Tezacaftor

12月20日，福泰制药（Vertex）宣布新一代三联疗法Alyftrek（Vanzacaftor/Tezacaftor/Deutivacaftor，简称Vanza三联疗法）用于治疗囊性纤维化（CF）的新药申请（NDA）获FDA批准。 CF是一种罕见的、进行性、缩短寿命的遗传病，累及肺、肝、胰腺、胃肠道、鼻窦、汗腺和生殖道。全球有超过9.2万例CF患者。 CF由CFTR基因中的某些突变导致CFTR蛋白功能缺陷和/或细胞表面CFTR蛋白缺失而引起。儿童必须遗传两个有缺陷的CFTR基因（父母双方各一个）才会患病，这些突变可以通过基因检测识别。 虽然有许多不同类型的CFTR突变均可导致CF，但绝大多数CF患者至少存在一个F508del突变。CFTR蛋白功能缺陷和/或CFTR蛋白缺失会导致盐和水在许多器官的细胞中流入和流出过程不畅。若这种情况在肺部发生，会导致肺部粘液聚集、慢性肺部感染和进行性肺损伤，最终导致患者死亡。患者的中位死亡年龄为30多岁，但若得到恰当治疗，其生存率可得到提高。 Vanza三联疗法中的Vanzacaftor和Tezacaftor旨在通过促进CFTR蛋白的加工和运输，增加细胞表面CFTR蛋白数量，而Deutivacaftor是旨在增加送达细胞表面的CFTR蛋白的通道开放概率，以改善细胞膜上盐和水的流动。 FDA此次批准Vanza三联疗法上市主要是基于3项III期研究的积极结果。 RIDGELINE 105研究 该研究是一项单臂、开放标签临床试验（n=78），评估了Vanza三联疗法治疗6-11岁CF患者的长期疗效和安全性。研究的主要终点为安全性。 结果显示，Vanza三联疗法在6-11岁CF患者与12岁及以上CF患者中的安全性相似。此外，治疗24周，95%患者的汗液氯化物（SwCl）水平低于60mmol/L，53%患者的SwCl水平低于30mmol/L。 SKYLINE 102研究 该研究是一项随机、双盲、阳性药物对照临床试验（n=398），评估了vanza三联疗法对比Trikafta（Elexacaftor/Tezacaftor/Ivacaftor）治疗①存在F508del纯合子突变或杂合子突变且存在门控功能或残余功能突变或②不存在F508del突变且至少对一种囊性纤维化跨膜传导调节因子（CFTR）突变有反应的12岁及以上CF患者的疗效和安全性。研究的主要终点为预期一秒用力呼气量百分比（ppFEV1）相较于基线的绝对变化值。 结果显示，在ppFEV1主要终点方面，Vanza三联疗法非劣效于Trikafta。此外，多项关键次要终点达到了优效性标准。 SKYLINE 103研究 该研究是一项随机、双盲、阳性药物对照临床试验（n=573），评估了vanza三联疗法对比Trikafta（Elexacaftor/Tezacaftor/Ivacaftor）治疗①存在F508del纯合子突变或杂合子突变且存在门控功能或残余功能突变或②不存在F508del突变且至少对一种囊性纤维化跨膜传导调节因子（CFTR）突变有反应的12岁及以上CF患者的疗效和安全性。研究的主要终点为ppFEV1相较于基线的绝对变化值。 结果显示，在ppFEV1主要终点方面，Vanza三联疗法非劣效于Trikafta。此外，多项关键次要终点达到了优效性标准。 Vertex首席执行官兼总裁Reshma Kewalramani博士表示：“Alyftrek是我们第五个获得FDA批准的CFTR调节剂，代表了我们连续创新和改善囊性纤维化患者生活之旅中的另一个重要里程碑。20多年来，我们始终在坚持解决囊性纤维化的根本原因，治疗更多患有这种疾病的人，并使更多人可以正常发挥CFTR的功能——Alyftrek每天一次给药，对31种额外突变有效，并且可以实现比Trikafta更强的降低汗液氯化物水平能力，这是实现这一目标的又一步。” Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。 免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

Cystic fibrosis is a life-threatening genetic disorder that causes sticky mucus to build up in the lungs and digestive system. Credit: Iren_Geo via Shutterstock. Vertex Pharmaceuticals has secured two simultaneous US Food and Drug Administration (FDA) approvals for cystic fibrosis (CF) treatments, but both therapies come with boxed warnings for potential drug-induced liver injury including liver failure. The approvals include Alyftek (vanzacaftor/tezacaftor/deutivacaftor), described as a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) modulator, and an expanded label for Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor). Alyftek is approved for use with CF patients aged six years or older who have at least one F508del mutation or another CFTR mutation responsive to the therapy. It builds on the success of Trikafta by covering all mutations included in its label, along with an additional 31 CF-causing mutations. Trikafta was initially approved in 2019 for patients aged 12 years and older, but has now been approved for use in children as young as two years with at least one F508del mutation or a responsive CFTR mutation. Both therapies now carry boxed warnings for liver-related risks, the FDA’s most stringent safety label. Trikafta previously carried a precaution about elevated liver enzymes, but this has been elevated to a boxed warning. Patients using either therapy will require regular liver function monitoring. Alyftek’s approval follows positive results from three Phase III clinical trials, including two 52-week studies – SKYLINE 102 and SKYLINE 103 – comparing its efficacy to Trikafta in patients aged 12 years and older, and a 24-week open-label study, RIDGELINE 105, assessing safety and efficacy in children aged six to 11 years. The trials demonstrated that Alyftek met its primary and key secondary endpoints. Vertex used a priority review voucher to reduce the FDA’s review time for Alyftrek. These approvals further cement Vertex’s dominance in the CF market, which remains a significant revenue driver for the company. Trikafta generated $9.9bn in sales in 2023 and is projected to reach $10.1bn by 2030, according to GlobalData. Alyftek is forecasted to bring in $5.3bn in sales by the same year. GlobalData is the parent company of Pharmaceutical Technology. Cystic fibrosis is a life-threatening genetic disorder that causes sticky mucus to build up in the lungs and digestive system, causing lung infections and problems with digesting food. CFTR modulators like Alyftek and Trikafta work to improve protein function and slow disease progression but still don’t benefit every patient with cystic fibrosis. This leaves a gap in treatment options, a challenge that researchers are continuing to address through alternative therapeutic approaches, including messenger RNA (mRNA) therapies. Vertex teamed up with Moderna in 2020 to identify and develop lipid nanoparticles (LNPs) and mRNAs for the delivery of gene-editing therapies to treat CF. In December 2022, the FDA cleared an investigational new drug (IND) application for VX-522, a product of the collaboration that is delivered to the lung through inhalation of a CFTR mRNA encapsulated by a lipid nanoparticle. The candidate is currently being investigated in a Phase I/II study (NCT05668741).