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.