Discovery of Nivegacetor, an Advanced γ-Secretase Modulator, for the Treatment of Alzheimer’s Disease

Abstract Recent clinical data regarding amyloid-beta (Aβ) antibodies support the validity of reducing Aβ-amyloidosis or aggregated Aβ as a disease-modifying therapy for Alzheimer’s disease (AD). γ-Secretase (GS) remains an important target for the treatment of AD, and its pharmacological modulation, instead of inhibition, can deliver a safe treatment. Following extensive efforts to optimize the pharmacological and physicochemical properties (e.g., potency, selectivity, and solubility) of our previous clinical candidate, RO7185876, and to mitigate safety findings observed during advanced toxicology studies, we successfully identified RG6289 (nivegacetor). Herein, we report the comprehensive optimization process and the exploration of multiple chemical subseries that led to the discovery of the nivegacetor. Currently in Phase II clinical trials, nivegacetor is characterized by an improved safety profile and holds the potential to halt or delay amyloid accumulation and become an orally administered disease-modifying therapy for the treatment of AD.