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

<h2>Summary</h2><h3>Background</h3> 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. <h3>Methods</h3> 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. <h3>Findings</h3> 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. <h3>Interpretation</h3> LEVI-04 was well tolerated and showed significant improvements in pain and function. These results support supplementing endogenous p75NTR in treating osteoarthritis. <h3>Funding</h3> Levicept.