Rituximab Outperforms Other Drugs in RRMS

Pauline Anderson

January 11, 2018

In patients with newly diagnosed relapsing-remitting multiple sclerosis (RRMS), rituximab is superior to other disease-modifying treatments (DMTs) in terms of the patient's remaining on the drug and having a lower risk of switching because of disease breakthrough, a new analysis has shown.

In a retrospective cohort study using prospectively collected data, researchers looked at comparative "real-world" effectiveness of initial DMT choices for RRMS.

Dr Fredrik Piehl

"Efficacy-wise, safety-wise, and tolerability-wise, rituximab performs better than our traditional drugs," including injectable therapies like interferon β, and glatiramer acetate," Fredrik Piehl, MD, PhD, professor, neurology, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden, told Medscape Medical News.

"In terms of staying on the drug, the difference was striking with rituximab compared to the other drugs."

The study was published online January 8 in JAMA Neurology.

Increasing Confusion

Rituximab is a humanized monoclonal B-cell-depleting anti-CD20 antibody approved in the United States and elsewhere for the treatment of rheumatoid arthritis. Off-label use of this drug in patients with MS has recently increased considerably in Sweden, said Dr Piehl.

He noted the "increasing confusion" as to which MS drugs work best. Although data from randomized clinical trials (RCTs) are important, these studies "don't give us good information on comparative performance between different drugs" as they typically test one drug against placebo or against another, often older, drug, he said.

He added that RCTs often include "highly selected patient populations" that don't have major comorbidities and perhaps are enriched with patients who have milder disease.

"There is increasing awareness that you need 'real world' data that could give us an indication of the performance of various drugs."

Some research suggests that traditional MS drugs have "a pretty lousy performance," with one study finding that within 2 years, less than half of patients with MS remain on such drugs, noted Dr Piehl.

Patients sometimes discontinue traditional injectable drugs because of tolerability problems or lack of efficacy.

"This is not a recipe for success," said Dr Piehl, adding that lack of effect could put patients at risk for life-long neurologic deficits.

The new study included all patients in Stockholm and Västerbotten counties who received a diagnosis of RRMS from January 1, 2012, to October 31, 2015, and started their first DMT. Patients were identified through a national web-based MS registry and were observed until April 30, 2016.

Regional Differences

There are large regional differences in MS treatment approaches across Sweden. In Västerbotten, in the northern part of the country, almost all patients receive drugs "that are perceived as working better than standard platform therapies," while in Stockholm, patients are more likely to start with less effective drugs that are "generally perceived to be safer and less costly," said Dr Piehl.

The analysis included 494 patients (442 in Stockholm and 52 in Västerbotten), median age of 34.4 years, 32.0% of them men. Patients in Västerbotten were younger and had a higher Expanded Disability Status Scale (EDSS) score than those in Stockholm, suggesting a more active disease course. They also received treatment earlier.

In the Stockholm patients, 212 received an injectable DMT including interferon β and glatiramer acetate, 86 dimethyl fumarate, 78 rituximab, 46 natalizumab, 17 fingolimod, and 3 another agent. In the Västerbotten sample, 42 received rituximab, 4 natalizumab, 3 an injectable, and 3 another agent.

The primary outcome was discontinuation of therapy for any reason, including conversion to secondary progressive MS and pregnancy.

Secondary outcomes were relapses and gadolinium (Gd+) lesions on MRI, adverse events, and cause of therapy discontinuation.

The proportion of patients remaining on therapy was significantly higher for rituximab than for injectable DMTs, dimethyl fumarate, and natalizumab The annual discontinuation rates were 0.03 for rituximab, 0.53 for injectables, 0.32 for dimethyl fumarate, 0.38 for fingolimod, and 0.29 for natalizumab.

There was a higher hazard rate for drug discontinuation for all drug categories compared with rituximab. This was significant for all groups after adjustment for covariates including age, sex, baseline EDSS score, MS duration after diagnosis, relapse in the year before treatment started, region, and follow-up time.

The higher rate was also significant after adjustment separately for propensity scores that were estimated for each treatment group compared with rituximab.

The causes of therapy discontinuation differed between treatment groups. The most common causes among rituximab-treated patients were pregnancy (3.3%) and disease breakthrough (0.8%).

Relapse rates were significantly lower in rituximab-treated patients than in those receiving injectable DMTs (adjusted hazard ratio [HR], 4.3; 95% confidence interval [CI], 1.6 - 11.2; P < .01) and natalizumab (adjusted HR, 5.1; 95% CI, 1.2 - 22.2; P < .05). However, after adjustment for propensity score, the difference between rituximab and natalizumab was no longer significant (P = .05).

Dr Piehl noted that while the significance for better relapse protection with rituximab compared with natalizumab was "borderline," there is a much lower risk for progressive multifocal leukoencephalopathy (PML) with rituximab than with natalizumab (Tysabri, Biogen).

PML, a rare but potentially deadly infection that attacks the brain, can be caused by the JC virus. In patients in the study who were treated with natalizumab, 32% discontinued treatment because of positive results on JC virus serology.

A comparison of rituximab with dimethyl fumarate and fingolimod did not result in significant differences after adjustment for confounders.

Compared with rituximab, the adjusted odds ratio for Gd+ lesions was higher with injectable DMTs (9.3; 95% CI, 2.0 - 87.0; P = .02) and dimethyl fumarate (8.8; 95% CI, 1.5 - 168.2; P = .05), but not with fingolimod and natalizumab.

The statistical significance for all comparisons remained unchanged after adjustment only for propensity scores.

Milder adverse events (AEs) were more common with injectable DMTs than with rituximab. Grade 1 treatment-associated AEs were more common with dimethyl fumarate, with no difference for severe grades.

AEs did not differ significantly among rituximab, fingolimod, and natalizumab. One patient treated with natalizumab developed grade 4 sepsis but  fully recovered after treatment with intravenous antibiotics.

The overall drug survival was higher in Västerbotten compared with Stockholm. Relapses were less frequent in Västerbotten, with no recorded relapses over the first year and three during the second year.

There was no significant difference between counties regarding Gd+ lesions. Fewer AEs of all grades occurred in Västerbotten than in  Stockholm.

Rituximab outperformed other drugs in all the important categories, noted Dr Piehl. "If you're an MS patient, you want a drug that's effective, that's safe and has high degree of tolerability."

Growing Evidence

The new study results "add to the growing evidence base" pointing to the superiority of rituximab compared with MS-labeled drugs, said Dr Piehl.

He and his colleagues are launching a much larger nationwide study. "It will be biggest real-world study in MS," said Dr Piehl, adding that the aim is to enroll 3700 patients and follow them for 4 years to get some idea of longer-term efficacy.

Reached for a comment, Lily Jung Henson, MD, chief of neurology, Piedmont Healthcare, Atlanta, Georgia, praised the study, calling it "really interesting."

"At the very minimum, discontinuation of rituximab compared to the other therapies was significantly lower, suggesting better efficacy, and possibly less side effects."

Dr Jung-Henson added that moving forward, she would be keen to see how rituximab fares in comparison to ocrelizumab.  

Ocrelizumab (Ocrevus, Roche), another humanized monoclonal antibody targeting CD20-positive B cells, was approved last year in the United States for treatment of relapsing and primary progressive MS treatment and, according to Dr Piehl, will likely soon be approved for this indication in Europe.

But while ocrelizumab is "biosimilar" to rituximab, it is much costlier, said Dr Piehl. "Rituximab is many many times cheaper."

Dr Jung-Henson noted that it wasn't clear from the study why there is such a disparity between the two counties with respect to the discontinuation rate. 

The study was funded by a grant from the Swedish Medical Research Council and by the Stockholm County, Karolinska Institutet, the Foundation for Clinical Neuroscience at Umeå University Hospital, and Neuroförbundet. Dr Piehl has received unrestricted academic research grants from Biogen, Genzyme, the manufacturer of alemtuzumab, and Novartis and compensation to his department for lectures and advisory boards from Biogen, Genzyme, and Novartis, which have been exclusively used for the support of research activities. Dr Jung-Henson has disclosed no relevant financial relationships.

JAMA Neurol. Published online January 8, 2018. Abstract

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