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

Systemic Lupus Erythematosus Clinical Trial

— MISSION  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03393013
• Other study ID #: KZR-616-002
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: February 20, 2018
• Est. completion date: August 4, 2022

Study information

• Verified date: March 2024
• Source: Kezar Life Sciences, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 69
• Est. completion date: August 4, 2022
• Est. primary completion date: August 4, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic
• Lupus Nephritis
• Nephritis
• Systemic Lupus Erythematosus

Intervention

Drug:
• KZR-616
Subcutaneous Injection of KZR-616

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Kezar Life Sciences, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Colombia,  Mexico,  Peru,  Poland,  Russian Federation,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Kezar Life Sciences, Inc. corporate website