Rilzabrutinib for patients with moderate-to-severe asthma with uncontrolled symptoms: a double-blind, placebo-controlled, phase 2 study.

Bruton's tyrosine kinase (BTK) plays a key part in immune cell signalling involved in airway inflammation, and its inhibition might improve asthma control.

Bruton's 酪氨酸激酶（BTK）在涉及气道炎症的免疫细胞信号传导中起着关键作用，其抑制可能会改善哮喘控制。

We aimed to explore the effects of BTK inhibition by oral rilzabrutinib on asthma control as well as safety in participants with moderate-to-severe asthma with uncontrolled symptoms.

我们旨在探讨口服rilzabrutinib对中重度哮喘患者哮喘控制以及安全性的影响，这些患者的症状未得到控制。

Methods

This double-blind, placebo-controlled, phase 2 study, which was done at 48 centres across 13 countries, enrolled people aged 18-70 years with physician-diagnosed moderate-to-severe asthma for at least 12 months with uncontrolled symptoms on inhaled glucocorticoids plus a long-acting β2-adrenergic agonist.

这项双盲、安慰剂对照的2期研究在13个国家的48个中心进行，招募了18-70岁的患者，这些患者被医生诊断为中重度哮喘至少12个月，并且在吸入性糖皮质激素加长效β2肾上腺素能激动剂治疗下症状未得到控制。

In two staggered cohorts, participants were randomly assigned (1:1) to rilzabrutinib 800 mg per day orally or matching placebo (low-dose cohort), and rilzabrutinib 1200 mg per day or matching placebo (high-dose cohort), with background therapy gradually withdrawn by weeks 4-9 and resumed at week 12.

在两个交错的队列中，参与者被随机分配（1:1）每天口服800毫克的rilzabrutinib或匹配安慰剂（低剂量队列），以及每天1200毫克的rilzabrutinib或匹配安慰剂（高剂量队列），背景治疗在第4-9周逐渐停用，并在第12周恢复。

The primary endpoint was the proportion of participants with a loss-of-asthma-control (LOAC) event during treatment and was assessed in the modified intention-to-treatpopulation, which included all randomly assigned participants who received at least one dose of study drug.

主要终点是治疗期间失去哮喘控制（LOAC）事件的参与者比例，并在修改意向治疗人群中进行评估，该人群包括所有接受至少一剂研究药物的随机分配参与者。

A key secondary endpoint was asthma control assessed by the 5-item Asthma Control Questionnaire in the modified intention-to-treatpopulation.

一个关键的次要终点是通过5项哮喘控制问卷评估的哮喘控制情况，在修改后的意向治疗人群中进行评估。

Safety was assessed in all randomly assigned participants who received at least one dose of study drug.

所有随机分配并至少接受一次研究药物剂量的参与者都进行了安全性评估。

The trial was registered on ClinicalTrials.gov, NCT05104892.

该试验已在ClinicalTrials.gov上注册，注册号为NCT05104892。

Results

310 participants were screened for eligibility, with 196 (122 female and 74 male) randomly assigned in the low-dose cohort between Jan 6, 2022, and Feb 22, 2023 (32 to rilzabrutinib 800 mg per day and 32 to placebo) and randomly assigned in the high-dose cohort between Feb 23 and Nov 14, 2023 (64 to rilzabrutinib 1200 mg per day and 68 to placebo).

共有310名参与者接受了资格筛选，其中196名（女性122名，男性74名）在2022年1月6日至2023年2月22日期间被随机分配到低剂量队列（每天800毫克的rilzabrutinib 32人，安慰剂32人），并在2023年2月23日至11月14日期间被随机分配到高剂量队列（每天1200毫克的rilzabrutinib 64人，安慰剂68人）。

Over 12 weeks, LOAC events occurred in 12 (38%) participants with rilzabrutinib 800 mg per day versus 16 (50%) with placebo (relative risk reduction 25%; absolute risk difference 12·3%; odds ratio 0·57 [95% CI 0·20-1·61], p=0·29); and 12 (19%) with 1200 mg per day versus 20 (29%) with placebo (relative risk reduction 36%; absolute risk difference 8·8%; 0·58 [0·25-1·35], p=0·21).

在12周的研究期间，每日800毫克的rilzabrutinib治疗组中有12名（38%）参与者发生了LOAC事件，而安慰剂组有16名（50%）（相对风险降低25%；绝对风险差异12.3%；比值比0.57 [95% 置信区间 0.20-1.61]，p=0.29）；每日1200毫克的rilzabrutinib治疗组中有12名（19%）参与者发生了LOAC事件，而安慰剂组有20名（29%）（相对风险降低36%；绝对风险差异8.8%；比值比0.58 [95% 置信区间 0.25-1.35]，p=0.21）。

Asthma control improvements were observed as early as week 2 with rilzabrutinib compared with placebo and sustained up to week 12 without background therapy (least-squares mean difference -0·59 [95% CI -1·07 to -0·10], p=0·018, for the 800 mg per day group; -0·54 [-0·86 to -0·21], p=0·0013, for the 1200 mg per day group).

与安慰剂相比，从第2周开始就观察到rilzabrutinib对哮喘控制的改善，并且这种改善一直持续到第12周，期间没有使用背景治疗（每日800毫克组的最小二乘均值差异为-0.59 [95% 置信区间 -1.07 到 -0.10]，p=0.018；每日1200毫克组的最小二乘均值差异为-0.54 [-0.86 到 -0.21]，p=0.0013）。

The most frequent adverse eventwith rilzabrutinib was diarrhoea.

rilzabrutinib 最常见的不良事件是腹泻。

No increase in infections was observed with either dose of rilzabrutinib.

无论是哪种剂量的 rilzabrutinib，都没有观察到感染的增加。

interpretation

BTK inhibition with rilzabrutinib was associated with a numerical decrease in LOAC events that was not statistically significant.

rilzabrutinib进行BTK抑制与LOAC事件的数值减少相关，但这种减少在统计学上并不显著。

However, continued meaningful asthma symptom improvements over 12 weeks were observed, despite background therapy withdrawal, potentially identifying a novel mechanism to treat uncontrolled symptomatic asthma.

然而，尽管撤除了背景治疗，但在12周内仍观察到有意义的哮喘症状持续改善，这可能识别出一种治疗未控制症状性哮喘的新机制。

funding

Sanofi.

赛诺菲。