PROJECT SUMMARY / ABSTRACT There are more than 22 million individuals in the United States with a substance use disorder (SUD). SUDs are a collection of chronic disorders often characterized by drug-seeking behavior manifesting as a cycle of substance intoxication and binging, followed by withdrawal, and craving states that contribute to compulsive relapses, often driven by non-compliance with treatment medications. Despite decades of research into SUD causes and treatment, more than 108,000 Americans died from drug overdoses in 2021, most involving opioids. Existing pharmacological SUD treatments merely act as a substitute for the misused drug or temporarily improve abstinence but do not reduce the cravings associated with SUD. Despite the overwhelming addiction crisis, few therapies exist, and those that are available have low efficacy. Novel pharmacological treatments are urgently needed. Recent research has suggested that psychoplastogenic compounds (PCs) can reduce drug dependence. This drug abuse cessation is linked to the induction of neuritogenesis and increased neuroplasticity, a hallmark of PCs. As a PC, ketamine promises to be a better SUD pharmacotherapy that can reduce cravings, promote permanent recovery, and treat non-opioid SUDs; however, currently available formulations have several adverse side effects including sedation, dissociative effects, and abuse liability. CP110 encapsulates ketamine in polymer microparticles that slowly release the drug over time as the polymer degrades. This slow release at low levels over time will reduce side effects. The monthly administration will reduce non-adherence and improve retention and provide better patient outcomes. The long-term goal is to develop a new SUD pharmacotherapeutic that will improve abstinence, treat non-compliant patients, reduce cravings, and effectively treat those SUDs that have no effective pharmacological treatments. Our hypothesis is that delivering ketamine at a low level over time will offer a better safety profile than currently available ketamine formulations while improving adherence. Releasing ketamine at low levels will also lengthen the time of neuroplasticity enhancement that is believed to provide more permanent recovery. The Specific Aims are as follows: 1) Validate ketamine release over 28-days in rats, and 2) Validate efficacy of CP110 and demonstrate reduced dissociation in rats. The objective of this project is to continue development of CP110, a novel, long- acting injectable (LAI) ketamine formulation that maintains therapeutic levels for 28-days by validating in vivo pharmacokinetics and demonstrating reduced dissociation. In Phase II, we will conduct an investigational new drug (IND) enabling studies required for an FDA application. Hence, the studies proposed here are important precedents to support a future clinical program for CP110. Market approval for CP110 could address the $2.7 billion global SUD market and fulfill the unmet medical need of an improved SUD therapeutic to provide better therapeutic outcomes for patients.

PROJECT NARRATIVE There are more than 22 million individuals in the United States with a substance use disorder (SUD). Current pharmacotherapies are inadequate resulting in an unmet need. In this SBIR, Consegna Pharma Inc. plans to develop a novel SUD therapeutic, a long-acting injectable ketamine, that is expected to address these inadequacies and provide better therapeutic outcomes, aid in a more permanent recovery, reduce cravings, improve retention and compliance, and, in addition to treating opioid SUDs, also provide a breakthrough therapy for non-opioid SUDs such as cannabis and stimulants.