by Justin Jackson, Medical Xpress

Credit: Pixabay/CC0 Public Domain

Massachusetts General Hospital coordinated the first four platform trials within the HEALEY ALS platform to evaluate potential treatments for amyotrophic lateral sclerosis (ALS), with results published in various JAMA journals.

None of the tested agents (zilucoplan, verdiperstat, CNM-Au8, and pridopidine) met primary or secondary endpoints, but the trials demonstrated the platform's capacity for efficient and cost-effective therapeutic assessment.

ALS is a fatal neurodegenerative disorder with a lifetime risk of approximately 1 in 400. Most patients die from respiratory failure within two to three years of symptom onset. Effective disease-modifying therapies have yet to be found.

HEALEY ALS platform trial researchers employed a design allowing concurrent investigation of multiple agents within a shared infrastructure. Fifty-four U.S.-based clinical sites participated, all under the Northeast Amyotrophic Lateral Sclerosis Consortium.

Each trial randomized patients in a 3:1 treatment-to-control ratio, pooling approximately 160 control patients across the four trials. Patients underwent 24 weeks of treatment with options for open-label extensions. Bayesian shared parameter models estimated disease rate ratios, with values below 1 indicating potential clinical benefit.

Zilucoplan, a C5 complement inhibitor, was halted early due to futility. Verdiperstat, an oral myeloperoxidase inhibitor, showed no benefit in any assessed outcomes. CNM-Au8, a gold particle suspension aimed at improving cellular energetics, failed to meet primary endpoints but suggested potential benefits in neurofilament light chain levels and survival at lower doses. Pridopidine, a sigma-1 receptor agonist, showed nominal significance in 2 of 63 exploratory endpoints among patients with recent disease onset.

In an editorial published in JAMA, "Platform Trials in ALS, " John Turnbull, MD, Ph.D., of McMaster University, praises the platform's success in swiftly identifying ineffective interventions, an essential step in ALS drug development.

Turnbull noted that the platform's pooled-control model, Bayesian analysis and interim futility checks allowed rapid and efficient testing of multiple drugs in parallel. Challenges included variability in disease progression (a common issue in ALS research) and the trial's broad inclusion criteria potentially obscuring subgroup benefits.

Turnbull raised some concern about the trial's 24-week duration, questioning whether such a short window could miss potential longer-term benefits, especially considering ALS's highly variable disease course.

While large pharmaceutical companies may prefer conventional trial models, Turnbull said this "courageous and innovative" platform could be attractive for academic centers and smaller firms seeking to develop new ALS therapies. Future trials may refine entry criteria and consider extended durations to enhance the detection of meaningful clinical effects.

More information: John Turnbull, Platform Trials in ALS, JAMA (2025). DOI: 10.1001/jama.2025.0100 Sabrina Paganoni et al, Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis, JAMA Network Open (2025). DOI: 10.1001/jamanetworkopen.2024.59058 Verdiperstat in Amyotrophic Lateral Sclerosis, JAMA Neurology (2025). DOI: 10.1001/jamaneurol.2024.5249 CNM-Au8 in Amyotrophic Lateral Sclerosis, JAMA (2025). DOI: 10.1001/jama.2024.27643 Pridopidine in Amyotrophic Lateral Sclerosis, JAMA (2025). DOI: 10.1001/jama.2024.26429  Journal information: JAMA Network Open, Journal of the American Medical Association, Archives of Neurology

Sabrina Paganoni et al, Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis, JAMA Network Open (2025). DOI: 10.1001/jamanetworkopen.2024.59058

Verdiperstat in Amyotrophic Lateral Sclerosis, JAMA Neurology (2025). DOI: 10.1001/jamaneurol.2024.5249

CNM-Au8 in Amyotrophic Lateral Sclerosis, JAMA (2025). DOI: 10.1001/jama.2024.27643

Pridopidine in Amyotrophic Lateral Sclerosis, JAMA (2025). DOI: 10.1001/jama.2024.26429

© 2025 Science X Network