TOPLINE:

LEVI-04, a p75 neurotrophin receptor fusion protein that inhibits neurotrophin-3, demonstrated a dose-dependent reduction in pain by week 17 among patients with knee osteoarthritis (OA), compared with placebo. The treatment exhibited a favorable safety profile with no increased incidence of rapidly progressive OA.

METHODOLOGY:

• Researchers conducted a randomized placebo-controlled phase 2 trial enrolling participants with knee OA from Denmark, Hong Kong, Poland, Moldova, and the Czech Republic between October 2022 and 2023 to assess the efficacy, safety, and tolerability of LEVI-04.
• The study included 518 adults (mean age, 64.0 years; 56% women) with painful knee OA (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain scores ≥ 4 out of 10) and radiographic confirmation (Kellgren-Lawrence grade ≥ 2).
• Participants were randomly assigned to receive monthly intravenous infusions of LEVI-04 at doses of 0.3 mg/kg (n = 130), 1.0 mg/kg (n = 130), or 2.0 mg/kg (n = 129) or a saline placebo (n = 129) through week 16, with safety follow-up extending to week 30.
• The primary endpoint was the change in WOMAC pain scores from randomization to week 17. Secondary endpoints included changes in WOMAC physical function and stiffness subscale, patient global assessment, and Staircase-Evoked Pain Procedure scores and responder analyses for at least a 30% and 50% reduction in WOMAC pain at weeks 5 and 17.
• Safety assessments encompassed treatment-emergent adverse events, surveillance with radiographic imaging and MRI at screening and week 20, and independent adjudication of joint events by a committee.

TAKEAWAY:

• At week 17, all LEVI-04 doses demonstrated improvements in WOMAC pain vs placebo: Least squares mean differences were -0.51 (P = .023) for 0.3 mg/kg, -0.62 (P = .015) for 1.0 mg/kg, and -0.79 (P = .0024) for 2.0 mg/kg. Effect sizes (standardized mean difference) at week 17 were 0.28 (95% CI, 0.52-0.04), 0.33 (95% CI, 0.58-0.09), and 0.43 (95% CI, 0.68-0.19) for the respective dose groups.
• All LEVI-04 doses showed statistically significant improvements in WOMAC physical function (P < .05 for all) and WOMAC stiffness (P < .001 for all) at week 17 compared with placebo.
• A higher proportion of participants in all LEVI-04 groups achieved at least a 50% reduction in WOMAC pain scores than those in the placebo group at week 5 (P = .0027 for 0.3 mg/kg; P = .0037 for 1.0 mg/kg; and P < .0001 for 2.0 mg/kg), with sustained effects through week 17.
• LEVI-04 was well tolerated, with similar rates of serious adverse events, treatment-emergent adverse events, and joint issues, such as rapidly progressive OA, among the treatment groups. The incidence of severe or treatment-related adverse events was low and comparable between LEVI-04 and placebo groups.

IN PRACTICE:

“[The] results support the potential of LEVI-04 as a novel treatment for knee osteoarthritis, improving pain and physical function, and reducing disease burden, coupled with an acceptable side effect profile. Longer duration phase 3 trials will seek to replicate clinical efficacy and assess long-term joint health,” the authors of the study wrote.

SOURCE:

The study was led by Philip G. Conaghan, MBBS, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, England. It was published online on March 28, 2026, in The Lancet.

LIMITATIONS:

Quality-of-life measures were not included, and the safety follow-up period after the primary endpoint was relatively short. The patient population lacked greater ethnic and race diversity.

DISCLOSURES:

This study received support from Levicept, which also provided support for medical writing. Some authors reported receiving support for attending meetings or serving on speakers bureaus for multiple companies. Many authors disclosed having consulting relationships and holding stock options with Levicept and other companies. One author reported being an employee and shareholder of NBCD, which was contracted by Levicept for study support. Two authors reported being employees of Levicept, and one other author is the chief scientific officer and founder of the company.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.