#ECTRIMS2019 – Is Rituximab a Reasonable Option for MS Patients? Yes, Researcher Says

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by Ana Pena PhD |

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#ECTRIMS2019 rituximab hot topic

Editor’s note: This is the second story in a three-part report examining the question, “Is rituximab a reasonable alternative treatment for MS?”, which was a topic discussed at this year’s Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Here, we take an in-depth look at the arguments presented in favor of rituximab. 


Is rituximab a reasonable alternative treatment for multiple sclerosis (MS)?

Fredrik Piehl, MD, PhD, says yes, explaining in his presentation at ECTRIMS why he believes rituximab is a reasonable therapeutic option for MS.

Piehl is a neurologist and professor at Karolinska University Hospital and Karolinska Institute in Sweden.

He is also the principal investigator of a large, long-term observational study called COMBAT-MS (NCT03193866), the purpose of which is to investigate whether rituximab offers advantages over other commonly used disease-modifying treatments (DMTs) in relapsing-remitting MS (RRMS) patients. Both untreated patients and patients switching from a previous first-line DMT are being enrolled.

The study is taking place in Sweden and is a collaboration between the Karolinska Institutet and the Kaiser Permanente, Southern California. It is funded by U.S.-based Patient-Centered Outcomes Research Institute.

Determining risk-benefit

Assessing the risk-benefit profile of a given therapy “is complex because different patients respond differently, and they also have different susceptibilities to risk,” Piehl said.

To address this in the most reliable way, clinicians turn to randomized controlled trials.

“We have accumulated data from randomized controlled trials with anti-CD20s, and so far, only ocrelizumab [Ocrevus] has completed a Phase 3 trial program, and it’s approved in Europe and the U.S. But we don’t know … how these therapies compare to relevant alternatives, including highly effective drugs,” Piehl said.

Of note, there is a Phase 3 trial — called RIFUND-MS (NCT02746744) — now taking place in Sweden to compare the efficacy and safety of rituximab (marketed as MabThera) infusions versus Tecfidera (dimethyl fumarate) pills, an approved first-line therapy, in patients with early RRMS or clinically isolated syndrome (CIS). No results have been reported yet.

Rituximab’s use in Sweden has grown over time, and currently “approximately half of all patients [are] on rituximab compared to all other types of DMTs,” Piehl said, which, he says, is due not only to increasing use of the therapy in patients who have never before taken an MS medication, but also due to second-line use.

Data between 2012 and 2018 from the Swedish MS registry shows that many RRMS patients switch therapy within two years of starting a new treatment.

“Roughly between 30–40% up to 70% switch within two years,” usually due to poor effectiveness or side effects. And this is something “probably not good for patients, and not good for healthcare systems.” But data show a “slightly different” scenario with rituximab, Piehl said, referring to fewer switches.

Beyond risk-benefit, “tolerability is also important” for patients, he emphasizes.

As part of the COMBAT-MS trial, Piehl and his colleagues asked patients and clinicians, “What is the most important long-term goal with a DMT?”

“Patients tell us ‘preserving quality of life,’ and we and our colleagues say ‘lowering the risk of accumulating disability.'”

Real-world data

Randomized controlled trials are the gold standard to measure a therapy’s effect, but they have limitations.

According to Piehl, patient studied in trials have very specific characteristics (usually they don’t have major co-morbidities, or coexisting conditions) and may not represent the high diversity of patients seen in the real world.

In addition, trials run for a limited amount of time and often lack ideal endpoints (objectives) or ideal comparators. They also have limited ability to identify rarer but potentially severe side effects.

Consequently, to investigate rituximab’s effectiveness, Piehl and his team turned to real-world data, collected from clinical practice. He presented the findings from four of these “key studies.”

One study compared the outcomes for RRMS patients switching from Tysabri (natalizumab) to either rituximab or Gilenya (fingolimod) after testing positive for the John Cunningham virus (JCV).

JCV is a virus that may lead to progressive multifocal leukoencephalopathy (PML), a life-threatening infection of the brain. Treatment with Tysabri, Gilenya, and Tecfidera can increase the risk of having PML, which prompts a switch in treatment for patients who are JCV-positive.

Within 1.5 years of stopping Tysabri, 1.8% of rituximab users and 17.6% of Gilenya users experienced a clinical relapse. Moreover, contrast‐enhancing MRI lesions were found in 1.4% of patients taking rituximab versus 24.2% of those taking Gilenya. The rate of adverse events and treatment discontinuation also favored rituximab treatment.

“Rituximab performs better than fingolimod [Gilenya] both with regard to efficacy and safety,” Piehl said.

In a population-based study, rituximab was assessed as the initial treatment for patients with newly diagnosed RRMS in terms of effectiveness and discontinuation rates, compared with injectables (interferons, glatiramer acetate), Tecfidera, Gilenya, and Tysabri.

“Comparing with the interferons, dimethyl fumarate [Tecfidera], and natalizumab [Tysabri], we see better drug survival [lower treatment discontinuation rates], and also a very low incidence of relapses and adverse events” with rituximab, Piehl said.

Another study compared the efficacy, safety, and medication persistence of escalation therapy with rituximab, Tysabri, and Gilenya, following a relapse in RRMS patients using first-line injectables (interferons and glatiramer acetate). The annualized drug discontinuation rate was lower for rituximab.

“Rituximab and natalizumab [Tysabri] perform approximately equally, but with regard to drug survival [treatment discontinuation] and the problem with JCV, with natalizumab, it’s worse than with rituximab,” Piehl said.

Furthermore, in the fourth study, assessing rituximab treatment in a large and mixed group of 822 MS patients, “adverse events and also the appearance of contrast-enhancing lesions or relapses was very low,” he said.

Rituximab seems safe

Regarding safety, Piehl emphasized that randomized controlled trials are not ideal to detect some side effects.

“When a drug is approved, it’s not 100% sure we know all about risks,” he said. “With natalizumab [Tysabri], PML problems were detected after approval. Daclizumab [Zynbryta] was actually withdrawn [in 2018] due to safety problems; with regard to alemtuzumab [Lemtrada], [the European Medicines Agency] has initiated a safety review due to apparently rather high mortality rates.”

Typically, safety concerns for B-cell-depleting anti-CD20 therapies include infusion reactions and increased susceptibility to infections due to the immunosuppressive effect of these treatments.

In the COMBAT-MS study, researchers are assessing these risks based on data from hospitalized infections nationwide with the Swedish National MS registry, and comparing it with the general population.

Relative to injectable therapies, Gilenya, and Tysabri “we can see there is a non-significant trend for more severe infections with rituximab that might increase over time,” Piehl said.

A preliminary study presented at ECTRIMS compared the tolerability and the depletion of antibodies (immunoglobulins, Ig) in 161 RRMS patients starting Ocrevus in the U.S. (at the Rocky Mountain MS Clinic, Utah) versus 311 Swedish patients starting rituximab.

With Ocrevus, “there is a significant decrease in IgG [immunoglobulin G, the most abundant type of antibody] levels up to one year, whereas their levels with rituximab are stable,” Piehl said. Low IgG levels are known to potentially increase the risk of infections.

Moreover, more patients stopped Ocrevus due to side effects (6.8% of the patients) than did those on rituximab (2.6%).

“It’s unlikely that ocrelizumab [Ocrevus] will turn out to be a safer alternative if their IgG trend is true, and we know that hypogammaglobulinemia [low IgG levels] is a potential problem with these types of therapies,” Piehl said.

Regarding cancer risk, updated data from a study presented at ECTRIMS last year, showed that compared with Gilenya and Tysabri, the risk for any type of invasive cancer is lower with rituximab, even “a little bit lower than in the general population,” Piehl said.

Concerning breast cancer in particular, he said, “we detected six breast cancers in rituximab-treated females; that corresponds to 8.9 per 10,000 person-years. From the trials with ocrelizumab [Ocrevus], there were slightly higher numbers [26.1 per 10,000 person-years]. We have to wait for further data with a longer follow-up.”

Regarding pregnancy and the risk of disease reactivation in the post-partum period (after delivery) due to treatment suspension, data shared at ECTRIMS “tells us that compared to untreated patients, rituximab-treated women have half the risk of having a post-partum relapse, whereas natalizumab [Tysabri]-treated patients have twice as high as the untreated,” Piehl said.

“With regard to pregnancy outcomes, we don’t see really a safety signal,” he said.

Combined Swedish and U.S. data presented at ECTRIMS of 106 babies exposed to rituximab prior to and during pregnancy show “no increase in adverse pregnancy outcomes compared to expected national incidence rates,” while relapses were lower than expected for this patient population and “far lower” than in Tysabri-treated patients, its researchers wrote.

As for mortality, data presented last year at ECTRIMS showed that from January 2011 to February 2018, there were two deaths in patients treated with rituximab in Sweden.

“Compared to the matched general population, that’s slightly lower than expected,” Piehl said.

All these data suggest that “anti-CD20 therapies have an attractive risk-benefit at least short-medium term. We have to do more studies to look at long-term effects. I think that especially severe infections are a potential problem, maybe not cancer,” Piehl said.

He also emphasized that the “safety data with rituximab is in line with two decades of use in rheumatoid arthritis. However, we do need to do further comparative studies against other CD20” therapies. Studies addressing optimal dosing and dosing intervals are also needed.

Piehl concluded his presentation by highlighting that “rituximab is a reasonable alternative to approved MS” therapies, but patients “should be invited to shared decision-making.”

To read the other side of the rituximab debate presented at ECTRIMS, go here.