Novel methods for nicotinic receptor modulation in the treatment of post-operative pain

The National Institute of General Medical Sciences awarded Epigen Biosciences Inc. $699,998 on September 12, 2025, under the Biomedical Research and Research Training program (CFDA 93.859) to develop novel methods for nicotinic receptor modulation in treating post-operative pain.

Epigen will test EPGN2325, a novel formulation of the positive allosteric modulator PNU120596, in pre-clinical models of chronic pain in collaboration with the University of Chicago. The work targets α7 nicotinic acetylcholine receptors as a non-opioid analgesic pathway. The research addresses the clinical need for alternatives to opioids, which carry limited efficacy, serious adverse reactions, and high addictive potential in chronic pain populations. The proposed approach will establish proof-of-concept for EPGN2325's utility in post-surgical pain by evaluating its ability to reverse cholinergic hypofunction associated with acute and chronic pain states.

The period of performance runs through August 31, 2027. Work is performed in California. This is a Project Grant, the assistance type typical for investigator-initiated biomedical research under NIGMS's mission to support basic research that advances disease diagnosis, treatment, and prevention.

Abstract

Upwards of 50 million individuals are afflicted by chronic pain in the USA, with 3 million of these individuals suffering from neuropathic pain, which can stem from known causes including surgical procedures, injury, cancer, and HIV/aids. While opiates are a mainstay of analgesic use, they offer limited benefit to chronic pain sufferers due to variable efficacy, serious adverse reactions and a high addictive potential. Thus, there is renewed interest for developing non-opioid compounds with improved analgesic efficacy and reduced adverse reactions. Nicotinic receptors (NACHRS) have been viewed as promising targets for non-opioid analgesics. Specifically, Α7 NACHRS offer an intriguing potential target for analgesic drugs. Α7 agonists and positive allosteric modulators (PAMS) have demonstrated robust analgesic efficacy in several rodent models of acute and chronic pain. Chronic pain was recently shown to suppress acetylcholine levels in a descending pain modulatory center, the ventrolateral periaqueductal gray area (VLPAG). This observation highlights the potential utility of PAMS, to boost receptor activation via endogenous cholinergic tone and may reverse the cholinergic hypofunction associated with acute and chronic pain states. As allosteric modulators, PAMS offer an attractive solution to drug discovery based on the potential for exquisite selectivity in modulating Α7 NACHRS. Despite significant research the most promising PAM discovered is PNU120596 (PNU). Epigen has developed a novel formulation suitable (EPGN2325) for its evaluation in therapeutic applications. Recent data suggests an opportunity for its utility in post-surgical pain. In this proposal, a two-pronged approach will be adopted. In the first, in collaboration with university of chicago (UC), EPGN2325 will be tested in pre-clinical models of chronic pain with the goal of establishing Α7 NACHRS (and EPGN2325) as an approach to treatment of post-surgical pain. In the second, an approach to develop an oral approach to post-surgical pain based on Α7 NACHRS will be undertaken. In this approach epigen will conduct limited medicinal chemistry around PNU to resolve issues identified from adme profiling for oral use. A lead molecule from this effort will be tested in pain models at UC. Collective data will determine the utility of Α7 nachr activation for pain management and if successful, identify a potential candidate for development.