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Off-label rituximab (Rituxan) led to fewer relapses over 2 years than dimethyl fumarate (Tecfidera) in people with early relapsing-remitting multiple sclerosis (MS), the phase III trial showed.

Relapses occurred in 3% of people on rituximab and in 16% on dimethyl fumarate (risk ratio 0.19, 94% CI 0.06-0.62, P=0.0060) over 24 months, reported Anders Svenningsson, MD, PhD, of the Karolinska Institute and Danderyd Hospital in Stockholm, and co-authors.

More people on rituximab, an anti-CD20 B-cell depleting monoclonal antibody, were free of new MRI-detected disease activity over the 2-year period than those on dimethyl fumarate (79% vs 63%, P=0.019), the researchers said in .

"Our findings suggest that rituximab might provide superior efficacy to dimethyl fumarate, although the fact that patients and treating clinicians were not masked to treatment means that our findings cannot be considered definitive," Svenningsson and co-authors wrote.

"Because rituximab is available at a lower price than dimethyl fumarate in some countries, rituximab could be an attractive treatment option, especially in resource-limited settings, although further studies are needed to confirm cost-effectiveness," they added.

In recent years, two drugs targeting anti-CD20-expressing B cells -- ocrelizumab (Ocrevus) and ofatumumab (Kesimpta) -- have been approved for MS, noted Robert Naismith, MD, and Anne Cross, MD, both of Washington University in St. Louis, in an .

Rituximab, which is in the U.S. for people with non-Hodgkin lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis, was studied in the phase II trial of relapsing-remitting MS over a decade ago.

"After the success of the phase II HERMES study, in which rituximab reduced the number of inflammatory brain lesions and clinical relapses compared with placebo, development of anti-CD20 therapies shifted from rituximab, which is a chimeric mouse and human antibody, to the fully humanized monoclonal antibody, ocrelizumab," Naismith and Cross observed.

"Between publication of the HERMES trial in 2008 and regulatory approval of ocrelizumab in 2017, numerous centers throughout the world adopted use of off-label rituximab in their management of patients with multiple sclerosis," the editorialists added. "Multiple studies with various designs have highlighted the apparent high-efficacy of rituximab in patients with relapsing multiple sclerosis but, despite these encouraging results, randomized and blinded studies were few."

RIFUND-MS screened patients at 17 Swedish university and community hospitals between July 2016 and December 2018. Researchers randomized participants to either 240 mg of oral dimethyl fumarate twice daily or 1,000 mg of intravenous rituximab followed by 500 mg every 6 months.

The primary outcome was the proportion of patients experiencing at least one relapse, defined as subacute onset of new or worsening neurological symptoms lasting more than 24 hours and preceded by 30 days or more of clinical stability. A total of 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis.

Eligible participants had been diagnosed with relapsing-remitting MS or clinically isolated syndrome, had a disease duration of 10 years or less, were untreated or exposed only to interferon or glatiramer acetate, and had evidence of clinical or radiological disease activity in the past year.

Mean age of participants was 33.5 and two-thirds were women. Baseline (EDSS) scores averaged 1.6 in the rituximab group and 1.7 in the dimethyl fumarate group.

About half of participants of dimethyl fumarate stopped treatment or switched to rituximab during the course of the study: 14 did so because of relapse, 11 because of new disease activity found on MRI, 16 due to side effects, and seven cited no reason. Only three participants in the rituximab group discontinued.

Gastrointestinal symptoms and flush were common in the dimethyl fumarate group (65 events each, 47.4 per 100 patient years). Other side effects did not differ in a clinically significant way between the drugs, Svenningsson and co-authors noted. "There were no safety concerns," they wrote.

While RIFUND-MS clearly establishes rituximab's superiority on imaging and clinical outcomes over oral dimethyl fumarate, it does not establish superiority or non-inferiority of rituximab to the FDA-approved anti-CD20 therapies ocrelizumab and ofatumumab, Naismith and Cross pointed out.

"For countries and regions where the anti-CD20 therapies that are approved for multiple sclerosis are available, the drugs that have been more rigorously studied remain treatments of choice," the editorialists wrote. "But for countries where anti-CD20 therapies approved for multiple sclerosis are unavailable, the data from the RIFUND-MS trial suggest that rituximab might be considered."

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