Therapeutic Agent for Rapid Reversal of Methamphetamine Intoxication

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PROJECT SUMMARY This effort addresses the urgent need for a safe rapidly acting reversal agent for methamphetamine. Methamphetamine (meth) is the fastest growing drug of abuse in the US and has become a significant burden on the health care system, accounting for over 200,000 emergency room visits and nearly 10,000 deaths annually. As yet, no current therapeutics are available to treat meth intoxication. The long-term objective is to obtain FDA approval for sale and marketing of CS-1103, a small-molecule sequestrant, for treatment of acute meth intoxication. CS-1103 selectively binds meth in blood and dramatically accelerates its removal from the body by clearance into the urine, representing a new approach to reversal of drug effect: remove the cause and remove the effect. CS-1103 was well-tolerated and provided rapid long-lasting reversal of acute meth intoxication in pilot pre-clinical studies in rodent and non-human primate (NHP). It is proposed here to complete all necessary preclinical studies and Chemistry, Manufacturing and Controls (CMC) requirements to obtain Investigational New Drug (IND) approval from the FDA and then complete the first-in-human Phase I clinical trial for CS-1103. These significant milestones on the path to FDA approval will be achieved via completion of the following Aims: Aim 1 will establish a chemical process to manufacture CS-1103 under Current Good Manufacturing Practices (cGMP). A batch of cGMP material will be produced for pre-clinical and clinical trials. An injectable formulation will be developed and characterized. Aim 2 will establish the safety and efficacy profile of CS-1103 for reversal of methamphetamine intoxication in pre-clinical IND-enabling studies. Standard toxicology, pharmacokinetics, and pharmacodynamics studies will be conducted per FDA requirements. A detailed dose- ranging study in NHP will be performed to establish a safe initial human dose; the end-point will be the maximum safe/well tolerated dose. A pre-IND meeting will be held with FDA to set protocols and requirements. Aim 3 will establish a protocol for the first-in-human Phase I clinical trial of CS-1103. The protocol will include: estimate of number of subjects; description of safety exclusions and inclusion criteria; description of dosing plan including duration, dose, dose escalation, and schedule; all details critical to safety; dosing escalation rules and stopping criteria; and discussion of rationale for intended dose, duration, schedule, and route of administration. Expected outcome is filing of complete IND package with FDA. Aim 4 will establish the safety and dose level of CS-1103 in an FDA Phase I trial. This study will be conducted on healthy, drug-naive volunteers. Expected outcome is that CS-1103 will be safe at doses anticipated to be effective for reversal of acute methamphetamine intoxication.