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Should Rituximab Be Considered for Relapsing Forms of MS?
Some Specialists Make the Case for It

Article In Brief

A report from the Institute for Clinical and Economic Review said that newer monoclonal antibody therapies work but cost too much to be cost-effective. MS experts question why a lower-priced, older drug—rituximab—has not been more widely used.

A new assessment of monoclonal antibody therapies approved to treat relapsing forms of multiple sclerosis (MS) found that they are clinically effective but priced too high to be considered cost-effective.

The draft report issued by the Institute for Clinical and Economic Review (ICER) underscored the frustration that neurologists and their patients have experienced for years over the always-rising prices of the most effective name-brand treatments available.

As expected, ICER said ocrelizumab (Ocrevus), ofatumumab (Kesimpta), and natalizumab (Tysabri) were not cost-effective when compared to the leading oral treatment, dimethyl fumarate. Based on ICER's estimated price, ublituximab—a new monoclonal antibody currently being reviewed by the US Food and Drug Administration (FDA)–also will cost too much to be considered cost-effective.

John R. Corboy, MD, FAAN, co-director of the Rocky Mountain Multiple Sclerosis Center at the University of Colorado Anschutz Medical Campus, noted that the ICER assessment did not, however, include rituximab, a monoclonal antibody used heavily in some parts of the US, though almost never in others, as an off-label treatment for MS.

In its report issued Oct. 17, ICER estimated that the annual price for rituximab (biosimilar and branded forms) ranges from $4,000 to $9,000. The bestselling monoclonal antibody used to treat MS is ocrelizumab, which costs between six and 13 times more than rituximab.

“It almost breaks my heart to think of the money that could have been saved had we been able to routinely use rituximab over the last decade,” said Dr. Corboy, the Charles Elliot Morris Chair in Neurology at CU. “We know how to save money in MS, and that is telling the insurance companies they have to approve the use of rituximab.”

Widespread use of rituximab is curtailed by insurers refusing to cover it, and some neurologists are leery about prescribing it. In the October report, ICER said rituximab appears to be similarly effective to other monoclonal antibodies in reducing relapse rates, but it did not include rituximab in its cost-effectiveness analysis because of insufficient evidence on how it affects disease progression.

Nonetheless, ICER did point to a recent meta-analysis of randomized controlled trials (RCT) and observational data that supports the efficacy of rituximab on reducing confirmed disability progression.

“There is wider use of rituximab for MS treatment outside of the US due to its similar mechanism of action to other monoclonal antibodies, RCT, and real-world efficacy and safety data, and lower price, particularly now that biosimilars are available,” the report said. “These factors should be taken into consideration by clinicians, patients, and health plans when deciding whether to use rituximab for first-line treatment of MS.”


“It almost breaks my heart to think of the money that could have been saved had we been able to routinely use rituximab over the last decade. We know how to save money in MS, and that is telling the insurance companies they have to approve the use of rituximab.”—DR. JOHN R. CORBOY

How to Save Millions

When Annette Langer-Gould, MD, PhD, joined Kaiser Permanente as a clinician scientist in 2009, she didn't expect to be calibrating the efficacy and cost of treatments for more than 5,000 patients with MS. Or that she'd discover that rituximab was the lynchpin to a treatment strategy that improves patient outcomes while reducing costs.

“But when I got into the clinic, it was very clear that there was a huge unmet need for the MS patients,” said Dr. Langer-Gould, regional lead for translational neuroscience for Kaiser Permanente's Southern California Permanente Medical Group.

At the time, the majority of their patients with multiple sclerosis were treated by general neurologists, who tended to use an escalation approach to treatment, reserving highly effective drugs until late in the course of the disease, if at all.

“And when they finally did get it, it was too late,” Dr. Langer-Gould said. “I was seeing so many patients like this that I said, ‘This isn't working. We need to create a program. There needs to be more structure, and there needs to be a lot of education.’”

The initial goal was to increase the early use of highly effective treatments, defined as those that had (1) outperformed a comparative treatment in at least one head-to-head RCT and/or (2) demonstrated a large effect in an RCT with patients who had highly active relapsing MS or a positive RCT conducted in patients who relapsed on modestly effective disease-modifying treatments.

“I was surprised when, after a short time, administrators at Kaiser-Permanente noticed that the new treatment strategy reduced drug costs for MS patients,” Dr. Langer Gould said. “That prompted development of its MS Treatment Optimization Program (MSTOP) designed to both improve MS outcomes and reduce expenditures.”

The MSTOP formulary prioritized the lowest-cost treatments when their safety and efficacy profiles were similar. Among highly effective treatments, natalizumab and rituximab made the cut. (Fingolimod was initially included but removed when safety concerns emerged.) One interferon-beta and one glatiramer acetate product, chosen each year based on the best negotiated price, were also included on the formulary.

In a recent Annals of Clinical and Translational Neurology article, Dr. Langer-Gould and her colleagues compared the MSTOP approach used in the Kaiser-Permanente Southern California region with another region of similar size that did not prioritize highly effective treatments.

They found that, over seven years, the Southern California region spent $162 million less on disease-modifying treatments than the comparator region. And the increased use of highly effective treatments was correlated to a 69 percent decline in annual relapse rates among patients in the Southern California region.

Kaiser-Permanente's annual spending on disease-modifying treatments in 2018 was actually less than it was in 2011, despite an 11 percent increase in the number of patients being treated.

By the end of the study, 80 percent of the patients being treated with highly effective treatments were using rituximab. In 2019, Dr. Langer-Gould and her colleagues published a risk-stratified treatment algorithm for MS that relies heavily on rituximab. One reason is that having an infusion—typically every six to 12 months—makes it easier for patients to adhere to their treatment plan than taking a pill once or twice a day, particularly if the cost of therapy is a problem.

“Patients love this treatment,” she said. “They often tell us, ‘I forget that I have MS between my infusions.’”


“I was surprised when, after a short time, administrators at Kaiser-Permanente noticed that the new treatment strategy reduced drug costs for MS patients. That prompted development of its MS Treatment Optimization Program designed to both improve MS outcomes and reduce expenditures.”—DR. ANNETTE LANGER-GOULD

Why Rituximab Is Off-Label for MS

Rituximab, a monoclonal chimeric human/mouse antibody, is an FDA-approved treatment for non-Hodgkin lymphoma, rheumatoid arthritis, and some other conditions. Unlike MS therapies that target T cells, rituximab targets the CD20 surface antigen present on B lymphocytes.

Results of the phase 2 HERMES trial, published in the New England Journal of Medicine in 2008, demonstrated its efficacy in treating relapsing-remitting MS.

Genentech, which makes rituximab, chose not to pursue a phase 3 trial needed to seek FDA approval as an MS therapy. Instead, it sought and received in 2017 FDA approval for ocrelizumab, which targets B-cells in the same way that rituximab does.

Genentech's decision sparked criticism that the company was putting profits over patients. Rituximab's US patent protection expired in 2016, opening the floodgates for lower cost biosimilars to emerge. Ocrelizumab, meanwhile, has become the leading monoclonal antibody used to treat MS, with a list price of more than $68,000 a year.

Ocrelizumab quickly became a blockbuster, generating at least $1 billion a year in revenue, but Dr. Corboy sees it as equivalent to rituximab.

“I'm always stunned when a new drug is approved that is similar to drugs already available, and we somehow forget there's something similar already staring us in the face,” he said. “The thing here is rituximab, which is still staring us in the face.”

He started using rituximab as a cost-effective and efficacious option at CU, the Denver Health Medical Center and the Veterans Health Administration more than a decade ago. Dr. Corboy also successfully lobbied government payers—the Colorado Medicaid agency and the Medicare administrative contractor for Colorado—to cover rituximab as a first-line therapy for MS.

Writing in Neurology in 2016, Dr. Corboy and Ilya Kister, MD, a professor in the department of neurology at NYU Grossman School of Medicine, recommended the use of rituximab to improve MS care while controlling costs. But the idea never caught on broadly.

Indeed, the Rocky Mountain Multiple Sclerosis Center is one of the few centers in the country where rituximab and other B-cell depleting therapies dominate, said Enrique Alvarez, MD, PhD, assistant medical director for neurology at the University of Colorado. He estimates they are used to treat about 80 percent of the center's patients.

“We think these drugs have a lot of benefit and risk-wise are probably safer than some of the other drugs that we have in the MS space,” said Dr. Alvarez, who has published real-world outcome studies on the efficacy and safety of rituximab.

Rituximab—or, more commonly, one of its biosimilars—accounts for about 40 percent of the center's B-cell depleting prescriptions.

“Our decision between using rituximab versus ocrelizumab is predominantly based on who's paying,” he said. “Our rituximab patients tend to be on Medicaid and Medicare while UnitedHealthcare and Anthem like ocrelizumab.”

Anne Cross, MD, a professor of neurology and the Manny and Rosalyn Rosenthal-Dr. John Trotter MS Chair in Neuroimmunology at Washington University in St. Louis, started one of the first clinical trials to study B-cell depletion by rituximab as an MS therapy in 2002.

All three of the anti-CD20 monoclonal antibodies are similarly effective, in her view, but she currently only prescribes rituximab for a few patients who started using it before its competitors got FDA approval. One reason is that her institution wants physicians to prescribe FDA-approved agents whenever possible.

Because ocrelizumab is humanized and ofatumumab is a human monoclonal antibody, those therapies have less chance of triggering development of antibodies against the drug itself than rituximab, a chimeric antibody that continues to have mouse components in the monoclonal antibody.

“I don't think that's a deal breaker by any means, but the fact is we have two FDA-approved agents, and most of the time we're able to get insurance companies to pay for them,” she said.

Rituximab Use in Other Countries

The European Medicines Agency (EMA), which regulates prescription drugs in the European Union and the European Economic Area, has not approved rituximab as an MS therapy.

Swedish physicians can prescribe off-label medicines without seeking prior approval when they consider it appropriate to do so. Anders Svenningsson, MD, PhD, professor of neurology and head of neuroimmunology at the Karolinska Institutet Danderyd Hospital in Stockholm, and his colleagues started using rituximab on a limited basis soon after the original phase 2 trial was published in 2008. As its effectiveness became apparent, they started doing small-scale studies to learn more.

In the years since, rituximab has gained traction in Sweden, although its use varies widely from one region to another. By June 2017, more than 53 percent of patients in Sweden who started a disease-modifying therapy were prescribed rituximab, according to the Swedish MS register.


“This strengthens the concept that we have been working on in Sweden for many years, that very early treatment with highly effective treatment is an extremely effective way of shutting down MS.”—DR. ANDERS SVENNINGSSON

As pharmaceutical companies selling EMA-approved treatments for MS saw their revenues erode, they started complaining that neurologists were inappropriately using off-label therapies despite on-label options being available, Dr. Svenningsson said.

He decided the best way to stop that attack was to provide the same level of scientific evidence that would be needed to receive EMA approval.

“I just thought that we had to document this by the book to justify the use and also to show that we do treat our patients according to the highest scientific evidence,” he said.

To that end, he led the phase 3 RIFUND-MS trial, published in The Lancet Neurology in August, that provided that justification. Two-hundred people diagnosed with relapsing-remitting MS recruited at 17 sites in Sweden were randomly assigned to receive dimethyl fumarate at the approved dose or rituximab at an initial dose of 1,000 mg followed by 500 mg at six-month intervals.

Over a two-year period, three patients on rituximab experienced one relapse each, compared to 16 patients receiving dimethyl fumarate. That translates to an 81 percent lower relapse risk for patients receiving rituximab.

After two years, 68 percent of patients on rituximab had no evidence of disease activity, compared to 54 percent of patients receiving dimethyl fumarate.

Patients in both groups generally saw improvements in their scores on the Expanded Disability Status Scale, although the researchers noted that the trial had too few patients to detect differences in disability worsening in 24 months.

The RIFUND-MS trial may be too small for the EMA to approve rituximab for MS, but Dr. Svenningsson thinks the findings will prompt more neurologists to use it as a first-line therapy—and he hopes that more US insurers may be convinced to cover it.

The trial had one takeaway that Dr. Svenningsson is eager to disseminate: Both rituximab and dimethyl fumarate were more effective than the researchers had expected, and he thinks that is because highly effective treatments were started so early. On average, treatment with one of the highly effective treatments slowed relapses after just more than one year of disease duration.

“This strengthens the concept that we have been working on in Sweden for many years, that very early treatment with highly effective treatment is an extremely effective way of shutting down MS,” he said. “There are still things that you have to work with for the patient, but we almost never have to worry about new relapses or new lesions in our patients. We have known this for several years, but now it's also formally demonstrated.”

Sweden is one of several European countries prioritizing rituximab for MS.

“Germany is very close to not only allowing the use of rituximab without any prior authorization requests but also adding an additional fee for safety monitoring, which could be viewed as an incentive to use it,” Dr. Langer-Gould said.


“Our decision between using rituximab versus ocrelizumab is predominantly based on who's paying. Our rituximab patients tend to be on Medicaid and Medicare while UnitedHealthcare and Anthem like ocrelizumab.”—DR. ENRIQUE ALVAREZ

Writing in Frontiers in Immunology in 2021, a group of Italian researchers made the case that rituximab should be approved by regulators as a first-line treatment for MS: “An increasing body of evidence from randomized clinical trials and real-world data suggest that rituximab is a highly effective alternative in both relapsing and progressive MS, with a low discontinuation rate, related to a good benefit/risk profile, and a good compliance,” they wrote. “This use could be officially recognized by national regulatory authorities, according to specific procedures, to ensure equal access for patients to a safe and effective option.”


Drs. Gould and Svenningsson had no disclosures. Dr. Cross received honoraria for consulting with Biogen, EMD Serono, Novartis, Horizon, Jazz Pharmaceuticals, Janssen, Bristol Myers Squibb, and Genentech/Roche TG Therapeutics. She received support from EMD Serono for travel to a meeting.

Link Up for More Information

• Kister I, Corboy JR. Reducing costs while enhancing quality of care in MS Neurology 2016;87(15): 1617–1622.
• Langer-Gould A, Cheng SC, Li BH, et al. The multiple sclerosis treatment optimization program Ann Clin Transl Neurol 2021;8(11): 2146–2154.
• Langer-Gould A, Klocke S, Beaber B, et al. Improving quality, affordability, and equity of multiple sclerosis care Ann Clin Transl Neurol 2021;8(4) 980–991.
• Langer-Gould A, Cheng SC, Li BH, et al. Decreasing multiple sclerosis treatment expenditures and improving quality at the health system level Ann Neurol 2022;92(2): 164–172.
• Asha MZI, Al-Asaad Y, Khalil SFH. The comparative efficacy and safety of anti-CD20 monoclonal antibodies for relapsing-remitting multiple sclerosis: A network meta-analysis IBRO Neurosci Rep 2021;11: 103–111.
• Hauser SL, Waubant E, Arnold DL, et al. B-Cell depletion with rituximab in relapsing-remitting multiple sclerosis N Engl J Med 2008; 358:676–688.
• Svenningsson A, Frisell T, Burman J, et al. 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 Lancet Neurol 2022;21(8): 693–703.