Denali Therapeutics’ amyotrophic lateral sclerosis (ALS) drug has racked up another clinical miss this year, leaving the company to mull the asset’s future.
The therapy, dubbed DNL343, is designed to activate the protein complex eIF2B, protecting neurons by preventing further aggregation of the TDP-43 protein. A phase 2/3 readout from a Massachusetts General Hospital trial at the start of the year showed that DNL343 was unable to slow ALS progression compared to placebo after 24 weeks or improve secondary outcomes like muscle strength and respiratory function.
At the time, Denali pinned its hopes on additional analyses of the trial data assessing the drug's effect on neurofilament light (NfL)—a biomarker of neuronal damage—as well as specific subgroups of patients and longer-term treatment data.
But the biotech announced in a Securities and Exchange Commission filing March 5 that these additional analyses hadn’t demonstrated a treatment effect on NfL in either the 24-week trial or in a 28-week open-label treatment extension.
As a result, Denali is moving to halt the extension arm of the trial, with the data to be presented at a future medical meeting.
The company isn’t quite ready to abandon the drug, however. For now, the biotech said it “intends to assess potential future development opportunities for DNL343.”
Related
Rival AbbVie and Denali prospects flunk phase 2/3 ALS tests, denting hopes for shared mechanism
Denali isn’t the only company to struggle in ALS. The same Massachusetts General Hospital trial also evaluated AbbVie and Calico’s eIF2B agonist, called fosigotifator, which was equally unsuccessful.
The continuing failure of DNL343 may have implications for Bristol Myers Squibb, which paid Evotec a $20 million option fee to license an eIF2B candidate in 2021. BMS’ phase 1 pipeline includes an eIF2B activator that is in development in Alzheimer’s disease.
In a note to clients, William Blair analysts described the latest updates on DNL343 as “disappointing but largely expected following the previous update on the failed study.”
The analysts are more focused on Denali’s Hunter syndrome enzyme replacement therapy, tividenofusp alfa (tivi), also known as DNL310. A phase 1/2 study last month showed the treatment met its primary safety endpoints and reduced key biomarkers of the disease.
“Much more relevant to our investment thesis will be updates in 2025 on the accelerated approval BLA filing (still on track for early 2025) for tivi to treat Hunter syndrome and potential acceptance and approval in late 2025 or early 2026,” the analysts added.