ALS Prospects Reach Phase 3

MD Magazine NeurologyDecember 2017
Volume 7
Issue 8

Two experimental treatments for amyotrophic lateral sclerosis (ALS) have progressed to phase 3 clinical trials and are closer to becoming therapeutic options for a condition that, until this year, had only 1 drug approved by the FDA in the last 22 years.

Results from a phase 3 trial with the tyrosine kinase inhibitor masitinib (AB Science) were presented at the American Neurological Association meeting in San Diego, California, on October 16.1 On the same day, BrainStorm Cell Therapeutics announced enrollment for a phase 3 trial of a mesenchymal stem cell (MSC) treatment (NurOwn, Brain-Storm Cell Therapeutics).2

Earlier this year, the FDA approved edaravone (Radicava, Mitsubishi Tanabe Pharma America), a neuroprotective drug that acts as a free radical scavenger, for treating ALS. This came 22 years after the approval of riluzole (Rilutek, Covis Pharma, and others). At the 28th International Symposium on ALS/MND (motor neuron disease) held December 8 to10 in Boston, Massachusetts, the researchers shared some of their experiences with developing edavarone.


Angela Genge, MD, director of the Clinical Research Unit, and ALS Clinic at Montreal Neurological Institute and Hospital in Quebec, Canada, contrasted the encouraging results of the masitinib phase 3 trial (AB10015) with many unsuccessful efforts with other agents over 2 decades. “The overwhelming majority of human clinical trials in ALS have failed to demonstrate clinical efficacy,” she indicated. “There remains a persistent and urgent unmet medical need in ALS.

“Masitinib simultaneously targets microglia, macrophage, and mast cell activity in both the central and peripheral nervous system,” Genge explained. In a press release, the manufacturer indicates that the effect of masitinib on a limited number of kinases in mast cells and microglia inhibits the activation of the inflammatory process and “can have an effect on the symptoms associated with some inflammatory and central nervous system diseases and the degeneration of these diseases.”

In the double-blind trial, 394 patients in 34 sites in 9 countries were randomized to receive 48 weeks of treatment with riluzole in combination with placebo or with masitinib in either a 4.5-mg/kg or 3.0-mg/kg daily dose. Patients were differentiated by duration and severity of ALS symptoms at baseline and by symptom progression, with “normal progressors” having ALS symptom worsening by <1.1points/ month on the ALS Functional Rating Scale, Revised (ALSFRS-R), and “faster progressors” by ≥1.1 points/month.

Genge reported that those receiving 4.5 mg/kg/day of masitinib with riluzole demonstrated a 27% slower deterioration in ALSFRS-R—rated symptoms at 48 weeks than did those receiving placebo with riluzole. In secondary efficacy measures, this group showed a 29% slower deterioration in quality of life as measured on the Amyotropic Lateral Scelrosis Assessment Questionnaire (ALSAQ-40), and a 22% slower deterioration in respiratory function. Genge noted that those with milder symptoms and/or shorter duration of illness showed enhanced masitinib treatment effect. In the measure of survival-to-event end point, marked by a deterioration in ALSFRS-R of 9 points from baseline or death, Genge indicated that the patients receiving masitinib 4.5 mg/ kg/day had a significant 25% delay in disease progression (20 months vs 16 months with placebo).

Genge described the safety profile of masitinib as acceptable, noting that benefit from its combination with riluzole was related to dose and to the duration of disease prior to treatment. “The positive benefit—risk balance of study AB10015 signals that masitinib provides a significant new therapeutic option in an ALS population,” she concluded.


A phase 3 trial of the NurOwn mesenchymal stem cell platform has begun enrolling toward a target cohort of approximately 200 faster progressors. These patients with a more aggressive disease course are ostensibly more difficult to treat, but they were among the most responsive in the NurOwn phase 2 trials.

Ralph Kern, MD, chief operating officer and chief medical officer of BrainStorm Cell Therapeutics, told MD Magazine® that patients with ALS who experience faster deterioration have a particular need for innovative treatment. "This is a very important group of patients who currently, even with the 2 approved therapies right now, really don’t have their needs met,” he said.

The trial is being conducted at several ALS treatment centers in the United States, including sites in California, where the state has contributed funding from the California Institute for Regenerative Medicine (CIRM). The CIRM funding follows the 2004 passage of Proposition 71, the California Stem Cell Research and Cures Act, which supported scientists coming to the state to conduct stem cell research. The funding has subsequently been expanded to expedite projects such as late-stage clinical trials that can potentially benefit patients with unmet medical needs.

The NurOwn treatment involves autologous harvesting of the patient’s bone marrow-derived mesenchymal stem cells, propagating them ex vivo and inducing them to secrete neurotrophic factors (NTF). These MSC-NTF cells are then retransplanted into the patient intrathecally by standard lumbar puncture, where it is expected that neurons and glial cells will take up the neurotrophic factors secreted by the transplanted cells.

Robert Miller, MD, director of the Forbes Norris MDA/ALS Research and Treatment Center at California Pacific Medical Center (CPMC) in San Francisco, California, said in a statement, “NurOwn cells have the important advantage of being autologous, so patients do not need to be immunosuppressed. In addition, the production process is relatively straightforward, and the harvesting and delivery of cells is much less invasive than other stem cell systems that have been tested in the clinic.”2

Kern elaborated on the production process, noting 2 significant advances have been made over the course of development. “The changes in the process over the [past] 10 years have been primarily around the practical aspects of cryopreserving the cells, to make it easier to maintain the cells and then allow them to be used at a later date,” he said.

In addition, there has been a substantial reduction of the cycle time from harvesting the bone marrow—derived MSC to making the treatment available. “We’ve been able to shorten the time, for example, from thawing the cells that are cryopreserved to being available for injection to 7 days, which is an incredible technological achievement and important for making this a treatment for repeated dosing,” Kern said.

Patients in the trial will be randomized to receive 3 intrathecal administrations of the autologous MSC-NTF cells or placebo at bimonthly intervals. The course of illness will be evaluated with the ALSFRS-R 28 weeks after the first treatment. Biomarkers will also be tracked, including cell-secreted NTF, inflammatory factors, and cytokines in the cerebrospinal fluid and serum.


Edaravone was approved by the FDA in May for use in treating ALS. The approval was expedited by the orphan drug program, with review of the pivotal studies that had supported its approval in Japan. The clinical trials and studies of edaravone over the 13-year drug development period were compiled in a supplement that was recently published in the journal Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration.3

An initial phase 3 trial, which did not demonstrate statistical superiority to placebo across the total study population, was followed by post hoc analysis and a subsequent clinical trial that verified its efficacy in a well-defined subpopulation. The study cohort responsive to edaravone had an ALS diagnosis classified as “definite” or “probable” according to both the El Escorial and the revised Airlie House diagnostic criteria, and within 2 years of initial ALS symptoms onset at the time of study entry.

One of the 4 symposium presentations on edaravone by researchers at Mitsubishi Tanabe Pharma America examined the value of that subsequent analysis in preventing an effective compound from being abandoned.

The presentation by Joseph Palumbo, MD, vice president and head of Medical Science and Translational Research, was titled, “Towards More Efficient Clinical Trial Design in ALS: Lessons From the Edaravone Development Program.” He highlighted the importance in ALS clinical trial designs to use well-defined patient populations to reduce heterogeneity and appropriate end points, including using the ALSFRS-R to measure functional decline and the ALSAQ-40 to measure quality of life.

“We hope to show that the Study 19 inclusion criteria produce a population that represents the nature of ALS—true diagnosis with a steady progression from a functional baseline&mdash;that is generalizable to the full range of…patients [with ALS],” Palumbo said.


1. Genge A. Masitinib in the treatment of amyotrophic lateral sclerosis (ALS). Paper presented at


142nd American Neurological Association Annual Meeting; October 16, 2017, San Diego, CA.

2. BrainStorm enrolls first patients in phase 3 trial of NurOwn in ALS [news release]. Hackensack, NJ, and Petach Tikva, Israel: BrainStorm Cell Therapeutics; October 16, 2017. zhtml?c=142287&p=irol-newsArticle&ID=2308633. Accessed October 16, 2017.

3. Writing group on behalf of the


(MCI-186) ALS 19 study group.

Open-label 24-week extension study



(MCI-186) in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18:(suppl 1):55-63. doi: 10.1080/21678421.2017.1364269.

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