Vitamin B12 injections are sometimes proposed by neurologists to ALS patients. Patients often decide to start the treatment because of the perceived low risk of side effects and the potential benefit to their quality of life. It is typically shipped as a sealed frozen package with several vials containing a 25-mg injectable dose. Patients are typically advised to inject 50 mg of B12 daily, which is 100 times the daily recommended dose. Usually, ALS patients recognize some benefits from the injections, such as increased energy, reduced fatigue, and improved balance. However, the high cost of injection, lack of insurance coverage, and inconsistent syringes are significant challenges faced by patients.
High-dose methylcobalamin treatment involves intramuscular injection of 25mg to 50mg of methylcobalamin twice a week, which is 50 to 100 times the dose of existing drug injections.
A phase II/III clinical trial for ALS patients was started in Japan, and the results were published in 2019. 373 ALS patients who had been onset for less than 3 years were recruited for a methylcobalamin clinical trial with three branches where patients have daily administrated 50mg, 25mg, or a placebo. It was conducted over 3.5 years. As a result, the methylcobalamin group showed a tendency to show better results in terms of the decline in ALSFRS-R, but the difference was not significant, and overall efficacy could not be demonstrated to Japanese authorities.
However, when a subanalysis was conducted only for patients who were enrolled within 12 months of onset (close to diagnostic), the 50 mg group, the 25 mg group, and the placebo group showed less decline in ALSFRS-R and a longer time to the primary endpoint. Post-analysis is frowned on because in small groups there are always statistical flukes and it's easy to cherry-pick some of these to prove whatever. But here the size of the trial was a bit larger than usual so there was more confidence in the findings.
The difference in decline in ALSFRS-R between the 50 mg group and the placebo group was statistically significant. Based on these results, a clinical trial (JETALS trial) was conducted in 2017 to confirm the reproducibility of the subanalysis, and the results were announced in May 2022. Results were reported on this blog.
In the JETALS study, 130 ALS patients within 12 months of onset were recruited and assigned to a twice-weekly 50 mg group or a placebo group. As a result, the reduction in ALSFRS-R score at 16 weeks was −2.66 in the methylcobalamin 50 mg group and −4.63 in the placebo group, which was significantly better in the active drug group.
There was no difference in side effects of the drug between placebo or methylcobalamin-treated participants. There was a marked reduction in serum homocysteine levels. Homocysteine is neurotoxic and has been associated with ALS cases but also with Alzheimer's and Parkinson's diseases. It may be a byproduct of methionine metabolism and there are a few studies that discuss the influence of diet on homocysteine via methionine in diet. High levels of methionine can be found in eggs, meat, and fish; sesame seeds, Brazil nuts.
These results are better than most previous drug results in ALS, but indeed it does not stop the disease progression. Based on these results, it was announced in January 2024 that a new drug application for methylcobalamin had been submitted in Japan.
Eisai Co. announced last week that it has obtained manufacturing and marketing authorization approval for amyotrophic lateral sclerosis (ALS) treatment “Rozebalamin® for Injection 25 mg” (mecobalamin) in Japan as a treatment for slowing progression of functional impairment in amyotrophic lateral sclerosis.
It should be noted that 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. This is a bit confusing as ALSFRS-R and ALSAQ-40 while not identical are similar enough, ALSAQ-40 adds a well-being dimension to the usual questionnaire. How could ALSFRS-R show an improvement if it's not reflected in ALSAQ-40?
As UK's Alsa-Mnd remarks, as the drug was only tested on participants early in the disease process, it is unclear if the treatment would be appropriate for participants with more advanced diseases.
In addition, Alsa-Mnd says it may not have been a truly blinded trial as methylcobalamin treatment results in a marked change in urine color which could mean that participants may have known whether they were receiving a placebo or methylcobalamin, and that could have influenced results (including a potential “nocebo” effect). This is supported by the fact that the placebo group appeared to worsen their rate of disease progression once the trial commenced.
It's possible that regulation agencies are afraid of the considerable political pressure from patient organizations who accuse them of being inactive, and that as for Alzheimer's disease and (temporarily) for AMX0035/Relyvrio they prefer to authorize new drugs even if they are ineffective, instead of waiting decades for an effective drug.