B-Cell Depleter Nabs Phase III Win in Autoimmune Kidney Disease

The B-cell depleting agent obinutuzumab (Gazyva) was superior to the immunosuppressant tacrolimus in inducing remissions in primary membranous nephropathy, the global phase III MAJESTY trial showed.

By week 104, 37% of patients in the obinutuzumab group achieved complete remission — defined as a urinary protein-to-creatinine ratio of 0.3 or lower alongside a stable estimated glomerular filtration rate (eGFR) — compared with just 6% in the tacrolimus group (P<0.001).

The monoclonal antibody also improved overall response, defined as complete or partial remission (51% vs 13%, P<0.001), reported researchers led by Fernando Fervenza, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.

“The benefit of obinutuzumab appeared to be consistent across all prespecified subgroups, including patients who were considered to be at higher risk for treatment failure,” they wrote in the New England Journal of Medicine. The findings were simultaneously presented at the European Renal Association annual congress in Glasgow.

“Primary membranous nephropathy is the most common cause of idiopathic nephrotic syndrome in adults without diabetes,” the authors noted.

While current treatment options such as RAAS blockade, immunosuppressive therapy, glucocorticoids, cytotoxic medications, and calcineurin inhibitors are often effective, they carry substantial side effects including hypertension, nephrotoxicity, infertility, and infections, Fervenza’s team explained.

Obinutuzumab, which is approved to treat chronic lymphocytic leukemia, follicular lymphoma, and lupus nephritis, is a glycoengineered type II anti-CD20 monoclonal immunoglobulin G1 antibody. It “has been associated with enhanced antibody-dependent cell-mediated cytotoxicity and phagocytosis, enhanced direct B-cell death, and less reliance on complement-dependent cytotoxicity as compared with type I anti-CD20 antibodies — features that result in more profound and durable B-cell depletion,” the researchers explained.

Another anti-B cell drug, rituximab, previously demonstrated superiority to the immunosuppressant cyclosporine for maintaining remission of proteinuria for up to 24 months in the landmark MENTOR trial, also led by Fervenza.

“Although the percentage of patients who had complete remission at 24 months with obinutuzumab in the MAJESTY trial (37%) was similar to the percentage with rituximab in the MENTOR trial (35%), cross-trial comparisons are difficult,” the authors underscored. “Unlike the MENTOR trial, this trial had strict criteria related to kidney-function stability for remission.”

“Nevertheless, it is notable that the percentage of patients with an early response was higher with obinutuzumab in this trial” — with complete remissions in 24% at 12 months versus 14% with rituximab in MENTOR — “and the peak percentage of patients who had complete remission in this trial was attained by week 76 (36%), whereas the peak in complete remission in the MENTOR trial did not occur until week 104,” the researchers added.

Fervenza and colleagues also noted that not all patients respond to rituximab, particularly those with high baseline levels of anti-PLA2R autoantibodies, underscoring the need for more effective therapies.

For MAJESTY, 142 patients across 11 countries were randomized 1:1 to receive either intravenous obinutuzumab or oral tacrolimus. About 70% of participants were men, average age was about 50 years, roughly 70% were white, while 21% and 29% of the two arms, respectively, were Asian, and 4% and 1% were Black. Previous immunosuppressive therapy had been administered in roughly 30% of patients across both arms.

The trial consisted of an open-label treatment phase, an escape treatment phase for a subgroup of participants, a long-term follow-up phase, and a safety follow-up.

Obinutuzumab was administered via IV infusion at a dose of 1,000 mg on day 1 and during weeks 2, 24, and 26. Tacrolimus was administered orally at an initial dose of 0.05 mg/kg/day, which was adjusted to maintain a target trough concentration of 5 to 7 ng/mL through week 52, followed by an 8-week taper.

Remission of proteinuria occurred in 49% of the obinutuzumab group versus 6% of the tacrolimus group. Relapse after achieving complete or partial remission occurred in only 12% of patients (six of 52) in the obinutuzumab group compared with 58% (21 of 36) in the tacrolimus group.

Average eGFR remained stable with obinutuzumab, while tacrolimus was tied to a transient reduction from baseline. A greater decrease in mean anti-PLA2R autoantibody level was also observed with obinutuzumab.

An exploratory analysis showed that among patients with high anti-PLA2R autoantibody levels at baseline, significantly more achieved immunologic remission with obinutuzumab versus tacrolimus (69% vs 13%). In this high-risk subgroup, complete remission occurred in 40% of the obinutuzumab arm without any in the tacrolimus arm.

Safety profiles were comparable between the two arms. Adverse events of grade 3 or higher occurred in 22% of the obinutuzumab group and 19% of the tacrolimus group. There were 61 and 57 infections per 100 patient-years, respectively.

Two patients on obinutuzumab and six on tacrolimus discontinued treatment due to adverse events. One patient in each trial group died while receiving escape therapy with obinutuzumab, though the deaths were deemed unrelated to the study drug.

Because of the different routes of administration, the trial was open-label. The authors noted that the 104-week follow-up was insufficient to fully characterize long-term safety and hard clinical outcomes, such as progression to end-stage kidney disease, but these endpoints will be evaluated in a 2-year extension phase.