DESCRIPTION (provided by applicant): Long Term Goal: Regulatory approval and commercialization of EMB-001 for cocaine use disorder (CUD). Problem/Unmet Need: In 2013, the US had 1.5 million current cocaine users aged 12 or older (1) representing 12% of the illicit drug use population; illicit drug use cost the US over $193 billion in 2007 (4). Unfortunately, no medications are approved for the treatment of CUD and very few are in clinical trials. Thus, while CUD remains a significant problem for our nation, treatment options are lacking. Embera NeuroTherapeutics' Solution: Embera is developing EMB-001 for the treatment of moderate- severe CUD. Embera's approach builds on 20+ years of NIH-funded research into the role of stress and the hypothalamo-pituitary-adrenal axis in addiction by Dr. Nicholas Goeders (Embera's scientific founder). EMB-001 is a combination of two FDA-approved but mechanistically distinct stress response inhibitors: the cortisol synthesis inhibitor metyrapone (MET) and the benzodiazepine oxazepam (OX). Doses of MET and OX that failed to reduce cocaine self-administration in rats produced a significant reduction in cocaine self- administration when co-administered. Results from a pilot clinical study suggested that co-administration of MET and OX could reduce cocaine use by cocaine-dependent human subjects. This grant application proposes work to advance EMB-001 through a Phase 2 proof-of-concept study as a treatment for CUD. Specific Aims: Specific Aim 1: Complete an FDA-mandated Phase 1b safety clinical trial to assess for possible interactions between EMB-001 and cocaine. Specific Aim 2: Manufacture EMB-001 drug product needed for a Phase 2 clinical trial (SA3). Specific Aim 3: Complete a Phase 2 clinical trial of safety and efficacy of EMB-001 in CUD. Further development of EMB-001 for the treatment of CUD will be warranted if the abstinence rate in either of the EMB-001 arms in the Phase 2 trial is statistically superior to placebo and safety is acceptable. Given the lack of approved products for CUD, the potential for FDA approval with a single positive Phase 3 study and supportive data exists, as well as the strong possibility of fast track, breakthrough and/or priority review designations to expedite approval. Strength of this application is the sound rationale for efficacy, as well as preliminary efficacy data in animals and humans. The ongoing Phase 1 study to be completed in September 2015 is expected to greatly mitigate safety concerns, which may be the greatest risk to the program, prior to any NIDA expenditure under this grant.

PUBLIC HEALTH RELEVANCE In 2013, the US had 1.5 million current cocaine users aged 12 or older, (1) representing 12% of the illicit drug use population; illicit drug use cost the US ove $193 billion in 2007, on par with the costs of diabetes (4). Embera's EMB-001 combines two FDA-approved agents that target the stress response associated with substance use disorders via two different mechanisms, and has the potential to be the first approved treatment for cocaine use disorder (CUD). This U01 grant application, in conjunction with substantial private funding, is designed to advance EMB-001 through a proof-of-concept Phase 2 clinical trial in subjects with CUD, with the ultimate goal of providing to patients an effective outpatient treatment option and addressing the significant impact on families and costs associated with this disease.