For the first time ever, investigators identified a treatment benefit that extends the time to clinical conversion in RIS and reduces new or newly-enlarging T-weighted hyperintense lesions.
After initial data was presented at the 2022 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, investigators have published the full dataset from the pivotal ARISE study (NCT02739542) of dimethyl fumarate (Tecfidera; Biogen) in patients with radiologically isolated syndrome (RIS).1
In a cohort of 87 patients who met the 2009 RIS criteria, findings showed that treatment with dimethyl fumarate significantly reduced risk of first clinical demyelinating event by 82% during a 96-week treatment period (hazard ratio [HR], 0.18; 95% CI, 0.05-0.63; P = .007). All told, this was the first time a disease-modifying effect had been shown in this patient population, with the thought that early treatment may prevent clinical conversion to multiple sclerosis (MS).
"Given fundamental differences between healthcare delivery systems and clinical practices, additional international efforts that aim to expand our findings are warranted," 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, and colleagues, wrote. "An increase in knowledge related to early treatment may not only result in modifications in how people are diagnosed and risk-stratified but also transform our approach to care toward effectively preventing or delaying the first onset of symptomatic disease itself."
A total of 59 (68%) participants completed the 96-week study. After 96 weeks, 33% of patients on placebo and 7% on active drug demonstrated a first acute neurological symptom associated with central nervous system demyelination. Of the 3 exacerbations identified in the dimethyl fumarate group, 1 presented symptoms localized to the brainstem and 2 to the spinal cord. Within the placebo group, a total of 14 seminal clinical events were identified with symptoms localizing to the brain (n = 1), brainstem (n = 1), spinal cord (n = 8), long sensory (n = 9), and motor tracks (n = 3).
The effect dimethyl fumarate had on patients was evident in adjusted Cox proportional hazards regression model as well, even after adjusting for sex, age at the time of diagnosis, MS family history, Expanded Disability Status Scale (EDSS) score, T2-weighted hyperintense volume, and the presence of gadolinium-enhancing lesions (HR, 0.07; 95% CI, 0.01-0.45; P = .005). When using the Bayesian approach, the HR for the risk of a first clinical event during the 96-week treatment period was 0.20 (95% credible interval, 0.11-0.35) for dimethyl fumarate vs placebo.
New and/or newly-enlarging T2-weighted hyperintense lesions at the end of the study period were present in 31% of those on placebo and 26% of dimethyl fumarate-treated patients. Of those with MRI advancement, 6 of 8 individuals in the placebo group and 1 of 7 in the dimethyl fumarate group converted to a first clinical event. Patients on active treatment saw significant reductions in cumulative number of these lesions vs placebo even after adjusting for the number of gadolinium-enhancing lesions at baseline (0.12 vs 0.62; rate ratio, 0.20; 95% CI, 0.04-0.94; P = .042).
Exposure to dimethyl fumarate was associated with a lower change in mean T2-weighted lesion volume over time in both the unadjusted and adjusted analyses; however, statistical significance was not achieved (dimethyl fumarate: 0.005 cubic centimeters vs placebo: 0.04 cubic centimeters; P = .332). Statistical analysis of dimethyl fumarate on gadolinium-enhancing lesions could not be performed, as only 1 person on active treatment experienced this. None of the participants within the placebo group demonstrated gadolinium-enhancement at the 96-week time point. At baseline. 37 of the 87-patient cohort (42%) had Expanded Disability Status Scale scores higher than 1, while at the 96-week visit, 35 of 57 (63%) remaining participants had scores higher than 1.
At ECTRIMS 2022, NeurologyLive® caught up with Okuda to discuss the findings, and the significance they have to both the RIS and MS community, respectively. In the video below, Okuda shared his perspective on the data, as well as what additional data would be helpfully to assess further, and thoughts on the timing of therapy initiation in relation to the diagnosis of RIS.