Tezacaftor-Ivacaftor 治疗纯合子 Phe508del 突变型囊性纤维化患者的疗效

Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del.

机构信息

From National Jewish Health, Denver (J.L.T.-C.); Hôpital Robert Debré, Assistance Publique-Hopitaux de Paris, Paris (A. Munck); University College Dublin School of Medicine, St. Vincent's University Hospital, Dublin (E.F.M.); University Medical Center, Utrecht, the Netherlands (C.K.E.); University Children's Hospital Zurich, Zurich, Switzerland (A. Moeller); Vertex Pharmaceuticals, Boston (C.S., L.T.W., E.P.I., C.M., Y.L., J.L.-H.); and Imperial College and Royal Brompton Hospital and Harefield NHS Foundation Trust, London, and Queens University, Belfast - all in the United Kingdom (J.S.E.).

出版信息

N Engl J Med. 2017 Nov 23;377(21):2013-2023. doi: 10.1056/NEJMoa1709846. Epub 2017 Nov 3.

DOI:10.1056/NEJMoa1709846

PMID:29099344

Abstract

BACKGROUND

Combination treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) modulators tezacaftor (VX-661) and ivacaftor (VX-770) was designed to target the underlying cause of disease in patients with cystic fibrosis.

METHODS

In this phase 3, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial, we evaluated combination therapy with tezacaftor and ivacaftor in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation. Patients were randomly assigned in a 1:1 ratio to receive either 100 mg of tezacaftor once daily and 150 mg of ivacaftor twice daily or matched placebo for 24 weeks. The primary end point was the absolute change in the percentage of the predicted forced expiratory volume in 1 second (FEV) through week 24 (calculated in percentage points); relative change in the percentage of the predicted FEV through week 24 (calculated as a percentage) was a key secondary end point.

RESULTS

Of the 510 patients who underwent randomization, 509 received tezacaftor-ivacaftor or placebo, and 475 completed 24 weeks of the trial regimen. The mean FEV at baseline was 60.0% of the predicted value. The effects on the absolute and relative changes in the percentage of the predicted FEV in favor of tezacaftor-ivacaftor over placebo were 4.0 percentage points and 6.8%, respectively (P<0.001 for both comparisons). The rate of pulmonary exacerbation was 35% lower in the tezacaftor-ivacaftor group than in the placebo group (P=0.005). The incidence of adverse events was similar in the two groups. Most adverse events were of mild severity (in 41.8% of patients overall) or moderate severity (in 40.9% overall), and serious adverse events were less frequent with tezacaftor-ivacaftor (12.4%) than with placebo (18.2%). A total of 2.9% of patients discontinued the assigned regimen owing to adverse events. Fewer patients in the tezacaftor-ivacaftor group than in the placebo group had respiratory adverse events, none of which led to discontinuation.

CONCLUSIONS

The combination of tezacaftor and ivacaftor was efficacious and safe in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation. (Funded by Vertex Pharmaceuticals; EVOLVE ClinicalTrials.gov number, NCT02347657 .).

摘要

背景

囊性纤维化跨膜电导调节因子（CFTR）调节剂特扎卡托（VX-661）和依伐卡托（VX-770）的联合治疗旨在针对囊性纤维化患者疾病的根本原因。

方法

在这项 3 期、随机、双盲、多中心、安慰剂对照、平行组试验中，我们评估了特扎卡托和依伐卡托联合治疗在 12 岁及以上囊性纤维化且纯合子 CFTR Phe508del 突变的患者中的疗效。患者以 1:1 的比例随机分配，接受每日 100mg 特扎卡托和每日 2 次 150mg 依伐卡托或匹配的安慰剂治疗 24 周。主要终点是通过第 24 周时预计 1 秒用力呼气量（FEV）的百分比的绝对变化（以百分点计算）；通过第 24 周时预计 FEV 的百分比的相对变化（以百分比计算）是关键次要终点。

结果

在 510 名接受随机分组的患者中，509 名患者接受了特扎卡托-依伐卡托或安慰剂治疗，475 名患者完成了 24 周的试验方案。基线时的平均 FEV 占预计值的 60.0%。特扎卡托-依伐卡托优于安慰剂的绝对和相对 FEV 百分比变化分别为 4.0 个百分点和 6.8%（均<0.001）。特扎卡托-依伐卡托组的肺部恶化率比安慰剂组低 35%（P=0.005）。两组不良反应发生率相似。大多数不良反应为轻度（总体 41.8%的患者）或中度（总体 40.9%），特扎卡托-依伐卡托的严重不良反应（12.4%）比安慰剂（18.2%）少。共有 2.9%的患者因不良反应而停止使用分配的方案。特扎卡托-依伐卡托组比安慰剂组有更少的患者发生呼吸系统不良反应，无不良反应导致停药。