On May 5, 2017, the Food and Drug Administration approved edaravone (Radicava) for the treatment of patients with amyotrophic lateral sclerosis (ALS). Developed by Mitsubishi Tanabe Pharma Corporation, edaravone is the first FDA-approved treatment for ALS since the approval of riluzole (Rilutek) in 1995. Edaravone was originally developed as an acute stroke treatment and then later studied in two separate trials in Japan to assess its efficacy in treating ALS.
The first trial was a 24-week double-blind, placebo-controlled trial of edaravone in 206 ALS patients. Eligibility requirements for this study included a forced vital capacity of at least 70% of the predicted value and onset of illness within 3 years of study entry. Patients were randomized to receive either edaravone or placebo, and the ALS functional rating scale (ALSFRS-R) was used as the primary endpoint measurement. This study failed to show a benefit of using edaravone. However, subsequent analysis revealed that a subgroup of patients with shorter duration of illness had slower progression than did those in the placebo group. This subgroup analysis prompted a second study.
The second study , also conducted in Japan, was a 24-week, randomized, double-blind, placebo-controlled trial of edaravone in 137 ALS patients. The eligibility requirements for this study included a forced vital capacity of at least 80% predicted and onset of illness within 2 years of study entry. The primary endpoint measurement was the ALSFRS-R. Both groups of ALS patients began the trial with a mean ALSFRS-R score of 42 points out of the maximal 48 points. The trial showed that patients receiving placebo worsened by 7.5 points on the ALSFRS-R, while the patients receiving edaravone worsened by 5.0 points. The conclusion was that progression of ALS was about 33% less in the edaravone-treated group than in the placebo group. Edaravone was generally well tolerated with side effects of rash, injection site bruising, and gait difficulty being more common in the edaravone group.
Edaravone is administered intravenously and the standard dose of 60 mg takes about 1 hour to complete. The initial treatment cycle consists of once-daily dosing for 2 weeks, followed by a 2-week drug-free period. After the initial cycle, subsequent cycles consist of once-daily dosing for 10 days out of the next 2 weeks, followed by a 2-week drug-free period. The question of how long patients should take edaravone has not been resolved. The FDA did not define a limit to the duration of treatment. Some insurance companies have limited authorization to 6 months as that was the duration of treatment that showed benefit in the study. However, an open-label, 24-week extension of the second study showed that the change in ALSFRS-R was linear throughout the study. This suggests that the treatment benefit in patients with short duration of illness may continue for an additional 24 weeks. Thus, patients who have duration of illness of less than 2 years at presentation may benefit from 12 months of treatment.
The rigorous treatment schedule and IV administration of edaravone create additional concerns for ALS patients. Many patients will need to have a port placed. Patients with impaired mobility will need assistance with transportation to an infusion center. The time involved with taking all of these IV infusions will be considerable. Our experience at the Mayo Clinic reflects differing patient opinions. Some ALS patients with short duration of illness who clearly meet the criteria are not willing to commit to this form of therapy even if insurance will cover it. In contrast, some patients with advanced disease who do not meet the eligibility criteria have expressed the wish to try it.
To have access to edaravone in the United States, ALS patients must first complete an enrollment form and register with a Mitsubishi Tanabe subsidiary called Searchlight. Searchlight creates a Searchlight patient ID and conducts a benefit investigation to determine if the patient’s insurance will cover edaravone treatment. If the patient’s insurance approves edaravone, arrangements are made to ship the drug to the site or company that will perform the infusions. Insurance companies have taken different approaches to the approval of edaravone for ALS patients. Some insurers require that the patient meets the eligibility requirements of the Japanese study that showed benefit (duration of illness less than 2 years from symptom onset and forced vital capacity of at least 80% predicted). These strict criteria will exclude many patients. Other insurers have required only the diagnosis of ALS and the physician’s order. The cost of edaravone is estimated to be around $145,500 per year. The actual out-of-pocket cost to patients will vary depending on their specific insurance plans. In-home infusion of edaravone is another option patients can consider. Patients can pay the separate charges for in-home infusion if their insurance plans do not cover this.
The costs of edaravone are substantial. Beyond the expenses for the medication and infusion services, the patient faces the burden of committing time to frequent IV infusions and potential complications associated with having a port placed. Many ALS patients have decided against pursuing edaravone, suggesting that the perceived costs exceed the perceived benefits. Many ALS patients have started edaravone treatment with the belief that slowing of progression is worth the costs. It is too soon to know if those who have started edaravone will remain committed to the treatment for 6-12 months. Despite the differing approaches to edaravone treatment, it can be agreed upon that it is good to have a new treatment for ALS and that we must continue working to find therapies effective in substantially slowing or stopping the progression of ALS.
Ms. Chang is a research intern, and Dr. Ross is a professor of neurology and director of the ALS Clinic, at Mayo Clinic Arizona in Scottsdale. Dr. Ross reported serving as the Mayo Clinic Arizona site primary investigator for the ALS investigational drug NP001.
