A multiple-dose double-blind randomized study to evaluate the safety, pharmacokinetics, pharmacodynamics and analgesic efficacy of the TRPV1 antagonist JNJ-39439335 (mavatrep).

Background And Aims: This double-blind (DB), randomized, placebo-controlled, sequential-group, multiple-ascending dose, phase 1 study evaluated safety, pharmacokinetics and pharmacodynamics of JNJ-39439335 in healthy men (part 1), and in participants with knee osteoarthritis (part 2).

Methods: Both parts 1 and 2 consisted of screening (upto 21 days), 21-day DB treatment phase [eight participants/group: JNJ-39439335 (part 1: 2-50 mg; part 2: 10-50 mg): n=6; placebo: n=2] and follow-up (total study duration ~10 weeks).

Results: Plasma concentrations and systemic exposure of JNJ-39439335 increased in slightly higher than dose-proportional fashion (steady-state reached by day 14). Renal excretion of JNJ-39439335 was negligible. Marked dose-related increases in pharmacodynamic heat pain assessments were observed in JNJ-39439335-treated participants, which persisted throughout the treatment with no signs of tolerance with repeated dosing. No effect on pharmacodynamic cold pain or mechanical pain assessments were seen. Effects on pharmacodynamic capsaicin-induced flare assessments in JNJ-39439335-treated participants versus placebo were consistent with effects observed with single-dose, and did not demonstrate tolerance with multiple dosing. In participants with knee osteoarthritis, significant improvements versus placebo were observed in a stair-climbing-induced pain model. All JNJ-39439335-treated participants reported ≥1 treatment-emergent adverse events (TEAE); most common (≥50% incidence) TEAEs in part 1 were feeling hot (79%), thermohypoesthesia (71%), paresthesia (58%) and feeling cold (50%), and in part 2, were minor thermal burns (50%).

Conclusions: JNJ-39439335 (doses 2-50 mg) was well-tolerated, and associated with acceptable multiple-dose pharmacokinetic profile. JNJ-39439335 demonstrated sustained pharmacodynamic effects (heat pain perception, heat pain latency, capsaicin-induced flare), and an efficacy signal in participants with osteoarthritis pain.

Implications: Given the efficacy signal observed and the unique safety profile, larger phase 2 studies are needed to better understand the potential of JNJ-39439335 in the treatment of chronic pain. Analgesic efficacy of lower doses administered over a longer period of time and improved patient counseling techniques to reduce the minor thermal burns can be explored to minimize the adverse events.