B12 Slows Functional Decline in Early-stage ALS, Data Show
Treatment with ultrahigh-dose methylcobalamin — the physiologically active form of vitamin B12 — effectively slowed functional decline in people with early-stage amyotrophic lateral sclerosis (ALS) and moderate progression, data from a small Phase 3 trial in Japan show.
The findings confirm previous results from a Phase 2/3 trial and point to ultrahigh-dose methylcobalamin as a potential new therapy for early-stage ALS.
Larger studies are needed to confirm these results, the researchers noted.
The study, “Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial,” was published in the journal JAMA Neurology.
Vitamin B12, found in foods such as meat, fish, and dairy, is involved in several critical processes in the body, including nerve cell health and function. Previous studies in animal models and in ALS patients showed that injections of ultrahigh-dose methylcobalamin, a naturally occurring form of vitamin B12, could help improve the transmission of nerve signals between the brain and muscles.
Based on these findings, Eisai conducted a Phase 2/3 trial (NCT00444613) in Japan to evaluate the safety and efficacy of ultrahigh-dose methylcobalamin injections in 373 adults whose ALS symptoms began up to three years before enrollment.
Participants were randomly assigned to receive intramuscular, or into-the-muscle, injections of one of two doses of methylcobalamin (25 or 50 mg), or a placebo, twice a week for 3.5 years.
While both doses were safe, participants on methylcobalamin did not experience a significantly slower functional decline, as assessed with the ALS Functional Rating Scale Revised (ALSFRS-R), than those on a placebo, failing to meet the study’s main goal.
However, a later analysis looking specifically at patients with early ALS — those within one year from symptom onset — revealed that those given methylcobalamin had a significantly slower progression compared with those on a placebo.
Specifically, the higher dose was associated with a 45% lower decline in ALSFRS-R scores and a delay in the need for full ventilation support or death by nearly two years compared with a placebo.
As these patients were most likely classified as moderate progressors, the results suggested that 50 mg methylcobalamin injections could be “beneficial for patients with ALS in the early stage and with moderate progression rate,” the researchers wrote.
Still, these data were deemed insufficient by health authorities in Japan for approval of ultrahigh-dose methylcobalamin for treating people with ALS, leading Eisai to withdraw its regulatory application in 2016.
About a year later, the University of Tokushima in Japan, in collaboration with Eisai, launched a Phase 3 trial called JETALS (NCT03548311) to confirm the results of the prior analyses.
The study involved 130 ALS patients (74 men and 56 women) whose symptoms began within one year of enrollment and who progressed at a moderate rate, defined as a 1–2 point decrease in their ALSFRS-R scores over the three months preceding the trial.
Participants, with a mean age of 61 years, were randomly assigned to receive twice-weekly injections of either 50 mg of methylcobalamin or a placebo for 16 weeks (about four months).
About 90% of patients in both groups were also taking riluzole (an approved ALS therapy sold as Rilutek, Tiglutik, or Exservan) during the study.
A total of 126 patients completed the 16-week treatment period, and 124 chose to enter the open-label extended period, in which they will receive the therapy until March 2024.
Results showed that JETALS met its main goal, with methylcobalamin-treated patients showing significantly less decline in their ALSFRS-R scores than those given a placebo (2.66 vs. 4.63 points) — reflecting a 43% reduction.
Notably, a 45% slower decline in these scores was also observed with methylcobalamin in the group of patients who were also taking riluzole. This implied “that the combination of riluzole and methylcobalamin has a greater therapeutic effect than riluzole alone,” the researchers wrote.
These benefits were accompanied by a significant reduction in the blood levels of homocysteine, a molecule with neurotoxic effects that is elevated in ALS patients and whose conversion into another molecule is dependent on methylcobalamin.
There were no deaths or patients needing respiratory support, and changes in lung function and other functional and muscle measures were not significantly different between groups. This may be due to patients being in the early stages of ALS and not showing rapid progression, the team noted.
Methylcobalamin was generally tolerated well, with similar rates of adverse events compared with a placebo. There were no group differences in terms of laboratory findings, heart-related parameters, and vital signs.
These findings highlighted 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,” the researchers wrote.
Still, larger studies, including patients from other parts of the world and a longer treatment period, are needed to validate methylcobalamin’s therapeutic effects in this subset of ALS patients, the authors noted.
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