How an Innovative Trial Design May Change the ALS Treatment Landscape

NeurologyLiveFebruary 2020
Volume 3
Issue 1

The Healey ALS Platform Trial learns from successful cancer drug studies to identify and accelerate new treatments for the devastating disease.

Sabrina Paganoni, MD, PhD

Merit Cudkowicz, MD, MSc

A platform clinical trial, an innovative design with a single master protocol and placebo control arm for multiple candidate treatments that has been used to efficiently test and successfully launch new drugs for cancer, is now being applied by the Healey Center for ALS (amyotrophic lateral sclerosis) at Massachusetts General Hospital (MGH) to expedite clinical assessment of investigational agents for the terminal neuromuscular disease.

In contrast to the more lengthy and costly process of conducting controlled clinical trials of 1 candidate drug at a time—which has yielded only 1 FDA-approved compound for ALS (edaravone) since the first (riluzole) was approved in 1995—the Healey Center announced in September 2019 that it will launch a platform trial in 2020 with initially as many as 5 candidate drugs.

“As the field develops more understanding of disease pathophysiology and targets, and has a larger pipeline of treatments, the platform trial approach is a much more efficient, patient-supportive way to develop treatments,” Merit Cudkowicz, MD, MSc, director of the Healey Center, chief of neurology at MGH, and principal investigator of the platform trial, told NeurologyLive®.

The Sean M. Healey & AMG Center for ALS is named for its benefactor, then chairman and chief executive officer of the international asset management firm, Affiliated Managers Group, Inc. Within 6 months of being diagnosed with ALS in May 2018, Healey had raised approximately $40 million for the center to launch the platform trial initiative.

The Healey Center is collaborating with the network of clinical research and treatment sites in the Northeast ALS Consortium (NEALS) and working with each of the selected biotechnology firms to tailor platform trial study arms to the respective investigational products.

Bayesian statistical tools and a common control arm will facilitate the testing of multiple investigational drugs at the same time.

“We calculate that this approach cuts in half the time to finding effective treatments, lowers the number of people needed in trials by one-third, and increases participants receiving active treatment by two-thirds,” Cudkowicz said.

Cudkowicz and colleagues designed the platform trial and selected the most promising candidate products from proposals received from biotechnology innovators whom, Cudkowicz relayed in a previous interview, “have great ideas but not deep pockets.”1

The Healey Center received approximately 30 applications from 10 countries from its initial request for proposals. Ultimately, the center’s Therapy Evaluation Committee selected 5 therapies (TABLE).

“Each of the investigational products that will be tested in the platform trial has been tested in preclinical and early-phase trials in either ALS or other neurodegenenerative diseases,” Sabrina Paganoni, MD, PhD, assistant professor of PM&R at Harvard Medical

School and coprincipal investigator of the platform trial, told NeurologyLive®. “These other trials demonstrated the biological value of the products for ALS and the ability to engage their respective targets. They also helped guide dose selection and provided important information about the drugs’ safety profile,” Paganoni said.

Although large pharmaceutical manufacturers were welcome to propose candidate products for the platform trial, and companies like Biogen and Sanofi participated in trial design discussions, the proposals were received from smaller firms, with promising candidate products but fewer development resources.

READ MORE: Clene Banks on Novel Gold Nanotherapeutic for ALS and Beyond

“As a virtual biotech company, with a low head count and a focus on capital efficiency, the Healey platform provides an ideal framework for us to move our biologic into large-scale ALS clinical development,” Garry Redlich, chief executive officer of Implicit Bioscience, told NeurologyLive®, describing the opportunity that the platform trial provides for developing their investigational product, IC14. “Not only will the study be established and run by the most accomplished clinical researchers in the field, but NEALS and the Healey Center at MGH have established a great working relationship with the FDA,” he noted. “The biostatistical design supporting the platform study is based on more than 10,000 patient disease histories.”

“This is not a resource that any company, let alone a small biotech like Implicit Bioscience, could bring to bear in the effort to get this job done convincingly in such a short time frame,” Redlich acknowledged.

This sentiment was shared by Rob Etherington, president of Clene Nanomedicine. “What’s particularly important for a company such as Clene, and frankly all the companies involved, is that this is likely to be a registration study,” he told NeurologyLive®.

“There’s already been extensive conversation with the FDA,” Etherington said, “that if 1 or more of these drugs hits its primary end point and shows change in the ALS functional composite score ... that should be sufficient to take the drug to approval for a high-medical-need disease—patients in desperate need of care—such as ALS.”

FDA Guidance

The investigational new drug application for the platform trial was approved by the FDA in January 2020, ultimately granting a “may proceed” to 3 of the 5 drugs selected by the Therapy Evaluation Committee: CNM-Au8, verdiperstat, and zilucoplan. Paganoni said that the research team will work to incorporate IC14, pridopidine, and several other therapies over the next few months. Cudkowicz is confident that their approach to facilitating clinical research for ALS is consistent with FDA priorities and with the criteria in recently issued guidance.2

“We have had excellent meetings with the FDA, and they have been very helpful and supportive,” Cudkowicz said. “We plan to use a common DSB [data and safety monitoring board] and common safety monitoring approach for all regimens. The shared placebo group is critical to the purpose and success of the platform trial.”

The FDA’s role in encouraging such innovative trial design and drug development was described by Janet Woodcock, MD, director of the FDA Biologics Evaluation and Research, and Norman Sharpless, MD, director of the agency’s Center for Drug Evaluation and Research, in a joint statement in September 2019.3

“We recognize that scientific progress across different disease and therapeutic areas has been uneven, particularly lagging for complex neurological diseases, such as ALS,” Woodcock and Sharpless said.3 “We know that an important element of product development is working early and often with researchers and companies to help facilitate their clinical development programs. That’s why our final guidance recommends that researchers and companies interact with the FDA early in product development so that we can best advise on proposed development programs and the efficient design of trials to produce the data needed for FDA approval in order to get effective therapies to patients as efficiently as possible.”

The agency’s guidance for industry encourages trial design with master protocols that use a single infrastructure for the simultaneous evaluation of multiple drugs and to employ a common or shared placebo group. The guidance also promotes the use of adaptive designs, including the use of Bayesian features and enrichment strategies.

In addition, the agency's guidance to the industry also emphasizes the importance of evaluating agents across the severity stages of ALS.

“Although sponsors may have good reason to use prognostic enrichment to increase the likelihood of demonstrating a drug effect (eg, to enroll patients who are more likely to experience rapid progression) or to use predictive enrichment to direct therapy to patients with a particular disease characteristic (eg, a specific genotype or phenotype), sponsors should not unnecessarily exclude patients from trial enrollment based on characteristics such as age or disease stage unless scientifi- cally justified,” the guidance cautions.2

Each of the developers expressed agreement that the platform clinical trial should evaluate the investigational agents in a range of patients with ALS.

“We believe that all patients, including those with both familial and sporadic forms of ALS, could benefit from complement inhibition. For this reason, aside from the general patient entry criteria for the platform trial, we have not added any further requirements to the zilucoplan arm of the trial,” Simon Read, PhD, chief scientific officer of Ra Pharmaceuticals, told NeurologyLive®.

In addition to evaluating safety and efficacy of the interventions, the platform trial is also designed to inform the field on new biomarkers and outcome measures for ALS, according to Cudkowicz.

“We will include the best-known biomarkers and also collect data and samples to discover new ones,” she said. “In particular, we are planning on whole-genome sequencing in all participants; neurofilament [levels]; urine [neurotrophin receptor] P75; banking serum and plasma; and banking peripheral blood mononuclear cells for future induced pluripotent stem cell motor neuron—type studies.”

“We will also use a new approach for speech monitoring remotely,” Cudkowicz said. “Each arm may also include drug-specific biomarkers. The study is also designed for flexibility to easily add additional biomarkers if relevant.”

Platform for First-in-Class Interventions

The selected investigational agents are all first-in-class biotherapeutic innovations that were developed to treat neurodegenerative disorders, although not necessarily targeting ALS. Their inclusion in the platform clinical trial, however, could leapfrog other development directions to position them as viable therapeutic options for patients with ALS.


The formulation of CNM-Au8 is described as an orally adminis- tered, concentrated, aqueous suspension of pure faceted nanocrystalline gold that acts catalytically to support various intracellular biological reactions.

Etherington said that the product is directed at improving cellular bioenergetics which, he explained, is the improvement in the degenerative processes that increase with aging and accelerate in neurodegenerative disorders.

“We’re looking at an increase in both the NAD-positive/NADH ratio (ratio of the oxidized to reduced form of nicotinamide adenine dinucleotide, measured by phosphorous magnetic resonance spectroscopy) and a reduction in reactive oxygen species, which is effectively the by-product of what happens in cellular energy,” Etherington said.

“Mechanistically, what we see in the assays we’ve explored, in fact in the REPAIR trial program in Parkinson disease and patients with MS, is looking specifically at a sensitive quantification of what is happening with the bioenergetics metabolites within the brain and the bioenergetics membrane markers,” he said. “So, we’re looking at not just NAD-positive/NADH, but also at phosphocreatine, extracellular phosphate—a series of phosphate measures.”


The orally administered verdiperstat is an irreversible inhibitor of the enzyme myeloperoxidase (MPO), which is associated with increased oxidative stress and inflammation levels in the brain and spinal cord, according to Irfan Qureshi, MD, vice president of neurology at Biohaven Pharmaceutical.

Biohaven is now conducting a phase 3 clinical trial of verdiperstat in multiple system atrophy, for which there are now only symptom- atic and palliative therapies. The agent was originally developed by AstraZeneca, which conducted phase 1 and 2 trials that suggest it is generally safe, well tolerated, and has the potential to reduce microglial activation.

“The presence of large numbers of activated microglia is 1 of the hallmarks of neurodegeneration in ALS. MPO is a powerful pro-oxidant enzyme that is present in activated immune cells, including microglia,” Qureshi explained. “Inhibiting MPO is anticipated to ameliorate these pathological mechanisms, which are strongly implicated in the onset and progression of ALS,” he told NeurologyLive®.


Zilucoplan is a macrocytic peptide that binds to complement C5 to inhibit its cleavage into C5a and C5b in activation pathways, which have been linked with inflammation that can contribute to chronic central nervous system diseases.6

“The complement pathway is a fundamental component of the innate immune system and has been demonstrated to be involved in destruction in both peripheral and central motor neuron pathways in ALS,” Read said. “Robust preclinical data support the role for central and peripheral complement activation and deposition in ALS. In animal models, targeting complement delayed disease progression and extended survival.”

Read distinguished the small peptide from the larger monocolonal antibodies that have been used to therapeutically target complement, noting that zilucoplan appears to have greater tissue distri- bution and other properties that make it an optimal C5 inhibitor for evaluation in ALS.

“Importantly, we are working hand in hand with the Healey Center as we work toward trial initiation, and the relationship has been incredibly collaborative and productive,” Read said. “We’ve found a unique partner to allow us to efficiently conduct this trial, while also continuing to allocate our resources to our other ongoing clinical trials for zilucoplan, including a phase 3 trial for generalized myasthenia gravis and phase 2 trial for immune-mediated necrotizing myopathy.”

Qureshi shared this enthusiasm for the prospects of the platform trial. “We are in a new era for ALS therapy development, and we must think differently and boldly about how to find effective treatment for our patients,” he said. “To that end, we are excited to accelerate how therapies are developed for people with ALS, and this [platform] trial will help in that process.”

“I think we will be seeing many more platform trials in neurotherapeutics,” Cudkowicz said. “We are planning a symposium next summer for platform trials in neurology to bring together groups working on this approach, to share lessons and approaches.”

“We are in a new frontier for neurotherapeutics for ALS and other disorders,” she said. “It is a very hopeful time.”


1. Dunn A. First-of-its-kind trial in ALS spurs hope for brutal disease. Biopharmadive. September 25, 2019. Accessed January 6, 2020.

2. US Food and Drug Administration Center for Drug Evaluation and Research. Amyotrophic lateral sclerosis: developing drugs for treatment. Guidance for industry. September 2019. Accessed November 27, 2019.

3. FDA statement on final guidance to help advance development of novel treatments for ALS [news release]. September 23, 2019. Accessed January 6, 2020.

4. Couly S, Khalil B, Viguier V, et al. Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis [published online ahead of print November 7, 2019]. Hum Mol Genet. doi: 10.1093/hmg/ddz267.

5. Ionescu A, Gradus T, Altman T, et al. Targeting the sigma-1 receptor via pridopidine ameliorates central features of ALS pathology in a SOD1G93A model. Cell Death Dis. 2019;10:210. doi:10.1038/s41419-019-1451-2.

6. Carpanini SM, Torvell M, Morgan BP. Therapeutic inhibition of the complement system in diseases of the central nervous system. Front Immunol. 2019 Mar 4;10:362. doi:10.3389/fimmu.2019.00362.

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