Elexacaftor/Tezacaftor/Ivacaftor for Cystic Fibrosis and Rare CFTR Variants: In Vitro Translation to a Phase 3, Double-Blind, Randomized, Placebo-controlled Trial and Real-World Study.

Abstract

Elexacaftor/tezacaftor/ivacaftor, a CF transmembrane conductance regulator (CFTR) modulator, stabilizes and restores F508del-CFTR function, which is the most common CFTR variant. In multiple clinical and real-world studies, elexacaftor/tezacaftor/ivacaftor was shown to be safe and highly effective in people with CF carrying at least one F508del-CFTR (∼80% of people with CF). To characterize the response of rare, non-F508del CFTR variants to elexacaftor/tezacaftor/ivacaftor in vitro, and in clinical and real-world studies. We engineered Fischer rat thyroid (FRT) cells each of which express one of 620 rare exonic CFTR variants present in public databases and evaluated their in vitro response to elexacaftor/tezacaftor/ivacaftor. We evaluated efficacy and safety of elexacaftor/tezacaftor/ivacaftor in a 24-week randomized, placebo-controlled, Phase 3 trial (445-124) in participants with 1 of 18 rare variants and no F508del and in a real-world study (CFD-016) in people carrying 82 rare variants and no F508del. In FRT cells, 518 of 620 (84%) rare variants responded to elexacaftor/tezacaftor/ivacaftor. In 445-124, mean improvements were seen in the primary endpoint of percent predicted FEV1 (9.2 percentage points [95%CI:7.2,11.3;P<0.0001]), and secondary endpoints of sweat chloride (-28.3mmol/L [95%CI:-32.1,-24.5mmol/L;P<0.0001]) and CFQ-R RD (19.5points [95%CI:15.5,23.5;P<0.0001]). In CFD-016, improvements in lung function were seen after treatment initiation. In vitro, clinical, and real-world data support elexacaftor/tezacaftor/ivacaftor treatment in people carrying a range of CFTR variants and no F508del. The response of 84% of rare CFTR variants that produce protein to protein-stabilizing therapy suggests variants in many regions of the protein causes disease via protein destabilization.