Background/Purpose: Current treatments of osteoarthritis (OA) of the knee, such as NSAIDs, have significant limitations in both efficacy and safety. NEO6860 is a modality selective antagonist (shows full antagonism when activated by capsaicin, but little or no antagonism when activated by heat or low pH) at the cloned human transient receptor potential vanilloid subtype 1 (TRPV1) receptor. In a phase I study¹, NEO6860 showed good bioavailability and demonstration of pharmacodynamic effect as well as a target engagement.

Methods: This proof-of-concept, randomized, double blinded, placebo controlled, 3-period crossover, phase II study compared alternately 1 day (2 doses): NEO6860 (500 mg bid), placebo, and naproxen (500 mg bid) in a random sequence in 54 patients with OA (mean age: 61; mean BMI 29 kg/m2; 35% with hypertension, 14% with dyslipidemia and 10% with diabetes).

Results:

Pharmacokinetics (PK) data revealed that the exposure was approximately 1.6 times higher when compared with phase I at the same dose (C_max = 4337 ng/mL and 2770 ng/mL, respectively). An analgesic effect of NEO6860 was shown using Numerical Rating Scale (NRS) post-exercise at 3 and 24h, using a mixed ANCOVA Model, controlling for Period, Sequence and Treatment as fixed effects and baseline by period as covariate:

*: 8 h post dose was the primary endpoint; **: p <0.05 comparing naproxen to placebo.

This pattern was confirmed on NRS pre-exercise, Patient’s Global Impression of Change (PGIC) and, to a lesser extent, the WOMAC; however, the observed effect was below the hypothesis used for power estimate, explaining in part the P values ≥ 0.05. The safety profile was comparable to that in the prior phase I study, taking into consideration the unexpectedly higher level of exposure, and the two severe adverse events (AEs) reported (feeling hot and headache, each reported by one patient) were resolved within one day. Importantly, no hyperthermia and no change in heat pain perception were reported.

Conclusion:

In patients with OA pain, an analgesic effect was observed with NEO6860 while not showing the two AEs previously observed with TRPV1 antagonist, consistent with its modality selective mode of action. Future investigations should emphasize on: 1- reducing the NEO6860 dose, which may maintain the analgesic effect with multiple dosing, and 2- testing NEO6860 in combination with NSAIDs to improve analgesia and potentially alleviate safety concerns of current treatments of OA.

(1) Brown W et al. The Journal of Pain, 2017 June; 18(6):726-738.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/analgesic-potential-of-neo6860-a-modality-selective-trpv1-antagonist-in-osteoarthritis-knee-pain-results-of-a-randomized-controlled-proof-of-concept-trial/