Ultra-High Dose Drug Slows Functional Decline in Early ALS, Phase 3 Data Show

Pauline Anderson

May 12, 2022

An ultrahigh-dose of methylcobalamin slows functional decline by 43% in patients with early-stage amyotrophic lateral sclerosis (ALS), new research shows. The 50-mg dose was administered twice-weekly via intramuscular injection.

In the phase 3 study, efficacy was even greater for participants also taking riluzole, a drug that modifies glutamate and has been approved by the US Food and Drug Administration (FDA) to treat ALS.

"Our results confirm the disease-modifying, reproducible, and clinically meaningful effects of ultrahigh-dose methylcobalamin for patients in the early stages of ALS and with moderate progression rate," study investigator Yuishin Izumi, MD, PhD, professor, Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan, told Medscape Medical News.

The findings were published online May 9 in JAMA Neurology.

Building on Previous Research

ALS affects upper and lower motor neurons, resulting in progressive muscle weakness and atrophy. Previous research has shown time from symptom onset to use of invasive respiratory support or death is 20-48 months.

In addition to riluzole for the treatment of ALS, the FDA has approved edaravone, an antioxidant that slows nerve damage caused by harmful free radicals. However, the effectiveness of these two drugs is limited, the current investigators note.

Methylcobalamin, an active form of vitamin B12 analogue, helps eliminate homocysteine, which is neurotoxic and induces oxidative stress, mitochondrial dysfunction, inflammation, and motor neuron death. Plasma homocysteine levels are reported to be elevated in patients with ALS.

The post hoc analysis of a previous phase 2/3 trial showed the potential efficacy of methylcobalamin in patients with a moderate progression rate. The objective of the current trial was to confirm this suggested efficacy.

The study included ambulatory patients at 25 neurology centers in Japan who were diagnosed with definite or probable ALS and whose symptoms began within the previous year. These patients were included in a 12-week observation period.

At the end of this period, the 130 participants who remained ambulatory and had only a 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score were entered into a 16-week treatment period.

These patients (mean age, 61 years; 56.9% men) were randomly assigned to receive 50 mg of methylcobalamin or placebo administered intramuscularly twice a week. They could continue taking riluzole but not edaravone, which had not yet been approved during the previous trial.

One patient in the placebo group whose diagnosis was changed from ALS to cervical spinal canal stenosis was excluded from the analysis. As well, one patient in the placebo group and two in the methylcobalamin group discontinued treatment.

Primary Endpoint Met

The primary endpoint was change in ALSFRS-R total score. At 16 weeks, this total score was −2.66 in the methylcobalamin group and −4.63 in the placebo group, for a difference of 1.97 in favor of the active agent (95% CI, 0.44 - 3.50; P = .01).

In the 90% of patients taking riluzole concomitantly, the difference in favor of methylcobalamin was even greater (–2.11; 95% CI, 0.46 - 3.76; P = .01). The difference in ALSFRS-R total score between the active drug and placebo amounted to 43% in all patients and 45% in those using riluzole.

"The results suggest that riluzole and ultrahigh-dose methylcobalamin not only have an additive but possibly also a synergistic effect," Izumi said.

In addition, plasma homocysteine levels significantly decreased with methylcobalamin. Although Izumi said the changes in homocysteine levels did not correlate with those in ALSFRS-R scores, he noted homocysteine levels are affected by diet, smoking, and B-vitamin status, among other factors that were not adjusted for in the trial.

Methylcobalamin may exert a therapeutic effect independent of lowering homocysteine. For example, said Izumi, it might have antioxidant and anti-inflammatory effects and modulate the gut microbiome, and these mechanisms of action "may be synergistic."

There were no statistically significant between-group differences in secondary outcomes of change in percent forced vital capacity, Norris scale total score, and manual muscle test total score. However, there was a tendency toward smaller declines in these outcomes with methylcobalamin compared with placebo.

There were no deaths or 24-hour use of respiratory support during the treatment period.

Adverse events (AEs) were experienced by 62% of patients receiving the drug and 66% receiving placebo. AEs reported by at least 5% of patients in either group included constipation, nasopharyngitis, contusion, falls, back pain, and insomnia. There were no AEs leading to drug discontinuation.

Three patients did experience serious AEs not related to the investigational drug.

At the end of the treatment phase, 124 of the patients proceeded to an open-label phase of the study where all will receive the investigational drug.

"Desperate Need" for New Treatments

Commenting for Medscape Medical News, Stephen Goutman, MD, director of the Pranger ALS Clinic and associate professor of neurology in the Neuromuscular Program at the University of Michigan, Ann Arbor, said the study findings "appear promising" although "unfortunately, all clinical secondary endpoints were nonsignificant."

Most ALS patients would likely be ineligible for this treatment given the average time to get an ALS diagnosis is one year or more — or beyond the study inclusion criteria, noted Goutman, who was not involved with the research.

He stressed the "desperate need" for new therapies to slow ALS, and the importance of earlier diagnoses and earlier initiation of therapies — when they may be more effective.

A tool promoted by the ALS Association called "thinkALS" lists key clinical features of ALS that may lead clinicians to suspect a diagnosis much earlier in the disease process, said Goutman.

He added that further research in this field is needed. "Replication of the current findings in other ALS populations — at different ranges of disease duration and severity — across the globe is an important next step to determine treatment generalizability," he said.

"Studies longer than 16 weeks would also be beneficial to determine the long-term treatment effect," Goutman concluded.

The study was funded by a grant from the Japan Agency for Medical Research and Development and by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning, and Evaluation for Rare and Intractable Diseases, Health, Labour, and Welfare Sciences Research Grants, the Ministry of Health, Labour, and Welfare, Japan.

Izumi reported receiving grants from Japan Agency for Medical Research and Development, the Ministry of Health, Labor, and Welfare, Takeda Pharmaceutical Company Limited, and Sumitomo Dainippon Pharma Company Limited outside the submitted work. Goutman has disclosed no relevant financial relationships.

JAMA Neurol. Published online May 9, 2022. Abstract

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