Ultra-High-Dose Methylcobalamin Slows Functional Decline in ALS, New Findings Suggest

Findings from a placebo-controlled, double-blind, randomized phase 3 study (NCT03548311) showed that intramuscular injection of methylcobalamin 50 mg over a 16-week treatment period was safe and slowed functional decline in patients with early-stage amyotrophic lateral sclerosis (ALS).¹

Methylcobalamin, a medication used to treat vitamin B12 deficiency, resulted in a least squares (LS) mean difference of 1.97 points greater in ALS Functional Rating Scale-Revised (ALSFRS-R) total score than placebo at the conclusion of the randomized period (–2.66 vs –4.63; 95% CI, 0.44-3.50; P = .01). The results also showed that the therapy should be used in the ultra-high-dose rather than the 25-mg dose, with investigators suggesting that methylcobalamin "paradoxically upregulates gene transcription and thereby protein synthesis in vitro."

Lead author Ryosuke Oki, MD, neurologist, Tokushima University Graduate School of Biomedical Sciences, and colleagues evaluated 130 individuals who had ALS symptom onset within 1 year and presented with a 1- or 2-point decrease on ALSFRS-R total score during a 12-week observation period. Patients then entered a 16-week treatment period where they were randomized to either intramuscular injection of methylcobalamin at ultra-high-doses (50 mg) or placebo twice weekly.

A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. In a subgroup that received concomitant riluzole (Rilutek; Sanofi) (n = 116; 90%), the LS mean difference between methylcobalamin and placebo increased to 2.11 (95% CI, 0.46-.3.76; P = .01) in favor of the study medication. Oki et al wrote that these findings imply that the combination of riluzole and methylcobalamin has a "greater therapeutic effect than riluzole alone." Additionally, the difference in scores between the 2 treatment groups amounted to 43% in all of the patients and 45% in the patients with concomitant use of riluzole.

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During the 16-week treatment period, there were no reported deaths, no 24-hour use of respiratory support, nor use of invasive respiratory support. The rate of adverse events (AEs) was similar between the treatment arms, with AEs reported in 62% of those on methylcobalamin and 66% of those on placebo. Three serious AEs: cerebral infarction (methylcobalamin group), hemorrhoid surgery, and stenosis of the tracheostoma after laryngotracheal separation (placebo group), were all unrelated to the investigational drug.

Aside from the one individual, no others underwent a tracheostomy during the treatment period. For those on methylcobalamin, the 2 most common AEs were nasopharyngitis (11%) and contusion (11%), followed by constipation (6%), back pain (6%), insomnia (6%), and fall (3%). Notably, there were no differences in changes of laboratory measurements, electrocardiogram parameters, and vital signs between the 2 groups.

"We decided on using the 50-mg dose because the post hoc analysis of the previous trial with placebo and methylcobalamin 25 mg and 50 mg groups showed that methylcobalamin prolonged survival and inhibited ALSFRS-R decline in a dose-dependent manner," Oki et al wrote. "The effect of methylcobalamin on ALS may correlate with increasing dose in the nervous system. As the nervous system can retain an extremely small portion of the total dose, it would need much higher dose than other tissues."

This trial was optimized to replicate the results of the post hoc analysis in a 2019 trial published in the Journal of Neurology, Neurosurgery, and Psychiatry.² In that phase 2/3 study, 373 patients with ALS were randomly assigned to placebo, or 25 mg or 50 mg of methylcobalamin, with the primary end points being time to primary events (death or full ventilation) and changes in the ALSFRS-R score from baseline to week 182. At the conclusion of the treatment period, no significant differences were observed on the primary end point (minimal P = 0.087). However, in a post hoc analysis, those with early-stage ALS showed longer time intervals to the primary event (P <.025) and less decreases in the ALSFRS-R score (P <.025) than the placebo group.

REFERENCES
1. Oki R, Izumi Y, Fujita K, et al. Efficacy and safety of ultrahigh-dose methylcobalamin in early-stage amyotrophic lateral sclerosis. JAMA Neurol. Published May 9, 2022. doi:10.1001/jamaneurol.2022.0901
2. Kaji R, Imai T, Iwasaki Y, et al. Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase 2/3 randomized controlled study. J Neurol Neurosurg Psychiatry. 2019;90(4)451-457. doi:10.1136/jnnp-2018-319294