R01AG073177

A Phase 1b Multiple Ascending Dose Study of the Safety and Tolerability of BMS-984923 in Alzheimer's Disease

Brain synapse loss in Alzheimer's Disease (AD) has been tightly correlated with cognitive symptoms and is triggered initially by amyloid beta (Aβ) accumulation. We have described a pathway in which soluble Aβ oligomers (AβO) bind to cellular prion protein (PrP^C), thereby engaging metabotropic glutamate receptor subtype 5 (mGluR5) as a co-receptor, and activating PTK2B (PYK2) and FYN kinases to couple with tau pathology and synapse loss.

Interrupting mGluR5 function rescues preclinical AD phenotypes, making it an attractive drug target. However, mGluR5 has a physiological role as a glutamate receptor, and full inhibition impairs function. Consequently, typical antagonists have a narrow therapeutic window. We have identified a highly potent, orally bioavailable mGluR5 ligand that does not alter basal or glutamate activity but blocks AβO/PrP^C activation of mGluR5. This compound is considered a silent allosteric modulator, or SAM, for mGluR5, meaning "silent" with regard to glutamate, while antagonistic with regard to AβO/PrP^C.

Preliminary studies demonstrate robust efficacy of this SAM compound for multiple preclinical mouse AD phenotypes as treatment recovers synapse density, restores long-term potentiation, and returns memory performance. Preclinical studies indicate low toxicity and high tolerability at proposed therapeutic doses.

The overall goal is to develop disease-modifying oral therapy effective to slow, halt, or partially reverse AD progression both in the mild cognitive impairment (MCI) and mild dementia stages, which would substantially improve the lives of the nearly 6 million people in the US suffering from AD and many more worldwide, for whom no disease-modifying pharmacological treatments exist.

To evaluate the safety and tolerability of BMS-9884923 and to test its mechanism of action, we propose a Phase 1b trial coupled with a pilot study using novel in vivo imaging of synaptic density with PET. The imaging target is synaptic vesicle glycoprotein 2 (SV2), an essential synaptic vesicle membrane protein, with one of its isoforms, SV2A, ubiquitously expressed in virtually all synapses. We recently developed [¹¹C]UCB-J, a PET tracer for quantitative SV2A imaging in vivo. Our studies in amnestic MCI and dementia due to AD show widespread reductions of synaptic density that are most pronounced in the medial temporal lobe. Thus, [¹¹C]UCB-J PET can be used as an in vivo biomarker of synaptic density loss and regrowth in AD.

Our long-term goals are to develop an effective treatment for AD and a biomarker of treatment efficacy. Our central hypotheses are that BMS-984923 will be safe and well-tolerated, and that synaptic density PET will be an early marker of therapeutic response to treatments that target synapse restoration.

Completion of this study in AD participants will have a significant impact by:

1. Evaluating a drug for advancement in AD clinical trials,
2. Informing the design and methods of the subsequent trials with BMS-984923, and
3. Informing the use of synaptic density PET biomarkers in subsequent clinical trials.

Yale Univ

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]

Connecticut United States

State-Wide

Early Stage Clinical Trials for the Spectrum of Alzheimers Disease and Age-related Cognitive Decline (R01 Clinical Trial Optional) (PAR-18-877)

Amendment Since initial award the End Date has been extended from 08/31/24 to 08/31/26 and the total obligations have increased 129% from $1,967,865 to $4,500,015.