Efficacy and safety of EMA401 in peripheral neuropathic pain: results of 2 randomised, double-blind, phase 2 studies in patients with postherpetic neuralgia and painful diabetic neuropathy

Abstract

The analgesic efficacy and safety of 2 phase 2b studies of EMA401 (a highly selective angiotensin II type 2 receptor antagonist) in patients with postherpetic neuralgia (EMPHENE) and painful diabetic neuropathy (EMPADINE) were reported. These were multicentre, randomised, double-blind treatment studies conducted in participants with postherpetic neuralgia or type I/II diabetes mellitus with painful distal symmetrical sensorimotor neuropathy. Participants were randomised 1:1:1 to either placebo, EMA401 25 mg, or 100 mg twice daily (b.i.d) in the EMPHENE and 1:1 to placebo or EMA401 100 mg b.i.d. in the EMPADINE. The primary outcome for both the studies was change in weekly mean of the 24-hour average pain score, using a numeric rating scale from baseline to week 12. Both the studies were prematurely terminated due to preclinical hepatotoxicity on long-term dosing, although not observed in these studies. Out of the planned participants, a total of 129/360 (EMPHENE) and 137/400 (EMPADINE) participants were enrolled. The least square mean reduction in numeric rating scale pain score was numerically in favour of EMA401 100 mg arm in both EMPHENE (treatment difference: −0.5 [95% confidence interval: −1.6 to 0.6; P value: 0.35]) and EMPADINE (treatment difference: −0.6 [95% confidence interval: −1.4 to 0.1; P value: 0.10]) at the end of week 12. However, as the studies were terminated prematurely, no firm conclusion could be drawn but the consistent clinical improvement in pain intensity reduction across these 2 studies in 2 different populations is worth noting.

Improving Preclinical Development of Novel Interventions to Treat Pain: Insanity Is Doing the Same Thing Over and Over and Expecting Different Results

“…In other cases, preclinical screening for common adverse events fails to predict them occurring in humans, for example, lack of retching or vomiting in dogs, but severe nausea and vomiting in people from intrathecal neostigmine 37 or hepatobiliary toxicity in EMA401, an angiotensin receptor antagonist in development for the treatment of neuropathic pain. 4…”

“…Ziconotide is perhaps the best example of success coming from rodent research, but its clinical utility is limited by the need for continuous intrathecal infusion and its low therapeutic ratio. 3 Other targets discovered in rodents, such as nerve growth factor or cholinergic or angiotensin II receptors, 4,5 were indeed successfully translated to humans, but their clinical development has been delayed by toxicity and adverse event factors.…”

Nonopioid analgesics discovery and the Valley of Death: EMA401 from concept to clinical trial

“…However, no firm conclusions could be drawn because of the premature termination and that the 300-mg twice-daily dosing regimen was not assessed. 89 Importantly, for patients dosed with oral EMA401 Summary of mean pharmacokinetic parameters and oral bioavailability of EMA200, EMA300, EMA400, and EMA401 (Senantiomer of EMA400) in adult male SD rats (adapted from Smith and colleagues 103 AUC 0-' 5 area under the plasma concentration vs time curve from time zero extrapolated to infinity; Cl 5 systemic clearance; C max 5 peak plasma concentration after oral dosing; F (%) 5 oral bioavailability; t ½ 5 terminal elimination half-life; T max 5 time of C max after oral dosing; V d 5 volume of distribution; *value based on AUC0-t, where t is the last measurable plasma concentration. PAIN ® at 25 or 100 mg twice daily for up to 13 weeks, EMA401 was welltolerated and there were no changes in liver biochemical parameters during or after these trials were ceased.…”

“…PAIN ® at 25 or 100 mg twice daily for up to 13 weeks, EMA401 was welltolerated and there were no changes in liver biochemical parameters during or after these trials were ceased. 89 A possible mechanism for the unexpected hepatotoxicity in cynomolgus monkeys may involve acyl migration of EMA401 glucuronide to produce products with potential to form covalent adducts with liver proteins that may act as a hapten to the immune system, but this remains to be determined.…”

Advances in the treatment of neuropathic pain

“…A few drug classes acting on new targets have recently been assessed in neuropathic pain in proof-of-concept trials but are not clinically available. Antagonists of the angiotensin type II receptor [27] have been found effective in postherpetic neuralgia on the basis of one large-scale trial but two recent confirmatory studies were interrupted prematurely because of animal toxicity [28]. Newer antagonists of sodium channels available orally or topically have been assessed in trigeminal neuralgia [29] and postherpetic neuralgia [30].…”