Cystic fibrosis transmembrane conductance regulator modulators: precision medicine in cystic fibrosis

Abstract

Purpose of review: The aim of this study was to describe the newest development in cystic fibrosis (CF) care, CF transmembrane conductance regulator (CFTR) modulator therapies.

Recent findings: Phase II results showing CFTR modulator triple therapies are more effective than current CFTR modulators.

Summary: CFTR modulator therapy targets the protein defective in CF and boosts its function, but the drug must match mutation pathobiology. Ivacaftor, a CFTR potentiator, was the first modulator approved in 2012, with impressive improvement in lung function and other measures of disease in patients with gating and other residual function mutations (∼10% of CF patients). In 2015, the combination of lumacaftor, a CFTR corrector, and ivacaftor was approved for patients homozygous for the F508del mutation (∼40-50% of the CF population) with positive but less impressive clinical response and 10-20% incidence of intolerance. A next-generation CFTR corrector, tezacaftor, with ivacaftor equally effective and better tolerated than lumacaftor, has also received US Food and Drug Administration approval. Novel CFTR correctors, entering Phase 3 trials in triple modulator combination with tezacaftor-ivacaftor, appear substantially more effective for patients who are homozygous for the F508del mutation and can provide benefit for patients with a single F508del mutation. This offers promise of effective CFTR modulator therapy for nearly 90% of CF patients.

FIGURE 1.

Functional classification of cystic fibrosis transmembrane conductance regulator mutations causing cystic fibrosis with major examples in each class, associated approach to targeted CFTR modulator therapies and drug type nomenclature. Current approved drugs include the potentiator ivacaftor, the corrector lumacaftor and the corrector tezacaftor. AONs, antisense oligonucleotides; WT, wild type. Reproduced with permission from [7].