PROJECT SUMMARY Opioid use disorder (OUD) is a public health crisis. Current treatments show limited efficacy and fail to prevent relapse to drug use during attempted abstinence and drug-overdose are all too frequent. In collaboration with Eolas Therapeutics and the NIH Blueprint Neurotherapeutics Network, AstraZeneca has developed a potent and selective OX1 receptor antagonist (AZD4041/BPN-19302) with favorable drug-like physiochemical properties. Selective OX1 receptor antagonism by AZD4041 reduces the addiction-relevant behaviors in rodents and primates relevant to those commonly found in opioid use disorder patients. Specifically, AZD4041 reduced the motivation to consume opioids (or nicotine) and attenuated relapse-like drug seeking behaviors in laboratory animals while avoiding OX2 receptor-associated effects that could limit its potential as a novel treatment for OUD (e.g., sleep-promoting effects). AZD4041 did not have any non-specific behavioral effects in rodents or primates. AZD4041 shows favorable drug-like safety and pharmacokinetic (PK) profiles in rats and dogs. Based on these findings, we initiated a Phase 1 single ascending dose safety study in healthy volunteers (HV) (IND144437). To date in this trial, AZD4041 has shown a favorable PK and safety profile in human volunteers at exposures that encompass those predicted to have efficacy in OUD patients. In this proposal, during the UG3 phase, we will conduct the multiple ascending dose and respiratory safety assessments required to test the compound in OUD patients. Contingent upon the successful completion of the UG3 milestones, which include favorable safety, PK and respiratory depression profiles, we will advance to the UH3 phase, during which a proof of concept efficacy study will be conducted in patients suffering from OUD. Successful completion of the UH3 phase will deliver a selective OX1 receptor antagonist that is ready to advance to large-scale Phase 2 and 3 pivotal efficacy studies, based upon which AstraZeneca will make this promising and highly beneficial therapeutic widely available to OUD patients.

PROJECT NARRATIVE In collaboration with Eolas Therapeutics and the NIH Blueprint Neurotherapeutics Network, AstraZeneca developed AZD4041, a novel treatment for opioid use disorder. In preclinical studies, AZD4041 decreased the motivational properties of opioids and has proven safe in a single ascending dose Phase 1 clinical study. In this proposal, we will conduct the additional clinical safety and early proof-of-concept clinical studies necessary to advance AZD4041 to the clinic as a potentially transformative treatment for opioid use disorder.