Denali Therapeutics Reports Topline Results for DNL343 in Phase 2/3 ALS Trial

SOUTH SAN FRANCISCO, CA, USA | January 06, 2025 | Denali Therapeutics Inc. recently disclosed the preliminary findings from Regimen G of their Phase 2/3 HEALEY ALS Platform Trial, aimed at assessing the efficacy of the eIF2B agonist DNL343 for amyotrophic lateral sclerosis (ALS) treatment. Unfortunately, the study did not achieve its primary objective of demonstrating a significant reduction in disease progression compared to placebo. The primary endpoint was gauged through changes in disease severity via the ALS Functional Rating Scale-Revised (ALSFRS-R) and survival rates at the 24-week mark. Secondary measures, which included muscle strength and respiratory function, also failed to show significant differences between the DNL343 and placebo groups.

The primary analysis included 186 participants receiving DNL343 and 139 participants on placebo, with 63 directly in Regimen G and 76 from a concurrently enrolling regimen. Despite the lackluster efficacy results, DNL343 was determined to be safe and generally well tolerated. Further investigations are slated for later this year, focusing on neurofilament light (NfL) and other fluid biomarkers, as well as subgroup-specific data and extended findings from the treatment extension.

Carole Ho, M.D., Chief Medical Officer at Denali Therapeutics, emphasized the pressing need for improved ALS therapies, expressing gratitude for the collective efforts of participants, investigators, and the community in facilitating the HEALEY study. The study is deemed an advanced platform for evaluating DNL343's therapeutic promises in addressing ALS. Dr. Ho looks forward to more detailed analyses, including subgroup findings and treatment impacts on NfL, anticipated later this year.

Merit Cudkowicz, MD, MSc, principal investigator of the HEALEY trial and director of the Sean M. Healey & AMG Center for ALS, acknowledged the unexpected topline results but underscored the trial's value in enhancing ALS research understanding. She mentioned that additional subgroup analyses and biomarker assessments, including NfL, are pending, alongside long-term efficacy data from participants in the treatment extension period. Dr. Cudkowicz reaffirmed the dedication to comprehensively understanding DNL343's effects on ALS and intends to thoroughly evaluate the data before outlining the subsequent steps.

ALS remains the most common motor neuron disease in adults, affecting around 30,000 individuals in the U.S. and about 500,000 globally. It leads to progressive motor neuron degeneration, causing muscle weakness and atrophy. Understanding ALS biology and developing effective treatments is a pressing need.

DNL343 is an innovative small-molecule therapeutic candidate targeting eIF2B, a key regulator in the integrated stress response (ISR), which is overly active in ALS. This overactivity results in stress granules containing TDP-43, which harm neurons. In preclinical studies, DNL343 dissolved these granules and reduced ISR biomarkers. Early clinical trials showed that DNL343, administered once daily orally, was generally well tolerated and significantly penetrated cerebrospinal fluid, with robust inhibition of ISR pathway biomarkers in blood samples. However, DNL343 remains investigational, with its safety and efficacy profile yet to be fully established.

The HEALEY ALS Platform Trial, spearheaded by the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital in collaboration with the Northeast ALS Consortium, is a large-scale collaborative effort. It seeks to expedite ALS treatment development by evaluating multiple investigational therapies simultaneously, selecting candidates through expert ALS scientists and the Healey & AMG Center.

Denali Therapeutics, headquartered in South San Francisco, is a biopharmaceutical company focused on developing product candidates for neurodegenerative and lysosomal storage diseases, emphasizing genetically validated targets and delivery across the blood-brain barrier.