Novel 5-HT2A/mGluR5 Antagonist for Opioid Use Disorder - Opioid overdose deaths continue to be a major public health problem in the US requiring improvements in treatments for opioid use disorder (OUD). Despite current medication for addiction treatment (MAT), treatment dropout and substance use recurrence rates remain high. Thus, novel therapeutics to augment MAT to improve treatment outcomes and reduce opioid overdose deaths are needed. Prior research suggests that 5-HT2A and mGluR5 receptor antagonists could be useful in reducing impulsive responses to drug cues, improving negative emotionality, and reducing the overall rewarding value of reinforcing stimuli, and through these mechanisms improve treatment retention and reduce relapse in patients with OUD. Vivozon Inc, has developed VVZ-2417- a new chemical entity, which has a high selectivity for 5-HT2A and mGluR5 antagonism. In preclinical studies, VVZ-2471 reduces morphine self-administration, drug-induced reinstatement of morphine self-administration after forced abstinence, and morphine withdrawal symptoms precipitated by naloxone. In human studies, single and multiple ascending dose studies showed VVZ-2471 to be safe in healthy controls with the most common adverse events being dizziness and gastrointestinal symptoms, with no serious adverse events. Taken together, preclinical, and early clinical safety data all support further research on VVZ-2471 as a potential treatment for OUD. This project, which is a collaboration between Vivozon Inc and Virginia Commonwealth University, will establish preliminary safety and early efficacy data to support VVZ-2471 phase II clinical trials for a future NDA with the indication as an adjunctive treatment with buprenorphine for OUD. UG3: Specific Aim 1. Establish the preclinical safety of VVZ-2471 when administered in combination with opioids. Milestone 1. Completion of safety and drug-drug interaction (DDI) study in rodents for VVZ-2471 when administered in combination with buprenorphine and separately with fentanyl. Specific Aim 2. Complete human data collection and protocol development for IND submission for human phase Ib studies. Milestone 2. Completion of a 30-day chronic dosing safety study in controls with no study drug related SAEs or unanticipated problems affecting the UH3 IND. Milestone 3. Opening the IND without clinical hold for Phase 1b UH3 studies. UH3: Specific Aim 3. Assess VVZ-2471 as an adjunctive treatment with buprenorphine in OUD participants in a double-blind, randomized, placebo-controlled, double-blind phase 1b acute inpatient study assessing effects of adjunctive VVZ-2471 (vs. placebo) on the PK and PD properties related to safety in OUD patients stabilized on buprenorphine. Specific Aim 4. Complete a 14-day double-blind, randomized, placebo-controlled outpatient extension of the trial of participants in Aim 3, assessing chronic safety as the primary outcome with secondary outcomes of impulsivity, negative emotionality, and opioid cue-related attentional bias, and exploratory outcomes of opioid craving, subjective reward, withdrawal symptoms, non-prescribed substance use.
