OP0374 Clinical Meaningfulness of Pain Improvements and Time to Onset of Pain Relief of a Novel OA Therapy: Analyses from a Randomised Controlled Phase 2 Trial with LEVI-04, a Novel Neurotrophin-3 Inhibitor

Background: Novel therapies that improve both pain and function are urgently required for the treatment of osteoarthritis (OA). When evaluating new therapies, we need to understand their clinical meaningfulness, as well as time to onset of analgesia, which is important to patients. Neurotrophins (NT) are implicated in OA and other painful conditions. LEVI-04 is a first-in-class fusion protein, comprising two extracellular domains of the human p75 neurotrophin receptor (p75NTR) coupled via an immunosilent glycine linker to the constant fragment component of human immunoglobulin G1, with primary pharmacology inhibition of NT-3. Recent results [1] from a phase 2 RCT of LEVI-04 in people with moderate-to-severe painful knee OA demonstrated significant benefits on pain and function with a favourable safety profile. Objectives: To explore the clinical meaningfulness of pain improvements and time to onset of action of LEVI-04 in people with knee OA in a phase 2 trial. Methods: These analyses were based on data from a multicentre (Europe and Hong Kong), randomised controlled trial. Adults with painful (≥20/50 WOMAC and ≥4/10 average weekly NRS pain), and radiographic (KL≥2) knee OA were included in the trial. Participants received IV placebo or LEVI-04 (0.3, 1.0 or 2 mg/kg) at baseline and every 4 weeks (wks) up to wk16. The primary endpoint was change in WOMAC pain to wk17, with changes in WOMAC function, Staircase-Evoked Pain Procedure (StEPP), Patient Global Assessment (PGA), and average weekly NRS (NRS) pain also assessed. Clinical meaningfulness was examined using effect size, calculated for these endpoints using Cohen's d [2]. Time to onset of pain relief compared to placebo was explored, with data derived from the first 10 days of the daily NRS scale. Results: 518 participants were included in the intent-to-treat analyses. Participant characteristics were similar across the groups: mean age, 64.0 years; mean BMI, 29.84 kg/m 2 ; female participants, 56.4%. LEVI-04 significantly improved the primary endpoint, WOMAC pain score at wk 17 for all doses (0.3, 1.0 and 2.0 mg/kg) vs placebo: least squares (LS) mean (SE) change from baseline -2.79 (0.17), p=0.023; -2.89 (0.17), p=0.015; and -3.08 (0.17), p=0.002; vs -2.28 (0.17). StEPP pain scores were significantly reduced vs placebo at wk17: LS means were -2.5 (0.20), p=0.011, -2.6 (0.19), p=0.002; and -3.0 (0.20), p<0.001; vs -1.8 (0.20). PGA scores reduced significantly at all doses vs placebo: LS mean change -2.3 (0.18), p=0.018; -2.6 (0.18), p<0.001; and -2.8 (0.19), p<0.001); vs -1.7 (0.19). For NRS pain, a statistically significant improvement was observed for the 2.0 mg/kg dose vs placebo: LS mean change -2.88 (0.20) vs -2.09 (0.20), p=0.004. Calculated effect sizes were greater with LEVI-04 vs placebo, and increased with dose (Figure 1). LEVI-04 demonstrated a rapid time to onset of response vs placebo for all doses (LS mean change -0.88 (0.14), p=0.128; -1.00 (0.14), p=0.028; and -1.04 (0.14), p=0.017); respectively vs -0.59 (0.14) at Day 3 (Figure 2). Figure 1Standardised Effects (Cohen's d) by Outcome and Treatment Arm at Week 17. NRS, numerical rating scale; StEPP, Staircase Evoked Pain Procedure; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index. Figure 2LS Mean Change from Baseline in Daily Pain Score NRS (ITT). ITT, intent-to-treat; LS, least squares; NRS, numerical rating scale. Conclusion: Significant and clinically meaningful [3] improvement in pain, function, and other outcomes were observed with LEVI-04 vs. placebo in people with knee OA. These results suggest that LEVI-04 improves physical function and pain in people with knee OA, with a rapid onset of action, which are important treatment characteristics for people with knee OA. A phase 3 trial of LEVI-04 is planned. REFERENCES: [1] Conaghan P, et al. Arthritis Rheumatol. 2024;76 (suppl 9). [2] Cohen J. Statistical power analysis for the behavioral sciences (2nd ed.). New York: Lawrence Erlbaum Associates, 1988. [3] Dworkin RH, et al. J Pain. 2008;9(2):105-21. Acknowledgements: Participants and Site Staff involved in LEVI-04-21-02 clinical trial, and medical writing/editorial assistance provided by Cherry Bwalya, MSc. Disclosure of Interests: Philip G. Conaghan AbbVie, Janssen, Novartis, Sandoz, Alfasigma, Eli Lilly, Eupraxia, Formation Bio, Genascence, GSK, Grunenthal, Janssen, Kolon TissueGene, Levicept, Medipost, Moebius, Novartis, Stryker & Takeda, Nathaniel Katz Levicept. Ltd, Asger R. Bihlet: None declared, Laus Wullum: None declared, Kerry af Forselles Levicept Ltd, Levicept Ltd, Michael Perkins Levicept Ltd, Pfizer, Levicept Ltd, Bernadette Hughes Glaxo, Pfizer, Levicept Ltd, Pfizer, Levicept Ltd, Claire Herholdt Levicept Ltd, Levicept Ltd, Iwona Bombelka Levicept Ltd, Levicept Ltd, Simon Westbrook Levicept Ltd, Levicept Ltd. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

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