Investigational New Drug Development of Noribogaine for Alcohol Use Disorder

ABSTRACT DemeRx NB is a Miami-based clinical stage drug development company advancing noribogaine for the treatment for alcohol use disorder (AUD), based on accumulated knowledge of the drug’s pharmacology, toxicology and its potential clinical utility. Therapeutic agents for AUD have not progressed, and relapse rates in patients are high. Noribogaine hydrochloride is a new chemical entity azepinoindole that fits into a category of novel “psychoplastogen” therapeutic agents. Chronic exposure to alcohol sensitizes the reward system to alcohol- related cues, interferes with the processing of non-drug reward, increases impulsivity, and disrupts emotional regulation. There is a current shift in therapeutic strategy for complex brain disorders to focus less on rectifying single target “chemical imbalances” and more towards selective modulation of neural circuits. Noribogaine interacts with two or more CNS targets simultaneously and the drug has demonstrated predictive validity in animal models of AUD. Radioligand binding assays, nonclinical animal studies, and Phase 1 data from placebo- controlled trials of noribogaine do not suggest psychotropic effects or a potential for abuse. Noribogaine hydrochloride is a stable molecule that undergoes limited metabolic degradation in vitro. Cytochrome P450 inhibition studies indicate a low probability of drug-drug interactions. DemeRx NB has developed a scalable and reproducible GMP manufacturing process and characterized the crystalline ansolvate of noribogaine. Company milestones include development of assays/analytical methods for product characterization and release (potency, purity) and early stage in vitro and in vivo toxicology studies. Clinical pharmacokinetic studies have also been conducted in healthy volunteers and opioid dependent subjects, and safety have been characterized. DemeRx NB requests SBIR/STTR support for IND-enabling nonclinical studies including subchronic repeat dose toxicity studies and an EEG/EMG/EKG study, that are necessary to advance noribogaine to Phase 2 efficacy trials for AUD.