A moduli-selective antibody inhibits the pain receptor TRPV1 in cynomolgus monkeys without adverse temperature dysregulation

Abstract The multimodal, transient receptor potential vanilloid-1 (TRPV1) ion-channel, mediates pain sensation, is implicated in thermal hyperalgesia, and considered a highly promising target for pain management. However, TRPV1 has many complicated and entangled functions or modalities, whereas several first-generation small molecule TRPV1 antagonists, e.g., AMG517, have shown analgesic effects in the clinic, many caused target-related hyperthermia and loss of heat sensation. Consequently, all these programs were discontinued from further clinical development. We have produced a monoclonal antibody (OT-3607) with a concentration-dependent modality-selectivity, inhibiting capsaicin-activation without inhibiting heat-activation of TRPV1. Surprisingly, OT-3607 potentiates the heat sensor at low concentrations and short timescales. As investigated in a capsaicin-induced dermal blood flow model in cynomolgus monkeys, efficacy of OT-3607 was found to be superior compared to the antagonist AMG517. Moreover, harmful body temperature elevations or febrile conditions could not be observed in any of the animals. Given the need for new medicines for treatment of chronic pain conditions, and the ongoing opioid crisis, OT-3607 warrants further investigation.