Cooperative Agreement UG3DA061620

REGISTRATION DEVELOPMENT PROGRAM FOR LUCEMYRA (LOFEXIDINE) LABEL EXPANSION FOR OPIOID WITHDRAWAL TREATMENT IN ADOLESCENTS - PROJECT SUMMARY: AN ALARMING INCREASE IN THE RATE OF OPIOID ABUSE AMONG THE GENERAL POPULATION HAS RESULTED IN A PUBLIC HEALTH EMERGENCY SINCE 2017. THE STRIKING RISE IN OPIOID USE DISORDER HAS AFFECTED AMERICANS BROADLY, INCLUDING STEADY INCREASES IN ADOLESCENT DEATHS DUE TO OPIOID OVERDOSE. HOWEVER, A NUMBER OF BARRIERS EXIST FOR ADOLESCENTS TO GAIN ACCESS TO TREATMENT; AND CURRENT APPROACHES TO PHARMACOTHERAPY RELY ON THE OFF-LABEL USE OF OPIOIDS AND OTHER AGENTS USED IN ADULTS WITH OUD. THROUGH A SUCCESSFUL COLLABORATION WITH NIDA, USWM DEVELOPED LOFEXIDINE FOR THE MITIGATION OF OPIOID WITHDRAWAL SYMPTOMS IN ADULTS. THE FOOD AND DRUG ADMINISTRATION (FDA) APPROVED LOFEXIDINE TABLETS (LUCEMYRA) FOR THIS INDICATION IN MAY 2018. DUE TO THE ANTICIPATED UTILITY OF LOFEXIDINE FOR THE TREATMENT OF OPIOID WITHDRAWAL IN CHILDREN, USWM HAS COMPLETED ALL NONCLINICAL PREREQUISITES NECESSARY TO INITIATE STUDIES IN ADOLESCENTS AND ENGAGED WITH FDA TO CONFIRM THE APPROACH TO REGISTRATION. THE GOAL OF THIS PROJECT IS TO FURTHER NIDA-USWM COLLABORATION TO COMPLETE FDA DEVELOPMENT REQUIREMENTS FOR THE APPROVAL OF LUCEMYRA IN ADOLESCENTS. THE USE OF AN APPROVED MEDICATION FOR OPIOID WITHDRAWAL WILL PROVIDE NEEDED SAFE AND EFFECTIVE TREATMENT OPTIONS FOR THIS UNDERSERVED PATIENT POPULATION TO OPTIMIZE OPPORTUNITIES FOR INITIAL ENGAGEMENT IN TREATMENT AND TRANSITION TO LONGER TERM MAINTENANCE TREATMENT OPTIONS, INCLUDING BUPRENORPHINE AND EXTENDED-RELEASE NALTREXONE, RECOMMENDED IN CURRENT GUIDELINES. THE PROPOSED RESEARCH LEVERAGES AN EFFICIENT REGULATORY PATHWAY USING A FULL EXTRAPOLATION APPROACH WHEREIN PHARMACOKINETIC (PK) MODELING CAN BRIDGE ESTABLISHED ADULT EFFICACY TO ADOLESCENTS THROUGH LOFEXIDINE EXPOSURE MATCHING. THE APPROACH REQUIRES A PK STUDY IN ADOLESCENTS EXPERIENCING ACUTE OPIOID WITHDRAWAL TO IDENTIFY LUCEMYRA DOSES PRODUCING EXPOSURES ASSOCIATED WITH EFFICACY IN ADULTS, AND AN OPEN LABEL SAFETY STUDY TO PROVIDE ADEQUATE SAFETY DATA IN SUPPORT OF REGISTRATION REQUIREMENTS. KEY COMPONENTS OF THE PROGRAM INCLUDE: I) COMPLETION OF A PHASE 1 PK IN ADOLESCENTS TO COMPLETE EFFICACY REQUIREMENTS THROUGH EXPOSURE MATCHING PEDIATRIC EXTRAPOLATION PRINCIPLES (UG3 AIMS 1, 2) AND COMPLETION OF A FORMAL FDA MEETING TO CONFIRM THE REMAINING SCOPE OF THE DEVELOPMENT PROGRAM (UG3 KEY GO/NO GO MILESTONE), AND II) COMPLETION OF A PHASE 2 OPEN LABEL SAFETY STUDY WHICH, TOGETHER WITH THE INITIAL PHASE 1 STUDY, CAN BE INTEGRATED TO SATISFY THE SAFETY PACKAGE REQUIREMENTS FOR A SUPPLEMENTAL NEW DRUG APPLICATION (UG3 AIM 3, UH3 AIMS 1 & 3).