Clinical Development of a Therapeutic Agent for Rapid Reversal of Methamphetamine Intoxication - 1 PROJECT SUMMARY 2 There is an urgent need for a rapidly acting antidote for methamphetamine. Methamphetamine 3 (meth) is the fastest growing drug of abuse in the U.S., representing over 798,000 annual emergency department 4 (ED) visits, with deaths increasing 14-fold since 2015 (32,856 deaths in 2021 alone), yet no current therapeutics 5 are available to treat meth intoxication. Our objective is to obtain Federal Drug Administration (FDA) approval 6 for sale and marketing of CS-1103, a small-molecule sequestrant, to treat acute meth intoxication. CS-1103 7 selectively binds meth in blood and dramatically accelerates its removal from the body by clearance into the 8 urine, representing a new approach to the reversal of drug effect: remove the cause and remove the effect. 9 The indication for CS-1103 is to lower the level of methamphetamine in the human body. CS-1103 is 10 well-tolerated in rodent and canine and is highly effective in lowering the level of meth and rapidly reversing 11 its toxic effects in non-human primates. In our current U01 program (5U01DA053054-03), we have achieved 12 key milestones in current Good Manufacturing Practice (cGMP) manufacturing, Good Laboratory Practice (GLP) 13 toxicology and pharmacology studies, and held a pre-Investigational New Drug Application (IND) meeting with 14 the FDA. The current U01 will conclude with completion of the Phase 1a First-in-Human clinical trial. 15 We propose here to further develop CS-1103 by completing Phase 1b and Phase 2a clinical trials. These significant 16 milestones on the path to FDA approval will be achieved via completion of the following Aims: Aim 1 will 17 optimize manufacturing process and produce drug substance and drug product under cGMP. We 18 will produce drug substance and drug product that meet FDA requirements and generate a CMC document. 19 Expected outcome is 100 kg of CS-1103 and 5000 vials of drug product. Aim 2 will demonstrate the safety 20 and tolerability of CS-1103 in the presence of methamphetamine in a Phase 1b clinical trial. The 21 Phase 1b trial is a randomized, double-blinded, placebo-controlled 2-period crossover clinical study to evaluate 22 safety, tolerability, and PK of CS-1103 following a single IV dose after an IV dose of meth in 10 individuals with 23 meth use disorder not seeking treatment. Expected outcome is that CS-1103 is safe, and we can obtain FDA 24 approval to proceed to Phase 2a. Aim 3 will determine dosing requirements for CS-1103 in a Phase 25 2a clinical trial. The Phase 2a trial is an open-label, placebo-controlled, dose range-finding clinical study to 26 evaluate efficacy and dose-response of CS-1103. Single IV dose of CS-1103 will be administered after an IV dose 27 of meth in 64 individuals with meth use disorder not seeking treatment. Objectives are to: 1) establish dose 28 response of CS-1103 to remove meth from the body by quantification of meth in plasma and urine, 2) evaluate 29 efficacy of CS-1103 vs. time after administration of meth, and 3) select CS-1103 dose for Phase 2b/Phase 3 trials. 30 Expected outcome is FDA approval to proceed to the pivotal Phase 2b/Phase 3 trials.
