Ultra-high-dose methylcobalamin may reduce clinical progression in early-stage ALS

Ultra-high-dose methylcobalamin (MeCbl) slowed functional decline in individuals with early-stage amyotrophic lateral sclerosis (ALS) with moderate progression, the JETALS* study has shown.

There is a need for further treatments for ALS, owing to the limited efficacy of currently available treatments such as riluzole and edaravone. [Lancet Neurol 2018;17:416-422; Lancet Neurol 2017;16:505-51] “Initial studies have shown ultra-high-dose MeCbl to be a promising agent,” said the researchers.

Individuals who remained ambulatory and presented with a 1- or 2-point reduction in ALSFRS-R** total score during the 12-week observation period entered the 16-week treatment phase (n=130; mean age 61 years, 57 percent male). They were randomized 1:1 to receive IM MeCbl 50 mg or placebo twice weekly. During the double-blind phase, concomitant use of riluzole was allowed but not edaravone. [JAMA Neurol 2022;doi:10.1001/jamaneurol.2022.0901]

At week 16, least squares mean (LSM) difference in ALSFRS-R total score was greater with MeCbl than placebo (−2.66 vs −4.63; p=0.01). Of those who also used riluzole (n=116), LSM difference in ALSFRS-R score was 2.11, still in favour of MeCbl (p=0.01).

These translated to a 43-percent reduction in clinical deterioration with MeCbl in all patients and a 45-percent reduction among those who reported concurrent riluzole use, the researchers noted. “Our results indicate disease-modifying, reproducible, and clinically meaningful effects of ultra-high-dose MeCbl [in this patient setting].”

“[The results in the riluzole subgroup] imply that the combination of riluzole and MeCbl has a greater therapeutic effect than riluzole alone,” they added. Indeed, evidence shows that a combination of both drugs improved survival of motor neurons compared with monotherapy with either agent. [Neuroreport 2017;28:101-107]

There were similar incidences of adverse events (AEs) between the MeCbl and placebo arms (62 percent vs 66 percent). One serious AE (ie, cerebral infarction) was reported in the MeCbl arm, but this was not causally related to MeCbl.

There were no discontinuations owing to AEs, nor deaths, 24-hour use of noninvasive respiratory support, or use of invasive respiratory support during the treatment phase. It should be noted though that patients were in the early ALS stages and were not in rapid progression, and the treatment duration was shorter than the timeframe adopted for most ALS trials (ie, 24 weeks).

Homocysteine: A therapeutic target?

The levels of plasma homocysteine, which is deemed neurotoxic, are reportedly elevated in ALS patients. [FEBS Lett 2006;580:2994-3005; Neurology 2008;70:222-225] “[H]omocysteine induces excitotoxicity, oxidative stress, mitochondrial dysfunction, activation of inflammation, and motor neuron death,” said the researchers. As such, homocysteine could be a promising therapeutic target in neurological disorders. [Int J Geriatr Psychiatry 2012;27:592-600]

In the current study, plasma homocysteine concentration did drop significantly with MeCbl vs placebo (LSM difference, −1.71; p<0.001). However, other factors (ie, diet, smoking, baseline B-vitamin status, methylenetetrahydrofolate reductase genetic polymorphisms) that affect homocysteine levels should also be taken into context. “[These] were not adjusted in our trial,” the researchers noted.

Why high-dose?

“[Evidence suggests] that MeCbl at a higher concentration paradoxically upregulates gene transcription and thereby protein synthesis in vitro,” the researchers noted. High-dose MeCbl also reportedly promotes nerve regeneration compared with a lower dose. [Exp Neurol 2010;222:191-203] “These seem to reinforce the necessity of ultra-high-dose MeCbl for ALS treatment,” said the researchers.

“We decided on using the 50-mg dose because the post hoc analysis of the previous trial … showed that MeCbl prolonged survival and inhibited ALSFRS-R decline in a dose-dependent manner,” they continued. “The effect of MeCbl 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.”