SUMMARY Opioid use disorder (OUD) contributes to disability, loss of work, and over 100,000 overdose deaths per year in the U.S., emphasizing the critical need for novel medications for OUD treatment. Ibogaine, a psychoactive alkaloid from the Tabernanthe iboga shrub, has shown promise in interrupting opioid dependence, reducing withdrawal symptoms, and increasing abstinence rates, even after a single treatment. However, ibogaine's cardiotoxicity and neurotoxicity pose significant barriers to its development as a drug. To leverage ibogaine’s potential as an OUD therapeutic and address the risks to patient safety, we have developed a new class of synthetic iboga alkaloids, named “oxa-iboga”. These compounds show no pro-arrhythmic potential, no neurotoxic effects, and enhanced efficacy in OUD-relevant preclinical behavioral assays compared to ibogaine. We propose to advance one of these compounds, GM-3009, into clinical studies by advancing GMP-manufacturing and formulation of GM-3009, completing IND-enabling toxicity studies, and determining the expected therapeutic exposures of GM-3009 and target engagement via translational biomarkers. These studies will complete the UG3 portion of this grant. If successful, the proposal will advance to the UH3 portion, which will conduct first-in-human trials, including safety and tolerability studies in healthy volunteers (a single ascending dose study, SAD) and a safety study with exploratory measures of efficacy in OUD patients undergoing opioid withdrawal. The endpoint of the entire project is generation of clinical safety and preliminary efficacy data to support subsequent Phase 2 efficacy studies in OUD. The development of GM-3009 builds on decades of research on ibogaine and has the potential to deliver an innovative OUD therapy with rapid and long-term mitigation of acute and protracted withdrawal symptoms and cravings, which lead to non-medical opioid use.

PROJECT NARRATIVE Opioid use disorder (OUD) affects millions of people, while existing medications are not readily accessible and suffer from low patient compliance. Ibogaine, a natural substance, shows promise for OUD treatment, but poses considerable safety risks. Our team has developed a safer, synthetic alternative called "oxa-noribogaine" to revolutionize opioid addiction therapy and improve the lives of those struggling with substance use disorders.