近日，英国教堂阿勒顿医院Philip G Conaghan团队报道了LEVI-04治疗膝骨性关节炎的疗效和安全性。2026年3月28日，《柳叶刀》杂志发表了这一成果。

目前骨关节炎的治疗方法存在局限性。LEVI-04是一种p75神经营养因子受体（p75NTR）融合蛋白，可抑制神经营养因子-3。研究组评估了LEVI-04在膝骨关节炎患者中的疗效和安全性。

这项随机、安慰剂对照、双盲、2期试验在丹麦、香港、波兰、摩尔多瓦和捷克共和国入组了伴有疼痛（西安大略和麦克马斯特大学骨关节炎指数[WOMAC]疼痛评分≥4/10）且影像学证实的膝骨关节炎患者。参与者按1:1:1:1随机分组，每月静脉注射安慰剂或LEVI-04 0.3 mg/kg、1.0 mg/kg或2.0 mg/kg，持续至第16周，安全性随访至第30周。主要终点为意向治疗人群中从随机化至第17周WOMAC疼痛评分的变化。安全性分析包括所有接受研究药物的参与者。该试验已在ClinicalTrials.gov（NCT05618782）和欧盟临床试验数据库（EudraCT 2021-006540-28）注册。

在2022年10月19日至2023年10月23日期间，1598名筛选参与者中，518名（292名女性，226名男性；平均年龄64.0岁[SD 8.07]）被随机分配接受LEVI-04 0.3 mg/kg（n=130）、1.0 mg/kg（n=130）、2.0 mg/kg（n=129）或安慰剂（n=129）。一名未接受研究治疗的人员被排除在安全性分析之外。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WOMAC疼痛的最小二乘均值差异分别为：−0.51（95% CI −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。第17周时，0.3 mg/kg、1.0 mg/kg和2.0 mg/kg组的效应量（标准化均值差异）分别为0.28（95% CI 0.52至0.04）、0.33（0.58至0.09）和0.43（0.68至0.19）。LEVI-04未显示严重不良事件、治疗中出现的不良事件（0.3 mg/kg、1.0 mg/kg和2.0 mg/kg剂量组分别为75例[58%]、86例[66%]、83例[64%]，安慰剂组87例[67%]）或关节病变（包括快速进展性骨关节炎）的发生率增加。

研究结果表明，LEVI-04耐受性良好，并在疼痛和功能方面有显著改善。这些结果支持补充内源性p75NTR用于治疗骨关节炎。

附：英文原文

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

Author: Philip G Conaghan, Nathaniel Katz, Asger R Bihlet, Ali Guermazi, Dror Rom, Michael C Perkins, Bernadette Hughes, Claire Herholdt, Iwona Bombelka, Simon Westbrook

Issue&Volume: 2026/03/28

Abstract:

Background

Current therapies for osteoarthritis have limitations. LEVI-04 is a p75 neurotrophin receptor (p75NTR) fusion protein that inhibits neurotrophin-3. We assessed the efficacy and safety of LEVI-04 in individuals with knee osteoarthritis.

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. 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. The primary endpoint was change in WOMAC pain from randomisation to week 17 in the intention-to treat population. Safety analyses included all participants who received the study drug. This trial is registered with ClinicalTrials.gov, NCT05618782, and EU Clinical Trials database, EudraCT 2021-006540-28.

Findings

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). One person who did not receive the study treatment was excluded from the safety analysis. 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. 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. LEVI-04 showed no increased incidence in 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.

Interpretation

LEVI-04 was well tolerated and showed significant improvements in pain and function. These results support supplementing endogenous p75NTR in treating osteoarthritis.

DOI: 10.1016/S0140-6736(26)00131-5

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(26)00131-5/abstract