PROJECT SUMMARY/ABSTRACT In the United States, recreational cocaine use continues to represent a significant public health concern. In 2018, an estimated 5.5 million people recreationally self-administered cocaine by insufflation, inhalation, or injection. Many of these individuals are at risk of succumbing to acute cocaine intoxication, a condition in which life-threatening cardiovascular and neurological symptoms are experienced. The current standard of care consists primarily of supportive acute care directed at the specific symptoms expressed by individual patients. Despite the significant unmet medical need, no pharmacotherapies are approved for treating cocaine toxicity in the acute care setting. The development of a treatment that addresses the root cause of cocaine intoxication (i.e., circulating cocaine and its active metabolites), would allow clinicians to provide a potentially faster and safer intervention in the acute care setting. Furthermore, by directly removing the toxic offending agent from the systemic circulation, such a treatment could more effectively and comprehensively address the multiple medical risks and sequelae of cocaine intoxication. To fulfill this unmet need, Tonix is developing TNX-1300, a mutant recombinant bacterial cocaine esterase (CocE) that has been shown in a pilot Phase 2 clinical laboratory study to metabolize and reduce by ~90% systemic cocaine levels within 2 minutes of a single intravenous administration. In this U01 application, Tonix proposes to advance the TNX-1300 development program via the following specific aims: 1. conduct a Phase 2 proof-of-concept randomized trial of patients presenting to emergency department sites in a state of cocaine intoxication; 2. optimize CMC production of a GMP drug product batch for use in Phase 2 and 3 trials, including a lyophilization cycle; 3. facilitate completion of regulatory milestones, in particular the preparation and execution of an End of Phase 2 meeting with FDA; and 4. a commercialization program with key opinion leader development, target product profile testing, and market research with physicians, payers and patients, to inform the design of a future Phase 3 that will be fully developed and designed in Year 3 of this program. Successfully achieving the milestones outlined in this proposal would substantially advance this novel treatment approach to the stage of Phase 3 pivotal testing requisite for the New Drug Application and marketing approval.

PROJECT NARRATIVE The proposed project involves the development of a promising and novel candidate medication, TNX-1300, for the treatment of acute, life-threatening cocaine intoxication in an emergency department setting. TNX-1300 is a recombinant cocaine esterase derived from a bacterial enzyme, and which rapidly and completely breaks down cocaine in the blood, thereby reducing overall potential for cocaine toxicity. Given the prevalence of the severe adverse cardiovascular and neurological consequences of cocaine intoxication, coupled with the cost burden it places on acute care facilities, there is significant unmet need for a treatment that can be administered immediately to rapidly terminate all adverse health effects of cocaine in patients presenting with cocaine intoxication.