Development of a Novel Treatment for Benzodiazepine Addiction - Benzodiazepines (BZs) are prescribed widely as anxiolytics and sleep aids but their utility is limited by unwanted side effects such as addiction liability. This UG3/UH3 proposal is for non-clinical efficacy and investigational new drug (IND) enabling studies for developing the first medication to treat BZ misuse/use disorder. Based on our prior research and the success of partial agonist therapies for other use disorders, we have identified a drug candidate that acts as a mixed efficacy partial positive allosteric modulator (“mixed efficacy PAM”) therapy for BZ addiction. This compound (“IMP-001”) is a novel hemifumarate salt of an off-patent, anxiolytic development compound from Merck that has US patent support via the University of Mississippi Medical Center (UMMC). The Aims for the UG3 Phase of the proposal include (Aim 1) determination of binding to GABAA receptors in native rat CNS and functional selectivity at α1-α6 subunit-containing GABAA receptors for IMP-001, compared with the active pharmaceutical ingredient (API), MRK-898. We predict that the profile of IMP-001 will replicate with the API, i.e., the salt formulation will not alter selective efficacy or binding. To complete the UG3 Phase, we will conduct non-clinical efficacy studies (Aim 2) to assess the ability of oral doses of IMP-001 to induce anxiolytic and sedative-motor effects in rats, and to alter BZ self-administration (while not altering food self-administration) in monkeys. If all expected outcomes, driven by our Target Product Profile (TPP), are met, then IMP-001 will undergo further evaluation as a BZ addiction therapy and safety/toxicology studies for the UH3 Phase. Following scale-up synthesis of IMP-001, our first Aim for the UH3 Phase will focus on additional TPP-based studies in monkeys and rats, including assessment of chronic treatment during BZ self-administration, evaluation of anxiolytic potential; and evaluation of physical dependence potential. Aim 2 of the UH3 phase will consist of a series of non-GLP safety/toxicology studies. These studies include the following: (1) safety pharmacology, including off-target assessments, CiPA, mitochondrial toxicity, lysosomal perturbation assays, (2) drug metabolism and PK, including plasma protein binding, hepatocyte stability, metabolic stability, metabolite identification, metabolism-mediated drug interactions (CYP induction and inhibition), transporter-mediated drug interaction (human BCRP and MDR-1 mediated transport); and (3) toxicology, including dose range-finding non- GLP oral studies in dogs and rats. If all milestones for efficacy and safety are met, in Aim 3, we will pursue a pre-IND meeting with FDA in order to determine next steps in development. Aim 4 will consist of recommended studies by FDA, as well as the required GLP studies: hERG assays; respiratory testing in rats; cardiovascular testing in dogs; oral, 28-day toxicity study (with CNS safety pharmacology) in rats; GLP 28-day toxicity studies in beagle dogs; GLP Ames testing and GLP in vitro genetic toxicity tests. By the project's end, and if all endpoints are met, IMP-001will be submitted to FDA for assessment of suitability for initiating first-in-human (FIH) studies.
