Rodney Guy Scope: State Matching: Kentucky Network for Innovation & Commercialization (#KYNETIC#) Yr 4

Grants and Contracts Details


Our long-term goal is to develop the first FDA-approved medicine for methamphetamine (METH) use disorder (MUD). MUD is defined as compulsive, chronic, use of METH. The unmet need we are addressing is the lack of a medication for MUD. METH is a potent, highly-addictive, stimulant used by 2 million Americans annually that directly causes >15,000 deaths and an economic burden of $600 billion each year. MUD causes devastating health consequences for the individual (e.g., psychotic behavior, brain and heart damage, death) and harm to entire communities (e.g., crime, unemployment, child neglect or abuse, and other social harms). The total American market that we are targeting is the 0.5 million patients seeking MUD treatment among the 2 million American MUD patients. People who use METH experience 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 cellular uptake and reversing transport at the vesicular monoamine transporter-2 (VMAT2). Our solution is to develop the first medicine for MUD by blocking METH’s effects at VMAT2 and thus blocking METH-induced reward. In past cycles we selected the best of our potent, selective, and orally bioavailable VMAT2 inhibitors and demonstrated their safety and efficacy in MUD animal models. Herein, we propose work to complete qualification of the second animal species for toxicology testing required for an FDA IND and define any genotoxicity risk. Milestone 1 (Completed): Prepared our top 3 inhibitors and tested them using oral (PO) dosing in the METHsensitized rat locomotor model. Milestone 2 (Completed): Prepared 10 grams of UKY-21 and conducted PO dose-response studies in the rat METH self-administration assay to demonstrate a potent decrease of METH self-administration and that tolerance does not develop. Demonstrated high specificity relative to cocaine, but not to responding for food. De-risked potential side effects due to effects on food self-administration by showing lack of both appetite suppression and weight loss. Milestone 3 (Ongoing): Conducted formulation and metabolism studies and pharmacokinetic studies to show inhibitor levels in the brain and plasma and high potential for excellent human oral bioavailability. Conducted preliminary toxicology experiments at the therapeutic dose and demonstrated no evident toxicology. Initiated large scale synthesis (200 g) to support highdose toxicology and initiated a rat dose-ranging toxicology study to reach the regulatory limit. Initiated a reinstatement study in rats (a model of relapse). This work will complete by December 2022 (Cycle 5). In Cycle 6, we propose to identify all metabolites of UKY-21, explore genotoxicity risk, and qualify the dog as the second toxicology species. Successful completion of these studies will provide the necessary data to obtain outside investment of private and public funds for future IND-enabling studies.
Effective start/end date1/1/236/30/23


  • KY Economic Development Cab


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