Development of a Novel Chemokine Receptor Antagonist as a Treatment for Opioid Use Disorder

7. 项目总结

7. Project Summary Over 2.1 million Americans suffer from opioid use disorder (OUD) resulting in 47,000 deaths annually. Individuals seeking treatment must deal with limited access to qualified healthcare professionals, as well as barriers to getting medication assisted treatment (MAT). Common MAT treatments utilizing buprenorphine often require patients to experience withdrawal symptoms for several days prior to MAT initiation. Further, the stigma of OUD treatment, which could be reduced if patients received ambulatory care, acts as an additional hindrance to access and treatment. There is a paucity of options available for these individuals and the medical staff who treat them, as methadone, buprenorphine and naloxone, the standards of care, are often not successful in achieving treatment goals. Emerging evidence demonstrates that brain chemokine receptors control dopamine reward pathways and influence behavioral effects of drug abuse which can be blunted by chemokine receptor antagonists. CBP proposes to expand MAT capabilities for OUD with RAP-103, a small orally stable chemokine receptor antagonist peptide that block’s opioid acquisition, maintenance, and withdrawal. Our evidence indicates that RAP-103 has significant safety and efficacy advantages as a non-opioid for MAT use that blocks opioid self- administration in fixed-ratio tests that show reduction in total opioid consumed and in progressive-ratio experiments that show greatly reduced motivation to maintain opioid use. Additionally RAP-103 mitigates signs of naloxone induced opioid withdrawal in a rodent model of morphine dependence. In this project, our objective is to further demonstrate the feasibility of RAP-103 as a MAT agent and to progress to human testing. We intend to do this by optimizing the lowest dose at which RAP-103 mitigates opioid self-administration in progressive- ratio experiments in male and female rats. In view of the unique mechanism of RAP-103 action via chemokine receptor antagonism we will identify chemokine and cytokine changes in mesolimbic (VTA and nucleus accumbens) brain reward areas to provide a mechanism for how RAP-103 may mitigate the rewarding effects of opioids and other drugs of abuse. CBP has been conducting pre-clinical pharmacokinetic and toxicokinetic safety testing toward fulfilling requirements for filing an IND and conducting first-in-human safety testing. CBP has assembled a team of experienced MAT clinician/researchers to plan a clinical development program for an OUD use. We propose to conduct the additional pre-clinical safety tests that would support filing of an IND for an OUD treatment use of RAP-103 at the end of the program. CBP will advance clinical development of RAP-103 as a MAT for OUD with goals to provide safer treatment with no abuse risk, improve patient access, adherence, tolerance and treatment. The superior safety profile (no respiratory depression and abuse or diversion potential), reduced motivation to maintain opioid use, mitigation of withdrawal symptoms and oral bioavailability by once daily dosing would make RAP-103 a highly valuable addition to the OUD MAT toolbox, initially as an adjunctive therapy that can help overcome the underutilization of MAT access and use.