Background/Purpose: Immunoproteasome inhibition has demonstrated meaningful therapeutic potential in preclinical models of systemic lupus erythematosus (SLE) and lupus nephritis (LN). KZR-616 is a first-in-class selective immunoproteasome inhibitor, which has been shown to have a favorable safety and tolerability profile in early clinical trials.  Across 2 healthy volunteer studies, 100 subjects received KZR-616, up to 75 mg subcutaneously (SC), with target levels of immunoproteasome inhibition achieved with doses ≥30 mg. Here we report updated safety, tolerability and exploratory efficacy data from the Phase 1b portion of MISSION (KZR-616-002; NCT: NCT03393013) in which patients with active SLE or LN were treated with KZR-616.

Methods: SLE patients (per Systemic Lupus International Collaboration Criteria [SLICC] Classification Criteria) with SLEDAI ≥4 despite stable background therapy were enrolled in this open-label dose-escalation study and received KZR-616 at doses of 45 mg (Cohort 1), 60 mg (Cohort 2), 60 mg following a step-up dose (Cohorts 2a, 2b, 2c), or 75 mg (Cohort 3) SC weekly through Week 13 (W13) with 12 weeks of follow-up. Safety, tolerability, PK and PD and early efficacy measures were collected.

Results: Through Cohort 2c, 41 patients with SLE, including 2 patients with active, biopsy-proven proliferative LN, have enrolled in the MISSION Phase 1b study. The majority of TEAEs have been mild or moderate with transient injection-site reactions as the most common TEAE.  Improved tolerability was seen with a dose step-up strategy, use of the lyophilized formulation, subsequent doses, and use of pre-medications. To date, no patients have discontinued from later cohorts. All measures of disease activity (SLEDAI, Cutaneous Lupus Erythematosus Disease Area and Severity Index [CLASI], Tender and Swollen Joint Counts using 28 joints, Physician Global Assessment [PhGA], Patient Global Assessment [PtGA], and Patient Assessment of Pain [PtP]) improved from Baseline to W13 and were maintained or improved during the follow-up period compared to baseline. KZR-616 administration resulted in improvements in multiple serologic markers of disease activity as well as reduced expression of inflammatory gene expression modules. Both patients with active proliferative LN showed greater than 50% reductions in urine protein:creatinine ratios (UPCR) from baseline. 

Conclusion: KZR-616 demonstrated a favorable safety and tolerability profile at target doses of 45 and 60 mg weekly for 13 weeks. Step-up dosing, use of the lyophilized formulation, subsequent doses, and use of select pre-medications increased tolerability. KZR-616 demonstrated early signals of efficacy as evidenced by improvement in multiple disease activity and serologic markers, including reduction in proteinuria in 2 of 2 patients with LN. Weekly administration of 75 mg is currently being evaluated in Cohort 3, and a Phase 2 study of KZR-616 in active proliferative LN is open for enrollment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/treatment-of-sle-with-or-without-nephritis-with-the-immunoproteasome-inhibitor-kzr-616-updated-results-of-the-mission-study/