Denali and AbbVie’s ALS Candidates Fail Phase 2/3 Trials, Highlighting Challenges in ALS Research

Denali Therapeutics' DNL343 and AbbVie/Calico's fosigotifator failed to meet primary endpoints in the HEALEY ALS Platform Trial, a Phase 2/3 study aimed at slowing disease progression in amyotrophic lateral sclerosis (ALS) patients1 3 4.
The primary endpoint, measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) and survival through 24 weeks, was not met by either drug candidate1 3.
Key secondary endpoints, including muscle strength and respiratory function, also did not show significant improvements compared to placebo1 3.
Despite the overall failure, fosigotifator showed potential signals of efficacy at the exploratory high dose, particularly in slowing muscle strength decline and possibly in respiratory function3.
Both DNL343 and fosigotifator were found to be safe and well-tolerated, with no significant safety differences between doses1 3.
The HEALEY ALS Platform Trial has experienced multiple setbacks, including failures from other companies like Seelos Therapeutics and Amylyx Pharmaceuticals, highlighting the challenges in developing effective treatments for ALS2 5.
Further analyses, including subgroup analyses and biomarker measurements, are expected later in 2025 and may provide additional insights into the potential of these drug candidates1 3.