The opioid crisis in America is real and increasing. In 2017, over 47,600 American lives were lost due to an overdose of an opioid. The recent rise in illegally manufactured fentanyl shipped to the United States from sources around the globe have only increased the opioid epidemic and further accelerated a critical need to find and develop new therapies to address this scourge. This UG3/UH3 grant seeks funding to test a ?-aminobutyric acid subtype B positive allosteric modulator (GABAB PAM) compound, ASP8062, in 3 separate clinical studies. This target is one of the prioritized research approaches for NIDA to evaluate in trying to address the opioid crisis. This grant application will include two phase 1 studies to evaluate the impact of ASP8062 on side effects including respiratory depression when administered in combination with a) buprenorphine/naloxone and b) morphine. The third clinical study included in the grant is a phase 2 study in opioid use disorder (OUD) subjects testing ASP8062 or placebo in addition to an ongoing medication assisted treatment (MAT) program that includes buprenorphine-based therapy as cornerstone treatment. Studies have shown that the GABAB receptor is involved with reducing self-administration and drug-seeking behavior across several substances of abuse (i.e., opioids, alcohol, cocaine, nicotine) by suppressing dopamine release from key areas of the brain, including the prefrontal cortex, ventral tegmental area and the striatum. Baclofen, a GABAB receptor agonist, has yielded positive findings in nonclinical studies such as suppression of opioid, ethanol, cocaine or nicotine self-administration in rats. However, activation of GABAB receptors by direct-acting agonists induces side effects including sedation or somnolence, excessive weakness, vertigo and psychological disturbances. Centrally penetrant GABAB PAMs amplify the signaling of endogenous GABA to its receptor within the central nervous system and preserve the spatiotemporal nature of GABA neurotransmission, thus resulting in a lower incidence of undesirable side effects compared to orthosteric GABAB agonist drugs and optimizing compliance and prolonged, tolerable craving suppression. The sponsor will conduct these studies under a company IND. A pre-IND meeting with FDA is planned for Q4 2019 to confirm adequacy of the current nonclinical pharmacology and toxicology data package, clinical study subject populations, endpoints and safety monitoring. Upon execution of the studies included in this grant application, the sponsor will evaluate the data together with input from NIDA, and make a go/no-go decision for further internal investment for future development of ASP8062 in the management of OUD.
Despite some FDA?approved agents to help treat Opioid Use Disorder (OUD), which are underutilized due to their therapeutic limitations and side effects, OUD remains an unmet medical need as society in general and the United States in particular struggles to address the burgeoning Opioid Crisis. ASP8062 is a GABAB positive allosteric modulator (PAM) compound that has demonstrated signals of efficacy in nonclinical abuse deterrence models by decreasing cravings and self?administration of various substances of abuse. The proposed research will explore the effects of ASP8062 in Phase 1 and early Phase 2 clinical studies of OUD to evaluate safety and preliminary efficacy of the compound when used in combination with existing treatments.
