BOSTON -- The Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital in conjunction with Denali Therapeutics have announced the first participant-dosing in Regimen G of the HEALEY ALS Platform Trial testing DNL343.

The trial, led by the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital in collaboration with the Northeast ALS Consortium (NEALS), is a trial in which multiple investigational drugs are tested and evaluated simultaneously to accelerate the development of potential new ALS therapies. Drug candidates that enter the platform trial are chosen by a group of expert ALS scientists and members of the Healey & AMG Center Science Advisory Committee.

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-43. Buildup of TDP-43 is harmful and leads to neuronal degeneration. In the lab, 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 being developed by Denali Therapeutics Inc., a biotechnology company based in South San Francisco, Calif., and is not yet approved for use in any country.

"We look to forward to testing DNL343 for people with ALS,” said 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. “By starting enrollment for Regimen G, we are another step closer to establishing new and effective treatments for ALS.”

The HEALEY ALS Platform Trial is a large-scale collaborative effort made possible by contributions from patients and families, clinical trial sites, industry partners and research collaborators and several foundations.

“The HEALEY ALS Platform Trial continues to test multiple investigational drugs, and produce a wealth of data, samples, and tools to better understand ALS and to continue to advance the field of ALS clinical trials” said Suma Babu, MBBS, MPH, co-lead investigator of the regimen and physician investigator at the Healey & AMG Center for ALS at MGH. “We look forward to further evaluating DNL343 in ALS participants in an expeditious and scientifically rigorous manner in the platform trial.”

“We would like to express our sincere thanks to all the participants in the HEALEY ALS Platform Trial, and we are happy for this regimen of DNL343 to get underway” said Sabrina Paganoni, MD, PhD, co-principal investigator of the trial, physician scientist at the Healey & AMG Center, and Associate Professor of PM&R at Harvard Medical School. “Along with our industry partners, academic collaborators, foundations and benefactors, these critical milestones in the fight against ALS would not be possible without the robust partnership with the patient community.”

For more information about the HEALEY ALS Platform Trial, visit the website and register for the HEALEY ALS Platform Trial Weekly Q&A Webinars.


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 progressive muscle weakness and atrophy. There are currently few FDA therapies approved for treating ALS—riluzole, edaravone (IV and oral formulation), Relyvrio, and Qalsody. Nuedexta is also used for the symptomatic treatment of pseudobulbar affect (PBA) in people with ALS.

 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 on a quest to discover life-saving therapies for all individuals affected by ALS. Launched in November 2018, the Healey Center leverages a global network of scientists, physicians, nurses, caregivers, people with ALS and families working together to accelerate the pace of ALS therapy discovery and development.

Under the leadership of Merit Cudkowicz, MD and a Science Advisory Council of international experts, we are reimagining how to develop and test the most effective therapies to treat the disease, identify cures and, ultimately, prevent it.

The key to our success is our tightly integrated research and clinical efforts, encouraging opportunities to bring the challenges our patients face every day into our laboratories, focusing investigations on finding solutions that will make a meaningful difference to our patients without delay. Our collaborative efforts are designing more efficient and effective clinical trials while broadening access to these trials for people with ALS.