Innovative Platform Trial Reshapes the Future of ALS Drug Discovery and Evaluation
Key Findings
- The HEALEY ALS Platform Trial allows simultaneous testing of multiple investigational ALS therapies with efficient use of resources
- A shared protocol and infrastructure enable the use of a single placebo group and maximizes the number of patients receiving the active drug in each trial
- Results for the first four drugs validated the use of adaptive platform trials to rapidly evaluate drug candidates and determine their efficacy for ALS treatment
In February 2025, researchers, including members of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, published results from the first four drugs evaluated through the HEALEY ALS Platform Trial. Their findings validated the innovative approach to streamlining randomized placebo-controlled clinical trials evaluating ALS therapies.
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"The results reinforce the significant impact that perpetual, adaptive platform trials can have on ALS research," says Sabrina Paganoni, MD, PhD, co-director of the Neurological Clinical Research Institute (NCRI) at Mass General and first author on one of the studies. "These trials allow us to build on each success by consistently offering ALS patients access to the most promising treatments available."
Building a Better Discovery Pipeline
ALS offers unique perspectives on the difficulties of identifying and effectively assessing treatments for a highly heterogeneous disease. Because numerous research entities are developing ALS therapies, the challenge is less about identifying drug candidates than it is about quickly and effectively evaluating them in patients with a rapidly progressing disease.
Established in 2018, the Sean M. Healey & AMG Center for ALS offers the resources and infrastructure required to support an adaptive platform trial for ALS. This unique protocol enables simultaneous evaluation of multiple treatments and comparison of outcomes across similar patient cohorts. The approach not only speeds up patient access to experimental therapies but also delivers rapid feedback on the efficacy of both the drugs and the disease pathways they target.
"Something this ambitious requires the right people in the right place, significant resources, and a disease with worldwide interest and visibility," says Dr. Paganoni. ALS met these criteria with a robust drug development pipeline and a worldwide network of patients eager for options. "You also need catalysts to set things in motion and then sustain that momentum over a long period of time."
Those catalysts were Sean Healey, an investment banker diagnosed with ALS in 2018, and Merit Cudkowicz, MD, MSc, chair of the Department of Neurology and director of the Sean M. Healey & AMG Center for ALS. As an original co-founder of the Northeast ALS Consortium in 1995, Dr. Cudkowicz expanded what began as collaborations between nine academic centers into more than 150 research centers worldwide.
Healey's philanthropy and Dr. Cudkowicz's vision helped revolutionize clinical trials for ALS by streamlining drug candidate assessment. Although normally requiring years to design and fund, the HEALEY ALS Platform Trial, the first of its kind in the world, was underway within one year of design, with outcomes obtained on four different drugs within two years.
Learning About ALS by Treating It
In 2019, approximately 30 pharmaceutical companies submitted proposals for inclusion in the first platform trial for ALS. A prerequisite for inclusion was the existence of a strong scientific rationale, previous safety experience, and well-defined biomarkers signaling each drug's effect on a given biological process. This would allow evaluation of ALS-specific disease mechanisms and the drug's impact on their status.
The drugs ultimately chosen demonstrated strong preclinical evidence of efficacy in targeting different mechanisms involved in ALS progression—neuroinflammation, energy metabolism, and neurodegeneration. Including drugs with different mechanisms of action is important, as more knowledge is needed about the impact of different target pathways on disease status. These outcomes offer invaluable insight into both the drug's efficacy and the viability of specific disease mechanisms as therapeutic targets.
"The platform approach essentially allows multiple Phase 2 trials to rapidly screen drugs and provide clear decisions on whether to move forward with their assessment," explains Dr. Paganoni.
Data from these trials also help inform the design of subsequent studies and offer drug developers insight into directions for future developmental phases.
"We obviously want to find a drug that elicits a positive effect in ALS patients," says Dr. Paganoni. Regardless of the outcome, the platform trial provides knowledge that can't be obtained as quickly or definitively using other avenues. "Being deliberate in choosing which drugs to test and how to analyze their outcomes allows the trial to increase the collective understanding of how ALS works and where to look next."
Prioritizing ALS Patients
Perhaps the most attractive aspect of the platform trial is that the master protocol shared between regimens enables the placebo arms to be shared across studies. Of the approximately 160 patients enrolled in each trial, only a small percentage was randomized to the placebo group. For each regimen, the reported 3:1 ratio of patients receiving the active drug to those receiving a placebo is rare in clinical trials and enormously beneficial to patients.
"The shared infrastructure means that all patients enroll according to the same criteria across sites, enabling us to utilize a single, smaller placebo group between trial regimens," says Dr. Paganoni. The hope afforded by experimental therapies to patients with rapidly progressing disease prioritizes limiting the likelihood of their randomization to a placebo group. "This allows us to maximize the number of patients that will receive the active drug."
For each regimen in the platform trial, the primary efficacy outcome was a change in disease severity measured as patient function according to the ALS Functional Rating Scale and survival over a 24-week period. The therapeutic effect was quantified according to a statistical model developed for the platform trials that uses patient function/survival to estimate the slowing of disease progression.
Comprehensive clinical and biological data were also collected from each participant to fully characterize the effects of the drugs and gather important genomic, biomarker and digital data about the disease itself.
Their findings published in JAMA (2), JAMA Neurology, and JAMA Network Open revealed that none of the first four drugs met the primary endpoint. However, results in some of the secondary and exploratory analyses supported further testing for two of the drugs.
Other lead authors of these studies include James Berry, MD, MPH, chief of the Division of ALS and Motor Neuron Diseases at Mass General Brigham, and Suma Babu, MBBS, MPH, co-director of the NCRI at Mass General, as well as collaborators from other major academic medical centers.
Dr. Paganoni adds that the studies were the result of collaborations among several ALS investigators in the NEALS consortium, industry partners, and patient groups and foundations. The larger takeaway from their findings was that the platform trial model delivered the results rapidly and efficiently, as intended in the design, including:
- Speed: Four double-blind, randomized, placebo-controlled trials testing four different drugs in a large cohort of ALS patients were completed within two years from trial launch providing industry partners with clear data to inform their clinical development programs.
- Adaptability: Use of interim analyses enabled early termination of one regimen for futility, saving patients 279 trial visits and over 14,000 doses of the drug and potentially allowing their enrollment in other research studies.
- Flexibility: The master protocol enabled separate secondary analyses of individual regimens that generated drug-specific data, prompting additional studies for two of the drugs.
"We've known that adaptive platform trials increase patient access to experimental drugs, cut costs of performing clinical trials, and decrease the placebo burden on patients," says Dr. Paganoni. "These outcomes from the first four regimens provide evidence that they also increase the speed at which we learn about both the drugs and their targets."
Sharing Knowledge to Accelerate Progress
In 2024, the HEALEY ALS Platform Trial Study Group published an overview of their experience with the Platform Trials for ALS, along with lessons learned. Recognition of their success has increased interest in wider applications across the research landscape. Dr. Paganoni says that they've met with over 20 research groups requesting guidance on establishing platform trials. Those groups include one led by Anne-Marie Wills, MD, MPH, director of the CurePSP Center of Care at Mass General, who will be initiating a platform trial in 2025 to evaluate treatment options for progressive supranuclear palsy.
The adaptive aspect of platform trials allows the master protocol to be amended at any time. Such changes include adding new drug regimens or incorporating changes that alter how the trials are performed based on the learnings from prior years. With the publication of data for the first four regimens, they've "retired" the placebo data used in those studies and generated a revised master protocol in preparation for regimens being evaluated in 2025.
Dr. Cudkowicz says that some of the changes in the new master protocol include lengthening the testing period for each regimen, enrollment of participants earlier in the disease, and addition of promising biomarkers. "We're continuing to refine our patient-centered approach by including more options for remote visits and adding more sites to bring the trial even closer to where patients live," she explains. Having tested seven different drugs to date, they're slated to initiate testing of several new regimens in 2025 and 2026.
Dr. Paganoni adds that as part of their commitment to driving progress in ALS research, data from patients in the placebo arm of the original regimens are being deposited into public repositories accessible to researchers focused on ALS. The team will also share biological samples from placebo participants and genome sequences that can be used to identify and develop reliable ALS biomarkers, as well as generate discoveries in other neurodegenerative diseases.
"These findings and the evolution of the platform trial would not have been possible without the generosity and efforts of hundreds of patients and their families," says Dr. Paganoni. "Making placebo data and samples available amplifies their contribution to the future of ALS research and helping those fighting the same disease."