Cooperative Agreement UG3DA059286

A THERAPEUTIC AGENT TO LOWER THE LEVEL OF SYNTHETIC OPIOIDS IN THE BODY - 1 PROJECT SUMMARY 2 THERE IS AN URGENT NEED FOR A THERAPEUTIC THAT RAPIDLY DEACTIVATES AND REMOVES FENTANYL FROM 3 THE BODY. AS STATED BY DR. NORA VOLKOW, "DEATHS FROM FENTANYL ARE INCREASING IN SPITE OF NALOXONE, AND OVERDOSE 4 REQUIRES MULTIPLE NALOXONE DOSES." THIS IS A NATIONWIDE CRISIS, WITH OVER 73,000 OVERDOSE DEATHS ANNUALLY, AND 5 OVER 3M PEOPLE LIVING WITH OPIOID USE DISORDER. NALOXONE BLOCKS MU-OPIOID RECEPTORS FOR A SHORT PERIOD OF TIME 6 WITHOUT AFFECTING THE LEVEL OF FENTANYL IN THE BODY, WHICH CAN RESULT IN RENARCOTIZATION. A SINGLE-DOSE THERAPEUTIC 7 IS NEEDED THAT RESTORES RESPIRATION IMMEDIATELY AND REMOVES FENTANYL FROM THE BODY AT THE MAXIMUM POSSIBLE 8 RATE, THE GLOMERULAR FILTRATION RATE (GFR), ELIMINATING THE POSSIBILITY OF RENARCOTIZATION. 9 OUR THERAPEUTIC AGENT, CS-1103, WHICH WORKS DIFFERENTLY THAN NALOXONE, MEETS THIS NEED. AFTER 10 INJECTION, CS-1103 BINDS TO FENTANYL IN THE BLOODSTREAM, RAPIDLY REVERSING ITS EFFECTS, AND DRAMATICALLY INCREASES 11 THE RATE OF FENTANYL CLEARANCE INTO URINE TO NEAR THE GFR. IN SMALL AND LARGE ANIMAL MODELS, WE HAVE 12 DEMONSTRATED THAT CS-1103 IS EFFECTIVE AGAINST SYNTHETIC OPIOIDS, RANGING FROM FENTANYL TO CARFENTANIL, RESTORING 13 RESPIRATION IN 2-3 MIN, REVERSING MUSCLE RIGIDITY IN 1 MIN, PREVENTING RENARCOTIZATION AFTER A LETHAL DOSE OF 14 CARFENTANIL, AND RAPIDLY LOWERING OPIOID LEVELS IN THE BODY. FURTHERMORE, CS-1103 CAUSES MILDER OPIOID 15 WITHDRAWAL COMPARED TO NALOXONE, AND DOES NOT INTERFERE WITH THE ACTIVITY OF NALOXONE. 16 WE ARE CURRENTLY DEVELOPING IV CS-1103 TO TREAT ACUTE INTOXICATION CAUSED BY DRUGS OF ABUSE INCLUDING 17 METHAMPHETAMINE. WE HAVE COMPLETED ALL REQUIRED NONCLINICAL STUDIES AND ANTICIPATE COMPLETION OF THE FIRST- 18 IN-HUMAN PHASE 1A CLINICAL TRIAL IN MID-2023. BASED ON RESULTS TO DATE, WE BELIEVE THAT PHASE 1A HAS A HIGH 19 PROBABILITY OF SUCCESS, AS CS-1103: (1) IS A SINGLE USE DRUG; (2) HAS AN EXCELLENT SAFETY PROFILE IN GLP STUDIES IN 20 RAT AND CANINE WITH RAPID CLEARANCE, AT DOSES 500X THE EXPECTED HUMAN THERAPEUTIC DOSE, SIMILAR TO THE 21 SEQUESTRANTS BRIDION AND CAPTISOL; AND (3) IS HIGHLY EFFECTIVE AND SAFE IN NON-HUMAN PRIMATES (NHP). 22 OUR PRIMARY GOAL IN THIS EFFORT IS TO DEVELOP AN IV FORMULATION OF CS-1103 FOR TREATMENT OF FENTANYL INTOXICATION 23 AND OBTAIN FDA APPROVAL. THIS WILL BE ACHIEVED VIA COMPLETION OF SPECIFIC AIMS 1-5 (UG3) AND 6-9 (UH3): 24 AIM 1 WILL COMPLETE A PRE-IND MEETING WITH FDA FOR IV CS-1103. AIM 2 WILL ESTABLISH THE SAFETY/TOXICOLOGY 25 PROFILE OF IV CS-1103 IN THE PRESENCE OF FENTANYL, IN RAT. AIM 3 WILL DEMONSTRATE THAT IV CS-1103 LOWERS THE LEVEL 26 OF FENTANYL IN A DOSE-DEPENDENT MANNER, IN RAT. AIM 4 WILL SUBMIT IND FOR IV CS-1103. AIM 5 WILL ESTABLISH THE 27 SAFETY/DOSE LEVEL OF IV CS-1103, IN THE PRESENCE OF FENTANYL, IN A PHASE 1B CLINICAL TRIAL. AIM 6 WILL DETERMINE 28 EFFECTIVE CLINICAL DOSE OF CS-1103 TO TREAT FENTANYL INTOXICATION IN A PHASE 2A CLINICAL TRIAL. AIM 7 WILL DEMONSTRATE 29 EFFICACY OF IV CS-1103 IN LOWERING THE LEVEL OF FENTANYL AND RESTORING RESPIRATION, IN A PIVOTAL PHASE 2B TRIAL. AIM 30 8 WILL SUBMIT NDA FOR IV CS-1103. AIM 9 WILL PERFORM IND-ENABLING STUDIES FOR CS-1103 SUITABLE FOR IM 31 INJECTION AND/OR IN ADMINISTRATION. AIM 9 WILL BE COMPLETED USING OUR OWN FUNDS, TO EXPAND USE TO FIELD SETTINGS.