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 (1^st 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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/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/