Healey & AMG Center & the Northeast ALS Consortium announce results in platform trial with pridopidine

BOSTON – The Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital and the Northeast ALS (NEALS) Consortium today announced results from Regimen D of the HEALEY ALS Platform Trial evaluating pridopidine versus placebo in adults with amyotrophic lateral sclerosis (ALS).

Pridopidine is a highly selective sigma-1 receptor (S1R) agonist developed by Prilenia Therapeutics for the treatment of neurodegenerative disorders. The S1R is highly expressed in the brainstem and spinal cord, areas implicated in ALS and important for bulbar, speech and limb function. Loss of function (LOF) mutations in the S1R gene cause juvenile ALS and partial LOF mutations result in adult ALS. The S1R positively regulates key cellular pathways that are commonly impaired in ALS and other neurodegenerative diseases. In ALS cell culture and mouse models, pridopidine has been shown to be neuroprotective, specifically mediated via the activation of S1R.

The primary analysis, evaluating overall function as measured by the revised ALS functional rating scale and survival in the full analysis set from baseline through 24 weeks did not meet the criterion for success. Change in secondary endpoints measuring muscle strength and respiratory function were also not statistically different in the full analysis set between the active and placebo groups. Consistent with recent ALS trials, greater benefit of pridopidine was observed in certain prespecified analyses among the subset of participants who were within 18 months of onset of symptomatic weakness and among those within 18 months of onset who also met El Escorial criteria for definite ALS.

In addition, based on the mechanism of action of the drug and its potential relevance to bulbar and speech function, special attention was given to collecting and analyzing speech production using quantitative voice characteristics derived from data collected with a smartphone application (Aural Analytics, Scottsdale, AZ). Pre-specified analyses of speech production demonstrated substantial improvements in sustained phonation, speaking rate, articulation rate, and articulatory precision in participants taking pridopidine compared to those taking placebo. Consistent with the functional outcomes data, greater improvements in speaking rate and articulation rate were seen among participants within 18 months of onset who also met El Escorial criteria for definite ALS.

No safety issues were found in terms of tolerability, serious and non-serious adverse events, laboratory tests, or vital signs. The open-label extension part of the trial is ongoing.

In a post-hoc analysis of neurofilament light (NfL) levels, a biomarker of neuronal loss, pridopidine decreased NfL levels with an average reduction of 40% after 24 weeks compared to placebo in rapidly declining patients with symptom duration less than 18 months.

“The positive results on speech and bulbar function, and on overall function and breathing in people earlier in disease course, are very encouraging and deserve further investigation in a phase III trial. Those are sensitive measures of disease progression and may indicate a general benefit of pridopidine that we were not able to detect in this study," 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 Mass General, and the Julieanne Dorn Professor of Neurology at Harvard Medical School. “We are thankful to the many people who participated in this study and the staff at all the trial sites. This was a successful phase II trial where we learned a tremendous amount that will inform the follow-on clinical trials of pridopidine in ALS. These data will also have a broad impact on the way we evaluate speech in ALS, and on understanding response to treatments in different stages of ALS.”

The pridopidine regimen of the HEALEY ALS Platform Trial was co-led by Drs. Jeremy Shefner of Barrow Neurological Institute and Björn Oskarsson of the Mayo Clinic.

“We would like to extend our sincere gratitude to participants in the pridopidine regimen who committed their invaluable time and hope in the trial, as well as to the NEALS investigators and study staff who dedicated their effort and expertise," said Jeremy Shefner, MD, PhD, Professor of Neurology and Chief Medical Officer for Clinical Research, Barrow Neurological Institute. “We are encouraged by these results and the potential of pridopidine to treat people living with ALS and look forward to collaborating with Prilenia on the next steps of this drug development program.”

The HEALEY ALS Platform Trial was designed to accelerate the development of breakthrough treatments for persons with ALS by testing multiple drugs. The pridopidine regimen succeeded in providing comprehensive safety data and identifying the population that is most likely to respond to the drug. The pridopidine regimen was also the first trial to show positive effects on digital measures of speech, a critical function for people living with ALS.

“This trial represents an important contribution to ALS research,” said Björn Oskarsson, neurologist at Mayo Clinic in Florida. “In addition to providing information about the drug in ALS, it suggests a path for the future development of pridopidine. We learned a lot about the role of speech analysis as an efficient clinical trial endpoint, and this can help us move faster toward effective treatments for ALS.”

Pridopidine was the fourth compound evaluated in the platform trial. Regimen E, testing intravenous administration of trehalose, a product of Seelos Therapeutics, is ongoing. Regimens F and G are scheduled to begin enrolling participants in 2023.

The HEALEY ALS Platform Trial and this important milestone were 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.

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 (Rilutek, Tiglutik, Exservan), edaravone (Radicava, Radicava ORS), sodium phenylbutyrate/taurursodiol (Relyvrio), dextromethorphan/quinidine (Nuedexta).

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.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers, and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.