Edaravone for amyotrophic lateral sclerosis

Background:
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND), a progressive, degenerative disease of the central nervous system that primarily involves motor neurons (and their supporting astrocytes). ALS is rare, and incurable (fatal usually within 3 to 4 years of onset, with a small subset of patients surviving for longer). Patients experience muscle wasting, fasciculation, stiffness, spasticity and weakness, before eventual loss of ambulation, feeding and communication; death commonly results from respiratory failure or complications of prolonged immobility.¹

Edaravone is a novel drug that joins the limited range of existing disease-modifying treatments for ALS (riluzole and tofersen).¹ Riluzole is approved for treatment of ALS in Australia, while tofersen is only available via the Special Access Scheme.

Mechanism of action:
The exact mechanism by which edaravone exerts its therapeutic effect in patients with ALS is unknown. Edaravone is a free radical scavenger thought to reduce oxidative stress, which has been implicated in the pathogenesis of ALS.^1,2

Clinical trials:
Edaravone registration was primarily based on study MCI-186-19,^1,3 a 6-month multicentre, randomised, double-blind, placebo-controlled phase 3 trial conducted in Japan. Recruited patients (aged 20 to 75 years) were independently living with relatively mild ALS (grade 1 or 2), with disease duration 2 years or less, normal respiratory function (forced vital capacity of at least 80%), scores of at least 2 on all items of the Revised ALS Functional Rating Scale (ALSFRS-R), and intermediate disease progression during the 12-week pretreatment period (change in ALSFRS-R score of −1 to −4 points). Patients were randomised to either edaravone or matching placebo, administered intravenously over six 4-week treatment cycles (initial cycle of once-daily infusions for 2 weeks, then 2 weeks without treatment; subsequent cycles of 10 once-daily infusions within 2 weeks, then 2 weeks without treatment). Prior riluzole treatment could be continued provided the dosage and administration were not changed. Patients in the edaravone group had a smaller decline in ALSFRS-R score over 24 weeks (−5.01±0.64, n=68) than the placebo group (−7.50±0.66, n=66); between-group difference 2.49 (95% confidence interval [CI] 0.99 to 3.98, p=0.0013). Some, but not all, secondary outcomes favoured edaravone over placebo.

Although previous trials (MCI-186-16⁴ and its extension study MCI-186-17⁵) did not show a significant benefit for the studies' primary endpoints, post hoc analyses showed a favourable benefit from edaravone in a subpopulation with high likelihood of disease progression, which was subsequently used to define patient inclusion criteria for study MCI-186-19 (above).¹

Study MCI-186-18 was an exploratory study in patients with grade 3 ALS.⁶ This trial did not find a significant effect on change in ALSFRS-R score (edaravone: −6.52±1.78 versus placebo: −6.00±1.83).

A meta-analysis of randomised controlled trials and observational studies suggested there may be a mortality benefit with edaravone treatment, though the magnitude is uncertain.^7,8

Adverse effects:
Common adverse effects reported in clinical trials include contusion (bruising), gait disturbance, headache, eczema, contact dermatitis, respiratory disorder, rash, glycosuria and upper respiratory tract inflammation. Hypersensitivity and anaphylactic reactions have been reported during post-approval use. Edaravone ampoules contain sodium bisulfite which may cause allergic reactions, including anaphylactic symptoms and asthmatic episodes in susceptible individuals.^1,2

Dosage and administration:
The recommended dosage of edaravone is 60 mg (2 ampoules) diluted with 100 mL of 0.9% sodium chloride, administered as an intravenous infusion over 60 minutes according to the following schedule:²

• initial treatment cycle: once-daily dosing for 14 days, followed by a 14-day drug-free period
• subsequent treatment cycles: once-daily dosing on 10 days out of 14, followed by a 14-day drug-free period.

No dose adjustment is required in patients with renal or hepatic impairment.² Edaravone use is not recommended in patients undergoing renal replacement therapy.

Place in therapy:
There are limited treatment options for MND. Edaravone may slow disease progression in a specific subset of patients with early-stage ALS (within 2 years of disease onset) who reflect the inclusion criteria for the MCI-186-19 clinical trial. Efficacy has not been demonstrated in patients outside of this defined population.² The requirement for frequent and ongoing 60-minute intravenous infusions will present challenges in the delivery of this therapy. An oral formulation of edaravone has been approved for use in the USA; studies are underway to confirm its efficacy.⁹

This new drug comment was finalised on 8 September 2025.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

 

References

1. Therapeutic Goods Administration. Australian Public Assessment Report for Radicava. Canberra: Department of Health, Disability and Ageing; 2024. [cited 2025 Sep 8]
2. Therapeutic Goods Administration. Australian Product Information - RADICAVA edaravone 30 mg/20 mL concentrated injection ampoule. Department of Health, Disability and Ageing; 2023. [cited 2025 Sep 8]
3. Writing Group On Behalf Of The Edaravone 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 2017;16:505-12.
4. 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;15:610-7.
5. Writing Group On Behalf Of The Edaravone Als 17 Study Group. Exploratory double-blind, parallel-group, placebo-controlled extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2017;18:20-31.
6. Writing Group On Behalf Of The Edaravone Als 18 Study G. 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 2017;18:40-8.
7. Nourelden AZ, Kamal I, Hagrass AI, Tawfik AG, Elhady MM, Fathallah AH, et al. Safety and efficacy of edaravone in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis. Neurol Sci 2023;44:3429-42.
8. Pharmaceutical Benefits Advisory Committee. Public Summary Document – March 2024 PBAC Meeting: Edaravone. Pharmaceutical Benefits Scheme; 2024. [cited 2025 Sep 8]
9. Pattee GL, Genge A, Couratier P, Lunetta C, Sobue G, Aoki M, et al. Oral Edaravone - Introducing a Flexible Treatment Option for Amyotrophic Lateral Sclerosis. Expert Rev Neurother 2023;23:859-66.

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

Report all suspected adverse reactions to new drugs to enable continued monitoring of their benefit–harm balance.