Early enthusiasm that the MS drug dimethyl fumerate (DMF) might also slow disease progression in amyotrophic lateral sclerosis (ALS) has been curbed as findings from an Australian study showed that people taking the drug had no significant difference in outcomes at three years compared to placebo.

Approved as a first-line treatment for relapsing MS, the medication is thought to lower inflammation and oxidative stress, boosting regulatory T cell levels and suppressing  pro-inflammatory T cells. The pathway is also an  important pathogenic mechanism in ALS.

Researchers from multiple neurology centres around Australia and led by Professor Steve Vucic, Director of the Brain and Nerve Research Centre at Concord Hospital, investigated the safety and efficacy of the disease modifying treatment in 107 patients with ALS.

Writing in the Annals of Clinical and Translational Neurology, the group said that while the drug was well tolerated among the 72 patients randomised to take it there was no significant change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score compared to the 35 participants in the placebo group over the 36-month follow up period.

But, while there were no significant differences in other secondary outcome measures either including SI, MRC scores, respiratory function, and quality of life scores, Professor Vucic and colleagues said dimethyl fumarate ‘exerted a significant effect’ on the neurophysiological index score – a robust biomarker of disease progression in  ALS.

The rate of NI decline was reduced in the dimethyl fumarate group, with the ΔLSM 0.84 (0.51 to 2.22, p = 0.22). Although this difference was not significant, Professor Vucic said the finding suggests preservation of lower motor neuron function. But he added that this would need verification in a larger trial.

“It should be stressed that the present trial did not prespecify power calculations according to changes in NI. Future phase 2 trials could pre-specify NI as an outcome biomarker to determine efficiency of compound at an early stage of their development.”

Overall, dimethyl fumarate did not demonstrate any beneficial effect on survival compared with placebo (p = 0.09; hazard ratio >99), with the majority of participants in the dimethyl fumarate group (93.8%) and all in the placebo group being censored.

In total, 86.0% of participants experienced at least one adverse event during the study (dimethyl fumarate: 90.3%; placebo: 77.1%; p = 0.08, Table 3). Most adverse reactions were mild and included cutaneous flushes, urinary tract infection and upper respiratory tract infection in the study population.

Serious adverse events were reported in 18.7% of participants (19.4% in dimethyl fumarate group and 17.1% in placebo group), however these were not related to the study treatment.

Meanwhile investigators noted that there were no significant differences between treatment groups for the incidence of serious treatment emergent adverse events (TEAE), TEAEs leading to permanent or temporary study drug discontinuation, TEAEs leading to death and unexpected TEAEs.

The decline in the ALSFRS-R was smaller when compared with recent ALS clinical trials reporting significant differences in the primary endpoints, noted Professor Vucic who said those studies selected for ‘fast ALS progressors’, which the current study does not.

The edaravone trial reported an ALSFRS-R score of 7.52 in the active group at 36 months compared to 11.25 in placebo while the CENTAUR trial demonstrated a calculated decline of 11.16 among the treatment group compared to 14.94 in placebo.

“Future clinical trials should assess dimethyl fumarate efficacy in ‘fast progressing’ ALS patients”, the authors concluded.

The study is published in Annals of Clinical and Translational Neurology.