Dimethyl Fumarate (DMF) Fails to Slow ALS Progression in Trial
Dimethyl fumarate or DMF — an oral therapy approved for multiple sclerosis (MS) — was well-tolerated among adults with amyotrophic lateral sclerosis (ALS) but failed to significantly slow disease progression or to improve survival and quality of life in these patients, according to data from a Phase 2 trial.
Treatment with DMF was associated with reduced motor neuron damage relative to a placebo, but this difference was not statistically significant.
While these findings support an absence of DMF’s beneficial effects in this patient population, the researchers noted that participants showed an unusually slow disease progression during the study. Given that data, the team suggested that future trials should be done to test DMF in rapidly progressing ALS patients.
The study, “Safety and efficacy of dimethyl fumarate in ALS: randomised controlled study,” was published in the journal Annals of Clinical and Translational Neurology.
It was previously shown to alter the body’s immune response toward a more anti-inflammatory activity by increasing the number of regulatory T-cells — known as Tregs — and lowering the number of pro-inflammatory immune cells.
Tregs act as negative regulators of the immune system, meaning that they shut down excessive immune and inflammatory responses triggered by other immune cells, maintaining a healthy immune balance.
Notably, neuroinflammation is one of the key players in the development of ALS, and a shift toward an increase in pro-inflammatory immune cells in detriment of Tregs is associated with ALS severity and progression.
Given its effects on Tregs, DMF was expected to reduce inflammation and potentially slow disease progression in people living with ALS.
A Phase 2 clinical trial, called TEALS (ACTRN12618000534280), evaluated the safety and effectiveness of DMF in 107 adults who had been diagnosed with sporadic ALS in the two years prior to enrollment. The study was funded by the Australian FightMND and Medical Research Future Fund.
Recruited at Australian sites, the participants were randomly assigned to receive an oral capsule of either DMF (72 patients) or a placebo (35 patients), twice a day for 36 weeks (about nine months).
The patients were allowed to continue standard riluzole treatment — a long-approved therapy for ALS — if they had been on a stable dose for more than a month before screening. Riluzole is marketed as Rilutek, Tiglutik, and Exservan, depending on its mode of administration.
The study’s main goal was to assess changes in disease progression, as measured with the ALS Functional Rating Scale Revised (ALSFRS-R). Secondary goals included changes in survival, lower motor neuron function, lung function, levels of urinary neurotrophin receptor p75 (a marker of nerve cell damage), and quality of life, as well as safety measures.
Motor neurons are the specialized nerve cells that control voluntary movement. Both upper (brain) and lower (spinal cord) motor neurons are progressively damaged and lost in ALS.
Most of the participants were Caucasian (88.8%) and men (65.4%), and the mean age was 60. Demographic and clinical characteristics were comparable between the two groups at the study’s start. More than 76% of patients in both groups were on riluzole.
About 70% of the patients — 50 in the DMF group and 25 receiving the placebo group — completed the study, with similar discontinuation rates between groups (30.6% vs. 28.6% in the placebo group).
The results showed that the trial failed to meet any of its main and secondary goals, with no statistically significant trends favoring DMF over the placebo.
Notably, DMF-treated patients had a reduced decline in lower motor neuron function, compared with those given a placebo. However, this difference failed to reach statistical significance, meaning that mathematically it could be attributable to random chance.
The therapy was generally safe and well-tolerated, with most adverse events being mild in severity. Skin flushes, urinary tract infections, and upper respiratory tract infections were the most common side effects.
Flushing was significantly more frequent among DMF-treated patients, in keeping with the therapy’s known safety profile.
One patient from the DMF group died during the study, but this was deemed unrelated to treatment. There were no significant group differences for rates of serious adverse events, unexpected side effects, or adverse events leading to either treatment discontinuation or death.
These findings provided evidence of “safety and lack of efficacy of dimethyl fumarate in ALS,” with a potential beneficial effect on lower motor neuron function, “although this needs verification in a larger trial,” the researchers wrote.
Notably, the lack of an effect in disease progression may be attributed to an “unexpectedly small” decline in ALSFRS-R scores during the study, “with a 5.66-point decline in the dimethyl fumarate group and a 4.24-point decline in the placebo group,” the team wrote.
ALSFRS-R declines in other ALS trials have ranged from 6.93 to 14.94, the team noted, likely due to their restriction to rapidly progressing ALS patients only. Small therapeutic effects may be better detected among patients with faster disease progression.
As such, “future clinical trials should assess dimethyl fumarate efficacy in ‘fast progressing’ ALS patients,” the researchers concluded.