0992: Interim Results from the Phase 2 MISSION Study Evaluating Zetomipzomib (KZR-616), a First-in-Class Selective Immunoproteasome Inhibitor for the Treatment of Lupus Nephritis
NYU School of Medicine New York, NY, United States
Amit Saxena1, Samir Parikh2, Richard Furie3, Richard Leff4, Steven Hua4, Li Long5 and Noreen Henig4, 1NYU School of Medicine, New York, NY, 2The Ohio State University, Columbus, OH, 3Northwell Health, Great Neck, NY, 4Kezar Life Sciences, South San Francisco, CA, 5Kezar Life Sciences, Inc., South San Francisco, CA
Background/Purpose: Zetomipzomib is a first-in-class selective inhibitor of the immunoproteasome that is active in multiple autoimmune disease models, including murine models of SLE and LN. The MISSION study (NCT03393013) is a Phase 1b/2, open-label study to evaluate safety, tolerability, and preliminary efficacy of zetomipzomib in patients with SLE with ± LN. In the previously reported Phase 1b portion, zetomipzomib demonstrated a favorable safety and tolerability profile in patients with active SLE ± LN and resulted in improvement across multiple exploratory disease activity measures as well as biomarkers. Phase 2 fully enrolled in Nov 2021, and interim results from this signal-seeking study are reported here.
Methods: The MISSION Phase 2 study evaluated zetomipzomib 60 mg subcutaneously once weekly for 24 weeks (1st dose: 30 mg) in patients with active LN (Class III or IV ± Class V) with urine protein to creatinine ratio (UPCR) ≥1 despite stable background therapy with corticosteroids and at least one immunosuppressive. The primary endpoint was the number of patients with a 50% reduction in UPCR from baseline after 24 weeks of treatment. Safety, tolerability, UPCR, renal response parameters (e.g., complete renal response [CRR] and partial renal response [PRR])*, renal function, SLE disease activity and biomarkers were measured, and an interim analysis was performed. *CRR was defined as UPCR ≤0.5, eGFR ≥60 mL/min/1.73m2 or no worsening of eGFR from baseline of ≥25%, prednisone (or equivalent) ≤10 mg and no use of prohibited medication. PRR was defined as 50% reduction in UPCR and/or UPCR < 1 (if baseline UPCR < 3) and/or UPCR< 3 (if baseline UPCR ≥3), eGFR ≥60 mL/min/1.73m2 or no worsening of eGFR from baseline of ≥25% and no use of prohibited medication. CRR and PRR were calculated using absolute UPCR values.
Results: As of October 1, 2021, 10 patients had reached study week (W) 13; 80% were female with mean age 39.4 years, median LN duration 7.6 years, mean 24-hour UPCR 2.2 and mean eGFR 78.5 mL/min/1.73m2 at baseline. All 10 patients were on prednisone (or equivalent), 8 patients were also taking mycophenolate mofetil or mycophenolic acid, and 5 patients were also taking hydroxychloroquine. Five patients had reached the end of treatment visit (W25). Following 24 weeks of zetomipzomib therapy, 3 of 5 patients achieved a ≥50% reduction in UPCR; 4 of the 5 patients had renal responses (2 CRR and 2 PRR). Zetomipzomib administration improved UPCR and anti-dsDNA as early as W13 and was associated with a favorable safety and tolerability profile. The most common adverse event (AE) was injection site reaction. Most reported AEs were mild to moderate (≤Grade 2). Two Serious AEs were reported in 2 patients (1 related and 1 unrelated to treatment). There were no study discontinuations due to drug-related AEs. No opportunistic infections were reported.
Conclusion: An interim analysis of MISSION Phase 2 demonstrated that zetomipzomib added to stable background medications led to an overall renal response in 4 of the first 5 patients to complete treatment. Zetomipzomib maintained a favorable safety and tolerability profile over the six-month treatment period. The MISSION Phase 2 is fully enrolled, and an updated analysis of the completed study will be shared.
Disclosures: A. Saxena, Eli Lilly, AstraZeneca, GlaxoSmithKlein(GSK), Kezar Life Sciences, Bristol-Myers Squibb(BMS); S. Parikh, Bristol-Myers Squibb(BMS), GlaxoSmithKlein(GSK), Aurinia, Aurinia, Alexion, Kezar life sciences, NIH-NIDDK, EMD-Serono; R. Furie, AstraZeneca, Biogen; R. Leff, Kezar Life Sciences; S. Hua, Kezar Life Sciences; L. Long, Kezar Life Sciences, Inc.; N. Henig, Kezar Life Sciences.
