ALS Trials Fail to Meet Key Endpoints…But It’s Still a Win


The first platform trial for amyotrophic lateral sclerosis (ALS), which individually evaluated four experimental drugs, failed to meet key primary endpoints. Still, investigators view the trial as success, saying it marks a major milestone in ALS research because of the use of the platform model. By streamlining drug testing, this research approach could accelerate the development of effective treatments for a disease where time is critical.

Two of the four phase 2/3 multicenter, randomized double-blind studies showed encouraging signals, which means they’re now moving to phase 3 trials.

The new results illustrate exactly what a platform trial is supposed to do — weed out agents that don’t work and concentrate on those with more promise, principal investigator Merit E. Cudkowicz, MD, of the HEALEY ALS Platform Trial, and executive director of the Massachusetts General Brigham Neuroscience Institute, told Medscape Medical News.

ALS is a complex illness, but there’s a lot of new science and new drugs out there, and being able to rapidly cycle through them to pick the best ones to go forward with is a good approach for ALS. These are not failed trials,” Cudkowicz added.

Results of the four trials were published February 17 in JAMA,JAMA,JAMA Neurologyand JAMA Network Open.

Phase 3 Candidates

The results are the first from the phase 2/3 multicenter, randomized double-blind HEALEY ALS Platform Trial. The platform model involves continual enrollment and randomization of participants as treatment groups change.

This allows researchers to test multiple drugs simultaneously and to share infrastructure and placebo participants, potentially speeding up screening of novel experimental products.

Time to effective treatment is critical for ALS, a fast-progressing neurodegenerative disease that damages motor neurons, causing muscle weakness and atrophy. Most patients die from respiratory failure within 2-3 years of symptom onset.

There is an urgent need for new ALS therapies, as only a few US Food and Drug Administration–approved drugs exist. Riluzole blocks glutamate to protect nerve cells, while edaravone slows damage from free radicals, but both offer limited benefits.

In platform trials, pooling control group patients boosts efficiency and lowers costs compared with standard trials. Launched in 2020, the HEALEY Platform Trial is estimated to cut research costs by 30% and trial duration by 50%.

The current HEALY trials assessed four agents and their ability to slow disease progression over 24 weeks. The four trial medications included pridopidine, CNM-Au8, verdiperstat, and zilucoplan.

Participants had a mean age of 58 years, and two thirds were men. A 3-to-1 randomization favored treatment, with 120 treated patients and 160 pooled controls, increasing the chance of receiving active treatment.

The primary endpoint was change in disease severity as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed with the Bayesian statistical method and reported as disease rate ratio (DRR) with DRR less than 1 indicating treatment benefit relative to placebo.

Participants in the pridopidine trial were randomized to receive oral pridopidine, a sigma-1 receptor agonist, or placebo. Results no significant difference between pridopidine and placebo in the primary endpoint (DRR, 0.99; 95% credible interval [Crl], 0.80-1.21; probability of DRR

However, an exploratory analysis showed nominally significant slowing of progression in the pridopidine group on speaking rate (=.03) and articulation rate (P =.01), while other speech-related measures approached, but did not reach, statistical significance.

The signals seemed to be stronger in study participants with more rapid disease progression.

This agent is set for phase 3 testing, with enrollment expected to begin this year, said Cudkowicz.

In the trial of CNM-Au8, an oral suspension of gold nanocrystals, participants were randomized to CNM-Au8 (30 mg or 60 mg) or placebo.

The study showed no significant slowing of ALS progression with CNM-Au8 in combined or individual 30-mg and 60-mg groups vs placebo. The estimated DRR for ALSFRS-R and mortality was 0.97 (95% CrI, 0.783-1.175; posterior probability of DRR

However, researchers observed a potential benefit in neurofilament light chain measures. Neurofilament, a key nerve protein, appears in blood and spinal fluid as ALS damages nerve fibers and is increasingly considered the best biomarker to test the efficacy of ALS medications.

Cudkowicz noted a potential survival benefit in the lower-dose group during both the double-blind phase and the open-label extension. All participants could enter the extension phase after the 6-month trial.

“It’s not huge, but there’s definitely a signal; one dose was clearly better than the other,” she said. She also confirmed this is the second agent set for the phase 3 investigation.

Longer Trials Needed?

In an accompanying editorial, John Turnbull, MD, PhD, professor of medicine, faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada, suggested the trial of CNM-Au8 may not have been long enough, partly because of factors such as the length of the drug’s half-life.

“It is unknown whether a longer trial would have afforded positive results, but it is almost certain that any further trials of CNM-Au8 will be significantly longer than 24 weeks,” he wrote. “Regardless, there is a feeling by many in the ALS community that 6 months may be too short to evaluate the efficacy and safety of new agents.”

Cudkowicz noted that some drugs “take longer to kick in” and confirmed that phase 3 trials for both pridopidine and CNM-Au8 will extend beyond 24 weeks — potentially up to 48 weeks — though the exact duration is still being determined.

“You gain a lot of power by going a little longer, but by going too long, you risk dropouts. And it’s a big ask for patients to be in a double-blind trial for a long time. So, it’s a balance you have to think about for each drug,” she said.

In the verdiperstat trial, a selective myeloperoxidase inhibitor, patients were randomized to receive 600 mg of oral verdiperstat twice daily or placebo. The estimated DRR was 0.98 (95% CrI, 0.77-1.24; posterior probability = 0.57 for slowing disease progression [DRR

The zilucoplan trial, which tested a 0.3 mg/kg subcutaneous injection of the C5 complement inhibitor vs placebo, was stopped early for futility. The estimated DRR was 1.08 (95% CrI, 0.87-1.31; posterior probability of superiority, 0.24).

These findings were unexpected, as preclinical data suggested complement activation plays a role in ALS and complement inhibition has proven effective in other neurologic diseases like myasthenia gravis. Notably, the study confirmed complement inhibition in plasma.

The lack of efficacy of zilucoplan in ALS isn’t due to a failure to achieve its intended effect, explained the study’s investigator Sabrina Paganoni, MD, PhD, associate professor of physical medicine and rehabilitation at Harvard Medical School and co-director of the Neurological Clinical Research Institute at Massachusetts General Hospital and the Sean M. Healey & AMG Center for ALS, Boston.

“This is an important learning point,” said Paganoni. “The results point to the complement system as perhaps not being one of the main drivers of ALS disease progression.”

She noted that the results of this study are a prime example of the platform trial’s role in identifying agents that shouldn’t advance. “The point of the platform trial is to screen drugs in or out. So, from that point of view, the fact this trial was stopped early is actually an example of the success of the overall platform trial.”

While some ALS treatments may have a greater impact on patients with earlier-onset or rapidly progressing disease, this wasn’t the case for zilucoplan. “There was no signal that suggests that using a subpopulation or a different trial design could be valuable,” said Paganoni.

Researchers have results from three additional trials being tested on the HEALY platform. The trial of one of these — fosigotifator, an eIF2B activator — didn’t meet its primary outcome, but at an exploratory high dose, endpoints of muscle strength declined more slowly for both upper and lower extremities compared with placebo, and there was a potential signal towards slower decline in respiratory function.

A ‘Courageous’ First Attempt

In his editorial, Turnbull called the platform “a courageous and innovative first attempt at platform trials in ALS.”

However, he raised concerns about trial costs, noting that reductions were partly due to an infrastructure subsidized by charitable donations and grants. “Does the infrastructure require ongoing donations and grants and/or will the platform without these subsidies remain as cost-effective? Also, net costs for a trialed agent may not be lower if more extensive phase 3 testing is pursued.”

Turnbull noted that large pharmaceutical firms may favor traditional trials for greater control, flexibility, and global reach in securing regulatory approvals. He suggested platform trials in ALS might appeal more to academics or smaller companies willing to trade some flexibility for potential cost savings and efficiency.

In a comment provided by the Science Media Centre, Ahmad Al Khleifat, MB, PhD, senior research fellow at King’s College London, London, England, said that while the negative trial results “may seem discouraging, they provide critical insights.” He noted that the studies “highlight the efficiency of the platform approach in accelerating drug testing, laying the groundwork for future breakthroughs.”

Khleifat also questioned the reliance on survival and functional scores as primary outcome measures rather than biomarkers like neurofilament, which he said, “offer a more precise way to track disease progression.”

Like other experts, Yuishin Izumi, MD, PhD, professor and chair of Neurology at Tokushima University, Tokushima, Japan, views these studies as proof that platform trials can efficiently test multiple drugs, addressing cost and time challenges in drug development.

However, he also noted the significant hurdles in developing ALS treatments. “Detecting efficacy in trials that recruit a broad spectrum of ALS patients may not always be feasible,” he told Medscape Medical News.

Izumi emphasized the need for future studies to consider disease subtype, genotype, biomarkers, disease duration, and stage to identify patients more likely to respond. He cited a study of methylcobalamin, an active vitamin B12 analogue, as an example.

An early-phase trial enrolling patients within 36 months of disease onset showed no effect on functional decline. However, a post hoc analysis suggested potential benefits in those diagnosed within 12 months, leading to a successful phase 3 trial that targeted this subgroup.

“This highlights the importance of refining patient selection to enhance the likelihood of detecting treatment efficacy,” Izumi said.

He added that the success of phase 3 trials in the HEALEY ALS platform may depend on further stratifying patient groups, given the current modest efficacy signals.

The HEALEY ALS Platform Trial was supported by the AMG Charitable Foundation, Tackle ALS, The ALS Association, ALS Finding a Cure, Muscular Dystrophy Association, ALS ONE, Arthur M. Blank Family Foundation, I AM ALS, Tambourine ALS Collaborative Cohort, and others. Study drugs and partial funding were provided by respective pharmaceutical companies.

Cudkowicz reported receiving grants from Clene Nanomedicine. Paganoni reported receiving grants from Amylyx, Eledon, Alector, Seelos, Calico, Denali, National Institutes of Health, Centers for Disease Control and Prevention, and Department of Defence; consulting agreements from Amylyx, Revalesio, Bristol Myers Squibb, Clene Nanomedicine, Prilenia Therapeutics, Eikonizo, Sola, and PharmAust; personal fees from Arrowhead, Cytokinetics, Merck, Biogen, and Johnson & Johnson; and speaking fees from PeerView, Medscape Medical News, and i3 Health outside the submitted work. Turnbull reported no relevant disclosures. Khleifat reported no relevant disclosures.



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Publish date : 2025-02-24 12:00:20

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