POS0695 KZR-616, A SELECTIVE IMMUNOPROTEASOME INHIBITOR FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS FROM THE COMPLETED DOSE ESCALATION PHASE 1B PORTION OF THE MISSION STUDY

Background: KZR-616 is a first-in-class selective inhibitor of the immunoproteasome, which active in >15 autoimmune disease models, including murine models systemic lupus erythematosus (SLE)/lupus nephritis (LN). 1,2,3 Selective inhibition immunoproteasome modulates both innate and adaptive immune effector cells, resulting reduced inflammatory T helper cell subsets (Th1 Th17), increased regulatory decreased plasma cells autoantibodies. was well tolerated two healthy volunteer studies 100 subjects receiving up to 75 mg subcutaneously (SC). Target levels were observed at doses ≥30 mg. 3,4 currently Phase 2 for several indications, ongoing portion MISSION Study (KZR-616-002; NCT0339013) patients with LN. Objectives: Results completed 1b dose escalation study are reported. Methods: In open-label, multicenter, portion, SLE (per SLICC Classification Criteria) SLEDAI ≥4 despite stable background immunosuppressant, anti-malarial, and/or corticosteroid therapy administered weekly 45 (cohort 1), 60 2), following step-up 30 2a), (cohorts 2b, 2c) or 3) 13 weeks follow-up through Week 25 (W25); lyophilized formulation used cohorts 2c 3. The activity measures assessed were: SLEDAI-2K, Cutaneous Lupus Erythematosus Disease Area Severity Index (CLASI), 28 tender swollen joint counts, Physician Patient Global Assessments, Assessment Pain. Safety tolerability safety population (patients least one KZR-616). Results: enrolled 47 patients, proliferative most common treatment-emergent adverse events (TEAE) injection site reactions, mostly mild. Infections occurred low rate, there no reports peripheral neuropathy, prolonged hematologic AEs, clinically significant laboratory abnormalities. No discontinuations 2b 2c; serious AEs reported cohort 3 TEAEs consistent those earlier cohorts. Mean values all improved evaluable who 13-week treatment period, improvements generally maintained W25. All elevated anti-double-stranded DNA antibody (anti-dsDNA) baseline (n=7) had reduction 7 experiencing >50% their levels. Two LN UPCR experienced reductions SLEDAI-2K scores as anti-dsDNA Exposure KZR-616, similar that volunteers, dose-proportional across doses, accumulation observed. Conclusion: SC, once mg, appears be safe well-tolerated on 1b. At ≥45mg, efficacy noted, proteinuria serologic improvement quantifiable antibodies baseline. SC 24 being evaluated Based results MISSION, represents novel strategy treat diseases. References: [1]Basler M et al. Clin Exp Rheumatol 2015 (suppl 92);S74. [2]Muchamuel Ann Dis 2018;77(suppl 2);685. [3]Muchamuel ASN 2020 Virtual Conference. [4]Snyder B ACR/ARP 2019 Annual Meeting. [5]Fan RA Acknowledgements: Kezar Life Sciences acknowledges support investigators patient participants Disclosure Interests: Richard Furie Consultant of: Genentech;Kezar Sciences, Grant/research from: SV Parikh Aurinia Pharmaceuticals, BMS, GlaxoSmithKline, Pharmaceuticals;EMD-Serono, Jinhai Wang Shareholder Employee Darrin Bomba Leff [part-time], Christopher Kirk -- full-time employee, Noreen Henig