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

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

This was a Phase 1b/2, multi-center study in which patients received KZR-616, administered as a subcutaneous (SC) injection weekly for 13 weeks (Phase 1b) or 24 weeks (Phase 2).

Study Overview

• Status: Completed
• Conditions: Systemic Lupus Erythematosus; Lupus Nephritis
• Intervention / Treatment: Drug: KZR-616

Detailed Description

This was a Phase 1b/2, open-label, multi-center study in which patients received zetomipzomib administered as a SC injection weekly for either 13 weeks (Phase 1b) or for 24 weeks (Phase 2). In both phases, safety assessments continued for up to 12 weeks following the last dose of zetomipzomib.

Phase 1b was an open-label, multiple dose escalation study designed to evaluate the safety and tolerability of escalating doses of zetomipzomib when administered in addition to standard-of-care therapy in patients with SLE with or without nephritis. For each cohort, at least 6 patients were to be enrolled to assure the availability of at least 4 evaluable patients. Decisions to escalate, expand, or decrease the dose level or dosing frequency following the first 4 weeks of dosing for at least 4 evaluable patients in a cohort were made following review by a data monitoring committee (DMC).

The zetomipzomib formulations and doses administered by cohort in Phase 1b were:

• Cohort 1: zetomipzomib frozen maleate, 45 mg weekly × 13 weeks
• Cohort 2: zetomipzomib frozen maleate, 60 mg weekly × 13 weeks
• Cohort 2a: zetomipzomib frozen maleate, 30 mg weekly × 2 weeks, followed by 45 mg weekly × 2 weeks, followed by 60 mg weekly × 9 weeks
• Cohort 2b: zetomipzomib lyophile, 30 mg weekly × 1 week, followed by 60 mg weekly × 12 weeks
• Cohort 2c: zetomipzomib lyophile, 30 mg weekly × 1 week, followed by 60 mg weekly × 12 weeks (tolerability strategies cohort)
• Cohort 3: zetomipzomib lyophile, 30 mg weekly × 1 week, followed by 75 mg weekly × 12 weeks

The Phase 2 portion of the open-label study was designed to evaluate the renal response, safety, and tolerability of a single dose level (60 mg) of zetomipzomib administered weekly in addition to standard therapy in patients with active proliferative lupus nephritis (LN) (Class III or IV, with or without Class V disease) with a UPCR ≥1.0. Patients must have been on standard therapy for LN including at least 1 immunosuppressive agent. Zetomipzomib was administered as a SC injection weekly for 24 weeks (including a step up from an initial Week 1 dose of 30 mg).

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health
    • Parkville, Victoria, Australia, 3050
      • The Royal Melbourne Hospital
• Colombia
  • Atlantico
    • Barranquilla, Atlantico, Colombia, 080020
      • Clinica de la Costa
    • Barranquilla, Atlantico, Colombia, 080020
      • Centro Integral de Reumatologia de Caribe CIRCARIBE S.A.S
  • Bucaramanga
    • Santander, Bucaramanga, Colombia, 680003
      • Medicity SAS
  • Santander
    • Bucaramanga, Santander, Colombia, 680003
      • Servimed S.A.S.
  • Valle Del Cauca
    • Cali, Valle Del Cauca, Colombia, 076001
      • Clinica de Artritis Temprana
• Mexico
  • Mexico City, Mexico, 14080
    • Instituto Nacional de Cardiologia Ignacio Chavez
  • Mexico City, Mexico, 14080
    • Instituto Nacional de Ciencias Médicas y Nutricion "Salvador Zubiran"
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44160
      • Centro Integral de Reumatologia SA de CV
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64020
      • Hospital Universitario Dr Jose Eleuterio Gonzalez
• Peru
  • Lima, Peru, 15023
    • Investigaciones Clinicas SAC
  • Lima, Peru, 15431
    • Unidad de Investigacion en Reumatologia e Inmunologia Clinica San Juan Bautista
  • La Libertad
    • Trujillo, La Libertad, Peru, 13011
      • Centro de Investigación Clínica Trujillo E.I.R.L/ Clínica Peruano Americana S.A.
• Poland
  • Łódź, Poland, 90-368
    • Bioclinica
• Russian Federation
  • Kemerovo, Russian Federation, 650070
    • Medical Center Revma-Med
  • Kemerovo, Russian Federation, 650066
    • Kuzbass Clinical Hospital
  • Togliatti, Russian Federation, 445009
    • Tolyatti City Clinical Hospital #1
• Ukraine
  • Kyiv Governorate
    • Kyiv, Kyiv Governorate, Ukraine, 01135
      • Harmoniya Krasy
• United States
  • California
    • Los Angeles, California, United States, 990022
      • Academic Medical Research Institute
    • Upland, California, United States, 91786
      • Inland Rheumatology Clinical Trials, Inc.
  • Florida
    • Miami, Florida, United States, 33165
      • Hope Clinical Trials, Inc.
    • Miami, Florida, United States, 33136
      • SouthCoast Research Center, Inc.
    • Orlando, Florida, United States, 32808
      • Omega Research Maitland
    • Palm Harbor, Florida, United States, 34684
      • Arthritis Center, Inc
    • Tampa, Florida, United States, 33614
      • Advent Health Medical Group
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • New York
    • Great Neck, New York, United States, 11021
      • Northwell Health
    • New York, New York, United States, 10016
      • NYU Langone Orthopedic Center - Seligman Center for Advanced Therapeutics
    • Rochester, New York, United States, 14620
      • University of Rochester Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
  • South Carolina
    • Orangeburg, South Carolina, United States, 29118
      • SC Nephrology & Hypertension Center, Inc.
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Ramesh C. Gupta, MD
  • Texas
    • El Paso, Texas, United States, 79902
      • MedResearch, Inc.
    • Houston, Texas, United States, 77084
      • Accurate Clinical Management, LLC
    • Houston, Texas, United States, 77034
      • Accurate Clinical Research, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

Phase 1b:

• Fulfilled the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification for SLE
• Had a positive antinuclear antibody (ANA) titer, anti-double stranded DNA (dsDNA) antibody titer, or a positive anti-Smith antibody titer
• Had active SLE (as indicated by Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] score ≥4), and
• Had received at least 1 prior therapy for SLE

Phase 2:

• Had active proliferative LN (Class III or IV, with or without Class V disease)
• Had a UPCR ≥1.0 measured in 24-hour urine collection
• Had a histologic diagnosis of LN on renal biopsy within the prior 2 years; for biopsies > 1 year before the Screening visit, one of the following must also be present at screening: low C3, low C4, or anti-ds-DNA elevated to above normal range
• Fulfilled the 2012 SLICC classification for SLE
• Had a positive ANA titer, anti-dsDNA antibody titer, or anti-Smith antibody titer, and
• Were currently receiving ≥1 immunosuppressive agent at a stable dose and route of administration for ≥8 weeks. If the patient is also on corticosteroids then must be on a stable dose for ≥ 2 weeks prior to Baseline

Key Exclusion Criteria:

Phase 1b:

• Current or medical history of:

  • Central nervous system manifestations by autoimmune disease
  • Overlapping autoimmune condition that may affect study assessments/outcomes
  • Antiphospholipid syndrome with history of thromboembolic event of within the 52 weeks prior to Screening
  • Malignancy of any type, with exceptions for in situ cancer that has been completely excised and certain cancers >5 years ago
• Positive test at Screening for HIV, hepatitis B/C
• Major surgery within 4 weeks before signing informed consent form or planned major surgery during the study period

Phase 2:

• 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
  • Malignancy of any type within the last 5 years, with exceptions for appropriately excised and cured cervical carcinoma in situ or excised basal or squamous cell carcinomas of the skin
• Has received dialysis within the 52 weeks prior to Screening
• Positive test at Screening for HIV, hepatitis B/C
• Major surgery within 12 weeks before signing informed consent form or planned major surgery during the study period
• Use of investigational therapy or device, and/or participation in an investigational trial <8 weeks or 5 half-lives, whichever is longer, prior to Baseline; Patients who participated in Phase 1b of KZR-616-002 are excluded from Phase 2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: KZR-616 45 mg + standard of care therapy (Phase 1b); 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. Two Phase 1b cohorts received 45 mg at some point during the study. Cohort 1 received 45 mg zetomipzomib frozen maleate weekly for 13 weeks. Cohort 2a followed a step-up dosing procedure. Patients received zetomipzomib frozen maleate, 30 mg weekly for 2 weeks, followed by 45 mg weekly for 2 weeks then followed by 60 mg weekly for 9 weeks. KZR-616 was administered as a SC injection.	Drug: KZR-616; Subcutaneous Injection of KZR-616; Other Names: zetomipzomib
Experimental: KZR-616 60 mg + standard of care therapy (Phase 1b); 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. Four Phase 1b cohorts received 60 mg at some point during the study. Cohort 2 received 60 mg zetomipzomib frozen maleate weekly for 13 weeks. Cohorts 2a, 2b, and 2c all followed a step-up dosing procedure. Patients in Cohort 2a received zetomipzomib frozen maleate, 30 mg weekly for 2 weeks, followed by 45 mg weekly for 2 weeks then followed by 60 mg weekly for 9 weeks. Patients in Cohort 2b received zetomipzomib lyophile, 30 mg weekly for 1 week, followed by 60 mg weekly for 12 weeks. Patients in Cohort 2c (tolerability strategies cohort) received zetomipzomib lyophile, 30 mg weekly for 1 week, followed by 60 mg weekly for 12 weeks. KZR-616 was administered as a SC injection.	Drug: KZR-616; Subcutaneous Injection of KZR-616; Other Names: zetomipzomib
Experimental: KZR-616 75 mg + standard of care therapy (Phase 1b); 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. One Phase 1b cohort received 75 mg at some point during the study. Cohort 3 followed a step-up dosing procedure. Patients in Cohort 3 received zetomipzomib lyophile, 30 mg weekly for 1 week, followed by 75 mg weekly for 12 weeks. KZR-616 was administered as a SC injection.	Drug: KZR-616; Subcutaneous Injection of KZR-616; Other Names: zetomipzomib
Experimental: KZR-616 60 mg + standard therapy (Phase 2); 60 mg dose level of KZR-616 selected based on data from the phase 1b dose escalation and administered to patients with active lupus nephritis in combination with standard therapy including at least one immunosuppressive agent. KZR-616 was administered as a SC injection weekly at a dose of 60 mg for 24 weeks (including a step-up from an initial Week 1 dose of 30 mg). ** See Limitations/Caveats for additional information	Drug: KZR-616; Subcutaneous Injection of KZR-616; Other Names: zetomipzomib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: Number of Patients Who Experienced at Least One Treatment-Related Treatment-Emergent Adverse Event	The safety and tolerability of zetomipzomib (KZR-616) when administered as a subcutaneous injection weekly for 13 weeks in adult patients with systemic lupus erythematous (SLE) with and without nephritis, as assessed by number of patients who experienced at least one treatment-related treatment-emergent adverse event. For additional information about the safety and tolerability of KZR-616, please reference the adverse events section of this posting.	25 weeks
Phase 2: 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: PK of KZR-616 (Cmax)	This is the maximum observed plasma concentration (Cmax) observed after administration of KZR-616 at Week 5. The PK parameters were calculated using all timepoints at which the concentration was measured, ie. predose and 5, 15, 30 minutes, 1, 2, 4, and 8 hours postdose.	8 hours
Phase 1b: PK of KZR-616 (Tmax)	This is the time to maximum observed plasma concentration (tmax) observed after administration of KZR-616 at Week 5. The PK parameters were calculated using all timepoints at which the concentration was measured, ie. predose and 5, 15, 30 minutes, 1, 2, 4, and 8 hours postdose.	8 hours
Phase 1b: PK of KZR-616 (AUC)	This is the area under the curve (AUC) from predose through 8 hour postdose observed after administration of KZR-616 at Week 5. The PK parameters were calculated using all timepoints at which the concentration was measured, ie. predose and 5, 15, 30 minutes, 1, 2, 4, and 8 hours postdose.	8 hours
Phase 2: Number of Patients With a Partial Renal Response	Number of patients with a partial renal response (PRR) after 24 weeks of treatment, as defined by: For this outcome measure, Primary UPCR criterion was used (a 50% reduction of UPCR and reduction of UPCR to <1.0 if baseline UPCR was <3.0 (or reduction of UPCR to <3.0 if baseline was ≥3.0)); eGFR of greater than or equal to 60 mL/min/1.73 m^2 or no worsening of eGFR from baseline of greater than or equal to 25%; No use of prohibited medication Count of patients below includes those who satisfy all three of the above criteria.	24 weeks
Phase 2: Safety and Tolerability of KZR-616 When Administered as a SC Injection Weekly for 24 Weeks	Exposure adjusted adverse event incidence rate for Injection Site Reactions and Systemic Injection Reactions. For additional information about the safety and tolerability of KZR-616, please reference the adverse events section of this posting.	37 weeks
Phase 1b: Recommended Phase 2 Doses of Zetomipzomib When Administered as a Subcutaneous Injection	The safety data from Phase 1b were used to determine a recommended dose of zetomipzomib to administer to patients with active proliferative lupus nephritis in Phase 2 of this study. As pre-specified in the study protocol, this outcome measure was to be determined qualitatively through discussion of relevant information from the Phase 1b portion of the trial at a data monitoring committee meeting.	25 weeks

Collaborators and Investigators

• Sponsor: Kezar Life Sciences, Inc.
• Investigators: Study Director: Kezar, Kezar Life Sciences, Inc.

Publications and helpful links

Helpful Links

• Kezar Life Sciences, Inc. corporate website

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2018
• Primary Completion (Actual): August 4, 2022
• Study Completion (Actual): August 4, 2022

Study Registration Dates

• First Submitted: December 21, 2017
• First Submitted That Met QC Criteria: January 4, 2018
• First Posted (Actual): January 8, 2018

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 7, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: systemic lupus erythematosus; open-label; lupus nephritis; lupus; nephritis; proteasome; lupus erythematosus; immunoproteasome inhibition; selective proteasome inhibition; active proliferative lupus nephritis
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Connective Tissue Diseases; Glomerulonephritis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Lupus Erythematosus, Systemic; Nephritis; Lupus Nephritis
• Other Study ID Numbers: KZR-616-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No