Project Grant R44DA050386

IND-ENABLING DEVELOPMENT OF A LONG-DURATION ANTAGONIST TO TREAT OPIOID OVERDOSE - PROJECT SUMMARY / ABSTRACT MORE THAN 80,000 AMERICANS DIED IN 2021 FROM FENTANYL AND OTHER HIGH-POTENCY OPIOIDS. THE EMERGENCE OF ILLICIT, HIGHLY POTENT SYNTHETIC OPIOIDS SUCH AS FENTANYL IS A KEY CONTRIBUTING FACTOR TO THE RECENT SPIKE IN OPIOID- RELATED MORTALITY, INCREASING TEN-FOLD SINCE 2016. WHILE THE MU OPIOID RECEPTOR (MOR) ANTAGONIST NALOXONE HAS PROVEN INVALUABLE AS AN OPIOID OVERDOSE ANTIDOTE, NALOXONE SUFFERS FROM A VERY SHORT DURATION OF ACTION (HALF- LIFE ~1 HOUR) AND IS LESS EFFECTIVE AGAINST NEWER, LONGER-ACTING OPIOIDS, INCLUDING FENTANYL (HALF-LIFE ~7-10 HOURS). THIS LEADS TO A HIGHLY LETHAL AND INCREASINGLY PREVALENT PHENOMENON KNOWN AS "RENARCOTIZATION," WHEREBY AN OVERDOSE PATIENT REVIVED WITH NALOXONE RE-ENTERS AN OVERDOSE STATE FROM RESIDUAL FENTANYL IN THE BODY. TO COUNTER RENARCOTIZATION, NALOXONE MUST BE GIVEN REPEATEDLY AND AT SIGNIFICANTLY HIGHER DOSES. WHILE USUALLY ACHIEVABLE IN A HOSPITAL, RENARCOTIZATION IS OFTEN NOT RECOGNIZED OR MONITORED FOR OUTSIDE OF A MEDICAL SETTING AND MAY LEAD TO UNEXPECTED DEATH. A CRITICAL, UNMET NEED EXISTS TO DEVELOP A LONG-ACTING MOR ANTAGONIST FORMULATION THAT PREVENTS RENARCOTIZATION BY PROVIDING 12-24 HOURS OF PROTECTION TO ALLOW OPIOID LEVELS TO DROP BELOW DANGEROUS LEVELS. THE OBJECTIVE OF THIS PROJECT IS TO ADVANCE DEVELOPMENT OF CP216, A NOVEL, LONG-ACTING NALOXONE FORMULATION THAT UTILIZES AN INNOVATIVE DESIGN TO ADDRESS BOTH PRIMARY AND SECONDARY OVERDOSE THROUGH A COMBINATION OF FREE FORM NALOXONE FOR IMMEDIATE EFFECT AND MICROENCAPSULATED NALOXONE FOR SUSTAINED PROTECTION. THIS NEW FORMULATION WILL BE ESPECIALLY USEFUL IN RURAL AREAS, WHERE ACCESS TO EMERGENCY MEDICAL SERVICES IS OFTEN DELAYED, OR FOR WARFIGHTERS POISONED BY WEAPONIZED OPIOIDS THAT NEED SUSTAINED PROTECTION WHILE TRANSPORTED TO DEFINITIVE MEDICAL CARE. OTHER ATTEMPTS TO ADDRESS RENARCOTIZATION USING HIGH OR FREQUENT DOSES OF NALOXONE OR NALMEFENE HAVE LIMITED PROTECTION FOR HIGH-POTENCY OPIOIDS AND CAN INDUCE PRECIPITATED OPIOID WITHDRAWAL (POW) IN THOSE WITH OPIOID DEPENDENCE. POW IS A SEVERE AND POTENTIALLY LIFE-THREATENING CONDITION AND FOR THIS REASON CAUSES SOME OVERDOSE VICTIMS TO REFUSE CONTINUED NALOXONE TREATMENT AFTER RESCUE. STILL OTHER EFFORTS TO CHEMICALLY MODIFY NALOXONE ARE SUBJECT TO SIGNIFICANT REGULATORY AND TECHNICAL RISK. CONSEGNA'S DRUG (CP216) IS APPROVABLE THROUGH THE ACCELERATED 505(B)(2) REGULATORY PATHWAY AND IS, ACCORDING TO RECENT STUDIES, UNLIKELY TO INDUCE POW AND WOULD THEREFORE GAIN MORE ACCEPTANCE AMONG OVERDOSE PATIENTS. CONSEGNA BELIEVES THIS PROJECT WILL HAVE A POSITIVE IMPACT ON PUBLIC HEALTH BY LEADING TO THE FIRST SAFE AND EFFECTIVE PRODUCT TO COMPLETELY ADDRESS RENARCOTIZATION.