Marking Gains in Developing, Delivering Treatment for ALS

MD Magazine NeurologySeptember 2017
Volume 7
Issue 6

The availability of a new drug to slow progression of amyotrophic lateral sclerosis (ALS) leads a spate of recent news and research related to this disease. Other developments include evaluations of using older drugs to treat ALS, more specific genetic screening, and insight into the patient’s perspective on management of the most troubling symptoms.

The US Food and Drug Administration (FDA) approved edaravone (Radicava) in May, and by June 30 the manufacturer, MT Pharma America, announced enrollment of more than 700 sites in its National Infusion Center Directory to accommodate the drug’s August rollout. “Our teams have been working diligently to enroll as many infusion center sites as possible in advance of Radicava becoming available in the US, to ensure the treatment process is as smooth and convenient as possible for physicians and their patients,” Atsushi Fujimoto, president of MT Pharma America, told the press.

The FDA approval of the drug is notable not only because it is just the second drug approved to treat ALS in 22 years—the first since riluzole (Rilutek, from Covis Pharma) in 1995—but also because it was approved through the orphan drug program for expedited review and without clinical trials in the United States. Instead, the FDA accepted data from the pivotal studies supporting the approval of the drug in Japan.

“After learning about the use of edaravone to treat ALS in Japan, we rapidly engaged with the drug developer about filing a marketing application in the United States,” Eric Bastings, MD, deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, said in the May 5 announcement of the approval.

Edaravone involves a 28-day intravenous infusion cycle. The drug acts as a free radical and peroxynitrite scavenger to counter oxidative damage to cell membranes, although it is not known whether that is the mechanism by which it slows the decline of physical function in patients with ALS.


Fingolimod (Gilenya, from Novartis Pharmaceuticals), which is used to treat relapsing forms of multiple sclerosis, is generally safe for and well tolerated by patients with ALS, according to phase 2 results of a study examining its use for treatment of ALS. The drug, which reduces available lymphocytes in central nervous system inflammation, was investigated in a phase 2 trial for patients with ALS. The results of the 4-week, placebo-controlled study, involving 30 participants, were posted online on June 29 in Muscle and Nerve.

The investigators anticipate that larger trials will assess efficacy in ALS. “Given that the short-term safety profile had caused concern in early trials in multiple sclerosis and hints of deleterious effects on FEV1 [forced expiratory volume in 1 second] had been reported, this hurdle needed to be cleared prior to consideration of fingolimod for further study in people with ALS,” said study co-author James Berry, MD, MPH, of the Neurological Clinical Research Institute at Massachusetts General Hospital, in Boston, and colleagues.

Pyrimethamine (Daraprim, from Turing Pharmaceuticals), a decades-old drug to treat malaria, was studied in what the investigators characterized as the largest prospective clinical and biological investigation of patients with familial ALS (fALS) in the literature to date. All patients were confirmed to have a mutation of the cytoplasmic free radical—scavenging enzyme Cu/Zn superoxide dismutase (SOD1).

SOD1 mutations have been linked with 3% to 23% of fALS cases and 1% to 3% of sporadic ALS (SALS) cases. Results of the phase 1/2 study, reported in the June issue of Annals of Neurology, showed that pyrimethamine reduced the amount of SOD1 in the cerebrospinal fluid (CSF) by a mean 13.5% in the 22 patients able to complete the 36-week study (32 enrolled).

Although phase 3 trials will determine whether the drug action corresponds to clinical effects on the disease, this study met its primary endpoint. “To our knowledge, this is the first study in humans with ALS that targeted and achieved a significant reduction of an ALS biomarker in the CSF: the content of SOD1,” said study coauthor Dale Lange, MD, of the Department of Neurology, Weill Cornell Medical College, in New York, NY, and colleagues.


An advance in the specificity of genetic screening for ALS focuses on the presence variants with higher probability of being pathogenic, which is a departure from broad comparisons of the frequency of variants in patients and healthy controls. This new approach may find SALS to be less “sporadic” and more like fALS, revealing pathogenic factors that might ultimately be targeted for therapeutic intervention.

Summer Gibson, MD, of the Department of Neurology at the University of Utah School of Medicine, in Salt Lake City, and colleagues combined screening patients with SALS for 33 genes linked with ALS with Meta- SVM, a second-generation validated pathogenicity-prediction computer model. While 28.7% of the 87 patients were found to carry any variant in the 33 genes, just 17.2% carried a variant with high probability of pathogenicity—significantly higher than in 324 healthy controls.

In the study, published online on June 21 in the journal Neurology, Summers and colleagues said that “the relative effect of ALS-associated genes is stronger when variant pathogenicity is considered instead of only variant rarity.”

In an accompanying editorial titled “Is All ALS Genetic?” Peter Anderson, MD, PhD, of the Department of Pharmacology and Clinical Neuroscience at Umeå University, in Sweden, pointed out that although the advanced technique resulted in fewer SALS patients screening positive for the more pathogenic variants, “this should not be taken as evidence that genetics do not play a predisposing role for the majority of SALS cases, just that we are not yet able to reveal it.”


The top complaint among patients with ALS is also the least-treated symptom, according to a survey aimed at revealing the patient’s perspective on management of ALS symptoms.

Self-reported patient accounts of symptomatic care are rare and often combined with physician-reported information, noted Katharine Nicholson, MD, of the Neurological Clinical Research Institute at Harvard Medical School in Boston, and colleagues. “The patient’s perspective on symptom prevalence and treatment effectiveness is crucial to the development of clinical trials aimed at symptom management,” they said.

The researchers surveyed 1873 patients with ALS, identified from registrants of the Muscular Dystrophy Association. Results from 575 respondents, published online on July 1 in Muscle and Nerve, indicate that fatigue (90%), muscle stiffness (84%), and muscle cramps (74%) are the most prevalent symptoms, with fatigue, stiffness, and shortness of breath reported as the most bothersome. Although fatigue was most prevalent, it was also least treated. Approximately 10% of patients with that complaint received treatment for it, compared with at least 50% receiving treatment for constipation, anxiety, or depression.

The respondents reported treatments for fatigue as the least effective, as well, with treatments for sialorrhea, sleep difficulty, and muscle stiffness also ranking low for effectiveness. The best-treated conditions included anxiety, depression, and shortness of breath.

In accompanying commentary, Stephen Goutman, MD, MS, of the Department of Neurology at the University of Michigan, in Ann Arbor, and Zachary Simmons, MD, of the Department of Neurology at Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania, observed that with a cure for ALS remaining elusive, most intervention strategies must focus on optimizing quality of life through symptom management. “Our job is to use our patients’ insights and their collective wisdom, not only to identify the most effective symptom management strategies but [also] to implement them aggressively in a process of shared decision making with our patients,” they said.

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