Medical Policy

 

Subject: Edaravone (Radicava®)
Document #: DRUG.00108 Publish Date:    04/25/2018
Status: Reviewed Last Review Date:    03/22/2018

Description/Scope

This document addresses the use of edaravone (Radicava) (Mitsubishi Tanabe Pharma Development America, Inc., Jersey City, NJ). Edaravone is a free radical scavenger approved by the U.S. Food and Drug Administration (FDA) for the treatment of amyotrophic lateral sclerosis (ALS).

Position Statement

Medically Necessary:

Edaravone is considered medically necessary for the treatment of amyotrophic lateral sclerosis when all of the following criteria are met:

  1. Individual is diagnosed with definite or probable amyotrophic lateral sclerosis (based on El Escorial/revised Airlie House criteria* or Awaji-Shima criteria*); and
  2. Onset of amyotrophic lateral sclerosis has been less than 2 years; and
  3. Japan ALS severity classification grade* less than 3; and
  4. Score of 2 or more points on each single ALSFRS-R* item at time of therapy initiation.

Investigational and Not Medically Necessary:

Edaravone is considered investigational and not medically necessary when the criteria above are not met and for all other indications.

*See definition section below for description

Rationale

On May 5th, 2017, the FDA approved Radicava (edaravone injection) for the treatment of ALS, a rapidly progressive neurological disease. Radicava is administered as an intravenous infusion by a health care professional.

Results of an early phase II clinical trial (Yoshino, 2006) indicated that edaravone may delay the progression of symptoms in some individuals with ALS. A 36-week confirmatory study (Abe, 2014) was conducted to further evaluate the efficacy and safety of edaravone in subjects with ALS. A total of 206 subjects were randomized to receive either placebo (saline) or edaravone IV infusion. The trial consisted of a 12-week pre-observation period followed by a 24-week treatment period between May 2006 and September 2008 at 29 Japanese sites. Inclusion criteria were: age 20-75 years, diagnosis of definite, probable or probable laboratory-supported ALS, forced vital capacity (FVC) of at least 70%, duration of disease within 3 years, and change in revised ALS functional rate scale (ALSFRS-R) score during the pre-observation period of –1 to –4 points. Exclusion criteria included: reduced respiratory function and complaints of dyspnea; complications that might impact evaluation of drug efficacy, such as Parkinson’s disease, schizophrenia and dementia; complications that require hospitalization such as liver, cardiac and renal diseases; infections requiring antibiotics; deteriorated general condition; creatinine clearance 50 ml/min or below; and undergoing cancer treatment. The primary efficacy endpoint was change in ALSFRS-R scores during the 24 weeks of treatment. Upon study completion, data failed to demonstrate the efficacy of edaravone for treatment of ALS. Adverse events occurred in 88.5% (92/104) of subjects in the placebo group and 89.2% (91/102) of subjects the edaravone group. The authors indicated that the results of this trial would be helpful to identify the population for which edaravone could be expected to show efficacy. On the basis of that information, a phase III study was designed.

A phase III trial evaluated the efficacy and safety of edaravone in a 24-week open-label extension period after a 24-week double-blind period (Writing Group, 2017a). A total of 137 subjects were randomized 1:1 to receive edaravone or placebo after a 12-week pre-observation period. Selection criteria included: definite or probable ALS; Japan ALS severity classification grade less than 3; scoring 2 or more points on each single ALSFRS-R item at screening; forced vital capacity 80% or greater; and ALS duration 2 years or less. Most (93%) of these subjects were living independently at the time of screening. Subjects were treated with six cycles of 60 mg edaravone or a matching placebo treatment. The primary efficacy endpoint was a change in ALSFRS-R score at week 24. Safety endpoints included adverse events, adverse drug reactions, and laboratory tests (hematology, blood chemistry, and urinalysis). Upon study completion, the mean change in ALSFRS-R score was –7.50 ± 0.66 (placebo) and –5.01 ± 0.64 (edaravone). Adverse events were similar in both groups (84.1% in the edaravone group and 83.8% in the placebo group). The most common adverse events were contusion and dysphagia (16% and 13% of subjects, respectively). Incidence of adverse drug reactions was 2.9% (edaravone) and 7.4% (placebo). There were no serious adverse drug reactions or adverse events that resulted in death. Investigators concluded that subjects meeting the protocol inclusion criteria had less functional loss at 6 months and less quality of life deterioration compared to those receiving placebo treatment. According to the authors, “Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria.”

After the phase III trial, an open-label, 24-week extension study was completed to determine the longer-term safety and efficacy of edaravone (Writing Group, 2017b). A total of 123 of the original 137 subjects were randomized to either continue treatment with edaravone (E-E group; n=65) or start edaravone instead of the former placebo (P-E group; n=58). The change in the ALSFRS-R score was –4.1 ± 3.4 and –6.9 ± 5.1 from baseline to the end of the study and –8.0 ± 5.6 and –10.9 ± 6.9 for the 48-week timespan in the E-E group and P-E group, respectively. Common adverse effects for both groups included nasopharyngitis, respiratory disorders, constipation, dysphagia, and contusion. A total of 6 subjects died during the study: 2 in the E-E group and 4 in the P-E group. However, the drug was deemed “not reasonably possible” in causing the deaths. The authors did not find any sudden deterioration in the ALSFRS-R scores or safety concerns, but they noted that “long-term treatment for efficacy and safety remains for a future issue.”

Researchers performed a small, 24-week, double-blind, randomized study to determine the safety and efficacy of edaravone for ALS individuals with a Japan ALS severity classification of grade 3 (individuals requiring assistance eating, excreting, or ambulating) (Writing Group; 2017c). A total of 25 individuals were randomized 1:1 to either receive edaravone or a placebo. During the study, edaravone was discontinued for 4 individuals in the edaravone group and none in the placebo group. At the end of the study, the researchers did not find a statistically significant difference between the two groups for ALSFRS-R scores, %FVC, the Modified Norris scale, amyotrophic lateral sclerosis assessment questionnaire (ALSAQ-40) scores, grip strength, or pinch grip strength. Disease progression occurred in 4 subjects in the edaravone group and 3 subjects in the placebo group. Due to the small study sample, the efficacy and safety of edaravone for ALS grade 3 individuals is inconclusive and needs further study.

Evidence for the benefit of edaravone has only been demonstrated in patients with early ALS, as defined in the pivotal trial. Additional data from registries and follow-up studies are needed to clarify the utility of edaravone for people in different stages of the illness.

Although the published evidence focuses on the use of edaravone for the treatment of ALS, it has also been studied for other indications including, but not limited to, the treatment of acute stroke (Nakase, 2011) and acute myocardial infarction (Tsujita, 2006). However, at this time the published evidence is insufficient to support the safety and efficacy of edaravone for any indication other than as treatment for certain cases of ALS.

Background/Overview

ALS (commonly known as Lou Gehrig’s disease) is a refractory and progressive neuromuscular disease that attacks nerve cells in the spine and brain that are responsible for controlling voluntary movement. It is estimated that approximately 5 persons per 100,000 in the United States are affected with ALS. The cause of the disease is not known; although, some scientific evidence suggests that genetics and environment may have a role. Median survival from onset to death in ALS is reported to vary from 20 to 48 months.

There is no known cure for ALS. However, there are treatments available that can help control symptoms and manage the disease. To date, only one other ALS disease modifying drug has been approved by the U.S. FDA (riluzole [Rilutek®]). Other treatments may include nutritional support, breathing support, physical therapy, and speech therapy.

Definitions

ALS functional rating scale (revised) (ALSFRS-R): A commonly used functional rating system for persons with ALS (Cedarbaum, 1999):

Awaji-Shima criteria: Diagnostic criteria used for ALS (Douglass, 2010; Hardiman, 2011) consisting of the following categories:

Clinically definite ALS is defined on clinical or electrophysiological evidence, demonstrated by the presence of upper and lower motor neuron signs in the bulbar region and at least two spinal regions, or the presence of upper and lower motor neuron signs in three spinal regions.
Clinically probable ALS is defined on clinical or electrophysiological evidence, demonstrated by upper and lower motor neuron signs in at least two spinal regions, with some upper motor neuron signs necessarily rostral to the lower motor neuron signs.
Clinically possible ALS is defined on clinical or electrophysiological signs of upper and lower motor neuron dysfunction in only one region, or upper motor neuron signs alone in two or more regions, or lower motor neuron signs rostral to upper motor neuron signs.

El Escorial/revised Airlie House criteria (El Escorial is also known as Airlie House): Diagnostic criteria for ALS (Brooks, 2000; Douglass, 2010). Designed for research purposes to ensure appropriate inclusion of subjects into clinical trials. Consists of the following categories:

Clinically Definite ALS is defined on clinical evidence alone by the presence of upper motor neuron (UMN), as well as lower motor neuron (LMN) signs, in the bulbar region and at least two spinal regions or the presence of UMN and LMN signs in three spinal regions.
Clinically Probable ALS is defined on clinical evidence alone by UMN and LMN signs in at least two regions with some UMN signs necessarily rostral to (above) the LMN signs.
Clinically Probable - Laboratory-Supported ALS is defined when clinical signs of UMN and LMN dysfunction are in only one region, or when UMN signs alone are present in one region, and LMN signs defined by EMG criteria are present in at least two regions, with proper application of neuroimaging and clinical laboratory protocols to exclude other causes.
Clinically Possible ALS is defined when clinical signs of UMN and LMN dysfunction are found together in only one region or UMN signs are found alone in two or more regions; or LMN signs are found rostral to UMN signs and the diagnosis of Clinically Probable - Laboratory-supported ALS cannot be proven by evidence on clinical grounds in conjunction with electrodiagnostic, neurophysiologic, neuroimaging or clinical laboratory studies. Other diagnoses must have been excluded to accept a diagnosis of clinically possible ALS.

Japan ALS severity classification grade: A Japanese ALS classification grade based on the severity of the disease. The grade ranges from 1 to 5 as follows (Abe, 2014):

  1. Able to work or perform housework;*
  2. Independent living but unable to work;*
  3. Requiring assistance for eating, excretion, or ambulation;  
  4. Presence of respiratory insufficiency, difficulty in coughing out sputum, or dysphagia; and
  5. Using a tracheostomy tube, tube feeding, or tracheostomy positive pressure ventilation.

**Individuals who can eat a meal, excrete, or move with oneself alone, and do not need assistance in everyday life.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

 

C9493

Injection, edaravone, 1 mg [Radicava]

J3490

Unclassified drugs [when specified as edaravone (Radicava)]

 

 

ICD-10 Diagnosis

 

 

G12.21

Amyotrophic lateral sclerosis

 

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Abe K, Itoyama Y, Sobue G, 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):610-617.
  2. 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; 1(5):293-299.
  3. Cedarbaum JM, Stambler N, Malta E, 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; 169(1-2):13-21.
  4. Chiò A, Logroscino G, Traynor BJ, et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology. 2013; 41(2):118-130.
  5. Douglass CP, Kandler RH, Shaw PJ, McDermott CJ. An evaluation of neurophysiological criteria used in the diagnosis of motor neuron disease. J Neurol Neurosurg Psychiatry. 2010; 81(6):646-649.
  6. Hardiman O, van den Berg LH, Kiernan MC. Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2011; 7(11):639-649.
  7. Kalin A, Medina-Paraiso E, Ishizaki K, et al. A safety analysis of edaravone (MCI-186) during the first six cycles (24 weeks) of amyotrophic lateral sclerosis (ALS) therapy from the double-blind period in three randomized, placebo-controlled studies. Amyotroph Lateral Scler Frontotemporal Degener. 2017; 18(sup1):71-79.
  8. Nakase T, Yoshioka S, Suzuki A. Free radical scavenger, edaravone, reduces the lesion size of lacunar infarction in human brain ischemic stroke. BMC Neurol. 2011; 11:39.
  9. Tsujita K, Shimomura H, Kaikita K, et al. Long-term efficacy of edaravone in patients with acute myocardial infarction. Circ J. 2006; 70(7):832-837.
  10. Writing Group; Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017a; 16(7):505-512.
  11. Writing Group; Edaravone (MCI-186) ALS 19 Study Group. Open-label 24-week extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2017b; 18(sup1):55-63.
  12. Writing Group; Edaravone (MCI-186) ALS 18 Study Group. Exploratory double-blind, parallel-group, placebo-controlled study of edaravone (MCI-186) in amyotrophic lateral sclerosis (Japan ALS severity classification: Grade 3, requiring assistance for eating, excretion or ambulation). Amyotroph Lateral Scler Frontotemporal Degener. 2017c; 18(sup1):40-48.
  13. 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; 7(4):241-245.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Edaravone. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated November 15, 2017. Available at: http://www.micromedexsolutions.com. Accessed on February 10, 2018.
  2. Edaravone Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio. Lexi-Comp., Inc. January 4, 2018. Accessed on February 10, 2018.
  3. Radicava [Product Information], Jersey City, NJ. MT Pharma America, Inc., May 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209176lbl.pdf. Accessed on February 15, 2018.
Websites for Additional Information
  1. ALS Association. What is ALS. 2016. Available at: http://www.alsa.org/about-als/what-is-als.html. Accessed on February 15, 2018.
  2. Centers for Disease Control and Prevention. Prevalence of Amyotrophic Lateral Sclerosis - United States, 2012–2013. Available at: https://www.cdc.gov/mmwr/volumes/65/ss/ss6508a1.htm. Accessed on February 15, 2018.
  3. National Institute of Neurological Disorders and Stroke (NINDS). Amyotrophic lateral sclerosis (ALS) fact sheet. Updated June 2013. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet. Accessed on February 15, 2018.
Index

Edaravone
MCI-186
Radicava

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed

03/22/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. The document header wording updated from “Current Effective Date” to “Publish Date.” Rationale, References and Websites sections updated.

 

10/01/2017

Updated Coding section with 10/01/2017 HCPCS coding changes.

New

05/15/2017

MPTAC review. Initial document development.

Preliminary Discussion

05/04/2017

MPTAC review. Pre-FDA approval review.