R01AG088524

A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF LHP588 IN SUBJECTS WITH P. GINGIVALIS-POSITIVE ALZHEIMER'S DISEASE - SUMMARY/ABSTRACT A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF LHP588 IN SUBJECTS WITH P. GINGIVALIS-POSITIVE ALZHEIMER'S DISEASE GIVEN THE INCREASING INCIDENCE OF AD WORLDWIDE, THERE IS AN URGENT UNMET NEED FOR PRECISION MEDICINE APPROACHES THAT COULD PREVENT OR DELAY COGNITIVE DECLINE EXPERIENCED BY ALZHEIMER’S DISEASE (AD) PATIENTS. MOUNTING EVIDENCE SUGGESTS THAT LIFE EXPOSURE TO BRAIN-PENETRANT PATHOGENS COULD CONTRIBUTE TO THE ETIOLOGY OF AD. ONE MICROBIAL AGENT RECENTLY ASSOCIATED WITH AD IS PORPHYROMONAS GINGIVALIS (PG). PG IS BEST KNOWN FOR ITS ROLE IN CHRONIC PERIODONTITIS , BUT EPIDEMIOLOGIC AND OTHER STUDIES ALSO STRONGLY IMPLY ITS CONTRIBUTION TO COGNITIVE DECLINE. CRITICALLY, PG VIRULENCE FACTORS, PROTEASES CALLED GINGIPAINS HAVE BEEN IDENTIFIED IN POST-MORTEM AD BRAINS, AT RATES SIGNIFICANTLY HIGHER THAN AGE-MATCHED CONTROLS. GINGIPAIN LOADS HAVE SHOWN A POSITIVE CORRELATION WITH AD SEVERITY, BRAIN TAU LEVELS, AND UBIQUITIN PATHOLOGY. OUR TEAM PREVIOUSLY DEVELOPED A SMALL-MOLECULE, BRAIN-PENETRANT, ORALLY BIOAVAILABLE, FIRST-GENERATION, COVALENT GINGIPAIN INHIBITOR CALLED COR388 (ATUZAGINSTAT), WHICH MITIGATED MANY AD- ASSOCIATED NEUROPATHOLOGICAL FEATURES IN PRECLINICAL IN VITRO AND ANIMAL STUDIES. AFTER OBTAINING U.S. FOOD & DRUG ADMINISTRATION (FDA) PERMISSION, WE CONDUCTED A LARGE, PHASE-II/III, PLACEBO-CONTROLLED, RANDOMIZED CLINICAL TRIAL OF ATUZAGINSTAT ADMINISTERED TO MILD-TO-MODERATE DEMENTIA SUBJECTS (MMSE RANGING 12-24) FOR 48 WEEKS. TARGET ENGAGEMENT WAS VERIFIED ALONG WITH DOSE-DEPENDENT REDUCTION OF SYSTEMIC PG INFECTION. THE PRESPECIFIED SUBGROUP ANALYSIS MOST RELEVANT TO THE MECHANISM OF ACTION INDICATED DOSE-DEPENDENT EFFICACY IN PATIENTS WITH PG-POSITIVE (PG+) SALIVA (N=242), WITH A REDUCTION OF THE AD ASSESSMENT SCALE-COGNITIVE SUBSCALE 11 (ADAS-COG11) SCORES BY 57% COMPARED TO BASELINE (P=0.02). HOWEVER, BECAUSE OF HEPATIC SAFETY CONCERNS, DEVELOPMENT OF ATUZAGINSTAT WAS DISCONTINUED. WE, AT LIGHTHOUSE PHARMACEUTICALS, HAVE NOW DEVELOPED A SECOND-GENERATION, ORALLY BIOAVAILABLE GINGIPAIN INHIBITOR CALLED LHP588. RIGOROUS IN VITRO AND ANIMAL STUDIES HAVE DEMONSTRATED IMPROVED TARGET ENGAGEMENT AND REDUCED TOXICITY OF LHP588 COMPARED TO ATUZAGINSTAT. IN A PHASE I STUDY COMBINING A SINGLE-ASCENDING-DOSE AND A 10-DAY MULTIPLE-ASCENDING-DOSE, LHP588 WAS WELL TOLERATED AND THERE WAS NO EVIDENCE OF HEPATIC TOXICITIES AT ANY DOSE. USING OUR EXPERIENCE WITH ATUZAGINSTAT AND THE DEVELOPMENT OF LHP588, WE FORMULATED THE HYPOTHESIS THAT LHP588 CAN PROVIDE INCREASED TARGET ENGAGEMENT WITH REDUCED SAFETY RISKS TO SLOW DOWN COGNITIVE DECLINE IN PATIENTS SUFFERING FROM PG-POSITIVE (PG+) MILD-TO-MODERATE AD. TO TEST OUR HYPOTHESIS, WE WILL DEPLOY A RIGOROUSLY DESIGNED PHASE II, DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED, 3-ARM, PARALLEL GROUP CLINICAL TRIAL TERMED SPRING (STOPPING PROGRESSION OF PORPHYROMONAS GINGIVALIS-ASSOCIATED AD). THOROUGH SCREENING WILL SELECT AD SUBJECTS WITH PG+ SALIVA AND PLASMA P-TAU-217 LEVELS ABOVE 0.42 PG/ML, WHICH IS ASSOCIATED WITH AMYLOID PLAQUE POSITIVITY ACROSS RACIAL AND ETHNIC GROUPS. ENROLLED STUDY PARTICIPANTS (N=300; MINIMUM OF 30% OF DIVERSE SUBJECTS) WILL BE RANDOMIZED 1:1:1 TO 25 OR 50 MG LHP588 TAKEN ORALLY ONCE-A-DAY, OR MATCHING PLACEBO, FOR 48 WEEKS. IMPORTANTLY, THE FDA PROVIDED A “STUDY MAY PROCEED” LETTER AFTER REVIEW OF OUR INVESTIGATIONAL NEW DRUG (IND) APPLICATION. IN AIM 1, WE WILL ASSESS SAFETY AND TOLERABILITY IN AD SUBJECTS ADMINISTERED LHP588. IN AIM 2, WE WILL TEST FOR TARGET ENGAGEMENT BY MEASURING PG DNA LEVELS IN SALIVA AND ANTI-PG IGG LEVELS IN SERUM. IN AIM 3, WE WILL DETERMINE DRUG EFFICACY VS. PLACEBO USING CLINICAL ASSESSMENTS OF DEMENTIA, I.E., COGNITION (ADAS- COG11, WHICH IS THE PRIMARY EFFICACY MEASURE), OTHER CLINICAL MEASURES, BIOMARKERS, INCLUDING BRAIN ATROPHY ESTIMATED BY VMRI, AND PLASMA LEVELS OF P-TAU-217. SUCCESS OF OUR SPRING TRIAL WILL WARRANT CARRYING OUT AT LEAST ONE LARGER CONFIRMATORY PHASE III STUDY FOR FUTURE

Lighthouse Pharmaceuticals

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

California United States

State-Wide

Early- and Late-Stage Clinical Trials for the Spectrum of Alzheimer's Disease/Alzheimer's Disease-Related Dementias and Age-Related Cognitive Decline (R01 Clinical Trial Optional) (RFA-AG-25-011)