LEVI-04 Improves Pain, Function in Knee Osteoarthritis, with Philip Conaghan, MBBS, PhD

LEVI-04, a first-in-class p75 neurotrophin receptor-Fc fusion protein, has shown promising and clinically meaningful improvements in pain and physical function among patients with moderate-to-severe knee osteoarthritis (OA).

Findings from the multicenter, randomized, placebo-controlled phase 2 trial were presented by Philip Conaghan, MBBS, PhD, Director, NIHR Leeds Biomedical Research Centre, and Professor of Musculoskeletal Medicine at University of Leeds at the American College of Rheumatology (ACR) Convergence 2025, held October 24–29 in Chicago, Illinois.

The trial enrolled 518 adults with radiographically confirmed (Kellgren-Lawrence grade ≥2) and symptomatic knee OA (≥4/10 WOMAC and ≥4/10 average weekly pain). Participants were randomized to receive intravenous placebo or LEVI-04 at doses of 0.3, 1.0, or 2.0 mg/kg at baseline and every 4 weeks through week 16. The primary endpoint was change in WOMAC pain at week 17, with additional assessments of WOMAC function, stiffness, patient global assessment (PGA), and average weekly numerical rating scale (NRS) pain.

Across all doses, LEVI-04 achieved statistically significant improvements in WOMAC pain versus placebo, with effect sizes that met or exceeded those typically reported for NSAIDs. Improvements increased with higher doses, underscoring a dose-response relationship. Clinical meaningfulness was further supported by results from the Staircase-Evoked Pain Procedure (StEPP), a standardized measure of pain on movement. A greater proportion of participants treated with LEVI-04 achieved the minimum clinically important difference (MCID) of 2 points in the StEPP versus placebo, with statistical significance observed in the 1.0 and 2.0 mg/kg groups.

Phase 3 studies are now being planned to confirm the efficacy and safety of LEVI-04 and further evaluate its long-term impact on pain and functional outcomes in knee OA. HCPLive spoke with Conaghan to learn more about LEVI-04 and its potential advantages for people with osteoarthritis.

"What we see that more people on LEVI-04 for all 3 doses achieved a clinically relevant reduction in that step function. So in other words, they were able to do more steps. Their pain related to steps was reduced, and that's really important for osteoarthritis, which is a disease where all the pain is related to how much you walk," Conaghan said.

Conaghan's disclosures include AbbVie/Abbott, Alfasigma, Eli Lilly, Eupraxia, Formation Bio, Galapagos, Genascence, Grunenthal, Janssen, Kolon TissueGene, Levicept, Medipost, Moebius Medical, Novartis, Orion, Pacira, Sandoz, Stryker, and Takeda.

Reference

Conaghan P, Katz N, Bihlet A, et al. 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 (StEPP). Presented at: ACR Convergence 2025; October 24-29; Chicago, Illinois. Poster #2101