Addendum to the 2023 clinical practice guidelines for amyotrophic lateral sclerosis in Japan: approval and integration of novel disease-modifying therapies

Abstract

Amyotrophic lateral sclerosis (ALS) is an intractable motor neuron disease characterized by progressive degeneration of motor neurons with varying degrees of frontotemporal lobe dysfunction. This English summary of the addendum to the Japanese clinical practice guidelines for ALS outlines major recent advances in pharmacological therapy in Japan. Following the development of the 2023 guidelines, three additional medications—oral edaravone, high-dose intramuscular mecobalamin, and tofersen—have been introduced. Oral edaravone, with its ease of administration, demonstrates pharmacokinetics comparable to the intravenous formulation. High-dose mecobalamin reduces functional decline when initiated early in the disease course. Tofersen, an antisense oligonucleotide, is the first gene-targeted therapy approved in Japan for patients with copper/zinc superoxide dismutase gene-related ALS, highlighting the importance of genetic testing and counseling in all ALS cases. This addendum provides updated expert consensus recommendations for the use, dosing, and monitoring of these therapies, while emphasizing the need for thorough communication about the ethical and psychological dimensions of genetic testing. It also addresses practical considerations for combination therapy, noting that up to three or four anti-ALS agents are now available in Japan. The long-term safety and efficacy of these therapies, as well as their potential synergistic or additive effects, remain to be clarified through real-world data and prospective registries. The objectives of this addendum are twofold: to present these advances and recommendations in English to foster international collaboration, and to inform the global ALS community about the latest therapeutic strategies in Japan. In addition, ongoing efforts to harmonize clinical evaluation standards and promote international clinical trials are highlighted, with the goal of improving patient outcomes and advancing ALS research worldwide.