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

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.

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.. 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)