Taladegib for the treatment of idiopathic pulmonary fibrosis (ENV-IPF-101): a multicentre, randomised, double-blind, placebo-controlled, phase 2a trial.

Currently, there is no cure for IPF, and available anti-fibrotics only slow the rate of decline in lung function in IPF.

目前，尚无针对IPF的治愈方法，现有的抗纤维化药物仅能减缓IPF患者肺功能下降的速度。

We aimed to assess the safety and efficacy of taladegib (ENV-101), an Hh pathway inhibitor, in IPF in a phase 2a, proof-of-concept clinical trial.

我们旨在评估Hh通路抑制剂taladegib（ENV-101）在特发性肺纤维化（IPF）中的安全性和有效性，这是一项2a期的概念验证临床试验。

Methods

ENV-IPF-101 was a randomised, double-blind, placebo-controlled, phase 2a trial conducted at 16 clinical sites in Australia, Canada, Malaysia, Mexico, and South Korea for patients with IPF older than 40 years who were not treated with concurrent IPF therapy.

ENV-IPF-101是一项随机、双盲、安慰剂对照的2a期临床试验，在澳大利亚、加拿大、马来西亚、墨西哥和韩国的16个临床试验中心进行，针对40岁以上的IPF患者，这些患者未接受过同时进行的IPF治疗。

Patients were randomly assigned to taladegib 200 mg or placebo equivalent once daily, orally for 12 weeks, with a 6-week follow-up.

患者被随机分配接受每日一次口服200毫克taladegib或等效安慰剂，持续12周，随后进行6周的随访。

The primary outcomes were safety in the intention-to-treatpopulation and change from baseline in forced vital capacity (FVC) in the efficacy-evaluable population.

主要结果是意向治疗人群中安全性以及在有效评估人群中基线时的用力肺活量（FVC）变化。

Exploratory outcomes were measures of fibrosis on high-resolution CT (HRCT) in the efficacy-evaluable population.

在可评估疗效的人群中，通过高分辨率计算机断层扫描(HRCT)测量纤维化的结果是探索性结果。

This study is registered with ClinicalTrials.gov, NCT04968574.

这项研究已在ClinicalTrials.gov上注册，注册号为NCT04968574。

Results

Between Aug 12, 2021, and July 28, 2023, 41 patients were randomly assigned to the taladegib group (n=21; three [14%] female and 18 [86%] male) or the placebo group (n=20; four [20%] female and 16 [80%] male).

在2021年8月12日至2023年7月28日期间，41名患者被随机分配到taladegib组（n=21；3名[14%]女性和18名[86%]男性）或安慰剂组（n=20；4名[20%]女性和16名[80%]男性）。

All treatment-emergent adverse events possibly or probably related to the study drug were grade 1 or 2, all except one were mild or moderate in severity, and none were serious adverse events.

所有可能或可能与研究药物相关的治疗后不良事件均为1级或2级，除了一例外，其余均为轻度或中度，没有严重不良事件。

The most common treatment-emergent adverse events in the taladegib group were dysgeusia (12 [57%] of 21), muscle spasms (12 [57%] of 21), and alopecia (11 [52%] of 21); none of these events were reported in the placebo group, for which the most common adverse events reported were diarrhoea (four [20%] of 20), headache (three [15%] of 20), and dizziness (one [5%] of 20).

taladegib组中最常见的治疗后不良事件是味觉障碍（21人中有12人[57%]）、肌肉痉挛（21人中有12人[57%]）和脱发（21人中有11人[52%]）；这些事件在安慰剂组中均未报告，该组中最常见的不良事件是腹泻（20人中有4人[20%]）、头痛（20人中有3人[15%]）和头晕（20人中有1人[5%]）。

Patients treated with taladegib had an improvement from baseline in FVC and across multiple HRCT-based measures of disease.

接受taladegib治疗的患者在用力肺活量（FVC）和基于高分辨率计算机断层扫描（HRCT）的多种疾病测量指标上从基线开始有所改善。

Between-group differences in change from baseline to week 12 favoured taladegib for the efficacy measures of percent predicted FVC (3·95% [95% CI 0·31-7·60]; p=0·035; mean change from baseline of 1·9% in the taladegib group vs -1·3% for placebo), total lung capacity by HRCT (257·0 mL [95% CI 86·8-427·2]; p=0·0040; mean change from baseline of 206·67 mL in the taladegib group vs -55·58 mL in the placebo group), and percent quantitative interstitial lung disease (p=0·047; mean change from baseline of -9·4% in the taladegib group vs 1·1% in the placebo group).

从基线到第12周的变化中，与安慰剂组相比，taladegib组在以下疗效指标上显示出优势：预测用力肺活量百分比（3·95% [95% 置信区间 0·31-7·60]；p=0·035；taladegib组基线平均变化为1·9%，而安慰剂组为-1·3%），高分辨率计算机断层扫描测定的总肺容量（257·0 mL [95% 置信区间 86·8-427·2]；p=0·0040；taladegib组基线平均变化为206·67 mL，而安慰剂组为-55·58 mL），以及定量间质性肺病百分比（p=0·047；taladegib组基线平均变化为-9·4%，而安慰剂组为1·1%）。

No deaths occurred during the trial.

试验期间没有发生死亡事件。

interpretation

The acceptable safety profile and efficacy analyses of taladegib support further investigation in a phase 2b trial in patients with IPF (WHISTLE-PF).

塔拉地格布的安全性和有效性分析结果令人满意，支持在特发性肺纤维化(IPF)患者中进行2b期临床试验（WHISTLE-PF）的进一步研究。

funding

Endeavor BioMedicines.

努力生物医药公司。