Denali Therapeutics has announced topline results from the phase 2/3 Healey ALS Platform Trial, which evaluated the effects of its drug candidate DNL343. The study did not meet the primary efficacy endpoint of slowing disease progression in comparison with a placebo, as measured using the ALS Functional Rating Scale-Revised (ALSFRS-R).
What is ALS?
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a progressive neurodegenerative disorder that affects nerve cells in the brain and spinal cord. It leads to the gradual loss of muscle control, as motor neurons responsible for sending signals to muscles degenerate and die. Over time, individuals with ALS experience increasing difficulty in speaking, swallowing, and breathing. While the exact cause of ALS is not fully understood, genetic and environmental factors are believed to play a role. Currently, there is no cure for ALS, but ongoing research aims to develop effective treatments to slow its progression and improve quality of life.
It is believed that ALS prevalence varies by region, with estimates ranging from approximately four to six per 100,000 individuals. This suggests that, worldwide, there are between 300,000 to 450,000 people living with ALS at any given time
For the analysis of the primary endpoint, 186 patients who received DNL343 were compared to 139 patients who received a placebo over the course of 24 weeks. While the drug candidate was found to be safe and well tolerated, the ALSFRS-R showed no significant change in disease severity over time. Key secondary endpoints looking at muscle strength and respiratory function were also not statistically different between both patient groups.
Understanding the Role of DNL343 and Macrocycles
DNL343 is a small molecule drug that acts as an agonist of eIF2B, which regulates the integrated stress response (ISR). The ISR has been reported to be overactive in patients with ALS, causing the accumulation of the TDP-43 protein, which is involved in the process of neuronal degeneration.
Early clinical studies showed that DNL343 was able to penetrate the cerebrospinal fluid and inhibit the ISR pathway in blood samples from study participants. To further understand the effects of the drug candidate, Denali Therapeutics is expecting additional analysis of the clinical trial data later this year. These will include the analysis of neurofilament light (NfL) and other biomarkers, as well as data from patient subgroups and from a treatment extension period.
“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,” said Merit Cudkowicz, professor of neurology at Harvard Medical School, director of the Sean M Healey & AMG Center for ALS, and principal investigator and sponsor of the Healey ALS Platform Trial. “We have additional pre-specified subgroup analyses and biomarker work, including NfL, pending from this regimen, as well as long-term efficacy data from participants who continued in the active treatment extension period. We remain deeply committed to fully understanding the effects of DNL343 in ALS and will further evaluate the data before determining next steps.”
“Better treatment options for individuals with ALS are critically needed,” said Carole Ho, Chief Medical Officer of Denali Therapeutics. “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.”
