Rapid and clinically meaningful pain relief in knee OA with novel neurotrophin inhibitor

LEVI-04 offers rapid, dose-dependent, and clinically meaningful pain and functional improvements in knee osteoarthritis (OA). New phase 2 data highlight that pain relief can occur as early as day 3, supporting further investigation of the agent.

In OA, novel therapies that improve both pain and function are urgently required. For patients, both clinically meaningfulness and time to onset of analgesia are important outcomes. Therefore, the analysis presented by Prof. Philip Conaghan (Leeds University, United Kingdom) explored these outcomes in a recent randomised, placebo-controlled phase 2 knee OA trial investigating LEVI-04 [1]. LEVI-04 is a fusion protein composed of 2 extracellular domains of the p75 neurotrophin receptor fused to the Fc portion of human IgG1. It selectively inhibits neurotrophin-3, a signalling protein involved in chronic pain pathways.

Data on this phase 2 trial has been previously presented at the American College of Rheumatology (ACR) 2024 meeting. In this study, 518 participants with radiographically confirmed knee OA (Kellgren-Lawrence grade ≥2) received intravenous LEVI-04 at 0.3 mg/kg, 1.0 mg/kg, or 2.0 mg/kg every 4 weeks for 16 weeks. Primary endpoint data at week 17 showed all 3 LEVI-04 doses significantly reduced Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores compared with placebo. More than 50% of the LEVI- 04-treated participants reported ≥50% reduction in pain, and >25% reported ≥75% reduction at weeks 5 and 17 [2]. Significant improvements were also observed in physical function, stiffness, and the patient's global assessment (PGA).

The current analysis focused on time to onset of pain relief, using daily numerical rating scale (NRS) pain scores from the first 10 days. Clinical meaningfulness was also evaluated using standardised effect size (SES), calculated for WOMAC pain, function, stiffness, PGA, Staircase-Evoked Pain Procedure (StEPP) pain intensity scores, and average daily pain scores at week 17.

“A pretty rapid onset of pain relief was seen, which is a desirable clinical attribute, with significance at day 3,” Prof. Conaghan commented. At day 3, least squares mean change from baseline in daily pain score ranged from -0.88 in the lowest LEVI-04 dose (P=0.128) to -1.04 in the highest dose group (P=0.017), compared with -0.59 in the placebo group.

The SES analysis, where all parameters mentioned above were included, showed a clear dose-response effect. “The SES of non-steroidal anti-inflammatory drugs (NSAIDs) typically ranges from 0.3 to 0.5; in the higher LEVI-04 dose, we see even greater pain responses,” Prof. Conaghan commented (see Figure).

Figure: The standardised effect size (SES) of LEVI-04 compared to other OA treatments [1]



NSAIDs, non-steroidal anti-inflammatory drugs; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Although pain and function usually improve in parallel, LEVI-04 elicited disproportionately greater improvements in function, suggesting a unique mode of action. “Function was even more improved than pain,” Prof. Conaghan said.

The favourable safety and efficacy profile of this drug, currently available as an intravenous formulation, supports continued investigation, with a phase 3 trial underway to validate these findings.

1. Conaghan P, et Clinical meaningfulness of pain improvements and time to onset of pain relief of a novel OA therapy: analyses from a randomised controlled phase 2 trial with LEVI-04, a novel neurotrophin-3 inhibitor. OP0374, EULAR 2025, 11–14 June, Barcelona, Spain.
2. Conaghan P, et al. Arthritis Rheum 2024;76 (Suppl. 9).

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Posted on 8 August 202525 August 2025