Rituximab Outperforms Tecfidera at Preventing Relapses in Phase 3 Trial

Multiple sclerosis (MS) patients treated with rituximab were more than five times less likely to experience a relapse compared with patients given Tecfidera (dimethyl fumarate), according to data from a Phase 3 clinical trial.

Patients on the experimental therapy also were 32% more likely to have no evidence of disease activity during the trial, meaning that they experienced no relapses, no new or enlarging lesions, and no disability progression.

“The excellent efficacy and low cost of rituximab could make it an attractive first choice for newly diagnosed MS patients, not least in resource-poor areas,” Anders Svenningsson, MD, PhD, a professor at Karolinska Institutet, said in a university press release.

The results were published in The Lancet Neurology, in the study “Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial.” The trial was funded by the Swedish Research Council.

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Rituximab is an anti-CD20 therapy that is administered via infusion into the bloodstream and works by depleting B-cells, a type of inflammatory immune cell that drives MS damage.

The medication is approved for certain B-cell cancers, but has never been formally approved for MS, where it has been used off-label for many years. Yet, it works much like other anti-CD20 monoclonal antibodies that have been approved to treat MS, including Kesimpta (ofatumumab) and Ocrevus (ocrelizumab).

“Since the patent [on rituximab] has expired, there is no incentive from the pharmaceutical company holding the marketing rights to apply for a new indication,” said Svenningsson, a co-author of the study.

While accumulating evidence supports the use of rituximab for MS, well-controlled Phase 3 trials comparing it against standard therapies are needed before it “can be officially recommended for multiple sclerosis by regulatory bodies,” the researchers wrote.

Rituximab as MS treatment: Phase 3 trial results

In this Phase 3 clinical trial, called RIFUND-MS (NCT02746744), investigators compared rituximab against Tecfidera, an approved oral treatment for relapsing MS types.

The study recruited 200 people diagnosed with relapsing-remitting MS or clinically isolated syndrome less than 10 years prior to enrollment, at 17 sites in Sweden. The average age of the patients was just over 33 years, about two-thirds were female, and the vast majority had the relapsing-remitting type and had never before used a disease-modifying therapy for MS.

Participants were randomly assigned to receive Tecfidera according to the approved dosing schedule, or rituximab at 1,000 mg for the first dose and 500 mg every six months thereafter. All but five participants completed the study — four withdrew consent or were lost to follow-up, and one was found not to actually have MS.

The study’s main goal was to compare the effect of the treatments on relapse rates. The trial originally was planned to last two years, though there was some variability in follow-up times and treatment schedules due to interruptions as a result of the COVID-19 pandemic. Of note, several of the researchers have links to pharmaceutical companies.

Over the course of the study, 16 patients on Tecfidera experienced relapses (15 had one relapse, and one had two relapses). Among those on rituximab, three patients experienced one relapse each — statistical analyses showed that the relapse risk was 81% lower for patients on rituximab.

“A strikingly high proportion (97%) of patients allocated to rituximab were relapse-free during the entire 24-month observation period,” the researchers wrote.

After two years, significantly more patients on rituximab than Tecfidera had no evidence of disease activity (68% vs. 54%). The time to disease activity was markedly longer for patients on rituximab.

Disability outcomes, measured with the Expanded Disability Status Scale, did not differ significantly between the treatment groups after two years. The researchers noted that improvements in scores, meaning less disability, were generally seen with both medications.

“It should be noted that the RIFUND-MS trial was not [statistically] powered to detect differences in disability worsening because 24 months is too short for detecting treatment-related differences in disability in a population of this size,” the team wrote.

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Frequency of treatment side effects

The frequency of side effects was generally similar among patients on either treatment, with more frequent digestive complaints and treatment discontinuations in the Tecfidera group. One patient on rituximab developed a serious lung condition called bronchiectasis, which was deemed possibly related to the therapy.

“The safety profiles of the investigated drugs were as expected, with no new safety concerns emerging,” the researchers concluded.

Broadly, the team said that rituximab’s inflammation-suppressing efficacy here is comparable to that of other anti-CD20 MS treatments already in use. Still, the researchers stressed that rituximab may be a useful alternative because it is available at lower cost than other such therapies used for MS.

“The low-dose rituximab protocol used in this study currently comes at a cost of approximately only a tenth of the price of [Ocrevus] in Sweden, and thus might become an attractive treatment option in resource-limited settings,” they wrote.

“Further studies, including larger populations and formal health-economic evaluations, are needed to position rituximab properly in the treatment scheme of multiple sclerosis,” the team added.