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

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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 (PRPC), 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/PrPC 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/PrPC. 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.