SECTION TWO – GENERAL MODULATOR REFERENCES FROM 2020

THERE MAY BE SOME DUPLICATES AS THEY WILL HAVE BEEN FIRST PICKED UP WHEN PUBLISHED ON LINE 

2020              2020                   2020

B L Aalbers R W Hofland I Bronsveld K M de Winter-de Groot H G M Arets A C de Kiviet M M M van Oirschot-van de VenM A KruijswijkS SchotmanS MichelC K van der EntH G M Heijerman.   Females With Cystic Fibrosis Have a Larger Decrease in Sweat Chloride in Response to lumacaftor/ivacaftor Compared to Males.   J Cyst Fibros  2020 May 21;S1569-1993(20)30135-1. [Pubmed]
A study to explore which patient-related factors influence sweat test response to CFTR modulators, as well as examining the correlation between the sweat chloride response and ppFEV1 or BMI response, using systematically collected real-life clinical data.
160 CF patients were identified who had used lumacaftor/ivacaftor (ORKAMBI) for at least six months. Of these patients, age, sweat chloride levels, ppFEV1 weight and BMI at the start of treatment and after 6 months were collected retrospectively. Pearson and Spearman tests were performed to assess correlations.
Results: Females compared to males in this group showed a larger response in sweat chloride (mean difference 10.6 mmol/l, 95% CI: 5.7-15.4) and BMI (mean difference 0.27 kg/m2, 95% CI: 0.01-0.54). A modest but significant correlation was found between patient weight and sweat chloride response (Pearson R = 0.244, p = 0.001), which diminished upon correction for the other factors. The correlation between sex and sweat chloride response remained; R = 0.253, p = 0.001. Sweat chloride response did not correlate with ppFEV1 change or BMI change at 6 months after start of therapy.

The authors concluded that the Sweat chloride response is larger in females compared to males, which also explains the negative correlation of weight with the response in sweat chloride concentration after start of lumacaftor/ivacaftor (ORKAMBI). Sweat chloride response does not correlate with the responses in ppFEV1and BMI. This information may help the interpretation of sweat test results acquired for the follow up and evaluation of CFTR modulating treatments and warrants further investigation into the underlying mechanisms of sex differences in response to CFTR modulators.

Dr B L Aalbers is in the Department of Pulmonology, University Medical Center Utrecht, the Netherlands.

Conclusions: Treatment with ivacaftor plus best supportive care versus best supportive care alone is not cost-effective at or near commonly accepted WTP thresholds.

Keel Wherry is  the Director, Health Economics and Outcomes Research at Medtronics, Minneapolis, MN, USA.

 B L Aalbers K M de Winter-de Groot H G M Arets R W Hofland A C de Kiviet M M M van Oirschot-van de Ven M A Kruijswijk S Schotman S Michel C K van der Ent H G M Heijerman.  Clinical Effect of lumacaftor/ivacaftor in F508del Homozygous CF Patients With FEV 1 ≥ 90% Predicted at Baseline. J Cyst Fibros. 2020 Jul;19(4):654-658.doi: 10.1016/j.jcf.2019.12.015. Epub 2020 Jan 7. [Pubmed]
 Objective: The first available CFTR modulator combination for homozygous F508del patients, lumacaftor/ivacaftor (ORKAMBI) , has not been tested in patients with percentage predicted (pp)FEV1 > 90 in the phase III trials. The objective of this study is to share real life experience about treatment results in this group.   In this retrospective observational study, patients aged 6 years or older starting on lumacaftor/ivacaftor in standard care were in strict follow up. For these patients, data were obtained about FEV1, BMI, CFQ-R and sweat chloride before start and after 6 months of treatment, and data about FEV1 and BMI were recorded every 3 months. Exacerbations were recorded continuously.
Results: They identified 40 patients with a ppFEV1 ≥ 90 at the start of lumacaftor/ivacaftor who had been in follow up for at least 12 months. After 12 months, ppFEV1 was unchanged, whereas mean absolute change in BMI was +0.88 (p = 0.001) with a mean change in SDS for BMI of +0.26 (p = 0.014). Mean CFQ-R overall score at 6 months improved by 2.6% (p = 0.004) and mean decrease in sweat chloride was -27.3 mEq/L (p = 0.000). Exacerbation rate declined from 1.03 to 0.53/person/year (p = 0.003). One patient discontinued treatment in the first 12 months because of progression of CFRLD, two paused treatment but resumed later.
Conclusion: Homozygous F508del patients starting lumacaftor/ivacaftor at ppFEV1 ≥ 90 improved significantly in nutritional status, sweat chloride levels and exacerbation rate, but did not respond in ppFEV1. Treatment is well tolerated in this patient group. These effects make it worth considering to treat this group of patients with lumacaftor/ivacaftor.

Dr B L Aalbers is in the Department of Pulmonology, University Medical Center Utrecht, the Netherlands.

Albright JC, Houck AP, Pettit RS. Effects of CFTR modulators on pharmacokinetics of tobramycin during acute pulmonary exacerbations in the pediatric cystic fibrosis population [published online ahead of print, 2020 Jun 22]. Pediatr Pulmonol. 2020;10.1002/ppul.24917.
Individuals with cystic fibrosis (CF) require higher dosages of aminoglycosides due to an increased volume of distribution (Vd ) and clearance. Optimal dosing of aminoglycosides in the CF population is essential as repeated exposure to aminoglycosides during acute pulmonary exacerbations increases risk of nephrotoxicity and ototoxicity. To date, no studies have evaluated whether chronic CFTR modulator therapy affects pharmacokinetics of aminoglycoside antibiotics in CF patients. The objective of this study was to determine if the addition of a CFTR modulator affects elimination rate (Ke ) for intravenously administered tobramycin in the pediatric CF population
This retrospective study included patients aged 2 to 18 years with CF receiving chronic therapy with a CFTR modulator. Patients included had an admission both pre- and post-chronic CFTR modulator therapy during which they received therapy with IV tobramycin.

The pharmacokinetic parameters of intravenously administered tobramycin during admission for acute pulmonary exacerbation do not appear to change significantly after initiating chronic therapy with a CFTR modulator. Empiric dose adjustments for patients on CFTR modulators are not recommended. This article is protected by copyright. All rights reserved.

Dr Jared C  Albright is at the Riley Hospital for Children at IU Health, Indianapolis.

Allobawi R, Ghelani DP, Schneider-Futschik EK. Metabolomic Description of Ivacaftor Elevating Polymyxin B Mediated Antibacterial Activity in Cystic Fibrosis Pseudomonas aeruginosa. ACS Pharmacol Transl Sci. 2020;3(3):433-443. Published 2020 Apr 27. doi:10.1021/acsptsci.0c00030 [Pubmed]

Dr Elena Schneider- Futschik

We have demonstrated that ivacaftor displays synergistic antibacterial activity in combination with polymyxin B against polymyxin-resistant Pseudomonas aeruginosa that commonly colonizes the lungs of people with cystic fibrosis (CF). However, the underlying mechanism(s) remain unclear. In the present study, we employed untargeted metabolomics to investigate  synergistic killing mechanism of polymyxin B in combination with ivacaftor against a polymyxin-susceptible P. aeruginosa FADDI-PA111 (polymyxin B MIC = 2 mg/L) and a polymyxin-resistant CF P. aeruginosaFADDI-PA006 (polymyxin B MIC = 8 mg/L). Metabolites were extracted at 3 h after treatments with polymyxin B alone (2 μg/mL for FADDI-PA111 and 4 μg/mL FADDI-PA006 P. aeruginosa), ivacaftor alone (8 μg/mL), and in combination. Polymyxin B monotherapy induced significant perturbations in the glycerophospholipid and fatty acid metabolism pathways against FADDI-PA111 and to a lesser extent in FADDI-PA006. In both strains, treatment with ivacaftor alone induced more pronounced perturbations in glycerophospholipid and fatty acid metabolism pathways than that with polymyxin B alone. This highlights the unique antimicrobial mode of action of ivacaftor. Pathway analysis revealed that in combination treatment, polymyxin B mediated killing is elevated by ivacaftor, largely due to the inhibition of cell envelope biogenesis via suppression of key membrane lipid metabolites (e.g., sn-glycerol 3-phosphate and sn-glycero-3-phosphoethanolamine) as well as perturbations in peptidoglycan and lipopolysaccharide biosynthesis. Furthermore, significant perturbations in the levels of amino sugars and nucleotide sugars, glycolysis, the tricarboxylic acid cycle, and pyrimidine ribonucleotide biogenesis were observed with the combination treatment. These findings provide novel mechanistic information on the synergistic antibacterial activity of polymyxin-ivacaftor combination.

Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia

Margarida D AmaralMargarida C QuaresmaInes Pankonien.What Role Does CFTR Play in Development, Differentiation, Regeneration and Cancer?Int J Mol Sci 2020 Apr 29;21(9):E3133.doi: 10.3390/ijms21093133. [Pubmed]

   Margarida Quaresma

         Margarida Amaral

One of the key features associated with the substantial increase in life expectancy for individuals with CF is an elevated predisposition to cancer, firmly established by recent studies involving large cohorts. With the recent advances in cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and the increased long-term survival rate of individuals with cystic fibrosis (CF), this is a novel challenge emerging at the forefront of this disease. However, the mechanisms linking dysfunctional CFTR to carcinogenesis have yet to be unravelled. Clues to this challenging open question emerge from key findings in an increasing number of studies showing that CFTR plays a role in fundamental cellular processes such as foetal development, epithelial differentiation/polarization, and regeneration, as well as in epithelial-mesenchymal transition (EMT).
Here, we provide state-of-the-art descriptions on the moonlight roles of CFTR in these processes, highlighting how they can contribute to novel therapeutic strategies. However, such roles are still largely unknown, so we need rapid progress in the elucidation of the underlying mechanisms to find the answers and thus tailor the most appropriate therapeutic approaches.

From the BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Portugal.

– A very interesting detailed and timely review of this important subject from Margarida Amaral’s laboratory.

Aoyama BCMogayzel PJ.  Ivacaftor for the treatment of cystic fibrosis in children under six years of age. 
Expert Rev Respir Med.
 
2020 Mar 17:1-11. doi: 10.1080/17476348.2020.1741352. [Epub ahead of print]  [Pubmed]
The authors reviewed the sentinel studies that lead to the approval of the use of ivacaftor in people with CF age six months and older with at least one CFTR gene mutation that is responsive to ivacaftor based on clinical trial and/or in vitro data. Children with CF have the greatest potential to benefit from CFTR modulator therapy when it is initiated prior to the development of permanent damage; however, challenges remain regarding use of ivacaftor in the youngest pediatric population.                      Ivacaftor is safe and effective CFTR modulator that can be prescribed in children over six months of age with at least one CFTR gene mutation that is responsive to ivacaftor.

From the Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins University School of Medicine, Baltimore,

Elizabeth Baker William T HarrisSteven M RoweSarah B RutlandGabriela R Oates.  Tobacco smoke exposure limits the therapeutic benefit of tezacaftor/ivacaftor in pediatric patients with cystic fibrosis.  J Cyst Fibros  2020 Oct 3;S1569-1993(20)30870-5.doi: 10.1016/j.jcf.2020.09.011.Online ahead of print.[Pubmed]

   Elizabeth Baker

Objectives: Tobacco smoke exposure reduces CFTR functional expression in vitro and contributes to acquired CFTR dysfunction. We investigated whether it also inhibits the clinical benefit of CFTR modulators, focusing on tezacaftor/ivacaftor, approved in February 2018 for individuals with CF age ≥12 years.
Methods: A retrospective longitudinal analysis of encounter-based data from the CF Foundation Patient Registry (2016-2018) compared the slope of change in lung function (GLI FEV1% predicted) before and after tezacaftor/ivacaftor initiation in smoke-exposed vs unexposed age-eligible pediatric patients. Tobacco smoke exposure (Ever/Never) was determined from caregiver self-report. Statistical analyses used hierarchical linear mixed modeling and fixed effects regression modeling.
Results: The sample included 6,653 individuals with a total of 105,539 person-period observations. Tezacaftor/ivacaftor was prescribed to 19% (1,251) of individuals, mean age 17 years, mean baseline ppFEV1 83%, 28% smoke-exposed. Tezacaftor/ivacaftor users who were smoke-exposed had a lower baseline ppFEV1 and experienced a greater lung function decline. Over two years, the difference in ppFEV1 by smoke exposure among tezacaftor/ivacaftor users increased by 1.2% (7.6% to 8.8%, p<0.001). In both mixed effects and fixed effects regression models, tezacaftor/ivacaftor use was associated with improved ppFEV1 among unexposed individuals (1.2% and 1.7%, respectively; p<0.001 for both) but provided no benefit among smoke-exposed counterparts (0.3%, p = 0.5 and 0.6%, p = 0.07, respectively).

Conclusion: Tobacco smoke exposure nullifies the therapeutic benefit of tezacaftor/ivacaftor among individuals with CF aged 12-20 years old. To maximize the therapeutic opportunity of CFTR modulators, every effort must be taken to eliminate smoke exposure in CF.

Dr Elizabeth Baker is in the department of sociology at University of Alabama at Birmingham, Birmingham, AL, USA

I M Balfour-Lynn J A King.  CFTR Modulator Therapies – Effect on Life Expectancy in People With Cystic Fibrosis.  Paediatr Respir Rev   2020 May 26;S1526-0542(20)30081-6. doi: 10.1016/j.prrv.2020.05.002. Online ahead of print. [Pubmed]

    Ian Balfour-Lynn

CFTR modulators have dramatically changed the clinical course of CF in those fortunate enough to receive them. Inevitably, randomised controlled trials during the development of these drugs are too short to use mortality as an outcome. Evidence for their effect on life expectancy are best gained from real world registry studies specifically looking at mortality, but these are only available for ivacaftor to date. Therefore, indirect evidence must be obtained by looking at outcomes known to affect mortality and seeing the effect of these drugs on those outcomes

Dr Ian Balfour-Lynn is a consultant paediatrician at the Royal Brompton Hospital, London

Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, Burgel PR, Tullis E, Castaños C, Castellani C, Byrnes CA, Cathcart F, Chotirmall SH, Cosgriff R, Eichler I, Fajac I, Goss CH, Drevinek P, Farrell PM, Gravelle AM, Havermans T, Mayer-Hamblett N, Kashirskaya N, Kerem E, Mathew JL, McKone EF, Naehrlich L, Nasr SZ, Oates GR, O’Neill C, Pypops U, Raraigh KS, Rowe SM, Southern KW, Sivam S, Stephenson AL, Zampoli M, Ratjen F.  The Future of Cystic Fibrosis Care: A Global Perspective. Lancet Respir Med Jan 2020;8(1): 65-124   [Pubmed]

      Felix Ratjen

     Scott Bell

The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis, which was once a fatal disease of infants and young children. However, although life expectancy for people with cystic fibrosis has increased substantially, the disease continues to limit survival and quality of life, and results in a large burden of care for people with cystic fibrosis and their families. Furthermore, epidemiological studies in the past two decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognised in many regions of the world. The Lancet Respiratory Medicine Commission on the future of cystic fibrosis care was established at a time of great change in the clinical care of people with the disease, with a growing population of adult patients, widespread genetic testing supporting the diagnosis of cystic fibrosis, and the development of therapies targeting defects in the cystic fibrosis transmembrane conductance regulator (CFTR), which are likely to affect the natural trajectory of the disease. The aim of the Commission was to bring to the attention of patients, health-care professionals, researchers, funders, service providers, and policy makers the various challenges associated with the changing landscape of cystic fibrosis care and the opportunities available for progress, providing a blueprint for the future of cystic fibrosis care. The discovery of the CFTR gene in the late 1980s triggered a surge of basic research that enhanced understanding of the pathophysiology and the genotype-phenotype relationships of this clinically variable disease. Until recently, available treatments could only control symptoms and restrict the complications of cystic fibrosis, but advances in CFTR modulator therapies to address the basic defect of cystic fibrosis have been remarkable and the field is evolving rapidly. However, CFTR modulators approved for use to date are highly expensive, which has prompted questions about the affordability of new treatments and served to emphasise the considerable gap in health outcomes for patients with cystic fibrosis between high-income countries, and low-income and middle-income countries (LMICs). Advances in clinical care have been multifaceted and include earlier diagnosis through the implementation of newborn screening programmes, formalised airway clearance therapy, and reduced malnutrition through the use of effective pancreatic enzyme replacement and a high-energy, high-protein diet. Centre-based care has become the norm in high-income countries, allowing patients to benefit from the skills of expert members of multidisciplinary teams. Pharmacological interventions to address respiratory manifestations now include drugs that target airway mucus and airway surface liquid hydration, and antimicrobial therapies such as antibiotic eradication treatment in early-stage infections and protocols for maintenance therapy of chronic infections. Despite the recent breakthrough with CFTR modulators for cystic fibrosis, the development of novel mucolytic, anti-inflammatory, and anti-infective therapies is likely to remain important, especially for patients with more advanced stages of lung disease. As the median age of patients with cystic fibrosis increases, with a rapid increase in the population of adults living with the disease, complications of cystic fibrosis are becoming increasingly common. Steps need to be taken to ensure that enough highly qualified professionals are present in cystic fibrosis centres to meet the needs of ageing patients, and new technologies need to be adopted to support communication between patients and health-care providers. In considering the future of cystic fibrosis care, the Commission focused on five key areas, which are discussed in this report: the changing epidemiology of cystic fibrosis (section 1); future challenges of clinical care and its delivery (section 2); the building of cystic fibrosis care globally (section 3); novel therapeutics (section 4); and patient engagement (section 5). In panel 1, we summarise key messages of the Commission. The challenges faced by all stakeholders in building and developing cystic fibrosis care globally are substantial, but many opportunities exist for improved care and health outcomes for patients in countries with established cystic fibrosis care programmes, and in LMICs where integrated multidisciplinary care is not available, and resources are lacking at present. A concerted effort is needed to ensure that all patients with cystic fibrosis have access to high-quality health care in the future.

Scott Bell and Felix Ratjen coordinated the Commision and reviewed and edited all sections of the paper.

Prof. Scott Bell of the Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.  Previous editor of the JCF.

Prof. Felix Ratjen of the Division of Respiratory Medicine, Department of Paediatrics Translational Research Programme, Hospital for Sick Children, University of Toronto, Toronto, Canada

-This really impressive article by 38 of the world’s experts with 522 references can be unreservedly recommended for anyone who wishes a detailed comprehensive readable review of the subject.

Bose SJKrainer GNg DRSSchenkel MShishido HYoon JSHaggie PMSchlierf MSheppard DNSkach WR. Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR. J Cyst Fibros. 2020 Jan 2. pii: S1569-1993(19)30989-0. doi: 10.1016/j.jcf.2019.12.009. [Epub ahead of print] [Pubmed]
The treatment of cystic fibrosis (CF) has been transformed by orally-bioavailable small molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), which restore function to CF mutants. However, CFTR modulators are not available to all people with CF and better modulators are required to prevent disease progression. Here, they review selectively recent advances in CFTR folding, function and pharmacology. They highlight ensemble and single-molecule studies of CFTR folding, which provide new insight into CFTR assembly, its perturbation by CF mutations and rescue by CFTR modulators. They discuss species-dependent differences in the action of the F508del-CFTR mutation on CFTR expression, stability and function, which might influence pharmacological studies of CFTR modulators in CF animal models. Finally, they illuminate the identification of combinations of two CFTR potentiators (termed co-potentiators), which restore therapeutically-relevant levels of CFTR activity to rare CF mutations. Thus, mechanistic studies of CFTR folding, function and pharmacology inform the development of highly effective CFTR modulators.

The first author of this multinational paper is S J Bose from the School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1TD, UK

Pierre-Régis Burgel Anne Munck Isabelle Durieu Raphaël Chiron Laurent Mely Anne Prevotat  et al, French Cystic Fibrosis Reference Network Study GroupReal-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients With Cystic Fibrosis. Am J Respir Crit Care Med. 2020 Jan 15;201(2):188-197. doi: 10.1164/rccm.201906-1227OC. [Pubmed]

Pierre-Regis Burgel

To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life post approval setting. The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society’s recommendations.
Main findings – Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or non-respiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses

Dr Pierre-Régis Burgel is at the Faculty of Medicine, Paris Descartes CPSC.

Chevalier BHinzpeter A. The influence of CFTR complex alleles on precision therapy of cystic fibrosis.  J Cyst Fibros. 2020 Mar;19 Suppl 1:S15-S18. doi: 10.1016/j.jcf.2019.12.008. Epub 2019 Dec 26.[Pubmed]      CFTR is an extensively studied gene and multiple sequence variants have been identified, many of which still need to be defined as neutral or disease causing. Complex alleles are defined when at least two variants are identified on the same allele. Each pathogenic variant can affect distinct steps of the CFTR biogenesis. As CFTR modulators are being developed to alleviate specific defects, pathogenic variants need to be characterized to propose adequate treatments. Conversely, cis-variants can affect treatment response when defects are additive or if they alter the binding or efficacy of the modulator. Hence, complex alleles increase the complexity of CFTR variant classification and need to be assigned as neutral, disease causing or modulating treatment efficacy. This review was based on a symposium session presented at the 16th ECFS Basic Science Conference, Dubrovnik, Croatia, 27 to 30 March, 2019.

Both authors from INSERM U1151, Institut Necker Enfants Malades, Paris, France; Université Paris Descartes, Paris, France. Electronic address: benoit.chevalier@inserm.fr.

Claudio CostantiniMatteo PuccettiMarilena ParianoGiorgia RengaClaudia StincardiniFiorella D’OnofrioMarina M BelletBarbara CelliniStefano GiovagnoliLuigina Romani. Selectively targeting key inflammatory pathways in cystic fibrosisEur J Med Chem 2020 Nov 15;206:112717.doi: 10.1016/j.ejmech.2020.112717.Epub 2020 Aug 9.[Pubmed]
The development of modulators targeting the basic defect of CFTR has represented a major breakthrough in CF therapy, but the impact on inflammation has remained enigmatic. The emerging scenario taking hold in the field points to inflammation as a major, somehow missed, therapeutic target for prevention of lung decline. Not surprisingly, the development of anti-inflammatory drugs is taking its share in the drug development pipeline. But the path is not straightforward and targeting inflammation should be balanced with the increased risk of infection. The strategy to restore the homeostatic regulation of inflammation to efficiently respond to infection while preventing lung damage needs to be based on identifying and targeting endogenous immunoregulatory pathways that are defective in CF.

The authors provide an overview of anti-inflammatory drugs currently approved or under investigation in CF patients, and present our recent studies on how the knowledge on defective immune pathways in CF may translate into innovative and selective anti-inflammatory therapeutics.Through the discovery of naturally occurring molecules or their synthetic mimics, this review emphasizes the critical importance of selectively targeting key inflammatory pathways to preserve immunocompetence in CF patients.

Claudio Costantini is a post-doctoral researcher in the Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy.

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

Jane C Davies Claire E Wainwright Gregory S Sawicki Mark N HigginsDaniel CampbellChristopher Harris Paul Panorchan Eric Haseltine Simon Tian Margaret Rosenfeld ARRIVAL Study GroupIvacaftor in Infants Aged 4 to <12 Months With Cystic Fibrosis and a Gating Mutation: Results of a 2-Part Phase 3 Clinical TrialAm J Respir Crit Care Med 2020 Oct 7. doi: 10.1164/rccm.202008-3177OC.Online ahead of print.[Pubmed]

          Jane Davies

Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here we report results for cohorts aged 4 to <12 months. Objectives: Evaluate safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with ≥1 gating mutation.
Methods: ARRIVAL is a single-arm phase 3 study. Infants received ivacaftor 25 or 50 mg every 12 hours based on age and weight for 4 days in part A and 24 weeks in part B.
Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (4 participated in both). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild/moderate. In part B, cough was the most common adverse event (n=10 [58.8%]). Five infants (part A: n=1 [8.3%]; part B: n=4 [23.5%]) had serious adverse events, all considered not/unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5 × upper limit of normal at week 24. No other adverse trends in laboratory tests, vital signs, or electrocardiogram parameters were reported. Sweat chloride levels and measures of pancreatic obstruction improved.

Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with ≥1 gating mutation. Clinical trial registration available at www.clinicaltrials.gov, ID:NCT02725567.

Prof Jane Davies is at the National Heart & Lung Institute, Imperial College London and Royal Brompton Hospital, London, United Kingdom of Great Britain and Northern Ireland; j.c.davies@imperial.ac.uk.

Davies JC, Sermet-Gaudelus I, Naehrlich L, Harris RS, Campbell D, Ahluwalia N, Short C, Haseltine E, Panorchan P, Saunders C, Owen CA, Wainwright CE; VX16-661-115 Investigator Group.   A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation.     J Cyst Fibros. 2020 Sep 21:S1569-1993(20)30811-0. doi: 10.1016/j.jcf.2020.07.023. Online ahead of print.Free article. [Pubmed]
Background: The CFTR modulator tezacaftor/ivacaftor was efficacious and generally safe and well tolerated in Phase 3 studies in participants ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous with a residual function-CFTR mutation (F/F or F/RF respectively). We evaluated tezacaftor/ivacaftor’s efficacy and safety over 8 weeks in participants 6 through 11 years of age with these mutations.
Methods: Participants were randomized 4:1 to tezacaftor/ivacaftor or a blinding group (placebo for F/F, ivacaftor for F/RF). The primary endpoint was within-group change from baseline in the lung clearance index 2·5 (LCI2·5) through Week 8. Secondary endpoints were change from baseline in sweat chloride (SwCl), cystic fibrosis questionnaire-revised (CFQ-R) respiratory domain score, and safety.
Results: Sixty-seven participants received at least one study drug dose. Of those, 54 received tezacaftor/ivacaftor (F/F, 42; F/RF, 12), 10 placebo, and 3 ivacaftor; 66 completed the study. The within-group change in LCI2·5 was significantly reduced (improved) by -0·51 (95% CI: -0·74, -0·29). SwCl concentration decreased (improved) by -12·3 mmol/L and CFQ-R respiratory domain score increased (improved, nonsignificantly) by 2·3 points. There were no serious adverse events (AEs) or AEs leading to tezacaftor/ivacaftor discontinuation or interruption. The most common AEs (≥10%) in participants receiving tezacaftor/ivacaftor were cough, headache, and productive cough.
Conclusions: Tezacaftor/ivacaftor improved lung function (assessed using LCI) and CFTR function (measured by SwCl concentration) in participants 6 through 11 years of age with F/F or F/RF genotypes. Tezacaftor/ivacaftor was safe and well tolerated; no new safety concerns were identified.

Dr Jane Davies is Professor at the National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom

Danahay HLLilley SFox RCharlton HSabater JButton BMcCarthy CCollingwood SPGosling M. TMEM16A Potentiation: A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis. Am J Respir Crit Care Med. 2020 Jan 3. doi: 10.1164/rccm.201908-1641OC. [Epub ahead of print] [Pubmed]

     Henry Donahay

Rationale: Enhancing non-CFTR mediated anion secretion is an attractive therapeutic approach for the treatment of cystic fibrosis and other muco-obstructive diseases. Objectives: To determine the effects of TMEM16A potentiation upon epithelial fluid secretion and mucociliary clearance. Methods: The effects of a novel low molecular weight TMEM16A potentiator (ETX001) were evaluated in human cell and animal models of airway epithelial function and mucus transport. Measurements & Main Results: Potentiating the activity of TMEM16A with ETX001 increased the Ca2+-activated Cl- channel activity and anion secretion in human bronchial epithelial cells from cystic fibrosis patients without impacting on calcium signalling. ETX001 rapidly increased fluid secretion and airway surface liquid height in cystic fibrosis human bronchial epithelial cells under both static and conditions designed to mimic the shear stress associated with tidal breathing. In ovine models of mucus clearance (tracheal mucus velocity and mucociliary clearance), inhaled ETX001 was able to accelerate clearance both when CFTR function was reduced by administration of a pharmacological blocker and when CFTR was fully functional. Conclusions: Enhancing the activity of TMEM16A increases epithelial fluid secretion and enhances mucus clearance independent of CFTR function. TMEM16A potentiation is a novel approach for the treatment of patients with cystic fibrosis and non-CF muco-obstructive diseases. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

De Jong E, Garratt LW, Looi K, Lee AHY, Ling KM, Smith ML, Falsafi R, Sutanto EN, Hillas J, Iosifidis T, Martinovich KM, Shaw NC, Montgomery ST, Kicic-Starcevich E, Lannigan FJ, Vijayasekaran S, Hancock REW, Stick SM, Kicic A; WAERP, Arest CF. Ivacaftor or lumacaftor/ivacaftor treatment does not alter the core CF airway epithelial gene response to rhinovirus.   J Cyst Fibros. 2020 Jul 17:S1569-1993(20)30796-7. doi: 10.1016/j.jcf.2020.07.004. Online ahead of print. [Pubmed]

      Emma De Jong

Background: Aberrant responses by the cystic fibrosis airway epithelium during viral infection may underly the clinical observations. Whether CFTR modulators affect antiviral responses by CF epithelia is presently unknown. We tested the hypothesis that treatment of CF epithelial cells with ivacaftor (Iva) or ivacaftor/lumacaftor (Iva/Lum) would improve control of rhinovirus infection.
Methods: Nineteen CF epithelial cultures (10 homozygous for p.Phe508del as CFTR Class 2, 9 p.Phe508del/p.Gly551Asp as Class 3) were infected with rhinovirus 1B at multiplicity of infection 12 for 24 h. Culture RNA and supernatants were harvested to assess gene and protein expression respectively.
Results: RNA-seq analysis comparing rhinovirus infected cultures to control identified 796 and 629 differentially expressed genes for Class 2 and Class 3, respectively. This gene response was highly conserved when cells were treated with CFTR modulators and were predicted to be driven by the same interferon-pathway transcriptional regulators (IFNA, IFNL1, IFNG, IRF7, STAT1). Direct comparisons between treated and untreated infected cultures did not yield any differentially expressed genes for Class 3 and only 68 genes for Class 2. Changes were predominantly related to regulators of lipid metabolism and inflammation, aspects of epithelial biology known to be dysregulated in CF. In addition, CFTR modulators did not affect viral copy number, or levels of pro-inflammatory cytokines produced post-infection.

Conclusions: Though long-term clinical data is not yet available, results presented here suggest that first generation CFTR modulators do not interfere with core airway epithelial responses to rhinovirus infection. Future work should investigate the latest triple modulation therapies

Emma de Jong is at Senior Research Officer at the Telethon Kids Institute Respiratory Research Centre, Nedlands, 6009, Western Australia, Australia.

Hugo R de Jonge Maria C Ardelean Marcel Jc Bijvelds Paola Vergani  Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeasFEBS Lett  . 2020 Oct 28.  doi: 10.1002/1873-3468.13971. Online ahead of print. [Pubmed]

Hugo de Jonge

Cystic fibrosis transmembrane conductance regulator (CFTR) is an unusual ABC transporter. It acts as an anion-selective channel that drives osmotic fluid transport across many epithelia. In the gut, CFTR is crucial for maintaining fluid and acid-base homeostasis, and its activity is tightly controlled by multiple neuro-endocrine factors. However, microbial toxins can disrupt this intricate control mechanism and trigger protracted activation of CFTR. This results in the massive faecal water loss, metabolic acidosis and dehydration that characterise secretory diarrhoeas, a major cause of malnutrition and death of children under 5 years of age. Compounds that inhibit CFTR could improve emergency treatment of diarrhoeal disease. Drawing on recent structural and functional insight, we discuss how existing CFTR inhibitors function at the molecular and cellular level. We compare their mechanisms of action to those of inhibitors of related ABC transporters, revealing some unexpected features of drug action on CFTR. Although challenges remain, especially relating to the practical effectiveness of currently available CFTR inhibitors, we discuss how recent technological advances might help develop therapies to better address this important global health need.

Dr Hugo R de Jonge is a scientist in the Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.

Dr Henry Danahay is co-founder of Enterprise Therapeutics Ltd, Brighton, head of biology and Hon. Senior Research Fellow University of Sussex

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

de Vries JM, Green D, Kucera JN, Fabbrini AL, Kidder M, Brown J, Wilsey M. Cystic Fibrosis-Related Pancreatic Cysts Decrease in Size and Number Upon Treatment With Cystic Fibrosis Transmembrane Conductance Regulator Modulators. Pancreas. 2020;49(6):e50-e51. doi:10.1097/MPA.0000000000001567 [Pubmed]

Michael Wilsey

No access to abstract  at time of reviewing – although the title contains the message!

Dr J M de Vries is in the Department of Pediatric Gastroenterology and Nutrition, Johns Hopkins All Children’s Hospital.

Dr. Wilsey specializes in pediatric gastroenterology, hepatology and nutrition in the Department of Medicine. He became chief of the medical staff in January 2020 and is vice chair of the Department of Gastroenterology

Egan ME.  Emerging Technologies for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Restoration in all People with CF.   Pediatr Pulmonol. 2020 Jul 18. doi: 10.1002/ppul.24965. Online ahead of print.[Pubmed]

          Mary Egan

These therapies optimize the function of the patients’ endogenous mutant Cystic FibrosisTransmembrane Conductance Regulator (CFTR), which results in return of CFTR channel function. 2019 will be remembered as a landmark year for the Cystic Fibrosis (CF) community because it marks the year when effective modulator therapy became available for most CF patients. It is unlikely that this approach will provide a game changing therapy for all. In part because the response to even the most promising modulator therapy is variable and an area of active investigation. Also, there are about 10% of patients with CF who don’t produce a mutant protein to modulate, potentiate or optimize and for these patients such therapies are unlikely to be of significant benefit. Efforts to develop small molecule therapy to promote protein production in patients with nonsense mutations such as PTC124 has proved to be far more challenging than predicted.

There is a need to develop new therapeutic approaches that can work for this patient population. These new therapies will be genetic-based therapies that include ribonucleic acid (RNA) therapies, deoxyribonucleic acid (DNA) therapies and gene editing technologies. Each approach will result in functional CFTR expression in CF affected cells. Ideally, these approaches would require less frequent dosing than effective modulators, which are given daily. For instance, RNA based treatments could be given periodically.

Ultimately, treatment with certain gene-altering treatments could be given once in a lifetime and lead to a permanent cure.  In this review which is based on Plenary 1 from the North American Cystic Fibrosis Conference in 2019 which is based on Plenary 1 from the North American Cystic Fibrosis Conference in 2019 the potential of RNA therapies, gene transfer therapies and gene editing therapies for the treatment of CF are reviewed, as well as the challenges that will need to be faced as we harness the power of these emerging therapies towards a one-time cure.

 Dr Marie E Egan is  Professor of Pediatrics (Respiratory) and of Cellular and Molecular Physiology; Director Cystic fibrosis Center and Vice Chair of Research Pediatrics, School of Medicine, Yale University, New Haven, CT, USA.

Ryosuke FukudaTsukasa Okiyoneda.  Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitylation as a Novel Pharmaceutical Target for Cystic Fibrosis. Pharmaceuticals (Basel)   2020 Apr 22;13(4):E75. doi: 10.3390/ph13040075  Full text [Pubmed]

Tsukasa Okiyoneda

Ryosuke Fukuda

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene decrease the structural stability and function of the CFTR protein, resulting in cystic fibrosis. Recently, the effect of CFTR-targeting combination therapy has dramatically increased, and it is expected that add-on drugs that modulate the CFTR surrounding environment will further enhance their effectiveness. Various interacting proteins have been implicated in the structural stability of CFTR and, among them, molecules involved in CFTR ubiquitylation are promising therapeutic targets as regulators of CFTR degradation. This review focuses on the ubiquitylation mechanism that contributes to the stability of mutant CFTR at the endoplasmic reticulum (ER) and post-ER compartments and discusses the possibility as a pharmacological target for cystic fibrosis (CF)

Ryosuke Fukuda is Research Associate in the Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University,  Japan.

Tsukasa Okiyoneda is Associate Professor, Kwansei Gakuin University

(Ubiquitination: The “kiss of death” process for a protein. In ubiquitination, a protein is inactivated by attaching ubiquitin to it. Ubiquitin is a small molecule. It acts as a tag that signals the protein-transport machinery to ferry the protein to the proteasome for degradation).

Monica GelzoPaola IacotucciMafalda CaputoGustavo CerneraMarika ComegnaVincenzo CarnovaleGaetano CorsoGiuseppe Castaldo.  Lumacaftor/ivacaftor improves liver cholesterol metabolism but does not influence hypocholesterolemia in patients with cystic fibrosis. J Cyst Fibros   2020 Jun 22;S1569-1993(20)30779-7.doi: 10.1016/j.jcf.2020.06.015.Online ahead of print.  [Pubmed]
 Cystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor (ORKAMBI) CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508).Aim of this study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment. Baseline parameters in homo-deltaF508 patients were compared to those in CF patients compound heterozygous for F508del mutation and another severe mutation (hetero-deltaF508).
Methods: Cholesterol metabolism was evaluated measuring plasma phytosterols and cholestanol, as intestinal absorption markers, and lathosterol, as liver biosynthesis marker. We quantified serum vitamin E, as nutritional marker. We evaluated liver injury by aspartate aminotransferase (AST) and alanine transaminase (ALT), biliary injury by γ-glutamyltransferase (γGT) and AP, and the liver function by bilirubin and albumin.
Results: Before the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor (ORKAMBI) treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced.
Conclusions: These data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor (ORKAMBI) does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.

Monica Geizo is in the Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy; CEINGE – Biotecnologie avanzate, Naples, Italy.

George A, Smith B, Sawicki GS, Goetz DM. Survey of Patients with Cystic Fibrosis and Caregivers Decisions Regarding CFTR Modulators [published online ahead of print, 2020 Jun 26]. Pediatr Pulmonol. 2020;10.1002/ppul.24926. doi:10.1002/ppul.24926   [Pubmed]
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators are a novel approach to CF management that has become more readily available chronic CF therapies for certain populations of patients with CF. A cross-sectional survey of adults with CF and caregivers of pediatric patients with CF was done in two CF Centers to better understand the decision-making process including the potential influence of social media, CF care-teams, and family members on their decision whether to begin a CFTR modulator.
For the 90 participants, the most common influences in the decision to start modulator therapy were the CF providers/care teams (n=63), parents (n=49) and individuals with CF (n=27). The most impactful influence in the decision-making process were providers/care team (n=47) and parents (n=18). Social media was an influence for only 12 respondents, with an overall positive impact. Information from the CF Foundation was an influence for 12 participants and the main influence for 6 participants.

The most common reasons for stopping LUM-IVA were having TEZ-IVA as an option (n=25) and side-effects (n=15). Family and CF clinicians were the two main influences on the decision to initiate modulator therapy. CF clinicians were seen to be the most influential source. Social media had less influence on the decision-making process than expected despite the wide presence of the CF community online.

Dr Ashish George is in the Dept of Pediatrics, University at Buffalo, Buffalo, NY, United States.

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.

George A, Smith B, Sawicki GS, Goetz DM. Survey of Patients with Cystic Fibrosis and Caregivers Decisions Regarding CFTR Modulators [published online ahead of print, 2020 Jun 26]. Pediatr Pulmonol. 2020;10.1002/ppul.24926. doi:10.1002/ppul.24926   [Pubmed]
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators are a novel approach to CF management that has become more readily available chronic CF therapies for certain populations of patients with CF. A cross-sectional survey of adults with CF and caregivers of pediatric patients with CF was done in two CF Centers to better understand the decision-making process including the potential influence of social media, CF care-teams, and family members on their decision whether to begin a CFTR modulator.
For the 90 participants, the most common influences in the decision to start modulator therapy were the CF providers/care teams (n=63), parents (n=49) and individuals with CF (n=27). The most impactful influence in the decision-making process were providers/care team (n=47) and parents (n=18). Social media was an influence for only 12 respondents, with an overall positive impact. Information from the CF Foundation was an influence for 12 participants and the main influence for 6 participants.

The most common reasons for stopping LUM-IVA were having TEZ-IVA as an option (n=25) and side-effects (n=15). Family and CF clinicians were the two main influences on the decision to initiate modulator therapy. CF clinicians were seen to be the most influential source. Social media had less influence on the decision-making process than expected despite the wide presence of the CF community online.

Dr Ashish George is in the Dept of Pediatrics, University at Buffalo, Buffalo, NY, United States.

Geurts MHde Poel EAmatngalim GDOka RMeijers FMKruisselbrink Evan Mourik PBerkers Gde Winter-de Groot KMMichel SMuilwijk DAalbers BLMullenders JBoj SFSuen SWFBrunsveld JEJanssens HMMall MAGraeber SYvan Boxtel Rvan der Ent CKBeekman JMClevers H. CRISPR-Based Adenine Editors Correct Nonsense Mutations in a Cystic Fibrosis Organoid Biobank. 
Cell Stem Cell.
 
2020 Feb 13. pii: S1934-5909(20)30019-9. doi: 10.1016/j.stem.2020.01.019. [Epub ahead of print][Pubmed]

Maarten Geurts 

Hans Clevers

Adenine base editing (ABE) enables enzymatic conversion from A-T into G-C base pairs. ABE holds promise for clinical application, as it does not depend on the introduction of double-strand breaks, contrary to conventional CRISPR/Cas9-mediated genome engineering. Here, the authors describe a cystic fibrosis (CF) intestinal organoid biobank, representing 664 patients, of which ~20% can theoretically be repaired by ABE. We apply SpCas9-ABE (PAM recognition sequence: NGG) and xCas9-ABE (PAM recognition sequence: NGN) on four selected CF organoid samples. Genetic and functional repair was obtained in all four cases, while whole-genome sequencing (WGS) of corrected lines of two patients did not detect off-target mutations. These observations exemplify the value of large, patient-derived organoid biobanks representing hereditary disease and indicate that ABE may be safely applied in human cells.

Dr Maarten Geurts is a PhD student at the Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, the Netherlands and working in the Clevers Group

Professor Hans Clevers is leader of the Clevers Group and Chief Scientific Officer/Director Research of the Princess Máxima Center for pediatric oncology, Utrecht

Guimbellot JSRyan KJAnderson JDLiu ZKersh LEsther CRRowe SMAcosta EP.  Variable cellular ivacaftor concentrations in people with cystic fibrosis on modulator therapy.  J Cyst Fibros. 2020 Feb 7. pii: S1569-1993(20)30035-7. doi: 10.1016/j.jcf.2020.01.011. [Epub ahead of print) [Pubmed]

Edward P Acosta

Jennifer S Guimbellot

The development of CFTR modulators has transformed the care of patients with cystic fibrosis(CF). Although the clinical efficacy of modulators depends on their concentrations in target tissues, the pharmacokinetic properties of these drugs in epithelia are not utilized to guide patient care. The authors developed assays to quantitate ivacaftor in cells and plasma from patients on modulator therapy, and analyses revealed that cellular ivacaftor concentrations differ from plasma concentrations measured concurrently, with evidence of in vivo accumulation of ivacaftor in the cells of patients.

While the nature of this study is exploratory and limited by a small number of patients, these findings suggest that techniques to measure modulator concentrations in vivo will be essential to interpreting their clinical impact, particularly given the evidence that ivacaftor concentrations influence the activity and stability of restored CFTR protein.

Dr Jennifer S Guimbellot is a respiratory paediatrician at the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama and the Department of Pediatrics, Division of Pulmonary and Sleep Medicine, UAB, Birmingham, Alabama.,

Professor Edward Acosta is Professor; Director, Division of Clinical Pharmacology and the Antiviral Pharmacology laboratory in the University of Alabama, Birmingham

Gostelie R, Stegeman I, Berkers G, Bittermann J, Ligtenberg-van der Drift I, Kipshagen PV, de Winter-de Groot K, Speleman L.  The impact of ivacaftor on sinonasal pathology in S1251N-mediated cysticfibrosis patients.   PLoS One. 2020 Jul 20;15(7):e0235638. doi: 10.1371/journal.pone.0235638. eCollection 2020 Free article. [Pubmed]
Eight patients with cystic fibrosis with an S1251N mutation, treated with the potentiator ivacaftor were investigated. Ivacaftor (Kalydeco, VX-770) therapy. Computed tomography imaging of paranasal sinuses. Nasal nitric oxide concentration measurements and nasal endoscopy.  Primary outcome is opacification of paranasal sinuses examined with computed tomography scan analysis and scaled by the modified Lund-Mackay score before and one year after treatment. Secondary outcomes are nasal nitric oxide concentration levels, sinonasal symptoms and nasal endoscopic findings before and approximately two months and in some cases one year after treatment.
Results: Computed tomography scan analysis showed a significant decrease in opacification of the majority of paranasal sinuses comparing the opacification score per paranasal sinus before and after one year of treatment with ivacaftor. Median nasal nitric oxide levels significantly improved from 220.00 (IQR:136.00-341.18) to 462.84 (IQR:233.17-636.25) (p = 0.017) parts per billion. Likewise, the majority of sinonasal symptoms and nasal endoscopic pathology decreased or resolved at two months after the use of ivacaftor.
Conclusion and relevance: Ivacaftor appears to improve sinonasal outcome parameters and thereby sinonasal health in patients with cystic fibrosis with an S1251N mutation.

Fromm the University Medical Center, Utrecht University, Utrecht, The Netherlands.

Guhr Lee TN, Cholon DM, Quinney NL, Gentzsch M, Esther CR Jr. Accumulation and persistence of ivacaftor in airway epithelia with prolonged treatment.   J Cyst Fibros. 2020 Jun 11:S1569-1993(20)30123-5. doi: 10.1016/j.jcf.2020.04.010. Online ahead of print.[Pubmed]

      Tara Guhr Lee

Current dosing strategies of CFTR modulators are based on serum pharmacokinetics, but drug concentrations in target tissues such as airway epithelia are not known. Previous data suggest that CFTR modulators may accumulate in airway epithelia, and serum pharmacokinetics may not accurately predict effects of chronic treatment.
CF (F508del homozygous) primary human bronchial epithelial (HBE) cells grown at air-liquid interface were treated for 14 days with ivacaftor plus lumacaftor or ivacaftor plus tezacaftor, followed by a 14-day washout period. At various intervals during treatment and washout phases, drug concentrations were measured via mass spectrometry, electrophysiological function was assessed in Ussing chambers, and mature CFTR protein was quantified by Western blotting.
During treatment, ivacaftor accumulated in CF-HBEs to a much greater extent than either lumacaftor or tezacaftor and remained persistently elevated even after 14 days of washout. CFTR activity peaked at 7 days of treatment but diminished with further ivacaftor accumulation, though remained above baseline even after washout.

Conclusions: Intracellular accrual and persistence of CFTR modulators during and after chronic treatment suggest complex pharmacokinetic and pharmacodynamic properties within airway epithelia that are not predicted by serum pharmacokinetics. Direct measurement of drugs in target tissues may be needed to optimize dosing strategies, and the persistence of CFTR modulators after treatment cessation has implications for personalized medicine approaches.

Dr Tara Nicole Guhr Lee is a Research Technician in the Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina School of Medicine.

Jonathan L Gillan Donald J DavidsonRobert D GrayTargeting Cystic Fibrosis Inflammation in the Age of CFTR Modulators: Focus on Macrophages. Eur Respir J  2020 Dec 10;2003502.doi: 10.1183/13993003.03502-2020.Online ahead of print.[Pubmed]

Robert B Gray

Cystic fibrosis is a life-shortening, multiorgan, autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most prominent clinical manifestation in CF is the development of progressive lung disease characterised by an intense, chronic inflammatory airway response that culminates in respiratory failure, and ultimately death. In recent years, a new class of therapeutics which have the potential to correct the underlying defect in CF, known as CFTR modulators, have revolutionised the field. Despite the exciting success of these drugs, their impact on airway inflammation, and its long-term consequences, remain undetermined. In addition, studies querying the absolute requirement for infection as a driver of CF inflammation have challenged the traditional consensus on CF pathogenesis, and also emphasise the need to prioritise complementary anti-inflammatory treatments in CF. Macrophages, often overlooked in CF research despite their integral role in other chronic inflammatory pathologies, have increasingly become recognised as key players in the initiation, perpetuation, and resolution of CF lung inflammation, perhaps as a direct result of CFTR dysfunction. These findings suggest that macrophages may be an important target for novel anti-inflammatory interventional strategies to effectively treat CF lung function decline. This review will consider evidence for the efficacy for anti-inflammatories in the treatment of CF, the potential role of macrophages, and the significance of targeting these pathways at a time when rectifying the basic defect in CF, through use of novel CFTR modulator therapies, is becoming increasingly viable.

Jonathan L Gillian is a PhD student and Dr Robert Gray is NRS Senior Clinical Fellow & Hon. Consultant Respiratory Physician at the University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, UK.

Hahn A, Burrell A, Ansusinha E, Peng D, Chaney H, Sami I, Perez GF, Koumbourlis AC, McCarter R, Freishtat RJ, Crandall KA, Zemanick ET.   Airway microbial diversity is decreased in young children with cystic fibrosiscompared to healthy controls but improved with CFTR modulation.  Heliyon. 2020 Jun 1;6(6):e04104. doi: 10.1016/j.heliyon.2020.e04104. eCollection 2020 Jun. Free PMC article.  [Pubmed]

           Andrea Hahn

The study objective was to test for differences in the upper airway microbiome of children with CF and healthy controls and age-related differences in children with CF.
Oropharyngeal swabs and clinical data were obtained from 25 children with CF and 50 healthy controls aged ≤6 years. Bacterial DNA was amplified and sequenced for the V4 region of 16S rRNA marker-gene. Alpha diversity was measured using operational taxonomic units (OTUs), Shannon diversity, and the inverse Simpson’s index. Beta diversity was measured using Morisita-Horn and Bray-Curtis and Jaccard distances. General linear models were used for comparison of alpha diversity measures between groups to account for differences in demographics and exposures. Mixed effects general linear models were used for longitudinal comparisons 1)   between children with CF of different ages and 2) between children with CF receiving CF transmembrane conductance regulator (CFTR) modulators, children with CF not receiving CFTR modulators, and healthy controls to adjust for repeated measures per subject.

Children with CF were more likely to have received antibiotics in the prior year than healthy controls (92% vs 24%, p < 0.001). Controlling age, race, ethnicity, length of breastfeeding, and having siblings, children with CF had a lower richness than healthy controls: OTUs 62.1 vs 83, p = 0.022; and trended toward lower diversity: Shannon 2.09 vs 2.35, p = 0.057; inverse Simpson 5.7 vs 6.92, p = 0.118. Staphylococcus, three Rothia OTUs, and two Streptococcus OTUs were more abundant in CF children versus healthy controls (all p < 0.05). Bray-Curtis and Jaccard distances, which reflect overall microbial community composition, were also significantly different (both p = 0.001). In longitudinally collected samples from children with CF, Morisita-Horn trended toward more similarity in those aged 0-2 years compared to those aged 3-6 years (p = 0.070). In children >2 years of age, there was a significant trend in increasing alpha diversity measures between children with CF not receiving CFTR modulators, children with CF receiving CFTR modulators, and healthy controls: OTUs 63.7 vs 74.7 vs 97.6, p < 0.001; Shannon 2.11 vs 2.34 vs 2.56, p < 0.001; inverse Simpson 5.78 vs 7.23 vs 7.96, p < 0.001.

Conclusions: Children with CF have lower bacterial diversity and different composition of organisms compared with healthy controls. This appears to start in early childhood, is possibly related to the use of antibiotics, and may be partially corrected with the use of CFTR modulators.

Dr Andrea Hahn is an infectious disease specialist and investigator in the Division of Infectious Diseases, Children’s National Hospital, Washington, DC, USA.

Harris JKWagner BDZemanick ETRobertson CEStevens MJHeltshe SLRowe SMSagel SD. Changes in Airway Microbiome and Inflammation with Ivacaftor Treatment in Patients with Cystic Fibrosis and the G551D Mutation.  Ann Am Thorac Soc. 2020 Feb;17(2):212-220. doi: 10.1513/AnnalsATS.201907-493OC.[Pubmed]

It remains unclear how improving CFTR function modifies existing airway infection and inflammation.  This study aimed to compare sputum microbiome and markers of inflammation before and after 6 months of ivacaftor treatment. The study included 31 people with CF, ages 10 years and older, with at least one G551D CFTR allele and an forced expiratory volume in 1 second (FEV1) of 40% predicted or greater who were enrolled in the GOAL (G551D Observational) study. Sputum samples were collected either by induction (n = 14) or by spontaneous expectoration (n = 17) before and 6 months after initiation of ivacaftor.  Changes in bacterial community indices by sequencing of 16S rRNA amplicons, total and specific bacterial load, and a panel of proteases, antiproteases, and inflammatory cytokines were determined.

The cohort that spontaneously expectorated sputum had a lower FEV1, a higher proportion with Pseudomonas aeruginosa infection, and higher concentrations of sputum inflammatory markers compared with the cohort that provided sputum by induction, no significant changes in bacterial diversity, specific bacterial pathogens, or markers of inflammation were observed in these subjects. Neither total bacterial load nor presence of Pseudomonas changed significantly between paired samples with ivacaftor treatment. Younger patients experienced more shifts in their microbial communities than older patients.

The authors concluded 6 months of ivacaftor treatment were not associated with significant changes in airway microbial communities or measures of inflammation. These data suggest that concomitant antimicrobial and anti-inflammatory treatments will still be needed to manage airway disease in patients with CF treated with highly effective CFTR modulator therapy, especially in older patients with more advanced disease.

-These findings are not unexpected as the situation in the airways will have passed from the uninfected CFTR state to the chronic progressive inflammatory phase where restoration of CFTR will not affected the progression of the damaging chronic inflammation.

Katherine B HisertTimothy P Birkland. Kelly Q SchoenfeltMatthew E LongBrenda GroganSuzanne CarterW Conrad LilesEdward F McKoneLev BeckerAnne M Manicone. Ivacaftor Decreases Monocyte Sensitivity to Interferon-γ in People with Cystic Fibrosis. ERJ Open Res 2020 Apr 19;6(2):00318-2019.doi: 10.1183/23120541.00318-2019.eCollection 2020 Apr.[Pubmed]   (http://bit.ly/2TeI6LG)     Free article

This study demonstrates that initiation of the CFTR modulator ivacaftor in people with cystic fibrosis and susceptible CFTR mutations causes an acute reduction in blood monocyte sensitivity to the key proinflammatory cytokine IFN-γ   ……..”Studies examining individuals before and after initiation of CFTR modulators have revealed novel functions of CFTR and shown that CFTR modulators do not reverse all disease manifestations [35]. Thus, knowledge of the post-modulator cystic fibrosis disease state is crucial for understanding what continued therapies will be needed for people with cystic fibrosis and what new challenges may arise”…….

Dr Katherine Hisert is in the Dept of Medicine, University of Washington, Seattle, WA,

Jarosz-Griffiths HHScambler TWong CH Lara-Reyna SHolbrook JMartinon FSavic SWhitaker PEtherington CSpoletini GClifton I6Mehta AMcDermott MFPeckham D. Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis.  Elife. 2020 Mar 2;9. pii: e54556. doi: 10.7554/eLife.54556.[Pubmed]  Free full text

Thomas E Scambler

Heledd Jarosz-Griffiths

Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1β, caspase-1 activity and ASC speck release (Scambler et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1β was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1β declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1β and pro-IL-1β mRNA.

This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.

Co-authors – Dr Heledd H Jarosz-Griffiths is in Leeds Institute of Medical Research at St James’s and the Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, United Kingdom.
Dr Thomas Scambler of the Institute of Medical Research at St James’s, University of Leeds and the Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, United Kingdom.

Comments from the journal Editors, (Jos WM van der Meer and Siroon Bekkering, Radboud University, Netherlands) – “the paper convincingly shows the auto-inflammatory characteristics of CF, and its dependence on NLRP3. The underlying mechanisms have been thoroughly studied. With that, the paper is innovative and provides insights that will be clinically relevant, especially as it will probably have consequences for new treatment modalities”.

Lead authors (Dr Thomas Scambler and Dr Heledd Jarosz-Griffiths, St James’ University Hospital) comment “Blocking the sodium channel (ENaC) in combination with therapies targeting chemical cytokines (IL-18 and IL-1b) which are over-produced in CF is a potential strategy to reduce inflammation in CF, and may help combat the onset of secondary diseases such as diabetes and joint disease.”

Expert Opinion: Globally, nonsense mutations account for ~11% of all described gene lesions causing inherited monogenetic diseases. In CF and nephropathic cystinosis, they comprise from 10-12% of the disease-causative alleles. ELX-02 is in development as a therapeutic for patients with these alleles as in vitro and in vivo data demonstrated dose-dependent read-through of nonsense mutations to produce full-length, functional proteins. Since read-through efficiency varies between alleles, and mRNA context, careful consideration of target patient populations is required. The results to date support the on-going Phase 2 clinical evaluations of ELX-02 as a read-through agent.

Eitan Kerem Malena Cohen-CymberknohReuven Tsabari Michael WilschanskiJoel ReiterDavid ShoseyovAlex Gileles-HillelThea Pugatsch Jane C Davies Christopher Short ClareSaunders CynthiaDeSouza  James C Sullivan Jamie R DoyleKeval Chandarana.  Ivacaftor in People With Cystic Fibrosis and a 3849+10kb C T or D1152H Residual Function Mutation Ann Am Thorac Soc 2020 Oct 23. doi: 10.1513/AnnalsATS.202006-659OC.Online ahead of print. [Pubmed]
Ivacaftor’s clinical effects in the residual function mutations 3849+10kb C →T and D1152H warrant further characterization.
Objectives: Evaluate ivacaftor’s effect in people with cystic fibrosis aged ≥6 years with 3849+10kb C→T or D1152H residual function mutations; explore the correlation between ivacaftor-induced organoid-based cystic fibrosis transmembrane conductance regulator function measurements and clinical response to ivacaftor.
Methods: Participants were randomized (1:1) in this placebo-controlled crossover study; each treatment sequence included two 8-week treatments with an 8-week washout period. The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 8. Additional endpoints included lung function, patient-reported outcomes, and in vitro intestinal organoid-based measurements of ivacaftor-induced cystic fibrosis transmembrane conductance regulator function.
Results: Of 38 participants, 37 completed the study. The primary endpoint was met; the Bayesian posterior probability of improvement in lung clearance index2.5 with ivacaftor vs placebo was >99%. Additional endpoints improved with ivacaftor. Safety findings were consistent with ivacaftor’s known safety profile. Dose-dependent swelling was observed in 23/25 viable organoid cultures with ivacaftor treatment. Correlations between ivacaftor-induced organoid swelling and clinical endpoints were negligible to low.
Conclusions: In people with cystic fibrosis aged ≥6 years with a 3849+10kb C →T or D1152H mutation, ivacaftor treatment improved clinical endpoints vs placebo; however, there was no correlation between organoid swelling and change in clinical endpoints. The organoid assay may assist in identification of ivacaftor-responsive mutations but in this study did not predict magnitude of clinical benefit for individual people with cystic fibrosis with these two mutations.

– This failure of the organoid response to predict the magnitude of the response to the ivacaftor is disappointing.

Prof. Eitan Kerem is in the Department of Pediatrics and CF Center, Hadassah Hebrew University Medical Center , Jerusalem, Israel.

Kopp BT, Fitch J, Jaramillo L, Shrestha CL, Robledo-Avila F, Zhang S, Palacios S, Woodley F, Hayes D Jr, Partida-Sanchez S, Ramilo O, White P, Mejias A.  Whole-blood transcriptomic responses to lumacaftor/ivacaftor therapy in cystic fibrosis.  J Cyst Fibros. 2020 Mar;19(2):245-254. doi: 10.1016/j.jcf.2019.08.021. Epub 2019 Aug 29.[Pubmed]

Benjamin Kopp

Background: Cystic fibrosis (CF) remains without a definitive cure. Novel therapeutics targeting the causative defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are in clinical use. Lumacaftor/ivacaftor is a CFTR modulator approved for patients homozygous for the CFTR variant p.Phe508del, but there are wide variations in treatment responses preventing prediction of patient responses. We aimed to determine changes in gene expression related to treatment initiation and response.
Methods: Whole-blood transcriptomics was performed using RNA-Seq in 20 patients with CF pre- and 6 months post-lumacaftor/ivacaftor (drug) initiation and 20 non-CF healthy controls. Correlation of gene expression with clinical variables was performed by stratification via clinical responses.

Results: We identified 491 genes that were differentially expressed in CF patients (pre-drug) compared with non-CF controls and 36 genes when comparing pre-drug to post-drug profiles. Both pre- and post-drug CF profiles were associated with marked overexpression of inflammation-related genes and apoptosis genes, and significant under-expression of T cell and NK cell-related genes compared to non-CF. CF patients post-drug demonstrated normalized protein synthesis expression, and decreased expression of cell-death genes compared to pre-drug profiles, irrespective of clinical response. However, CF clinical responders demonstrated changes in eIF2 signaling, oxidative phosphorylation, IL-17 signaling, and mitochondrial function compared to non-responders. Top overexpressed genes (MMP9 and SOCS3) that decreased post-drug were validated by qRT-PCR. Functional assays demonstrated that CF monocytes normalized calcium (increases MMP9 expression) concentrations post-drug.

Conclusions: Transcriptomics revealed differentially regulated pathways in CF patients at baseline compared to non-CF, and in clinical responders to lumacaftor/ivacaftor.

Dr Benjamin T Kopp is in the Division of Pulmonary Medicine, Nationwide Children’s Hospital, Columbus,

OH, USA; Center for Microbial Pathogenesis, Nationwide Children’s Hospital, Columbus, OH, USA.

Kessler L. Can lumacaftor-ivacaftor reverse glucose-tolerance abnormalities in cystic fibrosis? J Cyst Fibros. 2020 May 5. pii: S1569-1993(20)30126-0. doi: 10.1016/j.jcf.2020.04.013. [Epub ahead of print] [Pubmed]

     Laurence Kessler

We are thankful to Manfred Ballmann and his colleagues for their interest in our recently published article [1]. By analyzing the effect of one year of lumacaftor–ivacaftor treatment on metabolic status in 40 cystic fibrosis patients affected by early glucose tolerance abnormalities, we observed an improvement in glucose tolerance, together with favourable changes in weight and pulmonary function. Furthermore, both one- and two-hour glycemia decreased in the subgroup, with improved oral glucose tolerance test (OGTT) categories. In their correspondence, Manfred Ballmann et al. propose that the effects of lumacaftor–ivacaftor should be interpreted with caution, due to the selected study population and natural history of glucose-tolerance abnormalities in cystic fibrosis.

The study population was composed of patients with either initial impaired glucose tolerance (IGT) or newly diagnosed cystic fibrosis-related diabetes (CFRD), since the moderate functional alteration of beta cells is still potentially reversible at this stage of the disease. We agree with Manfred Ballmann because, in our study, we did not consider the potential worsening of glucose tolerance in subjects with NGT after treatment. However, at this stage of CFRD, very early structural alterations of islets can be observed in the pancreata of CF patients. As such, CFRD suggests that the CFTR modulator is of low interest at this stage of the disease. Bogdani et al. [

2] have evaluated the morphology of tissue from very young CF children (<4 years of age), as well as adult patients with CF and CFRD. The relative number of beta cells in young CF tissue was reduced by 50% or more, when compared to age-matched controls. Furthermore, young CF tissue displayed significantly smaller insulin-positive areas. CFRD pancreata exhibited greater islet injury, with further reduction in islet density and a decreased relative number of beta cells. Together, these results strongly suggest that an early deficiency in beta-cell number in CF may contribute to the development of glucose intolerance in the young CF population and, later in life, to CFRD.

Although our analysis could not exclude any impact of the natural disease history, various longitudinal studies have reported spontaneous improvements in glucose tolerance in CF patients, as well as improvements in patients’ nutritional status and respiratory function. This is due to the natural disease history. To illustrate this point, Manfred Ballmann cited data from the Scheuing study [3], which observed substantial variability in glucose-tolerance abnormalities in CF, as a large cohort of 1128 CF patients benefited from 4643 OGTT over 9 years. Scheuing reported regression from CFRD to NGT in 21.7% of cases, which is comparable with our study data (22.2%, including 31 patients with IGT and 9 with CFRD). Interestingly, when we analyze Scheuing’s [3] data for patients with IGT, 40.1% of patients returned to NGT and 14.6% altered their glucose tolerance and developed a CFRD. Conversely, in our study, 58% of patients returned to NGT and no patients presented with diabetes. Obviously, analysis of these data should consider the limited number of patients involved in our study.

In comparison with other types of diabetes, CFRD is characterized by very particular abnormalities of glucose tolerance. Early postprandial hyperglycemia is indicated by one-hour glucose values at OGTT and by continuous glucose measurement, which may impact lung function and nutritional status for several years prior to the development of diabetes. Recently, research has highlighted a decrease in the incretin effect, together with the role of a CFTR chloride-channel defect, in terms of both beta-cell function and also in alpha cells. This facilitates better understanding of these particular glucose-tolerance abnormalities, as impaired suppressibility of the glucagon release has been reported in CF patients, after an OGTT that possibly contributes to the development of glucose intolerance [4]. From our perspective, it is impossible for our study to exclude the influence of the lumacaftor–ivacaftor on the improvement of glucose tolerance.

However, our study suggests that the CFTR modulator plays a positive role at the very early stage of glucose-tolerance abnormalities in CF, without being able to demonstrate whether this is a direct effect that targets CFTR, the consequence of an improvement in nutritional and respiratory status, or both. Currently, there is an overall lack of large studies that explore treatments for CFRD. As such, there is a need for more analysis of metabolic parameters in randomized studies that evaluate more effective CFTR modulators (e.g., the new triple-combination CFTR modulator [5].

  1. Misgault, B., et al., Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients. J Cystic Fibrosis.https://doi.org/10.1016/j.jcf.2020.03.002. (Abstract included in section 2020B of cysticfibrosis.online)
  2. Bogdani M.et alStructural abnormalities in islets from very young children with cystic fibrosis may contribute to cystic fibrosis-related diabetes  2017; 7: 17231https://doi.org/10.1038/s41598-017-17404-z
  3. Scheuing N.et al.High variability in oral glucose tolerance among 1,128 patients with cystic fibrosis: a multicenter screening study.PLoS ONE. 2014; 9e112578
  4. Edlund A.et al.CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells.Sci Rep. 2017; 7: 90https://doi.org/10.1038/s41598-017-00098-8
  5. Middleton P.G.et al.Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019; 381: 1809-1819      32387043

Laurence Kessler is Professor of Endocrinology and Diabetology at Strasbourg University Hospitals, France

Laselva O, Bartlett C, Popa A, Ouyang H, Gunawardena TNA, Gonska T, Moraes TJ, Bear CE. Emerging preclinical modulators developed for F508del-CFTR have the potential to be effective for ORKAMBI resistant processing mutants.  J Cyst Fibros   2020 Jul 30;S1569-1993(20)30807-9. doi: 10.1016/j.jcf.2020.07.015.Online ahead of print. [Pubmed]

     Onofrio Laselva

F508del is prototypical of Class 2 CFTR mutations associated with protein misprocessing and reduced function. Corrector compounds like lumacaftor partially rescue the processing defect of F508del-CFTR whereas potentiators like ivacaftor, enhance its channel activity once trafficked to the cell surface. We asked if emerging modulators developed for F508del-CFTR can rescue Class 2 mutations previously shown to be poorly responsive to lumacaftor and ivacaftor.
Methods: Rescue of mutant CFTRs by the correctors: AC1, AC2-1 or AC2-2 and the potentiator, AP2, was studied in HEK-293 cells and in primary human nasal epithelial (HNE) cultures, using a membrane potential assay and Ussing chamber, respectively.
Results: In HEK-293 cells, we found that a particular combination of corrector molecules (AC1 plus AC2-1) and a potentiator (AP2) was effective in rescuing both the misprocessing and reduced function of M1101K and G85E respectively. These findings were recapitulated in patient-derived nasal cultures, although another corrector combination, AC1 plus AC2-2 also improved misprocessing in these primary tissues. Interestingly, while this corrector combination only led to a modest increase in the abundance of mature N1303K-CFTR it did enable its functional expression in the presence of the potentiator, AP2, in part, because the nominal corrector, AC2-2 also exhibits potentiator activity.
Conclusions: Strategic combinations of novel modulators can potentially rescue Class 2 mutants thought to be relatively unresponsive to lumacaftor and ivacaftor.

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

Lopes-Pacheco M CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine, Front Pharmacol.  2020 Feb 21;10:1662. doi: 10.3389/fphar.2019.01662. eCollection 2019. [Pubmed]  (Full version on internet)

Miquelas Lopez-pacheco

Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients’ lives with short- and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF

Marcus A Mall ENaC inhibition in cystic fibrosis: potential role in the new era of CFTR modulator therapiesEur Respir J 2020 Jul 30;2000946.doi: 10.1183/13993003.00946-2020.Online ahead of print [Pubmed]

     Marcus A Mall

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are the first approved drugs targeting underlying epithelial ion/fluid transport defects in patients with cystic fibrosis (CF). Current CFTR modulators restore mutant CFTR activity to up to ∼50% of normal CFTR Cl channel function, translating into improvements in percentage predicted FEV1 and other clinical outcomes. In addition, reductions in airway bacterial colonisation are observed; however, patients fail to eradicate bacteria over time and still experience pulmonary exacerbations, and long-term safety of CFTR modulator therapy remains unknown. Currently approved CFTR modulators are predicted to be effective for up to 90% of patients. A mutation-agnostic approach could address the remaining 10% with CFTR mutations unresponsive to CFTR modulator therapy and may act together with CFTR modulator therapy to further improve epithelial ion/fluid transport and clinical outcomes. Together with CFTR and other Cl channels, the epithelial Na+ channel (ENaC) is key to regulating airway surface liquid homeostasis. ENaC activity is limiting for Na+/fluid absorption and remains intact or may even be increased in CF airways, leading to increased Na+/fluid absorption, airway surface dehydration, impaired mucociliary clearance, bacterial infection, inflammation and progressive lung damage – the major cause of CF-related morbidity and mortality. Inhibition of ENaC in the airways is therefore an attractive therapeutic target to counteract airway surface dehydration and downstream consequences in CF lung disease. This review examines ENaC inhibition in CF therapy, and describes a new ENaC inhibitor with potential mutation-agnostic therapeutic benefit, both alone, and in synergy with CFTR modulators.

Professor Marcus Mall is at Department of Pediatric Pulmonology, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin,  Berlin Institute of Health and the  German Center for Lung Research (DZL), associated partner site, Berlin.

Mayer-Hamblett N, van Koningsbruggen-Rietschel S, Nichols DP, VanDevanter DR, Davies JC, Lee T, Durmowicz AG, Ratjen F, Konstan MW, Pearson K, Bell SC, Clancy JP, Taylor-Cousar JL, De Boeck K, Donaldson SH, Downey DG, Flume PA, Drevinek P, Goss CH, Fajac I, Magaret AS, Quon BS, Singleton SM, VanDalfsen JM, Retsch-Bogart GZ.  Building global development strategies for cf therapeutics during a transitional cftr modulator era. J Cyst Fibros. 2020 Jun 7:S1569-1993(20)30161-2. doi:10.1016/j.jcf.2020.05.011. Online ahead of print. [Pubmed]

Nicole Mayer-Hamblett

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Nicole Hamblett is in the University of Washington, Seattle, WA; Seattle Children’s Hospital, Seattle, WA. Electronic address: nicole.hamblett@seattlechildrens.org.

Dr Miqueias Lopes-Pacheco is at Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal.

– This is a very detailed extensively referenced account of the present situation concerning modulators. The full text is available and can be recommended.

Misgault BChatron EReynaud QTouzet SAbely MMelly LDominique STroussier FRonsin-Pradel OGerardin MMankikian JCosson LChiron RBounyar LPorzio MDurieu IWeiss LKessler RKessler L.   Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients.  J Cyst Fibros. 2020 Mar 19. pii: S1569-1993(20)30073-4. doi: 10.1016/j.jcf.2020.03.002. [Epub ahead of print] [Pubmed
To investigate the effects of 1-year lumacaftor-ivacaftor treatment on abnormalities in glucose tolerance (AGT) in Phe508del homozygous cystic fibrosis (CF) patients.   Untreated CF patients with glucose intolerance or newly diagnosed diabetes were included in a prospective, observational study. After 1-year lumacaftor-ivacaftor treatment, AGT were evaluated by using oral glucose tolerance test.

Forty patients participated. 78% of patients had glucose intolerance and 22% diabetes at baseline. After one-year treatment, 50% of patients had normal glucose tolerance, 40% glucose intolerance, and 10% diabetes (p <0.001). The two-hour OGTT glycemia decreased from 171 (153-197) to 139 (117-162) mg/dL (p <0.001). 57.5% (n = 23) of patients improved their glucose tolerance with a significant decrease in both 1-hour (p<0.01) and 2-hour (p<0.001) OGTT glycemia.

The authors concluded improvements in AGT were observed following 1-year lumacaftor-ivacaftor treatment. Larger studies are needed to comprehensively assess CF transmembrane conductance regulator (CFTR) modulators.

Dr B Misgault  is at the Service d’endocrinologie, diabète et nutrition, Hôpitaux Universitaires de Strasbourg, place de l’hôpital, Strasbourg 67091, France

Munck A, Kerem E, Ellemunter H, Campbell D, Wang LT, Ahluwalia N, Owen CA, Wainwright C.  Tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for minimal function CFTR mutations.   J Cyst Fibros. 2020 Jun 13:S1569-1993(20)30128-4. doi: 10.1016/j.jcf.2020.04.015. Online ahead of print.  [Pubmed]

Anne Munck

Tezacaftor/ivacaftor is a CFTR modulator approved to treat people with cystic fibrosis (pwCF) who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function mutation (F/RF).
This randomized, double-blind, placebo-controlled Phase 3 study evaluated the efficacy, safety, tolerability, and pharmacokinetics (PK) of tezacaftor/ivacaftor in participants ≥12 years of age heterozygous for the F508del-CFTR mutation and a minimal function mutation (F/MF), which produces no CFTR protein or a protein unresponsive to tezacaftor/ivacaftor in vitro.
Participants were randomized 1:1 to receive tezacaftor/ivacaftor or placebo for 12 weeks. The primary endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) between the tezacaftor/ivacaftor and placebo groups through week 12. Key secondary endpoints included absolute change from baseline in CF Questionnaire-Revised respiratory domain scores and the number of pulmonary exacerbations through week 12 and the absolute change from baseline in body mass index at week 12. A prespecified interim analysis (IA) for futility was conducted when approximately 50% of a planned enrolment of 300 participants reached week 12 of the study.

At the time of the interim analysis 83 participants were randomized to tezacaftor/ivacaftor and 85 to placebo; 165 participants completed treatment. The study failed to demonstrate that tezacaftor/ivacaftor significantly improved ppFEV1 or any of the key secondary endpoints and was terminated for futility. The safety profile and PK parameters of tezacaftor/ivacaftor were similar to those reported in prior studies in participants ≥12 years of age with CF.

Conclusions: Tezacaftor/ivacaftor did not show a clinically meaningful benefit in participants with F/MF genotypes but was generally safe and well tolerated, consistent with the safety profile reported in other Phase 3 studies (NCT02516410).

Dr Anne Munck is at the Robert Debré Hospital, Assistance Publique-Hopitaux de Paris, Université Paris Diderot, Paris, France

Nash EFMiddleton PGTaylor-Cousar JL. Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators – an international survey. J Cyst Fibros. 2020 Mar 6. pii: S1569-1993(20)30067-9. doi: 10.1016/j.jcf.2020.02.018. [Epub ahead of print]  [Pubmed]

        Edward Nash

A survey was sent to lead clinicians of adult CF centres in Europe, the United Kingdom (UK), United States of America (USA), Australia and Israel requesting anonymised data on pregnancy outcomes in women using CFTR modulators before and during pregnancy and lactation. The survey identified 64 pregnancies in 61 women taking IVA (n = 31), LUM/IVA (n = 26) or TEZ/IVA (n = 7), resulting in 60 live births. In 44 pregnancies, CFTR modulators were either continued throughout pregnancy or temporarily stopped and then restarted. Two maternal complications were deemed related to CFTR modulator therapy; cessation of modulator therapy resulted in clinical decline in 9 women prompting resumption of therapy during pregnancy. No modulator-related complications were reported in infants exposed in utero and/or during breastfeeding.

CFTR modulators were reported to be generally well tolerated in pregnancy and breastfeeding, with only 2 maternal complications that were deemed related to CFTR modulator therapy. Women stopping CFTR modulators in pregnancy may experience a decline in clinical status and in the cases identified in this survey, restarting therapy led to a clinical improvement. Current experience remains limited and longer-term prospective follow-up is required to exclude delayed adverse effects.

Dr Edward Nash is a Pulmonologist West Midlands Adult Cystic Fibrosis Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham

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.

Nichols AL, Davies JC, Jones D, Carr SB. Restoration of exocrine pancreatic function in older children with cystic fibrosis on ivacaftor. Paediatr Respir Rev. 2020 Apr 14. pii: S1526-0542(20)30073-7. doi: 10.1016/j.prrv.2020.04.003. [Epub ahead of print] Review. [Pubmed]
Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Improvement in pancreatic function on ivacaftor has been reported in open label studies in 1-5 year olds. The mechanism by which ivacaftor might improve exocrine pancreatic function is unclear. Although the effect of ivacaftor on pancreatic function may be more significant in younger children, evidence is mounting that there may still be potential for improvement in older children on long term therapy.

Dr A L Nichols is in the Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK.

Olivereau LNave VGarcia SPerceval MRabilloud MDurieu IReynaud Q. Adherence to lumacaftor-ivacaftor therapy in patients with cystic fibrosis in France. 
J Cyst Fibros.
 
2020 Jan 2. pii: S1569-1993(19)30901-4. doi: 10.1016/j.jcf.2019.09.018. [Epub ahead of print] [Pubmed]
This retrospective study used pharmacy refills data to calculate proportion of days covered (PDC). Adherence was defined as a PDC ≥80%. A logistic regression analysis was conducted to examine factors associated with medication adherence.
Ninety-six patients were included in the final cohort for analysis. The mean PDC was 96%  ± 14 at 6 months, and 91% ± 17 at 12 months. The proportion of adherent patients was 89% and 83% at 6 and 12 months respectively. Age and ppFEV1 were found to affect medication adherence.
Considering the medico-economic impact of CFTR modulator therapy, high adherence rates to lumacaftor-ivacaftor found in this study are encouraging.

Dr L Olivereau is at the Pharmacie Centrale, Hospices Civils de Lyon, F-69230 Saint Genis Laval, France.

Perrem L, Ratjen F. Anti-inflammatories and mucociliary clearance therapies in the age of CFTR modulators. Pediatr Pulmonol. 2019;54 Suppl 3:S46S55. doi:10.1002/ppul.24364  [Pubmed]

Lucy Perrem

The combination of CFTR dysfunction, mucus obstruction, and infection drive an exaggerated and dysfunctional inflammatory response, which contributes to irreversible airway destruction and fibrosis. CFTR modulators, an exciting new class of drugs, increase the expression and/or function of CFTR variant protein and improve multiple clinical endpoints, such as lung function, pulmonary exacerbation rates, and nutritional status.
However, these genotype-specific drugs are not universally available, the clinical response is variable, and lung function still declines over time when bronchiectasis is established. Consequently, even in the age of CFTR modulators, we must target other important aspects of the CF airway disease, such as inflammation and mucociliary clearance. This review highlights the mechanisms of inflammation and mucus accumulation in the CF lung and discusses anti-inflammatory and mucociliary clearance agents that are currently in development focusing on compounds for which clinical trial data have recently become available.

Dr Lucy Perrem is in the Division of Respiratory Medicine, The Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada.

Joseph M Pilewski Kris De BoeckJerry A NickSimon TianCynthia DeSouzaMark HigginsRichard B Moss.   Long-Term Ivacaftor in People Aged 6 Years and Older with Cystic Fibrosis with Ivacaftor-Responsive Mutations. Pulm Ther . 2020 Sep 23. doi: 10.1007/s41030-020-00129-2. Online ahead of print. [Pubmed]

Joseph Pilewski

The study evaluated the long-term safety and efficacy of ivacaftor in people with CF aged 6 years and older with non-G551D-CFTR ivacaftor-responsive mutations. Efficacy and safety data from a phase 3, multicenter, open-label, extension study for participants from Study 110 (R117H-CFTR mutations), Study 111 (non-G551D-CFTR gating mutations), and Study 113 (n-of-1 pilot study in participants with residual CFTR function) were analyzed. Following washout from the randomized parent study, participants received oral ivacaftor 150 mg once every 12 h for 104 weeks.

Forty-one of 121 participants completed treatment through 104 weeks; 59 participants who did not complete the extension study continued treatment with commercial ivacaftor. The most common adverse events were pulmonary exacerbation (46.3%) and cough (33.9%). Most treatment-emergent adverse events were mild/moderate in severity and consistent with manifestations of CF or the ivacaftor safety profile. Rapid, durable improvement occurred across all efficacy endpoints.

Ivacaftor was generally safe and well tolerated with no new safety concerns for up to 104 weeks in people with CF with ivacaftor-responsive mutations. The pattern of improvement across efficacy endpoints was durable and generally consistent with parent-study outcomes.  (NCT01707290).

Dr Joseph M Pilewski is Associate Chief, Division of Pulmonary, Allergy & Critical Care Medicine and Associate Professor of Medicine, Cell Biology, Physiology & Pediatrics, University of Pittsburgh,

Melissa S PutmanLogan B GreenblattMichael BruceTaisha JosephHang LeeGregory SawickiAhmet UluerLeonard SicilianIsabel NeuringerCatherine M GordonMary L BouxseinJoel S Finkelstein. The Effects of Ivacaftor on Bone Density and Microarchitecture in Children and Adults with Cystic Fibrosis. J Clin Endocrinol Metab. 2020 Dec 1:dgaa890. doi: 10.1210/clinem/dgaa890. Online ahead of print  [Pubmed]

Melissa Putman

Context: Cystic fibrosis transmembrane conductance (CFTR) dysfunction may play a role in CF-related bone disease (CFBD). Ivacaftor is a CFTR potentiator effective in improving pulmonary and nutritional outcomes in patients with the G551D-CFTR mutation. The effects of ivacaftor on bone health are unknown.
Objective: To determine the impact of ivacaftor on bone density and microarchitecture in children and adults with CF.
Design: Prospective observational multiple cohort study.
Setting: Outpatient clinical research center within a tertiary academic medical center.
Patients or other participants: Three cohorts of age-, race-, and gender-matched subjects were enrolled: 26 subjects (15 adults and 11 children) with CF and the G551D-CFTR mutation who were planning to start or had started treatment with ivacaftor within three months (Ivacaftor cohort); 26 subjects with CF were not treated with ivacaftor (CF Control cohort); and 26 healthy volunteers.
Interventions: All treatments, including ivacaftor, were managed by the subjects’ pulmonologists.
Main outcome measures: Bone microarchitecture by high resolution peripheral quantitative computed tomography (HR-pQCT), areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) and bone turnover markers at baseline, 1, and 2 years.
Results: Cortical volume, area, and porosity at the radius and tibia increased significantly in adults in the Ivacaftor cohort. No significant differences were observed in changes in aBMD, trabecular microarchitecture, or estimated bone strength in adults or in any outcome measures in children.
Conclusions: Treatment with ivacaftor was associated with increases in cortical microarchitecture in adults with CF. Further studies are needed to understand the implications of these findings.

Dr Melissa S Putman is a paediatric and adult endocrinologist in the  Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA. and the Division of Endocrinology, Boston Children’s Hospital, Boston, MA.

Fiona QiuMark HabgoodElena K Schneider-Futschik   The Balance between the Safety of Mother, Fetus, and Newborn Undergoing Cystic Fibrosis Transmembrane Conductance Regulator Treatments during PregnancyACS Pharmacol Transl Sci . 2020 Aug 19;3(5):835-843. doi: 10.1021/acsptsci.0c00098. eCollection 2020 Oct 9. [Pubmed]

Elena Schneider-Futschik

The recent development of modulators of cystic fibrosis transmembrane conductance regulator (CFTR) has allowed the life expectancy of cystic fibrosis patients to increase substantially resulting in more women with cystic fibrosis reaching child-bearing age. This however raises the issue of whether long-term use of CFTR modulators during pregnancy and breastfeeding is safe for the fetus and newborn, especially for their developing brain. A very limited number of case reports available so far has shown that the fetus or breastfed newborn is likely to be exposed to maternally administered CFTR modulators. Potential impacts of drug exposure on the developing brain are of particular importance as the consequences might not be immediately noticeable upon birth but may manifest later in life as permanent neurobehavioral problems. In order for drugs in maternal circulation to enter the fetal brain, they must overcome the placental barrier followed by a series of brain barriers, each consisting of cellular components and physiological mechanisms such as efflux transporters. The extent of protection they offer during development will provide valuable insights into the potential entry and the effects of CFTR modulators in the developing brain. This review aims to explore the current understanding of the safety of CFTR modulators, especially ivacaftor, during pregnancy and breastfeeding, characterize the pharmacokinetics and pharmacodynamics of ivacaftor, both under normal conditions and during pregnancy, to provide context for its potential impact on the developing brain. Finally, we discuss the determinants that need to be taken into consideration when investigating the entry of drugs into the fetus and newborn.

Fiona Qiu is at the Department of Pharmacology & Therapeutics, Lung Health Research Centre, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia.

Dr Elena K Schneider-Futschik is the senior research fellow at the Institute

Dr Lara Pullen is a medical writer who has covered a wide range of topics.

Rang CKeating DWilson JKotsimbos T. Re-Imagining Cystic Fibrosis Care: Next Generation ThinkingEur Respir J. 2020 Mar 5. pii: 1902443. doi: 10.1183/13993003.02443-2019. [Epub ahead of print][Pubmed]

Tom Kotsimbos

Cystic fibrosis is a common multi-system genetically inherited condition, predominately found in individuals of Caucasian decent. Since the identification of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989, and the subsequent improvement in understanding of CF pathophysiology, significant increases in life-expectancy have followed. Initially this was related to improvements in the management and systems of care for treating the various affected organ systems. These cornerstone treatments are still essential for CF patients born today. However, over the last decade, the major advance has been in therapies that target the resultant genetic defect – the dysfunctional CFTR protein. Small molecule agents that target this dysfunctional protein via a variety of mechanisms have led to lung function improvements, reductions in pulmonary exacerbation rates and increases in weight and quality of life indices. As more patients receive these agents earlier and earlier in life, it is likely that general CF care will increasingly pivot around these specific therapies, although it is also likely that effects other than those identified in the initial trials will be discovered and need to be managed. Despite great excitement for modulator therapies, they are unlikely to be suitable or available for all: whether this is due to a lack of availability for specific CFTR mutations, drug-reactions or the health economic set-up in certain countries. Nevertheless, the CF community must be applauded for its ongoing focus on research and development for this life-limiting disease. With time, personalised individualised therapy would ideally be the mainstay of CF care.

– This is a clear summary of the future changing nature of CF care. As with many other such articles there is no mention of prevention.

Dr Tom Kotsimbos is Associate Professor and Head of Respiratory Medicine Laboratory, AIRMed Department, Central Clinical School, Monash University.

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

Giada Righetti is a PhD student in the Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV 3, 16132 Genoa, Italy.

Geraint B RogersSteven L TaylorLucas R HoffmanLucy D Burr.   The impact of CFTR modulator therapies on CF airway microbiology.   J Cyst Fibros 2020 May;19(3):359-364. doi: 10.1016/j.jcf.2019.07.008.Epub 2019 Aug  [Pubmed]

         Geraint Rodgers

Major historical advances in cystic fibrosis (CF) respiratory clinical care, including mechanical airway clearance and inhaled medications, have aimed to address the consequences of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. In contrast, CFTR modulator therapies instead target the underlying protein defect that leads to CF lung disease. The extent to which these therapies might reduce susceptibility to chronic lung infections remains to be seen. However, by improving airway clearance, reducing the requirement for antibiotics, and in some cases, through direct antimicrobial effects, CFTR modulators are likely to result in substantial changes in CF airway microbiology. These changes could contribute substantially to the clinical benefit associated with modulator therapies, as well as providing an important indicator of treatment efficacy and residual pathophysiology. Indeed, the widespread introduction of modulator therapies might require us to re-consider our models of CF airway microbiolo

Prof Geraint B Rogers is a molecular microbiologist and microbial ecologist. He is the Director, Microbiome Research at SAHMRI, leads a laboratory based within the Flinders University School of Medicine, Adelaide

Steven M RoweIeuan Jones  Mark T DransfieldNazmul HaqueStephen Gleason Katy A Hayes Kenneth Kulmatycki Denise P YatesHenry DanahayMartin Gosling David J RowlandsSarah S Grant    Efficacy and Safety of the CFTR Potentiator Icenticaftor (QBW251) in COPD: Results from a Phase 2 Randomized Trial  Int J Chron Obstruct Pulmon Dis  2020 Oct 5;15:2399-2409.doi: 10.2147/COPD.S257474. eCollection 2020.  Free PMC article [Pubmed]

Steven Rowe

Rationale: Excess mucus plays a key role in COPD pathogenesis. Cigarette smoke-induced cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction may contribute to disease pathogenesis by depleting airway surface liquid and reducing mucociliary transport; these defects can be corrected in vitro by potentiating CFTR.
Objective: To assess the efficacy of the CFTR potentiator icenticaftor in improving airflow obstruction in COPD patients with symptoms of chronic bronchitis.
Methods: In this double-blind, placebo-controlled study, COPD patients were randomized (2:1) to either icenticaftor 300 mg or placebo b.i.d. This non-confirmatory proof of concept study was powered for lung clearance index (LCI) and pre-bronchodilator FEV1, with an estimated sample size of 90 patients. The primary endpoint was change from baseline in LCI for icenticaftor versus placebo at Day 29; key secondary endpoints included change from baseline in pre- and post-bronchodilator FEV1 on Day 29. Key exploratory endpoints included change from baseline in sweat chloride, plasma fibrinogen levels, and sputum colonization.
Results: Ninety-two patients were randomized (icenticaftor, n=64; placebo, n=28). At Day 29, icenticaftor showed no improvement in change in LCI (treatment difference: 0.28 [19% probability of being better than placebo]), an improvement in pre-bronchodilator FEV1 (mean: 50 mL [84% probability]) and an improvement in post-bronchodilator FEV1 (mean: 63 mL [91% probability]) over placebo. Improvements in sweat chloride, fibrinogen and sputum bacterial colonization were also observed. Icenticaftor was safe and well tolerated.
Conclusion: The CFTR potentiator icenticaftor increased FEV1 versus placebo after 28 days and was associated with improvements in systemic inflammation and sputum bacterial colonization in COPD patients; no improvements in LCI with icenticaftor were observed.

Dr Steven M Rowe is Professor and Director, Cystic Fibrosis Research Centeris at the University of Alabama at Birmingham, Department of Medicine, Birmingham, AL, USA.

Shaw M, Khan U, Clancy JP, Donaldson SH, Sagel SD, Rowe SM, Ratjen F; PROSPECT Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network.  Changes in LCI in F508del/F508del patients treated with lumacaftor/ivacaftor: Results from the prospect study.   J Cyst Fibros. 2020 Jun 6:S1569-1993(20)30160-0. doi: 10.1016/j.jcf.2020.05.010. Online ahead of print. [Pubmed]
The PROSPECT study, a post-approval observational study in the U.S., showed no significant changes in lung function as measured by spirometry with clinical initiation of lumacaftor/ivacaftor. A sub-study within the PROSPECT study assessed the lung clearance index (LCI), as measured by multiple breath washout (MBW), a measure of lung function demonstrated to be sensitive among people with normal spirometry. Participants performed MBW prior to clinically initiating lumacaftor/ivacaftor therapy and for one year of follow-up. Similar to the whole PROSPECT study, this sub-study cohort (N = 49) had no significant absolute or relative changes in FEV1% predicted at any time point. LCI, however, decreased (improved) by 0.81 units or 5.3% (95% CI -9.7, -0.9%) at 1 month, 0.77 units or 5.9% at 3 months, 0.67 units or 5.9% at 6 months, and 0.55 units or 4.3% at 12 months. These results demonstrate the utility of the LCI in assessing treatment effects of relatively modest size in a heterogenous study population.

Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada.

Ranjani Somayaji Dave NicholsScott C Bell    Cystic fibrosis – Ten promising therapeutic approaches in the current era of care. Expert Opin Investig Drugs. 2020 Aug 3.doi: 10.1080/13543784.2020.1805733.Online ahead of print. [Pubmed]
 Introduction: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems. Research and innovations in novel therapeutic agents and health care delivery have resulted in dramatic improvements in quality of life and survival for people with CF. Despite this, significant disease burden persists for many and this is compounded by disparities in treatment access and care which globally necessitates further work to improve outcomes. Because of the advent of a numerous therapies which includes gene-targeted modulators in parallel with specialized care delivery models, innovative efforts continue.
Areas covered: In this review, the authors discuss the available data on investigational agents in clinical development and currently available treatments for CF. They also evaluate approaches to care delivery, consider treatment gaps and propose future directions for advancement.
Expert opinion: Since the discovery of the CF gene, CFTR modulators have provided a hallmark of success, even though it was thought not previously possible. This has led to reinvigorated efforts and innovations in treatment approaches and care delivery. Numerous challenges remain because of genetic and phenotypic heterogeneity, access issues, and therapeutic costs, but the collaborative approach between stakeholders for continued innovation fuels optimism.

Dr Ranjani Somayaji is Assistant Professor in the University of Calgary, Departments of Medicine | Microbiology, Immunology and Infectious Disease | Community Health Sciences. Institutional affiliations: Snyder Institute for Chronic Diseases | O’Brien Institute for Public Health

Jyoti SharmaKim M KeelingSteven M RowePharmacological approaches for targeting cystic fibrosis nonsense mutations.   Eur J Med Chem. 2020 Aug 15;200:112436.doi: 10.1016/j.ejmech.2020.112436.Epub 2020 May 21.    Free PMC article [Pubmed]

     Joyti Sharma

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder. The clinical manifestations of the disease are caused by ∼2,000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It is unlikely that any one approach will be efficient in correcting all defects. The recent approvals of ivacaftor, lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor represent the genesis of a new era of precision combination medicine for the CF patient population. In this review, we discuss targeted translational readthrough approaches as mono and combination therapies for CFTR nonsense mutations. We examine the current status of efficacy of translational readthrough/nonsense suppression therapies and their limitations, including non-native amino acid incorporation at PTCs and nonsense-mediated mRNA decay (NMD), along with approaches to tackle these limitations. We further elaborate on combining various therapies such as readthrough agents, NMD inhibitors, and corrector/potentiators to improve the efficacy and safety of suppression therapy. These mutation specific strategies that are directed towards the basic CF defects should positively impact CF patients bearing nonsense mutations.

Jyoti Sharma is in the Department of Medicine, University of Alabama at Birmingham (UAB), USA; Department of Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), USA

Dr Zhuqing Shi is from the Program for Personalized Cancer Care, NorthShore University Health System, Evanston, IL.

Shaw M, Khan U, Clancy JP, Donaldson SH, Sagel SD, Rowe SM, Ratjen F; PROSPECT Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network.  Changes in LCI in F508del/F508del patients treated with lumacaftor/ivacaftor: Results from the prospect study.   J Cyst Fibros. 2020 Jun 6:S1569-1993(20)30160-0. doi: 10.1016/j.jcf.2020.05.010. Online ahead of print. [Pubmed]
The PROSPECT study, a post-approval observational study in the U.S., showed no significant changes in lung function as measured by spirometry with clinical initiation of lumacaftor/ivacaftor. A sub-study within the PROSPECT study assessed the lung clearance index (LCI), as measured by multiple breath washout (MBW), a measure of lung function demonstrated to be sensitive among people with normal spirometry. Participants performed MBW prior to clinically initiating lumacaftor/ivacaftor therapy and for one year of follow-up. Similar to the whole PROSPECT study, this sub-study cohort (N = 49) had no significant absolute or relative changes in FEV1% predicted at any time point. LCI, however, decreased (improved) by 0.81 units or 5.3% (95% CI -9.7, -0.9%) at 1 month, 0.77 units or 5.9% at 3 months, 0.67 units or 5.9% at 6 months, and 0.55 units or 4.3% at 12 months. These results demonstrate the utility of the LCI in assessing treatment effects of relatively modest size in a heterogenous study population.

Dr M Shaw   Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada.

Schwarz C, Sutharsan S, Epaud R, Klingsberg RC, Fischer R, Rowe SM, Audhya PK, Ahluwalia N, You X, Ferro TJ, Duncan ME, Bruinsma BG.   Tezacaftor/ivacaftor in people with cystic fibrosis who stopped lumacaftor/ivacaftor due to respiratory adverse events [published online ahead of print, 2020 Jun 22]. J Cyst Fibros. 2020;S1569-1993(20)30730-X. doi:10.1016/j.jcf.2020.06.001

Carsten Schwarz

 Increased rates of respiratory adverse events have been observed in people ≥12 years of age with cystic fibrosis homozygous for the Phe508del-CFTR mutation treated with lumacaftor/ivacaftor, particularly in those with percent predicted forced expiratory volume in 1 s (ppFEV1) of <40%. The safety, tolerability, and efficacy of tezacaftor/ivacaftor were evaluated in people with cystic fibrosis homozygous for Phe508del-CFTR who discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.

Participants ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV1 of ≥25% and ≤90% were randomized 1:1 and treated with tezacaftor/ivacaftor or placebo for 56 days.

Of 97 participants, 94 (96.9%) completed the study. The primary endpoint was incidence of predefined respiratory adverse events of special interest (chest discomfort, dyspnoea, respiration abnormal, asthma, bronchial hyperreactivity, bronchospasm, and wheezing): tezacaftor/ivacaftor, 14.0%; placebo, 21.3%. The adverse events were mild or moderate in severity. None were serious or led to treatment interruption or discontinuation. Overall, the discontinuation rate was similar between groups. The mean (SD) ppFEV1 at baseline was 44.6% (16.1%) with tezacaftor/ivacaftor and 48.0% (18.1%) with placebo. The posterior mean difference in absolute change in ppFEV1 from baseline to the average value of days 28 and 56 was 2.7 percentage points with tezacaftor/ivacaftor vs placebo.

The authors concluded tezacaftor/ivacaftor was generally safe, well tolerated, and efficacious in people ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV1 of ≥25% and ≤90% who previously discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.

Dr Carsten Schwarz at the Christiane Herzog Zentrum Berlin/Charité-Universitätsmedizin Berlin, Berlin, Germany.

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.

Professor Stuart Elborn comments on this article as follows –

Elborn JS. Modulator treatment for people with cystic fibrosis: moving in the right direction. Eur Respir Rev. 2020 Mar 20;29(155). pii: 200051. doi: 10.1183/16000617.0051-2020. Print  2020 Mar 31.   Free full text [Pubmed]

Stuart Elborn

Stuart Elborn in this issue of the European Respiratory Review, describes Shteinberg and Taylor-Cousar’s article as providing a very useful review of the current state of play in Europe for CFTR modulators

There is a benefit from these therapies even in individuals with severely reduced FEV1 who are excluded from the trials in follow-up clinical studies, and people with CF benefit from a significant reduction in pulmonary exacerbations.                                                                                                                The adverse events and drug/drug interactions are comprehensively covered in the article by Shteinberg and Taylor-Cousar.  Drug/drug interactions are also important in this group of drugs as they interact with a number of hepatic enzymes important in drug metabolism. These are particularly relevant for antibacterial and antifungal agents, which are often used in people with CF.

Elborn suggests the delivery of healthcare services for people with CF is likely to evolve over the next decade with a wide implementation of highly effective modulator treatment. It is important for respiratory clinical teams and the wider group of specialists in the multidisciplinary team to understand how these drugs are used, the side-effects and potential for drug interactions. The article by Shteinberg and Taylor-Cousar provides a very useful summary of the current position.

Full texts of both these above articles are available and are excellent.

Katharine E SecundaJennifer S GuimbellotBorko JovanovicSonya L HeltsheScott D SagelSteven M RoweManu Jain.  Females with Cystic Fibrosis Demonstrate a Differential Response Profile to Ivacaftor Compared with MalesAm J Respir Crit Care Med 2020 Apr 15;201(8):996-998.doi: 10.1164/rccm.201909-1845LE.[Pubmed]

    Katherine Secunda

In this letter, the authors  report three novel findings. The first is that ivacaftor-treated females with CF had a greater reduction in PEx than males with CF, noting that the baseline rate was higher in females. Second, females had a greater reduction in sweat chloride in response to ivacaftor than males. Finally, the sweat chloride response to ivacaftor is correlated with baseline weight. These data suggest that although females and males with CF showed similar salutary responses to ivacaftor in FEV1 and BMI, there may be important differential responses based on both sex and body weight.

It should be noted that ivacaftor-mediated reductions in sweat chloride have recently been shown to correlate with attenuation of FEV1 decline, which suggests that decreases in sweat chloride may also correlate with reduced lung transplantation and mortality risk. Thus, one potential implication of our data is that optimization of CFTR modulator dosing based on maximal sweat chloride reduction may lead to reduced long-term risk for lung transplantation and mortality.

 Dr Katherine E Secunda is a pulmonologist at the Northwestern University Feinberg School of Medicine Chicago, Illinois.

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

Koliarne TongDaniel BarkerMegan FranceLucy BurrHugh GrevilleSimone VisserPeter MiddletonClaire WainwrightDouglas DorahyPeter Wark.  Lumacaftor/ivacaftor reduces exacerbations in adults homozygous for Phe508del mutation with severe lung disease.  J Cyst Fibros   2020 May;19(3):415-420.doi: 10.1016/j.jcf.2019.12.006. Epub 2019 Dec 15.[Pubmed]

Peter Wark

       Koliarne Tong

Background: Lumacaftor/ivacaftor (LUM/IVA) improves outcomes in cystic fibrosis (CF) patients homozygous for Phe508del with ppFEV1 > 40%. There is limited safety or efficacy data in patients with ppFEV1 < 40%. We determined whether LUM/IVA in patients with ppFEV1 < 40 would reduce the rate of pulmonary exacerbations.
Methods: This was a case control study performed on patients > 12 years, homozygous for Phe508del CFTR mutation and with ppFEV1 < 40%. Control subjects were matched for age, sex and ppFEV1, and had mutations ineligible for LUM/IVA. We assessed the rate of pulmonary exacerbations requiring intravenous antibiotics, the mean rate of change in ppFEV1 over 12 months and all adverse events.
Results: Data was collected from 7 Australian CF centres on 105 patients; 72 on LUM/IVA and 33 controls. LUM/IVA demonstrated a large reduction in exacerbations with an incident rate ratio of 0.455 (95%CI; 0.306 – 0.676), p < 0.001 after adjusting for the number of exacerbations in the previous 12 months. LUM/IVA prolonged the time to first exacerbation and reduced the rate of decline in ppFEV1 over 12 months. Adverse events were common; chest tightness or dyspnoea was experienced by 55% and resulted in cessation of treatment in 32%.
Conclusions: Treatment with LUM/IVA resulted in a substantially lower rate of pulmonary exacerbations, prolonged time to first exacerbation and slowed the rate of decline of ppFEV1 in participants with severe lung disease. Adverse reactions to LUM/IVA however were unacceptably frequent and resulted in a very high discontinuation rate.

Dr Koliarne Tong is Staff Specialist in Respiratory and Sleep at the Adult Cystic Fibrosis Centre, John Hunter Hospital, Australia.

Professor Peter Wark, the corresponding author, a senior staff specialist in Respiratory and Sleep Medicine at John Hunter Hospital, Newcastle and a conjoint Professor with the University of Newcastle

Tétard C, Mittaine M, Bui S, Beaufils F, Maumus P, Fayon M, Burgel PR, Lamireau T, Delhaes L, Mas E, Enaud R. Reduced Intestinal Inflammation with Lumacaftor/Ivacaftor in Adolescents with Cystic Fibrosis.  J Pediatr Gastroenterol Nutr. 2020 Jul 30. doi: 10.1097/MPG.0000000000002864. Online ahead of print. [Pubmed]
A chronic intestinal inflammation may occur in patients with cystic fibrosis (CF), while no therapeutic management is proposed. While Lumacaftor/Ivacaftor is well-known to modulate the defective cystic fibrosis transmembrane conductance regulator (CFTR) protein in lungs, no data are available on the impact of this treatment on CF intestinal disorders. The authors therefore investigated the evolution of intestinal inflammation after initiation of Lumacaftor/Ivacaftor in CF adolescents (median of follow-up: 336 days (IQR: 278;435)). Median fecal calprotectin concentrations decreased significantly after Lumacaftor/Ivacaftor initiation (102 μg/g (IQR: 69;210)) compared to the baseline (713 μg/g (IQR:148;852), p = 0.001).

To their knowledge, this study showed for the first time that CF-related intestinal inflammation is improved by Lumacaftor/Ivacaftor treatment.

From Centre Hospitalier Universitaire de Bordeaux, CHU Bordeaux, CRCM Pédiatrique, Bordeaux, France.

Silke van Koningsbruggen-RietschelKatja ConrathRainald Fischer Sivagurunathan SutharsanAxel KempaWolfgang GleiberCarsten SchwarzAndreas HectorNancy Van OsselaerArian PanoSam CorveleynDieudonné BwirireEva SantermansKarine MullerSusan BellaireOlivier Van de Steen . GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN). J Cyst Fibros. 2020 Mar;19(2):292-298. doi: 10.1016/j.jcf.2019.09.006. Epub 2019 Oct 5.[Pubmed]

Silke van Koningsbruggen

Background: Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy.
Methods: This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400mg/ivacaftor 250mg for ≥12weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics.
Results: Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75mg; n=14) or placebo (n=8) capsules twice daily for 28days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference-19.6mmol/L [95% confidence interval (CI) -36.0, -3.2], p=.0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI -0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected.
Conclusions: GLPG2737 was well tolerated and yielded significant decreases in sweat chloride concentration versus placebo in subjects homozygous for F508del receiving lumacaftor/ivacaftor, demonstrating evidence of increased CFTR activity when added to a potentiator-corrector combination.

Dr Silke van Koningsbruggen-Rietschel is a Pediatric Pulmonologist and Director of the CF Clinical Research Center at the Cystic Fibrosis Center, Children’s Hospital, University of Cologne, Faculty of Medicine and University Hospital Cologne, Germany.

Guido Veit Dillon F Da FonteRadu G AvramescuAiswarya PremchandarMiklos BagdanyHaijin XuDennis BensingerDaniel StubbaBoris SchmidtElias MatoukGergely L LukacsMutation-specific dual potentiators maximize rescue of CFTR gating mutants. J Cyst Fibros   2020 Mar;19(2):236-244.doi: 10.1016/j.jcf.2019.10.011. Epub 2019 Oct 31. [Pubmed]

     Guido Veit

The potentiator ivacaftor (VX-770) has been approved for therapy of 38 cystic fibrosis (CF) mutations (∼10% of the patient population) associated with a gating defect of the CF transmembrane conductance regulator (CFTR). Despite the success of VX-770 treatment of patients carrying at least one allele of the most common gating mutation G551D-CFTR, some lung function decline and P. aeruginosa colonization persist. This study aims at identifying potentiator combinations that can considerably enhance the limited channel activity of a panel of CFTR gating mutants over monotherapy.
The functional response of 13 CFTR mutants to single potentiators or systematic potentiator combinations was determined in the human bronchial epithelial cell line CFBE41o- and a subset of them was confirmed in primary human nasal epithelia (HNE).
Results: In six out of thirteen CFTR missense mutants the fractional plasma membrane (PM) activity, a surrogate measure of CFTR channel gating, reached only ∼10-50% of WT channel activity upon VX-770 treatment, indicating incomplete gating correction. Combinatorial potentiator profiling and cluster analysis of mutant responses to 24 diverse investigational potentiators identified several compound pairs that improved the gating activity of R352Q-, S549R-, S549N-, G551D-, and G1244E-CFTR to ∼70-120% of the WT. Similarly, the potentiator combinations were able to confer WT-like function to G551D-CFTR in patient-derived human nasal epithelia.
Conclusion: This study suggests that half of CF patients with missense mutations approved for VX-770 administration, could benefit from the development of dual potentiator therapy.

Wang Y, Zhao J, Cai Y, Ballard HJ. Cystic Fibrosis Transmembrane Conductance Regulator-dependent bicarbonate entry controls rat cardiomyocyte ATP release via pannexin1 through mitochondrial signalling and caspase activation. Acta Physiol (Oxf). 2020 May 9. doi: 10.1111/apha.13495. Epub ahead of print. [Pubmed]
Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in the heart, but its function there is unclear. CFTR regulates an ATP release pore in many tissues, but the identity and regulatory mechanism of the pore are unknown. The authors investigated the role of CFTR in ATP release from primary cardiomyocytes and ventricular wall in vivo.
They found that during simulated ischaemia, CFTR-dependent bicarbonate entry stimulated ATP and cytochrome c release from mitochondria; in the cytoplasm, cytochrome c activated caspase 3, which in turn activated Panx1, and ATP was released through the opened Panx1 channel.

Dr Y Wang is at the School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.

Kael WherryIan WilliamsonRichard H ChapmanKaren M Kuntz   Cost-Effectiveness of Ivacaftor Therapy for Treatment of Cystic Fibrosis Patients With the G551D Gating MutationValue Health 2020 Oct;23(10):1332-1339. doi: 10.1016/j.jval.2020.05.016. Epub 2020 Aug 16. [Pubmed]
Objectives: Cystic fibrosis (CF) is a rare genetic disease with no cure. Until recently, treatment has targeted symptoms of the disease and not the disease-causing genetic defect. Ivacaftor is included in a new class of breakthrough drugs targeting the genetic defects of CF. We sought to estimate the long-term cost-effectiveness of ivacaftor from a US payer perspective.
Methods: We developed an individual-level microsimulation model that followed a cohort of heterogeneous US CF patients over a lifetime. The primary outcome of interest was quality-adjusted life years (QALYs). We also compared unadjusted life years, count of acute pulmonary exacerbations, and count of lung transplants over a lifetime between patients treated with ivacaftor plus best supportive care and patients treated with best supportive care alone. We conducted one-way and probabilistic sensitivity analyses to test the impact of various model inputs and uncertainties.
Results: We found a substantial increase in QALYs, life years, and treatment costs over a lifetime for patients treated with ivacaftor plus best supportive care versus best supportive care alone. Discounted results for ivacaftor were 22.92 QALYs and $8 797 840 in total lifetime costs compared to 16.12 QALYs and $2 336 366 lifetime costs for best supportive care alone. The incremental cost-effectiveness ratios (ICERs) were $950 217 per QALY. Results from the probabilistic sensitivity analysis indicated a 0% chance that ivacaftor was cost-effective at a willingness-to-pay (WTP) threshold of $500 000 per QALY.

2021                    2021                      2021

Chilvers MA, Davies JC, Milla C, Tian S, Han Z, Cornell AG, Owen CA, Ratjen F. Long-term safety and efficacy of lumacaftor-ivacaftor therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a phase 3, open-label, extension study.    Lancet Respir Med. 2021 Jan 28:S2213-2600(20)30517-8. doi: 10.1016/S2213-2600(20)30517-8. Online ahead of print. [Pubmed]
Background: The safety and efficacy of 24 weeks of lumacaftor-ivacaftor combination therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation was previously shown in two phase 3 studies. Here, we report long-term safety and efficacy data.
Methods: In this phase 3, open-label, multicentre, extension study (study 110), we examined the long-term safety, tolerability, and efficacy of lumacaftor-ivacaftor in children pooled from two phase 3 parent studies (open-label study 011B and randomised, placebo-controlled study 109). The study was conducted at 61 clinics in the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK. Children with cystic fibrosis homozygous for the F508del-CFTR mutation who had received lumacaftor-ivacaftor or placebo in the parent studies were treated with lumacaftor-ivacaftor for up to 96 weeks; those who had received the combination therapy in the parent studies (the treatment-to-treatment group) received up to 120 weeks of treatment in total. Participants aged 6-11 years at the start of the parent study received lumacaftor 200 mg-ivacaftor 250 mg orally once every 12 h; those aged 12 years or older received lumacaftor 400 mg-ivacaftor 250 mg orally once every 12 h. The primary endpoint was safety and tolerability in all children who had received at least one dose of the study drug. Secondary endpoints included change from baseline in lung clearance index 2·5% (LCI2·5), sweat chloride concentration, body-mass index, and Cystic Fibrosis Questionnaire-Revised respiratory domain score. This extension study is registered with ClinicalTrials.gov, NCT02544451, and has been completed.
Findings: The extension study ran from Aug 13, 2015, to Aug 17, 2018. Of 239 children who enrolled in the study and received at least one dose of lumacaftor-ivacaftor, 215 (90%) completed 96 weeks of treatment. Most children (236 [99%] of 239 children) had adverse events that were mild (49 [21%] of 239) or moderate (148 [62%] of 239) in severity, and there was a low rate of adverse events leading to treatment discontinuation. The most frequently reported adverse events were common manifestations or complications of cystic fibrosis, such as cough and pulmonary exacerbation, or were consistent with the known safety profile of lumacaftor-ivacaftor in older children and adults. No new safety concerns were identified with extended lumacaftor-ivacaftor treatment. Children in the placebo-to-treatment group had improvements in efficacy endpoints consistent with those observed in the parent studies. Improvements observed in children treated with lumacaftor-ivacaftor in the parent study were generally maintained in the extension study.
Interpretation: Lumacaftor-ivacaftor therapy in children homozygousi for F508del-CFTR who initiated treatment at age 6-11 years was generally safe and well tolerated, and efficacy was sustained for up to 120 weeks. These data support the long-term use of lumacaftor-ivacaftor to treat children aged 6 years and older who are homozygous for the F508del-CFTR mutation.

Dr Mark Chilvers is Clinical Associate Professor, Division of Respiratory Medicine, Department of Pediatrics, Faculty of Medicine, University of British Columbia

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

Marie E Egan Emerging technologies for cystic fibrosis transmembrane conductance regulator restoration in all people with CFPediatr Pulmonol 2021 Feb;56 Suppl 1:S32-S39.doi: 10.1002/ppul.24965.  [Pubmed]

    Marie Egan

Although effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has the potential to change the lives of many patients with cystic fibrosis (CF), it is unlikely that these drugs will be a game changing therapy for all. There are about 10% of patients with CF who don’t produce a mutant protein tomodulate, potentiate, or optimize and for these patients such therapies are unlikely to be of significant benefit. There is a need to develop new therapeutic approaches that can work for this patient population and can advance CF therapies. These new therapies will be genetic-based therapies and each approach will result in functional CFTR protein inpreviously affected CF cells. In this review we will examine the potential of RNA therapies, gene transfer therapies, and gene editing therapies for the treatment of CF as well as the challenges that will need to be facedas we harness the power of these emerging therapies towards a one-time cure.

Marie Egan is Professor of Pediatrics and of Cellular and Molecular Physiology: Director, Cystic Fibrosis Center; Vice Chair for Research Department of Pediatrics, Yale School of Medicine.

Anabela S Ramalho Eva Fürstová Annelotte M Vonk Marc FerranteCatherine VerfaillieLieven Dupont Mieke Boon Marijke Proesmans Jeffrey M Beekman, Ifat SaroukCarlos Vazquez CorderoFrancois VermeulenKris De Boeck Belgian Organoid ProjectCorrection of CFTR function in intestinal organoids to guide treatment of cystic fibrosisEur Respir J 2021 Jan 5;57(1):1902426.doi: 10.1183/13993003.02426-2019. Print 2021 Jan.  [Pubmed]

     Anabela Ramalho

Given the vast number of cystic fibrosis transmembrane conductance regulator (CFTR) mutations, biomarkers predicting benefit from CFTR modulator therapies are needed for subjects with cystic fibrosis (CF). To study CFTR function in organoids of subjects with common and rare CFTR mutations and evaluate correlations between CFTR function and clinical data.
Intestinal organoids were grown from rectal biopsies in a cohort of 97 subjects with CF. Residual CFTR function was measured by quantifying organoid swelling induced by forskolin and response to modulators by quantifying organoid swelling induced by CFTR correctors, potentiator and their combination. Organoid data were correlated with clinical data from the literature.
Across 28 genotypes, residual CFTR function correlated (r2=0.87) with sweat chloride values. When studying the same genotypes, CFTR function rescue by CFTR modulators in organoids correlated tightly with mean improvement in lung function (r2=0.90) and sweat chloride (r2=0.95) reported in clinical trials. We identified candidate genotypes for modulator therapy, such as E92K, Q237E, R334W and L159S. Based on organoid results, two subjects started modulator treatment: one homozygous for complex allele Q359K_T360K, and the second with mutation E60K. Both subjects had major clinical benefit.
Measurements of residual CFTR function and rescue of function by CFTR modulators in intestinal organoids correlate closely with clinical data. Our results for reference genotypes concur with previous results. CFTR function measured in organoids can be used to guide precision medicine in patients with CF, positioning organoids as a potential in vitro model to bring treatment to patients carrying rare CFTR mutations.

Dr Anabela Santo Ramalho is in Dept of Development and Regeneration, Woman and Child Unit, CF Research Lab, KU Leuven, Leuven, Belgium.

Scott D Sagel Umer Khan Sonya L Heltshe John P Clancy Drucy 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)

Jane C DaviesClaire E Wainwright Gregory S SawickiMark N Higgins Daniel Campbell Christopher HarrisPaul PanorchanEric HaseltineSimon TianMargaret RosenfeldIvacaftor in Infants Aged 4 to <12 Months with Cystic Fibrosis and a Gating Mutation. Results of a Two-Part Phase 3 Clinical Trial. Am J Respir Crit Care Med   2021 Mar 1;203(5):585-593.doi: 10.1164/rccm.202008-3177OC.   33023304

      Jane Davies

Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here, we report results for cohorts aged 4 to <12 months.
Objectives: To evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with one or more gating mutations.
Methods: ARRIVAL is a single-arm phase 3 study. Infants received 25 mg or 50 mg ivacaftor every 12 hours on the basis of age and weight for 4 days in part A and 24 weeks in part B.
Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (four infants participated in both parts). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild or moderate. In part B, cough was the most common adverse event (n = 10 [58.8%]). Five infants (part A, n = 1 [8.3%]; part B, n = 4 [23.5%]) had serious adverse events, all of which were considered to be not or unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5× the upper limit of normal at Week 24. No other adverse trends in laboratory tests, vital signs, or ECG parameters were reported. Sweat chloride concentrations and measures of pancreatic obstruction improved.
Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with one or more gating mutations.

Further detail abstracted from the full text – This study of CFTR modulation in the first year of life suggests that ivacaftor can be safely administered to infants ≥4 months of age. Our findings are consistent with observations in older children and support treating the underlying cause of CF in children ≥4 months. Ivacaftor has a favourable safety profile; it was well tolerated at both doses tested, with no new safety concerns. Results of this study suggest improvements in CFTR function, no adverse effects on growth, and reductions in lipase concentrations with ivacaftor. Improvements in FE-1 and IRT concentrations (together with lipase data) support the potential of ivacaftor to delay or possibly minimize progressive exocrine pancreatic dysfunction. Studies evaluating a larger number of children for longer periods of time are needed to further test this hypothesis. Studies of pharmacokinetics and safety in younger infants are planned.
Substantial decreases in sweat chloride concentration were seen, which is a measure of CFTR function. Although the sample sizes were small, the mean improvement in sweat chloride concentration of −55.7 (SD, 16.2) mmol/L in these infants aged 4 to <12 months appears comparable with what has been reported in older children
Improvements in concentrations of FE-1, a biomarker of exocrine pancreatic function, were seen from baseline to 24 weeks (mean [SD] increases of 164.7 [151.9] μg/g and 99.8 [138.4] μg/g in ARRIVAL and KIWI, respectively).  Similarly, in the current report, mean (SD) improvement in FE-1 concentrations at Week 24 was 166.0 (140.6) μg/g. Eleven infants had baseline FE-1 concentrations of ≤200 μg/g, indicating pancreatic insufficiency, among whom seven of nine with paired data had regained pancreatic sufficiency at Week 24.
Although the clinical relevance of improvements in biomarkers of pancreatic function is unknown, the combined findings in children aged 4 to <24 months in ARRIVAL and aged 2–5 years in KIWI suggest a possible positive and protective effect of ivacaftor on pancreatic exocrine function early in life.

Jane Davies is a Professor in Paediatric Respirology & Experimental Medicine at the National Heart and Lung Institute and an Honorary Consultant in Paediatric Respiratory Medicine at the Royal Brompton & Harefield NHS Foundation Trust.

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

Bardin E, Pastor A, Semeraro M, Golec A, Hayes K, Chevalier B, Berhal F, Prestat G, Hinzpeter A, Gravier-Pelletier C, Pranke I, Sermet-Gaudelus I.   Modulators of CFTR. Updates on clinical development and future.  Eur J Med Chem. 2021 Mar 5;213:113195.doi: 10.1016/j.ejmech.2021.113195. Epub 2021 Jan 16. [Pubmed]

Emmanuelle Bardin

Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacologic therapy aiming to restore mutated CFTR expression and function. These CFTR “modulators” have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable number of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clinical trials of CFTR modulators.

Dr Emmanuelle Bardin is a post-doctoral researcher at the Institut Necker Enfants Malades. INSERM U1151, Paris, France. in 2020 she was awarded a European Cystic Fibrosis Society and Cystic Fibrosis Europe Post-Doctoral Research Fellowship to research into “Novel insights into the impact of CFTR modulators on the response of the cystic fibrosis respiratory epithelium to S. aureus infection”.