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NT-3 inhibitor relieves pain caused by osteoarthritis

Presented by
Prof. Philip Conaghan, University of Leeds, UK
Conference
ACR 2024
Trial
Phase 2
Doi
https://doi.org/10.55788/24bd4e75
The novel, first-in-class neurotrophin-3 (NT-3) inhibitor LEVI-04 demonstrated significant and clinically meaningful analgesia across all measures for patients with osteoarthritis (OA). A significant improvement was reported for all doses in functional measures and Patient Global Assessment (PGA). The study drug was well-tolerated.

LEVI-04 is a proprietary p75 neurotrophin receptor fusion protein (p75NTR-Fc) that modulates the nerve growth factor (NGF) pathway by inhibiting NT-3, and has shown to alleviate pain. Prof. Philip Conaghan (University of Leeds, UK) presented the main results of a randomised phase 2 study (NCT05618782) assessing the efficacy and safety of LEVI-04 in knee OA [1].

The study enrolled 518 participants with radiographic knee OA, who had a target knee score of ≥20 out of 50 on the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale. The participants’ mean age was about 64 years, mean BMI was around 30, and about 56% were women; the mean average daily pain Numeric Rating Scale (NRS) was between 4.0 and 9.0. Participants were randomised to 5 infusions, given 4 weeks apart, of placebo or 0.3, 0.1, or 2.0 mg/kg LEVI-04 through week 16. The primary endpoint was a change in WOMAC pain at week 17.

LEVI-04 in all 3 doses was significantly superior to placebo for the primary endpoint at week 17, but also already at week 5 (see Figure). After 17 weeks, the change in WOMAC pain in the placebo group was -2.28 compared with -2.79, -2.89, and -3.08 in the 0.3, 1.0, and 2.0 mg/kg groups, respectively.

Figure: Least square (LS) mean change from baseline in standardised WOMAC Pain [1]



All doses also yielded a significant benefit in explored secondary outcomes: WOMAC physical function, WOMAC stiffness, and PGA. At week 17, over 50% of the LEVI-04-treated participants reported a ≥50% reduction in pain; over 25% reported a ≥75% reduction. LEVI-04 was well-tolerated; the incidence of treatment-emergent and serious adverse events was comparable in all study arms. Rapidly progressive OA, the bane of anti-NGF therapy, was not a problem. Further work will unravel the efficacy and safety of this novel NT-3 inhibition strategy for OA. An oral formulation of LEVI-04 will be developed.

  1. Conaghan P, 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. Abstract L15, ACR Convergence 2024, 14–19 November, Washington DC, USA.

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