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

RATIONALE: 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). OBJECTIVES: To characterize the response of rare, non-F508del CFTR variants to elexacaftor/tezacaftor/ivacaftor in vitro, and in clinical and real-world studies. METHODS: We engineered Fischer rat thyroid (FRT) cells each of which express 1 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. MEASUREMENTS AND MAIN RESULTS: 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 < .0001]), and secondary endpoints of sweat chloride (-28.3 mmol/L [95% CI: -32.1, -24.5 mmol/L; P < .0001]) and CFQ-R RD (19.5 points [95% CI: 15.5, 23.5; P < .0001]). In CFD-016, improvements in lung function were seen after treatment initiation. CONCLUSIONS: 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.