Ongoing Study Examines Bruton Tyrosine Kinase Inhibitor (Zanubrutinib) as Therapy for Primary Membranous Nephropathy

Currently, there are no approved therapies for primary membranous nephropathy, but an ongoing study examines bruton tyrosine kinase as a potential therapeutic target.

The study was presented on November 2, 2023, at American Society of Nephrology’s Kidney Week at the Pennsylvania Convention Center. Led by Richard Lafayette, MD, FACP from Stanford University Medical Center in California, the trial has yet to reach any findings.

Primary membranous happens when the B cells produce pathogenic autoantibodies against M-type phospholipase A2 receptor (PlA2R) antibodies on podocytes, specialized cells of the kidney glomerulus. To avoid primary membranous nephropathy, the bruton tyrosine kinase inhibitor—specifically zanubrutinib—interferes with the B-cell receptor signaling pathway and could potentially serve as a therapeutic target.

“Zanubrutinib is a next-generation [bruton tyrosine kinase] inhibitor aimed to maximize [bruton tyrosine kinase] occupancy and minimize off-target effects,” the investigators wrote.

The Food and Drug Administration (FDA) had previously approved zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. Ian W. Flinn, MD, PhD, of the Sarah Cannon Research Institute at Tennessee Oncology told HCPLive this past January what zanubrutinib treatment was like—at least for patients with leukemia.

“Patients get that therapy for about a year, and then they can come off,” Flinn said. “They only have to stay on it for about a year because they get very deep remissions. It's a little bit of pain to give that therapy because it’s very intensive.”

Though, it is still up in the air how the treatment for patients with Primary Membranous Nephropathy will go. The 2-part, multicenter, phase 2/3 ALMOND trial currently evaluates zanubrutinib in adults aged 18-75 years old with a confirmed primary membranous nephropathy diagnosis through biopsy. The investigators designed part 1 as an open-label, single-arm, evaluating the efficacy and safety of zanubrutinib 160 mg two times a day for 64 weeks in 30 patients. The primary outcome was reduction in urine protein: creatinine ratio.

To be eligible for part 1 of the study, patients had to have a urine protein: creatinine ratio of > 3.5 based on 24 hours, as well as treatment with a tolerated dose of either an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker for > 24 weeks. Patients also needed to have adequate blood pressure control, and M-type phospholipase A2 receptor antibodies needed to be > 50 Ru/mL at the screening confirmation assessment.

Meanwhile part 2 was designed as a randomized, open-label, 3-arm with an active-control, evaluating zanubrutinib 160 mg two times a day, zanubrutinib 160 mg per day, or tacrolimus 0.05 kg per day for 64 weeks in 252 patients. The trial included 84 patients participated in each arm. The outcome was to evaluate the number of patients achieving complete remission.

Secondary outcomes of the study include safety, patients with treatment failure, immunological response, complete or partial remission, and relapse. Specifically for part 2, secondary outcomes include the time to complete remission or partial remission, time to first relapse, patients with > 30% estimated glomerular filtration rate reduction, and health-related quality of life assessments.

References

1. ^{Lafayette, R, Barbour, S, Chen, Y, et al. A Phase 2/3, Multicenter, Randomized, Active-Controlled, Open-Label Study to Evaluate the Efficacy and Safety of Zanubrutinib in Patients with Primary Membranous Nephropathy. American Society of Nephrology. November 2, 2023. https://www.asn-online.org/education/kidneyweek/2023/program-abstract.aspx?controlId=3962963. Accessed November 16, 2023.}
2. ^{Grossi, G. Ian Flinn, MD, PhD: Bruton's Tyrosine Kinase Therapy Offers Fewer Adverse Events for CLL, SLL. HCPLive. https://www.hcplive.com/view/ian-flinn-md-phd-bruton-s-tyrosine-kinase-therapy-offers-fewer-adverse-events-for-cll-sll. Accessed November 16, 2023.}