The gene for the cystic fibrosis transmembrane conductance regulator (CFTR), a cell membrane chloride channel, was first identified almost 30 years ago as the cause of and possible therapeutic target for treatment of cystic fibrosis (CF). Yet during this time, treatment has been largely supportive for this multisystemic progressive disease that affects about 80,000 people worldwide. In the last 10 years, CFTR-modulating small molecules that enhance chloride ion transport (CFTR potentiators) and improve intracellular trafficking of CFTR to the cell membrane (CFTR correctors) have shown promise and are even more effective when combined.
About two thirds of patients with CF have the homozygous Phe508del mutation of the CFTR gene and present with classic CF manifestations in one or more organ system (including the pulmonary, gastrointestinal, and genitourinary systems) that result from the pathologically thickened secretions associated with CF. The standard of care for these patients consists of double CFTR modulator therapy with tezacaftor (a CFTR corrector) and ivacaftor (a CFTR potentiator). When compared with placebo, this combination has demonstrated modest but statistically significant improvement in lung function, as measured by percent predicted FEV1 (a frequently studied and important marker for mortality and morbidity in CF research). Another 30% of patients are heterozygous for Phe508del mutation and a minimal-function CFTR mutation and present with variable manifestations of CF, but may still have severe disease. There is currently no approved modulator therapy for this group of patients.
In a randomized controlled study published in October in NEJM, Davies and colleagues examined the efficacy of VX-659, a next-generation CFTR corrector, in triple combination with tezacaftor and ivacaftor in both homozygous Phe508del and heterozygous Phe508del/minimal-function patients. VX-659, like tezacaftor, increases the amount of CFTR expressed at the cell surface, but through a different mechanism. In both genotypes, triple-combination therapy demonstrated improvement in absolute change from baseline in percentage of predicted FEV1 and sweat chloride concentration after 29 days of treatment, when compared with standard of care in the homozygous patients and placebo in the heterozygous patients. The absolute improvement from baseline in percentage of predicted FEV1 of triple-combination therapy was about 13% in the heterozygous group and about 10% in the homozygous group.
Dr. Fernando Holguin notes in the accompanying editorial: “It is unclear whether the effects on lung function can be sustained for longer periods of treatment or whether these compounds will effectively reduce exacerbation rates and address other meaningful outcomes, such as weight gain.” Nevertheless, these results are promising and represent therapeutic gains for the CF community, particularly in heterozygous phe508del/minimal-function patients who previously did not have modulator therapy in their armamentarium.
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Angela Castellanos is a general pediatrician and editorial fellow at the NEJM.