Dimethyl Fumarate Demonstrates Disease-Modifying Effect in Radiologically Isolated Syndrome

Findings from the pivotal ARISE study (NCT02739542) showed that early treatment with dimethyl fumarate (Tecfidera; Biogen) significantly reduced the risk of first clinical demyelinating event in patients with radiologically isolated syndrome (RIS). Presented at a late-breaker session at the 2022 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, October 26-28, in Amsterdam, Netherlands, this was the first study ever to show a benefit of disease-modifying therapy in patients with RIS.¹

The double-blind, multicenter study included 87 patients who met the 2009 RIS criteria who were randomly assigned 1:1 to either oral dimethyl fumarate 240 mg twice daily or placebo. The primary end point of time to onset of clinical symptoms attributable to central nervous system (CNS) demyelinating event at week 96 was highly reduced after treatment in the active treatment arm in both the unadjusted (hazard ratio [HR], 0.18; 95% CI, 0.05-0.63; P = .007) and adjusted (HR, 0.07; 95% CI, 0.01-0.45; P = .005) Cox proportional hazards regression model.

“These results support the concept of early treatment and intervention in the MS disease spectrum," lead investigator Darin Okuda, MD, professor of neurology and the director of Neuroinnovation and Multiple Sclerosis & Neuroimmunology Imaging Program at The University of Texas Southwestern Medical Center in Dallas, said during his presentation.

Okuda has been a pioneer in the space for many years, first coining the term RIS in 2009 following research completed by his group. RIS possesses MRI features highly typical for multiple sclerosis (MS) without clinical symptomatology suggestive of CNS demyelination. In this study, Okuda and colleagues hypothesized that earlier treatment intervention may extend the time to the first acute or progressive clinical event resulting from CNS demyelination and reduce new radiological activity. Similar to MS, it is believed that early treatment may result in more profound effects on reducing disability progression long-term.

Overall, treatment with dimethyl fumarate resulted in a risk reduction greater than 80% relative to placebo in the prevention of a first clinical event related to CNS demyelination. After adjusting for the number of gadolinium-enhancing lesions at baseline, there was a significant reduction in the number of new or newly-enlarged T2-weighted hyperintense lesions, a secondary end point, in the dimethyl fumarate arm compared with those on placebo (HR, 0.20; 95% CI, 0.04-0.94; P = .042). Gadolinium enhancement was present in only 1 individual at week 96, therefore statistical analysis could not be performed.

Although the active treatment arm had more moderate adverse reactions (31.8% vs 20.9%), the severe events were similar between groups (4.5% vs 9.3%). Between the 2 groups, the discontinuation rate was similar (dimethyl fumarate, n = 12; placebo, 13). Of note, 10 of the 87 individuals did not complete the full 96 week treatment periodn as the trial was prematurely terminated by the study sponsor because of slow pace in recruitment, Okuda said. If those individuals were to be excluded, the discontinuation rate would be 23% for the dimethyl fumarate group and 19% for those on placebo.

Okuda and colleagues' original research that characterized RIS was based off of a cohort study of 44 individuals, in which neurological examination at the initial MRI scan was shown to be normal in nearly all cases. While radiologic progression was identified in 59% of cases, only 10 patients converted to either clinically isolated syndrome or definite MS. Furthermore, the study showed that a presence of contrast-enhancing lesions on initial MRI was predictive of dissemination in time on repeat imaging of the brain (hazard ratio, 3.4; 95% CI, 1.3-8.7; P = .01).²

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REFERENCES
1. Okuda DT, Kantarci O, Lebrun-Frenay C, et al. Multi-center, randomized, double-blind assessment of dimethyl fumarate in extending the time to a first clinical demyelinating event in radiologically isolated syndrome (ARISE). Presented at: ECTRIMS Congress 2022; October 26-28; Amsterdam, Netherlands. LB
2. Okuda DT, Mowry EM, Beheshtian A, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology. 2009;72(9):800-805. doi:10.1212/01.wnl.0000335764.14513.1a