LEVI-04 holds potential to be the first disease-modifying therapy for knee osteoarthritis

LEVI-04 is a neurotrophin-3 inhibitor that significantly improved pain and function compared with placebo, though with increased adverse reactions during administration, in a phase 2 trial in patients with knee osteoarthritis [1]. Dr Simon Westbrook (Levicept Ltd, UK) presented additional data focusing on bone marrow lesions [2].

LEVI-04 (NCT05618782), a phase 2, randomised trial enrolling participants with symptomatic knee osteoarthritis (WOMAC pain ≥4/10 and Kellgren-Lawrence grade ≥2) who received intravenous LEVI-04 0.3, 1, or 2 mg/kg every two weeks or placebo. The analysis focused on the effect of treatment on bone marrow lesions (assessed by MRI). In total, 518 participants were enrolled in the trial.

Between 70% and 77% of participants presented with a bone marrow lesion at baseline. Following 20 weeks of treatment, significantly fewer participants with LEVI-04 1 mg/kg (46%) and 2 mg/kg (39%) had bone marrow lesions, compared with no change in the placebo group (72%). Furthermore, there was a significant, dose-dependent decrease in the total average bone marrow lesion area with LEVI-04 compared with placebo. Finally, this dose-dependent decrease in bone marrow lesion area was observed across all Kellgren-Lawrence grade subgroups (2, 3, and 4).

“Our phase 2 data showed statistically significant effects on analgesia and notable effects on stiffness and pain, but also demonstrated that a proportion of the analgesia and stiffness improvement is associated with the regression of bone marrow lesions,” concluded Dr Westbrook. “LEVI-04 holds promise as potentially the first therapy to modify structural signs and symptoms of osteoarthritis.”

1. Conaghan P, et al. LEVI-04, a novel neurotrophin-3 inhibitor, substantially improves pain and function without deleterious efects on joint structure in people with knee osteoarthritis: A randomized controlled phase II trial. ACR Convergence, 14–19 November 2024, Washington, DC, USA.
2. Westbrook S, et al. LEVI-04 significantly reduces bone marrow lesions and symptoms in knee osteoarthritis: Results from a phase II RCT ACR Convergence, 24–29 October 2025, Chicago, IL, USA.

Medical writing support was provided by Mihai Surducan, PhD.

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Posted on 29 October 2025