POS1153 PRELIMINARY EVALUATION OF THE SAFETY AND ANALGESIC EFFICACY OF THE TRPV1 AGONIST RTX-GRT7039 IN KNEE OSTEOARTHRITIS: A RANDOMISED, DOUBLE-BLIND, EXPLORATORY PHASE II STUDY (2024)

Abstract

Background: RTX-GRT7039 (resiniferatoxin; RTX), is a potent and selective agonist of the transient receptor potential vanilloid 1 (TRPV1) being developed for treatment of pain related to knee osteoarthritis (KOA). RTX-mediated activation of TRPV1-expressing neurones is followed by reversible defunctionalisation of the peripheral terminals of C- and A-delta nerve fibres that can lead to prolonged analgesia.

Objectives: The primary objective of this study (P03, Part 1) was to compare the analgesic effects of single intra-articular (IA) injections of RTX (0.5 mg and 2 mg; Euphorbia resinifera latex in the injectate solution) compared to placebo, at 3 and 6 months post-injection, in participants with chronic osteoarthritic (OA) knee joint pain. Secondary objectives were to evaluate the analgesic effects of RTX-GRT7039 versus placebo in terms of a responder analysis (percentage of subjects achieving ≥50% or ≥70% reduction in VAS pain score) and changes in WOMAC total and subscale scores (pain, physical function and stiffness). Safety and tolerability were also evaluated.

Methods: The study was conducted as a randomized, double-blind, placebo-controlled, single-dose trial of RTX-GRT7039. Eligible patients were aged 40 to 80 years with radiographic knee OA (Kellgren-Lawrence Grade 2-4 in the last 3 years) and a baseline VAS (0-100 mm) pain score ≥40mm on motion in the target knee, with or without pain medication. 67 subjects were randomized to treatment with either RTX 0.5 mg (N=24) or 2 mg (N=23), or placebo (N=20), administered IA into the index knee. IA ropivacaine (5 mL, 0.5%) was administered 15 mins before investigational medicinal product (IMP). VAS scores were used to evaluate pain on motion as the average of the last 2 days in a target knee between baseline and at 3 and 6 months post injection.

Results: Baseline demographic characteristics and OA pain scores were comparable across treatment groups. In the ITT population, a reduction in the VAS scores for pain on motion in the treated knee after IA injection was observed as early as the first trial visit post-injection (Day 8) with the effect lasting until the last trial visit (Month 6; Figure 1). Subjects receiving RTX reported a greater pain reduction than subjects receiving placebo. At the 3 months visit, there was a higher mean [SD] absolute reduction of VAS score (baseline corrected) in the RTX 0.5 mg group (37.43 [19.79]) and the 2 mg group (36.68 [34.16]) than in the placebo group (17.00 [23.09]). At 6 months, the mean (SD) absolute reduction of VAS score was 33.52 (22.89) in the RTX 0.5 mg group, 41.48 (32.57) in the 2 mg group, and 28.26 (25.02) in the placebo group. Consistent with these data, the RTX 0.5 mg and 2 mg treatment groups showed a greater reduction in WOMAC total and subscale scores (pain, physical function and stiffness) than the placebo group at both 3 and 6 months. The incidence of treatment emergent adverse events (TEAEs) in the RTX 2 mg group (78.3%) and placebo group (75.0%) were comparable, but lower in the RTX 0.5 mg group (62.5%). The most commonly reported TEAEs were arthralgia, back pain, nasopharyngitis and headache. The majority of TEAEs were mild and unrelated to IMP or ropivacaine. Seven SAEs were reported in 6 subjects [2 subjects (0.5 mg), 3 subjects (2 mg) 1 subject (placebo)], none of which were considered to be related to the IMP or ropivacaine. No safety concerns were raised based on other evaluated safety parameters. Injection site pain/procedural pain was expected after IA injection due to the mode of action of RTX-GRT7039 and was not recorded as a TEAE within 24 hours after IMP administration.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Thor Ostenfeld Grunenthal, Stefan Ivanavicius Grunenthal, Roman STANCIK: None declared, Philip G. Conaghan AbbVie, Eli Lilly, Novartis, AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Genascence, GSK, Grunenthal, Janssen, Levicept, Moebius Medical, Novartis, Stryker, Takeda, TrialSpark