#4210 ZETOMIPZOMIB DEMONSTRATES CLINICALLY MEANINGFUL IMPROVEMENT IN UPCR IN NEPHROTIC RANGE PROTEINURIA PATIENTS: RESULTS FROM THE OPEN-LABEL MISSION STUDY

Abstract

Abstract Background and Aims Prospective cohorts have shown that patients with LN and nephrotic range proteinuria at baseline have a lower probability of achieving renal response [1]. These patients may require more time due to slower proteinuria recovery. Results previously reported on the Phase 2, open-label MISSION study evaluating the safety and tolerability of zetomipzomib in active proliferative LN including patients with nephrotic range proteinuria, demonstrated clinically meaningful renal responses [2]. A post-hoc analysis of MISSION patients with nephrotic range proteinuria is presented here. Method In the MISSON Phase 2 study, patients with active proliferative LN (Class III or IV ± V) with 24-hour urine protein to creatinine ratios (UPCR) ≥1.0 mg/mg despite stable background therapy received 60 mg of zetomipzomib subcutaneously once weekly (first dose: 30 mg) in addition to stable background therapy for 24 weeks. End of treatment (EOT) was at Week (W) 25, and end of study (EOS) occurred at W37. The primary endpoint was the number of patients with ≥50% reduction in UPCR from baseline after 24 weeks of treatment. Nephrotic range proteinuria was defined as UPCR ≥3.0 mg/mg at baseline as per KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Results Of 17 evaluable patients who reached EOT, 4 patients had nephrotic range proteinuria, with 3 having hypoalbuminemia (serum albumin ≤3.5 g/dL) at baseline. Patients with nephrotic range proteinuria had mean LN duration of 4.14 years with mean 24-hour UPCR of 5.78 mg/mg, mean serum albumin of 3.0 g/dL, mean blood pressure of 124/81 mmHg and mean eGFR of 122.5 mL/min/1.73 m2. All 4 patients were on concomitant corticosteroids (mean dose: 19.81 mg/d), mycophenolate mofetil, hydroxychloroquine and antihypertensives. After 24 weeks of zetomipzomib treatment, 3/4 patients with nephrotic range proteinuria achieved ≥50% reduction in UPCR at W25 (EOT) and W37 (EOS, 12 weeks post-treatment) (Table 1). Serum albumin levels also improved and normalized by EOS in all 3 patients with hypoalbuminemia at baseline (Table 1). eGFR levels generally remained stable throughout the study. Reduction of daily steroid dose to 10 mg/day was observed in all 4 patients as early as W13 and at EOT/EOS while other background therapy doses remained stable throughout the study. Improvement and/or normalization in key serologic biomarkers, including anti-dsDNA and C3/C4, were also observed in patients with abnormal levels at baseline. Conclusion In this post-hoc subgroup analysis of MISSION Phase 2 study, zetomipzomib treatment demonstrated clinically meaningful improvement in UPCR and normalization of albumin levels in patients with nephrotic range proteinuria and hypoalbuminemia. These results further support the potential activity of zetomipzomib in hard-to-treat LN patients.