Scope: Rodney Guy:State Matching: Kentucky Network for Innovation & Commercialization (#KYNETIC#) Yr 3

Our long-term goal is to develop the first FDA-approved medicine for methamphetamine (METH) use disorder (MUD) often referred to as “METH addiction”. The unmet need we are addressing is that unlike other substance use disorders (e.g., tobacco, opioid, or alcohol), for which treatment consists of a therapeutic in combination with behavioral therapy to improve patient outcomes, there remains no FDA-approved medication for MUD. METH is a potent, highly addictive stimulant estimated to claim >15,000 lives and cost 600 billion dollars each year in the United States alone. Compulsive, chronic, use of METH leads to a MUD diagnosis. MUD causes devastating health consequences for the individual (e.g., psychotic behavior, brain and heart damage, and death), but its effects ripple throughout entire communities (e.g., crime, unemployment, child neglect or abuse, and other social harms). METH users experience a sudden “rush” and prolonged stimulation of movement, motivation, and reward centers in the brain due to increased extracellular concentrations of dopamine (DA, a neurotransmitter). METH increases extracellular DA by inhibiting uptake and reversing transport at the vesicular monoamine transporter-2 (VMAT2) protein. Our solution is to develop the first medicine for MUD by blocking METH’s effects at VMAT2 and thus blocking METH-induced reward. The total market for a MUD therapeutic includes the roughly 35 million people worldwide who used METH in the last year. Initially, we will focus on the 2 million American users, specifically targeting the 0.5 million who sought treatment for MUD in 2019. We propose to scale-up the chemical synthesis of our potent, selective, and orally bioavailable next generation VMAT2 inhibitors and demonstrate their safety and efficacy in proof-of-concept and gold standard MUD animal models. The studies are staged based on resource demands to ensure rapid progression through key value inflection points while minimizing time and compound waste. Milestone 1: Prepare 100 mg of our top three inhibitors and test them in oral (PO) dosing studies using a proof-of-concept, rapid, lower cost MUD animal model (METH-sensitized locomotor activity). Prepare 1 gram of the most efficacious compound and test it in PO dose-response locomotor studies. Milestone 2: Prepare 10 grams of the top compound and conduct PO dose-response studies in the gold-standard MUD animal model (METH self-administration). Conduct 7-day repeated dosing experiments that demonstrate the top compound specifically decreases METH self-administration at an oral dose that has no significant effect on responding for food (specificity), and shows no tolerance across repeated dosing. Milestone 3: Determine whether the top compound decreases reinstatement (a model of relapse) and conduct pharmacokinetic and toxicological experiments to assess dose-linearity, acute and repeated dose toxicology, and carefully characterize brain penetrance. Successful completion of these studies will provide the necessary data to obtain outside investment to fund future IND-enabling studies