Background/Purpose: When evaluating new osteoarthritis (OA) therapies, we need to understand their clinical meaningfulness. LEVI-04, a first-in-class p75 neurotrophin receptor-Fc fusion protein that primarily inhibits neurotrophin-3, demonstrated statistically significant benefits on pain and function in a phase II RCT in people with moderate-to-severe knee OA. Pain and physical function are usually assessed by patient-reported measures with varying recall periods and no allowance for variable activity levels. This trial also included the Staircase-Evoked Pain Procedure (StEPP) as a standardized measure of evoked pain on movement. The purpose of this study was to explore the clinical meaningfulness of improvements in pain and physical function with LEVI-04 and determine the proportion of participants achieving the minimum clinically important difference (MCID) in the StEPP for LEVI-04 compared to placebo.

Methods: These analyses were based on data from a multicentre, randomized controlled trial1. Adults with painful (≥4/10 WOMAC and ≥4/10 average weekly NRS pain), and radiographic (KL≥2) knee OA were included. Participants received IV placebo or LEVI-04 (0.3, 1.0 or 2 mg/kg) at baseline and every 4 weeks (wks) to wk16. The primary endpoint was change in WOMAC pain to wk17, with changes in WOMAC function, StEPP (where participants walk up and down a single, standardised stair 24 times, rating their pain intensity at the end), patient global assessment (PGA), WOMAC stiffness and average weekly NRS pain were also assessed. Clinical meaningfulness was examined using effect size, calculated using Cohen’s d. The proportion of LEVI-04-treated participants achieving a MCID of 2 points in the StEPP (on a 0–10 NRS for pain severity after performing the task) was calculated.

Results: The primary results from this trial are presented elsewhere1. 518 participants were randomized to 0.3, 1.0, and 2.0 mg/kg LEVI-04 or placebo. LEVI-04 significantly improved the primary endpoint, WOMAC pain at wk17 for all doses vs placebo. Calculated effect sizes were greater with LEVI-04 vs placebo and increased with dose (Figure 1). Similarly, a greater proportion of participants achieved the MCID for the StEPP with higher doses of LEVI-04, and statistical significance from placebo was seen in LEVI-04 1.0 and 2.0 mg/kg groups (Table 1).

Conclusion: Effect sizes at or above those reported for NSAIDs2 were observed with LEVI-04, especially with higher doses. LEVI-04 1.0 and 2.0 mg/kg resulted in significantly more patients achieving StEPP MCID, and at levels comparable or better than naproxen3.Phase 3 trials are in planning.References: 1.Conaghan P, et al. Arthritis Rheumatol. 2024;76 (suppl 9), 2. Dworkin RH, et al. J Pain. 2008;9(2):105-21, 3.Mayorga AJ, Scand J Pain, 2017: 134–143. < !

Standardized Effects (Cohen’s d) by Outcome and Treatment Arm at Week 17

Proportion of Participants who Achieve Minimum Clinically Important Difference in StEPP Assessment

« Back to ACR Convergence 2025

ACR Meeting Abstracts - https://acrabstracts.org/abstract/levi-04-a-novel-neurotrophin-3-inhibitor-demonstrates-clinically-meaningful-improvements-in-pain-and-physical-function-across-a-range-of-oa-outcomes-including-the-staircase-evoked-pain-procedure-s/