P-022 - Safety and Analgesic Effect of the TRPV1 Agonist RTX-GRT7039 in Osteoarthritis Knee Pain

Abstract Title: Safety and Analgesic Effect of the TRPV1 Agonist RTX-GRT7039 in Osteoarthritis Knee Pain

Background: Transient receptor potential vanilloid 1 (TRPV1) expression plays an important role in neuropathic and inflammatory pain and pain sensitization.^1,2 TRPV1-expressing neurons are present within the synovium and subchondral bone of the human osteoarthritis (OA) knee joint, making TRPV1 a potential treatment target for OA-related knee pain.^2-4 RTX-GRT7039 is an intra-articular (IA) injection comprising resiniferatoxin (RTX), a potent and selective agonist of TRPV1 in injectate solution.^5,6 RTX is a direct-acting neuronal analgesic that selectively targets and deactivates TRPV1-expressing nociceptors, which can durably suppress knee OA pain.^7,8 Preclinical animal models of OA have demonstrated reduced pain behaviors and long-term pain relief following IA administration of RTX.^9,10

Purpose/Objectives: The purpose of this study was to evaluate the safety, tolerability, and potential efficacy of RTX-GRT7039, a resiniferatoxin-based intra-articular injection, in individuals with chronic knee pain due to osteoarthritis (OA). The primary objective was to assess safety through monitoring treatment-emergent adverse events (TEAEs) and procedure-related pain. Tolerability was evaluated based on the participants' ability to endure the procedure and associated discomfort. Exploratory efficacy analyses focused on changes from baseline in pain on motion (measured by visual analogue scale [VAS] pain score) and total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores up to day 180 post-injection. The study also aimed to explore any dose-response relationship of RTX-GRT7039. Overall, RTX-GRT7039 demonstrated a favorable safety profile and showed potential for reducing pain and improving function in knee OA patients.

Methods: This trial (MTX-071-P02) was a Phase Ib/IIa, open-label, single-injection study with an exploratory and adaptive design. The primary objective was to evaluate the safety and tolerability of IA injection of low doses of RTX-GRT7039 based on the incidence, intensity, and severity of adverse events (AEs). Participants received a single IA dose of purified RTX-GRT7039 equivalent to a range of 0.25 to 2 mg of E. resinifera latex in injectate solution, with or without pretreatment with lidocaine or ropivacaine.

Results: Enrolled participants (N=24) baseline characteristics were typical of knee OA trials, with mean age 56.6 (±8.14) years, BMI 31.1 (±6.09), 54.2% female, and baseline pain visual analogue scale [VAS] 70.3 (±14.21) on a [0-100] scale. Structural OA severity was predominately moderate to severe, with Kellgren-Lawrence (KL) grades 2 (8.3%), 3 (50.0%), and 4 (41.7%). Treatment-emergent adverse events (TEAEs) were reported for 22 participants (91.7%). The most frequent TEAEs were general disorders and administration-site conditions and musculoskeletal and connective tissue disorders, each reported in 11 participants (45.8%) The majority of the reported treatment-related AEs were related to the injected knee (16 participants, 66.7%) and included the following: knee pain (13 participants, 54.2%); knee pressure (2 participants, 8.3%); and knee swelling (1 participant, 4.2%) in context of injection of the study drug/total volume of fluid injected. Procedure-related pain was transient, peaking at 0.5 hours post-injection and generally returning to baseline within 1.5 to 3 hours post-injection.

In all treatment groups, VAS pain on motion (previous 2 days) in the treated knee rapidly and notably decreased from baseline within the first 4 weeks and remained low or decreased further until month 6. On day 180, decreases in pain on motion of >50% and >70% from baseline were observed in 17 (70.8%) and 9 participants (37.5%), respectively. In all treatment groups, total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores decreased from baseline to day 7 and were maintained through day 180.

Conclusions/Implications for future research and/or clinical care: RTX-GRT7039 had a favorable safety profile following single IA doses (equivalent to 0.25 to 2 mg E. resinifera latex in the injectate solution) in participants with chronic pain due to knee OA. Procedural pain related to RTX-GRT7039 IA injection was expected and common but generally resolved within 3 hours postinjection. Exploratory efficacy analyses demonstrated reduction from baseline in VAS pain on motion and WOMAC pain from day 7 that was maintained through day 180. Likely due to small numbers, no clear dose-response relationship was observed.

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