Calico's Small Molecule eIF2B Activator Falls Short in ALS Trial

Calico, the Alphabet-backed biotech focused on aging and longevity, has encountered a hurdle in its efforts to develop treatments for amyotrophic lateral sclerosis (ALS). Massachusetts General Hospital’s Healy ALS Platform trial found that fosigotifator, a candidate developed in collaboration with AbbVie, failed to meet its primary endpoint, delivering no significant impact on slowing disease progression after 24 weeks of treatment.

The trial, a perpetual phase 2/3 study evaluating multiple ALS therapies, tested fosigotifator alongside Denali Therapeutics’ DNL343. Both drugs are designed to activate the protein complex eIF2B, a mechanism intended to protect neurons by preventing aggregation of the TDP-43 protein—one of the hallmarks of ALS. Neither candidate demonstrated meaningful improvement in secondary measures such as muscle strength or respiratory function, further clouding hopes for the eIF2B-targeting approach.

Despite the disappointing primary outcomes, there is some optimism. Exploratory data suggests that higher doses of fosigotifator might slow muscle strength decline and positively influence lung function. Such findings could guide future research, though the immediate setback highlights the difficulties in tackling ALS, a disease with an average survival time of just two to three years post-diagnosis.

See also: The Explosion of Therapeutic Modalities: Small Molecules, Biologics, and Everything in Between

Fosigotifator represents a flagship program within the expansive collaboration between Calico and AbbVie. Initiated in 2014 with $250 million in funding, the partnership has since grown to a total commitment of $1.25 billion, with additional infusions in 2018 and 2021. The alliance has focused on leveraging Calico’s computational biology expertise and AbbVie’s drug development infrastructure to address age-related diseases.

Meanwhile, Denali Therapeutics, facing its second ALS failure within a year, is pinning its hopes on subgroup analyses and biomarker results to salvage its DNL343 program.

Topics: Clinical Trials