Project Grant R01AG076565

FIRST IN HUMAN STUDY OF A TAU SELF-ASSOCIATION SMALL MOLECULE INHIBITOR IN HEALTHY VOLUNTEERS - PROJECT SUMMARY THIS PROGRAM IS FOCUSED ON DEVELOPING A DISEASE-MODIFYING DRUG FOR ALZHEIMER'S DISEASE (AD) BY ADVANCING ITS SMALL MOLECULE DRUG OLX-07010 INTO CLINICAL DEVELOPMENT. THERE ARE NO DISEASE-MODIFYING DRUGS FOR AD, AND THE PREVALENCE OF AD IS INCREASING WORLDWIDE. THIS PROGRAM IS PROGRESSING TO FILL THIS NEED WITH A DISEASE MODIFYING DRUG THAT, IF SUCCESSFUL, WILL HAVE A TREMENDOUS IMPACT ON THE MORE THAN 6.2 MILLION AMERICANS WHO CURRENTLY HAVE AD (PROJECTED TO BE 12.7 MILLION BY 2050) AND THEIR CAREGIVERS, AND WILL HELP REDUCE THE CURRENT COST OF $355 BILLION (PROJECTED TO BE $1.1 TRILLION BY 2050) TO OUR NATION (ALZHEIMER'S ASSOCIATION 2021 ALZHEIMER'S DISEASE FACTS AND FIGURES). KEY REQUIREMENTS FOR TREATING EARLY-STAGE AD INCLUDE SAFE, EFFICACIOUS, AND COST- EFFECTIVE THERAPEUTIC INTERVENTIONS. THIS SMALL MOLECULE, CNS DRUG-LIKE LEAD SUBSTANTIALLY FULFILLS THESE REQUIREMENTS BASED ON OUR PRELIMINARY RESULTS. THIS HIGHLY DIFFERENTIATED APPROACH TARGETS TAU SELF-ASSOCIATION AT THE BEGINNING OF THE TAU AGGREGATION CASCADE. SMALL MOLECULES WERE SCREENED AND OPTIMIZED USING IN VITRO ASSAYS TO SELECT MOLECULES THAT INHIBIT THE FORMATION OF TAU OLIGOMERS FROM TAU MONOMERS. IN VITRO PHARMACOLOGY AND PHARMACOKINETIC (PK) STUDIES IN MICE WERE USED TO SELECT A LEAD COMPOUND FOR EVALUATION OF IN VIVO EFFICACY. PREVENTIVE AND THERAPEUTIC STUDIES IN TWO MOUSE MODELS OF TAUOPATHY, REPRESENTING TAU AGGREGATION IN ALZHEIMER'S DISEASE (AD) AND FOUR-REPEAT-TAU TAUOPATHIES, DEMONSTRATED PROOF-OF-CONCEPT AND SUPPORTED THE SELECTION OF THIS COMPOUND FOR FURTHER DEVELOPMENT. MANUFACTURE OF KILOGRAM QUANTITIES FOR NON-CLINICAL SAFETY STUDIES (NCSS) AND DRUG PRE-FORMULATION WORK HAS BEEN COMPLETED. A GMP BATCH WAS ALSO PREPARED FOR THE MANUFACTURE OF OUR DRUG PRODUCT OLX-07010. A PRE-IND MEETING WRITTEN RESPONSE WITH FDA IS SCHEDULED FOR JULY 23, 2021 (PIND NUMBER 156701) TO FINALIZE DOSE SELECTION FOR THE 28-DAY GLP SAFETY STUDIES IN DOGS AND RATS. THE INVESTIGATIONAL NEW DRUG (IND) APPLICATION IS PLANNED FOR THE FIRST QUARTER IN 2022 TO ENABLE THE FIRST IN HUMAN (FIH) STUDIES THAT ARE THE SUBJECT OF THIS APPLICATION TO COMMENCE EARLY IN THE SECOND QUARTER OF 2022. THIS R01 PHASE 1A SINGLE-BLIND, RANDOMIZED, THREE-PART STUDY IS DESIGNED TO EVALUATE THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF THE TAU SELF-ASSOCIATION INHIBITOR, IN SINGLE ASCENDING DOSES, MULTIPLE ASCENDING DOSES, AND A SINGLE DOSE IN HEALTHY ELDERLY. THE AIM OF THIS APPLICATION IN YEAR 1 IS TO DEMONSTRATE SAFETY AND PK OF OLX- 07010 IN HEALTHY VOLUNTEERS AFTER SINGLE DOSING, AND DURING YEAR 2 THE AIMS ARE TO DEMONSTRATE SAFETY AND PK OF OLX-07010 IN HEALTHY VOLUNTEERS AFTER MULTIPLE DOSING, AND TO DEMONSTRATE SAFETY AND PK OF OLX-07010 IN HEALTHY ELDERLY VOLUNTEERS AFTER SINGLE DOSING. THESE STUDIES WILL ENABLE THE DETERMINATION OF DOSING FOR SUBSEQUENT PROOF-OF-CONCEPT STUDIES IN AD AND OTHER NEURODEGENERATIVE DISEASES.