MENTOR: Rituximab Is a Winner in Membranous Nephropathy

Pam Harrison

July 03, 2019

Rituximab (Rituxan, Genentech) should replace cyclosporine for the treatment of primary membranous nephropathy, say editorialists commenting on the results of the Membranous Nephropathy Trial of Rituximab (MENTOR) study.

Membranous nephropathy is the leading cause of nephrotic syndrome in white adults. Spontaneous remission occurs in approximately 30% of affected patients, and among patients who continue to have nephrotic syndrome, end-stage renal disease develops in 40% to 50% over a period of 10 years.

Of patients with membranous nephropathy, 70% to 80% have circulating autoantibodies to the phospholipase A2 receptor (PLA2R), and 1% to 3% have circulating antibodies to thrombospondin type-1 domain-containing 7A.

In the remaining patients, the target antigen is unknown, explain Fernando Fervenza, MD, PhD, Mayo Clinic, Rochester, Minnesota, and colleagues. The MENTOR results were published online  July 3 in the New England Journal of Medicine.

"At 24 months, 23 patients (35%) in the rituximab group and the cyclosporine group had a complete remission [and] the treatment effect of rituximab as compared with cyclosporine appeared to be consistent across subgroups defined according to age, proteinuria, anti-PLA2R antibody status, and history of immunosuppressive therapy at baseline," they write.

In an accompanying editorial, Piero Ruggenenti, MD, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy, and Giuseppe Remuzzi, MD, Istituto di Ricerche Farmacologiche Mario Negri, also in Bergamo, state, "The authors found a large difference between the rituximab group and the cyclosporine group regarding the percentage of patients with complete remission."

"This observation is one of the most important findings of the trial — indeed, it is well established that long-term prognosis in these patients seems to depend on the incidence of complete remission: patients who have complete remission at some time during the course of the disease rarely have end-stage renal disease," the editorialists stress.

MENTOR Study Details

"B-cell anomalies play a role in the pathogenesis of membranous nephropathy, [and] B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition," the researchers explain by way of background in their article.

MENTOR involved 130 patients with proteinuria levels in excess of 5 g/24 hours, on average, in 2 x 24-hour urine samples obtained within 14 days of each other.

They also had to have evidence of a decline in proteinuria of less than 50% despite having received a renin-angiotensin system (RAS) blocker for at least 3 months prior to study enrollment and a stable quantified 24-hour creatinine clearance of at least 40 mL/min/1.73m2.

All patients received best-practice supportive care. This included RAS blockers, blood pressure management targeting < 130/80 mmHg, dietary sodium restriction < 4 g/day, and dietary protein restriction to 0.8-1 g of protein/kg body weight/day during at least the previous 3 months before randomization, Fervenza and colleagues note.

Patients randomized to rituximab received 1000 mg of intravenous medication on days 1 and 15.

A second course of rituximab was given if proteinuria levels dropped by at least 25% at 6 months but patients did not achieve complete remission.

Those randomized to cyclosporine started at an oral dose of 3.5 mg/kg/day divided into two equal doses given every 12 hours. Target trough blood levels of cyclosporine ranged from 125 to 175 ng/mL.

If proteinuria was reduced by at least 25% at 6 months, cyclosporine was continued for another 6 months.

However, like rituximab, if proteinuria dropped by less than 25% at 6 months, the patient was deemed a treatment failure and cyclosporine was discontinued.

"The primary clinical outcome was the composite of complete or partial remission at 24 months," the authors explain.

Of Those on Rituximab, 60% Achieved the Primary Composite Endpoint

Specifically, at 12 months, 60% of those in the rituximab group achieved complete or partial remission compared with 52% of those in the cyclosporine group (P = .004 for noninferiority).

At 24 months, 60% of patients treated with rituximab reached the primary composite endpoint compared with 20% of those who received cyclosporine (P < .001 for both noninferiority and superiority).

Of patients in the rituximab group, 40% had failed treatment at 24 months compared with 80% in the cyclosporine group, at a hazard ratio of 0.34, the researchers observe.

Patients receiving cyclosporine tended to experience remission earlier than those who received rituximab, but those given rituximab caught up later.

The decline in proteinuria was also more pronounced in patients who achieved complete or partial remission in response to rituximab than it was for their cyclosporine counterparts.

"Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months," the researchers state.

As the authors note, blood pressure remained stable among those who received rituximab but it actually increased in those who received cyclosporine, although between-group differences in blood pressure leveled out between 18 and 24 months.

The incidence of grade 3 or higher adverse events was also slightly lower with rituximab than cyclosporine (52% vs 68%), and the incidence of serious adverse events was also lower with rituximab than cyclosporine (17% vs 31%; P = .06).

Because rituximab was given infrequently, adherence was better compared with twice-daily cyclosporine.

"The superiority of rituximab at 24 months appeared to be driven by the significantly lower incidence of relapse in the rituximab group than in the cyclosporine group during the observation period at months 13 to 24," Fervenza and colleagues note.

"And as shown in other studies involving patients who had a response to rituximab, proteinuria decline is gradual and the nadir may not be reached until 36 months after initiation of treatment," they indicate.

Treatment of Choice?

Commenting further on the study, Ruggenenti and Remuzzi point out that rituximab will probably not become the treatment of choice for all patients with membranous nephropathy as it may fail in up to 30% of patients, and other anti-CD20 antibodies such as ofatumumab may be required to induce adequate proteinuria remission.

On the other hand, the editorialists deplore the nearly 20 years it has taken since it was first shown that rituximab could induce remission of the nephrotic syndrome, during which time they wonder how many patients were exposed to the toxic side effects of alkylating agents.

"Randomized clinical trials...take years from design to completion, at times slowing clinical innovation," they write.

"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," they conclude.

The study was funded by Genentech and the Fulk Family Foundation. Fervenza has reported receiving research grants from Genentech. Remuzzi has reported receiving personal fees and nonfinancial support from Alnylam, Boehringer Ingelheim, Handok, and Inception Sciences Canada. Ruggenenti has reported no relevant financial relationships.

N Engl J Med. Published online July 3, 2019. Abstract

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