Denali's ALS Drug DNL343 Fails to Show Efficacy in Extended Trial, Casting Doubt on eIF2B Mechanism

Denali Therapeutics' amyotrophic lateral sclerosis (ALS) drug candidate, DNL343, has failed to demonstrate efficacy in an extended clinical trial, dealing a significant blow to the company's neurodegenerative disease pipeline. The disappointing results raise questions about the viability of eIF2B activation as a therapeutic approach for ALS and potentially other neurological disorders.

DNL343 Misses Key Biomarker Endpoints

Denali announced in a recent Securities and Exchange Commission filing that DNL343 did not show a treatment effect on neurofilament light (NfL), a crucial biomarker of neuronal damage, in either the initial 24-week trial or the subsequent 28-week open-label treatment extension. This outcome follows the drug's failure to slow ALS progression or improve secondary outcomes such as muscle strength and respiratory function in the initial phase 2/3 readout earlier this year.

The company had previously expressed hope that additional analyses of trial data, including the drug's effect on NfL and specific patient subgroups, would yield positive results. However, these expectations have not been met, prompting Denali to halt the extension arm of the trial.

Implications for eIF2B-Targeting Therapies

DNL343's continued lack of efficacy raises concerns about the broader potential of eIF2B activation as a therapeutic strategy. The drug is designed to activate the protein complex eIF2B, which is believed to protect neurons by preventing further aggregation of the TDP-43 protein, a hallmark of ALS pathology.

This setback may have implications beyond Denali, potentially affecting other companies pursuing similar approaches:

1. AbbVie and Calico's eIF2B agonist, fosigotifator, also failed in the same Massachusetts General Hospital trial.
2. Bristol Myers Squibb, which paid Evotec a $20 million option fee to license an eIF2B candidate in 2021, may need to reevaluate its strategy. BMS currently has an eIF2B activator in phase 1 development for Alzheimer's disease.

Denali's Path Forward

Despite the disappointing results, Denali is not yet ready to abandon DNL343 entirely. The company stated that it "intends to assess potential future development opportunities for DNL343." However, industry analysts, such as those at William Blair, described the latest updates as "disappointing but largely expected following the previous update on the failed study."

Denali's focus may now shift more heavily towards its Hunter syndrome enzyme replacement therapy, tividenofusp alfa (tivi), also known as DNL310. A recent phase 1/2 study showed that tivi met its primary safety endpoints and reduced key biomarkers of the disease. Analysts are now looking ahead to updates on the accelerated approval Biologics License Application (BLA) filing for tivi, which is expected in early 2025, with potential acceptance and approval anticipated in late 2025 or early 2026.