Scope: Jared Hammill:State Matching: Kentucky Network for Innovation & Commercialization (#KYNETIC#) Yr 2

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 cognitive 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 on 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 brain caused by increased extracellular concentrations of dopamine (DA, a neurotransmitter). METH increases extracellular DA by first 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 2 million Americans and as many as 35 million people worldwide who used METH in the last year. Initially, we will focus on the 0.5 million Americans who sought treatment for MUD in 2019. We propose to scale-up the chemical synthesis of our potent and selective next generation VMAT2 inhibitors and demonstrate their safety and efficacy in proof-of-concept and pivotal studies using MUD animal models. These studies are staged based on resource demands to ensure rapid progression through key value inflection points. Milestone 1: Prepare 100 mg of our top three next generation lead compounds for proof-of-concept subcutaneous (SC) dosing efficacy studies using a MUD animal model (METH-sensitized locomotor activity). Milestone 2: Prepare 1 gram of the most efficacious compound for pivotal SC dose-response locomotor studies to demonstrate a specific decrease in METH-sensitized locomotor activity compared to a saline control. Separate pharmacokinetic studies will determine brain penetrance. Milestone 3: Prepare 10 grams of the top compound, conduct proof-of-concept SC dose- response efficacy studies in the gold-standard MUD animal model (METH self-administration), and specificity studies (responding for food). Milestone 4: Conduct pivotal 7-day repeated oral dosing studies on METH self-administration to evaluate the development of tolerance, reinstatement (relapse), and specificity (responding for food). Successful completion of these studies will provide the necessary data to obtain outside investment to fund future IND-enabling studies.