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.

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons, leading to severe muscle weakness, respiratory failure, and early mortality. Despite extensive research, only riluzole and intravenous edaravone have been incorporated into the 2023 clinical practice guidelines for ALS management, published by the Japanese Society of Neurology (JSN; https://www.neurology-jp.org/guidelinem/als_2023.html) and summarized in English¹⁾.

During the past three years, the Ministry of Health, Labour and Welfare in Japan approved three additional agents, thereby broadening treatment options for ALS. In December 2022, the oral formulation of edaravone received marketing authorization, demonstrating pharmacokinetic equivalence to the intravenous formulation while providing improved convenience and adherence. In September 2024, high-dose intramuscular mecobalamin was approved based on a phase 3 investigator-initiated clinical trial that showed efficacy in slowing functional decline, particularly when treatment began in the early stages of the disease. In March 2025, tofersen—an antisense oligonucleotide designed to ‍target copper/zinc superoxide dismutase (SOD1) gene transcripts—was introduced into clinical practice for SOD1-related ALS (SOD1-ALS). This approval represented a major milestone in the medical field of Japan, as it was the first gene-targeted therapy for ALS to receive domestic authorization.

In response to these developments, an addendum to the Japanese ALS guidelines was created and approved by the JSN, ‍focusing specifically on drug-based treatments. This update summarizes the evidence, indications, dosing, monitoring, and integration of oral edaravone, high-dose mecobalamin, and tofersen. Because tofersen is indicated exclusively for SOD1-ALS, the addendum emphasizes the need for clear communi­cation with patients and their relatives regarding inheritance and genetic testing. Ethical and psychological factors should also be addressed when discussing genetic testing and its implications with patients and their families.

By presenting this addendum in English, we seek to inform the international ALS community about recent therapeutic advances in Japan and to foster global collaboration on innovative strategies to improve patient outcomes.

Recommendations from expert consensus: addendum to the 2023 clinical practice guidelines for ALS in Japan

Novel anti-ALS drugs approved in Japan

In the current therapeutic landscape in Japan, three pharmaceutical agents are widely used for the treatment of ALS: riluzole, edaravone, and high-dose mecobalamin. Edaravone is available in two formulations, intravenous infusion and oral. In addition, tofersen is covered by insurance for patients with ALS caused by pathogenic variants in SOD1.

Edaravone (oral formulation)

Edaravone is an antioxidant drug with established efficacy and safety and is recommended for the treatment of ALS¹⁾. It has also been used in the management of acute cerebral infarction. Insurance coverage for edaravone in ALS was approved in 2015, based on clinical trial data showing efficacy in early-stage cases. The approval was granted for its ability to slow the progression of motor dysfunction. In clinical studies, edaravone demonstrated a 33% reduction in the rate of decline on the ALS Functional Rating Scale–Revised (ALSFRS-R) over a six-month treatment period²⁾. The oral formulation of edaravone was launched in April 2023, after pharmacokinetic studies confirmed equivalence with the intravenous formulation and no additional safety concerns over 144 weeks^3)–5). Administration through a gastrostomy tube was also shown to have pharmacokinetics equivalent to oral intake⁵⁾. However, the efficacy of daily administration compared with intermittent dosing has not been established⁶⁾. According to the Drug Information Form, serious adverse effects—reported with unknown frequencies—include acute renal failure, nephrotic syndrome, fulminant hepatitis, hepatic dysfunction, jaundice, thrombocytopenia, granulocytopenia, disseminated intravascular coagulation, acute lung injury, rhabdomyolysis, shock, and anaphylaxis. Other reported side effects include elevated alanine ‍aminotransferase/aspartate aminotransferase, diarrhea, and fatigue (0.1–5%)⁷⁾.

The intravenous formulation is administered at a dose of 60 ‍mg per day by one-hour infusion, whereas the oral formulation is given once daily as a 2.1% suspension solution (5 ‍ml). Administration should follow an eight-hour fast. If an eight-hour fast is not feasible, the dose may be taken four hours after a low-fat meal or two hours after a light meal. After a high-fat meal, the medication should be taken at least eight hours later. Each treatment course lasts 28 days: the first course is administered continuously for 14 days, and subsequent courses are given for 10 of 14 days, followed by a 14-day drug-free interval, repeated in cycles.

High-dose mecobalamin

High-dose mecobalamin, also known as methylcobalamin, is an intramuscular injection form of active vitamin B₁₂. Each vial contains 25 ‍mg of crystalline mecobalamin powder, which is photosensitive and must be protected from light. Mecobalamin acts as a coenzyme for methionine synthase, an enzyme that converts homocysteine to methionine. In a 16-week randomized controlled trial (RCT) involving patients with laboratory-supported probable or higher grade ALS, as defined by the updated Awaji criteria⁸⁾ within one year of onset, treatment with high-dose mecobalamin reduced the decline in ALSFRS-R scores by 43% at 16 weeks⁹⁾. Based on these findings, the drug was launched in Japan in November 2024 as the third approved anti-ALS therapy. Although the precise mechanism of action has not been fully clarified, it is thought to involve inhibition of homocysteine-induced neurotoxicity and protein repair effects mediated by S-adenosylmethionine, which is produced by the condensation of methionine and adenosine. Experimental studies also suggest a protective effect against oxidative stress-induced axonal damage in mouse primary cultured neurons and in induced pluripotent stem cells¹⁰⁾. Serious adverse effects include anaphylaxis. Other reported effects include rash (less than 1%), leukocytosis (1%), injection-site reactions (less than 1%), and headache (frequency unknown). These adverse effects are consistent with those observed for the earlier mecobalamin injection solution (500 ‍μg) and are not unique to the high-dose formulation.

The administration method consists of intramuscular injection of two vials of mecobalamin (25 ‍mg each) per dose. Each vial is ‍dissolved in 2.3 ‍ml of saline and drawn into a 2-ml syringe. The ‍injections are given at two separate sites, with one vial administered at each site. This regimen is repeated twice weekly, with at least one day between doses. Although self-administration or administration by family members is possible, it involves several burdensome steps, including the risk of nerve injury during injection, the need for light-protected storage, and the requirement to dissolve the powder formulation before use. These considerations highlight the importance of clear procedural guidance and a supportive healthcare system to ensure safe and consistent administration. Furthermore, some patients may experience severe injection-site pain that is not related to nerve injury. If adverse effects occur, temporary discontinuation or dose reduction should be considered.

Between 2006 and 2014, a company-sponsored RCT involving 373 patients with ALS (≤3 years from onset, diagnosed according to the revised El Escorial criteria) showed no overall benefit in terms of time to event onset or ALSFRS-R decline¹¹⁾. However, in patients with a disease duration of less than one year, event-free survival was prolonged and functional decline was slowed. These findings prompted the aforementioned 2017–2019 investigator-initiated confirmatory RCT⁹⁾. In that trial, efficacy—measured by the rate of decline in ALSFRS-R scores—was observed only in patients within one year of disease onset, but a survival benefit was not demonstrated, likely owing to the short 16-week observation period⁹⁾. The pivotal trial allowed concomitant use of riluzole but excluded edaravone, and evidence regarding additive effects of mecobalamin in combination with riluzole or other therapies remains unavailable.

Tofersen

Tofersen is an antisense oligonucleotide and a form of nucleic acid therapy that targets the SOD1 messenger RNA, the most common causative gene in Japanese familial ALS^12)–14). Inheritance of SOD1 variants follows an autosomal dominant pattern, and treatment is limited to patients with pathogenic variants. The pathogenic mechanisms underlying SOD1-ALS are not yet fully understood, but are thought to involve the accumulation of mutant SOD1 protein with toxic gain-of-function effects. Tofersen binds to the 3' untranslated region of SOD1 messenger RNA, inhibiting translation and reducing synthesis of both mutant and wild-type SOD1 protein.

An international phase 3 trial of tofersen for SOD1-ALS (VALOR) included 72 patients in the active treatment group and 36 in the placebo group, followed over 28 weeks and followed by an extension study in which all participants received active treatment¹⁵⁾. At week 28, the change in total ALSFRS-R score from baseline, the primary endpoint, was −8.1 in the placebo group and −7.0 in the tofersen group, showing no statistically significant difference. However, intergroup differences in selected outcomes and favorable results in secondary measures supported the potential efficacy of tofersen for SOD1-ALS, leading to its approval in Japan in December 2024. At week 28, total SOD1 protein concentration in cerebrospinal fluid (CSF) decreased to a geometric mean ratio of 0.66 compared with baseline in the active treatment group. Plasma neurofilament light chain concentration, a biomarker known to rise in neurological disorders associated with axonal damage, decreased to a geometric mean ratio of 0.45. Both changes were statistically significant compared with placebo. Consistent improvements were also observed in other secondary endpoints, including percentage of slow vital capacity and the ALS-specific health-related quality of life scale (ALSAQ-5). Based on these results, tofersen was introduced in the United States in May 2023 and in Japan in March 2025.

Tofersen is administered intrathecally at a dose of 100 ‍mg (15 ‍ml). Lumbar puncture is performed to measure opening pressure, after which approximately 15 ‍ml of CSF is withdrawn before injecting one vial (100 ‍mg/15 ‍ml) of tofersen over 1–3 minutes. The first three doses are given at two-week intervals, followed by maintenance doses every four weeks. In clinical trials, ‍adverse events associated with tofersen included myelitis, radiculitis, optic disc edema, increased intracranial pressure, and ‍aseptic meningitis¹⁶⁾. For this reason, CSF pressure should be measured before administration, and regular CSF analysis—including cell count and protein concentration—should be conducted. Clinicians should remain vigilant for symptoms of these complications. In trial participants who developed severe adverse events such as myelitis, increased CSF cell counts and protein concentrations were consistently observed, although similar laboratory changes were sometimes noted in patients without severe events¹⁶⁾. In the extension phase of the trial, headaches were also reported in 52.5% of cases. As with other antisense oligonucleotide agents, additional risks include hematuria, proteinuria, glomerulonephritis, thrombocytopenia, and coagulation abnormalities. Therefore, complete blood counts, blood biochemistry, coagulation studies, and urinalysis should be performed prior to and throughout the course of tofersen therapy.

Treatment with tofersen must be guided by genetic testing performed in accordance with established recommendations, such as the Guidelines for Genetic Testing and Diagnosis in ‍Medical Care published by the Japanese Association of Medical Sciences (https://jams.med.or.jp/guideline/genetics-diagnosis_e_2022.pdf), and requires confirmation of SOD1 variants. In Japan, causative SOD1 variants have been reported ‍in 32–36% of familial ALS cases^12)–14) and in 1.6–2.3% of sporadic cases^12)14)17). All patients with ALS, including those with apparently sporadic disease, should receive information about genetic testing and counseling. The purpose and significance of testing should be clearly explained, and potential implications for relatives should be addressed. Patients should also receive appropriate support to ensure that they are able to make an informed decision. Identified SOD1 variants should be classified according to the American College of Medical Genetics and Genomics system¹⁸⁾. If a variant is classified as “pathogenic” and accompanied by neurological features of ALS, the diagnosis of SOD1-ALS can be confirmed. In cases involving variants of “likely pathogenic” or “uncertain significance,” careful evaluation—including consultation with a clinical geneticist—is required before deciding whether the patient is eligible for tofersen therapy.

Anti-ALS combination therapy with different mechanisms of action

At present, four medications for ALS are available in Japan (Table 1). None of these agents have demonstrated consistent efficacy in improving muscle strength or respiratory function (see “Conclusion and future perspectives”). The clinical value of these drugs lies in prolonging survival, as established for riluzole, and in slowing motor dysfunction, as shown for edaravone and high-dose mecobalamin. For patients without pathogenic SOD1 variants, combination therapy with the three available agents—riluzole, edaravone, and high-dose mecobalamin—may be considered. Currently, specific recommendations on the timing or sequencing of concomitant therapies remain unavailable. However, evidence supports the benefit of early initiation for each drug, including edaravone¹⁹⁾, high-dose mecobalamin⁹⁾, and tofersen¹⁵⁾. The optimal timing for the initiation of these medications, as well as the duration of their administration, is to be determined on a case-by-case basis, necessitating further evidence accumulation.

Table 1 Approved medications for ALS in Japan—update 2025.

Medications	Recommendations
• Riluzole, edaravone, and high-dose mecobalamin are covered by insurance for ALS treatment.
• Tofersen is indicated and covered by insurance exclusively for patients with ALS caused by pathogenic SOD1 variants.
• Strong opioids are covered by insurance for pain and respiratory distress in ALS.
• Muscle relaxants are covered by insurance for spasticity in ALS.
Disease-modifying therapies
Riluzole	• Riluzole is recommended for ALS (GRADE 2B).
	• Strong evidence supports prolonging survival until tracheostomy invasive ventilation. Evidence for delaying functional decline remains limited (EC).
	• Common side effects include dizziness, nausea, and anxiety. Severe liver dysfunction is a contraindication (EC).
Edaravone	• Edaravone is recommended for ALS (GRADE 2B).
	• Limited evidence supports delaying functional decline, with no evidence of survival benefit (EC).
	• Severe renal dysfunction is a contraindication. Renal function should be monitored with serum cystatin C, as creatine may be underestimated owing to muscle atrophy (EC).
	• Oral formulation is available and can also be administered via gastrostomy (EC).
High-dose mecobalamin	• Evidence supports reduced functional decline in patients within one year of onset, but not within three years of onset (EC).
	• No survival benefit has been demonstrated to date (EC).
Tofersen	• Evidence supports reduced SOD1 protein in cerebrospinal fluid and reduced plasma neurofilament light chain, a surrogate biomarker for neuroaxonal damage in SOD1-related ALS (EC).
	• Administration requires repeated lumbar punctures, with risks including headache, meningitis, radiculitis, myelitis, and elevated intracranial pressure (EC).

This table has been revised by extracting approved drugs from “Table 2. Medications” in the published English summary¹⁾. Items that have been updated are indicated in bold font. The GRADE definitions regarding the strength of recommendations were also described in the previous report¹⁾. Refer to the report for recommendations regarding alternative therapies and regenerative therapies. ALS: amyotrophic lateral sclerosis, EC: expert consensus recommendation, GRADE: Grading of Recommendations Assessment, Development, and Evaluation, SOD1: copper/zinc superoxide dismutase, SOD1: SOD1 gene.

How to explain inheritance in ALS

All patients with ALS should receive information about the principles of genetic inheritance. In the absence of a positive family history or consanguinity, the probability of hereditary transmission remains low. Genetic testing and counseling should be offered as part of patient care, with careful attention to ethical considerations.

A systematic review of published studies on hereditary and familial ALS, based on prospective population-based registry data, estimated that patients with a family history account for 5.1% of all ALS cases²⁰⁾. Furthermore, a prospective study in Japan found that 3.0% of sporadic ALS cases carried pathogenic variants in known causative genes¹⁴⁾. When discussing the etiology of ALS, clinicians should explain that although a subset of cases is hereditary, the likelihood of inheritance is low in the absence of a positive family history or consanguinity.

In recent years, the identification of causative genes for ALS has advanced understanding of the disease pathophysiology. Genetic research provides valuable information for patients, but clinicians must also account for the psychological burden on relatives, as the diagnosis of a genetic disease directly affects them. Therapeutic management of hereditary ALS has also progressed, exemplified by the recent approval of tofersen, a nucleic acid therapy for cases associated with SOD1 variants. In sporadic cases, clinicians should still explain genetic information to patients and their close relatives, ensuring that the discussion reflects ongoing advances in treatment and research.

Genetic information related to intractable diseases often brings more disadvantages than advantages, except in situations where it directly enables therapeutic intervention, as in SOD1-ALS. In families with a strong history of ALS, patients are frequently aware of the possibility of heredity. Nonetheless, explanations should take into account potential resistance to accepting a confirmed hereditary diagnosis and concerns about social stigma. When considering genetic testing, clinicians should provide a comprehensive explanation of the unique characteristics of genetic information: its immutability (once known, it cannot be changed), shared nature (its relevance extends beyond the individual to family members), predictive nature (its ability to indicate the risk of future disease), and ambiguity (the interpretation of results may not always be clear). Collaboration with genetic experts, including genetic counselors, is essential to ensure ongoing support.

In Japan, genetic counseling systems are being developed, and reference to guidelines such as the aforementioned Guidelines for Genetic Testing and Diagnosis in Medical Care (https://jams.med.or.jp/guideline/genetics-diagnosis_e_2022.pdf) and other published guidance is advisable²¹⁾. Furthermore, because familial ALS is rare and the disease progresses rapidly in ‍some cases, recruiting participants for clinical trials remains challenging. To address this, a prospective registry study for familial ALS—the Japan Familial ALS Trial-ready Registry (J-‍FAST)—was launched in 2023 to facilitate rapid initiation of clinical trials.

Methods

Guideline panel composition

The working group that developed this addendum consists of ‍13 core members (authors) led by M.A., formally approved as the ALS Clinical Practice Guideline Development Committee by the Board of Directors of the JSN in January 2020¹⁾. In addition, three collaborators (K.I., K.B., and K.F.) contributed. The group includes 15 neurologists and one nurse (Y.N.).

Literature search

Starting with the initial meeting on January 4, 2025, the drafting committee held five meetings, concluding on June 28, 2025. During this period, committee members conducted literature searches in three databases—Cochrane Library, PubMed, and Ichushi-Web—for English and Japanese papers published between January 2022 and June 2025. The anti-ALS drugs profiled in this addendum—oral edaravone, high-dose mecobalamin, and tofersen—still lack sufficient clinical evidence, as reflected by the limited number of independent studies. As a result, developing recommendations through a systematic review was not feasible, and the addendum was instead prepared based on expert consensus.

Management of competing interests

The chairman, members, research collaborators, evaluation and coordinating members, and external reviewers of the guideline development committee reported their individual conflicts of interest to the Conflict of Interest Committee of the JSN. The JSN manages conflicts of interest in accordance with the Common Guidelines for Conflict of Interest in Medical Research. Eight members met the conflict of interest disclosure criteria of the JSN. Financial support for this addendum was provided solely by the JSN, which covered expenses related to the conference and paper submission expenses, as well as the establishment of the online video platform. Committee members received no remuneration other than reimbursement for transportation costs related to conference participation.

Conclusion and future perspectives

Since the development of the 2023 revised edition of the clinical practice guidelines for ALS management in Japan, which helped improve and standardize treatment and care, notable progress has been achieved over the past three years. To provide updated information relevant to clinical practice, this addendum has been published together with this English summary.

For ALS cases involving pathogenic SOD1 variants, combination therapy with up to four agents, including tofersen, has become available. Real-world data have reported improvements in respiratory function and total ALSFRS-R scores in some patients treated with tofersen²²⁾²³⁾. Additional evidence is needed to clarify the relationship between SOD1 genotype and treatment efficacy, as well as the potential benefits of early administration on symptom improvement²⁴⁾.

When administering high-cost drugs such as tofersen, it is essential to fully consider the patient's financial burden. Japan has a specific medical expense payment system under the Act on Medical Care for Patients with Intractable Diseases. In this system, hereditary ALS can be diagnosed when a patient has a known pathogenic gene variant and exhibits upper and lower motor neuron signs in one body region. However, mild cases are not able to benefit from this system. The advent of medications that demonstrate greater efficacy following earlier administration underscores the necessity for a reexamination of existing systems.

For cases without SOD1 variants, combination therapy with up to three agents is feasible. However, evidence remains insufficient regarding the survival-prolonging effects of individual agents (other than riluzole), the efficacy and safety of combination therapy, and whether synergistic or additive effects exist. Furthermore, the long-term effectiveness of the new anti-ALS drugs and their impact in advanced ALS remain uncertain. To address these gaps, the collection and analysis of real-world data, including prospective patient registries, will be essential.

Currently, most ALS clinical trials, particularly phase 3 studies, are conducted internationally; however, few include Japan, raising concerns about drug loss and development lag. Because no clinical evaluation guidelines for ALS treatments have yet been published in Japan, development of such guidelines began in 2024. Concurrently, standard operating procedures for the ALSFRS-R are being standardized across North America and Europe, with efforts directed toward international harmonization. Engaging in this process enables Japan to facilitate the domestic conduct of international ALS clinical trials, thereby helping to reduce drug loss and development delays.

In summary, this addendum reflects the latest progress in ALS ‍treatment, including the introduction of gene-targeted therapies. The publication of this English summary aims to promote collaboration with the global ALS community in overcoming this intractable disease, while taking cultural, social, and epidemiological differences into account.

Funding

This work was fully supported by the JSN.

Disclosure

The following authors report conflicts of interest related to this paper: Masashi Aoki (lecture fees from Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., and Mitsubishi Tanabe Pharma Corporation), Yuishin Izumi (lecture fees from Mitsubishi Tanabe Pharma Corporation and Eisai Co., Ltd.; research expenses from Eisai Co., Ltd.), Makoto Urushitani (lecture fees from Mitsubishi Tanabe Pharma Corporation, Biogen Inc., Eisai Co., Ltd., and AbbVie Inc.; research expenses from Astellas Pharma Inc. and KAN Research Institute ), Naoki Atsuta (lecture fees from Mitsubishi Tanabe Pharma Corporation and Biogen Inc.), and Osamu Kano (lecture fees from Chugai Pharmaceutical Co., Ltd.; scholarship donations from Eisai Co., Ltd. and Otsuka Pharmaceutical Co., Ltd.). All other authors declare no conflicts of interest.

A large language model (DeepL, https://www.deepl.com/ja/write) was partially employed to facilitate English language editing; nevertheless, the original manuscript is composed entirely by the authors.

Acknowledgments

The authors thank Kensuke Ikeda, Koji Fujita, and Kota Bokuda for their valuable comments and support. Appreciation is also extended to the Research Committee of CNS Degenerative Diseases (23FC1008), Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, and the Ministry of Health, Labour and Welfare of Japan for their support. The authors also gratefully acknowledge Katsuo Shimizu, Eiji Yamasaki, and Ayano Fukano from the secretariat of the JSN for their invaluable assistance, as well as Editage (www.editage.jp) for their expert English language editing services.

References

• 1)  Urushitani M, Warita H, Atsuta N, et al. The clinical practice guideline for the management of amyotrophic lateral sclerosis in Japan-update 2023. Rinsho Shinkeigaku 2024;64:252-271.
• 2)  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 2017;16:505-512.
• 3)  Genge A, Pattee GL, Sobue G, et al. Safety extension study of edaravone oral suspension in patients with amyotrophic lateral sclerosis for up to an additional 96 weeks of treatment. Muscle Nerve 2025. doi: 10.1002/mus.28451.
• 4)  Genge A, Pattee GL, Sobue G, et al. Oral edaravone demonstrated a favorable safety profile in patients with amyotrophic lateral sclerosis after 48 weeks of treatment. Muscle Nerve 2023;67:124-129.
• 5)  Shimizu H, Nishimura Y, Shiide Y, et al. Bioequivalence study of oral suspension and intravenous formulation of edaravone in healthy adult subjects. Clin Pharmacol Drug Dev 2021;10:1188-1197.
• 6)  Rothstein J, Genge A, De Silva S, et al. Efficacy and safety of once daily dosing vs. approved on/off dosing of edaravone oral suspension up to 48 weeks in patients with amyotrophic lateral sclerosis (study MT-1186-A02). Muscle Nerve 2025. doi: 10.1002/mus.28448.
• 7)  Mitsubishi Tanabe Pharma Corporation. Drug Information Form on RADICUT ORS. 2025.
• 8)  Geevasinga N, Loy CT, Menon P, et al. Awaji criteria improves the diagnostic sensitivity in amyotrophic lateral sclerosis: a systematic review using individual patient data. Clin Neurophysiol 2016;127:2684-2691.
• 9)  Oki R, Izumi Y, Fujita K, et al. Efficacy and safety of ultrahigh-dose methylcobalamin in early-stage amyotrophic lateral sclerosis: a randomized clinical trial. JAMA Neurol 2022;79:575-583.
• 10)  Eisai Co, Ltd.. Drug information form on Rozebalamin for injection. 2024.
• 11)  Kaji R, Imai T, Iwasaki Y, et al. Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study. J Neurol Neurosurg Psychiatry 2019;90:451-457.
• 12)  Naruse H, Ishiura H, Mitsui J, et al. Burden of rare variants in ‍causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS. J Neurol Neurosurg Psychiatry 2019;90:537-542.
• 13)  Nishiyama A, Niihori T, Warita H, et al. Comprehensive targeted next-generation sequencing in Japanese familial amyotrophic lateral sclerosis. Neurobiol Aging 2017;53:194.e1-194.e8.
• 14)  Nakamura R, Sone J, Atsuta N, et al. Next-generation sequencing of 28 ALS-related genes in a Japanese ALS cohort. Neurobiol Aging 2016;39:219.e1-219.e8.
• 15)  Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med 2022;387:1099-1110.
• 16)  Lovett A, Chary S, Babu S, et al. Serious neurologic adverse events in tofersen clinical trials for amyotrophic lateral sclerosis. Muscle Nerve 2025;71:1006-1015.
• 17)  Akimoto C, Morita M, Atsuta N, et al. High-resolution melting (HRM) analysis of the Cu/Zn superoxide dismutase (SOD1) gene in japanese sporadic amyotrophic lateral sclerosis (SALS) patients. Neurol Res Int 2011;2011:165415.
• 18)  Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-424.
• 19)  Shefner J, Heiman-Patterson T, Pioro EP, et al. Long-term edaravone efficacy in amyotrophic lateral sclerosis: post-hoc analyses of Study 19 (MCI186-19). Muscle Nerve 2020;61:218-221.
• 20)  Byrne S, Walsh C, Lynch C, et al. Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2011;82:623-627.
• 21)  Roggenbuck J, Eubank BHF, Wright J, et al. Evidence-based consensus guidelines for ALS genetic testing and counseling. Ann Clin Transl Neurol 2023;10:2074-2091.
• 22)  Wiesenfarth M, Dorst J, Brenner D, et al. Effects of tofersen treatment in patients with SOD1-ALS in a “real-world” setting—12-month multicenter cohort study from the German early access program. EClinicalMedicine 2024;69:102495.
• 23)  Meyer T, Schumann P, Weydt P, et al. Clinical and patient-reported outcomes and neurofilament response during tofersen treatment in SOD1-related ALS—A multicenter observational study over 18 months. Muscle Nerve 2024;70:333-345.
• 24)  Benatar M, Wuu J, Andersen PM, et al. Design of a randomized, placebo-controlled, phase 3 trial of tofersen initiated in clinically presymptomatic SOD1 variant carriers: the ATLAS study. Neurotherapeutics 2022;19:1248-1258.

Abbreviations/Glossary

ALS

amyotrophic lateral sclerosis

ALSFRS-R

ALS functional scale-revised

CSF

cerebrospinal fluid

EC

expert consensus

GRADE

grading of recommendations assessment, development and evaluation

JSN

the Japanese Society of Neurology

RCT

randomized control trial

SOD1

Cu/Zn superoxide dismutase