The national epidemic of opioid addiction represents a public health crisis that demands new treatments. Saving lives from overdoses and launching patients into opioid free-conditions and total illness remission, requires transitioning through Opioid Withdrawal Syndrome (OWS). It is imperative that we find more effective treatments for the excruciating multiday experience of OWS because this syndrome is intensified by the opioid antagonist drugs naloxone and naltrexone, which are important to averting overdoses and facilitating long-term recovery. NIDA has recently published its `10 Most Wanted' medication development priorities in response to the opioid epidemic (Neuropsychopharmacology, 2019) which includes targeting of the glutamate AMPA receptor system. This project answers this call by developing the AMPA antagonist Tezampanel (TZP) which reduces hyperactivity in brain circuits involved in OWS, without relying on direct stimulation or antagonism of the opioid system. TZP has been shown to reduce OWS that is provoked by naltrexone in morphine habituated rats, and it is currently under evaluation by NIDA's Addiction Treatment Discovery Program (ATDP) that evaluates candidates in relevant preclinical models including cytochrome P450 assays to predict drug interactions. TZP has already been delivered to over 500 human subjects and found to be safe for a potential migraine indication (US IND 46,811). Proniras, the industrial partner in this application, holds an exclusive license from Eli Lilly for TZP development and commercialization; all data generated under the migraine program (prior pharmacokinetics, clearance, safety and efficacy in humans) will be cross referenced to a new IND for the OWS indication. The manufacturing of clinical grade TZP for IV delivery, new rodent studies (as directed by Dr. Toombs, co-PI, pharmacologist/Proniras), IND development meetings and submissions in year 1, will position our teams for initial human trials of TZP for OWS in year 2 (as directed by Dr. Chambers, co-PI, addiction psychiatrist). Both open label and blinded placebo controlled studies will be conducted in a secure, medically and psychiatrically monitored inpatient research setting at Indiana University in Indianapolis. With the efficacy and safety data from the UG3 phase, and guidance from NIDA and FDA, the co-PIs in the UH3 phase (years 3-5) will direct an expansion of the research program to 3 additional U.S. academic medical centers. These sites will conduct further testing of TZP in drug interaction studies (e.g. with opioids in non-treatment seeking subjects) and in alternative treatment contexts (in treatment seeking subjects) to replicate and expand on the UG3 findings. In total, the 5-year (UG3/UH3) project is expected to produce a rich safety and efficacy data set in over 250 subjects and form the basis for an end-of-phase 2 meeting with FDA. This will allow planning for a pivotal registration trial for TZP for OWS, and as a transitional treatment to long-term recovery on naltrexone.
This industry-academia collaboration will combine co-PI teams in pharmacology and addiction psychiatry to test and develop a totally novel target mechanism, AMPA receptor blockade, for opioid withdrawal syndrome. The agent, tezampanel (TZP), has a mechanism of action that fits NIDA's drug development priority list for opioid use disorders, and this agent may also have applicability for a broader spectrum comorbid mental illnesses and other addiction, which involve pathologies on glutamate neurotransmission. This porject will include preclinical, proof-of-concept clinical trials, and multi-site clinical trials to develop TZP as a significant treatment advance for FDA approval that will help us stem the tide of the massive public health crisis of the opioid epidemic.
