Does Free Radical Scavenger Edaravone Slow ALS?

Series - 26th International Symposium on ALS/Motor Neurone Disease:

Edaravone, a medication that scrubs cells of toxic free radicals, may help a subset of people with amyotrophic lateral sclerosis. That was the upshot of a presentation at the International Symposium on ALS/MND, held December 11 to 13 in Orlando, Florida. Koji Abe of Okayama University in Japan described results from two Phase 3 trials. The first found no treatment benefit, but in the second, Abe and colleagues identified a subgroup of mildly symptomatic participants whose decline seemed to slow down on edaravone. This second trial, completed in 2014, led to regulatory approval in June of 2015 of edaravone intravenous infusions for ALS in Japan.

Dutch businessman Bernard Muller, who spoke at the meeting about his efforts to promote ALS research in the wake of his own diagnosis, said he hopes for a similar benefit from an oral formulation of edaravone that is being tested in Europe. Meeting attendees buzzed about an announcement on December 10, 2015, from Muller’s pharmaceutical company, Treeway, of positive Phase 1 results. Now, Treeway plans a Phase 2/3 study.

Brian Dickie of the Motor Neurone Disease Association in the U.K., which organized the conference, told Alzforum he felt “cautiously optimistic” about the “hints of efficacy” in the edaravone results. 

Edaravone

Also called MCI 186, edaravone is a drug originally developed by Mitsubishi Pharma Corporation. It was approved in Japan for the treatment of stroke in 2002, and subsequently in China, and India, where generic versions of the drug also are available. Physicians prescribe it to clear away free radicals and protect neurons following cerebral infarcts. The small organic compound neutralizes lipid peroxyl radicals and peroxynitrite, preventing injury to blood vessels and neurons in the brain (Yoshida et al., 2006; Fujisawa et al., 2015). 

Abe and colleagues wondered if it might protect motor neurons in ALS, too. In rodent models, it slows progression and preserves motor neuron populations (Ikeda and Iwasaki, 2015; Ito et al., 2008; Aoki et al., 2011). 

At the conference, Abe described his work taking edaravone to Phase 3 in ALS. Starting with an open-label, Phase 2 study in 15 ALS patients, two weeks of daily infusions of 60 milligrams of edaravone repeated every month for six months seemed to slow the march of their symptoms as measured by the ALS-Functional Rating Scale. In the ALS-FRS, physicians score people on 12 categories such as speech, walking, and breathing. On average, the participants lost nearly five points on this 48-point scale in the six months leading up to the trial, versus two points during the six months they received edaravone. Moreover, the concentration of 3-nitrotyrosine, a marker for oxidative stress, in their cerebrospinal fluid dropped to nearly undetectable levels (Yoshino and Kumura, 2006). 

Based on those preliminary results, Abe and colleagues started the first randomized, double-blind, placebo-controlled Phase 3 study (Abe et al., 2014). As he described at the meeting, the researchers recruited 205 volunteers who had fairly mild ALS and were living independently. All developed symptoms within three years before the study start, and scored 70 percent or higher on forced vital capacity, a measure of exhalation volume. All met standard criteria for the diagnosis of ALS (Brooks et al., 2000). Study physicians classified some as either clinically definite or clinically probable ALS, with symptoms of both upper and lower motor neuron degeneration in multiple body parts. Others fell into a category called clinically probable-laboratory supported ALS; this meant they had fewer clinical symptoms, such as problems only in one body part, but their ALS diagnosis was supported by laboratory tests such as electromyography or neuroimaging to eliminate other possible diagnoses.

The researchers monitored the volunteers for 12 weeks before starting the treatment. All participants lost one to four points on the ALS-FRS during that time, suggesting their ALS was getting worse and a potential treatment benefit would be measurable. In this study, 121 people received edaravone infusions, and 104 a placebo solution, over 24 weeks. Results were disappointing: On average both treatment and control groups lost about six points on the ALS-FRS (Abe et al., 2014). 

Abe and colleagues wondered if a subgroup might have benefitted, since ALS researchers have recently begun to suspect that certain treatments will work only for specific groups of people. Re-analysis of the data uncovered a more mildly affected subgroup that had a “small but significant benefit” from the edaravone treatment, Abe told Alzforum. These people had definite or probable ALS based on clinical symptoms, but their disease had started two years or less before the trial and their forced vital capacity was still 80 percent or higher. They scored at least two points in each of the 12 ALS-FRS categories, indicating they had not completely lost any one function.

People with clinically definite or probable ALS who had had ALS for longer and had lower lung capacity reaped no benefit from edaravone. Curiously, the ostensibly mildest subgroup—people with the clinically probable laboratory-supported diagnosis—did not benefit either. Researchers at the meeting had no explanation for why only some patients responded.

The Japanese researchers initiated a new Phase 3 trial focusing on people who did benefit, namely those with clinically probable or definite ALS, forced vital capacity of 80 percent or higher, and at most two years of ALS duration. Dickie and other researchers at the meeting praised the Japanese scientists for not simply trusting the post-hoc analysis, but testing that subgroup again. This time Abe and colleagues recruited 137 people, splitting them between treatment and placebo arms. Over 24 weeks, those on edaravone lost five points on the ALS-FRS, compared to 7.5 in the placebo group, a statistically significant difference, Abe reported. The authors are continuing to monitor edaravone’s effects in a post-market survey now that it has been approved in Japan. It should reveal whether edaravone can prolong life, Abe said.

Robert Miller of the Forbes Norris MDA/ALS Research Center in San Francisco commented that the subgroup Abe described seemed rather odd—its subjects' disease was mild enough that they could live on their own, but had progressed far enough to achieve a high level of diagnostic certainty. They might be people with fast-progressing disease, Miller speculated in an email to Alzforum, or people with a particular version of the disease that spreads to multiple body parts early on.

The efficacy in this subgroup suggests that early treatment will be most beneficial, he said. “Ideally, a longer study that would include survival would be highly desirable,” Miller said. “However, ALS is a terrible disease and these results are to me quite convincing of a beneficial effect on disease progression.” Nonetheless, he worried about the cost and logistics of a treatment that requires repeated infusions.

Muller hopes to solve that exact problem. Muller first heard about edaravone on a trip to Japan, as he described in the final session of the meeting. His company, Treeway, is pursuing an oral version of the drug, which would be more convenient for chronic treatment of ALS. (People who receive edaravone after stroke only need it for two weeks.) In two Phase 1 studies, Treeway administered multiple doses of the oral formulation to healthy volunteers, and single doses to people with ALS, Treeway CEO Inez de Greef told Alzforum. The drug seemed safe and well-tolerated, according to a company press release. While Treeway provided no data to directly compare with the intravenous formulation, de Greef said that adequate amounts of the oral drug entered the blood. The company plans to start a Phase 2/3 trial in 2016. It will run for at least a year, de Greef said, and include survival as an outcome.

Muller received a standing ovation after describing how his ALS diagnosis led him to apply his business skills to fundraising and research. His other projects include the worldwide sequencing initiative Project MinE, which Muller said currently stands at 7,000 ALS genomes (see Jul 2015 news). He called for more collaboration between patients and drug developers to speed up the time between a drug concept and its approval. “The patient’s voice should always be embedded in the process,” he said.—Amber Dance

 

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References

News Citations

  1. Divvying Up the Ice-Bucket Dollars: Looking Long-Term

Paper Citations

  1. Yoshida H, Yanai H, Namiki Y, Fukatsu-Sasaki K, Furutani N, Tada N. Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury. CNS Drug Rev. 2006;12(1):9-20. PubMed.
  2. Fujisawa A, Yamamoto Y. Edaravone, a potent free radical scavenger, reacts with peroxynitrite to produce predominantly 4-NO-edaravone. Redox Rep. 2015 Jul 21; PubMed.
  3. Ikeda K, Iwasaki Y. Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse. PLoS One. 2015;10(10):e0140316. Epub 2015 Oct 15 PubMed.
  4. Ito H, Wate R, Zhang J, Ohnishi S, Kaneko S, Ito H, Nakano S, Kusaka H. Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. Exp Neurol. 2008 Oct;213(2):448-55. Epub 2008 Jul 31 PubMed.
  5. Aoki M, Warita H, Mizuno H, Suzuki N, Yuki S, Itoyama Y. Feasibility study for functional test battery of SOD transgenic rat (H46R) and evaluation of edaravone, a free radical scavenger. Brain Res. 2011 Mar 25;1382:321-5. PubMed.
  6. Yoshino H, Kimura A. Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study). Amyotroph Lateral Scler. 2006 Dec;7(4):241-5. PubMed.
  7. Abe K, Itoyama Y, Sobue G, Tsuji S, Aoki M, Doyu M, Hamada C, Kondo K, Yoneoka T, Akimoto M, Yoshino H, Edaravone ALS Study Group. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7-8):610-7. Epub 2014 Oct 6 PubMed.
  8. Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293-9. PubMed.

External Citations

  1. Treeway
  2. Phase 3 study
  3. Phase 3 trial
  4. Project MinE

Further Reading

Papers

  1. Kamat CD, Gadal S, Mhatre M, Williamson KS, Pye QN, Hensley K. Antioxidants in central nervous system diseases: preclinical promise and translational challenges. J Alzheimers Dis. 2008 Nov;15(3):473-93. PubMed.
  2. Kaur C, Ling EA. Antioxidants and neuroprotection in the adult and developing central nervous system. Curr Med Chem. 2008;15(29):3068-80. PubMed.
  3. van Muiswinkel FL, Kuiperij HB. The Nrf2-ARE Signalling pathway: promising drug target to combat oxidative stress in neurodegenerative disorders. Curr Drug Targets CNS Neurol Disord. 2005 Jun;4(3):267-81. PubMed.
  4. Mead RJ, Higginbottom A, Allen SP, Kirby J, Bennett E, Barber SC, Heath PR, Coluccia A, Patel N, Gardner I, Brancale A, Grierson AJ, Shaw PJ. S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis. Free Radic Biol Med. 2013 Apr 19;61C:438-452. PubMed.

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