Background
Methylcobalamin, the biologically active form of vitamin B12, has been shown to contribute to central nervous system health. In Japan, low-dose formulations of methylcobalamin are approved for the treatment of peripheral neuropathies and anemia resulting from vitamin B12 deficiencies. Based on the outcomes of a Phase 3 clinical trial, an ultra-high dose of methylcobalamin (50 mg) was approved in Japan on September 24, 2024, for the treatment of ALS/MND. This drug is manufactured and marketed by the pharmaceutical company Eisai under the trade name Rozebalamin.
| Approved in: | Commercial Name: |
| Japan | Rozebalamin® |
Proposed Mechanism of Action
The precise mechanism of action of methylcobalamin in ALS/MND remains to be fully elucidated. Preclinical investigations suggest potential therapeutic benefits through targeting oxidative stress, glutamate toxicity, and apoptosis, pathways implicated in ALS/MND (The ALS Untangled Group, 2015). Furthermore, methylcobalamin has been demonstrated to reduce elevated plasma homocysteine levels in individuals living with ALS/MND (PALS), a factor known to exhibit toxicity to motor neuron-like cells in culture (Zoccolella et al., 2008; Hemendinger et al., 2011). In a rodent model of sciatic nerve injury, high-dose methylcobalamin administration promoted nerve regeneration and functional recovery (Okada et al., 2010). Although in vivo and in vitro studies utilizing ALS/MND models have yielded encouraging findings, the putative mechanism of action remains to be fully clarified (Ito et al., 2017; Ikeda et al., 2015).
Clinical Trials
Two small studies showed that intramuscular administration of high methylcobalamin dose for 2 weeks (25 or 50 mg/day) was safe and well tolerated with some suggestion of potential clinical benefit (Kaji et al., 1998; Izumi et al., 2008).
Based on these early trial results, Eisai initiated a phase 2/3 clinical trial in 44 centres in Japan, exploring the effects of high doses of methylcobalamin in 373 people living with ALS/MND within three years of symptom onset (Clinicaltrials.gov ID: NCT00444613, Kaji et al., 2019). Participants were randomly assigned to receive twice weekly injections of either 25 mg methylcobalamin, 50 mg methylcobalamin, or placebo, for a duration of 182 weeks. Primary outcome measures were survival and ALSFRS. Both concentrations of methylcobalamin were found to be safe and well tolerated however, the primary endpoints were not met in either group. Post hoc analysis revealed a difference in disease progression (measured by ALSFRS) and time to event in those participants who joined the trial within one year of symptom onset (early-stage), suggesting a potential action of high concentration of methylcobalamin in early phase of the disease (Kaji et al., 2019). To validate this result, a new study called Japan Early-Stage Trial of Ultrahigh-Dose Methylcobalamin for ALS (JETALS) was launched.
The JETALS trial was a randomised controlled phase 3, double-blinded study hosted across 25 neurology centres in Japan between October 2017 and September 2019. The trial enrolled 130 people within 1 year of symptom onset with moderate progression, defined as a 1- to 2-point decrease in their ALSFRS-R score during a 12-week observational period prior to treatment. Participants received twice weekly injections of either 50 mg methylcobalamin or placebo, over a period of 16 weeks. Of these 130 participants 90% were concurrently taking riluzole. Participants in the methylcobalamin vs. placebo group experienced a 1.97 (95% CI, 0.44-3.50; P = .01) difference in the ALSFRS-R score between the at week 16. The trial included a total of 63 people per arm. Furthermore, a reduction in the concentration of homocysteine in the plasma of people treated with methylcobalamin was found. Homocysteine has been linked to neurotoxicity and found to be elevated in the blood of PALS, its expression is modulated by treatment with vitamin B12 (Zoccolella et al., 2008; Hemendinger et al., 2011), however, homocysteine levels were not correlated with ALSFRSR scores in this study. Additionally, muscle strength, forced vital capacity and Norris scale scores did not show significant differences compared to the placebo group. This study had several limitations. Notably, it was shorter than most ALS/MND trials (16 weeks), and due to methylcobalamin’s effect on urine colour, participants may have discerned whether they received the drug or placebo (Oki et al., 2022). Despite these limitations, this clinical trial led to the approval of an ultra-high dose of methylcobalamin in Japan for ALS/MND treatment.
Dose and Administration
In Japan, the approved dose of methylcobalamin for treatment of ALS/MND in adults is 50 mg a day, twice a week, injected intramuscularly.
Reported Side Effects
Ultra-high dose methylcobalamin is generally well tolerated. In the JETALS study, side effects were reported with an incidence of 7.7% in the treatment group and included constipation, pain at the site of the injection, fever, irregular heart rhythms and rash. Methylcobalamin is also known to cause reddening of the urine, with no associated health concerns.
Current Status
Rozebalamin has shown encouraging results in preclinical models and a specific subset of people with ALS/MND. While oral formulations of vitamin B12 are easily accessible over-the-counter, their efficacy for ALS/MND remains unproven. Furthermore, the quality of over-the-counter supplements can be inconsistent, and high doses may be detrimental to health (The ALS Untangled Group, 2015). The Alliance will continue to update this document with new information as they become available.
Disclaimer: Consult with your doctor to determine if Rozebalamin is an option for you. Always disclose your medical history, including any drugs, natural supplements, or herbal medicines currently being used. Your doctor will determine the right plan for your needs.
SOURCES
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Ikeda, K., Iwasaki, Y., & Kaji, R. (2015). Neuroprotective effect of ultra-high dose methylcobalamin in wobbler mouse model of amyotrophic lateral sclerosis. Journal of the neurological sciences, 354(1-2), 70–74.
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