Sean M. Healey & AMG Center Announces Topline Results in HEALEY ALS Platform Trial with eIF2B Agonist DNL343

Sean M. Healey & AMG Center Announces Topline Results in HEALEY ALS Platform Trial with eIF2B Agonist DNL343 

• Primary endpoint of overall function (ALSFRS-R) and survival, and key secondary endpoints of muscle strength and respiratory function, were not met at 24 weeks. 
• Overall, DNL343 was found to be safe and well-tolerated. 
• Additional analyses, including neurofilament light (NfL) and other fluid biomarkers, pre-specified sub-group analyses and analyses from the active treatment extension period are expected later in 2025.

 
BOSTON – The Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital today announced topline results from an analysis of Regimen G evaluating DNL343, an eIF2B agonist developed by Denali Therapeutics Inc., in adults with amyotrophic lateral sclerosis (ALS). 

For the primary analysis, a total of 186 participants who were randomized to receive DNL343 treatment were compared to 139 participants randomized to receive placebo in this Regimen (n=63) or shared from a concurrently enrolling regimen (n=76).  

The primary endpoint of overall function as measured by the ALS functional rating scale-revised (ALSFRS-R) and survival from baseline through 24 weeks was not met. Key secondary endpoints, measuring muscle strength and respiratory function, were also not statistically different between the active and placebo groups at week 24. Overall, DNL343 was found to be safe and well-tolerated. Additional analyses, including pre-specified subgroup analyses, longer term clinical effects from the active treatment extension period data, target engagement, NfL and other disease biomarker data are expected later in 2025.   

“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,” says Merit Cudkowicz, MD, MSc, principal investigator and sponsor of the HEALEY ALS Platform Trial, director of the Sean M. Healey & AMG Center for ALS, chief of the Department of Neurology at MGH, and the Julieanne Dorn Professor of Neurology at Harvard Medical School. “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.” 

Regimen G is co-led by Suma Babu, MBBS, MPH, and Sabrina Paganoni, MD, PhD, physician investigators at the Healey & AMG Center for ALS at MGH. 

“Every study contributes valuable insights that bring us one step closer to finding effective therapies for this challenging disease,” said Drs. Babu and Paganoni. “We are grateful to the participants and their families for their dedication and support in this critical research.” 

The HEALEY ALS Platform Trial was made possible by funding from The AMG Charitable Foundation, Tackle ALS, The ALS Association, ALS Finding A Cure®, ALS ONE, The Muscular Dystrophy Association, Arthur M. Blank Family Foundation, I AM ALS, Tambourine ALS Collaborative and countless individuals who support the HEALEY ALS Platform Trial. 

For updates on the trial, please join our HEALEY ALS Platform Trial webinars. 

The HEALEY ALS Platform Trial is a patient-centric clinical trial designed in collaboration with the Northeast ALS Consortium (NEALS) to accelerate the development of breakthrough treatments for persons with ALS by testing multiple drugs (regimens) at the same time with efficient use of patient, scientific, and operational resources. So far, seven regimens have been included in the trial and more regimens will become available soon, with the goal of adding approximately three regimens per year. Data derived from the trial, if positive, could be used to support the potential approval of an investigational medication. Moreover, results from the trial, even when negative, can advance current knowledge related to the mechanisms underlying ALS and aid in the development of new biomarkers, laying the foundation for new avenues of scientific inquiry. 

Background on ALS  
Amyotrophic lateral sclerosis (ALS) is the most prevalent adult-onset progressive motor neuron disease, affecting approximately 30,000 people in the U.S. and an estimated 500,000 people worldwide. ALS causes the progressive degeneration of motor neurons, resulting in muscle weakness and atrophy. There is an urgent need to understand the biology of ALS and to develop effective therapies.  

About DNL343 

DNL343 is a novel investigational ALS therapy that targets eIF2B, a central regulator of the integrated stress response (ISR). The ISR appears to be overactive in ALS, leading to the formation of stress granules containing TDP-431,2. Buildup of TDP-43 is harmful and leads to neuronal degeneration. In preclinical data, inhibition of the ISR by DNL343 dissolves TDP-43 containing stress granules and decreases ISR biomarkers. The safety, pharmacokinetics, and pharmacodynamics of DNL343 have been characterized in both healthy participants and people with ALS, in a Phase 1 (N=47) and a Phase 1b (N=29) study, respectively, with dosing for up to 28 days. Results from both studies demonstrated that once-daily oral dosing with DNL343 was generally well tolerated and exhibited extensive cerebrospinal fluid (CSF) penetration. In addition, robust inhibition of biomarkers associated with the ISR pathway was observed in blood samples from study participants. DNL343 is an investigational therapeutic and has not been approved by any regulatory authority for any commercial use. 

Fang, MY et al. “Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD.” Neuron 2019 Sep 4;103(5):802-819 
Luan, W et al. “Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS and FTD.” Mol Psychiatry 2023 Jun;28(6):2445-2461 

 

About the Sean M. Healey & AMG Center for ALS at Mass General   

At the Sean M. Healey & AMG Center for ALS at Mass General, we are committed to bringing together a global network of scientists, physicians, nurses, foundations, federal agencies, and people living with ALS, their loved ones, and caregivers to accelerate the pace of ALS therapy discovery and development.  
 
Launched in November 2018, the Healey & AMG Center, under the leadership of Merit Cudkowicz, MD and a Science Advisory Council of international experts, is reimagining how to develop and test the most promising therapies to treat the disease, identify cures and ultimately prevent it.  
 
With dozens of active clinical trials and lab-based research studies in progress right now, we are ushering in a new phase of ALS treatment and care. Together, we will find the cures.