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

Abstract

Background:KZR-616 is a first-in-class selective inhibitor of the immunoproteasome, which is active in >15 autoimmune disease models, including murine models of systemic lupus erythematosus (SLE)/lupus nephritis (LN).1,2,3 Selective inhibition of the immunoproteasome modulates both innate and adaptive immune effector cells, resulting in reduced inflammatory T helper cell subsets (Th1 and Th17), increased regulatory T cells, and decreased plasma cells and autoantibodies. KZR-616 was well tolerated in two healthy volunteer studies of 100 subjects receiving up to 75 mg subcutaneously (SC). Target levels of immunoproteasome inhibition were observed at doses ≥30 mg.3,4 KZR-616 is currently in Phase 2 studies for several autoimmune indications, including the ongoing Phase 2 portion of the MISSION Study (KZR-616-002; NCT0339013) in patients with LN.Objectives:Results of the completed MISSION Phase 1b dose escalation portion of the study are reported.Methods:In the open-label, multicenter, dose escalation Phase 1b portion, SLE patients (per SLICC Classification Criteria) with SLEDAI ≥4 despite stable background immunosuppressant, anti-malarial, and/or corticosteroid therapy were administered weekly KZR-616 subcutaneously at doses of 45 mg (cohort 1), 60 mg (cohort 2), 60 mg following step-up doses of 30 mg and 45 mg (cohort 2a), 60 mg following a step-up dose of 30 mg (cohorts 2b, 2c) or 75 mg following a step-up dose of 30 mg (cohort 3) for 13 weeks with follow-up through Week 25 (W25); a lyophilized formulation was used for cohorts 2b, 2c and 3. The disease activity measures assessed were: SLEDAI-2K, Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), 28 tender and swollen joint counts, Physician and Patient Global Assessments, and Patient Assessment of Pain. Safety and tolerability were assessed in the safety population (patients receiving at least one dose of KZR-616).Results:The Phase 1b portion of MISSION enrolled 47 SLE patients, including 2 patients with active proliferative LN. The most common treatment-emergent adverse events (TEAE) were injection site reactions, which were mostly mild. Infections occurred at a low rate, and there were no reports of peripheral neuropathy, prolonged hematologic AEs, or clinically significant laboratory abnormalities. No discontinuations were observed in cohorts 2b and 2c; no serious AEs were reported in cohort 3 and TEAEs were consistent with those reported in earlier cohorts. Mean values of all measures of disease activity improved in evaluable patients who completed the 13-week treatment period, and improvements were generally maintained at W25. All patients with elevated anti-double-stranded DNA antibody (anti-dsDNA) levels at baseline (n=7) had a reduction in levels with 3 of 7 experiencing a >50% reduction in their levels. Two of two patients with active proliferative LN had a >50% reduction in UPCR and experienced reductions in SLEDAI-2K scores as well as anti-dsDNA levels. Exposure to KZR-616, similar to that reported in healthy volunteers, was dose-proportional across doses, and no accumulation was observed.Conclusion:KZR-616 SC, once weekly for 13 weeks up to 75 mg, appears to be safe and well-tolerated in patients with active SLE on stable background therapy in the MISSION Phase 1b. At doses ≥45mg, efficacy was noted, including improvements in proteinuria in two of two patients with LN and serologic improvement in all 7 patients with quantifiable levels of anti-dsDNA antibodies at baseline. KZR-616 60 mg SC weekly for 24 weeks is currently being evaluated in the MISSION Phase 2 in patients with LN. Based on the results of MISSION, inhibition of the immunoproteasome with KZR-616 represents a novel strategy to treat autoimmune diseases.