LEVI-04, a novel neurotrophin-3 (NT3) inhibitor, has shown significant improvements in pain and function for individuals suffering from knee osteoarthritis (OA). The phase 2 trial results, presented at the American College of Rheumatology (ACR) Convergence 2024, indicate that LEVI-04 was well-tolerated and led to clinically meaningful outcomes.
The randomized, placebo-controlled trial involved 518 participants with knee OA, who were administered 4 weekly intravenous infusions of LEVI-04 at varying doses (0.3, 1.0, or 2.0 mg/kg) or placebo. Participants were evaluated through week 16, with the primary endpoint being the change in WOMAC pain score until week 17. Secondary outcomes included assessments of function, Patient Global Assessment, and the proportion of patients achieving over 50% pain reduction.
Targeting Neurotrophin Pathways
According to Philip Conaghan, MBBS, PhD, director at the National Institute for Health & Care Research Leeds Biomedical Research Centre, LEVI-04's mechanism of action primarily targets the NT3 pathway while weakly binding to nerve growth factor (NGF). This is a strategic approach to potentially avoid adverse events associated with previous NGF-targeting therapies, such as rapidly progressive OA. "So those drugs worked for analgesic efficacy, but had some unacceptable side effects, and this new mode of action, we hoped would provide the analgesic efficacy without the side effects," Conaghan noted.
Efficacy and Safety Results
The trial data revealed that all LEVI-04 doses achieved statistical significance in both primary and secondary endpoints at weeks 5 and 17 (P < .05). More than half of the patients treated with LEVI-04 experienced a minimum of 50% reduction in pain, and over 25% reported at least a 75% reduction in pain at weeks 5 and 17, based on a covariate-adjusted ANCOVA model.
Furthermore, LEVI-04 demonstrated a favorable safety profile, with no increased incidence of serious adverse events, treatment-emergent adverse events, or joint pathologies, including rapidly progressive OA, compared to the placebo group. The incidence of anti-drug antibodies was low, with only a small number of participants testing positive, and all at the lowest limit of detection.
Future Implications
Conaghan expressed optimism about the potential of LEVI-04 beyond osteoarthritis pain, suggesting it could extend to other pain indications. He also raised the possibility of structure modification through the neurotrophin mechanisms of action, though he emphasized that this remains in the early stages of exploration and requires further investigation in phase 3 trials.
Alternative Approaches
The article also briefly mentions semaglutide as another promising therapy for reducing knee OA pain in individuals with obesity. A recent study showed that weekly injections of semaglutide 2.4 mg led to significantly greater reductions in body weight and pain related to knee OA compared to placebo. This highlights the importance of weight management in addressing OA symptoms, as noted by Henning Bliddal, MD, MSci., from The Parker Institute, Copenhagen University Hospital, Denmark. "There is a significant need for non-surgical and sustainable treatment options for those living with obesity-related osteoarthritis."
