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FDA Approves Edaravone for ALS: Phase 3 Trial Finds It Slows Progression

Robinson, Richard

doi: 10.1097/01.NT.0000520844.95657.e4
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The US Food and Drug Administration approved edaravone for amyotrophic lateral sclerosis based on the results of a Japanese study that found the drug slowed disease progression compared with controls.

The United States Food and Drug Administration approved edaravone (Radicava) in May for treatment of amyotrophic lateral sclerosis (ALS), and the drug could be available as early as August, according to the Japanese-based study sponsor, Mitsubishi Tanabe Pharma. Edaravone is only the second drug to be approved for ALS in the US since riluzole (Rilutek) was approved in 1995.

The approval was based on the results of a randomized, double-blind trial of 137 ALS patients in Japan who were in the early phases of the disease, reported in the May 15 online edition of The Lancet. The investigators found that there was less functional decline after 24 weeks of treatment in these patients compared to placebo. There are not yet any published data on whether edaravone provides benefits beyond 24 weeks, delays the need for tracheostomy, or extends survival.

The trial was also the basis for the 2015 approval of edaravone in Japan for ALS treatment. In Japan, it is also approved for treatment of ischemic stroke.

Endaravone is a free radical scavenger. Cellular studies in ALS animal models and in ALS patients have shown an increase in oxidative damage from free radicals, and damage from free radicals is hypothesized to be implicated in the pathogenesis of the disorder.

The pivotal trial grew out of a larger trial that tested edaravone's ability to slow functional decline in a larger group of ALS patients within three years of diagnosis, with forced vital capacity (FVC) of at least 70 percent of expected. No benefit was seen in the group as a whole. But a post-hoc analysis suggested a slowing of decline in a subgroup of patients, those early in the disease, and with good respiratory and motor function who were nonetheless progressing.

That led investigators at Mitsubishi Tanabe Pharma, the owners of the drug, to design the trial that led to its approval. It enrolled patients within two years of diagnosis, with FVC of at least 80 percent of expected, and who scored at least two points (out of a maximum of four) on each item in the ALS Functional Rating Scale-Revised (ALSFRS-R). The scale ranks function on 12 activities, covering bulbar, gross motor, fine motor, and respiratory function. Observation during a 12-week pre-treatment period ensured that patients were declining prior to randomization.

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Patients received intravenous infusions of edaravone at 60 mg per day or placebo for the first 14 days, followed by 14 days off-treatment, then infusions on 10 of the next 14 days, then 14 days off. The latter cycle was repeated until the end of the 24-week trial. Each infusion lasted approximately one hour. The drug was well tolerated; the most common adverse effects were bruising, gait disturbance, and rash.

Both groups of patients began the trial with an ALSFRS-R score of about 42, out of a maximum of 48. By the end of treatment, the 68 patients receiving placebo had worsened by 7.5 points, while the 69 patients receiving edaravone had worsened by 5.0 points (p=0.0013), a reduction in decline of 33 percent. A 2010 survey of ALS researchers identified a change of 20 percent or greater in the slope of the ALSFRS-R as “clinically meaningful.”



Based on these results, the company submitted a new drug application to the FDA last summer. The FDA has regulations and guidelines that allow approvals based solely on trials conducted in other countries, as long as they adhered to clinical and ethical standards.

A year's worth of treatment at the drug's current price (without consideration of insurance discounts or reimbursements) would cost approximately $146,000, according to the drug sponsor Mitsubishi Tanabe Pharma. The company has said it will provide the drug at no charge to those without insurance who meet income and certain other requirements. In addition, eligible patients may receive the therapy free for up to two months while awaiting a decision about insurance coverage.

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In an accompanying editorial to the Lancet study, two ALS experts — Orla Hardiman, MD, FRCP, FAAN, clinical professor of neurology and director of the National ALS Clinic and Irish ALS Research Group at the Trinity College Institute of Neuroscience in Dublin, and Leonard H. van den Berg, MD, professor of neurology and chair in experimental neurology of motor neuron diseases at the University Medical Center Utrecht in the Netherlands — wrote that while the study findings suggested a potentially useful therapeutic agent, several limitations were important to consider.

They noted that the stringent inclusion criteria that were applied in the current study — reflecting the clinical characteristics of the apparent responders identified by post-hoc analysis — might preclude many patients from participating in a future trial; they estimated that based on the criteria fewer than 7 percent of patients with ALS would be eligible for enrollment in a trial.





In addition, they said that “while it is biologically plausible that sub-cohorts of patients might respond differentially to targeted therapies, how to select such patients remains a conundrum, as at present there are no reliable markers of pathobiology.” Finally, they wrote, “although the side-effect profile does not suggest toxicity, the treatment regimen of intravenous infusions for 10-14 days each month is inconvenient and potentially costly, and the longer-term efficacy of the drug and patient adherence to the intravenous treatment has not been established.”

These limitations notwithstanding, other ALS experts were encouraged by the study findings and FDA approval. “The approval by the FDA is terrific news for our patients and the ALS field,” said Merit D. Cudkowicz, MD, chief of the neurology service and director of the ALS Clinic at Massachusetts General Hospital in Boston. “This is the first drug since riluzole to be approved for people with ALS that slows disease progression.” Nuedexta is approved for the management of pseudobulbar affect in ALS, she noted, but does not alter the course of the disease.

The positive results seen in the trial “may reflect a clinical design strategy, that in relatively small studies, it is easier to see an effect in the participants if the group is more homogeneous in their progression and faster,” she added. “It might also mean that the effect is best if given early. I am not sure that at this time we have the information to know which of these possibilities is best supported.”

Terry D. Heiman-Patterson, MD, director of the Center for Neurodegenerative Disorders and professor of neurology at the Lewis Katz School of Medicine at Temple University in Philadelphia, added: “The fact that there was testing only in a subset of people with ALS does not mean that it does not have an effect in others. I am hopeful that as we treat with edaravone we will learn more about the response and effects on disease in all patients in order to identify who is best to treat. That is the next step.”

“The approval of edaravone is also a huge advance for the ALS field because it sets an example of a regulatory path to approval of treatments,” Dr. Cudkowicz added. “We now know that if we can demonstrate an effect on function over a six-month period in people with ALS, that there is a pathway for regulatory approval in the United States for a treatment. This is huge, positive news for patients, families, physicians and scientists developing treatments for ALS and for the industry.”

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              © 2017 American Academy of Neurology