Progress in precision medicine in cystic fibrosis: a focus on CFTR modulator therapy

Abstract

The genetic multisystem condition cystic fibrosis (CF) has seen a paradigm shift in therapeutic approaches within the past decade. Since the first clinical descriptions in the 1930s, treatment advances had focused on the downstream consequences of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion channel. The discovery of the gene that codes for CFTR and an understanding of the way in which different genetic mutations lead to disruption of normal CFTR function have led to the creation and subsequent licensing of drugs that target this process. This marks an important move towards precision medicine in CF and results from clinical trials and real-world clinical practice have been impressive. In this review we outline how CFTR modulator drugs restore function to the CFTR protein and the progress that is being made in this field. We also describe the real-world impact of CFTR modulators on both pulmonary and multisystem complications of CF and what this will mean for the future of CF care.

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“…Regarding CFTR modulators, IVA (a first‐generation modulator) is known as a potentiator that binds to defective CFTR on the cell surface, keeping the chloride gate opened; LUM and TEZ (first‐generation modulators) as well as ELX (next‐generation modulator), are known as correctors that bind to different sites on defective CFTR proteins, increasing the number of mature CFTR proteins on the cell surface. 7 , 8 Some studies have tested the combination of LUM/IVA and reported rescue of CFTR function with positive results in patients with a homozygous c.1521_1523delCTT mutation.…”

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“…It has been deduced that individuals homozygous for mutations I-III tend to have less functional CFTR protein, leading to worse phenotypes. On the other hand, patients with class IV-VI mutations frequently have a milder phenotype [ 4 ].…”

“…Given that declining lung function and pulmonary exacerbations are the leading causes of death in CF patients, all trials documented patient improvement based on these parameters. Furthermore, because pulmonary function tests are easily measurable and quantifiable, they have become the primary outcome of interest in clinical trials [ 4 ]. Elexacaftor/tezacaftor/ivacaftor improved forced expiratory volume in one second (FEV1) by 14 points in Phe508del heterozygotes at 24 weeks compared to placebo and by 10 points in homozygotes at four weeks, over tezacaftor/ivacaftor.…”

“…It commonly forms when the amino acid phenylalanine (Phe) gets deleted from the allele at location 508 (Phe508del). At least one copy of this mutation can be found in up to 90 percent of all CF patients, with over half being homozygous for Phe508del [ 4 ]. In patients with these mutations, the CFTR protein gets synthesized; however, it is misfolded, hindering its presentation to the cell surface [ 5 ].…”

“…Based on their function, the CFTR modulators are classified into four types: potentiators, correctors, stabilizers, and amplifiers. The fact that these medicines are orally accessible gives it the advantage of restoring protein function systematically, which in turn prevents the disease from progressing to a fatal stage [ 4 ]. Combining lumacaftor or tezacaftor (CFTR correctors) with ivacaftor (CFTR potentiator) in patients homozygous for the Phe508del mutation have significantly improved lung function.…”