Novel neurotrophin-3 inhibitor offers ‘real hope’ for patients with osteoarthritis pain
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WASHINGTON — Patients treated with a novel neurotrophin-3 inhibitor demonstrated significant reductions in osteoarthritis knee pain across all dosing levels, according to data presented at ACR Convergence 2024.
“There is a huge unmet need for new, effective therapies to aid in the management of osteoarthritis and other musculoskeletal pain,” Philip Conaghan, MD, director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine at the University of Leeds, in the United Kingdom, told Healio. “There is evidence from previous studies that targeting nociceptive nerve signaling can help reduce OA pain, but therapies targeting only nerve growth factor resulted in an uncommon side effect of joint problems called rapidly progressive OA.
“Levicept had developed a new therapy targeting neurotrophin 3, and the preliminary studies suggested it would be effective without joint toxicity,” he added.
This therapy, currently known as LEVI-04 (Levicept), is a p75NTR-Fc, first-in-class fusion protein that supplements endogenous p75NTR, modulates neurotrophin levels and inhibits neurotrophin 3, according to the researchers. To examine the safety and efficacy of LEVI-04 in patients with knee OA, Conaghan and colleagues conducted a phase 2, multicenter randomized clinical trial. The 20-week study included 518 patients with OA in Europe and Hong Kong who demonstrated WOMAC scores of at least 4 and a Kellgren-Lawrence grade of at least 2.
Participants were randomly assigned IV placebo four times weekly, or doses of the study drug at 0.3 mg/kg, 0.1 mg/kg or 2 mg/kg through week 16. Follow-up occurred through week 30. Change in WOMAC pain at week 17 served as the primary endpoint. Function, Patient Global Assessment (PGA) and >50% pain responders served as secondary endpoints.
According to the researchers, the primary endpoint was met for all three doses of LEVI-04 (P < .05 vs. placebo for all). More than half of patients who received LEVI-04 reported a reduction in pain of 50% or greater at weeks 5 and 17, while more than 25% reported a 75% or greater reduction in pain at those same time points.
Meanwhile, safety data showed four serious adverse events across active therapy arms and three serious adverse events in the placebo arm. Treatment-emergent adverse event rates were comparable across the study groups.
“The two most important findings from this RCT are, firstly, that all doses of the new therapy were able to significantly reduce osteoarthritis pain,” Conaghan said. “Secondly, within the 20 weeks follow-up of the study, there was no increased incidence of adverse joint pathologies.
“These findings are very important because they strongly warrant undertaking of subsequent longer duration and larger RCTs to enable this product to progress to registration, and hopefully clinical practice in a timely fashion,” he added. “These findings also open a new field for exploring selected neurotrophin modulation as a treatment for nociceptive pain.”
Aside from the positive results for LEVI-04 specifically, Conaghan said he sees a bright future for medications that employ this mechanism in general.
“There is real hope that we have a potential new therapy for the signs and symptoms of osteoarthritis that, if confirmed in subsequent trials, may also offer potential treatment for other painful musculoskeletal conditions,” he said.
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Conaghan P. Abstract L15. Presented at: ACR Convergence 2024; Nov. 14-19, 2024; Washington, D.C.
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