Specific Aims: Illicit and prescribed stimulants provide major challenges in the US. In a recent year, almost 7.5 million Americans reported cocaine or methamphetamine use. More than 32 million amphetamine prescriptions were written for disorders including attention deficit hyperactivity disorder and narcolepsy. 1.75 million Americans reported cocaine or amphetamine or use disorders. There were more than 212,000 admissions to stimulant use disorder treatment programs. A “fourth wave” of US drug overdose deaths includes many individuals who use stimulants. However, individuals who seek to quit stimulant use have no pharmacological treatment approved by FDA. Medication development portfolios aimed at treating stimulant use disorders should include new drugs acting at novel targets that are as well-supported as possible, a priori, by human and other data. Robust human, mouse model and pharmacologic data now support PTPRD (receptor type protein tyrosine phosphatase D) as a novel target for treatment of stimulant use disorders and, perhaps, their prevention. Human PTPRD genomic variants are associated with: a) vulnerability to develop a stimulant use disorder, b) the extent of reward from stimulant administration and c) levels of brain PTPRD expression. Mice that express less PTPRD display less reward from stimulants. We have characterized an initial PTPRD phosphatase inhibitor, 7-BIA, and a more potent/selective congener, NHB1109. NHB1109 features support its development as a medication. We can now synthesize NHB1109 readily from commercially-available precursors. NHB1109 is selective. It displays greater potency at PTPRD than at most other tyrosine phosphatases. It has no significant activity in EUROFINS screens of targets of current drugs. NHB1109 is bioavailable in rats after oral dosing. It is relatively stable. It has intellectual property protection. It substantially reduces cocaine conditioned place preference in wildtype mice, but not in PTPRD knockouts. Acute or repeated NHB1109 doses up to 300 mg/kg provide no toxicity. Mice survive 2,000 mg/kg gavage doses, but develop a dose-limiting toxicity, ileus. This exciting identification of NHB1109 as a novel, potent, selective small molecule PTPRD phosphatase inhibitor with proof of in vivo pharmacological activity in reducing stimulant reward and a reasonable therapeutic index leads us to seek Avant Garde support. We will move NHB1109 forward through IND-enabling work, initial use in humans and completion of phase I human studies. We will continue studies of backup compounds should NHB 1109 display unanticipated limitations. We will complete antecedents to FDA IND approval including metabolic, two-species toxicity and carcinogenicity screens. We will receive IND approval and complete first in human, ascending dose and repeated dose research volunteer studies, including those with amphetamine challenge doses. We will advance development of NHB1109 to address unmet needs in treating devastating stimulant use disorders via these UG3 and UH3 Aims: UG3 Aim 1: To develop pharmacologic and toxicologic evidence in vitro and in two species that robustly support an IND application for use of NHB1109 (or backup compounds if required) in normal human research volunteers. UG3 Aim 2: To develop pharmacologic and toxicologic evidence in two species that robustly support an IND application for use of challenge doses of stimulants along with NHB1109 in normal human research volunteers. Milestones for the end of the UG3 support period: Filing a successful FDA IND application for NHB1109 human use without, then with, amphetamine challenge doses. UH3 Aim 1: To complete good manufacturing practices syntheses, formulations for human use, ascending dose and repeated dose studies with monitoring of toxicities and pharmacokinetic/pharmacodynamic properties in normal human research volunteers. UH3 Aim 2: To complete repeated dose studies with challenge doses of amphetamine in normal human research volunteers with monitoring of toxicities and pharmacokinetic/pharmacodynamic properties in normal human research volunteers. To complete antecedents to longer use in humans. Milestones for the end of the UH3 period of support: Robust data on NHB1109 tolerability, toxicities and pharmacokinetics/pharmacodynamics in humans, some of whom also receive challenge doses of amphetamine. Initial pilot data for stimulant reward in NHB1109- vs placebo-treated research volunteers. These data will set the stage for subsequent and more definitive phase II work to test NHB1109 effects on reward from amphetamine and ability to maintain abstinence in treatment-seeking individuals with stimulant use disorders. The data will enable subsequent use in prevention studies. They will provide strong bases for further development of NHB1109 with continuing NIDA and pharma partnerships.

Narrative/relevance: Human and mouse studies now identify roles for PTPRD variation in drug reward, addiction and ability to quit, while PTPRD phosphatase inhibitors reduce reward from stimulants. We have synthesized and tested 70 novel PTPRD ligands, identifying NHB1109's potency, selectivity, oral bioavailability and efficacy in reducing stimulant reward in rodents. We will advance NHB1109 to and through phase I testing in humans, allowing subsequent human tests that will validate NHB1109 as a novel agent for treatment of stimulant use disorders and, perhaps, their prevention.