In vitro pharmacology, chronic toxicology, and embryo-fetal development studies to demonstrate safety of GSM-779690 - Project Summary/Abstract Alzheimer disease (AD) is a chronic neurodegenerative disease that develops over decades, with accumulation of amyloid-β (Aβ)-plaques that induce neuritic changes; these changes lead to glial inflammatory responses and to the accumulation of neurofibrillary tangles, whose temporal and regional distribution correlates with cognitive loss. Consistent with the chronology of the disease, the amyloid hypothesis of AD has been a major focus of therapeutic efforts. Recently, the refinement of humanized monoclonal antibodies (mAbs) that bind with high affinity to soluble and insoluble protofibril forms of Aβ to facilitate their removal by Fc receptor-mediated phagocytosis have been shown to slow disease progression and have validated the therapeutic benefit of treatment approaches targeting amyloid. Although these new mAb treatments offer hope, the significant costs, serious side effects, and limited benefit remain major concerns. The use of small molecules aimed at decreasing total Aβ production by inhibiting BACE-1 or γ-secretase have failed to demonstrate efficacy and often resulted in adverse cognitive effects, likely due to on-target inhibition of important proteolytic functions. Distinct from inhibitory strategies, γ-secretase modulation does not inhibit γ-secretase activity, but rather allosterically alters the cleavage of substrates lowering the net production of Aβ42 (the most pathogenic Aβ species) and Aβ40, while increasing to the shorter non-fibrillar Aβ38 and Aβ37 peptides. The selective attenuation of Aβ42 using a small molecule γ-secretase modulator (GSM) represents a safer alternative that targets amyloid than complete pathway inhibition and may prove to be more effective in delaying or even arresting AD progression. Our goal is to develop a GSM as a preventative and/or a disease modifying treatment for AD in adults with autosomal dominant AD (ADAD) and other high-risk populations, such as individuals with Down syndrome (DS) and APOE ԑ4 homozygotes. We have developed GSM-779690 (compound 3) which exhibits an in vitro IC50 value of 5.3 nM for the attenuation of Aβ42, displays a good ADMET (absorption, distribution, metabolism, excretion, and toxicology) profile, and demonstrates excellent in vivo potency (brain Aβ42 levels in mice falls below the limits of the assay at 10 mg/kg p.o.). Extensive pharmacological/toxicological evaluation, of GSM-779690 is nearing completion, including definitive Good Laboratory Practice (GLP) Investigational New Drug (IND)-enabling studies. Preparation of an IND application is underway for filing with FDA in January of 2025. A phase 1 single ascending dose/multiple ascending dose clinical trial for the evaluation of GSM-779690 in healthy participants is schedule for March of 2025. To continue the development of this promising therapy, we propose the conduct of phase II-enabling studies, including a 6-month chronic toxicology study with recovery in rats, embryo-fetal development (EFD) toxicity studies in rats and rabbits, and in vitro safety pharmacology studies. Successful completion of these studies will support the advancement of GSM-779690 to phase 2 clinical evaluation as a potential treatment for AD, moving this critically needed therapy closer to the clinic.
