Mechanism and Efficacy of a Novel Opioid Adjuvant

PROJECT SUMMARY Managing the complex risk-benefit profile of opioid therapeutics is a significant challenge for pain patients and the physicians that treat them. Prescription opioid analgesics provide excellent pain relief but also put patients in danger of severe adverse effects such as depression, dependence, abuse, and addiction. The opioid crisis in the United States reflects these risks as over 2.4 million Americans suffer from opioid use disorder, and over 50,000 patients die yearly. Clinical guidelines address the problem of prescription opioid abuse and addiction by urging physicians to minimize opioid doses. However, years of decreasing doses and a narrow therapeutic window limit the ability to decrease doses further without losing pain relief effectiveness. Despite decades of research, we still do not have a total opioid replacement. In the absence of an opioid replacement, there is a critical unmet need for new technologies that minimize the risks associated with prescription opioids. Amalgent Therapeutics, Inc. is addressing this need by developing a novel and proprietary opioid adjuvant. Adjuvants provide an alternative strategy to addressing the problem of opioid use disorder. Our preliminary data show that this adjuvant increases opioid pain-relieving efficacy by at least four-fold, allowing a substantial decrease in effective opioid doses. In addition, our data show that the adjuvant mitigates the abuse potential of opioids, prevents the development of opioid tolerance, and restores effectiveness in neuropathic pain. Amalgent plans to bring this adjuvant technology to market in AMGT-0220, a fixed-dose combination therapeutic that combines the adjuvant with a currently marketed opioid. Importantly, the adjuvant is currently approved and marketed for use in non-pain indications. The combination of two approved drugs is regulated by the FDA under the 505(b)2 new drug approval pathway. This regulatory pathway allows decades of previously acquired safety and clinical data to support IND submissions for AMGT-0220. The ability to leverage existing data substantially derisks the AMGT-0220 development program and provides an accelerated path to the clinic. In this Phase 1 SBIR proposal, we propose work to provide further mechanistic and dosing information for the adjuvant. In Aim 1, we investigate the mechanism by which the adjuvant increases opioid pain-relieving efficacy and calculate the minimal concentration needed to decrease opioid doses. In Aim 2, we directly the ability of the adjuvant to decrease the dose of opioid needed for analgesia in an animal model of post-surgical pain. The work proposed here will support a Phase 2 application for the nonclinical and clinical development of AMGT-0220.