Phase I Amount
$1,393,153
While opioids are the most effective pain-killers, their use for pain management often develops into an opioid use disorder (OUD). Death from an opioid overdose (by 115 Americans every day) is in most cases caused by opioid-induced respiratory depression (OIRD). A new opioid formulation that retains the desired analgesic properties but lacks deadly respiratory and unwanted addictive effects, remains an unmet clinical need. Quivive Pharma is developing the first immediate-release opioid formulation with both prophylactic respiratory depression protection and abuse-deterrent properties, which contains the generic opioid Hydrocodone (HC), combined with a sub-therapeutic dose of the FDA-approved respiratory stimulant Doxapram (DOX). The unique formulation is designed to deliver effective pain relief with decreased risk of OIRD. In addition to improving safety, DOX serves as an abuse-deterrent by producing unpleasant, but not dangerous, anxiogenic effects in case of abuse by overconsumption, while having no negative impact on opioid analgia in the therapeutic range. Quivive Pharma has completed in vivo efficacy studies as well as extensive preclinical safety and pharmacokinetics (PK) studies following a Pre-IND meeting with FDA. No adverse clinical signs have been noted in rats, dogs, or monkeys following oral treatment with DOX. The promising results achieved so far support this direct access to an SBIR Phase II application to perform a first in human validation of the proposed approach. In particular, a single ascending dose (SAD) proof-of-concept clinical study of DOX co- administered with HC will be performed with 35 healthy, non-dependent, recreational opioid users in collaboration with the Cleveland Clinic. This study will assess for the first time the safety, tolerability, and pharmacodynamics of the combination drug in human subjects. The safety evaluation (Aim 1) will include the monitoring of Adverse Events (AEs) and vital signs. Also, serum chemistry, hematology, and urinalysis will be performed together with physical examinations and electrocardiogram monitoring. Finally, patients enrolled will complete the Columbia Suicide Severity Rating Scale questionnaire to assess suicidality. A PK assessment (Aim 2) will demonstrate that Plasma PK of HC is unaffected by the combination with DOX, the exposure of oral DOX increases with the dose administered, and the time to reach the maximum concentration of DOX is consistent with that of HC. The pharmacodynamics assessments (including evaluation of respiratory function, drug liking, and pupil size) will enable the identification of the optimal DOX dose to safely counteract HC-induced respiratory depression (Aim 3). After the successful completion of this SBIR Phase II project, a Multiple Ascending Dose Study of DOX co-administered with HC in healthy, non- dependent, recreational opioid users will be performed to ensure that the HC/DOX ratios identified in this study are well tolerated in human subjects following repeated administration.
Public Health Relevance Statement: PROJECT NARRATIVE Every day, 115 Americans die from opioid-induced respiratory depression as a result of an opioid overdose. A new opioid formulation that retains the desired analgesic properties but lacks deadly respiratory and unwanted addictive effects would support the current national opioid crisis. Quivive Pharma is developing the first immediate-release opioid formulation, containing the generic opioid Hydrocodone and a sub-therapeutic dose of the FDA-approved respiratory stimulant Doxapram, which delivers both prophylactic respiratory depression protection and abuse-deterrent properties.
Project Terms: Americas; 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; Barbiturates; Benzodiazepines; Benzodiazepine Compounds; Body Temperature; Buprenorphine; Carbon Dioxide; CO2; Carbonic Anhydride; Chemistry; Clinical Research; Clinical Study; Hydromorphone; Dihydromorphinone; Dilaudid; Dilaudid HP; Dimorphone; Hydromorphon; Hydrostat; Hymorphan; Laudacon; Laudicon; Novolauden; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Doxapram; Drug Combinations; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Electrocardiogram; ECG; EKG; Electrocardiography; Health; Hematology; Hydrocodone; Dihydrocodeinone; Hycodan; Hycon; Medicine; Methadone; Adanon; Althose; Dolophine; Methadose; Monkeys; opiate abuse; opiate drug abuse; opioid drug abuse; opioid abuse; Painful; Pain; Patients; Pharmacokinetics; Drug Kinetics; Medical Inspection; Physical Examination; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Publishing; Pupil; Questionnaires; Common Rat Strains; Rat; Rats Mammals; Rattus; Relapse; respiratory mechanism; Respiration; respiratory function; Respiratory physiology; Risk; Safety; fatal attempt; fatal suicide; intent to die; suicidality; Suicide; Technology; Time; Urinalysis; Generations; Measures; Price; pricing; Businesses; depressive symptoms; Emotional Depression; depression symptom; depressive; Mediating; Blood gas; human subject; improved; Chronic; Clinical; Phase; Ensure; Evaluation; Blood Serum; Serum; Visual; Respiratory Depression; depressed breathing; depression of breathing; Ventilatory Depression; Opiates; Opioid; analog; Collaborations; Respiratory Stimulants; Therapeutic; Pulse; Physiologic pulse; pupillary light reflex; pupillary reflex; Pupil light reflex; Diastolic Pressure; Diastolic blood pressure; Severities; Oral; Clinic; prophylactic; respiratory; meetings; American; Prevention; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; Pharmacodynamics; Sampling; Property; preventing; prevent; Legal; Address; Dose; NIDA; National Institute on Drug Abuse; National Institute of Drug Abuse; in vivo; Enrollment; enroll; Funding Opportunities; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Validation; Monitor; design; designing; Outcome; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; FDA approved; preclinical safety; pre-clinical safety; phase 2 study; phase II study; prescription opioid; licit opioid; opiate medication; opioid medication; prescribed opiate; prescribed opioid; prescription opiate; opioid use disorder; opiate use disorder; Formulation; efficacy study; opioid epidemic; opiate crisis; opioid crisis; opioid overdose; opiate overdose; opiate related overdose; opioid drug overdose; opioid induced overdose; opioid intoxication; opioid medication overdose; opioid poisoning; opioid related overdose; opioid toxicity; opioid mortality; opiate deaths; opiate mortality; opioid deaths; opioid overdose death; opioid related death; pain relief; relieve pain; opioid user; Opiate user; Opioid drug user; PWUO; people who use opioids; persons who use opioids; Opioid replacement therapy; Opiate replacement therapy; Opiate substitution therapy; Opiate substitution treatment; Opioid maintenance therapy; Opioid maintenance treatment; Opioid replacement treatment; Opioid substitution therapy; Opioid substitution treatment; first-in-human; first in man; safety assessment; mortality risk; death risk; adverse event monitoring; ventilation; Helping to End Addiction Long-term; HEAL Initiative; Helping End Addiction Long-term; Helping End Addiction Longterm; Helping to End Addiction Longterm
