Fosigotifator (ABBV-CLS-7262): A Comprehensive Monograph on an eIF2B Activator in Clinical Development for Neurodegenerative and Psychiatric Disorders

Executive Summary

Fosigotifator (ABBV-CLS-7262) is a first-in-class, orally bioavailable, central nervous system (CNS)-penetrant small molecule being developed as an activator of eukaryotic initiation factor 2B (eIF2B). This enzyme is a critical regulator of the Integrated Stress Response (ISR), a fundamental cellular pathway implicated in the pathophysiology of numerous age-related and neurodegenerative diseases. The drug is the product of a strategic collaboration between Calico Life Sciences, a subsidiary of Alphabet focused on the biology of aging, and the global biopharmaceutical company AbbVie. This partnership has pursued a novel, pathway-centric development strategy, investigating Fosigotifator across three distinct therapeutic areas that share the common mechanistic link of chronic ISR activation: amyotrophic lateral sclerosis (ALS), Vanishing White Matter (VWM) disease, and Major Depressive Disorder (MDD).

The clinical development program for Fosigotifator has yielded a complex and nuanced profile. The largest and most advanced study, Regimen F of the HEALEY ALS Platform Trial, failed to meet its primary endpoint of slowing disease progression at the pre-specified primary dose. This outcome represented a significant setback for the program. However, a pre-specified analysis of an exploratory high dose revealed statistically significant and potentially clinically meaningful signals, demonstrating a marked slowing in the decline of both upper and lower extremity muscle strength. This finding, coupled with the drug's exceptionally benign safety profile across all studies, suggests that the primary dose was suboptimal and provides a clear, albeit challenging, path forward for the ALS indication.