Project Summary/Abstract More than 1.6 million individuals in the US meet criteria for an opioid use disorder, with millions more reporting use or misuse of opioid pain relievers in the past month. Along with an increase in opioid use disorders, a rise in opioid-related overdose deaths has occurred in the last decade. Chronic pain and opioid abuse are more prevalent than before constituting a public health crisis and exacting a heavy toll on patients, caregivers, physicians, and society. There is a current therapeutic challenge for managing opioid use, opioid withdrawal symptoms, chronic pain, and/or associated anxiety and depression. A severe need remains for alternative and safe therapeutic regimens that properly treat these conditions. We propose to develop a cannabinoid-opioid combination with opioid-sparing and synergistic analgesic effects to prevent opioid use disorder and overdose, addressing the current national opioid epidemic. BDH Pharma, LLC completed a proof-of-concept preclinical study of a fixed dose cannabinoid-opioid combination that demonstrated opioid-sparing and synergistic analgesic effects, with the combination providing greater analgesia in a rodent model of chronic pain than a standard dose of the opioid alone. Building on that data, our SBIR Phase I grant supported a preclinical pharmacokinetic drug-drug interaction and safety study to determine if co-administration altered the pharmacokinetics and/or respiratory depression related to either compound in rodents. Study results indicated PK parameters remained unaltered, except for a decrease in half-life for the opioid. When measuring respiratory depression, we found that the presence of the cannabinoid was able to attenuate respiratory depression induced by the opioid. Taken together, study results have shown that our lead candidate, BDH-001, exhibits synergistic and opioid-sparing analgesic effects and does not display significant drug-drug interactions nor has any deleterious effects on respiratory depression. This suggests that BDH-001 may have improved analgesia with lower opioid doses and thereby lower the risk of dependence, withdrawal, diversion, abuse, and overdose. This proposal will continue the development of BDH-001 by completing pre-formulation and formulation studies to support co-formulation of our FDC for sublingual administration and provide required data for IND submission. These studies will support the selection of prototypes for short- term stability testing before the clinical supply manufacturing under GMP conditions and long- term stability testing. Upon completion of the proposed Phase II aims and subsequent IND submission, BDH-001 will be ready for the clinical phase of development with an initial indication of chronic low back pain.

Project Narrative The US is in the midst of an epidemic of opioid abuse and overdose and prescription opioids have become the “gateway drug” to opioid use disorder, heroin and illicit fentanyl use, and overdose. The development of novel therapeutics and biomedical strategies to prevent new cases of opioid misuse and addiction and to treat those with opioid use disorder are critical to address the current epidemic of opioid addiction and overdose. To achieve this goal, we propose studies that will build upon data obtained in our SBIR Phase I grant and advance the development of a fixed-dose cannabinoid-opioid combination analgesic that displays opioid sparing and synergistic analgesic effects resulting in lower risk of abuse, addiction, and overdose.