Zetomipzomib Reduces Proteinuria in Proliferative Lupus Nephritis

The investigators found no evidence of immunosuppression with zetomipzomib, such as immune cell depletion or infection.

Zetomipzomib, an investigational selective inhibitor of the immunoproteasome, reduces proteinuria in patients with lupus nephritis, across all proliferative classes, according to the findings of a small trial presented at the National Kidney Foundation’s 2023 Spring Clinical Meetings in Austin, Texas.

In the MISSION phase 2 trial, patients with lupus nephritis class 3 or 4 with or without class 5 received 60 mg zetomipzomib subcutaneously once weekly for 24 weeks. At baseline, patients’ urinary protein to creatinine ratio (UPCR) was 1.0 mg/mg despite stable background therapy. All patients were taking corticosteroids (mean dose 18.8 mg/d), 95.2% mycophenolate mofetil or mycophenolic acid, 66.7% hydroxychloroquine, and 9.5% azathioprine.

Overall renal response at week 25 occurred in 11 of the 17 treated patients (64.7%), including half or more patients in each biopsy class, Samir V. Parikh, MD, of The Ohio State University Wexner Medical Center in Columbus, and colleagues reported in a post hoc analysis. Overall response was defined as a 50% or greater reduction in UPCR. Complete renal response at 25 weeks occurred in 6 patients (35.3%). No one with mixed class lupus nephritis achieved complete response at 25 weeks, but 1 patient achieved it at 33 weeks. Complete renal response was defined as UPCR 0.5 or less, an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m2 or no eGFR decline greater than 25%, daily steroid use of 10 mg or less and no use of prohibited medication.

The mean eGFR was 104.7 mL/min/1.73 m2 at baseline. Kidney function remained stable over the 37 weeks of the study, Dr Parikh’s team reported.

At weeks 25 and 37, most patients (82.4% and 76.5%, respectively) achieved a daily corticosteroid dose of 10 mg or less. The investigators also observed improvements in key serologic biomarkers, including anti-double stranded DNA, C3, and C4. Urinary CD163, a marker of inflammation, decreased with zetomipzomib in 13 patients with pure class 3 or 4 lupus nephritis. Patients with mixed lupus nephritis declined urine biomarker analysis.

The investigators found no evidence of immunosuppression with zetomipzomib, such as immune cell depletion or infection.

Zetomipzomib has the potential to be a steroid-sparing immunomodulatory treatment for profilerative lupus nephritis, according to Dr Parikh’s team. The placebo-controlled phase 2b PALIZADE trial is underway to further assess the efficacy and safety of zetomipzomib.

Disclosure: This research was supported by Kezar Life Sciences. Please see the original reference for a full list of disclosures.

This article originally appeared on Renal and Urology News


Parikh SV, Saxena A, Leff R, Li E, Park E, Henig NR. Zetomipzomib is associated with clinically meaningful reduction of proteinuria in LN class III/IV with or without class V: post-hoc analysis from the open-label MISSION phase 2 study. Presented at: NKF 2023, Austin, Texas, April 11-15. Poster 331.