Denali Therapeutics Inc. (NASDAQ: DNLI) announced topline results from the Phase 2/3 HEALEY ALS Platform Trial, revealing that DNL343, an eIF2B agonist, failed to meet its primary endpoint in treating amyotrophic lateral sclerosis (ALS). The study, a part of the innovative HEALEY ALS Platform Trial, aimed to evaluate the efficacy of DNL343 in slowing disease progression compared to placebo.
The trial, known as Regimen G, compared 186 participants who received DNL343 with 139 participants who received a placebo. The primary endpoint was assessed by measuring the change in disease severity over time using the ALS Functional Rating Scale-Revised (ALSFRS-R) and survival through week 24. Key secondary endpoints included measurements of muscle strength and respiratory function.
Lack of Efficacy
The results indicated that DNL343 did not demonstrate a statistically significant impact on slowing disease progression compared to the placebo group. Furthermore, key secondary endpoints, such as muscle strength and respiratory function, also showed no significant differences between the two groups at week 24.
Safety and Tolerability
Despite the lack of efficacy, DNL343 was found to be safe and well-tolerated among the participants. This finding is crucial as it suggests that the drug does not pose significant adverse effects, which is an important consideration for future research and potential combination therapies.
Future Analyses
Denali Therapeutics plans to conduct further analyses of the study data, including assessments of neurofilament light (NfL) and other fluid biomarkers. These analyses will also include data from pre-specified subgroups and extended findings from the active treatment extension period. The company anticipates these additional analyses will be available later in 2025.
Carole Ho, M.D., Chief Medical Officer of Denali Therapeutics, stated, "Better treatment options for individuals with ALS are critically needed. We look forward to a more comprehensive analysis of the study results as additional analyses, including pre-specified subgroup analyses and treatment effects on NfL, become available later in 2025."
HEALEY ALS Platform Trial
The HEALEY ALS Platform Trial, led by the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH), is a collaborative effort designed to accelerate the development of new treatments for ALS. It allows for the simultaneous evaluation of multiple investigational therapies, making the drug development process more efficient.
Merit Cudkowicz, MD, MSc, principal investigator and sponsor of the HEALEY ALS Platform Trial, commented, "Though the initial top-line 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. We remain deeply committed to fully understanding the effects of DNL343 in ALS and will further evaluate the data before determining next steps."
About ALS
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to muscle weakness and atrophy. Approximately 30,000 people in the U.S. and an estimated 500,000 people worldwide suffer from ALS. The urgent need for effective therapies remains a significant challenge in the medical community.
About DNL343
DNL343 is a novel small molecule therapeutic candidate designed to target eIF2B, a central regulator of the integrated stress response (ISR). The ISR is believed to be overactive in ALS, leading to the formation of stress granules containing TDP-43. By inhibiting the ISR, DNL343 aims to dissolve TDP-43 containing stress granules and decrease biomarkers of the ISR.
