J Kimple, Jennifer L Goralski, S Mehdi Nouraie, Barton F Branstetter, Amber D Shaffer, Joseph M Pilewski, Brent A Senior, Stella E Lee, Anna C Zemke. Elexacaftor-Tezacaftor- Ivacaftor improves sinonasal outcomes in cystic fibrosis. J Cyst Fibros 2022 Mar 14;S1569-1993(22)00051-0.doi: 10.1016/j.jcf.2022.03.002.Online ahead of print. Free article [Pubmed]

Amanda Stapleton

Background: Many individuals with cystic fibrosis (CF) have chronic rhinosinusitis resulting in nasal obstruction, sinus infections, and repeated surgeries. Elexacaftor-tezacaftor-ivacaftor is a highly effective modulator therapy approved for individuals aged 6 years or older with CF who have at least one F508del allele or other responsive mutation. The current study tests the hypothesis that ELX/TEZ/IVA improves sinonasal disease in CF.
Methods: The study was a pre/post, observational cohort study conducted at two sites. Participants underwent a study visit prior to starting ELX/TEZ/IVA and a second visit at a median of 9 months on therapy. Each visit included sinus CT scan, rigid nasal endoscopy, and sweat chloride measurement. Symptoms were measured with the 22 item Sinonasal Outcome Test at scheduled intervals during the study. Regression models were used to test for improvement in symptoms, endoscopy, and CT scales.
Results: The study enrolled 34 individuals, with a median age of 27 years (range 12-60). Symptoms improved within 7 days of therapy and plateaued by day 28. Endoscopic crusting resolved and nasal polyposis improved, with a decrease in size or resolution of polyps. Sinus opacification and mucosal thickening improved on CT radiographs with treatment.
Conclusions: Sinonasal symptoms improved rapidly and durably for at least 180 days on ELX/TEZ/IVA therapy. Objective measures of disease including endoscopic and CT findings improved with ELX/TEZ/IVA.

Dr Amanda L Stapleton is Associate Professor in the Department of Otolaryngology – Head and Neck Surgery, University of Pittsburgh, United States.

Thomas Simon FitzMaurice, Dilip Nazareth, Kapil Iyer, Martin Walshaw, Mohamed Al-Aloul. Elexacaftor/Tezacaftor/Ivacaftor as a Bridge to Lung Retransplant in a Recipient With Cystic Fibrosis. Exp Clin Transplant 2022 Mar 15.doi: 10.6002/ect.2021.0468.Online ahead of print. Free article [Pubmed]
The triple-combination cystic fibrosis transmembrane conductance regulator modulator elexacaftor/- tezacaftor/ivacaftor is known to improve lung function and have extrapulmonary benefits in people with cystic fibrosis. However, there is limited evidence for its use in patients with cystic fibrosis after lung transplant, where the donor lung expresses normal levels of the cystic fibrosis transmembrane conductance regulator. We describe the use of elexacaftor/tezacaftor/ivacaftor as a bridge to potential lung retransplant in a 37-year-old man with cystic fibrosis and chronic lung allograft dysfunction. Although forced expiratory volume in 1 second did not improve, the patient had decreased sputum volume, no pulmonary exacerbations of cystic fibrosis, and no longer required continuous antibiotic therapy. Pancreatic function, revised Cystic Fibrosis Questionnaire scores, sinus symptoms, weight, and corticosteroid dependence significantly improved. There were no reported side effects attributable to elexacaftor/tezacaftor/ivacaftor. However, the patient exhibited declined renal function, which had been initially attributed to lability in cyclosporin levels but which were corrected after lithotripsy for renal calculi.

Triple-combination modulators of the cystic fibrosis transmembrane conductance regulator may offer benefits to carefully selected individuals awaiting retransplant, balanced against the risk of worsened immunosuppressant level control.

Thomas Simon FitzMaurice is a Fellow in the Adult CF Unit, Liverpool Heart and Chest Hospital, Liverpool, United Kingdom and the Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.

Marco Zampoli, Nataliya Kashirskaya, Bulent Karadag, Luiz Vicente Ribeiro Ferreira da Silva Filho, Grace R Paul^, Christine Noke. Global access to affordable CFTR modulator drugs: Time for action! J Cyst Fibros 2022 Mar 24;S1569-1993(22)00083-2.doi: 10.1016/j.jcf.2022.03.006.Online ahead of print.[Pubmed]

There is no abstract so the article is reproduced here in view of its important content.

Marco Zampoli

“Whilst the incredible advancements in CF treatment are to be applauded and celebrated, the reality is that only a minority of people with CF in the rich global North are benefiting from CFTRm therapy. We are therefore very grateful and encouraged by the timely and important article by Jonathan Guo et al. published recently in the Journal which highlights the stark reality and disparity that exists in CF diagnosis and treatment across the world. According to their estimates based on available data, there are 57,076 people with undiagnosed CF across the world with the highest burden likely to be in the Middle East and India. Furthermore, only 12% of estimated 105,352 people captured in global CF registries are receiving Trikafta®/Kaftrio® and the majority of them are living in North America or Western Europe. We agree with their view that paucity of epidemiological data and lack of CF diagnosis capacity in low and middle-income countries (LMICs) are major barriers to advocating for effective and equitable treatment in these regions. However, there are significant CF populations living in LMICs such as South Africa, India, the Middle East, eastern Europe, and South America who currently have no access nor pathway to registration of Trikafta®/Kaftrio® which will undoubtably lead to increasing disparity in CF outcomes between the rich global North and poor global South. In these countries, the main barrier to accessing triple CFTRm therapy is not lack of diagnosis capacity, but profit-driven global market forces which are accountable more to shareholders than the health needs of the global CF community.

Global distribution and sales of CFTRm drugs and patents are in place until 2037 in many LMICs that are signatories to the World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights, effectively preventing manufacture and distribution of affordable generic alternatives in these countries. The current annual cost per patient of Trikafta®/Kaftrio® paid by countries with negotiated agreements is more than $250 000 which is prohibitive for governments and private health insurers in LMICs. Vertex Pharmaceuticals posted a net income of $5.7 billion in 2021 which is a bitter pill to swallow for CF communities in LMICs who are helpless and increasingly impatient with the injustice of their plight . Precedent exists where pharmaceutical companies holding patents have issued voluntary licenses to generic manufacturers to distribute, with profit, life-saving affordable generic drugs in LMICs for treatment of Human Immunodeficiency Virus, hepatitis-C and more recently COVID-19. It is time that the global CF community stand in solidarity in support of similar issuing of voluntary licenses for the manufacture and distribution of generic CFTRm drugs.

We appeal and urge that the Journal and CF patient organizations in the global North such as the Cystic Fibrosis Foundation and European CF Society adopt a stronger position and publish statements against the injustice of the disparity in access to CFTRm therapy for all people across the world living with CF who are eligible for this life-saving treatment. Cystic fibrosis clinicians, researchers and CF communities living in LMICs cannot endure and tolerate much longer reading and hearing about the ‘miracle’ outcomes of triple CFTRm drugs of the privileged minority in rich countries. In the meantime, we continue to patiently negotiate in good faith with Vertex Pharmaceuticals in the hope that CF communities in LMICs will soon have affordable access to this life saving treatment. But time is running out for many people slowly dying too early with CF.

Dr Marco Zampoli is Clinical Head: Cystic Fibrosis Clinic Red Cross War Memorial Children’s Hospital, National Director South African CF Registry Steering Committee, Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa

Eunjin Hong, Lisa M Almond, P S Chung, A Peter Rao, Paul M BeringerPBPK-led guidance for cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19. Clin Pharmacol Ther 2022 Mar 16.doi: 10.1002/cpt.2585. Online ahead of print. [Pubmed]

Eunjin Hong

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies including elexacaftor, tezacaftor, and ivacaftor (ETI) are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of COVID-19 with nirmatrelvir-ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug-drug interactions (DDI). However, CF population is more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options.
CYP3A-mediated DDI of ETI was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach. Modeling was performed incorporating physiological information and drug dependent parameters of ETI to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on pharmacokinetics of ETI. The ETI models were verified using independent clinical pharmacokinetic and DDI data of ETI with a range of CYP3A modulators. When ritonavir was administered on day 1 through 5, the predicted AUC ratio of ivacaftor (the most sensitive CYP3A substrate) on day 6 was 9.31, indicating that its metabolism was strongly inhibited.

Based on the predicted DDI, the dose of ETI should be reduced when co-administered with nirmatrelvir-ritonavir to elexacaftor 200mg-tezacaftor 100mg-ivacaftor 150mg on days 1 and 5, with delayed resumption of full dose ETI on day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor. The simulation predicts a regimen of ETI administered concomitantly with nirmatrelvir/ritonavir in people with CF that will likely decrease the impact of the drug interaction.

Eunjin Hong is a graduate student the Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA, 90033, USA.

Claire E Wainwright A New Era for Cystic Fibrosis and CFTR Modulator Trials in Infants. Am J Respir Crit Care Med 2022 Jul 20.doi: 10.1164/rccm.202207-1356ED.Online ahead of print.[Pubmed]
(Summary as no abstract)

Claire Wainwright

As CFTR modulator therapies becomes established in young children a new approach to clinical care is likely to evolve as people with CF live longer lives ensuring healthy ageing will become a priority
In open label trials nearly 11% of children had transaminases elevation more than 3x upper limit of normal. Details of trails in young infants remain to be decided – open label trials appear to be extending to infants. There may be unrecognised effects on the young developing child and will open label trials be adequate to recognise these problems?
As CFTR modulation becomes established clinically the window for randomised placebo-controlled trials has almost closed. Consumers, clinicians and researchers need to rapidly determine how we move forward in developing new CFTR modulator therapy for infants and decide whether infants are indeed “little adults” and whether benefits can be effectively inferred or whether they deserve the same degree of evidence as older people expect?

Claire E Wainwright is Professor of Paediatrics and Child Health University of Queensland, Brisbane, Australia

Brittany Miles, Jay Chacko, Mohammed Zaidan. The Impact of Elexacaftor/Ivacaftor/Tezacaftor on Cystic Fibrosis Patients Who Acquire COVID-19 Infection Cureus. 2022 Sep 17;14(9):e29276. doi: 10.7759/cureus.29276. eCollection 2022 Sep pubmed.ncbi.nlm.nih.gov/36277555
The combination of medication containing elexacaftor, ivacaftor, and tezacaftor (EIT) has dramatically impacted the treatment and prognosis for patients with cystic fibrosis (CF). Lung function, weight, and self-reported quality of life have improved for many of these patients, but little is known about whether this treatment will have a beneficial effect in preventing morbidity and/or mortality from respiratory infections such as COVID-19. EIT received Food and Drug Administration (FDA) approval shortly before the first cases of COVID-19 appeared in the United States. We performed an analysis using the TriNetX (Cambridge, MA, USA) research database to determine if patients being treated with EIT who became infected with COVID-19 experienced significantly different outcomes compared to patients who were not receiving it.

Brittany Miles is at Medical Education and Radiology, University of Texas Medical Branch, Galveston, USA.

Renée V. E. Dagenais, Victoria C. Suand Bradley S. Quon Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review. J Clin Med.2021 Jan; 10(1): 23. Published online 2020 Dec 23.doi: 10.3390/jcm10010023 [Pubmed]

[This article has been corrected.SeeJ Clin Med. 2022 January 10; 11(2): 318.[Pubmed] Mistake in Table 1. Reference citation [34] was wrong. The corrected Table 1 appears below. The authors state that the scientific conclusions are unaffected. The original article has been updated]

Renee Dagenais

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF), and are generally well-tolerated; however, real-world studies indicate the frequency of discontinuation and adverse events (AEs) may be higher than what was observed in clinical trials. The objectives of this systematic review were to summarize real-world AEs reported for market available CFTR modulators (i.e., ivacaftor (IVA), lumacaftor/ivacaftor (LUM/IVA), tezacaftor/ivacaftor (TEZ/IVA), and elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA)), and to identify ways in which the pharmacist on CF healthcare teams may contribute to mitigating and managing these AEs. The MEDLINE, EMBASE, CINAHL, and Web of Science Core Collection online databases were searched from 2012 to 1 Aug 2020. Full manuscripts or conference abstracts of observational studies, case series, and case reports were eligible for inclusion. The included full manuscripts and conference abstracts comprised of 54 observational studies, 5 case series, and 9 case reports. The types of AEs reported generally aligned with what have been observed in clinical trials. LUM/IVA was associated with a higher frequency of respiratory-related AE and discontinuation in real-world studies. A signal for mental health and neurocognitive AEs was identified with all 4 CFTR modulators. A systematic approach to monitoring for AEs in people with CF on CFTR modulators in the real-world setting is necessary to help better understand potential AEs, as well as patient characteristics that may be associated with higher risk of certain AEs. Pharmacists play a key role in the safe initiation and monitoring of people with CF on CFTR modulator therapies.

Renée V. E. Dagenais from the Adult Cystic Fibrosis Program, St. Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada. Department of Pharmacy, St. Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada and the Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada.

– This is a useful encyclopaedic article on the downside of the new modulator drugs

Hunter Ragan, Elizabeth Autry, Taryn Bomersback, Jennifer Hewlett, Lauren Kormelink, Julie Safirstein, Laura Shanley, Lisa Lubsch^. The use of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis post-liver transplant: A case series. Pediatr Pulmonol 2022 Feb;57(2):411-417.doi: 10.1002/ppul.25779.Epub 2021 Dec 12.[Pubmed]
Introduction:Cystic fibrosis (CF)-related liver disease (CFLD) manifests as a wide spectrum of hepatobiliary disease and can progress to need liver transplantation. Elexacaftor/tezacaftor/ivacaftor (elx/tez/iva) is a cystic fibrosis transmembrane conductance regulator modulator that has superior efficacy compared to previously approved modulators. Use of elx/tez/iva, should be approached with caution in individuals with CFLD or following liver transplantation due to possible increases in liver function tests (LFTs) and drug-drug interactions with several immunosuppressant medications.
Objective:The purpose of this case series is to explore if the use of elx/tez/iva is safe and tolerable in patients with CF postliver transplantation.
Methods:A retrospective case series including patients prescribed elx/tez/iva following liver transplantation and an immunosuppressive regimen consisting of drug therapy metabolized by P-glycoprotein was completed.
Results:Ten patients at six CF centers with a median age of 22.1 years (range 14-43.4 years) and the median time from the transplant of 6.9 years (range 0.6-22 years) were included. Most patients (8, 80%) received a reduced or full dose of elx/tez/iva for a mean duration of 10.4 months (range 7-12 months). Fluctuations in LFTs occurred in all patients (10, 100%) and led to therapy discontinuation in two patients (20%). Elx/tez/iva initiation resulted in elevations in tacrolimus trough concentration in seven patients (70%). Most patients who tolerated elx/tez/iva had symptomatic and quality of life improvement, increased body mass index, and maintained or improved lung function.

Conclusion:Initiation of elx/tez/iva in patients with CF who received liver transplantation may be safe with clinical benefits.

Thomas S FitzMaurice, Caroline McCann, Dilip Nazareth, Matthew Shaw, Paul S McNamara, Martin J Walshaw^.Measuring the effect of elexacaftor/tezacaftor/ivacaftor combination therapy on the respiratory pump in people with CF using dynamic chest radiography. J Cyst Fibros 2022 Jan 28;S1569-1993(22)00027-3. doi: 10.1016/j.jcf.2022.01.007.Online ahead of print. [Pubmed]

Thomas S FitzMaurice

Background: The CFTR modulator elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) leads to significant improvement in the symptoms and spirometry of people with cystic fibrosis (pwCF), but little evidence exists to understand its effect on respiratory pump function. Dynamic chest radiography (DCR) is a novel cineradiographic tool that identifies and tracks the chest wall and diaphragm throughout the breathing cycle, alongside fluoroscopic images of the chest of diagnostic quality.

Methods: In this observational work, we examined the spirometry and DCR of 24 pwCF before and after starting ELX/TEZ/IVA. DCR automatically tracked the hemidiaphragm midpoints and projected lung area (PLA) during tidal and deep breathing manoeuvres.
Results: ppFEV₁ (61±18 to 73±22, P<0.001) and ppFVC (77±16 to 88±15, P<0.001) improved significantly. DCR demonstrated a significant increase in hemidiaphragm excursion on both the right (18±11 to 26±9 mm, P<0.001) and left (21±11 to 31±11 mm, P<0.001) sides, as well as maximum hemidiaphragm speed during inspiration (right 22±14 to 31±11 mm/s, P=0.03; left 28±11 to 37±16 mm/s, P=0.02). PLA at end-expiration was significantly reduced (334±71 to 290±72cm², P<0.001), with a significant increase in ΔPLA (83±40 to 117±36cm², P<0.001).
Conclusions: DCR demonstrated significant improvements in hemidiaphragm excursion and ΔPLA in pwCF started on ELX/TEZ/IVA. These changes likely reflect a reduction in air trapping and improved elastic recoil of the chest, and are consistent with improvements seen in spirometry. The changes seen with DCR are physiologically plausible and correlate well with spirometry. DCR warrants further investigation as a tool for assessing the impact of CFTR-modulating therapies.

Thomas S FitzMaurice is a Fellow in the Adult CF Unit, Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool L14 3PE, UK; Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.

Aaron C Miller, Logan M Harris^, Joseph E Cavanaugh, Mahmoud Abou Alaiwa, David A Stoltz, Douglas B Hornick, Philip M Polgreen. The rapid reduction of infection-related visits and antibiotic use among people with cystic fibrosis after starting Elexacaftor-Tezacaftor-Ivacaftor. Clin Infect Dis 2022 Feb 10;ciac117.doi: 10.1093/cid/ciac117. Online ahead of print. [Pubmed

Aaron Miller

Background: People with cystic fibrosis (CF) routinely suffer from recurrent sino-pulmonary infections. Such infections require frequent courses of antimicrobials and often involve multidrug-resistant organisms. The goal of this study was to identify real-world evidence for the effectiveness of Elexacaftor-Tezacaftor-Ivacaftor (ELX/TEZ/IVA) at decreasing infection-related visits and antimicrobial use in people with CF.
Methods: Using IBM MarketScan data, we identified 389 enrollees with CF who began taking ELX/TEZ/IVA prior to 12/1/2019 and were enrolled from 7/1/2019-3/14/2020. We also identified a comparison population who did not begin ELX/TEZ/IVA during the study period. We compared the following outcomes in the 15 weeks before and after medication initiation: total healthcare visits, inpatient visits, infection-related visits, and antimicrobial prescriptions. We analyzed outcomes using both a case-crossover analysis and a difference-in-differences analysis, to control for underlying trends.
Results: For the case-crossover analysis, ELX/TEZ/IVA initiation was associated with 2.20 (95% CI: -3.26, -1.14) fewer overall healthcare visit-days, 0.16 (95% CI: -0.22, -0.11) fewer inpatient admissions, 0.33 (95% CI: -0.59, -0.07) fewer infection-related visit-days, and 0.78 (95% CI: -1.03, -0.54) fewer antibiotic prescriptions over a 15 week period. Results from the difference-in-differences approach were similar.

Conclusions: We show a rapid reduction of infection-related visits and antimicrobial use among people with CF after starting a therapy that was not explicitly designed to treat infections. Currently, there are over 30,000 people living with CF in the United States alone. Given that this therapy is effective for approximately 90% of people with CF, the impact on respiratory infections and antimicrobial use may be substantial.

Dr Aaron C Miller is at the Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.

Gregory S Sawicki, Mark Chilvers, John McNamara, Lutz Naehrlich, Clare Saunders, Isabelle Sermet-Gaudelus, Claire E Wainwright, Neil Ahluwalia, Daniel Campbell, R Scott Harris, Hildegarde Paz-Diaz, Judy L Shih, Jane C Davies. A Phase 3, open-label, 96-week trial to study the safety, tolerability, and efficacy of tezacaftor/ivacaftor in children ≥ 6 years of age homozygous for F508del or heterozygous for F508del and a residual function CFTR variant. J Cyst Fibros 2022 Feb 18;S1569-1993(22)00033-9.doi: 10.1016/j.jcf.2022.02.003.Online ahead of print.[Pubmed]

Gregory Sawicki

Background: Two previous Phase 3 studies (“parent studies”) showed that tezacaftor/ivacaftor was generally safe and efficacious for up to 24 weeks in children 6 through 11 years of age with cystic fibrosis (CF) and F508del/F508del (F/F) or F508del/residual function (F/RF) genotypes. We assessed the safety and efficacy of tezacaftor/ivacaftor in an open-label, 96-week extension study.
Methods: This was a Phase 3, 2-part, multicenter, open-label, extension study in children 6 through 11 years of age at treatment initiation (Study VX17-661-116; NCT03537651). The primary endpoint was safety and tolerability. Secondary endpoints were absolute change from baseline in lung clearance index_2.5 (LCI_2.5), sweat chloride (SwCl) concentration, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, and body mass index (BMI).
Results: One-hundred thirty children enrolled and received ≥ 1 dose of tezacaftor/ivacaftor; 109 completed treatment. Most (n = 129) had ≥ 1 treatment-emergent adverse event (TEAE), the majority of which were mild or moderate in severity and generally consistent with common manifestations of CF. Exposure-adjusted TEAE rates were similar to or lower than those in the parent studies. Five (3.8%) had TEAEs leading to treatment discontinuation. Efficacy results from the parent studies were maintained, with improvements in lung function, SwCl concentration, CFQR respiratory domain score, and BMI observed from parent study baseline to Week 96.
Conclusions: Tezacaftor/ivacaftor is generally safe and well tolerated, and treatment effects are maintained for up to 120 weeks. These results support long-term use of tezacaftor/ivacaftor in children ≥ 6 years of age with CF and F/F or F/RF genotypes.

Gregory S Sawicki is at the Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA,

Dirk Westhölter FabianSchumacher, Nuria Wülfinghoff, SivagurunathanSutharsan, Svenja Strassburg, Burkhard Kleuser, Peter A Horn, Sebastian Reuter, Erich Gulbins, Christian Taube, Matthias Welsner. CFTR modulator therapy alters plasma sphingolipid profiles in people with cystic fibrosis. J Cyst Fibros 2022 Feb 12;S1569-1993(22)00037-6.doi: 10.1016/j.jcf.2022.02.005.Online ahead of print. [Pubmed]

Dirk Westholter

Background: Sphingolipids, in particular ceramides, play an important role in the pathogenesis of cystic fibrosis (CF) lung disease. Ceramides seem to be dysregulated in people with CF (PWCF): An elevated ratio of ceramides C16Cer/ C24Cer has been linked to inflammation and disease severity. CFTR modulators might influence sphingolipid dysregulation in PWCF.
Methods: Sphingolipid profiles were retrospectively analyzed in serum from 112 PWCF and 96 healthy controls as well as in plasma from 25 PWCF before and after treatment with the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Lipid data were correlated with clinical parameters.
Results: There were significantly higher levels of long-chain ceramides C18Cer and C20Cer and of the very long-chain ceramide C24:1Cer in PWCF versus healthy controls. Sphingosine levels were significantly reduced and accurately distinguished PWCF from healthy controls. Treatment with ELX/TEZ/IVA was associated with a decrease in levels of long-chain ceramides C16Cer, C18Cer and C20Cer and very long-chain ceramide C24:1Cer. Plasma levels of the most abundant very long-chain ceramide C24Cer as well as sphingosine-1-phosphate increased. Consequently, the ratio of ceramides C16Cer/ C24Cer decreased. Sphingolipid levels showed weak correlations with clinical parameters.

Conclusions: These findings highlight the existence of a distinctive sphingolipid profile in blood from PWCF, which appears to be altered by ELX/TEZ/IVA therapy. Thus, strategies for sphingolipid remodeling need to be reassessed and adjusted in the light of highly effective CFTR modulator therapies.

Dirk Westhölter is in the Department of Pulmonary Medicine, University Hospital Essen- Ruhrlandklinik, Tüschener Weg 40, Essen 45239, Germany.

Ann Cheng, Olivia Baker, Uta Hill. Elexacaftor, tezacaftor and ivacaftor: a case of severe rash and approach to desensitisation. BMJ Case Rep 2022 Mar 2;15(3):e247042. doi: 10.1136/bcr-2021-247042. [Pubmed]

Ann Cheng

We present a case of severe rash following induction of elexacaftor, tezacaftor and ivacaftor (ELX/TEZ/IVA) in a young adult male cystic fibrosis patient. While rash is a commonly reported side effect which resolves in 1-2 weeks with minimal intervention, our patient had presented with fever and widespread rash prompting medication cessation. After a washout period, reintroduction with 1/2 tablet of ELX/TEZ/IVA produced a similar systemic response within 24 hours. Repeat attempt, this time with 1/8 tablet and increasing in increments of an eighth daily, was successful and has allowed our patient to experience the transformative benefits of ELX/TEZ/IVA including improved pulmonary function and reduced episodes of infective exacerbation. This case illustrates one of the most common side effects of ELX/TEZ/IVA triple therapy, and our experience of desensitisation to ELX/TEZ/IVA in a challenging case of rash.

Dr Ann Cheng is NIHR Academic Clinical Fellow in the Department of Infection, Immunity and Cardiovascular Disease, The University of Sheffield, Sheffield, UK. Also Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, UK.

Lauryn A Benninger, Cesar Trillo, Jorge Lascano. CFTR modulator use in post lung transplant recipients. J Heart Lung Transplant 2021 Dec;40(12):1498-1501.doi: 10.1016/j.healun.2021.08.009.Epub 2021 Aug 26. [Pubmed]

Lauryn Benninger

Clemence Martin

Clémence Martinis at the Université de Paris, Institut Cochin, InsermU1016, Paris, France; Respiratory Medicine and Cystic Fibrosis National Reference Center, Cochin Hospital, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; ERN-Lung CF network, Frankfurt, Germany.

Ciaran A Shaughnessy, Pamela L Zeitlin, Preston E Bratcher. Net benefit of ivacaftor during prolonged tezacaftor/elexacaftor exposure in vitro. J Cyst Fibros 2022 Mar 2;S1569-1993(22)00043-1.doi: 10.1016/j.jcf.2022.02.011.Online ahead of print. [Pubmed]

Ciaran A Shaughnessy

Background: A decrease in the lumacaftor-mediated increase in F508del-CFTR function and expression upon prolonged exposure to ivacaftor (VX-770) has previously been described. However, the efficacy observed with ivacaftor-containing CFTR modulator therapies in vivo is in conflict with these reports. We hypothesized that a portion of the apparent decrease in CFTR function observed after prolonged ivacaftor exposure in vitro was due to an increase in constitutive CFTR-mediated ion transport.
Methods: Human nasal epithelial (HNE) cells were obtained by brushings from three CF individuals homozygous for the F508del CFTR mutation. Differentiated epithelia were pre-treated with prolonged (24 h) exposure to either lumacaftor (VX-809; 3 µM), tezacaftor (VX-661; 3 µM), elexacaftor (VX-445; 3 µM), and/or ivacaftor (0.1-6.4 µM) or DMSO (vehicle control), and CFTR function was assayed by Ussing chamber electrophysiology.
Results: In cells treated with lumacaftor, constitutive CFTR activity was not increased at any concentration of co-treatment with ivacaftor. Constitutive CFTR activity was also unchanged in cells treated with the combination of tezacaftor and elexacaftor. An increase in constitutive CFTR activity above the DMSO controls was only observed in cells treated with the combination of tezacaftor and elexacaftor and co-treated with at least 0.1 µM ivacaftor.

Conclusions: These results demonstrate that ivacaftor is a critical component in the triple combination therapy along with tezacaftor and elexacaftor to increase constitutive CFTR function. This work further elucidates the mechanism of action of the effective triple combination therapeutic that is now the primary clinical tool in treating CF.

Ciaran A Shaughnessy is National Science Foundation Postdoctoral Fellow in the Department of Pediatrics, National Jewish Health, Denver, CO.

Amanda Stapleton

Amanda L Stapleton is Associate Professor in the Department of Otolaryngology – Head and Neck Surgery, University of Pittsburgh, United States.

Petersen MC, Begnel L, Wallendorf M, Litvin M. Effect of elexacaftor-tezacaftor-ivacaftor on body weight and metabolic parameters in adults with cystic fibrosis. Journal of Cystic Fibrosis. 21(2):265-271, 2022 03. [Pubmed]

Max Petersen

Background: Though weight gain has been reported in some clinical trials of CFTR modulators, the effect of elexacaftor-tezacaftor-ivacaftor on body weight, body mass index (BMI), blood pressure, lipids and glycemic control in the real-world setting remains incompletely described.

Methods: We performed a single-center, retrospective, observational analysis of the effect of elexacaftor-tezacaftor-ivacaftor on body weight and cardiometabolic parameters in 134 adult CF patients of the Washington University Adult Cystic Fibrosis Center. Body weight, BMI, and blood pressure were extracted from outpatient clinic visits for the year preceding and the period following the initiation of elexacaftor-tezacaftor-ivacaftor. Other metabolic parameters were extracted at baseline and at latest available follow-up
Results: A mean of 12.2 months of follow-up data was available for analysis. The mean rate of change in BMI was 1.47 kg/m²/yr (95% CI, 1.08 to 1.87) greater after initiation of elexacaftor-tezacaftor-ivacaftor. Significant increases in blood pressure were observed. In those without CFRD, random blood glucose and hemoglobin A1c were decreased after elexacaftor-tezacaftor-ivacaftor initiation. In those with CFRD, elexacaftor-tezacaftor-ivacaftor increased serum total cholesterol, HDL-cholesterol, and LDL-cholesterol.

Conclusions: In this single-center, retrospective, observational study of 134 adults with CF, initiation of elexacaftor-tezacaftor-ivacaftor was associated with increases in BMI at a mean follow up of 12.2 months. Changes in other cardiometabolic risk factors were also observed. Widespread use of elexacaftor-tezacaftor-ivacaftor may be expected to increase the incidence of overnutrition in the CF population.

Max C Petersen is in the Division of Endocrinology, Metabolism, & Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri, USA.

Kathleen J Ramos, Jennifer S Guimbellot, Maryam Valapour, Lauren E Bartlett, Travis Hee Wai, Christopher H Goss, Joseph M Pilewski, Albert Faro, Joshua M Diamond, CFLTC Study Group. Use of elexacaftor/tezacaftor/ivacaftor among cystic fibrosis lung transplant recipients. J Cyst Fibros 2022 Apr 23;S1569-1993(22)00098-4.doi: 10.1016/j.jcf.2022.04.009.Online ahead of print.[Pubmed]

Kathleen J Ramos

Background:Cystic fibrosis (CF) lung transplant (LT) recipients may warrant treatment with elexacaftor/tezacaftor/ivacaftor (ETI) to improve extrapulmonary manifestations of CF. Our objectives were to identify reasons for prescribing ETI after LT and evaluate changes in body mass index (BMI), hemoglobin A1c, hemoglobin, and liver enzymes.
Methods:This was an electronic health record-based cohort study, October 2019-September 2020, at 14 CF LT Consortium sites in North America. The study included CF LT recipients prescribed ETI after transplant. Differences in BMI, A1c, and hemoglobin were assessed with paired t-tests.
Results:There were 94 patients prescribed ETI; indications included sinus disease (68%), GI symptoms (39%), or low BMI (19%). Prescriptions were written by CF physicians (34%), LT physicians (27%), or physicians who practice both CF and LT (39%). Forty patients (42%) stopped ETI at a median of 56 days [IQR 26, 139] after start/prescription date. ETI was not associated with a significant change in BMI (0.2 kg/m², 95% CI [-0.1, 0.6], p = 0.150), but was associated with decreased A1c (0.4%, 95% CI 0.2, 0.7, p = 0.003), and increased hemoglobin for patients with anemia (0.6 g/dL, 95% CI 0.2, 1.0, p = 0.007). Three people (3%) stopped ETI due to elevated transaminases.

Conclusions:ETI is rarely prescribed for non-pulmonary indications after LT for CF. Further study is needed to determine the risks and benefits of ETI in the CF lung transplant population given the potential for drug interactions, side effects leading to discontinuation of ETI, and the possible mechanisms for ETI to positively impact long-term post-transplant outcomes.

Kathleen J Ramos is in the Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, 1959 NE Pacific Street, Box 356522, Seattle, WA 98195, USA.

David P Nichols, Alex C Paynter, Sonya L Heltshe, Scott H Donaldson, Carla A Frederick, Steven D Freedman and the other members of the PROMISE Study group. Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial. Am J Respir Crit Care Med. 2022 Mar 1;205(5):529-539 doi: 10.1164/rccm.202108-1986OC Free PMC article [Pubmed]

David Nichols

Rationale: The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs in at least 85% of people with CF.
Objectives: PROMISE is a post-approval study to understand the broad effects of ETI through 30 months’ clinical use in a more diverse U.S. patient population with planned analyses after 6 months.
Methods: Prospective, observational study in 487 people with CF age 12 years or older with at least one F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in percent predicted FEV₁ (ppFEV₁), sweat chloride concentration, body mass index (BMI), and self-reported respiratory symptoms.
Measurements and Main Results: Average age was 25.1 years, and 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor, whereas 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV₁ improved 9.76 percentage points (95% confidence interval [CI], 8.76 to 10.76) from baseline, cystic fibrosis questionnaire-revised respiratory domain score improved 20.4 points (95% CI, 18.3 to 22.5), and sweat chloride decreased -41.7 mmol/L (95% CI, -43.8 to -39.6). BMI also significantly increased. Changes were larger in those naive to modulators but substantial in all groups, including those treated with ivacaftor at baseline.

Conclusions: ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naive to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV₁ in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).

Dr David P Nichols is at the Department of Pediatrics, and. Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle Children’s Research Institute, Seattle, Washington.

Rebecca Keyte, Sophia Kauser, Michail Mantzios, Helen Egan^.The psychological implications and health risks of cystic fibrosis pre- and post- CFTR modulator therapy. Chronic Illn 2022 May 3;17423953221099042.doi: 10.1177/17423953221099042.Online ahead of print.[Pubmed]

Rebecca Keyte

Objectives: Cystic Fibrosis (CF) care is entering a period of personalised medicine with the emergence of CF transmembrane conductance regulator (CFTR) modulator therapies. Anecdotally individuals are reporting life-changing effects of modulator therapies, proposing an important area of study.
Methods: Twenty adult participants (males: 8, age range: 22-51 years, average FEV₁: 53.45%) were recruited via social media to participate in a semi-structured interview; 17 participants were currently taking Elexacaftor/Tezacaftor/Ivacaftor (Kaftrio).
Results: An appreciation of a “normal life” post-modulator therapy is paramount, with improvements in symptoms and quality-of-life bringing a more urgent imperative for the provision of effective support to encourage positive health and lifestyle choices.

Discussion: In this new era of CF care, there remains many challenges present for the CF community, with participants suggesting that proactive psychological support is required along with proactive awareness regarding health risk behaviours for the current and future CF generations.

Rebecca Keyte is in the Department of Psychology, School of Social Sciences, 34651 Birmingham City University, Birmingham, UK.

Insa Korten, Elisabeth Kieninger, Linn Krueger, Marina Bullo, Christa E Flück, Philipp Latzin, Carmen Casaulta, Claudia Boettcher Short-Term Effects of Elexacaftor/Tezacaftor/Ivacaftor Combination on Glucose Tolerance in Young People With Cystic Fibrosis-An Observational Pilot Study. Front Pediatr 2022 Apr 21;10:852551.doi: 10.3389/fped.2022.852551.eCollection 2022.[Pubmed]

Insa Korten

The effect of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on glucose tolerance and/or cystic-fibrosis-related diabetes (CFRD) is not well understood. We performed an observational study on the short-term effects of ELX/TEZ/IVA on glucose tolerance.
Methods:Sixteen adolescents with CF performed oral glucose tolerance tests (OGTT) before and 4-6 weeks after initiating ELX/TEZ/IVA therapy. A continuous glucose monitoring (CGM) system was used 3 days before until 7 days after starting ELX/TEZ/IVA treatment.
Results:OGTT categories improved after initiating ELX/TEZ/IVA therapy (p = 0.02). Glucose levels of OGTT improved at 60, 90, and 120 min (p < 0.05), whereas fasting glucose and CGM measures did not change.

Conclusion:Shortly after initiating ELX/TEZ/IVA therapy, glucose tolerance measured by OGTT improved in people with CF. This pilot study indicates that ELX/TEZ/IVA treatment has beneficial effects on the endocrine pancreatic function and might prevent or at least postpone future CFRD.

Insa Korten is in the Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Karen S Raraigh, Michelle H Lewis, Joseph M Collaco, Mary Corey, Christopher M Penland, Anne L Stephenson, Johanna M Rommens, Carlo Castellani, Garry R Cutting. Caution advised in the use of CFTR modulator treatment for individuals harboring specific CFTR variants. J Cyst Fibros 2022 May 5;S1569-1993(22)00108-4.doi: 10.1016/j.jcf.2022.04.019.Online ahead of print [Pubmed]

Karen S Raraigh

In December 2020, the U.S. Food and Drug Administration (FDA) expanded the list of CFTR variants approved for treatment with CFTR modulators drugs from 39 to 183. Clinicians should be aware that individuals harboring certain variants approved for treatment may not respond to or benefit from this therapy. After review, the expert panel leading the CFTR2 project identified four categories of variants that may not result in a clinical response to modulator treatment: 15 variants assigned as non CF-causing; 45 variants of unknown significance; six variants known or suspected to cause mis-splicing as their primary defect rather than an amino acid substitution; and eight variants known to occur together in cis with another deleterious variant not expected to lead to CFTR protein (nonsense or frameshift). The potential risks and benefits of CFTR modulator therapy should be considered carefully for individuals harboring these variants.

Karen S Raraigh is a genetic counsellor at the McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States

Maya Desai, Chris Hine, Joanna L Whitehouse^.Keith Brownlee, Susan C Charman, Prasad Nagakumar^. Who are the 10%? – Non eligibility of cystic fibrosis (CF) patients for highly effective modulator therapies. Respir Med 2022 Aug;199:106878.doi: 10.1016/j.rmed.2022.106878. Epub 2022 May 16. [Pubmed]

Maya Desai

Background:The availability of mutation-specific cystic fibrosis modulator therapies has the potential to improve the lives of children and adults with cystic fibrosis. The frequency of mutations causing defects in the cystic fibrosis transmembrane conductance regulator (CFTR) function varies between sub-groups in multi-ethnic populations. The profile of patients eligible for CFTR modulator ivacaftor/tezacaftor/elexacaftor (Kaftrio™) therapy based on ethnicity has not been reported in the United Kingdom CF population.
Methods:We conducted a descriptive cross-sectional analysis of patients in the UK CF Registry who had annual review data submissions in 2019. Data analysed included demographic characteristics, spirometry, chronic Pseudomonas status, nutrition, and CF related diabetes status. The genotype data was stratified by whether there was at least one copy of F508del or no copy of F508del as current eligibility for ivacaftor/tezacaftor/elexacaftor, or projected future eligibility, is defined as having at least one copy of F508del mutation.
Results:Data from 9887 patients were reviewed, 46.7% female, mean age 22.5 years. 8.6% (n = 852) patients had no copy of F508del making them ineligible for ivacaftor/tezacaftor/elexacaftor. Overall, 93.4% of patients were of white ethnicity, with a similar proportion of those with at least one F508del being white (95.6%). This was reduced to 70.0% of those with no F508del. The proportion of people of Asian ethnicity was much higher in the no F508del group (19.2% vs 1.2%). Compared with one F508del patients, the no F508del group were older (25.2 years vs 22.2 years, p < 0.001), had higher prevalence of pancreatic sufficiency (39.0% vs 14.9% p < 0.001), lower prevalence of chronic Pseudomonas infection (21.1% vs. 26.6%, p < 0.001), and higher best FEV₁from the previous year (proportion with greater than 70% FEV₁ predicted, 66.1% vs 63.0%, p = 0.005).

Conclusion:Patients from black, Asian and minority ethnic backgrounds are significantly less likely to be eligible for ivacaftor/tezacaftor/elexacaftor based on the current prescribing policy in the UK. At present this is the most highly effective CF modulator therapy available to treat people with CF. The CF community should urgently address the unmet need for effective targeted therapies for patients without F508del.

Maya Desai is Respiratory Clinical Lead in the Department of Cystic Fibrosis and Respiratory Medicine, Birmingham Women’s and Children’s Hospital, Steelhouse Lane, Birmingham, UK.

Lena Wucherpfennig, Simon M F Triphan, Sabine Wege, Hans-Ulrich Kauczor, Claus P Heussel, Niclas Schmitt, Felix Wuennemann, Victoria L Mayer, Olaf Sommerburg, Marcus A Mall, Monika Eichinger, Mark O WielpützMagnetic resonance imaging detects improvements of pulmonary and paranasal sinus abnormalities in response to elexacaftor/tezacaftor/ivacaftor therapy in adults with cystic fibrosis. J Cyst Fibros 2022 Apr 7;S1569-1993(22)00088-1.: 10.1016/j.jcf.2022.03.011.Online ahead of print.[Pubmed]

Lena Wucherpfennig

Background: Therapy with Elexacaftor/Tezacaftor/Ivacaftor (ETI) was recently approved for adult cystic fibrosis (CF) patients with at least one F508del mutation. However, its effects on structural and functional lung abnormalities and chronic rhinosinusitis have not been studied by imaging.
Methods: 19 adults with CF (mean age 31±9y, range 19-55y) underwent standardized chest magnetic resonance imaging (MRI), and nine also same-session sinonasal MRI, before (MRI1) and after (MRI2) at least one month (mean duration 5 ± 3mon) on ETI. 24 control CF patients (30±7y, range 20-44y) without ETI underwent longitudinal chest MRI, and eleven also sinonasal MRI, twice (mean interval 40±15mon). MRI was assessed using the validated chest MRI score and chronic rhinosinusitis (CRS)-MRI score. Forced expiratory volume in 1 s percent predicted (FEV1%) was measured in all patients.
Results: In controls, the chest MRI global score and CRS-MRI sum score were stable from MRI1 to MRI2. In patients under ETI, the chest MRI global score improved (-11.4 ± 4.6, P<0.001), mainly due to reduction of bronchiectasis/wall thickening and mucus plugging subscores (-3.3 ± 2.2 and -5.2 ± 1.5, P<0.001, respectively). The improvement in chest MRI score correlated well with improved FEV1% (r=-0.703, P<0.001). The CRS-MRI sum score also improved in patients under ETI (-6.9 ± 3.0, P<0.001), mainly due to a reduction of mucopyoceles in the maxillary and ethmoid sinus (-50% and -39%, P<0.05, respectively).

Conclusions: MRI detects improvements of chest MRI and CRS-MRI scores in adult CF patients who first received ETI, demonstrating reversibility of structural lung and paranasal sinus abnormalities in patients with established disease.

Dr Lena Wucherpfennig is in the Department of Diagnostic and Interventional Radiology, Subdivision of Pulmonary Imaging, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Im Neuenheimer Feld 156, 69120 Heidelberg, Germany; Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at University Hospital Heidelberg, Röntgenstr. 1, 69126 Heidelberg, Germany.

Sylvia Szentpetery, Kimberly Foil, Sara Hendrix, Sue Gray, Christina Mingora, Barbara Head, Donna Johnson, Patrick A Flume. A case report of CFTR modulator administration via carrier mother to treat meconium ileus in a F508del homozygous fetus. J Cyst Fibros 2022 Apr 11;S1569-1993(22)00095-9.doi: 10.1016/j.jcf.2022.04.005.Online ahead of print.[Pubmed]

Sylvia Szentpetery

We report elexacaftor-tezacaftor-ivacaftor (ETI) treatment of a F508del carrier who was pregnant with a F508del homozygous fetus. At 23-weeks gestation meconium ileus (MI) was evident on ultrasound including dilated, hyperechoic bowel, which persisted on subsequent imaging. Through shared decision-making, the mother began ETI at 32 weeks with intent to treat fetal MI. The ultrasound findings persisted at treatment day 13, but bowel dilation had resolved by imaging on treatment day 27. A female infant was delivered vaginally at 36 weeks with no complications. The mother continued ETI while breastfeeding. Stool elastase at age 2 weeks was 240 mcg/g. Sweat chloride measurement was 64 and 62 mEq/L. Maternal and infant liver function testing have been normal. Maternal ETI treatment likely led to resolution of the MI and there is evidence supporting continued infant benefit through breastmilk. Logistical and ethical considerations regarding treatment of a carrier mother for infant benefit are discussed.

Sylvia Szentpetery is a pediatric pulmonologist at the Medical University of South Carolina, Charleston, SC 29424, USA. Electronic address: szentpet@musc.edu.

Emily E Ricotta, D Rebecca Prevots, Kenneth N Olivier. CFTR modulator use and risk of nontuberculous mycobacteria positivity in cystic fibrosis, 2011-2018. ERJ Open Res 2022 Apr 11;8(2):00724-2021.doi: 10.1183/23120541.00724-2021.eCollection 2022 Apr. Free PMC article [Pubmed]

Emily Ricotta

Background: People with cystic fibrosis are at increased risk of pulmonary nontuberculous mycobacteria (NTM) disease. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are associated with reduced lung infection with pathogens like Pseudomonas aeruginosa and Staphylococcus aureus. This association has not been studied with NTM.
Methods:Using encounter-level data from the US Cystic Fibrosis Foundation Patient Registry from 2011 to 2018, we identified individuals aged >12 years with one or more NTM-negative sputum culture and information on receipt of ivacaftor therapy. We used a Cox proportional hazards model to assess the relationship between CFTR modulator usage (any and monotherapy versus combination therapy) and NTM sputum culture positivity, controlling for sex, least severe class of CFTR mutation, receipt of chronic macrolides, age, body mass index and percentage predicted forced expiratory volume.
Results:Out of 25 987 unique individuals, 17 403 individuals met inclusion criteria. During follow-up, 42% of individuals received CFTR modulator therapy, and 23% had incident NTM. The median (interquartile range) time to event was 6.1 (4.0-7.3) years for those ever receiving CFTR modulators compared to 4.0 (1.6-6.5) years in those never receiving CFTR modulators. CFTR modulator use was associated with a significantly reduced hazard of NTM culture positivity (hazard ratio (HR) 0.88, 95% CI 0.79-0.97); there was no significant difference in the hazard between those receiving ivacaftor monotherapy versus combination therapy (combination HR 1.01, 95% CI 0.79-1.23).

Conclusions:CFTR modulator therapy is associated with a decreased risk of NTM positivity in individuals with cystic fibrosis.

Emily E Ricotta is an epidemiologist in the Dept of Epidemiology and Population Studies Unit, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA.

Caitlyn Harvey, Sinead Weldon, Stuart Elborn, Damian G Downey, Clifford Taggart.The Effect of CFTR Modulators on Airway Infection in Cystic Fibrosis. Int J Mol Sci 2022 Mar 23;23(7):3513.doi: 10.3390/ijms23073513. [Pubmed]

The advent of Cystic fibrosis transmembrane receptor (CFTR) modulators in 2012 was a critical event in the history of cystic fibrosis (CF) treatment. Unlike traditional therapies that target downstream effects of CFTR dysfunction, CFTR modulators aim to correct the underlying defect at the protein level. These genotype-specific therapies are now available for an increasing number of CF patients, transforming the way we view the condition from a life-limiting disease to one that can be effectively managed.

Several studies have demonstrated the vast improvement CFTR modulators have on normalization of sweat chloride, CFTR function, clinical endpoints, and frequency of pulmonary exacerbation. However, their impact on other aspects of the disease, such as pathogenic burden and airway infection, remain under explored. Frequent airway infections as a result of increased susceptibility and impaired innate immune response are a serious problem within CF, often leading to accelerated decline in lung function and disease progression.

Current evidence suggests that CFTR modulators are unable to eradicate pathogenic organisms in those with already established lung disease. However, this may not be the case for those with relatively low levels of disease progression and conserved microbial diversity, such as young patients. Furthermore, it remains unknown whether the restorative effects exerted by CFTR modulators extend to immune cells, such as phagocytes, which have the potential to modulate the response of people with CF (pwCF) to infection. Throughout this review, we look at the potential impact of CFTR modulators on airway infection in CF and their ability to shape impaired pulmonary defences to pathogens.

Caitlyn Harvey is in the Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast BT9 7BL, UK.

Mitchell L Ramsey, Susan S Li, Luis F Lara, Yevgeniya Gokun, Venkata S Akshintala, Darwin L Conwell, John Heintz, Stephen E Kirkby, Karen S McCoy, Georgios I PapachristouAlpa Patel, Vikesh K Singh, Phil A Hart. Cystic fibrosis transmembrane conductance regulator modulators and the exocrine pancreas: A scoping review. J Cyst Fibros 2022 Aug 22;S1569-1993(22)00644-0.doi: 10.1016/j.jcf.2022.08.008.Online ahead of print.[Pubmed]
Background:Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve pulmonary outcomes in subjects with cystic fibrosis (CF); however, the effects on pancreatic manifestations are not well characterized. We hypothesized that CFTR modulators would improve measures of exocrine pancreatic function and outcomes.
Methods:We performed a systematic search to identify studies reporting measures of the exocrine pancreas in humans treated with CFTR modulators. Only studies reporting baseline and on-treatment assessments were included.
Results:Of 630 identified studies, 41 met inclusion criteria. CFTR modulators reduced acute pancreatitis events by 85% overall (rate ratio 0.15, 95% confidence interval (CI) 0.04, 0.52), with a greater effect seen in the subgroup with pancreas sufficient CF (PS-CF) (rate ratio 0.13 (95% CI 0.03, 0.53). Among 293 subjects with baseline and on-treatment evaluation of pancreas sufficiency, 253 were pancreas insufficient at baseline and 54 (21.3%) converted to pancreas sufficiency. Of 32 subjects with baseline FE-1 values <200 mcg/g, 16 (50%) increased to ≥200 mcg/g. Serum trypsin decreased by a mean of 565.9 ng/mL (standard deviation (SD) 311.8), amylase decreased by 38.2 U/L (SD 57.6), and lipase decreased by 232.3 U/L (SD 247.7).

Conclusions:CFTR modulator use reduces acute pancreatitis frequency and improves indirect measures of exocrine pancreas function. Future interventional studies that evaluate the mechanism and impact of CFTR modulators on acute pancreatitis and pancreas sufficiency in patients with CFTR dysfunction are warranted.Dr Mitchell L Ramsey is in the Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA

Benjamin C Lyman, Jessica Seay, Casey Contreary, Adrienne P Savant, Mary Lynn Dell, George C Hescock. lexacaftor-tezacaftor-ivacaftor overdose in an adolescent female with cystic fibrosis. Pediatr Pulmonol 2022 Aug 12.doi: 10.1002/ppul.26116.Online ahead of print.[Pubmed]

Benjamin C Lyman

Summary of the letter to the Editor A 15-year-old female with CF (621+1G>T and F508del), pancreatic insufficiency, CF-related diabetes requiring insulin, and recurrent major depressive and anxiety disor e ders was started on ETI approximately 10 months before an intentional ingestion of an estimated 42 pills of ETI (two 1-week blister packs) in a suicide attempt. Less than 1 h post-ingestion, she self-induced emesis, then presented to the emergency department (ED), where she also complained of increased sputum production consistent with a pulmonary exacerbation. Vital signs and physical exam were within normal limits for age. Complete blood count, comprehensive metabolic panel (CMP), coagulation markers, urine drug screen, salicylate, acetaminophen, ethanol, and electrocardiogram were within normal limits.
Maximum elevation in LFTs was seen at 12-day postingestion and noted to be 5.7 and 4.1 times the upper limit of normal for AST and ALT, respectively. Given the primary concern of liver damage with ETI toxicity, the patient’s ETI dose was held for 9 days. On day 10 postingestion, following LFT reduction to less than twice the upper limit of normal, the two pill, morning dose (ETI: 100-50-75 mg) was restarted. Her LFTs had an acute rise on day 12 postingestion; therefore, ETI was held for an additional day. On day 14 postingestion, the morning dose was again restarted. LFTs returned to normal range by day 19 postingestion. The nighttime dose (ivacaftor 150 mg) was restarted on day 28 postingestion, after sustained stabilization of LFTs..
In conclusion, as care for pwCF enters the modulator era, it is critical to partner with mental health providers, screen pwCF for mental health issues, and recognize the potential for worsening of mental health with modulators.

Benjamin C Lyman is a paediatrician at the Children’s Hospital New Orleans

Sarah Jane Schwarzenberg , Phuong T Vu, Michelle Skalland , Lucas R Hoffman, Christopher Pope, Daniel Gelfond, et al and the Promise Study Group. Elexacaftor/tezacaftor/ivacaftor and gastrointestinal outcomes in cystic fibrosis: Report of promise-GI. J Cyst Fibros
. 2022 Oct 21;S1569-1993(22)01384-4. doi: 10.1016/j.jcf.2022.10.003. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36280527/

Sarah Jane Schwarzenberg

med.umn.edu

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear.
Methods: PROMISE is a 56-center prospective, observational study of ETI in PwCF >12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex.
Results: 438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change.

Conclusions: After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve

Professor Sarah Jane Schwarzenberg at Pediatrics, University of Minnesota Masonic Children’s Hospital, Academic Office Building, 2450 Riverside Ave S AO-201, Minneapolis, MN 55454, USA.

Jennifer L Goralski , Sang Hun Chung , Agathe S Ceppe , Margret Z Powell, Muthu Sakthivel, Brian D Handly, Yueh Z Lee , Scott H Donaldson.Dynamic Perfluorinated Gas MRI Shows Improved Lung Ventilation in People with Cystic Fibrosis after Elexacaftor/Tezacaftor/Ivacaftor: An Observational Study. J Clin Med. 2022 Oct 19;11(20):6160. doi: 10.3390/jcm11206160. pubmed.ncbi.nlm.nih.gov/36294480/

Jennifer Goralski

UNC School of medicine

The availability of highly effective CFTR modulators is revolutionizing the treatment of cystic fibrosis (CF) and drastically improving outcomes. MRI-based imaging modalities are now emerging as highly sensitive endpoints, particularly in the setting of mild lung disease. Adult CF patients were recruited from a single center prior to starting treatment with E/T/I. The following studies were obtained before and after one month on treatment: spirometry, multiple breath nitrogen washout (MBW), 1H UTE MRI (structural images) and 19F MRI (ventilation images). Changes between visits were calculated, as were correlations between FEV1, lung clearance index (LCI), MRI structural scores, and MRI-based ventilation descriptors. Eight subjects had complete datasets for evaluation. Consistent with prior clinical trials, FEV1 and LCI improved after 28 days of E/T/I use. 1H UTE MRI detected improvements in bronchiectasis/airway wall thickening score and mucus plugging score after 28 days of therapy. 19F MRI demonstrated improvements in fractional lung volume with slow gas washout time (FLV↑tau2) and ventilation defect percentage (VDP). Improvements in FLV↑tau2 and VDP correlated with improvement in FEV1 (r = 0.81 and 0.86, respectively, p < 0.05). This observational study establishes the ability of 19F MRI and 1H UTE MRI to detect improvements in lung structure and function after E/T/I treatment. This study supports further development of 19F MRI and 1H UTE MRI as outcome measures for cystic fibrosis research and drug development.

Dr Jennifer Goralski is at Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, ; the Marsico Lung Institute/UNC Cystic Fibrosis Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, and the Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Renate Kos , Anne H Neerincx, Dominic W Fenn , Paul Brinkman , Rianne Lub , Steffie E M Vonk , Jolt Roukema, Monique H Reijers, Suzanne W J Terheggen-Lagro, Josje Altenburg Christof J Majoor, Lieuwe D Bos, Eric G Haarman , Anke H Maitland-van der Zee, Amsterdam Mucociliary Clearance Disease (AMCD) Research Group.. Real-life efficacy and safety of elexacaftor/tezacaftor/ivacaftor on severe cystic fibrosis lung disease patients. Observational Study Pharmacol Res Perspect. 2022 Dec;10(6):e01015. doi: 10.1002/prp2.1015. Free article pubmed.ncbi.nlm.nih.gov/36440690/

Renate Kos

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane conductance regulator modulator, which has shown efficacy in CF patients (≥6 years) with ≥1 Phe508del mutation and a minimal function mutation. In October 2019, ETI became available on compassionate use basis for Dutch CF patients with severe lung disease. Our objective was to investigate safety and efficacy of ETI in this patient group in a real-life setting. A multicenter longitudinal observational study was conducted to examine changes in FEV1 , BMI, and adverse events at initiation and 1, 3, 6, and 12 months after starting ETI. The number of exacerbations was recorded in the 12 months before and the 12 months after ETI treatment. Patients eligible for compassionate use had a FEV1 <40% predicted. Wilcoxon signed-rank test analyzed changes over time. Twenty subjects were included and followed up for up to 12 months after starting ETI. Treatment was well tolerated with mild side effects reported, namely, rash (15%) and stomach ache (20%) with 80% resolving within 1 month. Mean absolute increase of FEV1 was 11.8/13.7% (p ≤ .001) and BMI was 0.49/1.87 kg/m2 (p < .001-0.02) after 1/12 months, respectively. In comparison to the number of exacerbations pretrial, there was a marked reduction in exacerbations after initiation. Our findings show long-term effects of treatment with ETI in patients with severe CF lung disease in a real-life setting. Treatment with ETI is associated with increased lung function and BMI, less exacerbations, and only mild side effects.

Renate Kos is a PhD student in the Department of Respiratory Medicine, Amsterdam University Medical Centres – loc. AMC, Amsterdam, The Netherlands.

Lakshmi Viswanathan, Eric Bachman, Simon Tian, Neil Ahluwalia, Yaohua Zhang, Harold S Bernstein, Paul Panorchan^.Phase 1 Study to Assess the Safety and Pharmacokinetics of Elexacaftor/Tezacaftor/Ivacaftor in Subjects Without Cystic Fibrosis With Moderate Hepatic Impairment. Eur J Drug Metab Pharmacokinet 2022 Aug 29.doi: 10.1007/s13318-022-00791-8.Online ahead of print pubmed.ncbi.nlm.nih.gov/36036885/
Background and objective:Elexacaftor/tezacaftor/ivacaftor is highly effective in treating people with cystic fibrosis (pwCF) who have ≥ 1 responsive mutation. Liver disease occurs in approximately 10%-20% of pwCF. The objective of this study was to assess the safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor in people with moderate hepatic impairment, which is necessary to inform on its use and guide dosing recommendations.
Methods:The safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor were evaluated in subjects without CF with moderate hepatic impairment versus matched healthy controls. Twenty-two subjects (11 with moderate hepatic impairment and 11 healthy subjects) received half the standard adult daily dose of elexacaftor/tezacaftor/ivacaftor (elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 150 mg) orally for 10 days.
Results:Elexacaftor/tezacaftor/ivacaftor was safe and well tolerated in subjects with moderate hepatic impairment and healthy controls. On day 10, the mean values of the area under the curve during the dosing interval (AUC_τ) for total (bound and unbound) elexacaftor and its major active metabolite M23-elexacaftor were increased 1.25-fold (95% CI 1.01, 1.54) and 1.73-fold (95% CI 1.27, 2.35), respectively, in subjects with moderate hepatic impairment compared with matched healthy subjects. The mean values of AUC_τ for ivacaftor and tezacaftor were increased 1.50-fold (95% CI 1.09, 2.06) and 1.20-fold (95% CI 1.00, 1.43), respectively, while the mean value of AUC_τfor the active metabolite M1-tezacaftor was 1.29-fold lower [ratio of moderate hepatic impairment to healthy subjects (95% CI): 0.778 (0.655, 0.924)] in subjects with moderate hepatic impairment.

Conclusions:A dose reduction of elexacaftor/tezacaftor/ivacaftor is warranted in people with moderate hepatic impairment.

Lakshmi Viswanathan is a clinical pharmacologist with Vertex Phamaceuticals in Boston USA

— I wonder if the non-CF patients were expected to improve. Were they informed it was not for their benefit? This paper is available in full on publisher’s website

Raksha Jain, Alvit Wolf, Michal Molad, Jennifer Taylor-Cousar, Charles R Esther Jr , Michal Shteinberg. Congenital bilateral cataracts in newborns exposed to elexacaftor-tezacaftor-ivacaftor in utero and while breast feeding. J Cyst Fibros. 2022 Nov;21(6):1074-1076. doi: 10.1016/j.jcf.2022.10.004. Epub 2022 Oct 18. pubmed.ncbi.nlm.nih.gov/36266182/
Elexacaftor-tezacaftor-ivacaftor (ETI) is known to pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of ivacaftor in rats demonstrated infant cataracts, but cataracts were not reported in human infants exposed to ivacaftor. We describe 3 cases of infants exposed to elexacaftor-tezacaftor-ivacaftor (ETI) in utero and while breast feeding who were found to have bilateral congenital cataracts within six months of birth. None of the infants had significant visual impairment from the cataracts nor any report of elevated liver function testing. These data highlight the need to counsel females who continue ETI throughout pregnancy and while breast feeding to consider cataract screen for their infants.University of Texas Southwestern Medical Center, Dallas, TX, USA.

Brionna N Hudson, Hollyann R Jacobs, Alexander Philbrick, Xiaolong A Zhou, Michelle M Simonsen, Julie A Safirstein, Shannon M Rotolo^.Drug-induced acne with elexacaftor/tezacaftor/ivacaftor in people with cysticfibrosis. J Cyst Fibros 2022 Sep 7;S1569-1993(22)00657-9.doi: 10.1016/j.jcf.2022.09.002.Online ahead of print. pubmed.ncbi.nlm.nih.gov/36088208/

Brianna S Hudson

linkedin,com

Elexacaftor/tezacaftor/ivacaftor (ELX-TEZ-IVA) is a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator shown to improve lung function and reduce sweat chloride in people with Cystic Fibrosis (CF). The only commonly reported dermatologic adverse effect with CFTR modulators including ELX-TEZ-IVA is rash. In this case series, we describe 19 patients who reported new onset or worsening of acne after initiation of this drug to their CF pharmacist or another member of their CF care team. The mechanism and frequency of this adverse effect is unknown.

Dr Brionna N Hudson is at the College of Pharmacy Chicago State University

Divyalakshmi Bhaskaran, Kathryn Bateman. A case of Elexacaftor-Tezacaftor-Ivacaftor induced rash resolving without interruption of treatment. Case Reports J Cyst Fibros. 2022 Nov;21(6):1077-1079. doi: 10.1016/j.jcf.2022.06.011. Epub 2022 Jul 12. pubmed.ncbi.nlm.nih.gov/35840534/

Kathryn Bateman

The triple combination of Elexacaftor-Tezacaftor-Ivacaftor (ELX-TEZ-IVA) has been shown to markedly improve lung function in persons with cystic fibrosis (pwCF). An important adverse effect of the drug is rash, which was reported in clinical trials and highlighted in case reports. Our report demonstrates a similar adverse event with the drug in one of our patients with spontaneous resolution of the rash not necessitating cessation of treatment or desensitization to the drug as were done in other cases. We highlight through our report the heterogeneity of the clinical presentation of the rash when on triple therapy and the need for further studies to understand the immunological mechanism of this adverse event.

Divyalakshmi Bhaskaran is NIHR Academic Clinical Fellow, Leeds Teaching Hospitals NHS Foundation Trust, United Kingdom.

Kathryn Bateman is Cystic Fibrosis/Respiratory Medicine Consultant, Bristol Adult Cystic Fibrosis Centre, United Kingdom.

Marcus A Mall , Rossa Brugha , Silvia Gartner , Julian Legg, Alexander Moeller, Pedro Mondejar-Lopez, Dario Prais,, Tacjana Pressle , Felix Ratjen , Philippe Reix , Paul D Robinson, Hiran Selvadurai, Florian Stehling, Neil Ahluwalia , Emilio Arteaga-Solis, Bote G Bruinsma, Mark Jenning , Samuel M Moskowitz , Sabrina Noel , Simon Tian , Tanya G Weinstock , Pan Wu , Claire E Wainwright , Jane C Davies. Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study. Am J Respir Crit Care Med. 2022 Dec 1;206(11):1361-1369. doi: 10.1164/rccm.202202-0392OC Free PMC article /pubmed.ncbi.nlm.nih.gov/35816621/

Marcus A Mall

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study.
Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose).
Measurements and Main Results: The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity.

Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings.

Prof. Dr Marcus M Mall is head of the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin and Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany. German Center for Lung Research, Associated Partner, Berlin, Germany.

G Spoletini, L Gillgrass, K Pollard, N Shaw, E Williams, C Etherington, I J Clifton, D G Peckham. Dose adjustments of Elexacaftor/Tezacaftor/Ivacaftor in response to mental health side effects in adults with cystic fibrosis. J Cyst Fibros. 2022 Nov;21(6):1061-1065. doi: 10.1016/j.jcf.2022.05.001. Epub 2022 May 16 35585012 Free article pubmed.ncbi.nlm.nih.gov/35585012/

Giulia Spoletini

Introduction: Deterioration in mental health has been reported in a minority of individuals with cystic fibrosis starting elexacafor/tezacaftor/ivacaftor (ELX/TEZ/IVA). We report our experience of using sweat chloride and markers of clinical stability to titrate dose reduction with the aim of minimising adverse events and maintaining clinical stability.
Method: Adults (n = 266) prescribed ELX/TEZ/IVA, were included. Adverse events, sweat chloride, lung function and clinical data were collected.
Results: Nineteen (7.1%) individuals reported anxiety, low mood, insomnia and “brain fog” with reduced attention and concentration span. Thirteen underwent dose reduction with sweat chloride remained normal (<30 mmol l-1) or borderline (30-60 mmol l-1) in six (46.2%) and seven (53.2%) cases respectively. Improvement or resolution of AEs occurring in 10 of the 13 cases.

Conclusion: Dose adjustment of ELX/TEZ/IVA was associated with improvement in mental health AEs without significant clinical deterioration. Sweat chloride concentration may prove useful as a surrogate marker of CFTR function.

Giulia Spoletini is at the Regional Adult CF Centre, St James’s University Hospital, Leeds Teaching Hospital NHS Trust, Leeds, United Kingdom; Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.

Léa Okroglic, Pierre Sohier, Clémence Martin, Coralie Lheure , Nathalie Franck, Isabelle Honoré, Reem Kanaan, Pierre-Régis Burgel , Agnès Carlotti , Nicolas Dupin , Bénédicte Oulès. Acneiform Eruption Following Elexacaftor-Tezacaftor-Ivacaftor Treatment in Patients With Cystic Fibrosis. JAMA Dermatol. 2022 Nov 30;e225208. doi: 10.1001/jamadermatol.2022.5208. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36449298/

Benedicte Oules

Importance: A new treatment for cystic fibrosis combining 3 CFTR modulators- (ELX), tezacaftor (TEZ), and ivacaftor (IVA)-has recently been approved for cystic fibrosis treatment. The cutaneous adverse effects following treatment with this combination are poorly described in the literature.
Objective: To describe the clinicopathological features and treatment response of ELX-TEZ-IVA-associated acneiform eruptions in patients with cystic fibrosis.
Design, setting, and participants: This case series study was conducted in the Dermatology Department of Cochin Hospital, Paris, France, from July 2021 to June 2022 in collaboration with the Cochin Reference Center for Cystic Fibrosis. Referred patients were examined by senior dermatologists. All patients with cystic fibrosis treated with ELX-TEZ-IVA and referred for an acneiform rash were included.
Exposures: Treatment with ELX-TEZ-IVA.
Main outcomes and measures: Onset of acneiform rash, type of lesions, and degree of severity, as well as treatments initiated and response, were evaluated. When performed, skin biopsies were reviewed.
Results: This study included 16 patients (11 women [68.7%]) with a median (range) age of 27 (22-38) years. Six patients (37.5%) developed new-onset acneiform rashes, whereas 10 patients (62.5%) had a relapse (5 patients) or worsening (5 patients) of previous acne. The median (range) onset of acneiform rash was 45 (15-150) days. At inclusion, 11 patients (68.7%) had facial hyperseborrhea, 15 patients (93.7%) had noninflammatory lesions, and 14 (87.5%) had inflammatory lesions of seborrheic regions. Four patients (25.0%) had severe acne with deep inflammatory lesions and pitted scars. A specific pathological pattern of necrotizing infundibular crystalline folliculitis was observed in 4 patients. Topical acne treatments, antibiotics, and isotretinoin were used successfully in these patients, resulting in partial or complete remission in 12 patients (85.7% of patients reevaluated).

Conclusions and relevance: This case series study found that acneiform eruption is an adverse event associated with ELX-TEZ-IVA treatment in patients with cystic fibrosis. Most patients developed mild lesions. However, isotretinoin treatment may be necessary in some patients. The mechanism of ELX-TEZ-IVA-associated acneiform eruption is currently unknown, but the observation of necrotizing infundibular crystalline folliculitis in biopsied patients may guide further exploration.

Léa Okroglic is in the Department of Dermatology, Hôpital Cochin, AP-HP, AP-HP.Centre-Université Paris Cité, Paris, France.

2023 2023 2023

Daniel H Tewkesbury, Varinder Athwal, Rowland J Bright-Thomas, Andrew M Jones, Peter J Barry Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on liver tests at a large single adult cystic fibrosis centre. J Cyst Fibros. 2023 Jan 18;S1569-1993(23)00008-5. doi: 10.1016/j.jcf.2023.01.007. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36669962/
Background: Elexacaftor/tezacaftor/ivacaftor (E/T/I) therapy has resulted in substantial improvements in health status for many with cystic fibrosis. Monitoring of liver tests is recommended due to observed rises in transaminases in trials and cases of hepatotoxicity. Comprehensive data in large populations of unselected individuals and those with established CF related liver disease (CFLD) is lacking.
Methods: Patients prescribed E/T/I at a large, adult centre had liver tests monitored at least 3 monthly for 12 months. Changes in individual liver tests were analysed and abnormalities were compared in those with and without CFLD.
Results: 255 of 267 eligible patients were included. Mild rises in median ALT, AST and bilirubin from baseline to 3 months (all p < 0.001) within normal limits were noted which were sustained. There were no differences in changes in liver tests between those with or without CFLD. There was a significant difference in alkaline phosphatase for those with raised levels at baseline versus those with normal baseline level (-18.5 vs +2.0 IU/L, p = 0.002). Clinically significant rises in ALT and AST occurred in 8 (3.1%) and 6 (2.4%) cases respectively, with derangements in 2 individuals attributed to therapy.

Conclusions: E/T/I leads to a mild, likely clinically insignificant increase in ALT, AST and bilirubin after 3 months which is sustained but does not appear to increase further in the vast majority. Underlying CFLD should not be a barrier to treatment. Although there was a reduction in ALP when elevated at baseline, this was not unique to those with pre-existing CFLD.

Daniel H Tewkesbury is at the Manchester University NHS Foundation Trust, Manchester, UK; Division of Immunology, Immunity to Infection & Respiratory Medicine, University of Manchester, Manchester, UK.

Steven Levitte, Yonathan Fuchs, Russell Wise , Zachary M Sellers. Effects of CFTR modulators on serum biomarkers of liver fibrosis in children with cystic fibrosis. J Hepatol Commun. 2023 Jan 20;7(2):e0010. doi: 10.1097/HC9.0000000000000010. Free article pubmed.ncbi.nlm.nih.gov/36662672/

Steven Levitte. LinkedIn

The cystic fibrosis (CF) transmembrane conductance regulator corrector/potentiator combinations lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor improve sweat chloride, pulmonary function, and nutrition. Yet it is unclear whether they may also impact the progression of liver fibrosis, which is a substantial source of morbidity and mortality for patients with CF. We conducted a retrospective, single-center analysis of children and adolescents with CF treated with lumacaftor/ivacaftor and/or elexacaftor/tezacaftor/ivacaftor therapy, focusing on alterations in liver function tests and fibrosis indices using previously-established thresholds that corresponded with increased liver elastography.
In pairwise comparisons of before and during treatment timepoints, we found that those with CF-associated liver involvement experienced significant decreases in gamma-glutamyl transferase, aspartate aminotransferase-to-platelet index, and gamma-glutamyl transferase-to-platelet ratio while on lumacaftor/ivacaftor. These differences were not observed in patients treated with elexacaftor/tezacaftor/ivacaftor, nor were they observed in patients without underlying CF-associated liver disease. These results provide the first evidence that lumacaftor/ivacaftor may improve liver fibrosis in children and adolescents with CF and suggest it may be beneficial in the treatment of CF-associated liver disease

Steven Levitt is in the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford Univ

Debanjali Purkayastha, Kyla Agtarap, Kristy Wong, Onella Pereira, Jannie Co, Smita Pakhale, Salmaan Kanji. Drug-drug interactions with CFTR modulator therapy in cystic fibrosis: Focus on Trikafta®/Kaftrio®. J Cyst Fibros. 2023 Jan 16;S1569-1993(23)00004-8. doi: 10.1016/j.jcf.2023.01.005. Online ahead of print.pubmed.ncbi.nlm.nih.gov/36653239/

Debanjali Purkayastha LinkedIn

The combination of CFTR modulators ivacaftor, tezacaftor and elexacaftor (Trikafta®, Kaftrio®) significantly improve outcomes, including survival in a broad range of cystic fibrosis patients. These drugs have complicated metabolic profiles that make the potential for drug interactions an important consideration for prescribers, care providers and patients. Prolonged survival also increases risk of age-related disease and their associated pharmacotherapy, further increasing the risk of drug interactions and the need for increased vigilance amongst care providers. We systematically searched the literature for studies identifying and evaluating pharmacokinetic and pharmacodynamic drug interactions involving the components of Trikafta®/Kaftrio®. We also searched electronic databases of drugs for possible drug interactions based on metabolic profiles. We identified 86 potential drug interactions of which 13 were supported by 14 studies. There is a significant need for research to describe the likelihood, magnitude and clinical impact of the drug interactions proposed here.

Debanjali Purkayastha is a Pharmacy Resident at the University of Waterloo, Kitchener, ON, Canada.

Karen S McCoy , Jill Blind , Terri Johnson, Patti Olson, Laura Raterman , Shasha Bai, Mariah Eisner, Shahid I Sheikh, Stephan Druhan, Cody Young, Kimberly Pasley. Clinical change 2 years from start of elexacaftor-tezacaftor-ivacaftor in severe cystic fibrosis .Pediatr Pulmonol 2023 Jan 17. doi: 10.1002/ppul.26318. Online ahead of print. hpubmed.ncbi.nlm.nih.gov/36650567/

Karen S McCoy. ResearchGate

Rationale: Limited published research is available on the impact of elexacaftor/tezacaftor/ivacaftor (ETI) beyond the initial few months postdrug initiation, especially for those who initiated therapy via individual investigational new drug application. The experiences of patients with cystic fibrosis (CF) experiencing severe lung disease were reviewed for significant improvements in clinical symptoms and quality of life.
Objectives: To examine clinical outcomes 2 years post-ETI in patients with CF and advanced lung disease.
Methods: This single center institutional review board-approved, retrospective chart review assessed clinical markers (percent predicted forced expiratory volume in 1 s, weight, sweat chloride), quality of life and computed tomography scans in patients with advanced lung disease who met criteria for compassionate use/expanded access program due to high risk of death or transplant need within 2 years.
Results: Eighteen identified patients (ages 15-49 years) initiated drug between July and September 2019. Clinical markers indicated that therapy was well tolerated, not discontinued by any participant, and lab values did not indicate medical concern or discontinuation. Monitoring results indicated the safety of modulator therapy as there were no adverse clinical occurrences and all patients presented universal stabilization. There were no deaths and no transplants by the end of the study.

Conclusions: This study focused on patients with CF eligible for modulator therapy and were initiated due to advanced lung disease. Initiation of modulator therapy was deemed safe and resulted in objective positive changes in nutrition, cough, FEV1 , subjective reports of clinical status, level of activity, and a reduction in burden of treatment.

Karen S McCoy is professor at the Pulmonary and Sleep Medicine Division, Nationwide Children’s Hospital, Columbus, Ohio, USA.

Carmen Streibel, Corin C Willers , Orso Pusterla , Grzegorz Bauman, Enno Stranzinger, Ben Brabandt , Oliver Bieri, Marion Curdy, Marina Bullo, Bettina Sarah Frauchiger , Insa Korten, Linn Krüger, Carmen Casaulta, Felix Ratjen, Philipp Latzin, Elisabeth Kieninger. Effects of elexacaftor/tezacaftor/ivacaftor therapy in children with cystic fibrosis – a comprehensive assessment using lung clearance index, spirometry, and functional and structural lung MRI . J Cyst Fibros. 2023 Jan 10;S1569-1993(22)01432-1. doi: 10.1016/j.jcf.2022.12.012. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36635199/

Carmen Streibel

Background: With improvement in supportive therapies and the introduction of cystic fibrosis transmembrane conductance regulator (CFTR)-modulator treatment in patients with cystic fibrosis (CF), milder disease courses are expected. Therefore, sensitive parameters are needed to monitor disease course and effects of CFTR-modulators. Functional lung MRI using matrix-pencil decomposition (MP-MRI) is a promising tool for assessing ventilation and perfusion quantitatively. This study aimed to assess the treatment effect of elexacaftor/tezacaftor/ivacaftor combination regimen (ELX/TEZ/IVA) on measures of structural and functional lung abnormalities.
Methods: 24 children with CF underwent lung function tests (multiple breath washout, spirometry), functional and structural MRI twice (one year apart) before and once after at least two weeks (mean 4.7 ± 2.6 months) on ELX/TEZ/IVA. Main outcomes were changes (Δ) upon ELX/TEZ/IVA in lung function, defect percentage of ventilation (VDP) and perfusion (QDP), defect distribution index of ventilation and perfusion (DDIV, DDIQ), and Eichinger score. Statistical analyses were performed using paired t-tests and multilevel regression models with bootstrapping.
Results: We observed a significant improvement in lung function, structural and functional MRI parameters upon ELX/TEZ/IVA treatment (mean; 95%-CI): ΔLCI2.5 (TO) -0.84 (-1.62 to -0.06); ΔFEV1 (z-score) 1.05 (0.56 to 1.55); ΔVDP (% of impairment) -6.00 (-8.44 to -3.55); ΔQDP (% of impairment) -3.90 (-5.90 to -1.90); ΔDDIV -1.38 (-2.22 to -0.53); ΔDDIQ -0.31 (-0.73 to 0.12); ΔEichinger score -3.89 (-5.05 to -2.72).

Conclusions: Besides lung function tests, functional and structural MRI is a suitable tool to monitor treatment response of ELX/TEZ/IVA therapy, and seems promising as outcome marker in the future.

Carmen Streibel is in the Dept of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Switzerland.Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Switzerland.

Meliksah Arslan, Sarah Chalmers, Kelly Rentfrow Janelle M Olson , Vicki Dean , Mark E Wylam , Nadir Demirel. Suicide attempts in adolescents with cystic fibrosis on Elexacaftor/Tezacaftor/Ivacaftor therapy. Case Reports J Cyst Fibros. 2023 Feb 7;S1569-1993(23)00023-1. doi: 10.1016/j.jcf.2023.01.015. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36759252/

Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a recently approved cystic fibrosis (CF) transmembrane conductance regulator modulator therapy that has shown promising clinical and laboratory improvements on multiple organ systems in people with CF (pwCF). While original clinical trials found little to no effect on depression and anxiety, many post-marketing reports have suggested that ETI may be associated with adverse mental health effects. Here we report on two pwCF with adverse mental health effects shortly after starting ETI. Although many factors such as the burden of living with a chronic disease or widespread effects of the Covid-19 pandemic may have contributed to these events, similar reports have led to mounting concern that ETI may be the cause of such events. Regular mental health screening before the initiation of ETI and monitoring for signs and symptoms of mental diseases afterward should be a routine part of care, given the gravity of possible outcomes.

Meliksah Arslan is at the Marmara University School of Medicine, Istanbul, Turkey.

Christina J Bathgate, Emily Muther , Anna M Georgiopoulos, Beth Smith 4, Laura Tillman, Sonia Graziano, Marieke Verkleij, Paula Lomas 8, Alexandra Quittner. Positive and negative impacts of elexacaftor/tezacaftor/ivacaftor: Healthcare providers’ observations across US centers. Pediatr Pulmonol. 2023 Jun 2. doi: 10.1002/ppul.26527. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37265418/

Christina Bathgate

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) has been associated with unprecedented clinical improvements, transforming the management of cystic fibrosis (CF). However, side effects with implications for safety and well-being have been reported, including neuropsychiatric changes. This study aimed to better characterize the emerging positive and negative impacts of ETI.

Methods: The Cystic Fibrosis Foundation’s Mental Health Advisory Committee distributed a 26-item survey to US CF care teams to assess clinician observations of patient-reported experiences with ETI. Survey responses measured the prevalence of these effects in five domains: (1) positive physical and psychological effects, (2) sleep difficulties, (3) cognitive difficulties, (4) worsening mental health, and (5) concerns about the future and finances.

Results: Seventy-five healthcare providers responded from a pediatric, adult, and combined centers. Positive physical effects of ETI and increased optimism were reported in the upper quartiles (50%-100%) and rated as having a significant impact on daily functioning. Sleep and cognitive difficulties were reported in 1%-24%, with slight impacts on functioning, and psychological symptoms (e.g., increased stress, depression, anxiety) and new psychiatric medications were reported in 1%-24%, with moderate impacts. Concerns about the future were reported in 1%-24%, with minimal impacts.

Conclusion: Across US centers, providers most often observed positive physical effects of ETI. However, a variety of negative side effects were also reported, including sleep disruptions and worsening psychological functioning, which should be systematically monitored by CF teams. These national-level data are a first step in evaluating the prevalence and consequences of these side effects and can directly inform future studies

Christina Bathgate is in the Department of Medicine, National Jewish Health, Denver, Colorado, USA.

Liron Birimberg-Schwartz , Wan Ip , Claire Bartlett , Julie Avolio , Jeffrey M Beekman , Johanna Rommens, Lisa Strug , Christine E Bear , Theo J Moraes , Tanja Gonska. Validating organoid-derived human intestinal monolayers for personalized therapy in cystic fibrosis.Life Sci Alliance
. 2023 Apr 5;6(6):e202201857. doi: 10.26508/lsa.202201857. Print 2023 Jun. 37024122 Free PMC article pubmed.ncbi.nlm.nih.gov/37024122/

Liron Birimberg-Schwartz
gastro.on.ca

Highly effective drugs modulating the defective protein encoded by the CFTR gene have revolutionized cystic fibrosis (CF) therapy. Preclinical drug-testing on human nasal epithelial (HNE) cell cultures and 3-dimensional human intestinal organoids (3D HIO) are used to address patient-specific variation in drug response and to optimize individual treatment for people with CF.
This study is the first to report comparable CFTR functional responses to CFTR modulator treatment among patients with different classes of CFTR gene variants using the three methods of 2D HIO, 3D HIO, and HNE. Furthermore, 2D HIO showed good correlation to clinical outcome markers. A larger measurable CFTR functional range and access to the apical membrane were identified as advantages of 2D HIO over HNE and 3D HIO, respectively. Our study thus expands the utility of 2D intestinal monolayers as a preclinical drug testing tool for CF.

Liron Birimberg-Schwartz is in Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Toronto, Toronto, Canada.and Translational Medicine, The Hospital for Sick Children, Toronto, Canada.

— The subject is reviewed in detail in the Free PMC article

Julie K Bower, Nataliya Volkova, Neil Ahluwalia, Gurvaneet Sahota, Fengjuan Xuan, Anna Chin, Tanya G Weinstock, Josh Ostrenga, Alexander Elbert. Real-world safety and effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: Interim results of a long-term registry-based study. J Cyst Fibros
. 2023 Mar 22;S1569-1993(23)00066-8. doi: 10.1016/j.jcf.2023.03.002. Online ahead of print. Free article. pubmed.ncbi.nlm.nih.gov/36963986/

Julie K Bower
Vertex

Background: Phase 3 clinical trials showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in people with cystic fibrosis (CF) with ≥1 F508del-CFTR allele. To assess long-term effects of ELX/TEZ/IVA under real-world conditions of use, a 5-year observational registry-based study is being conducted. We report interim results from the first 2 years of follow-up.
Methods: The study included people with CF in the US Cystic Fibrosis Foundation Patient Registry (CFFPR) who initiated ELX/TEZ/IVA between October 2019 and December 2020. Pulmonary exacerbations (PEx), percent predicted forced expiratory volume in 1 second (ppFEV1), hospitalizations, bacterial pathogens, body mass index (BMI), CF complications and comorbidities, and liver function tests (LFTs) after treatment initiation were compared with the 5-year pre-treatment period. Death and lung transplantation were assessed relative to 2019 CFFPR data.
Results: 16,116 people with CF were included (mean treatment duration 20.4 months). Among those with 5 years of pre-treatment data, mean PEx/patient/year declined to 0.18 (95% CI: 0.17, 0.19) in Years 1 and 2 post-treatment from 0.86 (95% CI: 0.83, 0.88) in the baseline year (79% reduction), after a continued increase observed pre-treatment. Similarly, a decline in mean hospitalizations/patient/year was observed in Year 1 that was sustained in Year 2 (74% reduction from baseline year). The mean absolute change in ppFEV1 from baseline was +8.2 percentage points (95% CI: 8.0, 8.4) in Year 1 and +8.9 percentage points (95% CI: 8.7, 9.1) in Year 2, after a continued decline observed pre-treatment. Positive bacterial cultures decreased for all evaluated pathogens, and mean BMI increased by 1.6 kg/m2 (95% CI: 1.5, 1.6) by Year 2. No new safety concerns were identified based on evaluation of CF complications, comorbidities, and LFTs. The annualized rates of death (0.47% [95% CI: 0.39, 0.55]) and lung transplantation (0.16% [95% CI: 0.12, 0.22]) were considerably lower than reported in 2019 (1.65% and 1.08%, respectively).

Conclusions: ELX/TEZ/IVA treatment was associated with sustained improvements in lung function, reduced frequency of PEx and all-cause hospitalization, increased BMI, and lower prevalence of positive bacterial cultures. Additionally, there was a 72% lower rate of death and 85% lower rate of lung transplantation relative to the year before ELX/TEZ/IVA availability. These results, from the largest cohort of ELX/TEZ/IVA-treated people to date, extend our understanding of the broad clinical benefits of ELX/TEZ/IVA.

Julie K Bower is Associate Director of Clinical Epidemiology, Global Patient Safety at Vertex Pharmaceuticals, Boston, MA, United States of America.

Giuseppe Cimino
obbervatorio
malattierare

Introduction: Management of cystic fibrosis has recently stepped forward with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, although data on potential adverse effects are lacking for many categories of patients, such as pregnant women.
Methods: We report one of the first reports on the outcome of pregnancy in a woman treated with Elexacaftor/Tezacaftor/Ivacaftor during the second and third trimester of pregnancy, showing a significant improvement of respiratory status, compared with the first trimester when the medication was discontinued due to unknown and, therefore, potential teratogenic effects. Also, we performed the review of the existing literature on the topic

Results: The course of pregnancy was uneventful, with reference to major obstetric complications, and the patient delivered a healthy neonate. These results were similar to those coming from other short series of pregnant women affected by cystic fibrosis and treated with CFTR modulators during pregnancy.

Conclusions: Thus, despite the lack of evidence on the topic, the use of Elexacaftor/Tezacaftor/Ivacaftor in pregnancy seems to be apparently not associated with major adverse events, thus opening optimistic scenarios in terms of management of these patients.

Dr Giuseppe Cimino is at the Fibrosis Regional Reference Center, A.O.U. Policlinico Umberto I, Rome, Italy. and the Department of Maternal and Child Health and Urological Sciences, Sapienza University of Rome, Via del Policlinico, 155, 00161, Rome, Italy.

Stefanie Dillenhoefer , Dorothy Grogono , Ana Morales-Tirado.A year in review (2022): Modulators and COVID19, the story goes on….. Review J Cyst Fibros. 2023 Mar 6;S1569-1993(23)00065-6. doi: 10.1016/j.jcf.2023.03.001. Online ahead of print. Free PMC article pubmed.ncbi.nlm.nih.gov/36906393/

Stefanie Dillenhoefer
Linkedin

In this review the authors state they have aimed to cover some of the highlights of the cystic fibrosis (CF) literature in 2022, which again has been dominated by the SARS-CoV-2 (COVID-19) pandemic and modulator therapy. They have also explored other themes, such as novel findings in relation to pulmonary exacerbations, early lung disease and emerging areas for people with CF (pwCF).

– The free PMC article, accessed through the above PubMed link, is excellent and covers the main advances during the year.

Dr Stefanie Dillenhoefer is in the Department of Pediatric Pulmonology, Cystic Fibrosis Center, University Children’s Hospital of Ruhr University Bochum at St. Josef-Hospital, 44791 Bochum, Germany.

J Stuart Elborn , Francesco Blasi , Pierre-Régis Burgel , Daniel Peckham. Role of inhaled antibiotics in the era of highly effective CFTR modulators. Review Eur Respir Rev. 2023 Jan 11;32(167):220154. doi: 10.1183/16000617.0154-2022. Print 2023 Mar 31. Free article pubmed.ncbi.nlm.nih.gov/36631132/

Stuart Elborn

Recurrent and chronic bacterial infections are common in people with cystic fibrosis (CF) and contribute to lung function decline. Antibiotics are the mainstay in the treatment of exacerbations and chronic bacterial infection in CF. Inhaled antibiotics are effective in treating chronic respiratory bacterial infections and eradicating Pseudomonas aeruginosa from the respiratory tract, with limited systemic adverse effects. In the past decade, highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators have become a new therapy that partially corrects/opens chloride transport in patients with selected CFTR mutations, restoring mucus hydration and improving mucociliary clearance. The recent triple CFTR modulator combination is approved for ∼80-90% of the CF population and significantly reduces pulmonary exacerbations and improves respiratory symptoms and lung function. CFTR modulators have shifted the focus from symptomatic treatment to personalised/precision medicine by targeting genotype-specific CFTR defects. While these are highly effective, they do not fully normalise lung physiology, stop inflammation or resolve chronic lung damage, such as bronchiectasis. The impact of these new drugs on lung health is likely to change the future management of chronic pulmonary infections in people with CF. This article reviews the role of inhaled antibiotics in the era of CFTR modulators.

Prof. Stuart Elborn is in the Faculty of Medicine Health and Life Sciences, Queen’s University, Belfast, UK s.elborn@qub.ac.uk.

L R Caley , H H Jarosz-Griffiths , L Smith, L Gale, J Barrett , L Kinsey , V Davey , M Nash , A M Jones , J L Whitehouse , D Shimmin , R A Floto , H White , D G Peckham. Body mass index and nutritional intake following Elexacaftor/Tezacaftor/Ivacaftor modulator therapy in adults with cystic fibrosis. J Cyst Fibros. 2023 Jul 6;S1569-1993(23)00824-X. doi: 10.1016/j.jcf.2023.06.010. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37422432/
Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy is often associated with increased body mass index (BMI) in people with cystic fibrosis (CF). This is thought to reflect improved clinical stability and increased appetite and nutritional intake. We explored the change in BMI and nutritional intake following ETI modulator therapy in adults with CF.
Methods: Dietary intake, measured with myfood24®, and BMI were collected from adults with CF at baseline and follow-up as part of an observational study. Changes in BMI and nutritional intake in participants who commenced ETI therapy between time points were assessed. To contextualize findings, we also assessed changes in BMI and nutritional intake between study points in a group on no modulators.
Results: In the pre and post ETI threapy group (n = 40), BMI significantly increased from 23.0 kg/m2 (IQR 21.4, 25.3) at baseline to 24.6 kg/m2 (IQR 23.0, 26.7) at follow-up (p<0.001), with a median of 68 weeks between time points (range 20-94 weeks) and median duration of ETI therapy was 23 weeks (range 7-72 weeks). There was a significant decrease in energy intake from 2551 kcal/day (IQR 2107, 3115) to 2153 kcal/day (IQR 1648, 2606), p<0.001. In the no modulator group (n = 10), BMI and energy intake did not significantly change between time points (p>0.05), a median of 28 weeks apart (range 20-76 weeks).

Conclusions: These findings tentatively suggest that the increase in BMI with ETI therapy may not simply be attributable to an increase in oral intake. Further exploration into the underlying aetiology of weight gain with ETI therapy is needed.

L R Caley is at the Leeds Institute of Medical Research at St James’s, University of Leeds, UK; Department of Respiratory Medicine, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Danielle M Goetz, Carla K Frederick , Geovanny Perez , Drucy Borowit Airway clearance after highly effective CFTR modulators: Normalizing life and reducing treatment burden. Pediatr Pulmonol. 2023 May 26. doi: 10.1002/ppul.26502. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37232336/

Danielle Goetz

Objectives: Airway clearance therapy (ACT) is an important component of therapy for cystic fibrosis (CF) but is associated with significant treatment burden. Highly effective CFTR modulator therapy (HEMT) has improved pulmonary function for many people with CF (pwCF). We sought to understand changes in attitudes and practices about ACT in the post-HEMT era.
Study design: Surveys of CF community members and CF care team members.
Methodology: Separate surveys were created for the CF community and CF care providers to evaluate attitudes towards ACT and exercise in the post-HEMT era. We solicited answers from pwCF via the CF Foundation’s Community Voice and from CF care providers via CF Foundation listservs. Surveys were available between July 20 and August 3, 2021.
Results: Surveys were completed by 153 community members (parents of children and pwCF) and 192 CF care providers. Belief that exercise can substitute partially for ACT was endorsed similarly by community members (59%) and providers (68%). After starting HEMT, 36% of parents of children and 51% of adults did fewer ACT treatments including 13% who stopped ACT. Adults reported altering their ACT regimen more than parents of children, though the sample size was limited. Half of providers had changed their ACT recommendations for those on HEMT. Fifty-three percent of respondents had discussed changing ACT with their care team (36% of parents, 58% of pwCF).

Conclusions: Providers should be aware that ACT management changes may have been undertaken by pwCF who have pulmonary benefits of HEMT. Treatment burden should be considered in co-management decisions regarding ACT and exercise.

Danielle M Goetz is Clinical Associate Professor in the Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA.

Enery Gómez-Montes, Enrique Salcedo Lobato, Alberto Galindo, Diana García Alcázar, Cecilia Villalain, Maria Teresa Moral-Pumarega, Gerardo Bustos Lozano, Carmen Luna-Paredes. Prenatal cystic fibrosis transmembrane conductance regulator modulator therapy: A promising way to change the impact of cystic fibrosis. Case Reports Fetal Diagn Ther
. 2023 Mar 30. doi: 10.1159/000530261. Online ahead of print.pubmed.ncbi.nlm.nih.gov/36996799/

Enery Gomez-Montes
Research Gate

Introduction: Cystic fibrosis (CF) is a potentially severe disease. The development of new therapies with cystic fibrosis transmembrane conductance regulator (CFTR) modulators has been a great advance in the management of this condition because they improve the function of the faulty CFTR protein rather than palliate its consequences. CFTR modulator therapy improves pancreatic and lung function and, therefore, quality of life, with greater benefits the sooner treatment is started. For this reason, the use of these therapies is being approved for increasingly younger patients. Only two cases of pregnant women taking CFTR modulators therapy with CF fetuses have been reported, suggesting that it could resolve meconium ileus (MI) prenatally, and delay/prevent other consequences of CF.

Case presentation: We report a case of a healthy pregnant patient who underwent CFTR modulator therapy with elexacaftor-tezacaftor-ivacaftor (ETI) in order to treat her fetus with CF (F508del homozygous CFTR mutation) and MI. Ultrasound findings suggestive of MI were observed at 24 weeks. Both parents were tested for CFTR mutations, and both were carriers of the F508del CFTR mutation. The fetus was diagnosed with CF by amniocentesis at 26+2 weeks. Maternal ETI therapy was initiated at 31+1 weeks and no dilated bowel was observed at 39 weeks. There were no signs of bowel obstruction after birth. Maternal ETI treatment was continued during breastfeeding, with normal liver function. Immunoreactive trypsinogen in the newborn was 58.1 ng/mL, sweat chloride test was 80 mmol/l, and fecal elastase on the second day of life was 58 μg/g.

Discussion/conclusion: Prenatal ETI treatment, as well as during breastfeeding, could solve, prevent and/or delay CF complications.

Every Gômez-Montes is at Fetal Medicine Unit, Department of Obstetrics and Gynecology, Research Institute Hospital 12 de Octubre (imas12), Primary Care Interventions to Prevent Maternal and Child Chronic Diseases of Perinatal and Developmental Origin (RICORS Network), University Hospital 12 de Octubre, Complutense University, Madrid, Spain

Jennifer L Goralski , Jordana E Hoppe , Marcus A Mall, Susanna A McColley , Edward McKone , Bonnie Ramsey , Jonathan H Rayment , Phil Robinson , Florian Stehling , Jennifer L Taylor-Cousar, Elizabeth Tullis , Neil Ahluwalia, Anna Chin , Chenghao Chu , Mengdi Lu, Tao Niu , Tanya Weinstock , Felix Ratjen , Margaret Rosenfeld ; VX20-445-111 Study Group.Phase 3 Open-Label Clinical Trial of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged 2 Through 5 Years with Cystic Fibrosis and at Least One F508del Allele. Am J Respir Crit Care Med. 2023 Mar 15. doi: 10.1164/rccm.202301-0084OC. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36921081/

Jennifer Goralski
UNC School of Medicine

Rationale: Elexacaftor/tezacaftor/ivacaftor has been shown to be safe and effective in people with cystic fibrosis (CF) aged ≥6 years with ≥1 F508del-CFTR allele but has not been studied in younger children.
Objectives: To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of elexacaftor/tezacaftor/ivacaftor in children with CF aged 2 through 5 years.

Methods: In this Phase 3, open-label, two-part study (Parts A and B), children weighing <14 kg (on Day 1) received elexacaftor 80 mg once daily, tezacaftor 40 mg once daily, and ivacaftor 60 mg each morning and 59.5 mg each evening; children weighing ≥14 kg received elexacaftor 100 mg once daily, tezacaftor 50 mg once daily, and ivacaftor 75 mg every 12 hours.
Measurements and main results: The primary endpoints for Part A (15-day treatment period) were pharmacokinetics and safety and tolerability. For Part B (24-week treatment period), the primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics and absolute changes from baseline in sweat chloride concentration and lung clearance index2.5 (LCI2.5) through Week 24. Analysis of pharmacokinetic data from 18 children enrolled in Part A confirmed the appropriateness of the Part B dosing regimen. In Part B, 75 children (F508del/minimal function genotypes, n = 52; F508del/F508del genotype, n = 23) were enrolled and dosed. Seventy-four children (98.7%) had adverse events which were all mild (62.7%) or moderate (36.0%) in severity. The most common adverse events were cough, fever, and rhinorrhea. Decreases in sweat chloride concentration (-57.9 mmol/L [95% confidence interval [CI], -61.3 to -54.6]; n = 69) and LCI2.5 (-0.83 units [95% CI, -1.01 to -0.66]; n = 50) were observed from baseline through Week 24. Mean BMI was within the normal range at baseline and remained stable at Week 24.

Conclusions: In this open label study in children 2 through 5 years of age, elexacaftor/tezacaftor/ivacaftor treatment was generally safe and well tolerated, with a safety profile consistent with that observed in older age groups, and led to clinically meaningful reductions in sweat chloride concentration and lung clearance index. Clinical trial registration available at www.

Dr Jennifer L Goralski is at the University of North Carolina at Chapel Hill, North Carolina, United States and is Associate Director of the Adult Cystic Fibrosis Center

Andrea Granados , Christine L Chan, Amir Moheet, Timothy Vigers, Ana María Arbeláez, Katie Larson Ode. The impact of elexacaftor/tezacaftor/ivacaftor on body composition in a small cohort of youth with cystic fibrosis. Pediatr Pulmonol. 2023 Mar 17. doi: 10.1002/ppul.26388. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36929859

Andrea Granado
Docspot

Background: The effects of elexacaftor-tezacaftor-ivacaftor (ETI) on body composition in people with CF (pwCF) are unknown.
Methods: Dual-energy X-ray absorptiometry fat-free mass and fat mass adjusted for height (FMI) as well as oral glucose tolerance test derived measures of insulin secretion and sensitivity were compared before and after ETI initiation in eight pwC
Results: Patients median age: 22 years interquartile range (IQR: 16-28), 87.5% male, median time on ETI:11 months. Weight z-score increased from -0.52 to 0.18 (p = 0.014); FMI increased from 4.12 to 6.29 (p = 0.014). Insulin secretion (C pep iAUC/Gluc iAUC) increased from 8.71 to 14.21 (p = 0.021), insulin resistance (HOMA2 IR) increased from 0.73 to 1.25 (p = 0.014) and insulin sensitivity decreased (Matsuda) 8.88 to 5.58 (p = 0.036).

Conclusions: ETI resulted in increased weight and fat mass. BMI and muscle mass did not change. Both insulin secretion and insulin resistance increased. Longer-term metabolic consequences of ETI need further investigation.

Dr Andrea Granados is a pediatric endocrinologist in the Department of Pedaitrics, the Nicklaus Children’s Hospital, Miami, Florida USA

Emma L Guenther, Karen S McCoy , Mariah Eisner , Shasha Bai , Christopher J Nemastil , Kimberly J Novak, Terri Johnson, Emily M Stephan. Impact of chronic medication de-escalation in patients with cystic fibrosis taking elexacaftor, tezacaftor, ivacaftor: A retrospective review.J Cyst Fibros. 2023 Apr 15;S1569-1993(23)00082-6. doi: 10.1016/j.jcf.2023.03.018. Online ahead of print.pubmed.ncbi.nlm.nih.gov/37069044/
Background: This single-center, retrospective study evaluated the effects of de-escalating cystic fibrosis (CF) supportive therapies in patients on elexacaftor/tezacaftor/ivacaftor (ETI). For many with CF, the clinical benefit of ETI exceeds that of supportive therapies. Therefore, we anticipated patients would desire to discontinue many of their supportive therapies, leading to the creation of a de-escalation algorithm. If patients were clinically improved and stable on ETI, CF supportive therapies could be de-escalated quarterly in accordance with the algorithm.
Methods: The primary objective was to assess non-inferiority of supportive therapies de-escalation by comparing the absolute change in percent predicted (ppFEV1) from baseline to month 1 versus the absolute change from baseline to month 12 after initiating ETI with patients serving as their own control. A chart review of patients initiated on ETI from September 2019 through December 2020 was conducted. Inclusion criteria included those six years and older with at least one copy of F508del.
Results: The study included 174 patients. The mean ppFEV1 at baseline, month 1, and month 12 was 67%, 78%, and 87% respectively. The mean difference in absolute change in ppFEV1 from baseline to month 1 compared to baseline to month 12 after the initiation of ETI was 1.53% (95% CI: -0.49 to 3.55)

CONCLUSION: De-escalating supportive therapies for those on ETI was non-inferior to remaining on all supportive therapies. This suggests that medications may be able to be discontinued under the context of a de-escalation algorithm, which may decrease medication burden and cost and increase quality of life.

Emma L Guenther is in the Department of Pharmacy, Nationwide Children’s Hospital, Columbus, OH, USA.

Karen S McCoy.
ResearchGate

Karen S McCoy is professor at the Pulmonary and Sleep Medicine Division, Nationwide Children’s Hospital, Columbus, Ohio, USA.

Caoimhe McParland, Matthew Nunn, Theodore K Marras, Meredith Chiasson. Eradication of Mycobacterium abscessus infection in cystic fibrosis with initiation of Elexacaftor/Tezacaftor/Ivacaftor. Case Reports J Cyst Fibros. 2023 Apr 17;S1569-1993(23)00095-4. doi: 10.1016/j.jcf.2023.03.021. Online ahead of print pubmed.ncbi.nlm.nih.gov/37076409/
Mycobacterium abscessus is a nontuberculous mycobacterium that is often multi-drug resistant, difficult to eradicate and associated with a rapid decline in lung function in cystic fibrosis (CF). Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a combination CFTR modulator that improves lung function and decreases exacerbations, but limited data exists about its impact on respiratory infections. A 23-year-old male with CF (F508del, unknown) was diagnosed with Mycobacterium abscessus subspecies abscessus infection. He completed 12-weeks of intensive therapy, followed by oral continuation therapy. Antimicrobials were later discontinued for optic neuritis secondary to linezolid. He remained off antimicrobials with persistently positive sputum cultures. He then initiated ETI, and bronchoscopy eight months later suggested eradication of M. abscessus. By modulating CFTR protein function, ETI may improve innate airway defence mechanisms, facilitating the clearance of infections such as M. abscessus. This case highlights the potential positive implications of ETI on the challenging treatment of M. abscessus infections in CF.

Caoimhe McParland is in the Department of Medicine, Dalhousie University, Halifax, NS, Canada.

Cori L Daines , Tullis Elizabeth, Stefano Costa, Rachel Linnemann, Marcus A Mall, Edward McKone et al. VX17-445-105 Study Group. Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in pople with cystic fibrosis and at least one F508del allele : 144-week interim results from a 192-week open-label extension study. Eur Respir J 2023;62(6):220229 Free PMC article pubmed.ncbi.nlm.nih.gov/37945033/

Fig 12b Elizabeth Tullis
priming.org

Fig. 12a Cori L Daines
medicine.arizona.edu

Background: In two pivotal phase 3 trials, up to 24 weeks of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in patients with cystic fibrosis (CF) ≥12 years of age who have at least one F508del allele. The aim of this study is to assess long-term safety and efficacy of ELX/TEZ/IVA in these patients.
Methods: In this phase 3, open-label, single-arm extension study, participants with F508del-minimal function (from a 24-week parent study; n=399) or F508del–F508del (from a 4-week parent study; n=107) genotypes receive ELX/TEZ/IVA at the same dose (ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h). The primary end-point is safety and tolerability. A prespecified interim analysis was conducted when the last participant reached the Week 144 visit.
Results: At the Week 144 interim analysis, mean duration of exposure to ELX/TEZ/IVA in the extension study was 151.1 weeks. Exposure-adjusted rates of adverse events (AEs) (586.6 events per 100 participant-years) and serious AEs (22.4 events per 100 participant-years) were lower than in the ELX/TEZ/IVA treatment group in the 24-week parent study (1096.0 and 36.9 events per 100 participant-years, respectively); most participants had AEs classified as mild (16.4% of participants) or moderate (60.3% of participants) in severity. 14 participants (2.8%) had AEs that led to treatment discontinuation. Following initiation of ELX/TEZ/IVA, participants had increases in forced expiratory volume in 1 s (FEV₁) percentage predicted, Cystic Fibrosis Questionnaire-Revised respiratory domain score and body mass index, and had decreases in sweat chloride concentration and pulmonary exacerbation rates that were maintained over the interim analysis period. The mean annualised rate of change in FEV₁% pred was +0.07 (95% CI -0.12-0.26) percentage points among the participants.
Conclusions: ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the 24-week parent study. Participants had sustained improvements in lung function, respiratory symptoms, CF transmembrane conductance regulator function, pulmonary exacerbation rates and nutritional status. These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA.

Cori L Daines (fig.12a) is Professor of Pediatrics at University of Arizona, Banner University Medical Center, Tucson, AZ, USA
Elizabeth Tullis (fig12b) is Professor and Director of Adult CF Centre at St Michaels Hospital Toronto

Peter J Barry, Pierre-Regis Burgel. Cast no shadow: assessing the disease-modyfying the effects of elexacaftor/tezacaftor/ivacaftor Eur Respir J 2023Dec7;62(6):22302026 Comment on Daines CL, et al. Eur Respir J. 2023. PMID: 37945033 Free PMC article. Clinical Trial.

Fig. 12c Peter J Barry

The authors note the impressive effects of two recent trials in adults and one in children effective in restoring substantial function in up to 90%of individuals who are heterogenous for Phe508del. They make a number of observations. The trials were only 8-24 weeks long in a condition which is lifelong – although lung improvements were maintained for mean 151weeks. Trtial patients were selected and improvements were slightly less in treated patients in the CF patient registry. Other relevant factors include adherence to modulator therapy and other pulmonary therapies. The absence of lung function decline reported is questionable as some decline occurs even in healthy individuals and chronic inflammation and infection are reduced but not reversed entirely – but perhaps in young children? Some further information is required. Discontinuance overall was 6.7% – most commonly hepatic involvement but mean time of onset 384.6 days after onset so need for low threshold for liver screening.
The effect of a small rise in blood pressure and the increase in BMI will need consideration and following as will the rates of anxiety and depression.
“The trials of ETI confirm the promise of the parent studies, with an unanticipated further optimism generated by the longitudinal lung function data of what is achievable”. Further information on how ETI may affect other aspects of CF care and the extra pulmonary manifestations.
Finally the authors emphasise the problems of providing these effective but extremely costly treatments to all who would benefit. There is an urgent need for collaboration between licensing authorities, the pharmaceutical industry and governments, to ensure every eligible person with CF worldwide receives what should now be determined standard of care.

Dr Peter J Barry is consultant physician Manchester University NHS Foundation Trust and medical lead for the introduction of these preparations at Wythenshawe Hospital, Manchester

Georgene E Hergenroeder, Anna Faino , Gracia Bridges, Lauren E Bartlett , Jonathan D Cogen, Nicole Green , Sharon McNamara , David P Nichols, Kathleen J Ramos. The impact of elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin levels in people with cystic fibrosis. J Cyst Fibros. 2023 Aug 8;S1569-1993(23)00869-X. doi: 10.1016/j.jcf.2023.08.002. Online ahead of print.37563007 pubmed.ncbi.nlm.nih.gov/37563007

Georgene W Hergenroeder
UTHealth

This study aims to evaluate ETI’s impact on vitamin A, D, E, and international normalized ratio (INR, an indirect marker for Vitamin K) serum levels
Results: Two hundred and sixty-four participants met study inclusion, and 169 (64%) had post-ETI initiation vitamin levels. Median vitamin A levels increased from 422.0 to 471.0 mcg/L (p < 0.001), median vitamin D levels increased from 28.5 to 30.8 ng/mL (p = 0.003), and there were no significant changes in median vitamin E or INR. Vitamin A levels rose at a rate of 40.7 mcg/L/year (CI 11.3, 70.2) after ETI star
Conclusions: ETI initiation is associated with increased median vitamin A and vitamin D levels, but no change in median vitamin E or INR levels. Ongoing monitoring of vitamin levels after ETI initiation is needed to screen for potential deficiencies and toxicities, particularly in light of case reports of hypervitaminosis A following ETI initiation.

Dr Georgene E Hergenroeder (31) is in the Division of Pulmonary and Sleep Medicine, Seattle Children’s Hospital; Department of Pediatrics, University of Washington.

Margarete Olivier , Alexandra Kavvalou, Matthias Welsner, Raphael Hirtz, Svenja Straßburg, Sivagurunathan Sutharsan, Florian Stehling, Mathis Steindor. Real-life impact of highly effective CFTR modulator therapy in children with cystic fibrosis.Front Pharmacol
. 2023 May 9;14:1176815. doi: 10.3389/fphar.2023.1176815. eCollection 2023. pubmed.ncbi.nlm.nih.gov/37229253/

Margarete Olivier

Objective: To assess the intermediate term effects of elexacaftor/tezacaftor/ivacaftor in children with cystic fibrosis in a real-world setting. Methods: We performed a retrospective analysis of records of children with cystic fibrosis, who started elexacaftor/tezacaftor/ivacaftor between 8/2020 and 10/2022.
(Full details in PubMed link above)
Conclusion: In a real-world setting, elexacaftor/tezacaftor/ivacaftor therapy had beneficial clinical effects and a good safety profile in eligible children with cystic fibrosis comparable to previously published data from controlled clinical trials. The positive impact on pulmonary function tests and nutritional status seen after 3 months of elexacaftor/tezacaftor/ivacaftor therapy was sustained at 6 months follow-up.

Dr Margarete Olivier is at Pediatric Pulmonology and Sleep Medicine, Cystic Fibrosis Center, Children’s Hospital, University of Duisburg-Essen, Essen, Germany.

Hisham Ibrahim , Hammad Danish , David Morrissey, Kevin F Deasy , Mairead McCarthy , James Dorgan , Claire Fleming, Ciara Howlett , Sarah Twohig , Tamara Vagg , Desmond M Murphy , Michael Maher, Barry J Plant. Individualized approach to elexacaftor/tezacaftor/ivacaftor dosing in cystic fibrosis, in response to self-reported anxiety and neurocognitive adverse events: A case series.Front Pharmacol. 2023 Apr 27;14:1156621. doi: 10.3389/fphar.2023.1156621. eCollection 2023 Free PMC article pubmed.ncbi.nlm.nih.gov/37180712/

Fig 33 Hisham Ibrahim
3cf.ie

The prevalence of mental health disorders is high among people with Cystic Fibrosis. The psychological symptoms in CF are associated with poor adherence, worse treatment outcomes, and greater health utilization/cost. Mental health and neurocognitive Adverse Events (AEs) have been reported with all available Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators in small groups of patients. We report our experience with a dose reduction strategy in 10 of our patients on elexacaftor/tezacaftor/ivacaftor (7.9% of total number of patients) who self-reported developing intense anxiety, irritability, sleep disturbance and/or mental slowness after initiation of full dose treatment. Standard dose elexacaftor/tezacaftor/ivacaftor resulted in 14.3 points improvement in mean Percent Predicted Forced Expiratory Volume in 1 s (ppFEV1), and a mean difference in sweat chloride of -39.3 mmol/L. We initially discontinued and/or reduced therapy according to the AEs severity, with a subsequent planned dose escalation every 4-6 weeks guided by sustainability of clinical effectiveness, absence of AEs recurrence, and patients’ preferences. Clinical parameters including lung function and sweat chloride were monitored for up to 12 weeks to assess ongoing clinical response to the reduced dose regimen. Dose reduction resulted in resolution of self-reported mental/psychological AEs, without loss of clinical effectiveness (ppFEV1 was 80.7% on standard dose, and 83.4% at 12 weeks on reduced dose; sweat chloride was 33.4 and 34 mmol/L on standard and reduced dose, respectively). Furthermore, in a subgroup of patients who completed 24 weeks of the reduced dose regimen, repeat low dose Computed Tomography imaging showed a significant response when compared to pre-initiation of elexacaftor/tezacaftor/ivacaftor.

Dr Hisham Ibrahim (fig 33) is a consultant Respiratory Physician at the Cork Centre for Cystic Fibrosis (3CF), Cork University Hospital, University College Cork, Cork, Ireland.and the HRB Clinical Research Facility, University College Cork, Cork, Ireland.

Thomas Keens, Veena Hoffman , Ia Topuri , Ken Elder , Shannon Cerf , Kyra Mulder et al and the VX19-CFD-003 Study Group. Real-world effectiveness of elexacaftor/tezacaftor/ivacaftor on the burden of illness in adolescents and adults with cystic fibrosis. Heliyon
. 2024 Mar 26;10(7):e28508. doi: 10.1016/j.heliyon.2024.e28508. eCollection 2024 Apr 15. pubmed.ncbi.nlm.nih.gov/38586424/

Thomas Keens
Children’s Hospital LA

Background: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) aged ≥2 years. Here, we describe results from an observational study assessing change in burden of illness following initiating ELX/TEZ/IVA in real-world settings.
Methods: This US-based, multicenter, observational study used data from electronic medical records to evaluate real-world burden of illness before and after ELX/TEZ/IVA initiation in people with CF aged ≥12 years heterozygous for F508del and a minimal function mutation (F/MF) or an uncharacterized CFTR mutation. Endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 s (ppFEV1), body mass index (BMI) and BMI-for-age z-score, glycated hemoglobin (HbA1c), and numbers of pulmonary exacerbations (PEx).
Results: Overall, 206 people with CF were enrolled (mean [SD] age 22.5 [11.1] years; 192 [93.2%] with F/MF genotype). Mean follow-up was 15.6 (SD, 1.6) months. Improvements in ppFEV1 (7.3 [95% CI: 5.7, 8.8] percentage points) were observed from baseline through follow-up. Increases in BMI (1.40 [95% CI: 1.07, 1.77] kg/m2) and BMI-for-age z-score (0.14 [95% CI: 0.00, 0.28]) were also observed from baseline at 12 months. The estimated annualized rate of any PEx was 1.31 at baseline and 0.61 over follow-up (rate ratio 0.47 [95% CI: 0.39, 0.55]), with annualized rates of PEx requiring antibiotics and hospitalizations of 0.55 and 0.88 in the baseline period and 0.12 and 0.36 over follow-up (rate ratios 0.22 [95% CI: 0.15, 0.31] and 0.41 [95% CI: 0.32, 0.51]), respectively. Absolute change in HbA1c was -0.22 (95% CI: -0.38, -0.06) from baseline through follow-up.
Conclusions: ELX/TEZ/IVA treatment was associated with improved lung function, increased BMI, reduced frequency of PEx, and improved (i.e., reduced) HbA1c. These results confirm the broad clinical benefits of ELX/TEZ/IVA seen in clinical trials and show the potential for ELX/TEZ/IVA to improve maror of the CF Centrekers of glucose metabolism.

Thomas Keens is Director of the CF Center at the Children’s Hospital Los Angeles

Stephanie Kuek, Angela McCullagh, Eldho Paul, David Armstrong. Real world outcomes of CFTR modulator therapy in Australian adults and children. Pulm Pharmacol Ther. 2023 Aug 11;102247. doi: 10.1016/j.pupt.2023.102247. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37574040/
Background: Recent advances in CFTR modulator therapy have the potential to change the face of cystic fibrosis (CF). This retrospective observational study describes real world experience of the four available CFTR modulators in adults and children with CF in a single centre in Melbourne, Australia.
Method: Data was collected for all patients treated with CFTR modulators at MonashCF between May 2012 and September 2020. Primary outcomes included lung function, admission days and BMI/BMI centile over time. Adverse events and reasons for changing or ceasing medications were also analysed.
Results: 55% (74/133) adult and 46% (55/119) paediatric patients were treated with CFTR modulators. FEV1 increased in adults treated with ivacaftor (IVA) and elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) by 4.73% and 10.07% respectively, and BMI also improved in these groups. Nutrition improved in adults and children treated with lumacaftor/ivacaftor (LUM/IVA). There was no significant improvement in FEV1 or admission days with LUM/IVA or tezacaftor/ivacaftor (TEZ/IVA). 36% (31/85) ceased LUM/IVA, due to adverse effects in 81% (25/31). Of these, 92% (23/25) changed to TEZ/IVA, 78% (18/23) without significant adverse effects.

Conclusions: Our findings for LUM/IVA and TEZ/IVA are less encouraging than those seen in clinical trials, with no significant improvement in lung function or admission days and a higher rate of adverse effects with LUM/IVA compared with phase 3 clinical trials. TEZ/IVA was generally well tolerated by those who experienced side effects with LUM/IVA. The small number of patients treated with ELX/TEZ/IVA had improvements in all parameters. These findings support ongoing use of IVA for individuals with gating mutations, and transition to ELX/TEZ/IVA once available for patients with at least one Phe508del mutation.Department of Respiratory Medicine, Monash Children’s Hospital, 246 Clayton Road, Clayton, VIC, 3168, Australia.

Stephanie Kuek in the Department of Respiratory Medicine, Monash Children’s Hospital, 246 Clayton Road, Clayton, VIC, 3168, Australia.

Fig 33 Hisham Ibrahim
3cf.ie

Thomas Keens
Children’s Hospital LA

Thomas Keens is Director of the CF Center at the Children’s Hospital Los Angeles

Stephanie Kuek in the Department of Respiratory Medicine, Monash Children’s Hospital, 246 Clayton Road, Clayton, VIC, 3168, Australia.

Caoimhe McParland, Matthew Nunn, Theodore K Marras, Meredith Chiasson. Eradication of Mycobacterium abscessus infection in cystic fibrosis with initiation of Elexacaftor/Tezacaftor/Ivacaftor. Case Reports J Cyst Fibros
. 2023 Apr 17;S1569-1993(23)00095-4. doi: 10.1016/j.jcf.2023.03.021. Online ahead of print pubmed.ncbi.nlm.nih.gov/37076409/
Mycobacterium abscessus is a nontuberculous mycobacterium that is often multi-drug resistant, difficult to eradicate and associated with a rapid decline in lung function in cystic fibrosis (CF). Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a combination CFTR modulator that improves lung function and decreases exacerbations, but limited data exists about its impact on respiratory infections. A 23-year-old male with CF (F508del, unknown) was diagnosed with Mycobacterium abscessus subspecies abscessus infection. He completed 12-weeks of intensive therapy, followed by oral continuation therapy. Antimicrobials were later discontinued for optic neuritis secondary to linezolid. He remained off antimicrobials with persistently positive sputum cultures. He then initiated ETI, and bronchoscopy eight months later suggested eradication of M. abscessus. By modulating CFTR protein function, ETI may improve innate airway defence mechanisms, facilitating the clearance of infections such as M. abscessus. This case highlights the potential positive implications of ETI on the challenging treatment of M. abscessus infections in CF.

Caoimhe McParland is a respirologist and professor in the Department of Medicine, Dalhousie University, Halifax, NS, Canada

Paul McNally , Barry Linnane, Michael Williamson , Basil Elnazir, Christopher Short , Clare Saunders , Laura Kirwan , Rea David , Mariette P C Kemner-Van de Corput 8 , Harm A W M Tiddens , Jane C Davies , Des W Cox. The clinical impact of Lumacaftor-Ivacaftor on structural lung disease and lung function in children aged 6-11 with cystic fibrosis in a real-world setting. Respir Res. 2023 Aug 11;24(1):199. doi: 10.1186/s12931-023-02497-0. Free PMC article pubmed.ncbi.nlm.nih.gov/37568199/
Background: Data from clinical trials of lumacaftor-ivacaftor (LUM-IVA) demonstrate improvements in lung clearance index (LCI) but not in FEV1 in children with Cystic Fibrosis (CF) aged 6-11 years and homozygous for the Phe508del mutation. It is not known whether LUM/IVA use in children can impact the progression of structural lung disease. We sought to determine the real-world impact of LUM/IVA on lung structure and function in children aged 6-11 years.
Methods: This real-world observational cohort study was conducted across four paediatric sites in Ireland over 24-months using spirometry-controlled CT scores and LCI as primary outcome measures. Children commencing LUM-/IVA as part of routine care were included. CT scans were manually scored with the PRAGMA CF scoring system and analysed using the automated bronchus-artery (BA) method. Secondary outcome measures included rate of change of ppFEV1, nutritional indices and exacerbations requiring hospitalisation.
Results: Seventy-one participants were recruited to the study, 31 of whom had spirometry-controlled CT performed at baseline, and after one year and two years of LUM/IVA treatment. At two years there was a reduction from baseline in trapped air scores (0.13 to 0.07, p = 0.016), but an increase from baseline in the % bronchiectasis score (0.84 to 1.23, p = 0.007). There was no change in overall % disease score (2.78 to 2.25, p = 0.138). Airway lumen to pulmonary artery ratios (AlumenA ratio) were abnormal at baseline and worsened over the course of the study. In 28 participants, the mean annual change from baseline LCI2.5 (-0.055 (-0.61 to 0.50), p = 0.85) measurements over two years were not significant. Improvements from baseline in weight (0.10 (0.06 to 0.15, p < 0.0001), height (0.05 (0.02 to 0.09), p = 0.002) and BMI (0.09 (0.03 to 0.15) p = 0.005) z-scores were seen with LUM/IVA treatment. The mean annual change from baseline ppFEV1 (-2.45 (-4.44 to 2.54), p = 0.66) measurements over two years were not significant.

Conclusion: In a real-world setting, the use of LUM/IVA over two years in children with CF aged 6-11 resulted in improvements in air trapping on CT but worsening in bronchiectasis scores. Our results suggest that LUM/IVA use in this age group improves air trapping but does not prevent progression of bronchiectasis over two years of treatment.

Dr Paul McNally (fig.44 below) is Professor in the Respiratory Department, Children’s Health Ireland, Crumlin, Dublin, Ireland. and the RCSI University of Medicine and Health Sciences, Dublin, Irelan

Paul McNally, Karen Lester , Gavin Stone , Basil Elnazir , Michael Williamson , Des Cox, Barry Linnane, Laura Kirwan , David Rea , Paul O’Regan , Tom Semple , Clare Saunders , Harm A W M Tiddens, Edward McKone, Jane C Davies. Improvement in Lung Clearance Index and Chest CT Scores with Elexacaftor/Tezacaftor/Ivacaftor Treatment in People with Cystic Fibrosis Aged 12 Years and Older – The RECOVER Study. Am J Respir Crit Care Med. 2023 Sep 13. doi: 10.1164/rccm.202308-1317OC. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37568199/

Fig 44 Paul McNally RCSI.com

Rationale: Clinical trials have shown that use of Elexacaftor/Tezacaftor/Ivacaftor (ETI) is associated with improvements in sweat chloride, pulmonary function, nutrition and quality of life in people with CF. Little is known about the impact of ETI on ventilation inhomogeneity and lung structure.
Objectives: RECOVER is a real-world study, designed to measure the impact of ETI in people with CF. The primary endpoints were lung clearance (LCI2.5) and FEV1. Secondary endpoints included spirometry-controlled chest CT scores.
Methods: The study was conducted in seven sites in Ireland and the UK. Participants 12 years and older homozygous for the F508del mutation (F508del/F508del)) or heterozygous for F508del and a minimum function mutation (F508del/MF) were recruited prior to starting ETI and followed up over 12 months. LCI2.5 was measured using nitrogen multiple breath washout (MBW) at baseline, 6 and 12 months. Spirometry was performed as per ERS/ATS criteria. Spirometry controlled Chest CT scans were performed at baseline and 12 months. CT scans were scored using the Perth Rotterdam Annotated Grid Morphometric Analysis (PRAGMA) system. Other outcome measures include weight, height, Cystic Fibrosis Quality of Life, Revised (CFQ-R) questionnaire and sweat chloride.
Measurements and main results: 117 people with CF aged 12 and above were recruited to the study. Significant improvements were seen in LCI (-2.5, 95%CI -3.0, -2.0) and ppFEV1 (8.9, 95%CI 7.0 – 10.9), ppFVC (6.6, 95%CI 4.9 – 8.3) and ppFEF25-75% (12.4, 95%CI 7.8 – 17.0). Overall PRAGMA-CF scores reflecting airways disease (-3.46 , 95%CI -5.23 , -1.69). Scores for trapped air, mucus plugging and bronchial wall thickening improved significantly, but bronchiectasis scores did not. Sweat chloride levels decreased in both F508del/F508del (-43.1, 95%CI -47.4, -38.9) and F508del/MF (-42.8, 95%CI -48.5, -37.2) groups. CFQ-R Respiratory Domain (RD) scores improved by 14.2 points (95%CI 11.3, 17.2). At one year, sweat chloride levels were significantly lower in the F508del/F508del group compared to the F508del/MF group (33.93 v. 53.36, p<0.001).

Conclusions: ETI is associated with substantial improvements in LCI2.5, spirometry and PRAGMA-CF CT scores in people with CF aged 12 years and older. ETI led to improved nutrition and quality of life. People in the F508del/F508del group have significantly lower sweat chloride on ETI treatment compared to the F508del/MF group. Clinical trial registration available at www.

Dr Paul McNally (Fig 44) is Professor in the Respiratory Department, Children’s Health Ireland, Crumlin, Dublin, Ireland. and the RCSI University of Medicine and Health Sciences, Dublin, Ireland.

Peter G Middleton, Nicholas J Simmonds. Cystic fibrosis modulator therapy can reverse cystic bronchiectasis. Respirol Case Rep. 2023 Jun 12;11(7):e01172. doi: 10.1002/rcr2.1172. eCollection 2023 Jul. Free PMC article. pubmed.ncbi.nlm.nih.gov/37323158/

Fig 45 Peter Middleton
Author’s photo

Bronchiectasis is often considered progressive and irreversible, so cases of regression or reversal are an important step in understanding the underlying pathophysiological mechanisms. Cystic fibrosis, (CF) caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been a success story in personalized medicine. The recent development of CFTR modulator therapies has revolutionized care. Dramatic improvements in lung function, sputum production, daytime functioning, and quality of life are seen within weeks. However, the effect of long-term exposure to elexacaftor + tezacaftor + ivacaftor (ETI) on the structural abnormalities is at present unknown. This case series (see free PMC article) outlines three adults with CF who have demonstrated progressive improvement in the cylindrical, varicose and importantly cystic changes of bronchiectasis with prolonged ETI treatment. This raises the exciting question of reversibility of bronchiectasis as well as the mechanisms involved in the maintenance and progression of bronchiectasis as it relates to CF.

Prof. Peter Middleton (fig 45) is at the CF Service, Department Respiratory & Sleep Medicine Westmead Hospital Sydney New South Wales Australia and Westmead Clinical School University of Sydney Sydney New South Wales Australia.

Fig 49 Margarete Olivier kinderaerzte-am-handelshof.de/

Dr Margarete Olivier (fig 49) is at Pediatric Pulmonology and Sleep Medicine, Cystic Fibrosis Center, Children’s Hospital, University of Duisburg-Essen, Essen, Germany.

Sara Immacolata Orsini, Edoardo Marrani, Ilaria Pagnini, Giovanni Taccetti , Vito Terlizzi , Gabriele Simonini. Concomitant Use of Elexacaftor/Tezacaftor/Ivacaftor and Etanercept in a Cystic Fibrosis Patient with Juvenile Idiopathic Arthritis. Case Reports J Clin Med. 2023 Feb 21;12(5):1730. doi: 10.3390/jcm12051730. Free PMC article pubmed.ncbi.nlm.nih.gov/36902517/

Fig 50 Sara Orsini
LinkedIn

Patients with cystic fibrosis often complain of joint manifestations. However, only a few studies have reported the association between cystic fibrosis and juvenile idiopathic arthritis and addressed the therapeutic challenges of these patients. We describe the first paediatric case of a patient affected by cystic fibrosis, Basedow’s disease and juvenile idiopathic arthritis who was contemporarily treated with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) and anti-tumor necrosis factor α (anti-TNFα). This report seems to reassure regarding the potential side effects of these associations. Moreover, our experience suggests that anti-TNFα is an effective option in CF patients affected by juvenile idiopathic arthritis, and is even safe for children receiving a triple CFTR modulator.

Sara Immacolata Orsini (fig 50) is in the Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy.

Nikita Padmakumar, Haji Sheeraz Khan. A foetus with cystic fibrosis – To treat or not to treat? Respir Med Res. 2023 Mar 5;83:101006. doi: 10.1016/j.resmer.2023.101006. Online ahead of print. Free article pubmed.ncbi.nlm.nih.gov/37037055/
Background: Cystic fibrosis (CF) is an autosomal recessive health condition caused by gene mutations causing quantitative and or qualitative defect in the cystic-fibrosis transmembrane conductance regulator (CFTR) protein. CFTR defects lead to abnormal ion transport affecting multiple body systems. In CF thick secretions accumulate causing impairment in the pancreas, whole airways, gut and reproductive organs.
Cftr modulators and pregnancy: CFTR modulators have improved the quantity and quality of life of CF patients. There is limited literature on CFTR modulator use in pregnancy and its impact on foetal health. A recent case report described a child with CF being born with pancreatic sufficiency following in-utero CFTR modulator exposure. We review the potential impact of in-utero exposure to CFTR modulators, focusing on pancreatic function and future fertility of unborn individuals with CF.

Conclusion: CFTR modulator exposure in-utero is a new concept, therefore the consequences on foetal health remain uncertain. Foetal exposure to modulators could prevent pancreatic damage and infertility.

Nikita Padmakumar is in the Department of Paediatrics, Hull University Teaching Hospitals, NHS Trust, Hull HU3 2JZ, UK.

— There is a useful review of the present information on the use of modulators during pregnancy.

Linus Piehler, Ralf Thalemann, Christine Lehmann, Stephanie Thee, Jobst Röhmel, Zulfiya Syunyaeva, Mirjam Stahl, Marcus A Mall, Simon Y Graeber Effects of elexacaftor/tezacaftor/ivacaftor therapy on mental health of patients with cystic fibrosis. Front Pharmacol. 2023 Apr 21;14:1179208. doi: 10.3389/fphar.2023.1179208. eCollection 2023. pubmed.ncbi.nlm.nih.gov/37153809/#full-view-affiliation-3
Introduction: The CFTR modulator drug elexacaftor/tezacaftor/ivacaftor (ETI) was shown to improve CFTR function and clinical symptoms in patients with cystic fibrosis (CF) with at least one F508del allele. Recently, some case reports suggested potential side effects of ETI on mental health with an increase in depressive symptoms and even suicide attempts in patients with CF. However, the general effects of this triple combination therapy on the mental health status of patients with CF remain largely unknown.
Methods: We, therefore, performed a prospective, observational study in a real-life setting and investigated the relationship between initiation of ETI therapy and changes in mental health in adult patients with CF. We assessed Cystic Fibrosis Questionnaire-Revised (CFQ-R), Patient Health Questionnaire-9 (PHQ-9), Beck’s Depression Inventory – Fast Screen (BDI-FS) and Generalized Anxiety Disorder 7-item Scale (GAD-7) at baseline and 8-16 weeks after initiation of ETI. Results: In total, 70 adult patients with CF with at least one F508del allele and a median age of 27.9 years were recruited. After initiation of ETI, the CFQ-R respiratory domain score improved by 27.9 (IQR 5.6 to 47.2; p < 0.001). The PHQ-9 score of depressive symptoms decreased by 1.0 (IQR -3.0 to 0.3; p < 0.05) with an increase of 16.9% in the group with a minimal score after initiation of ETI and a decrease in the groups of mild (-11.3%) or moderate (-5.7%) scores compared to baseline. The BDI-FS score of depressive symptoms decreased from 1.0 (IQR 0.0-2.0) at baseline to 0.0 (IQR 0.0 to 2.0; p < 0.05) after initiation of ETI. The group with a minimal BDI-FS score increased by 8.0% after initiation of ETI, whereas the groups with mild (-4.9%), moderate (-1.6%) or severe (-1.6%) scores decreased compared to baseline. The GAD-7 score of anxiety symptoms did not change after initiation of ETI compared to baseline (0.0; IQR -2.0. to 0.0; p = 0.112).
Conclusion: Initiation of ETI improves symptoms of depression in adult patients with CF with at least one F508del allele. However, symptoms of anxiety do not change after short-term therapy with ETI.

Linus Piehler is in the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

— This is reassuring but there is the occasional report of an individual who appears to have developed significant mental disturbance after starting ETI treatment.

Fig.53 Debanjali Purkayastha

LinkedIn

Debanjali Purkayastha (fig 53) is a Pharmacy Resident at the University of Waterloo, Kitchener, ON, Canada.

Ramsey ML; Li SS; Lara LF; Gokun Y; Akshintala VS; Conwell DL; Heintz J;Kirkby SE; McCoy KS; Papachristou GI; Patel A; Singh VK; Hart PA.Cystic fibrosis transmembrane conductance regulator modulators and the exocrine pancreas: A scoping review. [Review]. Journal of Cystic Fibrosis. 22(2):193-200, 2023 03.pubmed.ncbi.nlm.nih.gov/36008229/

Fig 54 Mitchell Ramsey

Wexner medical center

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR)
modulators improve pulmonary outcomes in subjects with cystic fibrosis (CF); however, the effects on pancreatic manifestations are not well characterized. We hypothesized that CFTR modulators would improve measure of exocrine pancreatic function and outcomes.
METHODS: We performed a systematic search to identify studies reporting measures of the exocrine pancreas in humans treated with CFTR modulators.Only studies reporting baseline and on-treatment assessments were included. Of 630 identified studies, 41 met inclusion criteria.
Full results in PubMed link
CONCLUSION. CFTR modulator use reduces acute pancreatitis frequency and
improves indirect measures of exocrine pancreas function. The authors consider future interventional studies that evaluate the mechanism and impact of CFTR
modulators on acute pancreatitis and pancreas sufficiency in patients with CFTR dysfunction are warranted.

Dr Mitchell L Ramsey (fig 54) is Clinical Assistant Professor in the. Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH,
USA.

Ido Sadras, Malena Cohen-Cymberknoh, Eitan Kerem, Benjamin Z Koplewitz , Natalia Simanovsky, Michael Wilschanski, Liron Birimberg-Schwartz, Oded Breuer. Acute pancreatitis in pancreatic-insufficient cystic fibrosis patients treated with CFTR modulators. Case Reports J Cyst Fibros. 2023 Mar 11;S1569-1993(23)00064-4. doi: 10.1016/j.jcf.2023.02.013. Online ahead of print pubmed.ncbi.nlm.nih.gov/36914434/
Cystic fibrosis transmembrane conductance regulator modulator therapy is associated with substantial clinical benefit and improved quality of life in patients with cystic fibrosis (CF). While their effect on lung function has been clearly reported, we are still in the process of unraveling the full impact they have on the pancreas. We present two cases of pancreatic-insufficient CF patients who presented with acute pancreatitis shortly after commencing elexacaftor/tezacaftor/ivacaftor modulator therapy. Both patients were treated with ivacaftor for 5 years prior to elexacaftor/tezacaftor/ivacaftor initiation, but had no previous episodes of acute pancreatitis. We suggest that highly effective modulator combination therapy may restore additional pancreatic acinar activity, resulting in the development of acute pancreatitis in the interim until ductal flow is improved. This report adds to the growing evidence for possible restoration of pancreatic function in patients receiving modulator therapy, and highlights that treatment with elexacaftor/tezacaftor/ivacaftor may be associated with acute pancreatitis until ductal flow is restored, even in pancreatic-insufficient CF patients.

Ido Sadras is at the CF Center, Department of Pediatrics, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.

Laura Schaupp, Annalisa Addante, Mirjam Völler, Kerstin Fentker, Aditi Kuppe, Markus Bardua, Julia Duerr, Linus Piehler, Jobst Röhmel, Stephanie Thee, Marieluise Kirchner, Matthias Ziehm, Daniel Lauster, Rainer Haag, Michael Gradzielski, Mirjam Stahl , Philipp Mertins, Sébastien Boutin, Simon Y Graeber, Marcus A Mall. Longitudinal Effects of Elexacaftor/Tezacaftor/Ivacaftor on Sputum Viscoelastic Properties, Airway Infection and Inflammation in Patients with Cystic Fibrosis. Eur Respir J
. 2023 Jul 6;2202153. doi: 10.1183/13993003.02153-2022. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37414422/

Fig 58 Laura Schaupp

Charite-ppi.de

Background: Recent studies demonstrated that the triple combination CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and reduces pulmonary exacerbations in CF patients with at least one F508del allele. However, effects of ETI on downstream consequences of CFTR dysfunction, i.e. abnormal viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. The aim of this study was, therefore, to determine the longitudinal effects of ETI on airway mucus rheology, microbiome and inflammation in CF patients with one or two F508del alleles aged 12 years and older throughout the first 12 months of therapy.
Methods: In this prospective observational study, we assessed sputum rheology, the microbiome, inflammation markers and proteome before and 1, 3 and 12 months after initiation of ETI.
Results: In total, 79 patients with CF and at least one F508del allele and 10 healthy controls were enrolled in this study. ETI improved the elastic modulus and viscous modulus of CF sputum at 3 and 12 months after initiation (all p<0.01). Further, ETI decreased the relative abundance of Pseudomonas aeruginosa in CF sputum at 3 months and increased the microbiome α-diversity at all timepoints. ETI also reduced IL-8 at 3 months (p<0.05) and free NE activity at all timepoints (all p<0.001), and shifted the CF sputum proteome towards healthy.

Conclusions: Our data demonstrate that restoration of CFTR function by ETI improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one F508del allele over the first 12 months of therapy, however, without reaching levels close to healthy.

Dr Laura Schaupp (fig 58) is in the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany and the German Center for Lung Research (DZL), associated partner site, Berlin, Germany.

L Schembri, S Warraich, S Bentley, S B Carr, I M Balfour-Lynn. Impact of elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin levels in children with cystic fibrosis. J Cyst Fibros 2023 May 2;S1569-1993(23)00125-X. doi: 10.1016/j.jcf.2023.04.019. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/37142523/

Fig. 59 Laura Schembri
LinkedIn

Background: Children with cystic fibrosis are at risk of fat-soluble vitamin deficiency. CFTR modulators positively affect nutritional status. This study aimed to assess changes in serum vitamins A, D & E after starting ETI therapy to ensure levels were not abnormally high.
Methods: Retrospective review of annual assessment data over 3½ years, before and after starting ETI in a specialist paediatric CF centre, including vitamin levels.
Results: 54 eligible patients were included, aged 5-15 yrs (median age 11.5). Median time to post measurements was 171 days. Median vitamin A was increased (1.38 to 1.63 µmol/L, p<0.001). Three patients (6%) had high vitamin A post-ETI, compared with none at baseline; and 2 (4%) had low levels compared to 4 (8%) at baseline. No changes in vitamins D&E.

Conclusions: This study found increased vitamin A, sometimes to high levels. We recommend testing levels within 3 months of starting ETI

Laura Schembri (fig 59) is in the Department of Paediatric Dietetics, Royal Brompton Hospital, London, UK.

Mathias Schenkel , Dorna Ravamehr-Lake , Tomasz Czerniak , James P Saenz , Georg Krainer , Michael Schlierf , Charles M Deber. Impact of cholesterol and Lumacaftor on the folding of CFTR helical hairpins. Biochim Biophys Acta Biomembr. 2023 Jan 1;1865(1):184078. doi: 10.1016/j.bbamem.2022.184078. Epub 2022 Oct 22. pubmed.ncbi.nlm.nih.gov/36279907/

Fig. 60 Mathias Schenkel

Research Portal TU Dresden

Cystic fibrosis (CF) is caused by mutations in the gene that codes for the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR). Recent advances in CF treatment have included use of small-molecule drugs known as modulators, such as Lumacaftor (VX-809), but their detailed mechanism of action and interplay with the surrounding lipid membranes, including cholesterol, remain largely unknown. To examine these phenomena and guide future modulator development, we prepared a set of wild type (WT) and mutant helical hairpin constructs consisting of CFTR transmembrane (TM) segments 3 and 4 and the intervening extracellular loop (termed TM3/4 hairpins) that represent minimal membrane protein tertiary folding units. These hairpin variants, including CF-phenotypic loop mutants E217G and Q220R, and membrane-buried mutant V232D, were reconstituted into large unilamellar phosphatidylcholine (POPC) vesicles, and into corresponding vesicles containing 70 mol% POPC +30 mol% cholesterol, and studied by single-molecule FRET and circular dichroism experiments. We found that the presence of 30 mol% cholesterol induced an increase in helicity of all TM3/4 hairpins, suggesting an increase in bilayer cross-section and hence an increase in the depth of membrane insertion compared to pure POPC vesicles. Importantly, when we added the corrector VX-809, regardless of the presence or absence of cholesterol, all mutants displayed folding and helicity largely indistinguishable from the WT hairpin. Fluorescence spectroscopy measurements suggest that the corrector alters lipid packing and water accessibility. We propose a model whereby VX-809 shields the protein from the lipid environment in a mutant-independent manner such that the WT scaffold prevails. Such ‘normalization’ to WT conformation is consistent with the action of VX-809 as a protein-folding chaperone.

Mathias Schenkel (fig 60) is at CUBE – Center for Molecular Bioengineering, TU Dresden, Tatzberg 41, 01307 Dresden, Germany

Schwarzenberg SJ; Vu PT; Skalland M; Hoffman LR; Pope C; Gelfond D;
Narkewicz MR; Nichols DP; Heltshe SL; Donaldson SH; Frederick CA; Kelly A;
Pittman JE; Ratjen F; Rosenfeld M; Sagel SD; Solomon GM; Stalvey MS;
Clancy JP; Rowe SM; Freedman SD. Elexacaftor/tezacaftor/ivacaftor and gastrointestinal outcomes in cystic fibrosis: Report of promise-GI. Journal of Cystic Fibrosis. 22(2):282-289, 2023 03. pubmed.ncbi.nlm.nih.gov/36280527/

Fig. 62 Sarah Jane Schwarzenberg

HealthFiarview

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary
disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear.
METHODS: PROMISE is a 56-center prospective, observational study of ETI
in PwCF >12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires. Fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation.
Full details on the PubMed link
CONCLUSIONS: After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve.

Dr Sarah Jane Schwarzenberg (Fig 62) is Professor in the Department of Pediatrics, University of Minnesota Masonic Children’s Hospital, Academic Office Building, 2450 Riverside Ave S AO-201, Minneapolis.

Nikita Padmakumar is in the Department of Paediatrics, Hull University Teaching Hospitals, NHS Trust, Hull HU3 2JZ, UK.

— There is a useful review of the present information on the use of modulators during pregnancy.

Linus Piehler, Ralf Thalemann, Christine Lehmann, Stephanie Thee, Jobst Röhmel, Zulfiya Syunyaeva, Mirjam Stahl, Marcus A Mall, Simon Y GraeberEffects of elexacaftor/tezacaftor/ivacaftor therapy on mental health of patients with cystic fibrosis. Front Pharmacol. 2023 Apr 21;14:1179208. doi: 10.3389/fphar.2023.1179208. eCollection 2023. pubmed.ncbi.nlm.nih.gov/37153809/#full-view-affiliation-3
Introduction: The CFTR modulator drug elexacaftor/tezacaftor/ivacaftor (ETI) was shown to improve CFTR function and clinical symptoms in patients with cystic fibrosis (CF) with at least one F508del allele. Recently, some case reports suggested potential side effects of ETI on mental health with an increase in depressive symptoms and even suicide attempts in patients with CF. However, the general effects of this triple combination therapy on the mental health status of patients with CF remain largely unknown. Methods: We, therefore, performed a prospective, observational study in a real-life setting and investigated the relationship between initiation of ETI therapy and changes in mental health in adult patients with CF. We assessed Cystic Fibrosis Questionnaire-Revised (CFQ-R), Patient Health Questionnaire-9 (PHQ-9), Beck’s Depression Inventory – Fast Screen (BDI-FS) and Generalized Anxiety Disorder 7-item Scale (GAD-7) at baseline and 8-16 weeks after initiation of ETI. Results: In total, 70 adult patients with CF with at least one F508del allele and a median age of 27.9 years were recruited. After initiation of ETI, the CFQ-R respiratory domain score improved by 27.9 (IQR 5.6 to 47.2; p < 0.001). The PHQ-9 score of depressive symptoms decreased by 1.0 (IQR -3.0 to 0.3; p < 0.05) with an increase of 16.9% in the group with a minimal score after initiation of ETI and a decrease in the groups of mild (-11.3%) or moderate (-5.7%) scores compared to baseline. The BDI-FS score of depressive symptoms decreased from 1.0 (IQR 0.0-2.0) at baseline to 0.0 (IQR 0.0 to 2.0; p < 0.05) after initiation of ETI. The group with a minimal BDI-FS score increased by 8.0% after initiation of ETI, whereas the groups with mild (-4.9%), moderate (-1.6%) or severe (-1.6%) scores decreased compared to baseline. The GAD-7 score of anxiety symptoms did not change after initiation of ETI compared to baseline (0.0; IQR -2.0. to 0.0; p = 0.112). Conclusion: Initiation of ETI improves symptoms of depression in adult patients with CF with at least one F508del allele. However, symptoms of anxiety do not change after short-term therapy with ETI.

E de Poel, S Spelier, M C Hagemeijer, P van Mourik, S W F Suen, A M Vonk, J E Brunsveld, G N Ithakisiou, E Kruisselbrink, H Oppelaar , G Berker , K M de Winter de Groot , S Heida-Michel , S R Jans , H van Panhuis , M Bakker , R van der Meer , J Roukema, E Dompeling , E J M Weersink , G H Koppelman , A R Blaazer , J E Muijlwijk-Koezen , C K van der Ent, J M Beekman FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurpsing for rare cystic fibrosis genotypes. J Cyst Fibros. 2023 May 3;S1569-1993(23)00067-X. doi: 10.1016/j.jcf.2023.03.004. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37147251/
Background: Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF.

Methods: We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators.
Results: In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy.
Conclusion: This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies.

One-sentence summary: We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.

Dr Ellen de Poel is in the Department of Pediatric Respiratory Medicine, Wilhelmina Children’s Hospital, University Medical Center, Utrecht University, Utrecht, EA 3584, the Netherlands; Regenerative Medicine Utrecht, University Medical Center, Utrecht University, Utrecht, CT 3584, the Netherlands.

Debanjali Purkayastha
LinkedIn

Debanjali Purkayastha is a Pharmacy Resident at the University of Waterloo, Kitchener, ON, Canada.

Ido Sadras , Malena Cohen-Cymberknoh , Eitan Kerem, Benjamin Z Koplewitz , Natalia Simanovsky, Michael Wilschanski, Liron Birimberg-Schwartz, Oded Breuer. Acute pancreatitis in pancreatic-insufficient cystic fibrosis patients treated with CFTR modulators. Case Reports J Cyst Fibros. 2023 Mar 11;S1569-1993(23)00064-4. doi: 10.1016/j.jcf.2023.02.013. Online ahead of print pubmed.ncbi.nlm.nih.gov/36914434/
Cystic fibrosis transmembrane conductance regulator modulator therapy is associated with substantial clinical benefit and improved quality of life in patients with cystic fibrosis (CF). While their effect on lung function has been clearly reported, we are still in the process of unraveling the full impact they have on the pancreas. We present two cases of pancreatic-insufficient CF patients who presented with acute pancreatitis shortly after commencing elexacaftor/tezacaftor/ivacaftor modulator therapy. Both patients were treated with ivacaftor for 5 years prior to elexacaftor/tezacaftor/ivacaftor initiation, but had no previous episodes of acute pancreatitis. We suggest that highly effective modulator combination therapy may restore additional pancreatic acinar activity, resulting in the development of acute pancreatitis in the interim until ductal flow is improved. This report adds to the growing evidence for possible restoration of pancreatic function in patients receiving modulator therapy, and highlights that treatment with elexacaftor/tezacaftor/ivacaftor may be associated with acute pancreatitis until ductal flow is restored, even in pancreatic-insufficient CF patients.

Ido Sadras is at the CF Center, Department of Pediatrics, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.

Laura Schembri
LinkedIn

Conclusions: This study found increased vitamin A, sometimes to high levels. We recommend testing levels within 3 months of starting ETI

Laura Schembri is in the Department of Paediatric Dietetics, Royal Brompton Hospital, London, UK.

Mathias Schenkel

Mathias Schenkel is at CUBE – Center for Molecular Bioengineering, TU Dresden, Tatzberg 41, 01307 Dresden, Germany

Kevin W Southern, Carlo Castellani, Elise Lammertyn, Alan Smyth, Donald VanDevanter, Silke van Koningsbruggen-Rietschel and 36 authors. Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis. J Cyst Fibros. 2023 Jan;22(1):17-30. doi: 10.1016/j.jcf.2022.10.002. Epub 2022 Oct 28. Free article pubmed.ncbi.nlm.nih.gov/36916675/

Kevin Southern

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF. The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy.
We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF. Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy.

Consensus statements from the group.

1	For individuals with clinical features consistent with CF, disease-causing variants of the CFTRgene are those characterized as “CF-causing” or “varying clinical consequences” by an established and validated program (for example, CFTR2 or CFTR-France).
2	Individuals under consideration for CFTR modulator use should have molecular diagnostic testing of the CFTR gene that includes, at minimum, the most frequent variants known to be CF-causing in their population of origin. Further analysis may include exonic regions, intron-exon junctions, and presence of copy number variants, in the case of incomplete genotype after initial molecular testing.
3	CFTR gene variants should be considered of uncertain clinical significance in the absence of epidemiological or laboratory evidence. These variants should undergo further evaluation to determine their pathogenic or benign status and potential responsiveness to VST.
4	PwCF aged six years and older, with one or two F508del variants, should have daily treatment with triple modulator therapy (elexacaftor-tezacaftor-ivacaftor).
5	PwCF and at least one responsive non-F508del variant should be considered for mono (ivacaftor), dual (tezacaftor-ivacaftor) or triple CFTR modulator therapy (elexacaftor-tezacaftor-ivacaftor).
6	Children with CF with eligible CFTR gene variants should be offered treatment with ivacaftor from 4 months of age.
7	Children with CF who are homozygous for the F508del variant, aged 2–5 years, should be offered treatment with dual modulator therapy (Lumacaftor-ivacaftor).
8	Parent/carers of pre-school children with CF should be aware of the efficacy data and safety profile of VST before treatment start.
9	Before initiating treatment, pwCF and their families should have a detailed discussion with the CF team, outlining the impact of taking CFTR modulator therapy, backed up with written information.
10	Before starting CFTR modulator therapy, a detailed drug history should be obtained and cross checked with prescribing information about potential drug interactions.
11	Patients should be followed up at least every 3 months after initiating CFTR modulator therapy to monitor progress and screen for side effects.
12	CF teams should monitor adherence to CFTR modulator therapy, for example, by using pharmacy dispensing data.
13	Before commencing and once established on a VST, pwCF, in partnership with the physiotherapy team, may need to adapt and optimise their airway clearance technique and sinus treatments.
14	For pwCF starting a VST, the management of CFRD should be reviewed and adapted on an individual basis, considering clinical and nutritional status.
15	PwCF on VST should continue to receive regular monitoring of nutritional status and dietary intake, according to changing energy requirements.
16	Frequency of support of nutritional assessment should be individualized, depending on age, clinical status and CFTR modulator therapy.
17	CF teams should be familiar with the wide-ranging psychological impact of VST and prepare, advise and support pwCF and their caregivers as required, involving the CF psychologist when indicated.
18	Symptoms of depression and anxiety should be assessed pre-VST and no later than 3 months after starting.
19	Prior to initiating VST in women with CF, contraception and fertility should be reassessed, and appropriate counselling provided.
20	The decision to use VST during pregnancy should weigh the risk to maternal health in the event of withholding therapy and the lack of data regarding safety to the foetus.
21	Women treated with VST planning to breastfeed should be informed regarding lack of data on safety during breastfeeding.
22	PwCF and CFTR gene variant(s) with unclear response to modulator therapy should be offered referral to a centre with capacity for ex vivo testing of CFTR response, to potentially establish an individualized treatment plan, including with modulator therapies.
23	All pwCF with non-responsive CFTR gene variants should continue to receive high-quality CF-specialist multi-disciplinary care at a specialist or accredited CF centre.
24	It is important that pwCF and non-responsive CFTR gene variants are informed of clinical trials and supported to participate in trials.
25	For pwCF after solid organ transplant, VST should be considered for eligible patients after discussion of the potential risks and benefits between the patient, the CF team, and the transplant team.
26	For patients with a diagnosis of CFTR-related disorder, there is no evidence to support the use of VST outside of clinical trials.
27	For infants with an unclear diagnosis following newborn screening for CF (CRMS/CFSPID), the use of VST is not indicated.
28	For new high-cost CF therapies, a robust health technology assessment should evaluate the impact on pwCF and society.
29	Evidence used to inform reimbursement decisions using public money should be transparent and available to the public.
30	The CF community should advocate globally for equitable access to new therapies with proven efficacy for all pwCF.

– In this rapidly changing area of CF treatment this is a clear article with agreed consensus guidance on the use of the new modulators. The full article is available via the above PubMed link; it is excellent and throughly recommended.

Kevin W Southern , Jürg Barben, Stephen Goldring, Rachel Kneen, Suzanne Southward, Yashasvi Rajeev, Jane C Davies, Andrew Bush. Raised Intracranial Pressure in Three Children with Cystic Fibrosis Receiving Elexacaftor-Tezacaftor-Ivacaftor Modulator Therapy. Am J Respir Crit Care Med
. 2023 May 9. doi: 10.1164/rccm.202303-0380LE. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37159937/

Prof. Kevin Southern is at the University of Liverpool, Women’s and Children’s Health, Liverpool, Merseyside, United Kingdom of Great Britain and Northern Ireland; kwsouth@liv.ac.uk.

Mirjam Stahl , Jobst Roehmel, Monika Eichinger , Felix Doellinger , Lutz Naehrlich , Matthias V Kopp , Anna-Maria Dittrich , Christopher Lee, Olaf Sommerburg , Simon Tian , Tu Xu , Pan Wu, Aniket Joshi, Partha Ray , Margaret E Duncan , Mark O Wielpütz, Marcus A Mall Effects of Lumacaftor/Ivacaftor on Cystic Fibrosis Disease Progression in Children 2 through 5 Years of Age Homozygous for F508del-CFTR: A Phase 2 Placebo-controlled Clinical Trial. Ann Am Thorac Soc
. 2023 Mar 21. doi: 10.1513/AnnalsATS.202208-684OC. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36943405/

Mirjam Stahl

Rationale: Lumacaftor/ivacaftor (LUM/IVA) was shown to be safe and well tolerated in children 2 through 5 years of age with cystic fibrosis (CF) homozygous for F508del-CFTR in a phase 3 open-label study. Improvements in sweat chloride concentration, markers of pancreatic function, and lung clearance index2.5 (LCI2.5), along with increases in growth parameters, suggested the potential for early disease modification with LUM/IVA treatment.

Objective: To further assess the effects of LUM/IVA on CF disease progression in children 2 through 5 years of age using chest magnetic resonance imaging (MRI).
Methods: This phase 2 study had two parts: a 48-week, randomized, double-blind, placebo-controlled treatment period in which children 2 through 5 years of age with CF homozygous for F508del-CFTR received either LUM/IVA or placebo (Part 1) followed by an open-label period in which all children received LUM/IVA for an additional 48 weeks (Part 2). We report results from Part 1. The primary endpoint was absolute change from baseline in chest MRI global score at Week 48. Secondary endpoints included absolute change in LCI2.5 through Week 48 and absolute changes in weight-for-age, stature-for-age, and body mass index-for-age z-scores at Week 48. Additional endpoints included absolute changes in sweat chloride concentration, fecal elastase-1 levels, serum immunoreactive trypsinogen, and fecal calprotectin through Week 48. The primary endpoint was analyzed using Bayesian methods, where the actual Bayesian posterior probability of LUM/IVA being superior to placebo in the MRI global chest score at Week 48 was calculated using a vague normal prior distribution; secondary and additional endpoints were analyzed using descriptive summary statistics.

Results: Fifty-one children were enrolled and received LUM/IVA (n=35) or placebo (n=16). For the change in MRI global chest score at Week 48, the Bayesian posterior probability of LUM/IVA being better than placebo (treatment difference <0; higher score indicating greater abnormality) was 76%; the mean treatment difference was -1.5 (95% credible interval, -5.5 to 2.6). Treatment with LUM/IVA also led to within-group numerical improvements in LCI2.5, growth parameters, and biomarkers of pancreatic function as well as greater decreases in sweat chloride concentration compared with placebo from baseline through Week 48. Safety data were consistent with the established safety profile of LUM/IVA.

Conclusions: This placebo-controlled study suggests the potential for early disease modification with LUM/IVA treatment, including that assessed by chest MRI, in children as young as 2 years. Clinical trial registered with ClinicalTrials.gov (NCT03625466).

Mirjam Stahl is at the Charité Universitätsmedizin Berlin – Campus Virchow-Klinikum, 72217, Department of Pediatric Pulmonology, Immunology and Critical Care Medicine, Berlin, Germany; German Center for Lung Research (DZL), Berlin, Germany; Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany.

Carmen Streibel

Conclusions: Besides lung function tests, functional and structural MRI is a suitable tool to monitor treatment response of ELX/TEZ/IVA therapy, and seems promising as outcome marker in the future.

Carmen Streibel is in the Dept of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Switzerland.Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Switzerland.

P Tachtatzis, G Spoletini, I Clifton, C Etherington, D Peckham. Changes in liver biochemistry and tacrolimus levels following the introduction of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and liver transplant.J Cyst Fibros. 2023 May 8;S1569-1993(23)00129-7. doi: 10.1016/j.jcf.2023.04.023. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37164896/
Introduction: Elevated liver function tests (LFTs) are reported in individuals with cystic fibrosis (CF) starting elexacaftor/tezacaftor/ivacaftor (ETI). We report our experience with ETI in CF liver transplant patients.
Method: All CF liver transplant patients under the care of the Leeds CF team were commenced on ETI. Liver biopsies were performed when ALT >3 times upper limit of normal with or without bilirubin elevation. Treatment was guided by transplant hepatology and CF teams. Clinical data including lung function, LFTs and tacrolimus levels were collected.
Results: Four patients (3 male, 1 female) on tacrolimus were commenced on ETI. Median time post liver transplantation was 6.5 years. Three patients underwent liver biopsy. One biopsy was abnormal with immune-mediated liver injury, which responded to increased immunosuppression. Management of tacrolimus levels proved straightforward.

Conclusion: ETI therapy in CF post liver transplant recipients was encouraging. Normal liver biopsy provides re-assurance to continue treatment despite elevated LFTs.

Dr Phaedra Tachtatzis is consultant hepatologist at Liver Transplantation & Hepatology, Leeds Teaching Hospitals NHS Trust, Leeds, UK; Regional Adult Cystic Fibrosis Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Daniel H Tewkesbury is at the Manchester University NHS Foundation Trust, Manchester, UK; Division of Immunology, Immunity to Infection & Respiratory Medicine, University of Manchester, Manchester, UK.

Burhard Tummler.Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor-Ivercaftor. Front Pharmacol. 2023 Mar 21;14:1158207. doi: 10.3389/fphar.2023.1158207. eCollection 2023. pubmed.ncbi.nlm.nih.gov/37025483/ Free PMC article

Burkhard Tümmler
Medizinische Hochschule
Hannove

Triple combination therapy with the CFTR modulators elexacaftor (ELX), tezacaftor (TEZ) and ivacaftor (IVA) has been qualified as a game changer in cystic fibrosis (CF). We provide an overview of the body of literature on ELX/TEZ/IVA published between November 2019 and February 2023 after approval by the regulators. Recombinant ELX/TEZ/IVA-bound Phe508del CFTR exhibits a wild type conformation in vitro, but in patient’s tissue a CFTR glyoisoform is synthesized that is distinct from the wild type and Phe508del isoforms. ELX/TEZ/IVA therapy improved the quality of life of people with CF in the real-life setting irrespective of their anthropometry and lung function at baseline. ELX/TEZ/IVA improved sinonasal and abdominal disease, lung function and morphology, airway microbiology and the basic defect of impaired epithelial chloride and bicarbonate transport. Pregnancy rates were increasing in women with CF. Side effects of mental status changes deserve particular attention in the future.. Burkhard Tümmler is at the Dept. of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany and the Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover Medical School, Hannover, Germany.

— This is a comprehensive review of the post approved studies on published work up to the present. The free article is recommended.

Uluer AZ; MacGregor G; Azevedo P; Indihar V; Keating C; Mall MA; McKoneEF; Ramsey BW; Rowe SM; Rubenstein RC; Taylor-Cousar JL; Tullis E; Yonker LM; Chu C; Lam AP; Nair N; Sosnay PR; Tian S; Van Goor F; Viswanathan L; Waltz D; Wang LT; Xi Y; Billings J; Horsley A. Safety and efficacy of vanzacaftor-tezacaftor-deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials. The Lancet Respiratory Medicine. 11(6):550-562, 2023 06. Free article pubmed.ncbi.nlm.nih.gov/36842446/

Ahmet Uluer

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for
once-daily dosing.
METHODS and FINDINGS are included in the PubMed link
INTERPRETATION: Once-daily dosing with vanzacaftor-tezacaftor-deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These
results support the continued investigation of vanzacaftor-tezacaftor-deutivacaftor in phase 3 clinical trials compared with elexacaftor-tezacaftor-ivacaftor.

Dr Ahmet Z.Ukuer is at the Boston Children’s Hospital, Harvard Medical School,
Boston, MA, USA; Brigham & Women’s Hospital CF Center, Boston, MA, USA.

Claire Wainwright, Susanna A McColley, Paul McNally , Michael Powers, Felix Ratjen , Jonathan H Rayment , George Retsch-Bogart , Erica Roesch , Neil Ahluwalia , Anna Chin , Chenghao Chu, Mengdi Lu, Prema Menon, David Waltz 11, Tanya Weinstock, Laura Zelazoski, Jane C Davies; VX19-445-107 Study Group. Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged ≥6 Years with Cystic Fibrosis and At Least One F508del Allele: A Phase 3, Open-Label Clinical Trial. Am J Respir Crit Care Med. 2023 May 8. doi: 10.1164/rccm.202301-0021OC. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37154609/

Claire Wainwright

Rationale: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6 through 11 years with cystic fibrosis and ≥1 F508del-CFTR allele.
Objectives: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial.

Methods: In this phase 3, two-part (Part A and Part B), open-label extension study, children aged ≥6 years with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours while children weighing ≥30 kg received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose). The 96-week analysis of Part A of this extension study is reported here.
Measurements and main results: Sixty-four children (F/MF genotypes, n=36; F/F genotype, n=28) were enrolled and received ≥1 dose of ELX/TEZ/IVA. Mean (SD) period of exposure to ELX/TEZ/IVA was 93.9 (11.1) weeks. The primary endpoint was safety and tolerability. Adverse events and serious adverse events were consistent with common manifestations of cystic fibrosis disease. Overall, exposure-adjusted rates of adverse events and serious adverse events (407.74 and 4.72 events per 100 patient-years) were lower than in the parent study (987.04 and 8.68 events per 100 patient-years). One child (1.6%) had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. From parent study baseline at Week 96 of this extension study, mean ppFEV1 increased (11.2 [95% CI 8.3, 14.2] percentage points), sweat chloride concentration decreased (-62.3 [95% CI 65.9, -58.8] mmol/L), Cystic Fibrosis Questionnaire-Revised respiratory domain score increased (13.3 [95% CI 11.4, 15.1] points), and LCI2.5 decreased (-2.00 [95% CI -2.45, -1.55] units). Increases in growth parameters were also observed. The estimated pulmonary exacerbation rate per 48 weeks was 0.04. The annualized rate of change in ppFEV1 was 0.51 (95% CI -0.73, 1.75) percentage points per year.

Conclusions: ELX/TEZ/IVA continued to be generally safe and well tolerated in children aged ≥6 years through an additional 96 weeks of treatment. Improvements in lung function, respiratory symptoms, and CFTR function observed in the parent study were maintained. These results demonstrate the favorable long-term safety profile and durable clinical benefits of ELX/TEZ/IVA in this pediatric population. Clinical trial registration available at www. Clinicaltrials: gov, ID: NCT04183790.

Prof. Claire Wainwright is at the Royal Children’s Hospital, Respiratory Medicine, Brisbane, Queensland, Australia

Angela Wang, MinJae Lee, Ashley Keller, Sarah Jian, Karen Lowe, James D Finkle , Raksha Jain Sex differences in outcomes of people with cystic fibrosis treated with elexacaftor/tezacaftor/ivacaftor. J Cyst Fibros. 2023 May 25;S1569-1993(23)00139-X. doi: 10.1016/j.jcf.2023.05.009. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37244841/
Background: There is a well described sex-disparity in outcomes of individuals with cystic fibrosis (CF), with females faring worse than males. Given the dramatic improvement in overall health of people with CF using CF transmembrane conductance regulator (CFTR) modulator therapy, elexacaftor/tezacaftor/ivacaftor (ETI), the sex-disparity in CF warrants re-examination.
Methods: We evaluated the effects of ETI use by sex prior to versus after initiation of ETI by pulmonary exacerbations (PEx), percent predicted forced expiratory volume in one second (ppFEV1), presence of Pseudomonas aeruginosa in sputum cultures, and body mass index (BMI). We used univariate and multivariable longitudinal regression adjusting for key confounders, such as age, race, CFTR modulator taken prior to ETI and baseline ppFEV1.
Results: We included 251 individuals started on ETI between January 2014 to September 2022. We collected data for a mean of 5.45 years pre-ETI and 2.38 years post-ETI. We found the adjusted presence of PEx decreased more in males than females pre- to post-ETI with the odds of having a PEx in males being 0.57 (43% reduction) versus females 0.75 (25% reduction) (p = 0.049). We found no statistical difference by sex for ppFEV1, presence of Pseudomonas aeruginosa or BMI pre- to post-ETI by sex.

Conclusion: After treatment with ETI, there was a greater decline in PEx in males versus females. Long-term impact of ETI by sex is still unknown, but we will need to seek ways to effectively tailor care for individuals with CF and consider pharmacokinetic studies of ETI comparing males to females.

Angela Wang is at the School of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.

J Westhoff, S Barth, L Naehrlich. Drug desensitization to lumacaftor/ivacaftor: A fast lane to drug tolerance. Case Reports J Cyst Fibros. 2023 Apr 10;S1569-1993(23)00079-6. doi: 10.1016/j.jcf.2023.03.015. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37045685/
We present the case of a girl (now 11 years and 9 months old) with cystic fibrosis (F508del homozygote), who developed pruritic rash and urticaria six days after the first dose of the CFTR modulators lumacaftor/ivacaftor. The treatment was paused and had to be interrupted due to an immediate recurrence of the urticarial rash after rechallenge. We developed a drug desensitization protocol, aligned to protocols used for desensitization against oral antibiotics. In contrast to other published protocols, it was performed by rapidly increasing the dose of lumacaftor/ivacaftor granulate at 15 min intervals. The medication was continued without interruption, the rash did not reappear during follow-up of two years. This drug desensitization protocol provides a potential new therapeutic option for patients with drug hypersensitivity reactions to CFTR modulators, especially when there are no alternative treatments. Lumacaftor/ivacaftor is available as granulate, doses can be titrated during desensitization and used for long-term treatment.

Julia Westoff is in the Department of Pediatrics, Pediatric Pulmonology, Justus-Liebig-University Giessen, Germany.

Vered Wiesel , Micha Aviram , Meir Mei-Zahav, Miri Dotan, Dario Prais , Malena Cohen-Cymberknoh, Michal Gur, Ronen Bar-Yoseph , Galit Livnat , Aviv Goldbart , Guy Hazan , Itai Hazan , Inbal Golan-Tripto. Eradication of Nontuberculous Mycobacteria in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor: A Multicenter Cohort Study. J Cyst Fibros. 2023 May 10;S1569-1993(23)00133-9. doi: 10.1016/j.jcf.2023.05.003. Online ahead of print. pubmed.ncbi.nlm.nih.gov/37173154/
Background: The prevalence of nontuberculous mycobacteria (NTM) infections is rising in people with cystic fibrosis (pwCF). NTM infection, especially infection with Mycobacterium abscessus complex (MABC), is commonly associated with severe lung deterioration. The current treatment modalities, including multiple intravenous antibiotics, frequently fail to achieve airway eradication. Although treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to modulate the lung microbiome, data regarding its role in eradicating NTM in pwCF is lacking. Our aim was to evaluate the impact of ETI on the rate of NTM eradication in pwCF.
Methods: This retrospective multicenter cohort study included pwCF from five CF centers in Israel. PwCF aged older than 6 who had at least one positive NTM airway culture in the past two years and were treated with ETI for at least one year were included. The annual NTM and bacterial isolations, pulmonary function tests, and body mass index were analyzed before and after ETI treatment.
Results: Fifteen pwCF were included (median age 20.9 years, 73.3% females, 80% pancreatic insufficient). In nine patients (66%) NTM isolations were eradicated following treatment with ETI. Seven of them had MABC. The median time between the first NTM isolation and treatment with ETI was 2.71 years (0.27-10.35 years). Eradication of NTM was associated with improved pulmonary function tests (p<0.05).

Conclusions: For the first time, we report successful eradication of NTM, including MABC, following treatment with ETI in pwCF. Additional studies are needed to assess whether treatment with ETI can result in the long-term eradication of NTM.

Vered Wiesel is at the Medical School for International Health, Ben Gurion University, Beer Sheva, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

2024

Catherine R Armbruster, Yasmin K Hilliam, Anna C Zemke, Samar Atteih, Christopher W Marshall, John Moore, Junu Koirala, Leah Krainz, Jordan R Gaston , Stella E Lee, Vaughn S Cooper, Jennifer M Bomberger. Persistence and evolution of Pseudomonas aeruginosa following initiation of highly effective modulator therapy in cystic fibrosis. mBio. 2024 Apr 2:e0051924. doi: 10.1128/mbio.00519-24. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38564694/

Catherine R Armbruster
Dartmouth medicine

Today, more than 90% of people with cystic fibrosis (pwCF) are eligible for the highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy called elexacaftor/tezacaftor/ivacaftor (ETI) and its use is widespread. Given the drastic respiratory symptom improvement experienced by many post-ETI, clinical studies are already underway to reduce the number of respiratory therapies, including antibiotic regimens, that pwCF historically relied on to combat lung disease progression. Early studies suggest that bacterial burden in the lungs is reduced post-ETI, yet it is unknown how chronic Pseudomonas aeruginosa populations are impacted by ETI. We found that pwCF remain infected throughout their upper and lower respiratory tract with their same strain of P. aeruginosa post-ETI, and these strains continue to evolve in response to the newly CFTR-corrected airway. Our work underscores the continued importance of CF airway microbiology in the new era of highly effective CFTR modulator therapy.
Importance: The highly effective cystic fibrosis transmembrane conductance regulator modulator therapy Elexakaftor/Tezacaftor/Ivacaftor (ETI) has changed cystic fibrosis (CF) disease for many people with cystic fibrosis. While respiratory symptoms are improved by ETI, we found that people with CF remain infected with Pseudomonas aeruginosa. How these persistent and evolving bacterial populations will impact the clinical manifestations of CF in the coming years remains to be seen, but the role and potentially changing face of infection in CF should not be discounted in the era of highly effective modulator therapy.

Catherine Armbruster is in the Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.and the Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.

Elora Blaisonneau , Brendan Le Daré, Marion Mercerolle , Astrid Bacle , Louise Triquet , Marie-Noëlle Osmont , Chantal Belleguic, Elisabeth Polard. [Adverse effects of the tezacaftor/ivacaftor/elexacaftor combination that may lead to discontinuation: About a series of 10 cases] [Article in French].Therapie
. 2024 Jul 14:S0040-5957(24)00073-8. doi: 10.1016/j.therap.2024.06.005. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39174453/
The aim of this study is to describe the characteristics and evolution of adverse reactions to the tezacaftor/ivacaftor/elexacaftor combination that led to discontinuation and were reported to the Centre régional de pharmacovigilance (CRPV) in Rennes (France).
Materials and methods: A retrospective study was conducted from December 2021 to May 2023, focusing on cases of discontinuation of the tezacaftor/ivacaftor/elexacaftor combination due to the occurrence of one or more adverse effects, and reported to the CRPV of Rennes, France.
Results: Ten cases of drug discontinuation were reported to the Rennes CRPV (6 women/4 men). Adverse effects mainly involved neuropsychiatric disorders (n=6), followed by liver disorders (n=2), ear, nose and throat disorders (n=1), and digestive disorders (n=1). The average duration of treatment at discontinuation was 339.8 [39-668] days. The drug was reintroduced in 7 patients on average 48.7 [7-123] days after discontinuation, with a dosage adjustments (n=4) consisting of changes in dosing times or a reduction in daily doses, with varying success in alleviating adverse symptoms depending on the case.
Conclusion: This small case series suggests that neuropsychiatric adverse effects may occur more frequently than initially described after initiation of tezacaftor/ivacaftor/elexacaftor, and should be carefully screened and monitored. Dosage or administration schedule modifications may be considered for patients experiencing these adverse effects. Further pharmacovigilance studies are needed to better understand the adverse effect profiles of “caftors”, their possible risk factors, and the impact of adjusting dosing modalities.

Elora Blaisonnea is at the Pôle pharmacie, centre hospitalier universitaire de Rennes, 35000 Rennes, France.

Naïm Bouazza, Saïk Urien, Frantz Foissac, Laure Choupeaux, Gabrielle Lui, Léo Froelicher Bournaud. Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy. Clin Pharmacokinet. 2024 Mar;63(3):333-342. doi: 10.1007/s40262-023-01342-3. Epub 2024 Feb 4. pubmed.ncbi.nlm.nih.gov/38310629/
Background: A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols.Objectives and methods: The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability. The association between drug exposure and clinical response was also investigated.
Results: A total of 75 children were included in this PPK study, with 191 concentrations available for each compound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis was performed using Monolix software. A large interindividual variability was observed. The main sources of interpatient variability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratory volume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeks of treatment.

Conclusions: This study is the first analysis of lumacaftor/ivacaftor PPK in children with CF. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy. The use of therapeutic drug monitoring as a basis for dose adjustment in children with CF may be useful.

Naïm Bouazza is at the Université Paris Cité, EA7323, Paris, France; Unité de Recherche Clinique Necker Cochin, AP-HP, Paris, France; CIC-1419 Inserm, Cochin-Necker, Paris, France.

Pierre-Régis Burgel, Jean-Louis Paillasseur, Isabelle Durieu, Martine Reynaud-Gaubert, Rebecca Hamidfar, Marlène Murris-Espin, Isabelle Danner-Boucher, Raphaël Chiron, Sylvie Leroy, Benoit Douvry, Dominique Grenet, Laurent Mely, Sophie Ramel 13 , Sylvie Moncouquiol 14 , Espérie Burnet 15 , El Hassane Ouaalaya, Philippe Sogni, Jennifer Da Silva, Clémence Martin. Multisystemic Effects of Elexacaftor-Tezacaftor-Ivacaftor in Adults with Cystic Fibrosis and Advanced Lung Disease. Ann Am Thorac Soc. 2024 Apr 5. doi: 10.1513/AnnalsATS.202312-1065OC. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38579175/

Pierre-Regis Burgel
Institut Cochin

Rationale: Limited data exist on safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease.
Objective: To evaluate the effects of ETI in an unselected population of pwCF and advanced lung disease.
Methods: A prospective observational study, including all adults, aged 18 years and older, with a percent predicted FEV1 (ppFEV1)≤ 40 who initiated ETI from December 2019 to June 2021 in France was conducted. PwCF were followed until August 8th, 2022.Results: ETI was initiated in 434 pwCF with a median [interquartile range, IQR] ppFEV1=30 [25; 35], including 27 with severe CF liver disease and 183 with diabetes. PwCF were followed for a median [IQR] 587 [396; 728] days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was mostly due to lung transplantation (n=5) or death (n=4). Absolute increase in ppFEV1 by a mean +14.2% (95% CI, 13.1-15.4) occurred at 1 month and persisted throughout the study. Increase in ppFEV1 in the younger age quartile was almost twice that of the oldest quartile (P<0.001); body mass index <18.5 kg/m2 was found in 38.6% at initiation vs. 11.3% at 12 months (P=0.0001). Increase in serum concentrations of vitamin A and E, but not 25OHD3, was observed. Significant reduction in the % of pwCF using oxygen therapy, non-invasive ventilation, nutritional support, inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of diabetics.

Conclusion: ETI is safe in pwCF and advanced lung disease with multisystem pulmonary and extrapulmonary benefits.

Pierre-Régis Burgel is at the Cochin Hospital, APHP, Respiratory Medicine, Paris,

Pierre-Régis Burgel, Isabelle Sermet-Gaudelus, Emmanuelle Girodon, Isabelle Durieu, Véronique Houdouin, et al. French Cystic Fibrosis Reference Network study group. The expanded French compassionate programme for elexacaftor-tezacaftor-ivacaftor use in people with cystic fibrosis without a F508del CFTR variant: a real-world study. Lancet Respir Med. 2024 Aug 13:S2213-2600(24)00208-X. doi: 10.1016/S2213-2600(24)00208-X. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39151434/
Background: Elexacaftor-tezacaftor-ivacaftor has been approved in Europe for people with cystic fibrosis with at least one F508del CFTR variant. Additionally, it is approved by the US Food and Drug Administration (FDA) for people with cystic fibrosis with at least one of 177 rare variants. The aims of this study were to describe the clinical response to elexacaftor-tezacaftor-ivacaftor for people with cystic fibrosis without a F508del CFTR variant in France and to determine CFTR variant responsiveness to elexacaftor-tezacaftor-ivacaftor based on the observed clinical response.
Methods: The French compassionate programme expanded access to elexacaftor-tezacaftor-ivacaftor to people with cystic fibrosis, aged 6 years and older, without a F508del variant, excluding those with two variants previously characterised as non-responsive. Participants at France’s 47 cystic fibrosis centres were given a 4-6 week trial of elexacaftor-tezacaftor-ivacaftor and response was determined by a centralised committee based on evolution of clinical data, lung function, and sweat chloride concentration. Responsiveness of individual CFTR variants was derived from observed clinical responses
Findings: The first compassionnate programme was launched on May 19, 2022; by March 8, 2024, 516 people with cystic fibrosis had been identified for inclusion in this real-word study: 37 were not included due to the presence of two variants previously characterised as non-responsive to elexacaftor-tezacaftor-ivacaftor, and 479 (229 females [48%] and 250 males [52%]) received elexacaftor-tezacaftor-ivacaftor for 4-6 weeks. Among 443 participants who received no CFTR modulator before elexacaftor-tezacaftor-ivacaftor, 83 had at least one FDA-approved variant, of whom 81 (98%) were responders and continued elexacaftor-tezacaftor-ivacaftor; in responders, mean absolute change in sweat chloride was -44·5 mmol/L (95% CI -39·1 to -49·8) and percentage of predicted FEV1 (ppFEV1) was 11·1 percentage points (95% CI 8·4 to 13·7; both comparisons p<0·0001). Among 360 participants with no FDA-approved variant and no previous CFTR modulator, 177 (49%) were responders; in responders, mean absolute change in sweat chloride was -20·5 mmol/L (-17·2 to -23·8) and ppFEV1 was 13·2 percentage points (11·4 to 15·0; both comparisons p<0·0001). Among 36 participants who were receiving ivacaftor before elexacaftor-tezacaftor-ivacaftor, 32 (89%) continued elexacaftor-tezacaftor-ivacaftor. Of 251 individual CFTR variants, 64 (28 FDA-approved) were classified as responsive or possibly responsive to elexacaftor-tezacaftor-ivacaftor, and 123 (two FDA-approved) as non-responsive or possibly non-responsive to elexacaftor-tezacaftor-ivacaftor

Interpretation: In France, over half of the population with cystic fibrosis without a F508del variant responded to elexacaftor-tezacaftor-ivacaftor, with most responders having no FDA-approved variant. The treatment period was relatively short and further research is warranted to describe the long-term safety and effectiveness of elexacaftor-tezacaftor-ivacaftor in this population.

Funding: Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladies Rares MUCO-CFTR.

FranceeAlice Castaldo, Monica Gelzo, Paola Iacotucci, Annalisa Longobardi, Giovanni Taccetti, Vito Terlizzi, Vincenzo Carnovale. One year of treatment with elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis homozygous for the F508del mutation causes a significant increase in liver biochemical indexes.Front Mol Biosci. 2024 Jan 8:10:1327958. doi: 10.3389/fmolb.2023.1327958. eCollection 2023 Free PMC article pubmed.ncbi.nlm.nih.gov/38259684/

Introduction: Modulators of cystic fibrosis transmembrane conductance regulator mutated protein significantly improved the outcome of patients with cystic fibrosis (CF). We describe 63 patients who were independently followed up in two CF regional centers (i.e., Campania and Tuscany regions).
Methods: All patients were homozygous for the F508del mutation and were treated with lumacaftor/ivacaftor (LI) for 3 years, followed by 1 year of treatment with elexacaftor/tezacaftor/ivacaftor (ETI). We studied the biochemical parameters of liver damage and cholesterol metabolism.
Results: Beyond the improvement of BMI and lung function with LI treatment and even more with ETI, we found that the 3 years of LI treatment significantly improved liver function parameters (total and conjugated bilirubin, ALT, AP, and GGT), while the subsequent ETI treatment caused a significant increase of such parameters. Discussion: We confirm that treatment with LI does not correct hypocholesterolemia, whereas treatment with ETI significantly increases serum cholesterol. Such an increase is likely due to enhanced de novo biosynthesis, as indicated by the significant increase in serum lathosterol, and it is likely that the subsequent liver cholesterol accumulation may contribute to triggering inflammation and worsening liver biochemical indexes. The increase in serum bilirubin and ALT that we observed in approximately 94% and 84% of patients treated with ETI, respectively, suggests further investigation of the impact of ETI therapy on liver function indexes.

Alice Castaldo is in the Dipartimento di Scienze Mediche Traslazionali, Centro Regionale Fibrosi Cistica del Bambino – Pediatria, Università di Napoli Federico II, Naples, Italy.

Giuseppe Cimino, Sara Sorrenti, Manuel Murciano, Paola Galoppi, Fiorentina Ascenzioni, Bruno Botta, Roberto Brunelli ; Sapienza University Working Group on Cystic Fibrosis in Pregnancy. Use of elexacaftor/tezacaftor/ivacaftor combination in pregnancy. Review Arch Gynecol Obstet. 2024 Jan;309(1):9-15. doi: 10.1007/s00404-023-06962-5. Epub 2023 Mar 13. pubmed.ncbi.nlm.nih.gov/36907900/
Introduction: Management of cystic fibrosis has recently stepped forward with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, although data on potential adverse effects are lacking for many categories of patients, such as pregnant women.
Methods: We report one of the first reports on the outcome of pregnancy in a woman treated with Elexacaftor/Tezacaftor/Ivacaftor during the second and third trimester of pregnancy, showing a significant improvement of respiratory status, compared with the first trimester when the medication was discontinued due to unknown and, therefore, potential teratogenic effects. Also, we performed the review of the existing literature on the topic.
Results: The course of pregnancy was uneventful, with reference to major obstetric complications, and the patient delivered a healthy neonate. These results were similar to those coming from other short series of pregnant women affected by cystic fibrosis and treated with CFTR modulators during pregnancy.
Conclusions: Thus, despite the lack of evidence on the topic, the use of Elexacaftor/Tezacaftor/Ivacaftor in pregnancy seems to be apparently not associated with major adverse events, thus opening optimistic scenarios in terms of management of these patients.

Giuseppe Cimino is at the Cystic Fibrosis Regional Reference Center, A.O.U. Policlinico Umberto I, Rome, Italy and the Department of Maternal and Child Health and Urological Sciences, Sapienza University of Rome, Via del Policlinico, 155, 00161, Rome, Italy.

E De Wachter, JC Davies, NJ Simmonds, C Castellani, KM de Winter-de Groot, A Munck, M Proesmans, KW Southern and J Barben. Risk of false newborn screening after intra-uterine exposure to ETI Journal of Cystic Fibrosis, 2024-01-01, Volume 23, Issue 1, Pages 176-177, Letter to the editor

(part of letter) As coordinators and members of the European CF Society (ECFS) Diagnostic Network Working Group (DNWG) and the Neonatal Screening Working Group (NSWG), we would like to draw the attention to the potential effects of ETI therapy in pregnant woman on the outcome of NBS, with regard to the IRT level. Collins et al. have shown that ETI drug concentrations in umbilical cord blood are comparable to maternal serum levels and, as a result, therapeutic concentrations can be assumed to reach the foetus. [4] Should the newborn have CF, the IRT results could be reduced below the screening threshold leading to a false negative screen, as was already reported in one case. [5] A recent study showed decreased IRT levels in newborn carriers exposed to ETI, compared to newborn carriers who were not exposed to ETI. [6] This is likely also to be the case for the small proportion of women receiving Ivacaftor monotherapy, although we are not aware of data on pregnancies in this group.

This situation deserves special attention for all CF specialists who care for pregnant women with CF. Knowledge about the potential impact of ETI on newborn IRT levels should be shared by the CF adult physician caring for the mother with the obstetrician and midwife. For a reliable interpretation of a NBS result, it is of utmost interest to mention on the Guthrie card, taken on the third or fourth day of life, if the mother of the child has taken ETI during pregnancy. This already happens in some countries, for example Belgium and Switzerland, and allows the screening laboratory to process these samples differently, not relying on an initial IRT value. Depending on each country’s NBS strategy, details on which CFTR gene variants would be included in this failsafe measure may vary for dry bloodspot samples from newborn babies who were exposed to ETI in utero. Another option is to refer these children from CF mothers for a sweat test anyway.

Furthermore, data from literature show that ETI is also detectable in breastmilk, albeit at lower levels. [4] This implies that sweat chloride values in breastfed neonates that were exposed in utero to ETI may be falsely lowered and thus should be interpreted with caution and repeated following weaning should diagnostic doubt remain. [ 5 , 7 ]

On behalf of the ECFS Diagnostic Network Working Group (DNWG) and the Neonatal Screening Working Group (NSWG)

Scott H Donaldson , Timothy E Corcoran, Joseph M Pilewski, Peter Mogayzel, Beth L Laube, Evan R Boitet, Elex S Harris, Agathe Ceppe, Lloyd J Edwards, Kirby Zeman , Jihong Wu , Charles R Esther Jr, David P Nichols, William D Bennett, Steven M Rowe. Effect of elexacaftor/tezacaftor/ivacaftor on mucus and mucociliary clearance in cystic fibrosis. Observational Study. J Cyst Fibros 2024 Jan;23(1):155-160. doi:10.1016/j.jcf.2023.10.010. Epub 2023 Oct 14. pubmed.ncbi.nlm.nih.gov/37845149/

Scott Donalson
med.unc.edu

The effects of E/T/I on mucociliary clearance (MCC) and sputum properties are unknown. We, therefore, sought to characterize the effects of E/T/I on in vivo MCC and sputum characteristics hypothesized to impact mucus transport.
Methods: Forty-four participants ≥12 years of age were enrolled into this prospective, observational trial prior to initiation of E/T/I and had baseline measurement of MCC and characterization of induced sputum and exhaled breath condensate (EBC) samples. Study procedures were repeated after 1 month of E/T/I treatment.
Results: Average age was 27.7 years with baseline forced expiratory volume in 1 second (FEV1) of 78.2 % predicted. 52 % of subjects had previously been treated with a 2-drug CFTR modulator combination. The average whole lung MCC rate measured over 60 min (WLAveClr60) significantly improved from baseline to post-E/T/I (14.8 vs. 22.8 %; p = 0.0002), as did other MCC indices. Sputum% solids also improved (modelled mean 3.4 vs. 2.2 %; p<0.0001), whereas non-significant reductions in sputum macrorheology (G’, G”) were observed. No meaningful changes in exhaled breath condensate endpoints (sialic acid:urea ratio, pH) were observed.

Conclusions: E/T/I improved the hydration of respiratory secretions (% solids) and markedly accelerated MCC. These data confirm the link between CFTR function, mucus solid content, and MCC and help to define the utility of MCC and mucus-related bioassays in future efforts to restore CFTR function in all people with CF.

Scott Donaldson is at the Department of Medicine, Univ. North Carolina at Chapel Hill, USA.

Scott H Donaldson, Timothy E Corcoran, Joseph M Pilewski, Beth L Laube, Peter Mogayzel, Agathe Ceppe, Jihong Wu, Kirby Zeman, Steven M Rowe, David P Nichols, Alex H Gifford, William D Bennett^,Nicole Mayer-Hamblett; SIMPLIFY MCC. The effect of discontinuing hypertonic saline or dornase alfa on mucociliary clearance in elexacaftor/tezacaftor/ivacaftor treated people with cystic fibrosis: The SIMPLIFY-MCC Stdy. J Cyst Fibros doi: 10.1016/j.jcf.2024.02.003. Online ahead of print.pubmed.ncbi.nlm.nih.gov/38355350/

Many people with CF (pwCF) desire a reduction in inhaled treatment burden after initiation of elexacaftor/tezacaftor/ivacaftor. The randomized, open-label SIMPLIFY study showed that discontinuing hypertonic saline (HS) or dornase alfa (DA) was non-inferior to continuation of each treatment with respect to change in lung function over a 6-week period. In this SIMPLIFY substudy, we used gamma scintigraphy to determine whether discontinuation of either HS or DA was associated with deterioration in the rate of in vivo mucociliary clearance (MCC) in participants ≥12 years of age. While no significant differences in MCC endpoints were associated with HS discontinuation, significant improvement in whole and peripheral lung MCC was observed after discontinuing DA. These results suggest that pwCF on ETI with mild lung disease do not experience a subclinical deterioration in MCC that could later impact health outcomes after discontinuing HS, and in fact may benefit from improved MCC after stopping DA treatment.

Scott Donaldson is at the Department of Medicine and the Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Stephanie R Duehlmeyer, E Claire Elson, Christopher M Oermann. New Tic Disorder in a Child With Cystic Fibrosis Treated With Elexacaftor/Tezacaftor/Ivacaftor. J Pediatr Pharmacol Ther
. 2024;29(1):82-84. doi: 10.5863/1551-6776-29.1.82. Epub 2024 Feb 7. Free PMC article pubmed.ncbi.nlm.nih.gov/38332957/

Stephanie Duehlmeyer
Children’s Mercy Kansas

The widespread use of highly effective cystic fibrosis transmembrane-conductance regulator -modulator therapy has dramatically altered the lives of individuals with cystic fibrosis. Clinical trials leading to -modulator approval by the US Food and Drug Administration demonstrated improvements in major -outcome measures including pulmonary function, gastrointestinal symptoms, and quality of life. Subsequent clinical experience has confirmed significant improvement across these domains. Adverse effects reported -during clinical trials included headache and dizziness amongst others including upper respiratory infections, abdominal pain, diarrhea, rash, and elevated serum transaminases. Post marketing clinical experience has suggested that there may be additional central nervous system adverse effects resulting from modulator therapy. Reported events after initiation of cystic fibrosis transmembrane-conductance regulator modulator treatment include headaches and increased prevalence of mental health concerns including anxiety and depression.
We report a new tic disorder in a 7-year-old girl with cystic fibrosis treated with elexacaftor/tezacaftor/ivacaftor.

Stephanie R Duehlmeyer is in the Departments of Pharmacy (SRD, ECE) and Pediatrics (CMO) Children’s Mercy – Kansas City, MO.

Valentina Fainardi , Federico Cresta, Claudio Sorio, Paola Melotti , Emanuela Pesce , Michela Deolmi , Francesco Longo , Kleinfelder Karina , Susanna Esposito, Giovanna Pisi. Elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and rare mutations. Pediatr Pulmonol. 2024 Aug 30. doi: 10.1002/ppul.27211. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39212240/

Valentina Fairnardi
ResearchGate

Introduction: The triple combination of elexacaftor/tezacaftor/ivacaftor (ETI) has dramatically improved the outcome of people with Cystic Fibrosis (pwCF) with at least one F508del mutation. However, carriers of rare cystic fibrosis transmembrane conductance regulator (CFTR) variants are not candidates for this innovative treatment.
Methods: In this observational study, we report the results of the compassionate use of ETI in 10 pwCF carriers of rare mutations after 2 months of treatment. Rectal organoids and short-term cultures of nasal epithelium obtained from rectal suction biopsies and nasal brushing were obtained from four subjects.
Results: After 2 months of ETI, all patients (4 males, mean age 30.1 ± 13.3 years) showed a significant increase of FEV1% predicted values [+8.0 (3.5-12.7) %, p < 0.010], body mass index [+0.85 (0-1.22) kg/m2, p < 0.020] and cystic fibrosis questionnaire-revised [+19.5 (6.3-29.2) points, p < 0.009]. A significant decrease of sweat chloride concentration [-11.2 (-1.7 to -34.0) mmol/L, p < 0.020] and exacerbations [-1.5 (-2 to -1), p < 0.008] was also recorded. Overall, 7 out of 10 participants were considered full responders. All patients reported cough disappearance (n = 3) or reduction (n = 7). Long-term oxygen was discontinued in two out of three patients and one also stopped noninvasive ventilation and was removed from the lung transplantation waiting list.

Conclusions: Despite the limited number of cases, our results support the use of CFTR modulators in patients with rare CFTR variants that are not currently approved for ETI in Europe.

Valentina Fainardi is in the Dept of Medicine and Surgery, Cystic Fibrosis Unit, Pediatric Clinic, Parma, Italy.

Sonia Graziano , Francesca Boldrini , Gaia Romana Pellicano , Francesco Milo , Fabio Majo , Luca Cristiani , Enza Montemitro , Federico Alghisi , Sergio Bella , Renato Cutrera , Alessandro Giovanni Fiocchi , Alexandra Quittner , Paola Tabarini. Longitudinal Effects of Elexacaftor/Tezacaftor/Ivacaftor: Multidimensional Assessment of Neuropsychological Side Effects and Physical and Mental Health Outcomes in Adolescents and Adults. Chest. 2024 Apr;165(4):800-809. doi: 10.1016/j.chest.2023.10.043. Epub 2023 Nov 3. 37925143 pubmed.ncbi.nlm.nih.gov/37925143/

Sonia Graziano
CFF Conference 2022

Background: Italy initiated elexacaftor/tezacaftor/ivacaftor (ETI) for people with cystic fibrosis (pwCF) in July 2021. It has led to dramatic improvements in lung function, BMI, sweat chloride, and respiratory symptoms. However, few data are available on side effects or effects on a broad range of outcomes.
Research question: How does ETI affect mental health, cognitive processing, neuropsychological side effects, GI symptoms, and health-related quality of life over time?
Study design and methods: This was a prospective, “real-world” longitudinal study. Participants were recruited consecutively and evaluated at initiation (T0) and after 1 month, 3 months, and 6 months of starting treatment. Assessments included depression (nine-item Patient Health Questionnaire), anxiety (seven-item Generalized Anxiety Disorder), cognition (Symbol Digit Modalities Test), GI Symptom Tracker, and health-related quality of life (Cystic Fibrosis Questionnaire-Revised). Based on literature, an ad hoc questionnaire was developed to assess side effects: insomnia, headache, memory problems, “brain fog,” and concentration problems. Following descriptive analyses, longitudinal data were analyzed by using mixed models for repeated measures, controlling for age and sex when appropriate.
Results: Ninety-two consecutive pwCF (female/male, 46/46; mean age, 25.4 years) participated. FEV1 increased initially and then remained stable. BMI also increased significantly from T0 to 6 months (P < .01). Depression improved from T0 to 1 month (P < .001); however, no changes in anxiety were found. Cognitive processing improved from T0 to subsequent assessments. Positive changes were reported on the GI Symptom Tracker for stools and adherence challenges, although no changes were found for abdominal pain and digestion. Side effects occurred in 10% to 29%, with no reduction over time; insomnia increased significantly across time. Female participants reported more side effects than male participants (ie, insomnia, headache, concentration problems, brain fog).

Interpretation: This prospective study evaluated the effects of ETI using multiple measures. Significant improvements were found in many domains; however, side effects were reported by a substantial proportion of pwCF, with no improvements over time. Female participants reported more side effects than male participants. pwCF should be followed up systematically to assess the frequency of side effects after starting this new modulator.

Sonia Graziano is at the Psychology Unit, Child & Adolescent Psychiatry Unit, Allergy Division, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy.

Shijing Jia, Yizhuo Wang, Melissa H Ross, Jonathan B Zuckerman, Susan Murray, MeiLan K Han, Shannon E Cahalan, Blair E Lenhan, Ryan N Best, Jennifer L Taylor-Cousar, Richard H Simon, Linda J Fitzgeral, Jonathan P Troost, Suman L Sood, Alex H Gifford. Association between CFTR modulators and changes in iron deficiency markers in cystic fibrosis. J Cyst Fibros. 2024 Mar 14:S1569-1993(24)00030-4. doi: 10.1016/j.jcf.2024.03.002. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38490920/

Shijing Jia
NACFC 2022

Background: Iron deficiency (ID) is a common extrapulmonary manifestation in cystic fibrosis (CF). CF transmembrane conductance regulator (CFTR) modulator therapies, particularly highly-effective modulator therapy (HEMT), have drastically improved health status in a majority of people with CF. We hypothesize that CFTR modulator use is associated with improved markers of ID.
Methods: In a multicenter retrospective cohort study across 4 United States CF centers 2012-2022, the association between modulator therapies and ID laboratory outcomes was estimated using multivariable linear mixed effects models overall and by key subgroups. Summary statistics describe the prevalence and trends of ID, defined a priori as transferrin saturation (TSAT) <20 % or serum iron <60 μg/dL (<10.7 μmol/L).
Results: A total of 568 patients with 2571 person-years of follow-up were included in analyses. Compared to off modulator therapy, HEMT was associated with +8.4 % TSAT (95 % confidence interval [CI], +6.3-10.6 %; p < 0.0001) and +34.4 μg/dL serum iron (95 % CI, +26.7-42.1 μg/dL; p < 0.0001) overall; +5.4 % TSAT (95 % CI, +2.8-8.0 %; p = 0.0001) and +22.1 μg/dL serum iron (95 % CI, +13.5-30.8 μg/dL; p < 0.0001) in females; and +11.4 % TSAT (95 % CI, +7.9-14.8 %; p < 0.0001) and +46.0 μg/dL serum iron (95 % CI, +33.3-58.8 μg/dL; p < 0.0001) in males.

Ferritin was not different in those taking modulator therapy relative to off modulator therapy. Hemoglobin was overall higher with use of modulator therapy. The prevalence of ID was high throughout the study period (32.8 % in those treated with HEMT).
Conclusions: Iron deficiency remains a prevalent comorbidity in CF, despite availability of HEMT. Modulator use, particularly of HEMT, is associated with improved markers for ID (TSAT, serum iron) and anemia (hemoglobin).

Shijing Jia is clinical assistant professor in theDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

Amber James , Galvin Li , Rhonda List , Kevin Lonabaugh , Aaron D Smith , Andrew Barros , Lindsay Somerville , Dana Albon. Analysis of iron status after initiation of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis. Pediatr Pulmonol. 2024 Mar;59(3):669-678. doi: 10.1002/ppul.26805. Epub 2023 Dec 13. pubmed.ncbi.nlm.nih.gov/38088203/
Background: Iron deficiency is highly prevalent in people with cystic fibrosis (PwCF)While elexacaftor/tezacaftor/ivacaftor (ETI) has shown remarkable improvements in respiratory symptoms in PwCF, the effect of ETI on iron status remains unknown. This study aims to identify the effect of ETI on iron status in PwCF.Methods: A single-center retrospective cohort study of 127 adult PwCF was conducted to assess the impact of ETI on iron, ferritin, transferrin levels, and percent saturation of transferrin (PSAT). Data were collected from the electronic medical record from January 2017 to September 2022, encompassing 2 years before and after ETI initiation. The primary outcome was serum iron parameters: iron, ferritin, transferrin, and PSAT levels following ETI treatment. Secondary outcomes analyzed iron supplementation. Univariate and multivariate mixed-effects models were used for the analysis of ETI.

Dana P Albon
UVA Health

Results: After adjusting for covariates, following ETI initiation, the mean iron level increased by 20.24 μg/dL (p < .001), ferritin levels were 31.4% (p < .001) higher, PSAT showed a 5.09 percentage point increase (p < .001), and transferrin levels increased by 2.71 mg/dL (p = .439). Patients with and without iron supplementation experienced a significant increase in iron after ETI (p < .001).

Conclusions: ETI is associated with a significant increase in iron, ferritin, and PSAT levels. Patients with and without iron supplementation demonstrated a significant increase in iron. This study shows the benefits of ETI on iron status in PwCF. However, further translational studies are required to understand the impact of ETI on iron absorption and metabolism in PwCF.

Amber James is at the Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Dana Albon is Medical director of the UVA Adult Cystic Fibrosis Clinic,

Claire Kim, Mark Higgins, Lingyun Liu, Nataliya Volkova, Anna Zolin, Lutz Naehrlich ; ECFSPR Study Group. Effectiveness of lumacaftor/ivacaftor initiation in children with cystic fibrosis aged 2 through 5 years on disease progression: Interim results from an ongoing registry-based study. J Cyst Fibros. 2024 Feb 23:S1569-1993(24)00017-1. doi: 10.1016/j.jcf.2024.02.004. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38402082/

Claire Kim Datalead

Background: Lumacaftor/ivacaftor (LUM/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) ≥1 year of age. To assess the impact of early LUM/IVA initiation on CF disease progression, a 6-year observational study leveraging data from existing CF patient registries is being conducted in children with CF homozygous for F508del (F/F genotype) who were aged 2 through 5 years at treatment initiation. Here we present interim results from this study focusing on data from the European CF Society Patient Registry (ECFSPR).
Methods: The LUM/IVA cohort included children in the ECFSPR who started LUM/IVA between 15 January 2019 and 31 December 2020. Longitudinal trends in growth parameters, pulmonary exacerbations, hospitalizations, safety outcomes, and other effectiveness outcomes in the LUM/IVA cohort were compared to those in two modulator-naïve cohorts: (i) matched concurrent cohort heterozygous for F508del and a minimal function mutation (F/MF concurrent comparator cohort) and (ii) matched concurrent cohort with the F/F genotype from countries without commercial access to LUM/IVA as of 2020 (F/F concurrent comparator cohort).
Results: The LUM/IVA cohort matched to the F/MF concurrent comparator cohort had 681 children and the LUM/IVA cohort matched to the F/F concurrent comparator cohort had 183 children. LUM/IVA cohorts had increases in body mass index percentiles relative to the matched F/MF and F/F concurrent comparator cohorts (mean difference in change from baseline: 8.4 [95% CI: 5.5, 11.3] and 11.8 [95% CI: 5.9, 17.7], respectively). Increases in height and weight percentiles were also observed in the LUM/IVA cohort relative to the F/MF and F/F concurrent comparator cohorts. Reductions in pulmonary exacerbations and hospitalizations relative to baseline and the F/F concurrent comparator cohort were seen in 2021.
Conclusions: This interim analysis showed favorable trends in clinical outcomes, including growth parameters, pulmonary exacerbations, and hospitalizations, suggesting an early beneficial effect of LUM/IVA treatment in children aged 2 through 5 years at treatment initiation.

Claire Kim is Director at Vertex Pharmaceuticals Incorporated, Boston, MA, USA.

Aleksandra Kowalik, Emma Roberts, Anna Hedborg Harris, Marie Sund, Sara Wird, Ola Kvist, Lena Hjelte.Clinical outcomes of two infants with cystic fibrosis, including presence of the vas deferens, born to a woman with cystic fibrosis taking CFTR modulators during both pregnancies. Case Reports J Cyst Fibros. 2024 Jun 13:S1569-1993(24)00080-8. doi: 10.1016/j.jcf.2024.06.003. Online ahead of print. Full text via PubMed link pubmed.ncbi.nlm.nih.gov/38876833/

Aleksandra Kowalik is at the CF Centre, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.

Emma L Ledger , Daniel J Smith, Jing Jie Teh, Michelle E Wood, Page E Whibley , Mark Morrison, Joanna B Goldberg, David W Reid, Timothy J Wells. Impact of CFTR Modulation on Pseudomonas aeruginosa Infection in People With Cystic Fibrosis. J Infect Dis. 2024 Mar 5:jiae051. doi: 10.1093/infdis/jiae051. Online ahead of print pubmed.ncbi.nlm.nih.gov/38442240/

Emma L Ledger
X-com

P. aeruginosa strains (n = 105) were isolated from the sputum of 11 chronically colonized pwCF at baseline and up to 21 months posttreatment with elexacaftor-tezacaftor-ivacaftor or tezacaftor-ivacaftor. Phenotypic characterization and comparative genomics were performed.
Results: Clonal lineages of P. aeruginosa persisted after therapy, with no evidence of displacement by alternative strains. We identified commonly mutated genes among patient isolates that may be positively selected for in the CFTR-modulated lung. However, classic chronic P. aeruginosa phenotypes such as mucoid morphology were sustained, and isolates remained just as resistant to clinically relevant antibiotics.
Conclusions: Despite the clinical benefits of CFTR modulators, clonal lineages of P. aeruginosa persist that may prove just as difficult to manage in the future, especially in pwCF with advanced lung disease

Emma L Ledger is a PhD candidate at the Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia.

Danni Li , Martin Donnelley , David Parsons , Mark D Habgood , Elena K Schneider-Futschik. Extent of foetal exposure to maternal elexacaftor/tezacaftor/ivacaftor during pregnancy. Br J Pharmacol. 2024 Aug;181(15):2413-2428. doi: 10.1111/bph.16417. Epub 2024 May 21. pubmed.ncbi.nlm.nih.gov/38770951/

Danni Li
LinkedIn

Background and purpose: Cystic fibrosis (CF) patients are living longer and healthier due to improved treatments, e.g. cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI), with treatment possibly occurring in pregnancy. The risk of ETI to foetuses remain unknown. Thus the effect of maternally administered ETI on foetal genetic and structural development was investigated.
Experimental approach: Pregnant Sprague Dawley rats were orally treated with ETI (6.7 mg·kg-1·day-1 elexacaftor + 3.5 mg·kg-1·day-1 tezacaftor + 25 mg·kg-1·day-1 ivacaftor) for 7 days from E12 to E19. Tissue samples collected at E19 were analysed using histology and RNA sequencing. Histological changes and differentially expressed genes (DEG) were assessed
Key results: No overt structural abnormalities were found in foetal pancreas, liver, lung and small intestine after 7-day ETI exposure. Very few non-functionally associated DEG in foetal liver, lung and small intestine were identified using RNA-seq. 29 DEG were identified in thymus (27 up-regulated and two down-regulated) and most were functionally linked to each other. Gene ontology enrichment analysis revealed that multiple muscle-related terms were significantly enriched. Many more DEG were identified in cortex (44 up-regulated and four down-regulated) and a group of these were involved in central nervous system and brain development.

Conclusion and implication: Sub-chronic ETI treatment in late pregnancy does not appear to pose a significant risk to the genetic and structural development of many foetal tissues. However, significant gene changes in foetal thymic myoid cells and cortical neuronal development requires future follow-up studies to assess the risk to these organs.

Danni Li PhD is a research pharmacologist in the Department of Biochemistry & Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia.

— With all the serious problems relating to intrauterine drug exposure over the years, the authors’ comment that cortical neuronal development requires future follow up studies seems appropriate.

ochen G Mainz , Karen Lester , Basil Elnazir , Michael Williamson , Ed McKone , Des Cox , Barry Linnane , Carlos Zagoya , Franziska Duckstein, Anton Barucha , Jane C Davies, Paul McNally; RECOVER Study Group
Reduction in abdominal symptoms (CFAbd-Score), faecal M2-pyruvate-kinase and Calprotectin over one year of treatment with Elexacaftor-Tezacaftor-Ivacaftor in people with CF aged ≥12 years – The RECOVER study J Cyst Fibros. 2024 May;23(3):474-480. doi: 10.1016/j.jcf.2023.10.001. Epub 2023 Oct 7. pubmed.ncbi.nlm.nih.gov/37806792/

Jochen G Mainz
ResearchGate

Background: RECOVER is a multicentre post-approval study of Elexacaftor/Tezacaftor/Ivacaftor (ETI) in pwCF in Ireland and the UK. The CFAbd-Score is the first validated CF-specific patient reported outcome measure (PROM) focusing on gastrointestinal symptoms; it comprises 28 items in 5 domains. In a preliminary study, we previously reported reductions in abdominal symptoms (AS) in pwCF after 26 weeks of ETI-therapy using the CFAbd-Score.
Aim: to assess changes in AS in a second, large cohort and explore novel GI-biomarkers of gut inflammation and cell-proliferation in pwCF over one year of ETI-therapy.
Methods: Participants were recruited as part of the RECOVER study at 8 sites (Ireland&UK). The CFAbd-Score was administered prior to ETI-initiation, and subsequently at 1,2,6 and 12 months on treatment. Faecal M2-pyruvate kinase (M2-PK) and calprotectin (FC) were quantified in samples collected at baseline, 1 and 6 months.
Results: 108 CFAbd-Scores and 73 stool samples were collected at baseline. After 12 months of ETI-therapy, total CFAbd-Scores had significantly declined (15.0±1.4→9.8±1.2pts/p<0.001), and so had all its five domains of “pain” (16.9±2.0pts→9.9±1.8pts/p<0.01), “GERD” (14.4±1.8→9.9±1.6/p<0.05), “disorders of bowel movements” (19.2±1.4→14.1±1.5/p<0.01), “appetite” (7.0±1.1→4.6±1.2/p<0.01) and “impaired-QoL” (13.3±1.9→7.5±1.5/p<0.001). Levels of M2-PK and FC significantly decreased during ETI-therapy.

Discussion: In-depth analysis of AS with the CFAbd-Score reveals a statistically significant, clinically relevant and sustained improvement with ETI. We attribute this to high sensitivity of the implemented CF-specific PROM, developed and validated following FDA-guidelines. Furthermore, for the first time during ETI-therapy a significant decline in faecal M2-PK, a marker of inflammation and cell-proliferation, was found, in parallel to FC.

Jochen G Mainz is at the Brandenburg Medical School (MHB) University. Klinikum Westbrandenburg, Brandenburg an der Havel, Germany.

Richard D Maradiaga, Mitchell L Ramsey, Stephen E Kirkby, Lindsay A Sobotka. The Role of Cystic Fibrosis Transmembrane Conductance Regulator Modulators After Liver Transplantation in Persons With Cystic Fibrosis. Case Reports ACG Case Rep J. 2024 Jan 16;11(1):e01261. doi: 10.14309/crj.0000000000001261. eCollection 2024 Jan.Free PMC article pubmed.ncbi.nlm.nih.gov/38234978

Despite advances in treatment for cystic fibrosis (CF), liver disease remains a major contributor to morbidity and mortality for persons with CF. Therefore, liver transplantation may be considered in end-stage CF-related liver disease. We present a young patient with CF who underwent solo liver transplantation and has successfully restarted on elexacaftor/tezacaftor/ivacaftor without significant pulmonary or hepatic complications after transplant.

Richard D Maradiaga is an internist in the Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.

Nicole Mayer-Hamblett, Alex H Gifford, Margaret Kloster, Renee Russell, Andrew T Braun, Ronald L Gibson et al. Impact of Discontinuing Both Hypertonic Saline and Dornase Alfa After Elexacaftor/Tezacaftor/Ivacaftor in Cystic FibrosisAnn Am Thorac Soc
. 2024 Jul 23. doi: 10.1513/AnnalsATS.202404-366OC. Online ahead of print.pubmed.ncbi.nlm.nih.gov/39041864/

Nicole Mayer-Hamblett
Seattle Children’s

Objective To evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA.
Conclusions SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared to those who remained on both therapies. These data continue to inform a new era of post-modulator care of pwCF.

Nicole Mayer-Hamblett is at the University of Washington, Pediatrics, Seattle, Washington, United States. and Seattle Children’s Research Institute, Seattle, Washington, United States.

Paul McNally, Alvin Singh, Susanna A McColley, Jane C Davies, Mark Higgins, Meng Liu, Jennifer Lu, Violeta Rodriguez-Romero, Judy L Shih, Margaret Rosenfeld 6 ; VX15-770-124 Study Group. Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis. J Cyst Fibros https://onlinelibrary.wiley.com/doi/10.1002/lary.31447. 2024 Apr 4:S1569-1993(24)00042-0. doi: 10.1016/j.jcf.2024.03.012. Online ahead of print. Free article pubmed.ncbi.nlm.nih.gov/38580563/

Paul McNally
RCSI

Background: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF.
Methods: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. Results: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed.

Conclusions: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.

Paul McNally is at the RCSI University of Medicine and Health Sciences and Children’s Health, Dublin

Jessa E Miller, Eugene Oh, Aastha Khatiwada, Stephen M Humphries, Alexandra Wilson, Eszter K Vladar, David A Lynch, Jennifer L Taylor-Cousar, Daniel M Beswick. Two-Year Impact of Highly Effective Modulator Therapy on Olfactory Dysfunction. Laryngoscope 2024 apr 22 doi: 10.1002/lary.31447.Online ahead of print. pubmed.ncbi.nlm.nih.gov/38647113/

Jessa E Millar

Conclusion: Olfactory dysfunction in adults with CF did not improve in a clinically relevant manner after 2 years of ETI. Further study into mechanisms of olfactory loss in PwCF and the impact of early intervention on preventing or improving OD is warranted.

Jessa E Millar is in the Department of Otolaryngology-Head and Neck Surgery, University of California, Los Angeles, Los Angeles, California, U.S.A.

Nadia Nathan, Guillaume Thouvenin, Béatrice Dubern, Harriet Corvol.Elexacaftor/tezacaftor/ivacaftor can rescue pancreatic function in F508del homozygous children.Pediatr Pulmonol. 2024 Mar;59(3):788-790. doi: 10.1002/ppul.26794. Epub 2023 Dec 13.pubmed.ncbi.nlm.nih.gov/38088210/

Nadia Nathan Linkedin

No abstract available

Nadia Nathan is Professor at Service de Pneumologie Pédiatrique, Centre de Référence des Maladies Respiratoires Rares RespiRare, ssistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Trousseau, ASorbonne Université, Paris, France. and the Laboratory of Childhood Genetic Diseases, Inserm UMR_S933, Sorbonne Université, Paris, France.

Christabella Ng , Neele S Dellschaft, Caroline Hoad , Luca Marciani , Robin Spiller , Colin Crooks , Trevor Hill , Alex Menys , Jochen G Mainz , Helen Barr , Penny A Gowland , Giles Major , Alan R Smyth. A randomised crossover trial of tezacaftor-ivacaftor (SYMDEKO) for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes: a pilot study. NIHR Open Res. 2024 Mar 19:3:65. doi: 10.3310/nihropenres.13510.2. eCollection 2023. pubmed.ncbi.nlm.nih.gov/39139270/

Christabella Ng
X.com

(Shortened summary) We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA >360minutes [225,>360] vs. placebo 330minutes [285,>360], p=0.8) or secondary outcomes. There were no adverse events.
Conclusions: Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators.

Christabella Ng is at NIHR Nottingham Biomedical Research Centre, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK. and the Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham, England, UK.

Kimberly Pasley , Mary Lynn Dell, Anne May. Diagnosis and treatment of ADHD in pediatric patients during the first year of elexacaftor/tezacaftor/ivacaftor. Cystic fibrosis referencesPediatr Pulmonol
. 2024 Sep 6. doi: 10.1002/ppul.27246. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39239907/
Background: With elexacaftor/tezacaftor/ivacaftor (ETI), children with cystic fibrosis (CwCF) are living healthier lives with a focus on typical developmental issues such as attention deficit/hyperactivity disorder (ADHD). This paper characterizes CwCF with ADHD within the first year of ETI treatment.
Methods: This retrospective, observational analysis examines a subgroup of CwCF participating in a longitudinal study obtaining prospective data regarding the impact of ETI on mental health. All participants started on ETI were offered enrollment, with rolling enrollment as younger children became eligible. Clinical data regarding CF symptoms, mental health diagnoses, medications, changes in mental health symptoms and BMI were collected via chart review.
Results: Before ETI, ADHD diagnoses were identified in 21 children; an additional 3 were diagnosed within the first year. Eleven children were treated with ADHD medication at ETI initiation; nine children did not use ADHD medication during the study period. In the 1-year follow-up, four children started ADHD medication. Of the 11 who started ETI on ADHD medication, five increased doses, three changed medications and/or decreased dose, and one discontinued medication. Two children experienced no changes to their treatment.

Conclusion: Most CwCF on ADHD medication underwent changes in dosing and/or medication after ETI initiation. Several children were diagnosed with ADHD after starting ETI. The role of ETI in these recent diagnoses and treatment plans is unclear. Given the prevalence of pediatric ADHD diagnoses and the medication changes that were needed by this population, additional research is warranted to clarify the relationship between ETI and ADHD in CwCF.

Kimberley Pasley is a clinical psychologist in the Division of Pulmonary and Sleep Medicine, Nationwide Children’s Hospital, Columbus, Ohio, USA.

Nidhi Patel, Maria Ansar, Anh Pham, Kelly Thomsen, Cameron J McKinzie, Deepika Polineni, Charles R Esther Jr, Rebekah F Brown.Gilbert’s syndrome leads to elevated bilirubin after initiation of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis. Pediatr Pulmonol. 2024 Jan 5. doi: 10.1002/ppul.26831. Online ahead of print.pubmed.ncbi.nlm.nih.gov/38179880/

Nidhil Patel
blog-college.ku.edu

Nine people with cystic fibrosis (pwCF) were found to have isolated elevations in serum total bilirubin after starting elexacaftor/tezacaftor/ivacaftor (ETI) that were associated with Gilbert’s Syndrome. In longitudinal examination, total bilirubin levels increased substantially after initiation of ETI without elevations in liver transaminases in those with this syndrome. Because elevated bilirubin levels in Gilbert’s Syndrome are benign, ETI was able to be continued in these individuals. Genetic testing for this relatively common syndrome should be strongly considered for pwCF experiencing isolated hyperbilirubinemia after starting ETI, since appropriate diagnosis may help pwCF avoid unnecessary interruption in this therapy with significant health benefits in CF.

Nidhi Patel is at the Division of Pulmonary Disease, Critical Care and Sleep Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.

Tanvi Patel , Kimberly McBennett, Senthilkumar Sankararaman, Teresa Schindler, Krithika Sundaram, Nori Mercuri Minich, Sindhoosha Malay, Katherine Kutney. Impact of elexacaftor/tezacaftor/ivacaftor on lipid and fat-soluble vitamin levels and association with body mass index. Pediatr Pulmonol. 2024 Mar;59(3):734-742. doi: 10.1002/ppul.26823. Epub 2024 Jan 5. pubmed.ncbi.nlm.nih.gov/38179878/

Tanvi Patel
LinkedIn

Introduction: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve gastrointestinal absorption of nutrients and may result in changes in body mass index (BMI), serum lipids, and fat-soluble vitamin levels. We hypothesized that serum lipids and vitamin levels would increase with CFTR modulator therapy and that greater increase in lipids and vitamin levels would be related to greater increase in BMI.
Methods: A retrospective study was performed to evaluate the impact of elexacaftor/tezacaftor/ivacaftor (ETI) on nutritional parameters, serum lipids, and fat-soluble vitamin levels. Pre-ETI values (<2 years prior) and post-ETI values (>1 month after) were compared. Linear regression was used to evaluate whether change in BMI is associated with the change in lipid and/or vitamin levels and whether modulator duration is associated with the degree of rise in lipid and/or vitamin levels.
Results: Adults and adolescents with CF (n = 137) were evaluated before and 31-300 days after starting ETI. Median BMI (adults 21.9 vs. 23.5 kg/m2 ; adolescents 48 vs. 63 percentile) increased after initiation of ETI. Total cholesterol (126 vs. 154 mg/dL), low-density lipoprotein cholesterol (63 vs. 78 mg/dL), non-high-density lipoprotein cholesterol (84 vs. 102 mg/dL), and high density lipoprotein cholesterol (43 vs. 49 mg/dL) increased after ETI, while triglycerides and very low density lipoprotein did not change. Median values for vitamin D (34.5 vs. 38.0 ng/mL) and vitamin A (40.1 vs. 47.9 µg/dL) increased, while vitamin E did not change significantly. There was no significant correlation between BMI change or duration of modulator therapy with vitamin levels or lipid changes.

Conclusion: After initiation of ETI therapy, serum lipids increased in our population, but most values remained within the normal range. Vitamins A and D levels increased post-ETI and no changes were noted in vitamin E. No significant correlation between the degree of BMI change and the magnitude of increase in lipids or vitamin levels was found.

Tanvi Patel is an MD candidate at Case Western Reserve University School of Medicine, Cleveland, Ohio, USA and Loyola University School of Medicine, Maywood, Illinois, USA.

Hannah E Protich , Jean P Molleston, Molly Bozic, Rebecca S Pettit Elexacaftor/Tezacaftor/Ivacaftor use in Pediatric Cystic Fibrosis Patients with Advanced Liver Disease. J Cyst Fibros
. 2024 Apr 4:S1569-1993(24)00040-7. doi: 10.1016/j.jcf.2024.03.011. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38580564/

Hannah Protich
LinkedIn

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy extends the life expectancy of people with cystic fibrosis (PwCF). However, CFTR modulators have not been well studied in patients with cystic fibrosis liver disease (CFLD), specifically those with advanced liver disease with portal hypertension. The purpose of this report is to describe the use of elexacaftor/tezacaftor/ivacaftor (ETI) in pediatric CF patients with advanced CFLD.
Methods: This retrospective case series included PwCF < 18 years old with baseline advanced CFLD initiated on ETI.
Results: Eleven PwCF and advanced CFLD were treated with ETI; six started a reduced dose regimen. No patient required treatment interruption and four patients received dose changes related to increase in transaminase and/or bilirubin elevations. Mean (SD) change in ppFEV1 from prior to ETI to highest value during therapy was 14.27 % (4.25) (p = 0.007). When evaluating the group as whole, AST decreased from baseline to last reported -15.18 (23.23) units/L (p = 0.054) and ALT slightly increased 0.73 (39.13) units/L (p = 0.96). Bilirubin increased minimally overall for patients with mean change from baseline of 0.83 (1.33) mg/dL [range -0.5-3] (p = 0.17). A model for time on ETI showed a significant decrease in AST over time of 0.955 per month of ETI but no other liver biochemistries were significant. No patient experienced decompensation of CFLD.

Conclusion: ETI therapy in pediatric CF patients with advanced CFLD can be beneficial in improving pulmonary and nutritional outcomes without negative impact on liver biochemistries or hepatic outcomes. Close monitoring is recommended to ensure safety and tolerability.

Hannah E Protich is in the Dept. of Pharmacy, Riley Hospital for Children at IU Health, 705 Riley Hospital Drive, Simon Family Tower W6111, Indianapolis, IN, USA.

Bonnie Ramsey, Christoph U Correll, David R DeMaso, Edward McKone, Elizabeth Tullis, Jennifer L Taylor-Cousar, Chenghao Chu, Nataliya Volkova, Neil Ahluwalia, David Waltz, Simon Tian, Marcus A Mall. Elexacaftor/Tezacaftor/Ivacaftor Treatment and Depression-related EventReview Am J Respir Crit Care Med. 2024 Feb 1;209(3):299-306. doi: 10.1164/rccm.202308-1525OC. Free PMC article pubmed.ncbi.nlm.nih.gov/37890129/

Bonnie Ramsey
University
of Washington

Full abstract via PubMed link.

Conclusions: Our review of data from clinical trials, postmarketing reports, an ongoing registry-based ELX/TEZ/IVA postauthorization safety study, and peer-reviewed literature suggests that depression symptoms and depression-related events reported in pwCF treated with ELX/TEZ/IVA are generally consistent with background epidemiology of these events in the CF population and do not suggest a causal relationship with ELX/TEZ/IVA treatment.

Bonnie Ramsey is at Seattle Children’s Research Institute and Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.

Erica A Roesch, Abdelkader Rahmaoui, Robert A Lazarus, Michael W Konstan. The continuing need for dornase alfa for extracellular airway DNA hydrolysis in the era of CFTR modulators. Review Expert Rev Respir Med
. 2024 Aug 30:1-16. doi: 10.1080/17476348.2024.2394694. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39176450/ Full text available

Erica Roesch
uhhosniversity.org

Introduction: The availability of cystic fibrosis transmembrane conductance regulator (CFTR) modulators opens the possibility of discontinuing some chronic pulmonary therapies to decrease cystic fibrosis (CF) treatment burden. However, CFTR modulators may not adequately address neutrophilic inflammation, which contributes to a self-perpetual cycle of viscous CF sputum, airway obstruction, inflammation, and lung function decline.
Areas covered: This review discusses the emerging role of neutrophil extracellular traps in CF and its role in CF sputum viscosity, airway obstruction, and inflammation, based on a literature search of PubMed (1990-present). We summarize clinical trials and real-world studies that support the efficacy of dornase alfa (Pulmozyme) in improving lung function and reducing pulmonary exacerbation in people with CF (PwCF), and we discuss the potential role of dornase alfa in reducing airway inflammation. We also examine the findings of short-term trials evaluating the discontinuation of mucoactive therapy in PwCF receiving CFTR modulators.
Expert opinion: Long-term studies are needed to assess the impact of discontinuing mucoactive therapy in PwCF who are clinically stable while receiving CFTR modulatory therapy. Treatment decisions should take into account the severity of underlying lung disease. People with advanced CF will likely require ongoing mucoactive therapy.

Erica A Roesch is in the Dept of Pediatrics, Rainbow Babies and Children’s Hospital and Case Western Reserve University, Cleveland, OH, USA.

Sacha Spelier, Karin de Winter-de Groot, Natascha Keijzer-Nieuwenhuijze, Yves Liem, Kors van der Ent, Jeffrey Beekman, Lieke S Kamphuis. Organoid-guided synergistic treatment of minimal function CFTR mutations with CFTR modulators, roflumilast and simvastatin: a personalised approach. Eur Respir J. 2024 Jan 25;63(1):2300770. doi: 10.1183/13993003.00770-2023. Print 2024 Jan. 37857424 pubmed.ncbi.nlm.nih.gov/37857424/ Free PMC article
This study describes how preclinical research has guided a successful personalised clinical treatment regimen in a person with minimal function CFTR, upon a synergistic treatment regimen consisting of CFTR modulators, simvastatin and roflumilast https://bit.ly/3rDTHZL

Sacha Spellier is at the Department of Pediatric Respiratory Medicine, Wilhelmina Children’s Hospital, University Medical Center, Utrecht University, Utrecht, The Netherlands.& Regenerative Medicine Utrecht, University Medical Center, Utrecht University, Utrecht, The Netherlands.

Mirjam Stahl , Martha Dohna , Simon Y Graeber , Olaf Sommerburg , Diane M Renz, Sophia T Pallenberg et al. , Impact of Elexacaftor/Tezacaftor/Ivacaftor Therapy on Lung Clearance Index and Magnetic Resonance Imaging in Children with Cystic Fibrosis and One or Two F508del Alleles. Respir J 2024 Jun 20:2400004. doi: 10.1183/13993003.00004-2024. pubmed.ncbi.nlm.nih.gov/38901883/

Mirjam Stahl
Euro Resp Soc

The aim of this study was therefore to examine the effect of ETI on the LCI and the lung MRI score in children with CF and one or two F508del alleles aged 6 to 11 years.
Methods: This prospective, observational, multicenter, post-approval study assessed the longitudinal LCI up to 12 months and the lung MRI score before and three months after initiation of ETI.
Results: A total of 107 children with CF including 40 heterozygous for F508del and a minimal function mutation (F/MF) and 67 homozygous for F508del (F/F) were enrolled in this study. Treatment with ETI improved the LCI in F/MF children (-1.0; IQR, -2.0 to -0.1; p<0.01) and F/F children (-0.8; IQR, -1.9 to -0.2; p<0.001) from 3 months onwards. Further, ETI improved the MRI global score in F/MF (-4.0; IQR, -9.0 to 0.0; p<0.01) and F/F children (-3.5; IQR, -7.3 to -0.8; p<0.001).
Conclusions: ETI improves early abnormalities in lung ventilation and morphology in school-age children with CF and at least one F508del alleles in a real-world setting. Our results support early initiation of ETI to reduce or even prevent lung disease progression in school-age children with CF.

Mirjam Stahl is in the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

Mirjam Stahl, Jobst Roehmel, Monika Eichinger, Felix Doellinger, Lutz Naehrlich, Matthias V Kopp, Anna-Maria Dittrich, Olaf Sommerburg, Partha Ray, Anita Maniktala, Tu Xu, Sarah Conner, Aniket Joshi, Molly Mascia, Mark O Wielpütz, Marcus A Mall. Long-Term Impact of Lumacaftor/Ivacaftor Treatment on Cystic Fibrosis Disease Progression in Children 2 Through 5 Years of Age Homozygous for F508del-CFTR: A Phase 2, Open-Label Clinical Trial. Ann Am Thorac Soc. 2024 Aug 22. doi: 10.1513/AnnalsATS.202402-201OC. Online ahead of print. pubmed.ncbi.nlm.nih.gov/39173175/

Rationale: Clinical trials show that lumacaftor/ivacaftor (LUM/IVA) treatment has the potential to modify early cystic fibrosis (CF) disease progression in children as young as 2 years of age.
Objective: To assess the long-term impact of LUM/IVA treatment on CF disease progression in children aged 2 through 5 years.
Methods: This phase 2 trial had two parts: Part 1, a 48-week, randomized, double-blind, placebo-controlled study of LUM/IVA in children aged 2 through 5 years (previously reported) was followed by a 48-week open-label treatment period where all children received LUM/IVA (Part 2; reported here). Endpoints assessed in Part 2 included absolute changes from baseline in chest magnetic resonance imaging (MRI) global score at week 96; weight-for-age, stature-for-age, and body mass index (BMI)-for-age z-scores at week 96; lung clearance index (LCI2.5) through week 96; chest MRI morphological score, chest MRI perfusion score, weight, stature, BMI, and microbiology cultures (oropharyngeal swabs) at week 96; sweat chloride, serum levels of immunoreactive trypsinogen, fecal elastase-1 levels, and fecal calprotectin through week 96; and number of pulmonary exacerbations (PEx), time-to-first PEx, and number of CF-related hospitalizations.
Results: Forty-nine children received ≥1 dose of LUM/IVA in the open-label period (33 in the LUM/IVA to LUM/IVA group and 16 in the placebo to LUM/IVA group); mean exposure 47.1 (SD, 5.2) weeks. The mean absolute change in MRI global score (negative value = improvement) from baseline at Week 96 was -2.7 (SD 7.0; 95% CI, -5.2 to -0.1) in the LUM/IVA to LUM/IVA group and -5.6 (SD 6.9; 95% CI, -9.2 to -1.9) in the placebo to LUM/IVA group. Improvements in LCI2.5, sweat chloride concentration, and markers of pancreatic function and intestinal inflammation were also observed in both groups. Growth parameters remained stable in both groups. The majority of children had adverse events (AEs) considered mild (38.8%) or moderate (40.8%). Two (4.1%) children discontinued LUM/IVA treatment due to AEs (distal intestinal obstruction syndrome [n=1] and alanine aminotransferase increase [n=1]).

Conclusion: These findings confirm the potential for early LUM/IVA treatment to alter the trajectory of CF disease progression, including CF lung disease, in children as young as 2 years of age.

Mirjam Stahl is at Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology, and Critical Care Medicine, Berlin, Germany. The German Center for Lung Research (DZL), associated partner site, Berlin, Germany.
The Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany.

Michelle M Szabo , Sarah E Foushee, Chelsey M McPheeters, Adrian R O’Hagan , Allan M Ramirez, Emily A O’Reilly. Impact of elexacaftor/tezacaftor/ivacaftor on respiratory colonization in an adult cystic fibrosis clinic. Am J Med Sci. 2024 Feb 7:S0002-9629(24)01059-0. doi: 10.1016/j.amjms.2024.02.001. Online ahead of print.pubmed.ncbi.nlm.nih.gov/38336262/

Michelle M Szabo
ULHealth

Background: Little research has been completed on the correlation between cystic fibrosis (CF) modulator therapy and its effect on respiratory cultures in CF patients. This study evaluated the effect of elexacaftor/tezacaftor/ivacaftor (ETI) on respiratory colonization with Pseudomonas aeruginosa.
Methods: This single center, IRB approved, retrospective chart review compared patient data two years immediately prior to ETI initiation with patient data two years post-initiation from January 2017-December 2022. Patients were included in the study if they were at least 18 years old with a diagnosis of CF and had at least one month of ETI dispensed, at least one sputum culture obtained, and were currently on ETI. Those who had not been seen since ETI initiation or received a bilateral lung transplant were excluded. The primary outcome was rate of patients with respiratory colonization post-ETI. Colonization was defined as two or more positive P. aeruginosa cultures in a 12-month period. Decolonization was defined as three consecutive negative P. aeruginosa cultures after previous colonization. Key secondary outcomes included average time to discontinuation of mucolytic therapy and relative risk of pulmonary exacerbation.
Results: A significant reduction (p<0.001) in colonization with P. aeruginosa was observed with 49 patients in the pre-ETI group compared to 25 in the post-ETI group meeting the definition of colonization (n=79). Average time to discontinuation of mucolytic therapy was 14 months (p=0.002). Relative risk of pulmonary exacerbation was 4.80 (p<0.001).
Conclusions: ETI use resulted in reduced colonization with P. aeruginosa, discontinuation of mucolytic therapy, and decreased frequency of pulmonary exacerbation.

Michelle M Szabo is PGY-2 Ambulatory Care Pharmacy Resident, UofL Health-UofL Hospital, Louisville, KY, USA.

Don S Urquhart , Heather Dowle, Kellie Moffat, Jody Forster, Steve Cunningham, Kenneth A Macleod. Lung clearance index (LCI2.5 ) changes after initiation of Elexacaftor/Tezacaftor/Ivacaftor in children with cystic fibrosis aged between 6 and 11 years: The “real-world” differs from trial data. Pediatr Pulmonol. 2024 Feb 28. doi: 10.1002/ppul.26938. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38415920/

Don S Urquhart
Healio.com

Background: Elexacaftor in combination with Tezacaftor and Ivacaftor (ETI) became licensed in the United Kingdom in early 2022 for children aged 6-11 years with cystic fibrosis (CF) and an eligible mutation. Many in this age group have excellent prior lung health making quantitative measurement of benefit challenging. Clinical trials purport that lung clearance index (LCI2.5 ) measurement is most suitable for this purpose.
Objectives: This study aimed to understand the clinical utility of LCI2.5 in detecting change after commencing ETI in the real world.
Patient selection/methods: Baseline anthropometric data were collected along with spirometry (forced expiratory volume in 1 s [FEV1 ], forced vital capacityFV and LCI2.5 measures in children aged 6-11 years with CF before starting ETI. Measures were repeated after a mean (range) of 8.2 (7-14) months of ETI treatment. The primary endpoint was a change in LCI2.5 , with secondary endpoints including change in FEV1 and change in body mass index (BMI) also reported.
Results: Twelve children were studied (seven male, mean age 9.5 years at baseline). Our study population had a mean (SD) LCI2.5 of 7.01 (1.14) and FEV1 of 96 (13) %predicted at baseline. Mean (95% confidence interval) changes in LCI2.5 [-0.7 (-1.4, 0), p = .06] and BMI [+0.7 (+0.1, +1.3), p = .03] were observed, along with changes in FEV1 of +3.1 (-1.9, +8.1) %predicted.
Conclusions: Real-world changes in LCI2.5 (-0.7) are different to those reported in clinical trials (-2.29). Lower baseline LCI2.5 as a result of prior modulator exposure, high baseline lung health, and new LCI2.5 software analyses all contribute to lower LCI2.5 values being recorded in the real world of children with CF.

Don S Urquhart is in the Department of Paediatric Respiratory and Sleep Medicine, Royal Hospital for Children and Young People,and the Department of Child Life and Health, Edinburgh Bioquarter, University of Edinburgh, Edinburgh, UK.

Renske van der Meer, Erik B Wilms , Margot N Eggermont, Helena M Paalvast, Matthijs van Luin, Richard C J M van Rossen, Harry G M Heijerman. Elexacaftor/tezacaftor/ivacaftor in liver or kidney transplanted people with cystic fibrosis using tacrolimus, a drug-drug interaction study. J Cyst Fibros. 2024 Jan 29:S1569-1993(24)00007-9. doi: 10.1016/j.jcf.2024.01.008. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38290918/

Renske van der Meer
LinkedIn

Background: The use of elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis (pwCF) after solid organ transplantation is controversial because of potential drug-drug interactions (DDI) with tacrolimus. We aimed to improve insight into the safety and clinical benefits of co-administration of ETI and tacrolimus in liver or kidney transplanted adult pwCF.: In 5 pwCF, tacrolimus concentrations were monitored during 2 weeks before and 4 weeks after starting ETI treatment. Trough levels, area under the curve (AUC) and clinical effect of ETI were investigated. During the study (6 weeks in total) adverse events were monitored.
Results: The DDI between tacrolimus and ETI resulted in an increased exposure of tacrolimus in all subjects, the dose adjusted AUC0-24h was 1.79 (median) times higher at the end of the study. Five dose adjustments were performed in 4 subjects in order to attain tacrolimus target range. No adverse events were reported and all subjects showed clinical improvement during ETI treatment.

Conclusion: The clinical value of ETI treatment in kidney and liver transplanted pwCF is clear. The use of ETI may increase tacrolimus levels moderately. Therefore, we recommend close monitoring of tacrolimus trough levels in patients who start ETI.

Renske van der Meer is in the Department of Pulmonology and Adult CF Centre, Haga Hospital, Els Borst-Eilersplein 275, The Hague 2545 AA, The Netherlands.

Steffie E M Vonk, Rianne Lub, Els J M Weersink, Ulrich Beuers, Ron A A Mathôt, E Marleen Kemper, Josje Altenburg 4 ; Amsterdam Mucociliary Clearance Disease Research Group. Stepwise Introduction of Elexacaftor-Tezacaftor-Ivacaftor in Patients With Cystic Fibrosis and Liver Cirrhosis Child-Pugh A or B Using Clinical and Therapeutic Drug Monitoring: A Case Series. Clin Ther. 2024 Feb;46(2):154-158. doi:10.1016/j.clinthera.2023.11.003. Epub 2023 Dec 1 Free article .pubmed.ncbi.nlm.nih.gov/38042631

Steffie Vonk
Hyphenprojects.nl

Purpose: Cystic fibrosis (CF) is a monogenetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein and affecting multiple organs, including the lungs and liver. Almost 90% of people affected carry at least 1 Phe508del CFTR mutation. Medical treatment with the CFTR-modulating drug elexacaftor-tezacaftor-ivacaftor (ETI) has been proven to be efficacious in carriers of at least 1 Phe508del CFTR mutation. Use of ETI in patients with CF (pwCF) and liver cirrhosis is still controversial. Therefore, stepwise introduction of ETI in pwCF and liver cirrhosis Child-Pugh A or B was evaluated using clinical and therapeutic drug monitoring.
Methods: Seven consecutive pwCF received ETI. Four dosing steps were defined, at each of which the patients underwent clinical examination, routine blood tests, and therapeutic drug monitoring. Exposure of elexacaftor, tezacaftor, and ivacaftor was assessed by means of determination of AUC.
Findings: ETI was successfully introduced and maintained in all pwCF. In those with Child-Pugh B cirrhosis (n = 2), diminishment of the dose as recommended by the label resulted in AUC values that were lower than the mean AUC values in pwCF without hepatic impairment, as reported previously.
Implications: Despite the limitations of this small case series, stepwise elevation of ETI dose did not induce clinical adverse effects or increases in serum liver test results under strict clinical follow-up and therapeutic drug monitoring, and may allow tolerable introduction of this therapy in pwCF and cirrhosis Child-Pugh A and possibly B.

Steffie E M Vonk is in the Dept of Pharmacy and Clinical Pharmacology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Steffie E M Vonk, Josje Altenburg, Ron A A Mathôt, E Marleen Kemper; Amsterdam Mucociliary Clearance Disease (AMCD) Research Group. Correlation between trough concentration and AUC for elexacaftor, tezacaftor and ivacaftor. J Cyst Fibros. 2024 Mar 16:S1569-1993(24)00038-9. doi: 10.1016/j.jcf.2024.03.010. Online ahead of print Free article pubmed.ncbi.nlm.nih.gov/38494378/
Therapeutic drug monitoring (TDM) of elexacaftor, tezacaftor, ivacaftor (ETI) could be a useful tool to increase efficacy and decrease the risk of adverse effects in people with Cystic Fibrosis (pwCF). It is however unclear whether drug exposure should be monitored by assessment of trough (Cmin) levels or determination of the area under the curve (AUC). Hence, in this study the correlation between measured Cmin concentration and AUC was evaluated. Serial plasma samples, including Cmin, were drawn after administration of ETI in order to calculate the AUC and assess the correlation between the two parameters. A linear correlation between Cmin and AUC0-24h was found, with Pearson’s r correlation coefficients of 0.963, 0.908 and 0.860 for elexacaftor, tezacaftor and ivacaftor, respectively. Exposure of ETI may be monitored by assessment of Cmin levels.

Steffie E M Vonk is at Amsterdam UMC location University of Amsterdam, Department of Hospital Pharmacy & Clinical Pharmacology, Meibergdreef 9, Amsterdam, the Netherlands

Tezacaftor / Ivacftor / VX-445 (TRKAFTA or KAFTRIO)