Cooperative Agreement U01DA058548

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.