Background Zetomipzomib is a first-in-class selective inhibitor of the immunoproteasome that offers anti-inflammatory properties without significant immunosuppression.1 2
Methods The MISSION study is a Phase 1b/2, open-label study to evaluate safety, tolerability, and exploratory efficacy of zetomipzomib in patients with active systemic lupus erythematosus (SLE) ± lupus nephritis (LN). The Phase 1b portion included multiple dose escalation cohorts to evaluate the safety and tolerability of zetomipzomib in patients with SLE ± LN. The Phase 2 portion studied patients with active LN (Class III/IV ± V) to assess the efficacy and safety of zetomipzomib. Study schematics and endpoints are detailed in figure 1.
Results In the Phase 1b portion (47 patients enrolled, 35 patients completed study), zetomipzomib demonstrated a favorable safety/tolerability profile and resulted in improvement across multiple exploratory disease activity measures (table 1) and biomarkers including anti-dsDNA.3 In the Phase 2 portion (21 patients enrolled, 17 patients completed study), patients receiving 24 weeks of zetomipzomib treatment demonstrated clinically meaningful renal responses, which were maintained or increased through Week 37 (12 weeks post-treatment; end of study [EOS]); table 1. Of the 17 patients, 14 patients reduced glucocorticoids to ≤10 mg/d as early as Week 13, which was maintained through the EOS. Treatment with zetomipzomib also improved key SLE disease activity scores and serologic biomarkers including anti-dsDNA, C3/C4 (table 1). An exploratory inflammatory biomarker, urinary CD163, also decreased, and this reduction was highly correlated with UPCR reduction (R²=0.8894). The most common adverse event (AE) was injection site reaction of mild to moderate severity (Grade ≤2). No serious/opportunistic infections or immune cell depletion were reported.
Conclusions In the MISSION study, treatment with zetomipzomib in SLE/LN patients reduced proteinuria and improved biomarkers of disease activity, with lowered glucocorticoid dosing and without serious/opportunistic infections. Zetomipzomib has the potential to be a steroid-sparing immunomodulatory therapy for patients with SLE/LN.
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