VX-445 (ELEXACAFTOR)/TEZACAFTOR/IVACAFTOR  

“TRIKAFTA” (USA)          “KAFTRIO” (UK)

2018

2018 Keating DMarigowda GBurr LDaines CMall MAMcKone EFRamsey BWRowe SMSass LATullis EMcKee CMMoskowitz SMRobertson SSavage JSimard CVan Goor FWaltz DXuan FYoung TTaylor-Cousar JLVX16-445-001 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 F508delCFTR 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 F508delCFTR 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 GavioliNerli GuardadoFarah HaniffNouran DeiabEtty Vider.  A current review of the safety of cystic fibrosis transmembrane conductance regulator modulatorsJ 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 LaselvaClaire BartlettTarini N A GunawardenaHong OuyangPaul D W EckfordTheo 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 TRIKAFTATM 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 TRIKAFTATM 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 KannerZunaira ShujaPapiya ChoudhuryAnanya JainHenry 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 LaselvaJacqueline McCormackClaire BartlettWan IpTarini N A GunawardenaHong OuyangPaul D W EckfordTanja GonskaTheo J MoraesChristine 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 ORKAMBITM and TRIKAFTATM 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 TRIKAFTATM 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 TRIKAFTATMcombination. 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 VeitAriel RoldanMark A HancockDillon F Da FonteHaijin XuMaytham HusseinSaul FrenkielElias MatoukTony VelkovGergely 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 TindellAmanda SuSarah M Oros, Abner O RayapatiGopalkumar 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 ÇobanoğluUğur ÖzçelikErkan ÇakırTuğba Şişmanlar EyüboğluSevgi PekcanGüzin 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 RotoloStephanie DuehlmeyerSarah M SlackHollyann R JacobsBrian 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.

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.

Giada RighettiMonica CasaleMichele TonelliNara Liessi Paola FossaNicoletta PedemonteEnrico Millo Elena Cichero.  New Insights into the Binding Features of F508del CFTR Potentiators: A Molecular Docking, Pharmacophore Mapping and QSAR Analysis ApproachPharmaceuticals (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 (r2cv) = 0.74, a non-cross validated r2 (r2ncv) = 0.90, root mean square error (RMSE) = 0.347, and a test set r2 (r2pred) = 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 MTaylor-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 SouthernJared MurphyIan P SinhaSarah 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 StanojevicKatarina VukovojacJenna SykesFelix RatjenElizabeth TullisAnne L StephensonProjecting 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’CarrollCatherine CarrollBrenda GroganAnna ConnollyLynda O’ShaughnessyTrevor T NicholsonCharles G GallagherEdward F McKone.   Efficacy of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and advanced lung diseaseEur 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

Guido VeitChristian VaccarinGergely 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).

Jennifer L Taylor-CousarR 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.

Edith T ZemanickJennifer L Taylor-CousarJane DaviesRonald L GibsonMarcus A MallEdward F McKone et 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 DainesWayne 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 (1112). 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 (1315). Longer-term data from these extensions show ongoing safety and efficacy even in the youngest patients (1617).   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 StashowerPatrick CarrVirginia MillerBarrett ZlotoffNovel reaction to new cystic fibrosis medication TrikaftaClin 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 MartinE BurnetA Ronayette-PreiraP de CarliJ MartinL DelmasB PrieurP-R BurgelPatient perspectives following initiation of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis and advanced lung diseaseRespir 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 10th to August 21th2020 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.

Frédéric BecqSandra MirvalThomas CarrezManuella LévêqueArnaud BilletChristelle CorauxEdouard SageAnne 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.

Marika Comegna Vito TerlizziDonatello SalvatoreCarmela ColangeloAntonella Miriam Di LulloImmacolata Zollo Giovanni TaccettiGiuseppe CastaldoFelice 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.

Scott D SagelUmer KhanSonya L HeltsheJohn P ClancyDrucy BorowitzDaniel GelfondScott H DonaldsonAntoinette MoranFelix RatjenJill M VanDalfsenSteven M RoweClinical Effectiveness of Lumacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR. A Clinical TrialAnn 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/m2P < 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 FurstovaTereza DousovaJakub BeranekMalgorzata LibikLibor FilaMartin ModrakOndrej CinekMilan Macek JrPavel 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 SalvatoreCarmela ColangeloMichele D’AndriaGiovanni MarsicovetereDomenica PassarellaElexacaftor/tezacaftor/ivacaftor as rescue therapy in a patient with the cystic fibrosis genotype F508DELG1244EClin 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 BreuerDavid ShoseyovShifra KoretzNadia AlyanJoel ReiterMalena Cohen-CymberknohIsaiah WexlerEitan 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 SalvatoreAngela PepeVincenzo CarnovaleFabio MajoRita Padoan, Serena QuattrucciMarco SalvatoreDomenica TaruscioAnnalisa AmatoGianluca FerrariGiuseppe 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 ScullyPeter MarchettiGregory S SawickiAhmet UluerManuela CernadasRebecca E CagninaJohn C KennedyMelissa S PutmanThe effect of elexacaftor/tezacaftor/ivacaftor (ETI) on glycemia in adults with cystic fibrosisJ 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 BassJefferson N BrownellVirginia 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 KeoghRebecca CosgriffEleni-Rosalina AndrinopoulouKeith G BrownleeSiobhán B CarrKarla Diaz-OrdazEmily GrangerNicholas P JewellAlex LewinClemence LeyratDaniela K SchlüterMaarten van SmedenRhonda D SzczesniakGary 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 BenningerCesar TrilloJorge LascanoCFTR modulator use in post lung transplant recipientsJ 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 ZemanickJennifer L Taylor-CousarJane DaviesRonald L GibsonMarcus A MallEdward 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

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 baseline.
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