Project Summary Over 2.1 million Americans suffer from opioid use disorder (OUD) resulting in 47,000 deaths annually. Individuals seeking treatment must deal with stigma, limited access to qualified healthcare professionals and bureaucratic barriers to getting medication assisted treatment (MAT) and in addition often need to experience withdrawal symptoms prior to MAT which all add up to an ineffective system of access. Even on treatment, patients face several obstacles such as pain, craving, stress, shame, treatment inconsistency and relapse to be remain on an effective treatment regimen. This is just one of many steps needed towards long term abstinence and a more stable life. The path is harrowing, and there is a paucity of options available for these individuals and the medical staff who treat them. DMK proposes to expand MAT capabilities for OUD with DPI-125, with a small molecule, triple (mu, delta and kappa) opioid receptor agonist. Experimental, clinical and theoretical evidence suggests that DPI-125 has additional safety and efficacy advantages in terms of reduced respiratory depression (delta agonism) and reduced likability (kappa agonism) over currently available agonist and antagonist treatments. In this project, our objective is to demonstrate the feasibility of DPI-125 as a MAT agent. We intend to do this by identifying the lowest dose at which DPI-125 mitigates somatic signs of opioid withdrawal in a validated rodent model of morphine dependence. Current standard of care medications will be used as active comparators. It is anticipated that DPI-125 will be able to alleviate physiological symptoms of withdrawal, at potentially very low doses and with a rapid onset. This combined with its superior safety profile (reduced respiratory depression and abuse potential) would make it a highly valuable addition to the OUD armamentarium. Should efficacy of DPI-125 be equal or superior to that of methadone or buprenorphine, DMK Pharma will advance the clinical development of DPI-125 as a MAT for OUD with an intention to improve patient access, adherence, tolerance and treatment progress. Given that DPI-125 is a clinical stage asset, the potential of adding it to the MAT armamentarium for OUD could happen within just a few years of clinical development.