for Supplement Application The ultimate goal for our original project was to complete the proof-of-concept work, and the multitude of pharmacodynamic, pharmacokinetic, toxicokinetic, safety, and toxicology studies required by the FDA to apply for an IND. We are fully satisfied that we have generated a new chemical entity that acts at a novel binding site on the GABA-A receptor and acts in the gut by interacting with the microbiome, the enteric nervous system and the vagus nerve to block the significantly increased alcohol consumption in alcohol dependent animals after a period of forced abstinence (model of relapse). We have completed all non- clinical studies for an IND, and from our safety studies, we determined that our therapeutic dose in humans should be well below a dose that would produce any toxicity. The IND application is being written, but a critical issue remains to be addressed prior to IND submission. This issue centers on our plans to comply with the FDA Guidance for Industry ?cGMP for Phase 1 Investigational Drugs.? This Guidance details the processes, controls, quality checks on purity and stability, and fidelity of dosage delivery for producing the dosage forms to be used in the Phase 1 trials. The data and information on the production and testing of the Phase 1 dosage forms must be included with the IND application. We have worked with Catalent Pharma in the past to develop materials for dosing animals and have engaged them to produce the dosage forms for humans. The development, production, and control of formulations for humans was not an aim of our original application and funds were not allocated for this task. We are now asking for supplemental funds in order to develop and produce the human dosage forms so that we can submit the IND application. Achievement of this milestone will start us on the path for successful completion of clinical trials and to bringing an effective medication to those suffering from AUD to return them to a non-addicted lifestyle. Abstract from the Parent Grant Application Alcohol Use Disorder affects 7.9% of the U.S. population ages 18 and older and costs society over $223 billion per year in direct medical costs, accidents, and lost productivity. Current pharmacotherapy is only modestly effective and must be used in conjunction with psychosocial treatment. Primary care physicians are ill equipped to provide the currently necessary range of therapy for treating AUD and the modest effects of therapy generate a significant number of treatment failures. We have generated a novel molecule with action directly at one of the major neurotransmitter receptors altered by chronic excessive consumption of alcohol. We have also demonstrated in two different models of relapse drinking by alcohol dependent animals that our medication can reduce or prevent such relapse. Our preliminary studies on the safety and metabolism of our compound in animals provide confidence that the compound will have a good therapeutic index in human clinical trials. Prior to embarking on the trials in humans we, however, need for our drug to be approved for an IND by the Food and Drug Administration. To be able to accomplish this milestone we are proposing a series of SBIR Phase I, IND enabling studies, which include the development of an oral formulation which will be attractive for use with humans. In these SBIR Phase I studies we will also establish the blood and brain levels of our drug after oral administration in the newly developed formulation. In the SBIR Phase II studies we will produce our drug under cGMP conditions and scale up production to meet future clinical trials. The Phase II SBIR studies will be fully focused on completing all of the FDA required studies for the IND, including complete studies of in vitro metabolism and metabolite identification, in vivo studies of Absorption, Distribution, Metabolism, and Excretion, complete studies on safety and toxicology (including toxicokinetics) in two species (rats and dogs). These studies will include escalating acute dose studies and sub-chronic and chronic studies of up to six months duration because we anticipate that human studies may include long term maintenance of patients on our medication. If an IND designation is obtained, we anticipate launching a Phase I human safety trial with an arm of this study aimed at a clinical measure of craving in alcohol-dependent subjects. If this grant is funded and our medication reaches human trials, we anticipate introducing a more efficacious and much more highly utilized medication to treat AUD.

Public Health Relevance

The Global Status Report on Alcohol and Health released by the World Health Organization in 2014 detailed the massive health and economic costs of excessive alcohol consumption. Much of this excessive consumption and resultant cost is a product of individuals suffering from alcohol dependence (or alcohol use disorder (AUD) as it is currently called). We are developing a totally new medication to treat AUD. This medication has, in studies with alcohol-dependent animals, been shown to reduce alcohol consumption and prevent relapse. This grant is targeted at completing all the necessary studies on the metabolism and safety of our drug as required by the Food and Drug Administration to make our drug eligible for testing in humans.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Small Business Innovation Research (SBIR) Cooperative Agreements - Phase II (U44)
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Fertig, Joanne
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Lohocla Research Corporation
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Borghese, Cecilia M; Herman, Melissa; Snell, Lawrence D et al. (2017) Novel Molecule Exhibiting Selective Affinity for GABAA Receptor Subtypes. Sci Rep 7:6230
Tabakoff, Boris; Ren, Wenhua; Vanderlinden, Lauren et al. (2016) A novel substituted aminoquinoline selectively targets voltage-sensitive sodium channel isoforms and NMDA receptor subtypes and alleviates chronic inflammatory and neuropathic pain. Eur J Pharmacol 784:1-14