{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:32:50Z","timestamp":1791423170760,"version":"4.3.3"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011022","name":"Vertex Pharmaceuticals","doi-asserted-by":"publisher","award":["VX21-445-124"],"award-info":[{"award-number":["VX21-445-124"]}],"id":[{"id":"10.13039\/100011022","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>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 (\u223c80% of people with CF).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To characterize the response of rare, non-F508del CFTR variants to elexacaftor\/tezacaftor\/ivacaftor in vitro, and in clinical and real-world studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>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\u2009&amp;lt;\u2009.0001]), and secondary endpoints of sweat chloride (\u221228.3\u2009mmol\/L [95% CI: \u221232.1, \u221224.5\u2009mmol\/L; P\u2009&amp;lt;\u2009.0001]) and CFQ-R RD (19.5 points [95% CI: 15.5, 23.5; P\u2009&amp;lt;\u2009.0001]). In CFD-016, improvements in lung function were seen after treatment initiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ajrccm\/aamaf001","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T09:04:17Z","timestamp":1769159057000},"page":"327-337","source":"Crossref","is-referenced-by-count":11,"title":["Elexacaftor\/tezacaftor\/ivacaftor for cystic fibrosis and rare\n                    <i>CFTR<\/i>\n                    variants: in vitro translation to a phase 3, double-blind, randomized, placebo-controlled trial, and\u00a0real-world study"],"prefix":"10.1093","volume":"212","author":[{"given":"Carlo","family":"Castellani","sequence":"first","affiliation":[{"name":"IRCCS Istituto Giannina Gaslini , 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