Key points from article :
Efforts by AbbVie, Calico, and Denali Therapeutics to treat ALS by targeting the eIF2B protein complex have faced setbacks, as recent phase 2/3 trials failed to meet primary endpoints. Despite initial hopes, neither fosigotifator nor DNL343 significantly slowed disease progression or improved muscle strength and respiratory function after 24 weeks of treatment.
The drugs were tested in parallel under the HEALEY ALS Platform trial, which explores multiple therapeutic candidates to combat the progressive neurodegenerative disease. Both compounds aimed to protect neurons by preventing TDP-43 protein aggregation, but neither showed meaningful improvements compared to placebo.
However, early signs suggest a possible positive effect on muscle strength and lung function for high doses of fosigotifator, and further subgroup analyses may reveal more about DNL343’s potential benefits. Denali expressed a desire for longer trial durations, but shorter studies were preferred by ALS patients, given the disease's rapid progression.
Though the recent failures are disappointing, ongoing analyses and the possibility of longer-term trials keep the door open for these treatments. The findings may also impact other pharmaceutical players like Bristol Myers Squibb, which is pursuing similar eIF2B-targeting therapies for neurological conditions.
