PROJECT SUMMARY/ABSTRACT In response to PAR-22-202 “Grand Opportunity in Medications Development for Substance-Use Disorders (U01 Clinical Trial Optional),” this revised application (U01DA060704) requests 3 years of support to continue developing the novel opioid receptor antagonist methocinnamox (MCAM) for preventing opioid relapse after detoxification. MCAM will fill an unmet need for an orally bioavailable, shelf-stable, long-acting medication for preventing relapse. MCAM prevents and reverses the effects of µ-opioid receptor (MOR) agonists, including ultra-potent agonists such as fentanyl, in several species and by multiple routes of administration with a single dose being effective for >2 weeks. In vitro and in vivo studies have not identified any clinical adverse signs for MCAM over a >3,000-fold dose range. IND-enabling safety pharmacology and toxicology studies in rats and dogs (Charles River Laboratories) are complete and found no adverse clinical signs. Synthesis of MCAM (Veranova) was improved, increasing the yield, maleate was determined to be a preferred salt, two 1-kilogram batches of non-GMP MCAM were manufactured for non-clinical studies, ongoing stability studies are showing MCAM to be shelf stable for at least 9 months, and analytical methods for manufacturing GMP MCAM are being developed. In a pre-IND meeting in November 2023 (facilitated by Allucent), the FDA agreed with our proposed non-clinical and clinical programs. A use patent for MCAM was issued in 2019 and 3 other patents are pending. This application includes scientists with expertise in drug discovery and development, basic scientists who have studied MCAM extensively, clinicians with expertise testing medications for substance use disorders, as well as commercial CRO partners that will manufacture GMP MCAM (Veranova), synthesize deuterated MCAM (Moravek), conduct non-clinical toxicology and safety pharmacology studies (Charles River Laboratories), and serve as the regulatory agent to the FDA as well as manage clinical trials (Allucent; including a former senior pharmacology/toxicology reviewer who served in the Division of Anesthesia, Addiction Medicine and Pain Medicine, the Division that participated in the pre-IND meeting and will review the IND application). This revised application requests 3 years of support to continue developing MCAM with the following 4 specific aims. 1) Submit an IND for preventing relapse. 2) Complete Phase 1 and Phase 1b clinical trials with MCAM. 3) Plan a Phase 2 clinical trial with MCAM. 4) Conduct additional non-clinical toxicology and other studies as recommended by the FDA. Completing these aims, along with securing additional intellectual property protection through pending US patents, will further strengthen the feasibility of developing MCAM as a medication for preventing relapse after detoxification. Completing these aims will also significantly increase the value of this project to potential future partners and investors who have the expertise and financial resources to commercialize MCAM into a marketable product for preventing relapse as well as other possible indications (e.g., prevention and reversal of opioid overdose, prophylaxis for opioid poisoning/weaponization).

PROJECT NARRATIVE That the opioid crisis continues despite the availability of medications that are effective in many patients, underscores the need for new, more effective therapeutics. This revised application requests support to continue developing the novel opioid receptor antagonist methocinnamox (MCAM) for preventing relapse after detoxification. GMP MCAM will be manufactured, an IND application will be submitted to the FDA, Phase 1 and Phase 1b clinical trials as well as additional non-clinical safety pharmacology and toxicology studies will be conducted. MCAM has the potential to fill the unmet need for an orally bioavailable, shelf-stable, long-acting medication for preventing relapse.