Clinical Pearls & Morning Reports
In cystic fibrosis, deficiencies in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial anion channel, manifest as a complex multiorgan disease. Elucidation of the molecular consequences of CFTR mutations has supported the development of small-molecule modulators capable of restoring CFTR protein function. Barry et al. conducted a phase 3 trial that evaluated the magnitude of benefit of elexacaftor–tezacaftor–ivacaftor as compared with ivacaftor and tezacaftor–ivacaftor in patients 12 years of age or older with cystic fibrosis and Phe508del–gating or Phe508del–residual function genotypes. Read the NEJM Original Article here.
Q: What are gating and residual function CFTR mutations?
A: Processing and trafficking mutations (e.g., Phe508del, the most common CFTR mutation) reduce the quantity of CFTR on the cell surface, and channel-gating defects (e.g., Gly551Asp and other CFTR gating mutations) limit anion transport. CFTR mutations that result in lesser impairment of CFTR protein activity, collectively defined as residual function mutations, have also been identified. Most patients with gating or residual function CFTR mutations are heterozygous for the Phe508del mutation.
Q: What was the rationale for assessing elexacaftor–tezacaftor–ivacaftor in patients with Phe508del–gating or Phe508del–residual function genotypes?
A: Elexacaftor–tezacaftor–ivacaftor is a small-molecule CFTR modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with ivacaftor or tezacaftor–ivacaftor, the results of prior studies suggest that elexacaftor–tezacaftor–ivacaftor would provide additional clinical benefit in patients with Phe508del–gating and Phe508del–residual function genotypes by enhancing CFTR activity from the Phe508del allele.
A: Elexacaftor–tezacaftor–ivacaftor treatment improved lung function and sweat chloride concentration relative to an active control (ivacaftor or tezacaftor–ivacaftor). The mean absolute change in the percentage of predicted forced expiratory volume in 1 second from baseline (measured at the end of a run-in period) through week 8 with elexacaftor–tezacaftor–ivacaftor treatment (the primary end point) was 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6; P<0.001). In contrast, the mean absolute change with active control (ivacaftor or tezacaftor–ivacaftor) was 0.2 percentage points (95% CI, −0.7 to 1.1), reflecting a between-group difference of 3.5 percentage points (95% CI, 2.2 to 4.7; P<0.001).
A: Most patients had adverse events that were mild or moderate in severity and that were consistent with those observed in previous studies. Elexacaftor–tezacaftor–ivacaftor treatment resulted in changes in Cystic Fibrosis Questionnaire–Revised respiratory domain scores, relative to ivacaftor or tezacaftor–ivacaftor, that exceeded the established minimal clinically important difference (4.0 points), a finding that shows further abatement of respiratory symptoms in these patients.