Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis

Abstract

IMPORTANCEThe effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent.OBJECTIVE To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. DESIGN, SETTING, AND PARTICIPANTSThis was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1-or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo.INTERVENTIONS Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. MAIN OUTCOMES AND MEASURESThe primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set.RESULTS A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (−2.66 vs −4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups.CONCLUSIONS AND RELEVANCE Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period.

Association of smoking using with ALS risk and prognosis in China

“…Therefore, the epidemiological characteristics of ALS in Chinese are different from those in other countries. The mean age of onset in our study is 49.49 years old (SD 11.16), younger than patients form Japan and Europe, 61.0 16 and 63.79 years old 17 , respectively. However, in India, it is 51.6 years old 18 , lower than that in most other regions around the world.…”

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022

“…High-dose methylcobalamin, masitinib and AMX0035 were found to slow the decline in the ALSFRS-R score by 43% ( Oki et al, 2022 ), 25% ( Mora et al, 2020 ), and 25% ( Paganoni et al, 2020 ), respectively. Masitinib, AMX0035, and CNM-Au8 decreased the risk of death by 44% ( AB Science, 2017 ), 44% ( Paganoni et al, 2022 ), and 70% ( Meglio, 2022a ), respectively.…”

“…In this review, we have summarized 53 new drugs that have been assessed in clinical trials from 2020 to 2022 ( Figure 1 ). For anti-apoptotic drugs, high-dose methylcobalamin was found to reduce deterioration by 43% in a phase 3 study in Japan ( Oki et al, 2022 ). AMX0035 was recently approved by the FDA because it slowed the decline in the ALSFRS-R score and the risk of death by 44%, prolonged tracheostomy/PAV-free survival ( Paganoni et al, 2022 ) and prolonged survival by 10.6 months (Amylyx).…”

“…A phase 3, multicenter, placebo-controlled, double-blind, randomized trial conducted by Ryosuke Oki et al evaluated the efficacy and safety of ultrahigh-dose (50 mg) methylcobalamin ( Oki et al, 2022 ). A total of 130 Japanese patients who had been diagnosed within 1 year of ALS symptom onset were included in this study.…”

Amyotrophic Lateral Sclerosis Clinical Trials and Interpretation of Functional End Points and Fluid Biomarkers

“…Since 1996, 38 placebo-controlled trials enrolling more than 100 participants have been conducted evaluating therapies in amyotrophic lateral sclerosis (ALS) (Table 1). Of these, 6 studies reported statistically significant evidence of efficacy. The first study to demonstrate efficacy was that of riluzule, for which a survival association was noted in a large study of more than 900 participants observed for up to 18 months.…”