Preclinical to clinical translation for novel analgesic agents is limited.

Angiotensin II type 2 receptor antagonists are promising in rodent pain models.

The small molecule AT2 receptor antagonist, EMA401, progressed to clinical trials.

EMA401 (100 mg, oral) demonstrated efficacy over placebo in PHN in a Phase 2a trial.

Unexpected hepatotoxicity in a 39-week animal study terminated Phase 2b trials.

Translating promising preclinical pain relief data for novel molecules from drug discovery to positive clinical trial outcomes is challenging. The angiotensin II type 2 (AT2) receptor is a clinically-validated target based upon positive proof-of-concept clinical trial data in patients with post-herpetic neuralgia. This trial was conducted because AT2 receptor antagonists evoked pain relief in rodent models of neuropathic pain. EMA401 was selected as the drug candidate based upon its suitable preclinical toxicity and safety profile and good pharmacokinetics. Herein, we provide an overview of the discovery, preclinical and clinical development of EMA401, for the alleviation of peripheral neuropathic pain.

© 2023 The Author(s). Published by Elsevier Ltd.