Cooperative Agreement U01AG084528

IND ENABLING CMC/SAFETY/TOXICOLOGY STUDIES, SUBMISSION OF IND AND PILOT PHASE 1 CLINICAL TRIAL WITH PV-1950R VACCINE FOR LEWY BODY DEMENTIA (LBD) - PROJECT SUMMARY LEWY BODY DEMENTIA (LBD) AFFECTS 1.4 MILLION PEOPLE IN THE UNITED STATES AND IS THE SECOND MOST PREVALENT TYPE OF DEMENTIA IN THE COUNTRY. LBD INCLUDES INDIVIDUALS WHO INITIALLY PRESENT WITH A COGNITIVE-BEHAVIORAL DISORDER (DEMENTIA WITH LEWY BODIES) AND THOSE WHO INITIALLY PRESENT WITH A MOVEMENT DISORDER (PARKINSON'S DISEASE DEMENTIA). LBD IS EVEN MORE EXPENSIVE THAN ALZHEIMER'S DISEASE, AS DEMENTIA OCCURS AT AN EARLIER AGE OF DISEASE ONSET. IT PROGRESSES FASTER AND LEADS TO GREATER DISABILITY AND CAREGIVER BURDEN. CURRENTLY, THERE ARE NO MEDICATIONS THAT THE FDA HAS APPROVED TO TREAT LBD, AND ONLY A LIMITED NUMBER OF MEDICATIONS ARE BEING TESTED IN CLINICAL TRIALS, CREATING A SIGNIFICANT GAP IN AVAILABLE TREATMENTS FOR PATIENTS AND THEIR FAMILIES. THE KEY PATHOLOGY IN LBD IS THE AGGREGATION OF THE PRESYNAPTIC PROTEIN, ASYN, IN NEURONAL CELL BODIES (LEWY BODIES), NEURONAL PROCESSES (LEWY NEURITES), AND SYNAPSES AFFECTING THE NEOCORTEX, LIMBIC STRUCTURES, AND PERIPHERAL AUTONOMIC NEURONS. IMMUNOTHERAPY IS BEING EXPLORED AS A PROMISING TREATMENT OPTION FOR LBD, AS ANTIBODIES CAN PREVENT THE ACCUMULATION OR POSSIBLY INHIBIT THE SPREADING OF PATHOLOGICAL AGGREGATED ASYN THAT CONTRIBUTE TO THE DISEASE. OF PARTICULAR INTEREST TO THIS HYPOTHESIS IS THAT A PRODROMAL STATE OF LBD EXISTS IN THE FORM OF RAPID EYE MOVEMENT SLEEP BEHAVIOR DISORDER (RBD), ASSOCIATED WITH BRAINSTEM AND PERIPHERAL ASYN AGGREGATES PRECEDING LBD ONSET BY MORE THAN TWO DECADES, MAKING IT AN IDEAL TARGET FOR AN IMMUNOGENIC PREVENTIVE VACCINE. WE DEVELOPED A UNIVERSAL PLATFORM TECHNOLOGY IN THE LAST DECADE, ESPECIALLY FOR NEURODEGENERATIVE DISORDERS, AND MANUFACTURED TWO MULTITEP-BASED CGMP-GRADE VACCINES TARGETING PATHOLOGICAL AB AND TAU. ONE OF THESE VACCINES IS CURRENTLY IN A PHASE 1 TRIAL WITH EARLY AD INDIVIDUALS, AND ANOTHER WILL BE USED FOR A PHASE 1 TRIAL WITH COGNITIVELY UNIMPAIRED PARTICIPANTS. MORE RECENTLY, USING MULTITEP PLATFORM TECHNOLOGY, WE ALSO DEVELOPED FOUR VACCINES TARGETING DIFFERENT REGIONS OF PATHOLOGICAL ASYN AND TESTED THEIR IMMUNOGENICITY AND EFFICACY IN AN LBD MOUSE MODEL. THE MOST IMMUNOGENIC AND PRECLINICALLY EFFECTIVE VACCINE, PV-1950R TARGETING THREE B-CELL EPITOPES OF PATHOLOGICAL ASYN SIMULTANEOUSLY, HAS BEEN SELECTED TO MOVE FORWARD FOR IND-ENABLING STUDIES. OUR PRELIMINARY RESULTS SHOW THAT THIS VACCINE INDUCES HIGH TITERS OF ASYN ANTIBODIES IN THE LBD MOUSE MODEL AND REDUCES TOTAL AND PROTEINASE K RESISTANT ASYN, NEURODEGENERATION, AND BRAIN INFLAMMATION. ACCORDINGLY, IN THIS PROPOSAL, WE SUGGEST CONDUCTING PRE-CLINICAL IND-ENABLING STUDIES AND A PILOT PHASE 1 TRIAL ON THIS VACCINE TARGETING THREE B CELL EPITOPES OF PATHOLOGICAL ASYN. STUDIES WILL INCLUDE (I) MANUFACTURING OF ENGINEERING-RUN RECOMBINANT PROTEIN THAT IS, ACCORDING TO FDA GUIDANCE, SUFFICIENT FOR SAFETY/TOXICOLOGY STUDIES; (II) COMPLETING SAFETY/TOXICOLOGY STUDIES IN THE LBD MOUSE MODEL; (III) COMPLETING IMMUNOGENICITY AND OVERALL SAFETY STUDIES IN NON-HUMAN PRIMATES; (IV) MANUFACTURING CGMP PV-1950R/A BULK DRUG SUBSTANCE AND FILL/FINISHED DRUG PRODUCT, (IV) SUBMIT AND OBTAIN IND, AND (V) CONDUCT PILOT PHASE 1 CLINICAL TRIAL WITH HEALTHY VOLUNTEERS (PHASE 1A) AND WITH PATIENTS WITH RBD (PHASE 1B) WHO ARE AT THE RISK OF LBD.