Project Grant R44HL164201

DEVELOPMENT OF SUDAXINE FOR THE TREATMENT OF OPIOID INDUCED RESPIRATORY DEPRESSION (OIRD) IN THE PERI-OPERATIVE HOSPITAL SETTING - PROJECT SUMMARY OPIOID-INDUCED RESPIRATORY DEPRESSION (OIRD) IS A POTENTIALLY FATAL COMPLICATION OF TREATMENT WITH OPIOIDS. IN THE PERI-OPERATIVE SETTING, OPIOIDS ARE WIDELY USED TO PROVIDE ANALGESIA AND SUPPLEMENT SEDATION DURING GENERAL ANESTHESIA OR MONITORED ANESTHESIA CARE. HOWEVER, OVER 46% OF SURGICAL PATIENTS RECEIVING OPIOIDS WILL EXPERIENCE OIRD RANGING FROM PROBLEMATIC TO LIFE-THREATENING. THE USE OF NALOXONE, AN OPIOID RECEPTOR ANTAGONIST THAT IS EFFECTIVE AT REVERSING OIRD, IS LIMITED IN THE PERI-OPERATIVE SETTING BECAUSE IT ALSO REVERSES THE PAIN RELIEF PROVIDED BY THE OPIOID. THUS, THERE REMAINS A CRITICAL NEED TO DEVELOP A THERAPEUTIC THAT CAN REVERSE OIRD WHILE MAINTAINING THE ANALGESIC EFFICACY OF CLASSICAL OPIOID ANALGESICS. ATELERIX LIFE SCIENCES' SOLUTION TO OIRD IN THE PERI-OPERATIVE CARE SETTING IS SUDAXINE, A NOVEL SMALL MOLECULE THERAPEUTIC THAT SELECTIVELY TARGETS SIGNALING PATHWAYS DOWNSTREAM OF ACTIVATED OPIOID RECEPTORS TO ALLEVIATE OIRD WITHOUT REVERSING ANALGESIA. WE HAVE ALREADY PROGRESSED SUDAXINE THROUGH EARLY PRECLINICAL STUDIES INCLUDING IN VIVO EFFICACY AND SAFETY TESTING, AND PHARMACODYNAMIC AND PHARMACOKINETIC TESTING. OUR RESULTS HAVE DEMONSTRATED THAT SUDAXINE IS SAFE (NO ADVERSE CARDIORESPIRATORY OR THERMOREGULATORY EFFECTS) AND THAT THIS TARGETED APPROACH LEADS TO REVERSAL OF OIRD WITHOUT BLUNTING ANALGESIA. THUS, SUDAXINE HAS THE POTENTIAL TO DISRUPT THE CURRENT STANDARD OF CARE FOR OIRD IN THE PERI-OPERATIVE SETTING. IN THIS DIRECT TO PHASE II PROJECT, ATELERIX WILL FOCUS ON ADDITIONAL PRECLINICAL TESTING AND MANUFACTURING STEPS REQUIRED TO FACILITATE IND-SUBMISSION AND FUTURE CLINICAL TRIALS. THIS WILL BE ACCOMPLISHED THROUGH THE EXECUTION OF FOUR AIMS. IN AIM 1, WE WILL EVALUATE THE TOXICITY OF SUDAXINE BY CONDUCTING A NON-GLP SINGLE DOSE TOXICITY AND TOXICOKINETIC STUDY IN DOGS. IN AIM 2, WE WILL CONDUCT A DRUG-DRUG INTERACTION SCREEN. IN AIM 3, WE WILL CONDUCT IND-ENABLING GLP GENOTOXICITY, SAFETY PHARMACOLOGY, AND TOXICOLOGY STUDIES. AIM 4 WILL FOCUS ON MANUFACTURING GMP-GRADE SUDAXINE DRUG SUBSTANCE. A SUCCESSFUL OUTCOME OF THE PROJECT WILL LEAD TO A DISRUPTIVE AND GREATLY NEEDED THERAPEUTIC SOLUTION FOR THE TREATMENT OF OIRD IN THE PERI-OPERATIVE HOSPITAL SETTING. THE PROPOSED WORK WILL LAY THE FOUNDATION FOR THE DEVELOPMENT OF ADDITIONAL NOVEL RESPIRATORY STIMULANTS THAT CAN HAVE BROADER APPLICATIONS BEYOND PERI-OPERATIVE CARE AND ULTIMATELY UNLEASH THE GREATER POTENTIAL OF SUDAXINE TO TARGET UNMET NEEDS ASSOCIATED WITH THE OPIOID CRISIS.