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Review
. 2021 May;20(3):381-387.
doi: 10.1016/j.jcf.2021.01.007. Epub 2021 Jan 30.

Challenges in the use of highly effective modulator treatment for cystic fibrosis

Kathleen J Ramos  1 , Joseph M Pilewski  2 , Jennifer L Taylor-Cousar  3
Affiliations
Review

Challenges in the use of highly effective modulator treatment for cystic fibrosis

Kathleen J Ramos et al. J Cyst Fibros. 2021 May.

Abstract

The last decade has seen development of oral, small molecule therapies that address the basic cystic fibrosis transmembrane conductance regulator (CFTR) protein defect. Highly effective modulator treatment (HEMT) that is efficacious for a large majority of people living with cystic fibrosis (CF) promises to change the landscape of this chronic life-limiting disease. Some people living with CF have a CFTR genotype that renders them eligible for HEMT, but also have comorbidities that excluded them from the original Phase III clinical trials that led to US Food and Drug Administration approval. The purpose of this review is to address the use of HEMT in challenging situations, including initiation for those with advanced CF lung disease, and use after solid organ transplant, during pregnancy, and for individuals with CFTR-related disorders without a definitive diagnosis of CF.

Keywords: CFTR modulator; CFTR-related disorders; Lung transplant; Pregnancy.

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Conflict of interest statement

Declaration of Competing Interest Dr. Kathleen Ramos reports grants from Cystic Fibrosis Foundation, and a grant from the CHEST Foundation in partnership with Vertex Pharmaceuticals, outside the submitted work. Dr. Joseph Pilewski reports grants from the CF Foundation, Vertex, Breath Therapeutics, Celtaxsys, Incyte, Laurent and Translate Bio for research or clinical trial work, outside the submitted work and without personal fees. Dr. Jennifer Taylor-Cousar reports grants and personal fees from Gilead, grants from N30, grants and personal fees from Vertex, grants and personal fees from Proteostasis, grants from Bayer, personal fees from Novartis, personal fees from Genentech, personal fees from Protalix, personal fees from Santhera, personal fees from 4DMT, personal fees from Polarean Imaging, personal fees from Insmed, personal fees from Abbvie, grants and personal fees from Celtaxys, outside the submitted work; Service on the CF TDN Clinical Research Executive Committee; and Service as the Chair of the ATS Clinical Problems Assembly Program Committee.

Figures

Figure 1:
Figure 1:. CFTR modulator treatment for patients with cystic fibrosis and effect on lung function and sweat chloride concentration.
Abbreviations: CFTR = cystic fibrosis transmembrane conductance regulator; IVA = ivacaftor; FEV1 = forced expiratory volume in one second; ETI = elexacaftor/tezacaftor/ivacaftor; Res function=residual function (mutation allows some CFTR function and/or is responsive to CFTR modulators in vitro); Min function=minimal function (mutation produces no CFTR protein and/or does not respond to CFTR modulators in vitro) Changes in the graph for ETI use in patients with CF with mutations for which there were approved therapies in the U.S. (F508del/F508del and F508del/res function) reflect total predicted change compared to placebo. For example, the ETI bar for those homozygous for F508del reflects the addition of the effect of tezacaftor/ivacaftor versus placebo of 4% in the phase III(45) plus the effect of the addition of elexacaftor in those already on tezacafator/ivacaftor of 10% in the phase III trial(3).
Figure 2.
Figure 2.. Risks of continuation or discontinuation of highly effective modulator treatment (HEMT) during pregnancy.
The unknown risk to the fetus includes the potential risk of the development of cataracts based on demonstration of cataract formation in juvenile rats who were administered ivacaftor.(56)
See this image and copyright information in PMC

References

    1. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, Griese M, McKone EF, Wainwright CE, Konstan MW. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. New England Journal of Medicine 2011; 365: 1663–1672. - PMC - PubMed
    1. Middleton PG, Mall MA, Dřevínek P, Lands LC, McKone EF, Polineni D, Ramsey BW, Taylor-Cousar JL, Tullis E, Vermeulen F. Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele. New England Journal of Medicine 2019; 381: 1809–1819. - PMC - PubMed
    1. Heijerman HG, McKone EF, Downey DG, Van Braeckel E, Rowe SM, Tullis E, Mall MA, Welter JJ, Ramsey BW, McKee CM. 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. The Lancet 2019; 394: 1940–1948. - PMC - PubMed
    1. Food and Drug Administration (FDA). TRIKAFTA drug insert. 2020. Jan 12, 2021]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212273s002lbl.pdf.
    1. Shteinberg M, Taylor-Cousar JL. Impact of CFTR modulator use on outcomes in people with severe cystic fibrosis lung disease. European Respiratory Review 2020; 29. - PMC - PubMed

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