Accelerated drug-testing platform for ALS paves way for therapeutic innovation

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Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few treatment options. Since 2018, the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham healthcare system, has been working with national and international stakeholders to accelerate amyotrophic lateral sclerosis research by launching the first platform trial in amyotrophic lateral sclerosis to simultaneously test multiple drugs using shared trial infrastructure and placebo data. Findings from the first four drugs evaluated through the trial are published in papers appearing in JAMA, JAMA Neurology, and JAMA Network Open.

“Recent progress in the clinical sciences has fueled a large pipeline of drugs for amyotrophic lateral sclerosis that are waiting to be tested,” said Sabrina Paganoni MD PhD, co-director of the Neurological Clinical Research Institute (NCRI) at MGH. Paganoni is also an associate professor of Physical Medicine and Rehabilitation at Spaulding Rehabilitation. “For a quickly progressing disease like amyotrophic lateral sclerosis, trials need to be extraordinarily efficient to bring drugs to patients as rapidly as possible. A platform trial is the perfect approach for doing this.”

Unlike most clinical trials, which are established to test individual treatments, a platform trial takes a disease-based approach. This approach, which has been employed for cancer research, establishes common research protocols and resources to streamline parallel testing of many promising therapies in multi-center, double-blind, placebo-controlled studies.

“This groundbreaking approach has been shown to reduce the time to find an effective treatment by half and decrease costs by a third or more,” said Merit Cudkowicz MD MSc, director of the Sean M. Healey & AMG Center for ALS, principal investigator of the HEALEY ALS Platform Trial and executive director of the Mass General Brigham Neuroscience Institute. “It unites patients, clinicians, scientists and industry partners.”

By pooling placebo data across trials, the platform reduces the proportion of patients assigned to placebos to 25 percent, allowing more patients to receive investigational therapies. The platform is perpetual and adaptive, meaning new therapies can be added until effective treatments are identified.

Each of the first four trials included approximately 160 patients, with roughly 120 receiving an investigational drug and 40 receiving a placebo. As phase 2 trials, the goal of these studies was to rapidly assess drug candidates and determine whether to proceed with larger trials. Of the four regimens, two drugs (CNM-Au8 and pridopidine) are moving to phase 3 testing. Though neither met criteria demonstrating statistically significant benefit over 24 weeks, the phase 2 trials showed promising trends in other outcome measures and biomarkers and helped clarify dosage information and target populations, informing the phase 3 design.

“The platform trial is a unique opportunity to work collaboratively with several experts in amyotrophic lateral sclerosis around the country,” said James Berry MD MPH, first author of the paper reporting findings on CNM-Au8, chief of the MGH Division of ALS and Motor Neuron Diseases and co-director of the NCRI. The study of pridopidine was co-led by Jeremy Shefner MD PhD, of the Barrow Neurological Institute and Björn Oskarsson, MD, of the Mayo Clinic in Jacksonville, Florida. Shefner, alongside Cudkowicz, co-founded the Northeast ALS (NEALS) Consortium, a key HEALEY ALS Platform Trial collaborator. The other lead investigators of these four studies include Christina Fournier, MD, of Emory University, Jinsy Andrews, MD, of Columbia University, and Nicholas Maragakis, MD, of Johns Hopkins School of Medicine.

The two other drugs tested, zilucoplan and verdiperstat, will not move to phase 3 trials, though deidentified placebo data and samples will be shared in public databases for future research thus supporting additional research in amyotrophic lateral sclerosis and other neurodegenerative diseases. Three new trials from the platform have completed enrollment, and additional trials will launch in the future.

“These four papers and the initial few years of the platform trial have shown that when people work together, they can achieve more,” said Suma Babu MBBS MPH, codirector of the NCRI, who co-led the trial of verdiperstat. “An answer for amyotrophic lateral sclerosis will not come from one source, but from a larger ecosystem that unites the different pieces that are needed to bring change. There is hope, and there are people working hard to cure this complex disease in the best and most efficient way.”

Source: News Release
Massachusetts General Hospital
February 17, 2025