Review of CFTR modulators 2020

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are small molecules that directly impact the CFTR protein, improving the function of the CFTR chloride and bicarbonate channel. Beginning in 2012 with the Food and Drug Administration approval of the first CFTR modulator, ivacaftor, this class of medications has had largely positive effects on many outcomes in people with cystic fibrosis (PwCF), including lung function, growth, and other clinical parameters. There have been continued exciting developments in the current research on CFTR modulators, expanding beyond original studies. This first part of a three-part cystic fibrosis (CF) year in review 2020 will focus on research on CFTR modulators. In addition to reviewing new clinical insights, we describe work done on novel outcomes, adverse effects, issues related to cost, and next steps for clinical trials. The review focuses on articles from Pediatric Pulmonology published in 2020, but it includes articles from other journals that are of particular interest to clinicians. New developments in CF research continue to be brought forth to the CF community, deepening the understanding of this disease and improving clinical care.

Elexacaftor/tezacaftor/ivacaftor in children aged 6–11 years with cystic fibrosis, at least one F508DEL allele, and advanced lung disease: A 24‐week observational study

“…4 It has been shown that ivacaftor, lumacaftor, and tezacaftor (used singly or in combination) are safe and efficacious in children aged 6-11 years. 5 Furthermore, the results of a 24-week, Phase-III open-label trial of ETI have shown that the treatment was as safe and effective in CF patients aged 6-11 years with at least one F508del allele as in adults and adolescents. 6 However, as is usual in clinical trials, this study excluded patients with severe pulmonary impairment (defined as an FEV 1 of <40% of the predicted value).…”

Non‐pulmonary CFTR‐related symptom improvement with ivacaftor in p.Phe508del/p.Arg117His (7T) cystic fibrosis

“…CFTR modulators are clearly of value to a large number of people with CF, and quality of life parameters such as CFQ-R has been shown to improve in patients given CFTR modulators in trials. 3 Furthermore, there are reports of benefit from ivacaftor use for non-pulmonary manifestations such as pancreatitis. 8 Our patient had significant benefit with use of ivacaftor, with marked improvement in non-respiratory symptoms and subsequent quality of life.…”

“…1 The diagnosis of CF can be challenging for those who do not have typical symptoms, and this can raise issues about how they should be managed and whether it is appropriate to use CFTR modulators. 2,3 There are a number of mutations known to cause a variable phenotype, in particular the CFTR exon 4 Arg117His mutation. 2,4 This mutation exhibits reduced channel conductivity compared with wild type CFTR.…”

Diagnosis and Management of Pulmonary NTM with a Focus on Mycobacterium avium Complex and Mycobacterium abscessus: Challenges and Prospects

“…CFTR modulators are drugs that act by improving production, intracellular processing, and/or function of the defective CFTR protein. The management may include two correctors and a potentiator (e.g., elexacaftor-tezacaftor-ivacaftor) to restore the function of the mutant CFTR protein more fully [ 37 ]. CFTR modulators may prevent lung damage or improve lung function but there is no evidence supporting reversal of already damaged bronchi, suggesting that CF patients with structural damage will continue to be high risk for pulmonary NTM.…”