Project Grant R44AI155312

IND-ENABLING DEVELOPMENT OF HIV MATURATION INHIBITORS FORMULATED FOR USE AS EITHER ORAL OR LONG-ACTING PARENTERALLY ADMINISTERED AGENTS - PROJECT SUMMARY: WHILE CURRENTLY AVAILABLE HIV THERAPIES ARE HIGHLY EFFECTIVE, THEY ARE NOT CURATIVE. PATIENTS ARE REQUIRED TO REMAIN ON LIFE-LONG THERAPY WHICH IS ASSOCIATED WITH A VARIETY OF ADVERSE EFFECTS. VIRAL-MEDIATED DRUG RESISTANCE POSES AN INCREASINGLY SERIOUS PROBLEM, PARTICULARLY IN RESOURCE-LIMITED SETTINGS. THE DEVELOPMENT OF NEW CLASSES OF INHIBITORS THAT BLOCK VIRAL REPLICATION DISTINCT FROM THOSE TARGETED BY CURRENT THERAPIES IS A HIGH PRIORITY. MATURATION INHIBITORS (MIS) REPRESENT ONE SUCH CLASS OF HIV THERAPIES. MIS BLOCK VIRUS REPLICATION BY DISRUPTING THE CONVERSION OF THE CAPSID PRECURSOR PROTEIN, CA-SP1 (P25), TO THE MATURE FORM OF CAPSID, CA (P24) RESULTING IN THE RELEASE OF NON-INFECTIOUS VIRAL PARTICLES. UNLIKE PROTEASE INHIBITORS THAT BIND TO AND INHIBIT THE ACTION OF THE VIRAL PROTEASE, MIS DIRECTLY TARGET THE HIV-1 GAG PROTEIN. THIS DISTINCT MECHANISM OF ACTION ALLOWS MIS TO RETAIN FULL ACTIVITY AGAINST VIRUSES RESISTANT TO APPROVED CLASSES OF HIV DRUGS. CLINICAL PROOF-OF-CONCEPT FOR MIS WAS ESTABLISHED WITH THE FIRST-IN-CLASS MI, BEVIRIMAT (BVM). IN A SERIES OF TRIALS, BVM WAS SHOWN TO BE SAFE AND EFFECTIVE IN REDUCING HIV VIRAL LOAD IN INFECTED INDIVIDUALS, HOWEVER, A LACK OF UNIFORM PATIENT RESPONSE WAS OBSERVED. ANALYSIS OF PATIENT VIRUS REVEALED THAT A SINGLE AMINO ACID POLYMORPHISM IN THE SP1 REGION OF THE VIRAL GAG PROTEIN WAS A PRIMARY DETERMINANT OF PATIENT RESPONSE. THIS POLYMORPHISM INVOLVES A VAL TO ALA CHANGE AT SP1 AMINO ACID 7: V7A. APPROXIMATELY 50% OF HIV-1 ISOLATES CONTAIN V7 AND ARE HIGHLY SENSITIVE TO BVM WHILE THE REMAINING 50% CONTAIN A7 AND LACK SENSITIVITY. DFH PHARMA'S CURRENT EFFORTS FOCUS ON THE DEVELOPMENT OF NEXT GENERATION MIS WITH BROAD ANTI-HIV ACTIVITY. TWO OF THESE COMPOUNDS, DFH-1220001 AND DFH-1220002, EXHIBIT THE POTENCY, ADMET PROPERTIES AND LONG- ACTING FORMULATION POTENTIAL NECESSARY TO THE SUCCESSFUL DEVELOPMENT OF MODERN HIV THERAPEUTICS. THE GOALS OF THE WORK OUTLINED IN THIS APPLICATION WILL BUILD ON OUR SUCCESSFUL PHASE II PROJECT EFFORTS (9R42AI155312-02). DURING THE PHASE IIB PERIOD WE WILL I) SELECT A SINGLE 2ND GEN MI DEVELOPMENT CANDIDATE AND ADVANCE THAT CANDIDATE INTO IND-ENABLING STUDIES AND II) OPTIMIZE THE FORMULATION OF THE SELECTED CANDIDATE FOR DELIVERY AS A LONG-ACTING AGENT (LAA). THIS 2ND GOAL RECOGNIZES THAT THE HIV TREATMENT SPACE IS MOVING AWAY FROM DAILY ORAL DOSING TOWARDS FORMULATIONS THAT SUPPORT WEEKLY, MONTHLY OR EVEN LESS FREQUENT DRUG ADMINISTRATION. WE BELIEVE THAT OUR SUCCESS IN THIS AREA AS DEMONSTRATED IN THE PHASE II WORK WILL RESULT IN A NOVEL MI DRUG DEVELOPMENT CANDIDATE WITH LAA FORMULATION POTENTIAL ADVANCING INTO IND-ENABLING STUDIES.