Kezar Reports Positive Topline Results from Study in Lupus Nephritis
June 28, 2022
Kezar Life Sciences reported positive topline results from its MISSION phase 2 clinical trial evaluating zetomipzomib, a novel, first-in-class selective immunoproteasome inhibitor, in patients with active lupus nephritis.
Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE). LN is a disease comprising a spectrum of vascular, glomerular, and tubulointerstitial lesions and develops in approximately 50 percent of SLE patients within 10 years of their initial diagnosis. LN is associated with considerable morbidity, including an increased risk of end-stage renal disease requiring dialysis or renal transplantation and an increased risk of death. There are limited approved therapies for the treatment of LN. Management typically consists of induction therapy to achieve remission and long-term maintenance therapy to prevent relapse.
Zetomipzomib (KZR-616) is a novel, first-in-class, selective immunoproteasome inhibitor with broad therapeutic potential across multiple autoimmune diseases. Preclinical research demonstrates that selective immunoproteasome inhibition results in a broad anti-inflammatory response in animal models of several autoimmune diseases, while avoiding immunosuppression. Data generated from phase 1 clinical trials provide evidence that zetomipzomib exhibits a favorable safety and tolerability profile for development in severe, chronic autoimmune diseases.
The MISSION phase 2 clinical trial is an open-label study designed to demonstrate the responder rate of zetomipzomib in patients with active LN. During the 24-week treatment period, patients received 60 mg of zetomipzomib subcutaneously once weekly (first dose of 30 mg) in addition to stable background therapy. End-of-treatment (EOT) assessments occurred at Week 25, with completion of study at Week 37. Patients in the MISSION Phase 2 clinical trial received zetomipzomib without induction therapy, which represents a significant difference from other recently published trials in LN.
The primary efficacy endpoint for the trial was the proportion of patients achieving an overall renal response (ORR), measured as a 50 percent or greater reduction in urine protein to creatinine ratio (UPCR) at EOT. A key secondary efficacy endpoint was the number of patients with a complete renal response (CRR), measured as an absolute reduction in proteinuria values to a UPCR of 0.5 or less, with preserved renal function (eGFR), and corticosteroid use of 10 mg or less prednisone/prednisone equivalent and no use of prohibited medication.
In this phase 2 topline analysis, 17 of 21 patients enrolled in the trial reached end of treatment. Eleven of 17 patients (64.7 percent) achieved an ORR measured as a 50 percent or greater reduction in UPCR at EOT compared to baseline, the primary efficacy endpoint of the clinical trial. Six of 17 patients (35.2 percent) achieved a CRR of 0.5 UPCR or less, with all other protocol definitions satisfied.
Treatment benefit of zetomipzomib was maintained or deepened following the end of treatment, based on assessments at Week 29. A total of 94.1 percent of patients reached an ORR at Week 29, and six patients maintained a CRR. Mean daily prednisone background dosage was reduced from 19.2 mg at baseline to 9.1 mg at EOT and was further reduced at Week 29. Mean eGFR (estimated glomerular filtration rate) remained stable from baseline to EOT.
Zetomipzomib was well tolerated over the course of the treatment period. Adverse events were generally mild-to-moderate (Grade 1 or 2) consistent with previous reports. Most common treatment-emergent adverse events were injection site reaction, fever, headache, or nausea with or without vomiting. As previously reported, two patients experienced serious adverse events on the study. One patient had an acute protracted migraine related to zetomipzomib but completed treatment. The other patient discontinued following worsening pulmonary arterial hypertension, a urinary tract infection and an acute kidney injury, which were all deemed unrelated to zetomipzomib. Early terminations occurred in four out of 21 patients. No opportunistic or Grade 3 infections were reported in the trial.
“The MISSION phase 2 topline results show a clinically meaningful overall renal response to zetomipzomib after 6 months, without high-dose induction therapy. Patients in the trial also experienced reductions in extra-renal manifestations of lupus. Zetomipzomib appears to be immunomodulatory, well-tolerated and steroid-sparing—all important attributes for patients with autoimmune disease who are often young and active,” said Noreen Henig, Kezar’s chief medical officer. “Based on the strength of these results, we plan to continue developing zetomipzomib for patients with lupus nephritis, as well as evaluate development opportunities for systemic lupus erythematosus.”
Author: Rare Daily Staff
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