R44AA024905

According to the 2019 National Survey on Drug Use and Health, 14.1 million adults ages 18 and older had Alcohol Use Disorder, and approximately 825,000 people indicated heavy alcohol use. However, only about 8% of individuals who had AUD in 2018 received treatment. In part, the lack of treatment results from the paucity of effective therapeutics available to treat AUD, and research is ongoing to develop new therapeutic approaches. Lohocla Research Corporation has been developing such a therapeutic, called Nezavist, which was shown in nonclinical models to reduce alcohol relapse in dependent individuals. The goal of Lohocla is to produce a treatment for individuals, including those with AUD, who wish to reduce their alcohol consumption. Nezavist acts as a positive allosteric modulator of GABA-A receptors, acting at a novel site on the receptor distinct from other modulators such as benzodiazepines. The other novel characteristic of Nezavist is its site of action within the intestine, where Nezavist modulates the activity of the enteric nervous system and produces its effect on alcohol consumption through a gut-brain communication pathway. By this means, Nezavist can influence brain activity without itself entering the brain. This application is for a Phase IIB renewal of SBIR U44AA024905, which will support the completion and submission of an IND application to the FDA and the performance of Phase1 safety and tolerability clinical trials of Nezavist. During the course of the current SBIR grant, Lohocla developed a method to scale up the synthesis of Nezavist, using flow chemistry to circumvent hazardous steps, and obtained kilogram quantities of cGMP Nezavist. A spray-dried dispersion formulation has been produced that enhances bioavailability. In vitro ADME studies were performed, including determining pathways of metabolism, and investigating metabolic processes in tissues from several species, which assisted in the choice of species for in vivo toxicology and pharmacokinetics. In vitro interactions with transporters and CYP450 enzymes were also completed. The spray-dried dispersion formulation was used to assess pharmacokinetics and toxicology in several species, and the results of the toxicology studies provide the data needed to determine the dosing levels for the first-in-human studies. A pre-IND meeting was accomplished with a favorable outcome. Overall, Lohocla has completed most of the IND-enabling studies needed to progress to clinical trials, including the development of methods for administering the drug to humans. The proposed Phase IIB renewal includes completion of the mass balance study recommended by the FDA to be included in the IND application, and synthesis of cGMP formulation that can be used in the clinical trials. Once the IND is approved, Phase 1a and Phase 1b clinical trials are proposed. Concurrent with the clinical trials, a long-term nonclinical toxicology study in rat will be performed that will be needed to provide a NOAEL in order to proceed to human laboratory studies and Phase 2 clinical trials. A commercialization plan provides information on the market potential for Nezavist. The successful completion of the Phase IIB work will provide the basis for efficacy studies of a novel therapeutic approach to reduce excessive and harmful alcohol consumption.