Methylcobalamin
Background
Methylcobalamin is the biologically active form of vitamin B12 and is used in Japan
to treat peripheral neuropathy and megaloblastic anaemia. Methylcobalamin has
the ability to decrease levels of homocysteine, a molecule that can contribute to
neuronal degeneration which led to it being considered as a potential candidate for
ALS treatment.
Based on some small early-stage human studies, a Japanese pharmaceutical
company, Eisai, supported a Phase II/III clinical trial.
This trial was run between 2007 and 2014 in 51 sites in Japan with 360 participants.
The treatment regime was quite long (3.5 years)
(https://clinicaltrials.gov/ct2/show/NCT00444613), with participants receiving
placebo, or 25 or 50mg methylcobalamin twice a week via intramuscular injections.
Results from this initial trial showed that receiving methylcobalamin did not lead to
any significant differences either in survival rates or ALS functional scores, when
compared with placebo.
However, subsequent analysis of the data showed that methylcobalamin seemed to
have an effect in a sub-group of participants who received treatment earlier in their
disease journey (a year or less after symptom onset). These participants showed a
statistically significant decrease in the rate of disease progression (i.e., a decrease in
the rate of decline of the ALSFRS-R score), and also survived longer or took longer to
require ventilation support compared with the placebo group. The outcome of the
trial was published in January 2019 (“Ultra-high-dose methylcobalamin in
amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study”
https://jnnp.bmj.com/content/90/4/451).
However, this data was not considered sufficient for approval as an ALS/MND
treatment by the Japanese authorities because it was done after the initial study
results were obtained (post-hoc analysis) and such observations can be misleading.
In an attempt to validate the post-hoc findings, a new Phase 3 trial, JETALS
(https://clinicaltrials.gov/ct2/show/NCT03548311), was undertaken in 2017, which
focused on participants who seemed to respond well to the treatment from the first
trial i.e. those whose symptoms had begun 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).
Trial Design and Results
Participants received twice-weekly injections of either 50 mg of methylcobalamin or
a placebo for 16 weeks. An open-label extension was then made available to all trial
participants in which they will receive the therapy until March 2024.
The initial 16-week trial met its primary outcome, with methylcobalamin-treated
participants showing a 43% slower disease progression as measured by their ALSFRSR scores than those given a placebo (2.66 vs. 4.63 points over 16-weeks). Participants
receiving Riluzole as well as methylcobalamin showed similar results. There was no
difference in side effects of the drug between placebo or methylcobalamin-treated
participants. Although there were statistically significant reductions in ALSFRS-R,
other measures such as muscle strength, forced vital capacity and the ALSAQ-40 total
score, were not changed.
The results from this trial were published in May 2022 – “Efficacy and Safety of
Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis A
Randomized Clinical Trial” https://jamanetwork.com/journals/jamaneurology/articleabstract/2792228
There are several things to take into account for this study. As the drug was only
tested on participants early in the disease process, it is not clear if the treatment
would be appropriate for participants with more advanced disease. Methylcobalamin
treatment results in a marked change in urine colour which could mean that
participants may have known whether they were receiving placebo or
methylcobalamin and that could influence results (including a potential “nocebo”
effect). The fact that the placebo group appeared to worsen their rate of disease
progression once the trial commenced perhaps supports these concerns of a
potential unblinding effect. The open label extension data may well help to offset any
possible confounding effects. It should be considered that the 16-week trial duration
is shorter than most other trials which usually have a minimum 24-week duration.
Data from the open-label extension will be informative for the longer-term benefits
of this drug.
Summary
The SAC believes that the initial trial and follow-up stage 3 trial have demonstrated
promising results in a subset of early stage participants. The company have stated
they will file for approval from the Japanese authorities in 2023. Due to the short trial
duration and potential confounding effects (hastened placebo decline, possible
unblinding), it is difficult at this time to know the true efficacy, if any, of ultra highdose methylcobalamin in ALS/MND and any consideration of use should be at a
clinician’s discretion. The SAC suggests that data from the open label extension be
incorporated into analysis to better assess the efficacy of this treatment.
Updated March 2023