A Study of Zetomipzomib (KZR-616) in Patients With Active Lupus Nephritis (PALIZADE)

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of zetomipzomib (30 mg or 60 mg) compared with placebo in achieving renal response after 52 weeks of treatment in patients with active lupus nephritis (LN).

Detailed Description
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This study aims to investigate whether zetomipzomib, added to standard of care treatment in patients with active LN, is able to reduce disease activity over a treatment period of 52 weeks. The background standard of care therapy will be mycophenolate mofetil (MMF) and initial optional treatment with IV methylprednisolone, followed by a tapering course of oral corticosteroids. Patients are required to have a diagnosis of LN according to established diagnostic criteria and clinical and biopsy features suggestive of active nephritis. Patients will be randomized in a 2:1 ratio to receive either zetomipzomib (30 mg or 60 mg) or placebo administered as a subcutaneous injection once weekly for 52 weeks, followed by a 4-week safety follow-up period. Efficacy will be assessed by measuring the level of proteinuria (as measured by urine protein to creatinine ratio [UPCR]) and estimated glomerular filtration rate (eGFR) as compared to current standard of care treatment. Safety will also be assessed throughout the study to ensure an acceptable safety profile.

Official Title
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A Phase 2b, Randomized, Controlled Double-blind, Multicenter Study Comparing the Efficacy and Safety of Zetomipzomib (KZR-616) 30 mg or 60 mg With Placebo in Patients With Active Lupus Nephritis

Conditions
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Lupus Nephritis

Intervention / Treatment
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* Drug: zetomipzomib
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Body mass index of ≥18 kg/m^2 eGFR ≥30 mL/min/1.73 m^2 Unequivocally positive ANA test result and/or a positive anti-dsDNA serum antibody test Diagnosis of LN according to 2003 or 2018 ISN/RPS criteria and confirmed by renal biopsy performed within 12 months prior to Screening. UPCR ≥1.0 (Class III/IV +/-V) or UPCR ≥2.0 (Class V) Adequate hematologic, hepatic, and renal function Key Exclusion Criteria: Current or medical history of: Central nervous system manifestations of SLE Overlapping autoimmune condition that may affect study assessments/outcomes Antiphospholipid syndrome with history of thromboembolic event of within the 52 weeks prior to Screening Thrombocytopenia or at high risk for developing clinically significant bleeding or organ dysfunction requiring therapies (i.e., plasmapheresis or acute blood or platelet transfusions Solid organ transplant or planned transplant during study Malignancy of any type, with exceptions for non-melanoma skin cancers and certain cancers >5 years ago Has received dialysis within the 52 weeks prior to Screening Positive test at Screening for HIV, hepatitis B/C Known intolerance to MMF or equivalent and corticosteroids

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: zetomipzomib 30 mg + standard-of-care<br>Initial 30 mg dose of zetomipzomib, followed by weekly doses of 30 mg zetomipzomib through 52 weeks of the treatment period. | Drug: zetomipzomib<br>* Subcutaneous injection of zetomipzomib<br>* Other names: KZR-616;|
| Experimental: zetomipzomib 60 mg + standard-of-care<br>Initial 30 mg dose of zetomipzomib, followed by weekly doses of 60 mg zetomipzomib through 52 weeks of the treatment period. | Drug: zetomipzomib<br>* Subcutaneous injection of zetomipzomib<br>* Other names: KZR-616;|
| Placebo Comparator: placebo + standard-of-care<br>Initial 30 mg dose of placebo, followed by weekly doses (30 mg or 60 mg) of placebo through 52 weeks of the treatment period. | Drug: placebo<br>* Subcutaneous injection of placebo<br>* Other names: matching placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the efficacy of zetomipzomib | Proportion of patients achieving complete renal response (CRR), defined as: A UPCR ≤0.5 in one 24-hour urine sample (for primary endpoint and Week 53) or 2 consecutive first morning void urine samples (for all other time points) An eGFR ≥60 mL/min/1.73 m^2 or no confirmed decrease of >20% from Baseline eGFR. | Baseline through Week 37 | 
| To evaluate safety of zetomipzomib | Incidence and severity of adverse event (AE)s for each treatment group and patients treated with zetomipzomib compared with placebo | Baseline through Week 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Partial Renal Remission (PRR) | Proportion of patients achieving PRR, defined as: A ≥50% reduction of UPCR from Baseline, and to <1.0 if the Baseline UPCR was <3.0 or to <3.0 if the Baseline value was ≥3.0. | Baseline through Week 25, Week 37, and Week 53 | 
| CRR | Proportion of patients achieving CRR | Baseline through Week 25 and Week 53 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunoproteasome inhibition, selective immunoproteasome inhibition, complete renal response, partial renal response, glucocorticoids, steroids, SLE (systemic lupus erythematosus, UPCR (urine protein to creatinine ratio), eGFR (estimated glomerular filtration rate)