What is edaravone, used to treat amyotrophic lateral sclerosis (ALS) in adults?

What is Edaravone?

Edaravone is a free radical scavenger and antioxidant medication approved by the FDA for the treatment of amyotrophic lateral sclerosis (ALS) in adults. 1

Mechanism of Action

• Edaravone functions as a potent neuroprotective agent that prevents oxidative stress from inducing motor neuron death in ALS patients 2
• It inhibits nitration of tyrosine residues in the cerebrospinal fluid and has been shown to improve motor functions in mouse models of ALS 2
• The drug markedly reduces 3-nitrotyrosine (3NT) levels in cerebrospinal fluid, a marker for oxidative stress, to almost undetectable levels in most patients 3

FDA-Approved Formulations and Dosing

Intravenous Formulation

• The recommended dosage is 60 mg administered as an intravenous infusion over 60 minutes 1
• Initial treatment cycle: daily dosing for 14 days followed by a 14-day drug-free period 1
• Subsequent treatment cycles: daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods 1
• Available as 30 mg/100 mL in a single-dose polypropylene bag 1

Oral Formulation

• An oral suspension formulation (105 mg of edaravone in 5 mL aqueous suspension) was recently approved by the FDA for use in patients with ALS 4, 5
• The oral formulation replicates the dosing cycles of IV edaravone and can be administered orally or via percutaneous endoscopic gastrostomy (PEG) tube 4, 5
• After oral administration, edaravone is well absorbed and mainly eliminated in urine as the glucuronide conjugate 4

Clinical Efficacy Evidence

Supportive Evidence

• In early phase II studies, edaravone showed a 2.4-point difference in ALSFRS-R score decline over six months compared to the pre-treatment period (p = 0.039) 3
• The drug has been shown to slow down the loss of physical function in ALS patients by 33% compared to placebo in Japanese clinical trials 2
• FDA approval was based on clinical evidence from three clinical trials conducted in 368 ALS patients in Japan 2

Contradictory Evidence

• A large German multicenter propensity score-matched cohort study (2022) found no disease-modifying benefit with long-term intravenous edaravone therapy 6
• In this real-world study of 194 patients treated with edaravone versus 130 matched controls, disease progression did not differ between groups (ALSFRS-R points/month: -0.91 vs -0.85; P = 0.37) 6
• No significant differences were observed in survival probability, time to ventilation, or change in disease progression 6

Safety Profile

Common Adverse Events

• Most common treatment-emergent adverse events at 48 weeks include fall (22.2%), muscular weakness (21.1%), and constipation (17.8%) 5
• With IV formulation, the most common adverse reactions (≥10% of patients) are contusion, gait disturbance, and headache 1
• Drug-related adverse events occurred in 24.9% of patients, most commonly fatigue, dizziness, headache, and constipation 5
• Infections at infusion sites and allergic reactions were noted in 16% of patients receiving IV edaravone 6

Contraindications and Warnings

• Contraindicated in patients with a history of hypersensitivity to edaravone or any inactive ingredients 1
• Edaravone injection contains sodium bisulfite, which may cause allergic-type reactions, including anaphylactic symptoms and asthmatic episodes in susceptible people 1
• Patients should be advised to seek immediate medical care for hypersensitivity reactions 1
• Based on animal data, edaravone may cause fetal harm during pregnancy 1

Discontinuation Rates

• Only 8.6% of patients discontinued study drug due to treatment-emergent adverse events in the 48-week oral edaravone study 5
• No serious treatment-emergent adverse events were related to study drug 5

Clinical Context and Limitations

• Edaravone was the second drug approved by the FDA for ALS after a 22-year gap following riluzole's approval in 1995 2
• The drug is awaiting approval by the European Medicines Agency (EMA) 2
• The conflicting evidence between Japanese registration trials and real-world German data suggests that the clinical benefit of edaravone may be limited to specific ALS subpopulations or may not translate to broader real-world effectiveness 6, 3
• Long-term intravenous edaravone therapy was found to be feasible and mainly well tolerated, but may not provide clinically relevant additional benefit compared with standard therapy alone in unselected ALS populations 6