NEO6860, modality-selective TRPV1 antagonist: a randomized, controlled, proof-of-concept trial in patients with osteoarthritis knee pain

Abstract

Introduction:NEO6860 is a TRPV1 antagonist when activated by capsaicin but not by heat or pH, developed to relieve pain without the adverse events reported with non–modality-selective TRPV1 antagonists.Objective:The primary Objective of this study was to evaluate the analgesic efficacy and safety of NEO6860 after 1 day oral dosing in patients with Kellgren-Lawrence stage I, II or III osteoarthritis of the knee.Method:This randomized, double-blinded, 3-period crossover, phase II study compared 1 day (2 doses) of NEO6860 (500 mg twice a day), placebo, and naproxen in 54 patients with osteoarthritis knee pain. Primary endpoint was reduction in pain intensity (PI) on Numerical Rating Scale after exercise, using the staircase test, 8 hours after dose.Results:Level of PI, compared with baseline, was numerically lower during NEO6860 and naproxen periods vs placebo at 3 and 24 hours, but not at 8 hours after first dose. A statistically significant effect for naproxen and a trend for NEO6860 were observed at 3 and 24 hours. Least square means' (95% confidence interval) change in PI at 24 hours was −0.67 (−1.09 to −0.26), −0.97 (−1.39 to −0.55), −0.29 (−0.71 to 0.13) for NEO6860, naproxen, and placebo, respectively. NEO6860 exposure was ∼1.6 times higher compared with previous phase I. In this study, NEO6860 safety profile was less favorable than naproxen or placebo. Possibly NEO6860-related adverse events included: feel hot, headache, nausea, dizziness, fatigue, hypoaesthesia, and increased blood pressure.Conclusion:In this exploratory study, NEO6860 did not statistically significantly outperform placebo but showed an analgesic trend, without impacting body temperature and heat pain perception. Further studies are warranted to explore the potential of NEO6860 in other pain indications. We intent to optimize the dose and evaluate analgesic synergism with other mechanism.

A Guide to Targeting the Endocannabinoid System in Drug Design

“…NEO6860, a TRPV1 antagonist, was tested for osteoarthritis pain in a phase II trial. Thus far, it did not exhibit desired effects in comparison to placebo [347]. However, phase I trials showed analgesic activity.…”

Decursin Alleviates Mechanical Allodynia in a Paclitaxel-Induced Neuropathic Pain Mouse Model

“…As mentioned above, TRPV1 is an interesting target protein for treating CINP, because it directly mediates pain transition via a sudden increase in intracellular Ca 2+ . Previous in vivo studies have reported that AMG9801 and NEO6860 improved paclitaxel-induced peripheral neuropathy by inhibiting the function of TRPV1 [ 27 , 28 ]. Previous work has also shown that the expression of TRPV1 in small dorsal root ganglion neurons of rats was increased by treatment of oxaliplatin, which is an agent used in chemotherapy [ 27 , 28 ].…”

“…Previous in vivo studies have reported that AMG9801 and NEO6860 improved paclitaxel-induced peripheral neuropathy by inhibiting the function of TRPV1 [ 27 , 28 ]. Previous work has also shown that the expression of TRPV1 in small dorsal root ganglion neurons of rats was increased by treatment of oxaliplatin, which is an agent used in chemotherapy [ 27 , 28 ]. This increased TRPV1 expression contributed to the development of mechanical allodynia and thermal hyperalgesia in oxaliplatin-induced peripheral neuropathic pain rats [ 29 , 30 ].…”

Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases

“…Prolonged exposure to capsaicin desensitizes the receptor, and subsequently inactivates the local pain transmission. A phase II study of CNTX-4975, a synthetic trans-capsaicin, showed that 1 mg of CNTX-4975 via local injection reduced pain associated with walking and improved knee stiffness and physical function in patients with OA knee pain [ 406 ]. An oral TRPV1 antagonist, NEO6860, did not show significant improvement compared to placebo in phase II study [ 407 ].…”