From Manchester University NHS Foundation Trust, Manchester, United Kingdom (P.J.B.); Charité-Universitätsmedizin Berlin, the Berlin Institute of Health, and the German Center for Lung Research, Berlin (M.A.M.), and the Division of Cystic Fibrosis, Department of Pulmonary Medicine, University Medicine Essen-Ruhrlandklinik, University of Duisburg-Essen, Essen (S.S.) - all in Germany; Vall d'Hebron Barcelona Hospital Campus, Barcelona (A.A.); Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and the University of Milan - both in Milan (C.C.); Wilhelmina Children's Hospital-University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (K.M.W.-G.); Assistance Publique-Hôpitaux de Paris (AP-HP) Centre-Université de Paris Hôpital Cochin AP-HP, Paris (I.F.); Rainbow Babies and Children's Hospital, Cleveland (K.A.M.); St. Vincent's University Hospital, Dublin (E.F.M.); Seattle Children's Hospital, Seattle (B.W.R.); National Jewish Health, Denver (J.L.T.-C.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.A., L.S.J., S.M.M., V.P.-C., S.T., D.W., F.X., Y.Z.); the University of Alabama at Birmingham, Birmingham (S.M.R.); and the University of Kansas Medical Center, Kansas City (D.P.).
N Engl J Med. 2021 Aug 26;385(9):815-825. doi: 10.1056/NEJMoa2100665.
Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one allele, which indicates that this combination can modulate a single allele. In patients whose other allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear.
We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and -gating or -residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group.
After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group.
Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with -gating or -residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).
依伐卡托特-泰比卡托特-埃他卡托特是一种小分子囊性纤维化跨膜电导调节因子（CFTR）调节剂方案，已被证明在至少有一个 F508del 等位基因的患者中有效，这表明该组合可以调节单个 F508del 等位基因。在其他等位基因含有已被先前 CFTR 调节剂（依伐卡托或泰比卡托特-依伐卡托特）有效治疗的门控或残留功能突变的患者中，恢复 Phe508del CFTR 蛋白功能的额外获益尚不清楚。
我们进行了一项为期 3 期、双盲、随机、阳性对照试验，纳入了年龄在 12 岁及以上的囊性纤维化患者，基因型为门控或残留功能。在使用依伐卡托或泰比卡托特-依伐卡托特进行 4 周的导入期后，患者被随机分配接受依伐卡托特-泰比卡托特-依伐卡托特或阳性对照治疗 8 周。主要终点是依伐卡托特-泰比卡托特-依伐卡托特组从基线到第 8 周时预计用力呼气量（FEV）的绝对变化百分比。
在导入期后，132 名患者接受了依伐卡托特-泰比卡托特-依伐卡托特治疗，126 名患者接受了阳性对照治疗。依伐卡托特-泰比卡托特-依伐卡托特治疗后，预计 FEV 的百分比比基线升高了 3.7 个百分点（95%置信区间[CI]，2.8 至 4.6），比阳性对照升高了 3.5 个百分点（95%CI，2.2 至 4.7），汗液氯化物浓度比基线降低了 22.3mmol/L（95%CI，20.2 至 24.5），比阳性对照降低了 23.1mmol/L（95%CI，20.1 至 26.1）（所有比较均 P<0.001）。依伐卡托特-泰比卡托特-依伐卡托特治疗后囊性纤维化问卷修订呼吸域评分（范围为 0 至 100，分数越高表示生活质量越好）的变化为 10.3 分（95%CI，8.0 至 12.7），阳性对照组为 1.6 分（95%CI，-0.8 至 4.1）。两组不良事件的发生率相似；依伐卡托特-泰比卡托特-依伐卡托特组有 1 例（转氨酶升高）和阳性对照组有 2 例（焦虑或抑郁和肺部恶化）因不良事件而停止治疗。
依伐卡托特-泰比卡托特-依伐卡托特在门控或残留功能基因型患者中有效且安全，并与先前的 CFTR 调节剂相比具有额外的获益。（由 Vertex Pharmaceuticals 资助；VX18-445-104，ClinicalTrials.gov 编号，NCT04058353。）
