Efficacy and safety of LEVI-04 in patients with osteoarthritis of the knee: a randomised, double-blind, placebo-controlled, phase 2 trial.

LEVI-04 is a p75 neurotrophin receptor (p75NTR) fusion protein that inhibits neurotrophin-3.

LEVI-04 是一种 p75 神经营养因子受体（p75NTR）融合蛋白，能够抑制神经营养因子-3。

We assessed the efficacy and safety of LEVI-04 in individuals with knee osteoarthritis.

我们评估了LEVI-04在膝关节骨关节炎患者中的疗效和安全性。

Methods

This randomised, placebo-controlled, double-blind, phase 2 trial enrolled participants from Denmark, Hong Kong, Poland, Moldova, and the Czech Republic with painful (≥4/10 Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain scores) and radiographic knee osteoarthritis.

这项随机、安慰剂对照、双盲的2期试验招募了来自丹麦、香港、波兰、摩尔多瓦和捷克共和国的参与者，他们患有疼痛（≥4/10 西安大略和麦克马斯特大学骨关节炎指数 [WOMAC] 疼痛评分）和放射性膝关节骨关节炎。

Participants were randomised 1:1:1:1 to receive a monthly intravenous placebo or LEVI-04 0·3 mg/kg, 1·0 mg/kg, or 2·0 mg/kg through to week 16, with safety follow-up to week 30.

参与者按1:1:1:1的比例随机分配，接受每月一次的静脉注射安慰剂或LEVI-04 0.3 mg/kg、1.0 mg/kg或2.0 mg/kg，直至第16周，安全随访至第30周。

The primary endpoint was change in WOMAC pain from randomisation to week 17 in the intention-to treat population.

主要终点是从随机化到第17周时，意向治疗人群中WOMAC疼痛评分的变化。

Safety analyses included all participants who received the study drug.

安全性分析包括了所有接受研究药物的参与者。

This trial is registered with ClinicalTrials.gov, NCT05618782, and EU Clinical Trials database, EudraCT 2021-006540-28.

该试验已在ClinicalTrials.gov上注册，注册号为NCT05618782，并在欧盟临床试验数据库EudraCT上注册，注册号为2021-006540-28。

Results

Between Oct 19, 2022, and Oct 23, 2023, of 1598 participants screened, 518 (292 female and 226 male; mean age 64·0 years [SD 8·07]) were randomly assigned to receive LEVI-04 0·3 mg/kg (n=130), 1·0 mg/kg (n=130), or 2·0 mg/kg (n=129) or placebo (n=129).

在2022年10月19日至2023年10月23日期间，对1598名筛查参与者中，有518名（292名女性和226名男性；平均年龄64·0岁[标准差8·07]）被随机分配接受LEVI-04 0·3 mg/kg（n=130），1·0 mg/kg（n=130），或2·0 mg/kg（n=129）或安慰剂（n=129）。

One person who did not receive the study treatment was excluded from the safety analysis.

一名未接受研究治疗的受试者被排除在安全性分析之外。

At week 17, least squares mean difference in WOMAC pain versus placebo were -0·51 (95% CI -0·96 to -0·07), p=0·023; -0·62 (-1·07 to -0·17), p=0·015; and -0·79 (-1·24 to -0·35) p=0·0024 in the LEVI-04 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg groups, respectively.

在第17周，与安慰剂相比，LEVI-04 0.3 mg/kg、1.0 mg/kg和2.0 mg/kg组的WOMAC疼痛评分的最小二乘均值差异分别为-0.51（95%置信区间-0.96至-0.07），p=0.023；-0.62（-1.07至-0.17），p=0.015；以及-0.79（-1.24至-0.35），p=0.0024。

Effect sizes (standardised mean difference) at week 17 were 0·28 (95% CI 0·52 to 0·04), 0·33 (0·58 to 0·09), and 0·43 (0·68 to 0·19) for the 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg groups, respectively.

在第17周，0.3 mg/kg、1.0 mg/kg和2.0 mg/kg组的效果大小（标准化均值差异）分别为0.28（95%置信区间0.52至0.04）、0.33（0.58至0.09）和0.43（0.68至0.19）。

LEVI-04 showed no increased incidencein serious adverse events, treatment-emergent adverse events (75 [58%], 86 [66%], 83 [64%] in the 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg dose groups, respectively, and 87 [67%] placebo), or joint pathologies, including rapidly progressive osteoarthritis.

LEVI-04未显示严重不良事件发生率增加，治疗相关不良事件发生率分别为0.3 mg/kg组75例（58%）、1.0 mg/kg组86例（66%）、2.0 mg/kg组83例（64%），以及安慰剂组87例（67%），关节病理改变，包括快速进展性骨关节炎的发生率也未见增加。

interpretation

LEVI-04 was well tolerated and showed significant improvements in pain and function.

LEVI-04耐受性良好，并在疼痛和功能方面显示出显著改善。

These results support supplementing endogenous p75NTR in treating osteoarthritis.

这些结果支持在治疗骨关节炎时补充内源性p75NTR。

funding

Levicept.

Levicept。