Description
Edaravone (Radicava), a free radical scavenger and antioxidant, was approved by the U.S. Food and Drug Administration (FDA) in May 2017 for the treatment of ALS. Edaravone may provide neuroprotection against oxidative stress; however, the exact mechanism of action in ALS is unknown. 

Background
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a rapidly progressive, invariably fatal neurological disease that attacks neurons responsible for controlling voluntary muscles. The disease belongs to a group of disorders known as motor neuron diseases, which are characterized by the gradual degeneration and death of motor neurons. Eventually, all muscles under voluntary control are affected. Individuals lose their strength and the ability to move their arms, legs, and body. When muscles in the diaphragm and chest wall fail, individuals lose the ability to breathe without support of a ventilator. Individuals with ALS usually survive for only 3 to 5 years from the onset of symptoms. However, about 10 percent of those with ALS survive for 10 or more years.

The mechanism by which Radicava (edaravone) exerts its therapeutic effect in patients with ALS is unknown. It has been characterized as a free radical scavenger, which is thought to block radicals that mediate both neuronal and vascular damage.   

Policy
Edaravone is considered MEDICALLY NECESSARY for the treatment of amyotrophic lateral sclerosis in adult individuals who meet the following criteria:

1. The patient has been diagnosed with ALS; AND
2. ALS was diagnosed within the last two years; AND
3. The patient has normal respiratory function (FVC 80%); AND
4. The patient is able to live independently; OR 
5. The patient has retained most activities of daily living of 2 points or better on each individual item of the ALS Functional Rating Scale

Use of edaravone is considered investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY when the criteria above are not met and for all other indications. 

Policy Guidelines
Dosage Information
The recommended dosage of Radicava is an intravenous infusion of 60 mg administered over a 60-minute period according to the following schedule:

• An initial treatment cycle with daily dosing for 14 days, followed by a 14-day drug-free period
• Subsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods

Rationale 
The efficacy and safety of edaravone for amyotrophic lateral sclerosis (ALS) was examined in a double-blind, parallel-group, placebo-controlled, phase III trial. The 36-week confirmatory trial consisted of a 12-week pre-observation period followed by a 24-week treatment period. The eligible patient population included those who were diagnosed with ALS as defined as "definite ALS," "probable ALS" or "probable-laboratory-supported ALS," according to the revised EL Escorial for Airlie House criteria. With their baseline disease state, patients also must be able to eat a meal, excrete or move with oneself alone, and do not need assistance in everyday life. Patients must begin the trial within 3 years after onset of ALS and have an FVC of at least 70%. Patients who complain of dyspnea and have deterioration of respiratory function, among other criteria, were excluded from the study. Patients age 20 to 75 were randomized to receive either placebo (saline, n = 104), or edaravone (n = 102) 60 mg intravenously per day. A single treatment cycle consisted of 14 days of study drug administration period followed by a 14-day observation period. Study drugs were administered every day for 14 days in the administration period of the first cycle, and for 10 out of 14 days in the administration periods of cycles 2 to 6. The end of the administration period in each cycle was followed by a 14-day observation period. Primary efficacy endpoint was the change in ALSFRS-R score. Secondary endpoints were changes of FVC, grip strength (left/right mean), pinch strength (left/right mean), Modified Norris Scale score, ALSAQ-40 (ALS Assessment Questionnaire), and time to death or a specified state of disease progression (incapable of independent ambulation, loss of function in upper limbs, tracheotomy, artificial respirator with intubation or tube feeding). Changes in ALSFRS-R during the 24-week treatment were -6.35 ± 0.84 in the placebo group (n = 99) and -5.70 ± 0.85 in the edaravone group (n = 100), with a difference of 0.65 ± 0.78 (p = 0.411). The results with primary outcome, the inter-group difference in the change of the ALSFRS-R at the end of treatment, was not statistically significant. Of all of the secondary outcomes, edaravone only showed statistically significant benefit over placebo in pinch strength (-1.03 ± 0.15 placebo vs. -0.83 ± 0.15 edaravone; difference of 0.20 ± 0.14; p = 0.165). There were no significant differences in the safety profile reported between the two experimental groups. The authors admit that this study failed to demonstrate efficacy of edaravone to delay the progression of ALS.

There are additional completed studies that have unpublished results on edaravone's efficacy and safety as a treatment for ALS. These studies include, after a 12-week observation period, patients who meet the diagnostic criteria of the revised EL Escorial for Airlie House, have had onset of ALS symptoms less than 2 years, and can still function to the requirements stated in the inclusion criteria. Patients with certain organ and neurological dysfunction, have dyspnea or deteriorating respiratory function were excluded from these studies. The primary outcome measure of each of these trials is the score of the ALSFRS-R. Additional secondary outcome measures include, but are not limited to: period until death or a certain state (i.e., inability to walk alone, failure of arm function, tracheostomy, respirator installation, tubal feeding replenishment), % FVC, and others. The studies also examine adverse events, drug reactions, laboratory tests and sensory examinations.

References 

1. Abe K, Aoki M, Tsuji S, et al. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017 Jul;16(7):505-512.
2. Abe K, Itoyama Y, Sobue G, et al. Confirmatory double-blind, parallel-group, placebocontrolled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients.
3. Abe K, Itoyama Y, Sobue G, Tsuji S, Aoki M, Doyu M, et al. 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; 15(7–8):610–7.
4. ALS Association. Frequently Asked Questions about Radicava™ (Edavarone). Available at http://www.alsa.org/research/radicava/radicava-frequently-askedquestions.  html?referrer = https://www.google.com/. Accessed June 5, 2017.
5. Amyotroph Lateral Scler Frontotemporal Degener. 2014; 15(7–8):610–7.
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10. Cedarbaum JM, Stambler N, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. Journal of the Neurological Sciences 1999; 169: 13-21. Retrieved June 5, 2017 from http://www.alscareproject.org/whatisals/als-functionalratingscale-r.pdf 
11. Cedarbaum JM, Stambler N, Malta E, Fuller C, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999 Oct 31;169(1-2):13-21.
12. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. J Neurol Sci. 1999; 169(1): 13–21.
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22. MT Pharma. Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III [NCT00415519]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; 2000 Feb 29 - [cited 7/27/17]. Available from: http://clinicaltrials.gov/.
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25. MT Pharma. Radicava (edaravone) injection. 2017 [cited 7/27/17]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid = 0ce2c1c4-2a40-485c-b7cb-96a9b85d9d11.
26. Nagase M, Yamamoto Y, Miyazaki Y, Yoshino H. Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration. Redox Rep. 2016 May;21(3):104-12.
27. Nagase M, Yamamoto Y, Miyazaki Y, Yoshino H. Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration. Redox Rep. 2016 May;21(3):104-12.
28. National Institute of Neurological Disorders and Stroke. Amyotrophic Lateral Sclerosis (ALS) Fact Sheet. Retrieved from: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet#267654842. Accessed on: March 6, 2017.
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31. Product information for Radicava® (edaravone injection). MT Pharma America, Inc. Jersey City, NJ. May 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209176lbl.pdf. Accessed June 2017. 
32. Radicava [Prescribing Information]. Jersey City, NJ: MT Pharma America, Inc.; May 2017.
33. Subcommittee on Motor Neuron Diseases of World Federation of Neurology Research Group on Neuromuscular Diseases, El Escorial "Clinical Limits of ALS" Workshop Contributors. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 1994; 124: 96–107.

Coding Section 

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