Abstract The goal of this project is to advance to the clinic an oral drug candidate to treat cocaine use disorder (CUD). An estimated 1.3M persons in the US have CUD, and more than 19K people die each year from overdoses involving cocaine. There are no approved drug treatments for cocaine abuse. Most individuals seeking treatment for CUD receive only psychosocial treatments that have high treatment dropout and relapse rates. Omeros developed a novel class of small molecules that selectively inhibit phosphodiesterase 7 (PDE7). Cocaine inhibits the reuptake of dopamine and other monoamine neurotransmitters, eliciting dopamine surges that is considered the primary mechanism through which cocaine evokes reward and initiates addiction. The PDE7 class of inhibitors is thought to restore the physiological dopamine phasic-to-tonic ratio that is altered by chronic exposure to drugs of abuse to reduce craving. The Omeros PDE7 inhibitor, OMS182399, is orally available with pharmacokinetics that supports once-daily dosing. OMS182399 reduces cocaine seeking in preclinical animal models of CUD and is safe and tolerable in healthy volunteers. The objective of this U01 project is to advance OMS182399 toward clinical trials for CUD by completing required preclinical interaction/ toxicology studies and then performing a clinical study to test the safety, tolerability, PK and preliminary efficacy of OMS182399 in persons with CUD. This project meets the goals of PAR-19-327 in that it accelerates the development of a novel oral drug candidate to treat CUD, for which there are no approved drugs. Aim 1 is to conduct IND-enabling interaction/toxicology studies of OMS182399 in rats and non-human primates. Although prior studies showed that OMS182399 is safe in rats, cynomolgus monkeys and people, the FDA requires drug interaction safety studies to ensure that it is safe in people with CUD who may use cocaine while in treatment. Aim 2 is to prepare and submit an IND application for the clinical trial proposed in Aim 3. Omeros will write and submit an investigational new drug (IND) application with the FDA to test OMS182399 for safety, tolerability, PK and preliminary efficacy during concurrent cocaine administration in persons with CUD. Aim 3 is to conduct a 2-week randomized, single dose, double blind, parallel group, in- patient clinical study to compare the safety, tolerability, PK and preliminary efficacy of oral OMS182399 to placebo (vehicle solution) in the treatment of adults with CUD who receive concurrent intravenous cocaine. Outcomes will be tolerability, safety, subjective preliminary efficacy measures and pharmacokinetics. Successful completion of this project will lead to a future Phase II clinical proof-of-concept study to advance OMS182399 toward FDA approval for CUD, which will have vast public health implications.

Project Narrative This project addresses the critical need for an effective treatment for cocaine use disorder, for which there are no approved drugs. Successful completion of this project will lead to the development of the first oral treatment for cocaine use disorder that reduces cocaine craving and addiction. Given the millions of people worldwide with CUD and the tens of thousands of cocaine-related deaths each year, this new treatment will have enormous public health benefits.