LEVI-04 Improved Outcomes in Knee Osteoarthritis Compared With Placebo

LEVI-04 significantly and meaningfully improved pain, function, and other outcomes in people with osteoarthritis (OA) and was well-tolerated.¹

Data from a phase 2 trial were presented at the American College of Rheumatology (ACR) Convergence 2024, held November 14-19 in Washington, DC, by Philip Conaghan, MBBS, PhD, director, National Institute for Health & Care Research Leeds Biomedical Research Centre, and professor, Musculoskeletal Medicine, University of Leeds.

“LEVI-04 binds neurotrophin 3 (NT3) most strongly, and it binds NGF weakly. So that means if we get to therapeutic doses, we'll be modulating predominantly the NT3 pathway and not the NGF pathway. Why is that important? Because we know from the previous studies of NGF that while they showed good analgesic efficacy, they were associated with a small percentage of adverse events related to the joint, and in particular, rapidly progressive OA,” Conaghan told HCPLive® during the meeting. “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.”

The randomized trial enrolled 518 people with knee OA, WOMAC scores of at least 4, and KL scores of at least 2, across Europe and Hong Kong, to receive 4 weekly intravenous infusions of 0.3, 0.1 or 2 mg/kg LEVI-04 or placebo through week 16. Across groups, participants had mean ages ranging from 63.1–65.4 years and mean MBIs ranging from 29.3-30.3, and were 51.5%-61.5% female. The primary endpoint was change in WOMAC pain until week 17, with secondary outcomes including function, Patient Global Assessment and over 50% pain responders.¹

Conaghan and colleagues found that all doses met statistical significance on primary and secondary endpoints at weeks 5 and 17 (P <.05). Over half of patients treated with LEVI-04 had at least a 50% reduction in pain and over 25% had at least a 75% reduction in pain at weeks 5 and 17 on a covariate-adjusted ANCOVA model with Dunnett’s step-down testing procedure comparing active arms with placebo.¹

The investigators found that LEVI-04 was well-tolerated, with no increased incidence of serious adverse events (AEs), treatment-emergent AEs, and joint pathologies including rapidly progressive OA compared with placebo. There was a low incidence of anti-drug antibodies, with 9 participants testing positive pre-dosing, 6 at week 5 or week 20, and all at the lowest limit of detection.

“I think this opens the door for a whole lot of other pain indications… This will, I hope, move beyond osteoarthritis pain and into other areas, and it may also, through the many mechanisms of actions of neurotrophins, offer some hope for structure modification, but that's very early days, and we need to explore that in the phase 3 program,” Conaghan said.

Another promising therapy for reducing knee OA pain in people with obesity may already be approved for a number of other indications – semaglutide. Weekly injections of semaglutide 2.4 mg resulted in significantly greater reductions in body weight and pain related to knee OA than placebo in recent research.²

“Weight reduction along with physical activity is often a recommended approach to managing painful symptoms, but adherence can be challenging," lead investigator Henning Bliddal, MD, MSci., The Parker Institute, Copenhagen University Hospital, Denmark, said in a statement.² "There is a significant need for non-surgical and sustainable treatment options for those living with obesity-related osteoarthritis.”

REFERENCES

1. Conaghan P, Guermazi A, Katz N, et al. LEVI-04, a Novel neurotrophin-3 Inhibitor, Substantially Improves Pain and Function Without Deleterious Effects on Joint Structure in People with Knee Osteoarthritis: A Randomized Controlled Phase II Trial. Presented at: ACR Convergence 2024; November 14-19; Washington, DC. Abstract L15

2. Bliddel H, Bays H, Czernichow S, et al. Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis. N Engl J Med. 2024;391:1573-1583. doi: 10.1056/NEJMoa2403664