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Rituximab Tops Cyclosporine in Membranous Nephropathy

Rituximab (Rituxan) bested cyclosporine at inducing complete or partial remission of proteinuria over two years in membranous nephropathy patients at high risk for disease progression, researchers found.

In the Membranous Nephropathy Trial of Rituximab (MENTOR) study, 39 of 65 patients (60%) in the rituximab group and 13 of 65 (20%) in the cyclosporine group had complete or partial remission at 24 months (P<0.001 for both noninferiority and superiority), Fernando Fervenza, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and colleagues, reported online in the New England Journal of Medicine.

They noted that the superiority of rituximab at 24 months appeared to be driven by the significantly lower incidence of relapse in the rituximab group from months 13 to 24. At 12 months, 60% of those on rituximab and 52% of those on cyclosporine had achieved complete or partial remission (P=0.004 for noninferiority).

Additionally, 35% of rituximab-treated patients achieved complete remission at two years, compared with none of the patients in the cyclosporine group.

Earlier promising results from Fervenza’s group on the anti-CD20, B-cell-targeting monoclonal antibody were reported by MedPage Today in 2017.

In an accompanying editorial, Piero Ruggenenti, MD, of the Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, and Giuseppe Remuzzi, MD, of the Istituto di Ricerche Farmacologiche Mario Negri, both in Bergamo, Italy, lamented that two decades have passed since rituximab was first shown to induce remission of nephrotic syndrome.

“At this point, one wonders how many patients were exposed to the side effects of alkylating agents over that time,” they wrote. “Strategies that streamline clinical trials and reduce time and costs, as well as pinpoint the population of patients who are likely to benefit most, are still needed.”

Membranous nephropathy is the leading cause of nephrotic syndrome in white adults. While spontaneous remission occurs in approximately 30% of patients, end-stage renal disease develops in as many as 50% of those who continue to have nephrotic syndrome.

Since B-cell anomalies play a role in the pathogenesis of membranous nephropathy, the researchers hypothesized that B-cell depletion with rituximab might be as effective as cyclosporine for inducing and maintaining complete or partial remission of proteinuria.

The 22-center North American trial enrolled 130 membranous nephropathy patients from 2012 through 2015. Mean patient age was 52, and 77% were men. Three-quarters (74%) tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, and one patient was thrombospondin type-1 domain-containing 7A (THSD7A)–positive. Both are markers of idiopathic membranous nephropathy.

Patients were randomized to receive intravenous rituximab (two infusions 1,000 mg each, administered 14 days apart; repeated at 6 months in the case of partial response) or oral cyclosporine (starting at 3.5 mg/kg of body weight per day for 12 months).

The study’s primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Complete remission was defined as proteinuria of no more than 0.3 g per 24 hours and a serum albumin level of at least 3.5 g per deciliter, while partial remission was defined as a reduction in proteinuria of at least 50% from baseline plus final proteinuria of 0.3 g to 3.5 g per 24 hours, regardless of creatinine clearance or serum albumin level.

Among patients in remission, the decline in autoantibodies to anti-PLA2R was faster, greater, and more durable in the rituximab arm than the cyclosporine arm.

While the treatment effect of rituximab versus cyclosporine appeared consistent across subgroups by age, proteinuria, anti-PLA2R antibody status, and history of immunosuppressive therapy at baseline, a test for interaction with sex indicated a more pronounced benefit of rituximab in women than in men (P<0.001 for interaction). This was probably due to baseline imbalances in anti-PLA2R levels, Fervenza and colleagues explained.

Adverse events were comparable in both groups, at 71% and 78% in the rituximab and cyclosporine groups, respectively. Incidence of adverse events of grade 3 or higher was 52% in the rituximab group and 68% in the cyclosporine group, and the incidence of serious adverse events was 17% and 31%, respectively.

Among several study limitations, the investigators noted that owing to the cost and complexity of regimens, it was not feasible to blind patients and therapists to treatment assignments, and this could have affected treatment and assessment of disease status. In addition, they said, longer treatment or follow-up of patients whose proteinuria did not decrease by at least 25% at 6 months might eventually have increased the percentage of patients showing a response.

In their editorial, Ruggenenti and Remuzzi said the study lends support to substituting rituximab for cyclosporine in the treatment of primary membranous nephropathy.

They expressed doubt, however, that anti-CD20 antibodies will become the treatment of choice for all patients with membranous nephropathy.

“Rituximab therapy may fail in 25% to 30% of patients with nephrotic syndrome, owing to ineffective or transient depletion of nephritogenic antibodies or sensitization syndrome resembling serum sickness, which translates into resistance to treatment,” they wrote, adding that fully humanized anti-CD20 antibodies such as ofatumumab (Arzerra) may be better alternatives.

Among other innovative approaches, the editorialists noted that chimeric antigen receptor (CAR) technology could engineer T cells to express receptors containing the immunogenic domains of PLA2R and THSD7A. These could then selectively target the B-cell clones involved in the pathophysiology of the disease.

This study was funded by Genentech and the Fulk Family Foundation. Fervenza reported grants from Genentech and the Fulk Family Foundation during the conduct of the study, as well as support from Genentech, Janssen Pharmaceuticals, Mallinckrodt Pharmaceuticals, Alexion Pharmaceuticals, Alnylam Pharmaceuticals, and Ionis Pharmaceuticals outside of the submitted work. One co-author is supported by the Canadian Institutes of Health Research and several others reported various ties to private-sector companies.

Remuzzi reported personal fees and support from Alnylam, Boehringer Ingelheim, Handok, and Inception Sciences Canada outside of the submitted work.