A phase 2a trial of the IL-33 monoclonal antibody tozorakimab in patients with COPD: FRONTIER-4.

FRONTIER-4 (NCT04631016) investigated tozorakimab (an anti-interleukin-33 monoclonal antibody) in patients with moderate-to-severe COPD with chronic bronchitis receiving dual or triple inhaled therapy.

FRONTIER-4（NCT04631016）研究了托扎瑞单抗（一种抗白细胞介素-33单克隆抗体）在中度至重度慢性阻塞性肺疾病（COPD）伴有慢性支气管炎的患者中的作用，这些患者正在接受双重或三重吸入治疗。

Methods

FRONTIER-4 was a phase 2a, randomised, double-blind, placebo-controlledstudy.

FRONTIER-4 是一项2a期、随机、双盲、安慰剂对照研究。

Patients received tozorakimab 600 mg or placebo subcutaneously every 4 weeks for 24 weeks.

患者每4周皮下注射600毫克的托佐拉克单抗或安慰剂，持续24周。

The primary end‑point was change in pre-bronchodilator forced expiratory volume in 1 s (FEV1) from baseline to week 12.

主要终点是基线至第12周时，使用支气管扩张剂前的1秒钟用力呼气容积（FEV1）的变化。

Secondary outcomes included post-bronchodilator FEV1, time-to-first COPD composite exacerbation event and safety.

次要结果包括使用支气管扩张剂后的FEV1、首次COPD综合加重事件的时间以及安全性。

Results

The intent-to-treat population included 135 patients (tozorakimab, n=67; placebo, n=68).

意向治疗人群包括135名患者（托佐拉替单抗组，n=67；安慰剂组，n=68）。

At week 12 in the intent-to-treat population, tozorakimab showed a greater increase, although nonsignificant, from baseline in pre-bronchodilator FEV1 (least-squares mean difference (LSMD) 24 mL, 80% confidence interval(CI) -15-63 mL, p=0.216) and a significantly greater increase in post-bronchodilator FEV1 (LSMD 67 mL, 80% CI 17-116 mL, p=0.044) when compared with placebo.

在意向治疗人群中，至第12周时，托佐拉替单抗组与基线相比，尽管未达到统计学显著性，但其支气管扩张前FEV1（最小二乘均值差异（LSMD）24毫升，80%置信区间（CI）-15-63毫升，p=0.216）的增加大于安慰剂组，且在支气管扩张后FEV1（LSMD 67毫升，80% CI 17-116毫升，p=0.044）的显著增加也大于安慰剂组。

At week 12 in a prespecified subgroup of patients with at least two prior exacerbations, tozorakimab also showed improvements versus placebo in change from baseline in pre-bronchodilator FEV1 (LSMD 69 mL, 80% CI 9-130 mL, p=0.072) and post-bronchodilator FEV1 (LSMD 124 mL, 80% CI 47-201 mL, p=0.020).

在至少有两次加重的患者预先设定的亚组中，第12周时，托佐拉克单抗在基线至前支气管扩张剂FEV1的改变（LSMD 69 mL, 80% CI 9-130 mL, p=0.072）和基线至后支气管扩张剂FEV1的改变（LSMD 124 mL, 80% CI 47-201 mL, p=0.020）方面也显示出与安慰剂相比的改善。

Tozorakimab did not significantly reduce the risk of COPD composite exacerbation events (hazard ratio0.79, 80% CI 0.57-1.11, p=0.186) in the intent-to-treat population, although there were greater effects in patients with at least two prior exacerbations (hazard ratio0.61, 80% CI 0.37-1.00).

在意向治疗人群中，托佐拉克单抗并未显著降低COPD综合加重事件的风险（风险比0.79, 80% CI 0.57-1.11, p=0.186），尽管在至少有两次加重的患者中效果更大（风险比0.61, 80% CI 0.37-1.00）。

Results were similar in former and current smokers.

前吸烟者和当前吸烟者的结果相似。

Tozorakimab was well tolerated.

Tozorakimab的耐受性良好。

Conclusions

Although the primary end-point was not met in the intent-to-treat population, tozorakimab showed positive efficacy signals versus placebo in a subgroup of patients with COPD with a high risk of exacerbations.

尽管在意向治疗人群中未达到主要终点，但在高风险加重的慢性阻塞性肺疾病（COPD）患者亚组中，托佐拉单抗显示出与安慰剂相比的积极疗效信号。