Global Alliance For Tb Drug Development Inc

MODULATION OF PROTEIN PRODUCTION AND DEGRADATION AS AN INTEGRATED APPROACH TO RAPID STERILIZATION OF DRUG SENSITIVE AND RESISTANT MTB.

THE TB ALLIANCE ACTIVITY WILL SUPPORT RESEARCH STUDIES TO EVALUATE THE SAFETY AND EFFICACY OF NOVEL TB DRUGS AND TREATMENT REGIMENS, INCLUDING THE DEVELOPMENT AND REGULATORY AUTHORITY APPROVAL OF COMPOUNDS OR REGIMENS IN CLINICAL PHASE DEVELOPMENT. THE GOAL OF THIS ACTIVITY IS TO SUPPORT THE DISCOVERY OF BETTER, FASTER-ACTING, AND AFFORDABLE TB DRUGS.

HOST-DIRECTED APPROACHES TO TARGET GRANULOMA PATHWAYS FOR TREATMENT SHORTENING IN TUBERCULOSIS

CONSORTIUM FOR TB BIOMARKERS

CONSORTIUM FOR TB BIOMARKERS

QUALIFYING NEW PRE-CLINICAL MODELS FOR THE DEVELOP. OF TUBERCULOSIS DRUG

TB LATITUDE (LONG-ACTING TREATMENT INNOVATION FOR TUBERCULOSIS DRUG EFFECTIVENESS) - R220 - OPI SECTION 7 - PROJECT SUMMARY / ABSTRACT TUBERCULOSIS (TB) IS THE MOST COMMON CAUSE OF PREMATURE DEATH AMONG PEOPLE LIVING WITH HIV (PLWH), AND EFFECTIVE TB PREVENTION AND TREATMENT STRATEGIES ARE CRITICAL FOR PREVENTING TB-RELATED DEATHS IN PLWH. CURRENTLY A MINIMUM OF SIX MONTHS ORAL THERAPY WITH A MULTIDRUG REGIMEN IS REQUIRED FOR ACTIVE DRUG-SENSITIVE (DS-) OR DRUG-RESISTANT (DR-) TB, INCLUDING FOR PATIENTS WITH TB/HIV COINFECTIONS. RECENT APPROVALS IN HIV TREATMENT HAVE PAVED THE WAY FOR LONG-ACTING INJECTABLE (LAI) DRUG DEVELOPMENT IN INFECTIOUS DISEASES, INCLUDING TB WHERE THERE IS HIGH POTENTIAL TO IMPROVE ON CURRENT TREATMENT OPTIONS. THE ULTIMATE GOAL OF THIS PROJECT IS TO DEVELOP AN OPTIMIZED LAI-BASED REGIMEN FOR USE IN THE CONTINUATION PHASE OF ACTIVE TB TREATMENT TO MINIMIZE THE TOTAL “ACTIVE TREATMENT” DURATION TO TWO MONTHS OR LESS FOR BOTH DS- AND DR-TB. THIS WILL REPRESENT A SIGNIFICANT ADVANCEMENT IN THE TREATMENT OF TB BY REDUCING THE BURDEN ON PATIENTS WHO CURRENTLY MUST TAKE DAILY ORAL MEDICINES FOR UP TO SIX MONTHS OR LONGER. THE PROJECT’S FOUR KEY RESEARCH AIMS WILL FOCUS ON THE DEVELOPMENT OF FORMULATION TECHNOLOGIES FOR FOUR DRUGS FROM TB ALLIANCE’S PIPELINE (TBAJ-876, TBAJ-587, TELACEBEC, AND PRETOMANID) THAT HAVE APPROPRIATE ANTI-TB ACTIVITY AND PHYSICOCHEMICAL PROPERTIES AND SHOW PROMISE FOR AN LAI-BASED CLINICAL APPLICATION. THE FIRST PHASE OF THE PROJECT (R61 PHASE) WILL FOCUS ON FORMULATION DEVELOPABILITY, STABILITY AND IN VITRO RELEASE COMBINED WITH IN VIVO PHARMACOKINETICS (PK) AND PK MODELING (AIM 1). THIS WILL BE COMBINED WITH IN VIVO MOUSE INFECTION STUDIES TO EVALUATE THE PK/PD CORRELATION OF LAI-DRUG EXPOSURE AND EFFICACY (AIM 2). WE WILL SELECT UP TO FOUR DRUG AND FORMULATION TECHNOLOGY CONFIGURATIONS FOR CONTINUED ASSESSMENT AND SUPPORT TRANSITION TO THE R33 PHASE. THE SECOND PHASE OF THE PROJECT (R33 PHASE) WILL FOCUS ON THE NONCLINICAL STUDIES OF INJECTION SITE SAFETY AND TOLERABILITY, LAI STABILITY, AND GMP-COMPLIANT LAI FORMULATIONS FOR REGIMENS TO ENABLE INVESTIGATIONAL NEW DRUG (IND) APPLICATION(S) (AIM 3). LAI DRUG REGIMENS WILL BE SELECTED BASED ON A STRONG POTENTIAL TO ACHIEVE CURES WHEN ADMINISTERED FOLLOWING A SHORT ORAL LEAD-IN THERAPY (AIM 4). THE KEY GOAL OF AIM 4 WILL BE TO SHOW THAT A SINGLE COADMINISTRATION OF ONLY TWO LAI-FORMULATED DRUGS FOLLOWING AN ORAL LEAD-IN OF TWO MONTHS OR LESS IS FEASIBLE BASED ON THE COMPARATIVE ACTIVITY OF AN ALL-ORAL REGIMEN VERSUS AN ORAL LEAD-IN AND LAI CONTINUATION REGIMEN IN THE RELAPSING MOUSE MODEL (RMM) STUDIES.

HOST-DIRECTED PROTEOLYSIS-TARGETING CHIMERA (PROTAC) APPROACH TO TARGET INTRACELLULAR MYCOBACTERIUM TUBERCULOSIS (MTB)