A Study of KZR-616 in Patients With SLE With and Without Lupus Nephritis

Study Overview
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Brief Summary
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This is a Phase 1b/2, multi-center study in which patients will receive KZR-616, administered as a subcutaneous (SC) injection weekly for 13 weeks (Phase 1b) or 24 weeks (Phase 2).

Detailed Description
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The study consists of 2 parts: Part 1, Phase 1b, is an open-label multiple dose escalation study to evaluate the safety and tolerability of KZR-616 in patients with systemic lupus erythematosus (SLE) with and without lupus nephritis. The Phase 1b part of this study fully enrolled October 2020. Part 2, Phase 2, is an open-label study to evaluate the efficacy and safety of KZR-616 in patients with active proliferative lupus nephritis (LN) to assess the number of patients with a 50% reduction in UPCR after 24 weeks of weekly SC injections with KZR-616 when compared to baseline.

Official Title
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A Phase 1b/2 Study of KZR-616 in Patients With Systemic Lupus Erythematosus With and Without Nephritis

Conditions
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Lupus Nephritis, Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: KZR-616


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: PHASE 1b (fully enrolled): Male or female patients aged 18 to 75 (inclusive) Body Mass Index (BMI) of 18-40 kg/m2 Fulfills the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE Have at least one of the following at screening per central lab: Positive antinuclear antibody (ANA) test (1:80 or higher); or Anti-double stranded deoxyribonucleic acid (dsDNA) antibodies elevated to above normal (i.e. positive results); or Anti-Smith antibody elevated to above normal (i.e., positive results) Active SLE as indicated by a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score ≥4 at screening Must have received 1 or more of the following therapies for SLE, each administered at or higher than the minimum dose indicated for at least 12 weeks (unless discontinued or dose adjusted for documented drug-related toxicity or size/weight): Hydroxychloroquine 200 mg orally daily in combination with prednisone 10 mg daily or equivalent MMF orally 1 g/day or MPA orally 720 mg/day Methotrexate orally or SC 15 mg/wk., or leflunomide orally 10 mg/day Azathioprine (AZA) 100 mg/day or 6-mercaptopurine 50 mg/day (50 or 25 mg/day, respectively, permitted in cases of documented thiopurine methyltransferase [TPMT] polymorphism) orally Cyclosporine or tacrolimus at doses documented to maintain at least 100 or 5 ng/mL during the required duration, respectively Cyclophosphamide 500 mg intravenously (IV) every 2 weeks or 500 mg/m2 IV once monthly Belimumab 10 mg/kg IV every 2 weeks for 3 doses, followed by 10 mg/kg every 4 weeks; or 200 mg SC weekly Rituximab 1 g IV (may be given as 500 mg twice) Acceptable screening laboratory values of concern, including: Adequate hematologic criteria Adequate hepatic function eGFR ≥40 mL/min/1.73 m2 IgG ≥500 mg/dL Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (hCG) pregnancy test at screening and a negative urine pregnancy test prior to the first dose Male patients must use an effective contraception method (e.g. condom with spermicide) from signing the ICF until their completion of the study PHASE 2 (enrolling): Male or female patients aged 18 to 75 years (inclusive) BMI of ≥18kg/m2 Fulfills the 2012 SLICC classification criteria for SLE At least one of the following at Screening per central lab: Positive ANA test; or Anti-dsDNA antibodies elevated to above normal; or Anti-Smith antibody at Screening elevated to above normal Active lupus nephritis with UPCR ≥1.0 measured in 24-hour urine collection Currently receiving one or more immunosuppressive agents Renal biopsy with a histologic diagnosis of LN (ISN/RPS) Classes III, IV-S or IV-G, (A) or (A/C) +/- Class V Acceptable screening laboratory values of concern, including: Adequate hematologic criteria Adequate hepatic function eGFR ≥30mL/min/1.73 m2 IgG ≥500 mg/dL Female patients of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline Male patients with a partner of childbearing potential must be either congenitally sterile or surgically sterile (by vasectomy) or willing to use a condom in addition to having their female partner use another form of contraception Key Exclusion Criteria: PHASE 1b (fully enrolled): Active central nervous system involvement by autoimmune disease requiring specific therapeutic intervention within 60 days prior to first day of study treatment. Presence of another rheumatic (overlap) disease that may confound clinical assessments in the study. History of antiphospholipid syndrome with thromboembolic event within 12 months of screening or not on an adequate anticoagulation regimen. However, presence of antiphospholipid antibodies alone (without a history of thromboembolic event) is not exclusionary. Receipt of any of the following treatments within the following timeframes before Screening Systemic corticosteroids ≥ 100 mg prednisone or equivalent: 4 weeks Intra-articular therapies, such as corticosteroids or hyaluronic acid preparations: 4 weeks Intravenous Immunoglobulin (IVIg): 4 weeks Other non-biologic immunosuppressive agents, such as cyclosporine, tacrolimus: 4 weeks Cyclophosphamide: 12 weeks Cytokine antagonists, including but not limited to interleukin (IL)-1, IL-6, IL-17, IL-12/23, IL-23, interferon (IFN), integrin, and tumor necrosis factor (TNF)-α antagonists: 12 weeks B-cell-depleting therapies (e.g., rituximab): 24 weeks with levels of circulating cluster of differentiation 19+ (CD19+) B cells within normal limits or 48 weeks if CD19+ count is not available Belimumab, abatacept, or atacicept: 12 weeks Other biologics or investigational drugs: 8 weeks or 5 half-lives, whichever is longer Transfusion with blood, packed red blood cells, platelets or treatment with plasmapheresis or plasma exchange: 6 weeks Patient has had recent serious or ongoing infection, or risk for serious infection Acute or chronic infections: Requiring systemic antibiotic, antifungal, or antiviral (antimicrobial) therapy within 14 days of Week 1, Day 1 Requiring hospitalization or a course of IV antimicrobial therapy within 24 weeks prior to screening History of severe and/or disseminated viral infections, and/or opportunistic infections Known seropositivity for or active infection by human immunodeficiency virus (HIV) Active, chronic, or resolved hepatitis B or hepatitis C infection History of progressive multifocal leukoencephalopathy Active or latent tuberculosis (TB), as suggested by chest x-ray within the 12 weeks prior to screening and/or QuantiFERON®-TB Gold at Screening Receipt of a live-attenuated vaccine within 12 weeks of first day of study treatment (Week 1, Day 1) Primary immunodeficiency (unless otherwise considered, in the opinion of the investigator and medical monitor, to confer a clinically insignificant infection risk, such as deficiency in immunoglobulin A (IgA), C1q, C2, or C4 without a history of recurrent infections [3 or more infections in 1 year requiring antimicrobial therapy]) History of any concurrent illness that has required treatment with oral or parenteral corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to signing the ICF Clinical evidence of significant unstable or uncontrolled acute or chronic diseases History of cancer, except for in situ cancer that has been completely excised or has been curatively treated cancer with no sign of disease for > 5 years Major surgery within 4 weeks before signing the ICF or major surgery planned during the study period PHASE 2 (enrolling): Any of the following: dialysis within 12 months prior to screening, rapidly progressive glomerulonephritis (RPGN), chronic kidney disease not due to lupus nephritis, >50% sclerosed glomeruli on most recent renal biopsy Presence of another rheumatic (overlap) disease that may confound clinical assessments in the study. Secondary sicca or Sjogren's syndrome and antiphospholipid antibody syndrome are allowed History of antiphospholipid syndrome with history of thromboembolic event within 12 months of screening Active central nervous system involvement by autoimmune disease requiring specific therapeutic intervention within 60 days prior to first day of study treatment. Active or chronic infection Patient has or had any of the following: Progressive multifocal leukoencephalopathy Active or untreated latent TB, per QuantiFERON-TB Gold at Screening Receipt of a live-attenuated vaccine within 12 weeks of Baseline (Week 1, Day 1) Primary immunodeficiency (unless otherwise considered, in the opinion of the investigator and medical monitor, to confer a clinically insignificant infection risk, such as deficiency in IgA, C1q, C2, or C4 without a history of recurrent infections [3 or more infections in 1 year requiring antimicrobial therapy]) Primary hematopoietic cell or solid organ transplant Any active or suspected malignancy or history of documented malignancy within the last 5 years before Screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KZR-616 60 mg + standard therapy (Phase 2)<br>60 mg dose level of KZR-616 selected based on data from the Phase 1 dose escalation and administered to patients with active Lupus Nephritis in combination with standard therapy. | Drug: KZR-616<br>* Subcutaneous Injection of KZR-616<br>* Other names: KZR-616 Lyophile;|
| Experimental: KZR-616 45 mg + standard of care therapy (Phase 1b)<br>Dose escalation cohort of patients with SLE with and without nephritis to receive 45 mg dose level of KZR-616 in combination with standard of care therapy. This arm is fully enrolled and complete. | Drug: KZR-616<br>* Subcutaneous Injection of KZR-616<br>* Other names: KZR-616 Lyophile;|
| Experimental: KZR-616 60 mg + standard of care therapy (Phase 1b)<br>Dose escalation cohort of patients with SLE with and without nephritis to receive 60 mg dose level of KZR-616 in combination with standard of care therapy. This arm is fully enrolled and complete. | Drug: KZR-616<br>* Subcutaneous Injection of KZR-616<br>* Other names: KZR-616 Lyophile;|
| Experimental: KZR-616 75 mg + standard of care therapy (Phase 1b)<br>Dose escalation cohort of patients with SLE with and without nephritis to receive 75 mg dose level of KZR-616 in combination with standard of care therapy. This arm is fully enrolled and complete. | Drug: KZR-616<br>* Subcutaneous Injection of KZR-616<br>* Other names: KZR-616 Lyophile;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: To evaluate the safety and tolerability of KZR-616 | To evaluate the safety and tolerability of KZR-616 when administered as a SC injection weekly for 13 weeks in adult patients with SLE with and without lupus nephritis | Baseline through 25 weeks | 
| Phase 2: To assess the number of patients with lupus nephritis with a 50% reduction in UPCR | To assess the number of patients with lupus nephritis with a 50% reduction in UPCR after 24 weeks of weekly SC injections with KZR-616 when compared to baseline | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Identify Recommended Phase 2 dose levels (RP2Ds) of KZR-616 | Determined through assessment of all AEs and any dose limiting toxicities (DLTs) | 4 weeks | 
| Phase 1b: To characterize the PK of KZR-616 | To characterize the pharmacokinetics of KZR-616 | Day 1 | 
| Phase 2: To evaluate the safety and tolerability of KZR-616 when administered as a SC injection weekly for 24 weeks | Determined through assessment of all AEs | 37 weeks | 
| Phase 2: To characterize the efficacy of KZR-616 on parameters of renal function when administered as a SC injection weekly for 24 weeks | Determined through assessment of UPCR after 24 weeks when compared to baseline | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunoproteasome inhibition, selective proteasome inhibition, proteasome, lupus nephritis, lupus, nephritis, active proliferative lupus nephritis, open-label, systemic lupus erythematosus, lupus erythematosus