Denali Therapeutics revealed disappointing topline results from a phase 2/3 trial evaluating its eIF2B agonist, DNL343, in the treatment of amyotrophic lateral sclerosis (ALS).
The study did not meet the primary endpoint of efficacy in slowing disease progression (measured by the ALS Functional Rating Scale-Revised) when compared with placebo, according to an analysis of Regimen G of the phase 2/3 HEALEY ALS Platform Trial. Key secondary endpoints, measuring muscle strength and respiratory function, were also not statistically different between the active and placebo groups at week 24.
Overall, DNL343 was found to be safe and well tolerated. San Francisco-based Denali says it still has additional pre-specified subgroup analyses and biomarker work, including treatment effects on neurofilament light, expected in 2025.
DNL343 is a novel oral small molecule ALS therapeutic candidate that targets eIF2B, a central regulator of the integrated stress response (ISR) that appears to be overactive in ALS. In preclinical data, inhibition of the ISR by DNL343 dissolved TDP-43 containing stress granules and decreased biomarkers of the ISR.
Last month, Denali announced that it had begun dosing patients in a phase 2a Parkinson’s disease study of an investigational leucine-rich repeat kinase 2 (LRRK2) inhibitor being developed in partnership with Biogen.