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to placebo. There were no serious adverse events as EMA401 does not cross the blood-brain-barrier and so Central Nervous System (CNS) side-effects were avoided.

What happened next

The Phase 2a trial success of oral EMA401 led to the acquisition of Spinifex by Novartis in 2015 who commenced two Phase 2b clinical trials of oral EMA401 in patients with PHN (NCT03094195) or painful diabetic neuropathy (NCT03297294) in 2017. Unfortunately, these trials were terminated early due to unexpected liver toxicity at 39-weeks of chronic oral dosing in monkeys in 2019. Importantly, there were no signs of liver toxicity in patients who had received twice-daily oral EMA401 for up to 13-weeks.

Conclusions

A successful proof-of-concept Phase 2a clinical trial of EMA401 in patients with PHN, a type of peripheral neuropathic pain that is often intractable, provided clinical trial validation of the AT 2 receptor as a tractable target for the relief of neuropathic pain.

Implications/Discussion

Whether 2nd generation, small molecule AT 2 receptor antagonists will be devoid of hepatotoxicity in long-term animal toxicity studies, remains to be determined.

Declaration

Maree T Smith is named inventor on The University of Queensland (UQ) patents for the use of AT 2 receptor antagonists in neuropathic pain and chronic inflammatory pain. This discovery was commercialised by the UQ spinout company, Spinifex Pharmaceuticals Pty Ltd that was formed in 2005. Spinifex was acquired by Novartis in 2015, and clinical development was terminated by Novartis in 2019 because of unexpected hepatotoxicity in a long-term animal toxicity study.