Am J Respir Crit Care Med. 2026 Feb 1;212(2):327-337. doi: 10.1093/ajrccm/aamaf001.

Randomized, placebo-controlled, Phase 3 trial

Authors 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; and 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.

Elexacaftor/tezacaftor/ivacaftor

Efficacy and safety; primary endpoint: percent predicted FEV1; secondary endpoints: sweat chloride and CFQ-R RD

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.

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.