BARCELONA, Spain — Annual dosing of rituximab for relapsing-remitting multiple sclerosis (RRMS) was noninferior to the typical dosing schedule of once every 6 months, which could offer a more convenient and cheaper treatment option, new phase 3 trial results showed.

After 4 years of follow-up, investigators leading the randomized RIDOSE-MS trial reported no significant differences in relapse rate or incidence of new lesions in patients who received a 500-mg dose of rituximab once a year vs those who received 500 mg twice a year.

“These data indicate that anti-CD20 therapies have been dosed too high for the purpose of eliminating inflammatory activity in RRMS,” said Anders Svenningsson, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden.

The findings of the RIDOSE-MS trial were presented on September 26 at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2025.

Interest in a Lower-Dose Option

Rituximab was originally developed for hematologic malignancies and later adopted for use in autoimmune inflammatory diseases like rheumatoid arthritis. 

Off-label use of rituximab for RRMS is common today on the basis of results from a 2008 phase 2 placebo-controlled study that showed that 1000 mg of the rituximab administered intravenously on days 1 and 15 reduced relapses by about half at 48 weeks.

But that study and others of rituximab in RRMS used dosing schedules originally developed for hematologic diseases. There have been no dose-ranging trials of the disease-modifying therapy in MS.

Without those studies, it’s possible that a drug that has been used for nearly 20 years in MS may never have been used at an optimal dose. That possibility contributed to increased interest in investigating the efficacy and safety of lower doses of the disease-modifying therapy, Svenningsson explained.

In the noninferiority RIDOSE-MS trial, 207 patients with RRMS or clinically isolated syndrome naive to or without exposure to rituximab in the prior 2 years received a 1000 mg infusion at baseline and then a 500 mg infusion 6 months later before being randomized. 

The comparator arms were 500 mg infused every 6 months (n = 103) or the same dose infused once annually (n = 104).

The primary endpoint was no evidence of disease activity on the basis of freedom from clinical relapses, absence of confirmed disability progression, and absence of new or enlarging lesions on MRI.

Over the 4-year follow-up, both groups showed similar rates of disease control, with 12.6% in the 6-month arm showing no evidence of progression vs 13.6% in the 12-month arm (hazard ratio, 0.93; P = .853). 

Similarly, there were no significant differences between groups in the number of relapses (seven in the 6-month arm vs five in the 12-month arm) or in the number of new lesions (10 in the 6-month arm vs 12 in the 12-month arm). 

No Decrease in Infection Risk

As reported previously by Medscape Medical News, rituximab has been associated with a twofold increased risk for infection in RRMS compared with other disease-modifying therapies.

In the RIDOSE-MS study, annual dosing was not associated with a reduced risk for infection, with 190 infections reported in the 12-month arm vs 152 in the 6-month arm. 

This was disappointing, Svenningsson said, but noted that there was a smaller reduction in the immunoglobulin G levels (-0.17 g/L per year) and that CD-positive B lymphocyte levels recovered toward baseline in the 12-month arm.

This, at least, offers the potential of “long-term safety benefits from a lower accumulated dose over time,” he said.

While RIDOSE-MS shows that an annual 500-mg dose of rituximab is as safe and effective as a twice-yearly infusion, the trial is not a dose-ranging study, Svenningsson emphasized. It’s possible that other dosing schedules might be even safer with the same efficacy, he noted.

While further dose reduction studies of rituximab are needed, Svenningsson said that once a biomarker for monitoring treatment response is identified, individualized dosing could become the model for MS treatment.

“My own candidate marker for dosing is switched memory B-cells,” he said, citing his effort to optimize dosing for MS prevention while preserving immune function important to protection from diseases other than MS.

Building on Earlier Studies

The RIDOSE-MS trial results had been foreshadowed by nonrandomized studies, including a cohort study published earlier this year and led by Kristin Wesnes, PhD, Department of Neurology, St. Olavs Hospital, Trondheim, Norway.

That study included 305 patients treated with 500 mg infusions of rituximab initially every 6 months for 18 months, followed by 500 mg every 9 months. The findings showed no loss of efficacy with longer extensions.

“I can confirm that both our clinical experience and the results from our study support the findings of the RIDOSE-MS study,” Wesnes told Medscape Medical News.

“Similar to the RIDOSE-MS trial, we did not find any differences in infection tendency, but it is possible that this requires longer observation time,” added Wesnes, who was not part of the new trial.

Because all patients enrolled in RIDOSE-MS had been previously exposed to either rituximab or dimethyl fumarate, “the only question that remains somewhat unclear is whether it is safe to extend the intervals to 12 months after only 1 year of treatment in newly diagnosed, treatment-naive, young individuals with presumed higher risk of disease activity,” Wesnes said.

An ‘Important Framework’

Several researchers in the field who were not part of the RIDOSE-MS trial commented on the findings during a panel discussion at the meeting.

“For those who use rituximab for MS, these data provide an important framework for thinking about this drug,” said Stephen Hauser, MD, professor of neurology, University of California, San Francisco, who led the 2008 trial of rituximab that prompted many clinicians to include the drug in the treatment plan for patients with RRMS.

Relative to newer CD20 B-cell targeted therapies, such as ocrelizumab, rituximab remains attractive at many centers in the US because it offers substantial activity at a typically lower cost, Peter Calabresi, MD, director of the Multiple Sclerosis Center at Johns Hopkins Medicine, Baltimore, told Medscape Medical News.

This underscores the relevance of the RIDOSE-MS findings, he added.

“One result of these data is that it might spur interest in looking at the dosing of other B-cell targeted therapies,” said Calabresi, indicating that dose levels needed to suppress inflammatory activity might be different for MS than other indications.

This study received no commercial funding. Svenningsson reported having no potential conflicts of interest. Hauser reported having financial relationships with Accure Inc., Alector, and Annexon Biosciences. Calabresi reported having financial relationships with Biogen, Lilly, Genentech, and Novartis. Wesnes reported having no potential conflicts of interest.