Novel small molecule for ALS fails to meet primary endpoint in phase 2/3 study
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Topline results from a phase 2/3 clinical trial showed that an eIF2B agonist to treat ALS failed to meet its primary endpoint of slowing disease progression compared with placebo at week 24.
According to a press release from Denali Therapeutics Inc., the small molecule DNL343 was examined in the Healey ALS Platform study, whose primary endpoint was change in disease severity measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) through week 24.
In addition, the company said, secondary endpoints measuring muscle strength and respiratory function were not statistically significant between treatment and placebo groups at week 24.
The study included 186 participants who received treatment with DNL343 and 139 participants given either placebo from regimen G (n = 63) or shared from a concurrently enrolling regimen within the ongoing trial (n = 76).
Overall, according to the release, DNL343 was “safe and well tolerated.”
DNL343 was developed to target eIF2B, a central regulator of the integrated stress response (ISR), which is overactive in ALS. This overactivity leads to formation of stress granules containing TDP-43, whose buildup is a factor in neuronal degeneration.
Preclinical data demonstrated that ISR inhibition by DNL343 dissolves TDP-43 containing stress granules, which subsequently decreases ISR presence, per the release.
“Though the initial topline clinical results of this trial were not what we hoped, the data collected is valuable in helping to understand the next stage of ALS research,” Merit Cudkowicz, MD, MSc, principal study investigator and director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, said in the release. “We remain deeply committed to fully understanding the effects of DNL343 in ALS and will further evaluate the data before determining next steps.”
Denali said in the release that further data analysis is expected later this year, including neurofilament light and other fluid biomarkers.