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Semin Respir Crit Care Med 2023; 44(02): 186-195
DOI: 10.1055/s-0042-1758851
Review Article

CFTR Modulators: Current Status and Evolving Knowledge

Lucile Regard
1   Department of Respiratory Medicine and French Cystic Fibrosis National Reference Center, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France
2   Institut Cochin and Université de Paris, INSERM U1016, Paris, France
3   ERN Lung Cystic Fibrosis Network, Frankfurt, Germany
,
Clémence Martin
1   Department of Respiratory Medicine and French Cystic Fibrosis National Reference Center, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France
2   Institut Cochin and Université de Paris, INSERM U1016, Paris, France
3   ERN Lung Cystic Fibrosis Network, Frankfurt, Germany
,
Jennifer Da Silva
1   Department of Respiratory Medicine and French Cystic Fibrosis National Reference Center, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France
3   ERN Lung Cystic Fibrosis Network, Frankfurt, Germany
,
Pierre-Régis Burgel
1   Department of Respiratory Medicine and French Cystic Fibrosis National Reference Center, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France
2   Institut Cochin and Université de Paris, INSERM U1016, Paris, France
3   ERN Lung Cystic Fibrosis Network, Frankfurt, Germany
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Abstract

In the past decade, the medical management of people with cystic fibrosis (pwCF) has changed with the development of small molecules that partially restore the function of the defective CF transmembrane conductance regulator (CFTR) protein and are called CFTR modulators. Ivacaftor (IVA), a CFTR potentiator with a large effect on epithelial ion transport, was the first modulator approved in pwCF carrying gating mutations. Because IVA was unable to restore sufficient CFTR function in pwCF with other mutations, two CFTR correctors (lumacaftor and tezacaftor) were developed and used in combination with IVA in pwCF homozygous for F508del, the most common CFTR variant. However, LUM/IVA and TEZ/IVA were only moderately effective in F508del homozygous pwCF and had no efficacy in those with F508del and minimal function mutations. Elexacaftor, a second-generation corrector, was thus developed and combined to tezacaftor and ivacaftor (ELX/TEZ/IVA) to target pwCF with at least one F508del variant, corresponding to approximately 85% of pwCF. Both IVA and ELX/TEZ/IVA are considered highly effective modulator therapies (HEMTs) in eligible pwCF and are now approved for nearly 90% of the CF population over 6 years of age. HEMTs are responsible for rapid improvement in respiratory manifestations, including improvement in symptoms and lung function, and reduction in the rate of pulmonary exacerbations. The impact of HEMT on extrapulmonary manifestations of CF is less well established, although significant weight gain and improvement in quality of life have been demonstrated. Recent clinical trials and real-world studies suggest that benefits of HEMT could even prove greater when used earlier in life (i.e., in younger children and infants). This article shortly reviews the past 10 years of development and use of CFTR modulators. Effects of HEMT on extrapulmonary manifestations and on CF demographics are also discussed.

Keywords

cystic fibrosis - CFTR modulators - ivacaftor - tezacaftor - elexacaftor


Publication History

Article published online:
19 December 2022

© 2022. Thieme. All rights reserved.

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  • References

  • 1 Stephenson AL, Stanojevic S, Sykes J, Burgel PR. The changing epidemiology and demography of cystic fibrosis. Presse Med 2017; 46 (6, pt. 2): e87-e95
    CrossrefPubMedSearch in Google Scholar
  • 2 Shteinberg M, Haq IJ, Polineni D, Davies JC. Cystic fibrosis. Lancet 2021; 397 (10290): 2195-2211
    CrossrefPubMedSearch in Google Scholar
  • 3 Elborn JS. Cystic fibrosis. Lancet 2016; 388 (10059): 2519-2531
    CrossrefPubMedSearch in Google Scholar
  • 4 Bell SC, Mall MA, Gutierrez H. et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med 2020; 8 (01) 65-124
    CrossrefPubMedSearch in Google Scholar
  • 5 Veit G, Avramescu RG, Chiang AN. et al. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell 2016; 27 (03) 424-433
    CrossrefPubMedSearch in Google Scholar
  • 6 Cohen-Cymberknoh M, Shoseyov D, Kerem E. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life. Am J Respir Crit Care Med 2011; 183 (11) 1463-1471
    CrossrefPubMedSearch in Google Scholar
  • 7 Regard L, Martin C, Chassagnon G, Burgel PR. Acute and chronic non-pulmonary complications in adults with cystic fibrosis. Expert Rev Respir Med 2019; 13 (01) 23-38
    CrossrefPubMedSearch in Google Scholar
  • 8 Fajac I, Wainwright CE. New treatments targeting the basic defects in cystic fibrosis. Presse Med 2017; 46 (6, pt. 2): e165-e175
    CrossrefPubMedSearch in Google Scholar
  • 9 Eckford PD, Li C, Ramjeesingh M, Bear CE. Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. J Biol Chem 2012; 287 (44) 36639-36649
    CrossrefPubMedSearch in Google Scholar
  • 10 Accurso FJ, Rowe SM, Clancy JP. et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 2010; 363 (21) 1991-2003
    CrossrefPubMedSearch in Google Scholar
  • 11 Okiyoneda T, Veit G, Dekkers JF. et al. Mechanism-based corrector combination restores ΔF508-CFTR folding and function. Nat Chem Biol 2013; 9 (07) 444-454
    CrossrefPubMedSearch in Google Scholar
  • 12 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 Med 2015; 373 (03) 220-231
    CrossrefPubMedSearch in Google Scholar
  • 13 Taylor-Cousar JL, Munck A, McKone EF. et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med 2017; 377 (21) 2013-2023
    CrossrefPubMedSearch in Google Scholar
  • 14 Rowe SM, Daines C, Ringshausen FC. et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med 2017; 377 (21) 2024-2035
    CrossrefPubMedSearch in Google Scholar
  • 15 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. Lancet 2019; 394 (10212): 1940-1948
    CrossrefPubMedSearch in Google Scholar
  • 16 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 (19) 1809-1819
    CrossrefPubMedSearch in Google Scholar
  • 17 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 Med 2018; 379 (17) 1612-1620
    CrossrefPubMedSearch in Google Scholar
  • 18 Barry PJ, Mall MA, Álvarez A. et al; VX18-445-104 Study Group. Triple therapy for cystic fibrosis Phe508del-gating and -residual function genotypes. N Engl J Med 2021; 385 (09) 815-825
    CrossrefPubMedSearch in Google Scholar
  • 19 Boyle MP, Bell SC, Konstan MW. et al; VX09-809-102 study group. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med 2014; 2 (07) 527-538
    CrossrefPubMedSearch in Google Scholar
  • 20 Munck A, Kerem E, Ellemunter H. et al. Tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for minimal function CFTR mutations. J Cyst Fibros 2020; 19 (06) 962-968
    CrossrefPubMedSearch in Google Scholar
  • 21 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 (18) 1663-1672
    CrossrefPubMedSearch in Google Scholar
  • 22 Rowe SM, Heltshe SL, Gonska T. et al; GOAL Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014; 190 (02) 175-184
    CrossrefPubMedSearch in Google Scholar
  • 23 Davies JC, Wainwright CE, Canny GJ. et al; VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med 2013; 187 (11) 1219-1225
    CrossrefPubMedSearch in Google Scholar
  • 24 De Boeck K, Munck A, Walker S. et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros 2014; 13 (06) 674-680
    CrossrefPubMedSearch in Google Scholar
  • 25 Moss RB, Flume PA, Elborn JS. et al; VX11-770-110 (KONDUCT) Study Group. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med 2015; 3 (07) 524-533
    CrossrefPubMedSearch in Google Scholar
  • 26 Flume PA, Liou TG, Borowitz DS. et al; VX 08-770-104 Study Group. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest 2012; 142 (03) 718-724
    CrossrefPubMedSearch in Google Scholar
  • 27 Hebestreit H, Sauer-Heilborn A, Fischer R, Käding M, Mainz JG. Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation. J Cyst Fibros 2013; 12 (06) 599-603
    CrossrefPubMedSearch in Google Scholar
  • 28 Taylor-Cousar J, Niknian M, Gilmartin G, Pilewski JM. VX11-770-901 investigators. Effect of ivacaftor in patients with advanced cystic fibrosis and a G551D-CFTR mutation: Safety and efficacy in an expanded access program in the United States. J Cyst Fibros 2016; 15 (01) 116-122
    CrossrefPubMedSearch in Google Scholar
  • 29 Hubert D, Marguet C, Benichou J. et al; BRIO Study Group. Real-world long-term ivacaftor for cystic fibrosis in France: clinical effectiveness and healthcare resource utilization. Pulm Ther 2021; 7 (02) 455-468
    CrossrefPubMedSearch in Google Scholar
  • 30 Hubert D, Dehillotte C, Munck A. et al. Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2years of treatment with ivacaftor in a real-world setting. J Cyst Fibros 2018; 17 (01) 89-95
    CrossrefPubMedSearch in Google Scholar
  • 31 Volkova N, Moy K, Evans J. et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: data from national US and UK registries. J Cyst Fibros 2020; 19 (01) 68-79
    CrossrefPubMedSearch in Google Scholar
  • 32 Kirwan L, Fletcher G, Harrington M. et al. Longitudinal trends in real-world outcomes after initiation of ivacaftor. a cohort study from the cystic fibrosis registry of Ireland. Ann Am Thorac Soc 2019; 16 (02) 209-216
    CrossrefPubMedSearch in Google Scholar
  • 33 Hubert D, Chiron R, Camara B. et al. Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease. J Cyst Fibros 2017; 16 (03) 388-391
    CrossrefPubMedSearch in Google Scholar
  • 34 Burgel PR, Munck A, Durieu I. et al; French Cystic Fibrosis Reference Network Study Group. Real-life safety and effectiveness of lumacaftor-ivacaftor in patients with cystic fibrosis. Am J Respir Crit Care Med 2020; 201 (02) 188-197
    CrossrefPubMedSearch in Google Scholar
  • 35 Taylor-Cousar JL, Jain M, Barto TL. et al; VX14-809-106 Investigator Group. Lumacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR. J Cyst Fibros 2018; 17 (02) 228-235
    CrossrefPubMedSearch in Google Scholar
  • 36 Schwarz C, Sutharsan S, Epaud R. et al. Tezacaftor/ivacaftor in people with cystic fibrosis who stopped lumacaftor/ivacaftor due to respiratory adverse events. J Cyst Fibros 2021; 20 (02) 228-233
    CrossrefPubMedSearch in Google Scholar
  • 37 Burgel PR, Durieu I, Chiron R. et al; French Cystic Fibrosis Reference Network study group. Clinical response to lumacaftor-ivacaftor in patients with cystic fibrosis according to baseline lung function. J Cyst Fibros 2021; 20 (02) 220-227
    CrossrefPubMedSearch in Google Scholar
  • 38 Taylor-Cousar JL, Mall MA, Ramsey BW. et al. Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles. ERJ Open Res 2019; 5 (02) 00082-2019
    PubMedSearch in Google Scholar
  • 39 Griese M, Costa S, Linnemann RW. et al. Safety and efficacy of elexacaftor/tezacaftor/ivacaftor for 24 weeks or longer in people with cystic fibrosis and one or more F508del alleles: interim results of an open-label phase 3 clinical trial. Am J Respir Crit Care Med 2021; 203 (03) 381-385
    CrossrefPubMedSearch in Google Scholar
  • 40 Sutharsan S, McKone EF, Downey DG. et al; VX18-445-109 study group. Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial. Lancet Respir Med 2022; 10 (03) 267-277
    CrossrefPubMedSearch in Google Scholar
  • 41 Burgel PR, Durieu I, Chiron R. et al; French Cystic Fibrosis Reference Network Study Group. Rapid improvement after starting elexacaftor-tezacaftor-ivacaftor in patients with cystic fibrosis and advanced pulmonary disease. Am J Respir Crit Care Med 2021; 204 (01) 64-73
    CrossrefPubMedSearch in Google Scholar
  • 42 Martin C, Reynaud-Gaubert M, Hamidfar R. et al. Sustained effectiveness of elexacaftor-tezacaftor-ivacaftor in lung transplant candidates with cystic fibrosis. J Cyst Fibros 2022; 21 (03) 489-496
    CrossrefPubMedSearch in Google Scholar
  • 43 Nichols DP, Paynter AC, Heltshe SL. et al; PROMISE Study group. Clinical effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: a clinical trial. Am J Respir Crit Care Med 2022; 205 (05) 529-539
    CrossrefPubMedSearch in Google Scholar
  • 44 Davies JC, Wainwright CE, Sawicki GS. et al. Ivacaftor 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; 203 (05) 585-593
    CrossrefPubMedSearch in Google Scholar
  • 45 Rosenfeld M, Wainwright CE, Higgins M. et al; ARRIVAL study group. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med 2018; 6 (07) 545-553
    CrossrefPubMedSearch in Google Scholar
  • 46 Walker S, Flume P, McNamara J. et al; VX15-661-113 Investigator Group. A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis. J Cyst Fibros 2019; 18 (05) 708-713
    CrossrefPubMedSearch in Google Scholar
  • 47 Rosenfeld M, Cunningham S, Harris WT. et al; KLIMB study group. An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB). J Cyst Fibros 2019; 18 (06) 838-843
    CrossrefPubMedSearch in Google Scholar
  • 48 Zemanick ET, Taylor-Cousar JL, Davies J. et al. A phase 3 open-label study of elexacaftor/tezacaftor/ivacaftor in children 6 through 11 years of age with cystic fibrosis and at least one F508del Allele. Am J Respir Crit Care Med 2021; 203 (12) 1522-1532
    CrossrefPubMedSearch in Google Scholar
  • 49 Mall MA, Brugha R, Gartner S. et al; VX19-445-116 Study Group. Efficacy and safety of elexacaftor/tezacaftor/ivacaftor in children 6 through 11 years of age with cystic fibrosis heterozygous for f508del and a minimal function mutation: a phase 3B, randomized, placebo-controlled study. Am J Respir Crit Care Med 2022; 206 (11) 1361-1369
    CrossrefPubMedSearch in Google Scholar
  • 50 Sette G, Lo Cicero S, Blaconà G. et al. Theratyping cystic fibrosis in vitro in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells. Eur Respir J 2021; 58 (06) 2100908
    CrossrefPubMedSearch in Google Scholar
  • 51 Singh VK, Schwarzenberg SJ. Pancreatic insufficiency in cystic fibrosis. J Cyst Fibros 2017; 16 (Suppl 2): S70-S78
    CrossrefPubMedSearch in Google Scholar
  • 52 Megalaa R, Gopalareddy V, Champion E, Goralski JL. Time for a gut check: pancreatic sufficiency resulting from CFTR modulator use. Pediatr Pulmonol 2019; 54 (08) E16-E18
    CrossrefPubMedSearch in Google Scholar
  • 53 Munce D, Lim M, Akong K. Persistent recovery of pancreatic function in patients with cystic fibrosis after ivacaftor. Pediatr Pulmonol 2020; 55 (12) 3381-3383
    CrossrefPubMedSearch in Google Scholar
  • 54 Crowley J, Croinin K, Mullane D, Chróinín MN. Restoration of exocrine pancreatic function in child with lumacaftor/ivacaftor therapy in cystic fibrosis. J Cyst Fibros 2022; 21 (02) 264
    CrossrefPubMedSearch in Google Scholar
  • 55 Carrion A, Borowitz DS, Freedman SD. et al. Reduction of recurrence risk of pancreatitis in cystic fibrosis with ivacaftor: case series. J Pediatr Gastroenterol Nutr 2018; 66 (03) 451-454
    CrossrefPubMedSearch in Google Scholar
  • 56 Ramsey ML, Gokun Y, Sobotka LA. et al. Cystic fibrosis transmembrane conductance regulator modulator use is associated with reduced pancreatitis hospitalizations in patients with cystic fibrosis. Am J Gastroenterol 2021; 116 (12) 2446-2454
    CrossrefPubMedSearch in Google Scholar
  • 57 Gould MJ, Smith H, Rayment JH, Machida H, Gonska T, Galante GJ. CFTR modulators increase risk of acute pancreatitis in pancreatic insufficient patients with cystic fibrosis. J Cyst Fibros 2022; 21 (04) 600-602
    CrossrefPubMedSearch in Google Scholar
  • 58 Bellin MD, Laguna T, Leschyshyn J. et al. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes 2013; 14 (06) 417-421
    CrossrefPubMedSearch in Google Scholar
  • 59 Hayes Jr D, McCoy KS, Sheikh SI. Resolution of cystic fibrosis-related diabetes with ivacaftor therapy. Am J Respir Crit Care Med 2014; 190 (05) 590-591
    CrossrefPubMedSearch in Google Scholar
  • 60 Misgault B, Chatron E, Reynaud Q. et al. Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients. J Cyst Fibros 2020; 19 (05) 712-716
    CrossrefPubMedSearch in Google Scholar
  • 61 Gaines H, Jones KR, Lim J, Medhi NF, Chen S, Scofield RH. Effect of CFTR modulator therapy on cystic fibrosis-related diabetes. J Diabetes Complications 2021; 35 (06) 107845
    CrossrefPubMedSearch in Google Scholar
  • 62 Scully KJ, Marchetti P, Sawicki GS. et al. The effect of elexacaftor/tezacaftor/ivacaftor (ETI) on glycemia in adults with cystic fibrosis. J Cyst Fibros 2022; 21 (02) 258-263
    CrossrefPubMedSearch in Google Scholar
  • 63 Korten I, Kieninger E, Krueger L. et al. Short-term effects of elexacaftor/tezacaftor/ivacaftor combination on glucose tolerance in young people with cystic fibrosis-an observational pilot study. Front Pediatr 2022; 10: 852551
    CrossrefPubMedSearch in Google Scholar
  • 64 Sheikh SI, Long FR, McCoy KS, Johnson T, Ryan-Wenger NA, Hayes Jr D. Ivacaftor improves appearance of sinus disease on computerised tomography in cystic fibrosis patients with G551D mutation. Clin Otolaryngol 2015; 40 (01) 16-21
    CrossrefPubMedSearch in Google Scholar
  • 65 Douglas JE, Civantos AM, Locke TB. et al. Impact of novel CFTR modulator on sinonasal quality of life in adult patients with cystic fibrosis. Int Forum Allergy Rhinol 2021; 11 (02) 201-203
    CrossrefPubMedSearch in Google Scholar
  • 66 DiMango E, Overdevest J, Keating C, Francis SF, Dansky D, Gudis D. Effect of highly effective modulator treatment on sinonasal symptoms in cystic fibrosis. J Cyst Fibros 2021; 20 (03) 460-463
    CrossrefPubMedSearch in Google Scholar
  • 67 Beswick DM, Humphries SM, Balkissoon CD. et al. Machine learning evaluates improvement in sinus computed tomography opacification with CFTR modulator therapy. Int Forum Allergy Rhinol 2021; 11 (05) 953-954
    CrossrefPubMedSearch in Google Scholar
  • 68 Stapleton AL, Kimple AJ, Goralski JL. et al. Elexacaftor-tezacaftor-ivacaftor improves sinonasal outcomes in cystic fibrosis. J Cyst Fibros 2022; 21 (05) 792-799
    CrossrefPubMedSearch in Google Scholar
  • 69 Bailey J, Rozga M, McDonald CM. et al. Effect of CFTR modulators on anthropometric parameters in individuals with cystic fibrosis: an evidence analysis center systematic review. J Acad Nutr Diet 2021; 121 (07) 1364-1378.e2
    CrossrefPubMedSearch in Google Scholar
  • 70 King SJ, Tierney AC, Edgeworth D. et al. Body composition and weight changes after ivacaftor treatment in adults with cystic fibrosis carrying the G551 D cystic fibrosis transmembrane conductance regulator mutation: a double-blind, placebo-controlled, randomized, crossover study with open-label extension. Nutrition 2021; 85: 111124
    CrossrefPubMedSearch in Google Scholar
  • 71 Gramegna A, Aliberti S, Contarini M. et al. Overweight and obesity in adults with cystic fibrosis: an Italian multicenter cohort study. J Cyst Fibros 2022; 21 (01) 111-114
    CrossrefPubMedSearch in Google Scholar
  • 72 Litvin M, Yoon JC. Nutritional excess in cystic fibrosis: the skinny on obesity. J Cyst Fibros 2020; 19 (01) 3-5
    CrossrefPubMedSearch in Google Scholar
  • 73 Bass R, Brownell JN, Stallings VA. The impact of highly effective CFTR modulators on growth and nutrition status. Nutrients 2021; 13 (09) 2907
    CrossrefPubMedSearch in Google Scholar
  • 74 Bessonova L, Volkova N, Higgins M. et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax 2018; 73 (08) 731-740
    CrossrefPubMedSearch in Google Scholar
  • 75 Drummond D, Dana J, Berteloot L. et al. Lumacaftor-ivacaftor effects on cystic fibrosis-related liver involvement in adolescents with homozygous F508 del-CFTR. J Cyst Fibros 2022; 21 (02) 212-219
    CrossrefPubMedSearch in Google Scholar
  • 76 Kutney K, Donnola SB, Flask CA. et al. Lumacaftor/ivacaftor therapy is associated with reduced hepatic steatosis in cystic fibrosis patients. World J Hepatol 2019; 11 (12) 761-772
    CrossrefPubMedSearch in Google Scholar
  • 77 Despotes KA, Donaldson SH. Current state of CFTR modulators for treatment of cystic fibrosis. Curr Opin Pharmacol 2022; 65: 102239
    CrossrefPubMedSearch in Google Scholar
  • 78 Nash EF, Middleton PG, Taylor-Cousar JL. Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators – an international survey. J Cyst Fibros 2020; 19 (04) 521-526
    CrossrefPubMedSearch in Google Scholar
  • 79 Taylor-Cousar JL, Jain R. Maternal and fetal outcomes following elexacaftor-tezacaftor-ivacaftor use during pregnancy and lactation. J Cyst Fibros 2021; 20 (03) 402-406
    CrossrefPubMedSearch in Google Scholar
  • 80 Fortner CN, Seguin JM, Kay DM. Normal pancreatic function and false-negative CF newborn screen in a child born to a mother taking CFTR modulator therapy during pregnancy. J Cyst Fibros 2021; 20 (05) 835-836
    CrossrefPubMedSearch in Google Scholar
  • 81 Rowe SM, McColley SA, Rietschel E. et al; VX09-809-102 Study Group. Lumacaftor/ivacaftor treatment of patients with cystic fibrosis heterozygous for F508del-CFTR. Ann Am Thorac Soc 2017; 14 (02) 213-219
    CrossrefPubMedSearch in Google Scholar
  • 82 Konstan MW, McKone EF, Moss RB. et al. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med 2017; 5 (02) 107-118
    CrossrefPubMedSearch in Google Scholar
  • 83 Davis PB. Cystic fibrosis since 1938. Am J Respir Crit Care Med 2006; 173 (05) 475-482
    CrossrefPubMedSearch in Google Scholar
  • 84 Martin C, Hamard C, Kanaan R. et al. Causes of death in French cystic fibrosis patients: the need for improvement in transplantation referral strategies!. J Cyst Fibros 2016; 15 (02) 204-212
    CrossrefPubMedSearch in Google Scholar
  • 85 Coriati A, Ma X, Sykes J. et al. Beyond borders: cystic fibrosis survival between Australia, Canada, France and New Zealand. Thorax 2022; (e-pub ahead of print)
    CrossrefPubMedSearch in Google Scholar
  • 86 Thabut G, Christie JD, Mal H. et al. Survival benefit of lung transplant for cystic fibrosis since lung allocation score implementation. Am J Respir Crit Care Med 2013; 187 (12) 1335-1340
    CrossrefPubMedSearch in Google Scholar
  • 87 Burgel PR, Bellis G, Olesen HV. et al; ERS/ECFS Task Force on Provision of Care for Adults with Cystic Fibrosis in Europe. Future trends in cystic fibrosis demography in 34 European countries. Eur Respir J 2015; 46 (01) 133-141
    CrossrefPubMedSearch in Google Scholar
  • 88 Burgel PR, Bellis G, Elborn JS. Modelling future trends in cystic fibrosis demography using the French Cystic Fibrosis Registry: update and sensitivity analysis. Eur Respir J 2017; 50 (02) 1700763
    CrossrefPubMedSearch in Google Scholar
  • 89 Martin C, Legeai C, Regard L. et al. Major decrease in lung transplantation for patients with cystic fibrosis in France. Am J Respir Crit Care Med 2022; 205 (05) 584-586
    CrossrefPubMedSearch in Google Scholar
  • 90 Burgel PR, Burnet E, Regard L, Martin C. The changing epidemiology of cystic fibrosis: the implications for adult care. Chest 2022; (e-pub ahead of print)
    CrossrefPubMedSearch in Google Scholar
  • 91 Fajac I, Sermet I. Therapeutic approaches for patients with cystic fibrosis not eligible for current CFTR modulators. Cells 2021; 10 (10) 2793
    CrossrefPubMedSearch in Google Scholar