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.
Public Health Relevance Statement: PROJECT NARRATIVE In collaboration with our academic co-founders and the NHLBI Catalyze program, Atelerix is developing Sudaxine as a novel treatment for OIRD in the peri-operative setting where there is a critical need for an agent that reverses respiratory depression while preserving anesthesia. Our early proof-of-concept studies show that Sudaxine: 1) reverses respiratory depression induced by opioids in mice, rats, and dogs, and 2) preserves opioid- induced analgesia while stimulating respiratory drive, also in rats, mice, and dogs. Building on these promising results, our goal in this Phase II program is to conduct the additional preclinical and IND-enabling studies necessary to advance Sudaxine to first in man clinical trials.
Project Terms: Adult; 21+ years old; Adult Human; adulthood; Pain management; Pain Control; Pain Therapy; pain treatment; Analgesics; Analgesic Agents; Analgesic Drugs; Analgesic Preparation; Anodynes; Antinociceptive Agents; Antinociceptive Drugs; pain killer; pain medication; pain reliever; painkiller; Opioid Analgesics; opiate analgesia; opiate analgesic; opiate pain medication; opiate pain reliever; opioid analgesia; opioid anesthetic; opioid pain medication; opioid pain reliever; opioid painkiller; Anesthesia procedures; Anesthesia; General Anesthesia; Animals; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Certification; Clinical Trials; Complication; Cystine; L-Cystine; Cytochrome P450; Cytochrome P-450; Cytochrome P-450 Enzyme System; Cytochrome P450 Family Gene; P450; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Equilibrium; balance; balance function; Esters; Foundations; Future; Goals; Gold; Grant; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Healthcare Systems; Health Care Systems; Health Personnel; Health Care Providers; Healthcare Providers; Healthcare worker; health care personnel; health care worker; health provider; health workforce; healthcare personnel; medical personnel; treatment provider; Hospitals; Human; Modern Man; In Vitro; Institutes; Intubation; Isoenzymes; Isozymes; Lead; Pb element; heavy metal Pb; heavy metal lead; Metabolism; Intermediary Metabolism; Metabolic Processes; Methods; Liver Microsomes; Morbidity - disease rate; Morbidity; mortality; Mus; Mice; Mice Mammals; Murine; Naloxone; Patient Monitoring; Patients; Pharmacology; Common Rat Strains; Rat; Rats Mammals; Rattus; Opiate Receptors; Opioid Receptor; Safety; Signal Pathway; Testing; Time; Toxicology; Work; Caring; Perioperative Care; Titrations; analytical method; Clinical; Phase; Hepatic Cells; Hepatic Parenchymal Cell; Liver Cells; Hepatocyte; Respiratory Depression; depressed breathing; depression of breathing; Ventilatory Depression; Opiates; Opioid; Collaborations; Toxicokinetics; No-Observed-Effect Levels; NOEL; Respiratory Stimulants; Therapeutic; sedation; Sedation procedure; Absence of sensibility to pain; Feels no pain; No sensitivity to pain; analgesia; Absence of pain sensation; Life; programs; respiratory; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Operative Surgical Procedures; experience; genotoxicity; Toxicities; Toxic effect; Pharmacology and Toxicology; novel; Drug Interactions; Reporting; drug development; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; drug discovery; CP34; CYP3; CYP3A; CYP3A4; Cytochrome P450 3A4; Cytochrome P450, Subfamily IIIA, Polypeptide 4; Cytochrome P450PCN1; FAMILY III P450; Glucocorticoid-Inducible P450; Nifedipine Oxidase; P450C3; P450PCN1; Steroid-Inducible P450- III; CYP3A4 gene; Preparedness; Readiness; small molecule; Aromatic Compound-Inducible Cytochrome P-450; CP12; CYP 1A2; CYP1A2; Caffeine Demethylase; Cytochrome P-450 CYP1A2; Cytochrome P-450 LM4; Cytochrome P-450d; Cytochrome P450 1A2; Dioxin-Inducible P3-450; P(3)450; P3-450; P450 4; P450 Form 4; P450 orm 4; P450-P3; Phenacetin O-Dealkylase; CYP1A2 gene; CYP2B6; Cytochrome P450, Phenobarbital-Inducible; Cytochrome P450, Subfamily IIB, Polypeptide 6; CYP2B6 gene; Address; Dose; Data; pre-clinical testing; Preclinical Testing; in vivo; Perioperative; Monitor; Molecular; Process; Development; developmental; pre-clinical; preclinical; preclinical study; pre-clinical study; National Heart, Lung, and Blood Institute; NHLBI; cost; design; designing; Outcome; scale up; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; standard of care; safety testing; efficacy testing; Regimen; operation; Formulation; small molecule therapeutics; preclinical development; pre-clinical development; Opioid Antagonist; Opiate Antagonist; Opiate receptor antagonist; Opioid receptor antagonist; opioid epidemic; opiate crisis; opioid crisis; pain relief; relieve pain; preservation; first-in-human; first in man; pharmacokinetics and pharmacodynamics; PK/PD
