A Phase 2 Study of KZR-616 to Evaluate Safety and Efficacy in Patients With Active Polymyositis or Dermatomyositis

Phase 2

Completed

• Conditions: Polymyositis; Dermatomyositis
• Interventions: Drug: KZR-616; Drug: Placebo

• Registration Number: NCT04033926
• Lead Sponsor: Kezar Life Sciences, Inc.

Brief Summary

This was a Phase 2 randomized, double-blind, placebo-controlled, crossover, multicenter study to evaluate the safety, tolerability, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of treatment with KZR-616 in patients with active polymyositis (PM) or dermatomyositis (DM). Patients were evaluated for eligibility during the Screening Period. Eligible patients were stratified by diagnosis of DM or PM and randomized 1:1 to Arm A or Arm B of the study.

During the 32-week treatment period, patients received study drug subcutaneously (SC) once weekly with 2 treatment periods of 16 weeks each.

This study was conducted on an outpatient basis.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-07-23
• Study First Submitted QC: 2019-07-24
• Study First Posted: 2019-07-26
• Study Start: 2020-01-14
• Primary Completion: 2022-04-06
• Study Completion: 2022-04-06
• Results First Submitted: 2023-11-21
• Status Verified: 2023-12
• Results First Submitted QC: 2023-12-14
• Last Update Submitted: 2023-12-14
• Results First Posted: 2024-01-03
• Last Update Posted: 2024-01-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

1. Adult patients at least 18 years of age

2. Body Mass Index (BMI) of 18 to 40 kg/m^2

3. Diagnosis of probable or definite DM or PM by the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) Classification Criteria

4. Must have their data reviewed by an adjudication committee to confirm eligibility unless at least 1 of the following is present:

   1. Muscle biopsy with evidence of active myositis within the last 6 months prior to or at Screening
   2. Electromyography or magnetic resonance imaging with evidence of active myositis within the last 6 months prior to Screening
   3. A creatine kinase (CK) ≥4 × upper limit of normal (ULN).

5. Must have demonstrable muscle weakness as measured by the Manual Muscle Testing-8 muscle Groups (MMT-8) with a score ≥80/150 but ≤136/150 units and any 2 of the following:

   1. Physician Global Assessment (MDGA) visual analog scale (VAS) ≥2 cm
   2. Patient Global Assessment of Disease Activity (PtGADA) VAS ≥2 cm
   3. At least one muscle enzyme laboratory measurement ≥1.3 × ULN
   4. Myositis Disease Activity Assessment Tool (MDAAT) Extramuscular Global Activity VAS ≥1 cm.

6. Documented inadequate response OR have demonstrated documented toxicity or intolerance to prior standard of care therapies

7. Has had age-appropriate cancer screening that is up to date and negative for evidence of malignancy as per local standard of care

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Exclusion Criteria

1. Has significant muscle damage or has a muscle damage VAS score ≥5 cm on the MDI

2. Any other form of myositis or myopathy other than PM or DM

3. Any condition that precludes the ability to quantitate muscle strength

4. Has severe interstitial lung disease or has a pulmonary damage VAS score ≥5 cm on the Myositis Damage Index (MDI)

5. Presence of autoinflammatory disease

6. Use of nonpermitted medications or treatments within the specified washout periods prior to screening

7. Patient has had recent serious or ongoing infection, or risk for serious infection

8. Any of the following laboratory values at Screening:

   1. Estimated glomerular filtration rate <45 mL/min
   2. Hemoglobin <10 g/dL
   3. White blood cell (WBC) count <3.0 × 10^9/L
   4. Absolute neutrophil count (ANC) <1.5 × 10^9/L (1500/mm^3)
   5. Platelet count <100 × 10^9/L
   6. Serum AST or serum ALT >2.5 × ULN (unless considered consistent with muscle origin)
   7. Serum alkaline phosphatase >2.5 × ULN
   8. Total bilirubin >1.5 × ULN (3 × ULN for patients with documented Gilbert's syndrome)
   9. Thyroid stimulating hormone outside of the central laboratory normal range
   10. Immunoglobulin G (IgG) <500 mg/dL.

9. Presence of New York Heart Association Class III or IV heart failure, or uncontrolled blood pressure, or prolonged QT interval

10. Major surgery within 12 weeks before Screening or planned during the study period

11. Clinical evidence of significant unstable or uncontrolled diseases

12. Any active or suspected malignancy, including myeloproliferative or lymphoproliferative disorder, or history of documented malignancy within the last 5 years before Screening or within 3 years of diagnosis of myositis, except appropriately excised and cured cervical carcinoma in situ or basal or squamous cell carcinoma of the skin

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Arm A	Placebo	* Treatment Period 1: KZR-616 30 mg SC weekly for 2 weeks, then 45 mg SC weekly for 14 weeks * Treatment Period 2: Placebo SC weekly for 16 weeks
Arm B	KZR-616	* Treatment Period 1: Placebo SC weekly for 16 weeks * Treatment Period 2: KZR-616 30 mg SC weekly for 2 weeks, then 45 mg SC weekly for 14 weeks
Arm B	Placebo	* Treatment Period 1: Placebo SC weekly for 16 weeks * Treatment Period 2: KZR-616 30 mg SC weekly for 2 weeks, then 45 mg SC weekly for 14 weeks
Arm A	KZR-616	* Treatment Period 1: KZR-616 30 mg SC weekly for 2 weeks, then 45 mg SC weekly for 14 weeks * Treatment Period 2: Placebo SC weekly for 16 weeks

Primary Outcome Measures

Name	Time	Method
Mean Change in the Total Improvement Score (TIS) From Start to End of Zetomipzomib (KZR-616) Treatment Period	16 weeks in each Treatment Period (32 weeks total)	The primary efficacy endpoint was mean change from start to end of zetomipzomib (KZR-616) Treatment Periods in the Total Improvement Score (TIS), which ranges from 0 to 100 \[low of 0 to high of 100, where higher scores are better\]. Mean change in TIS was calculated by comparing the Baseline and post Baseline observations for patients in both KZR-616 treatment periods combined.; Note: TIS scores for placebo treatment periods are presented in this outcome measure but were not included in the primary outcome measure analysis.

Secondary Outcome Measures

Name	Time	Method
Proportion of Patients With TIS Response	16 weeks in each Treatment Period (32 weeks total)	The proportion of patients with an increase of ≥ 20 points on the TIS from start to end of zetomipzomib (KZR-616) treatment. TIS response is categorized by the following improvement thresholds: * Minimal response = TIS ≥ 20; * Moderate response = TIS ≥ 40; * Major response = TIS ≥ 60; This endpoint was assessed by comparing Week 16 versus Week 0 for patients allocated to Arm A and Week 32 versus Week 16 for patients allocated to Arm B. This re-baselining approach was utilized to maximize the precision for assessment of zetomipzomib effect in Arm B.
Number of Patients Meeting the International Myositis Assessment and Clinical Studies Group (IMACS) Definition of Improvement (DOI)	16 weeks in each Treatment Period (32 weeks total)	The IMACS DOI is ≥ 20% improvement in at least 3 of 6 core set activity measures, with no more than 2 core set activity measures (CSAMs) worsening by ≥ 25% (Manual Muscle Testing-8 Muscle Groups \[MMT-8\] could not be a worsening measure).
Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs	16 weeks in each Treatment Period (32 weeks total)	Mean percent change from baseline of the IMACS CSAMs consisting of: * Physician Global Assessment: physician assessment of patient's overall disease activity at present, high numbers indicate more severe disease activity \[0-10\]; * Patient Global Assessments of Disease Activity: patient assessment of their overall disease activity at present, high numbers indicate more severe disease activity \[0-100\]; * Manual Muscle Testing-8 Muscle Groups: scores range from 0 - 150, high scores are better; * Health Assessment Questionnaire-Disability Index: scores range from 0 - 3, high scores are worse; * Extramuscular Global Assessment of the Myositis Disease Activity Assessment Tool (2005 version): scores range from 0 - 10, high scores are worse; * Muscle enzymes (clinical laboratory assessments \[CLA\]): Summarize the most abnormal CLA (creatine kinase \[CK\], aldolase, lactate dehydrogenase \[LDH\], alanine aminotransferase \[ALT\], or aspartate aminotransferase \[AST\]) at baseline, lower scores are better
Mean Change in CDASI From Start to End of Zetomipzomib (KZR-616) Treatment	16 weeks in each Treatment Period (32 weeks total)	Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) is a clinician scored single-page instrument that separately measures activity and damage, which consists of three (3) activity measures and two (2) damage measures which are assessed over 15 body areas. Scores range from 0-100 for activity and from 0-32 for damage, with higher scores indicating more severe disease.
Mean Change in PP-NRS From Start to End of Zetomipzomib (KZR-616) Treatment	16 weeks in each Treatment Period (32 weeks total)	The Peak Pruritus Numeric Rating Scale (PP-NRS) is used to evaluate severity of itch in DM patients. Scores range from 0-10, with zero (0) representing no itch and ten (10) representing the worst itch imaginable within a 24-hour recall period.
PK of Zetomipzomib [KZR-616] (Cmax)	Up to 5 hours	This is the maximum observed plasma concentration (Cmax) observed after administration of the first dose of KZR-616 (either Week 0 or Week 16). The pharmacokinetic (PK) parameters were calculated using all timepoints at which the concentration was measured, ie. pre-dose and 30 minutes, and 4 hours post-dose, with an additional sample obtained at 0.25, 1, or 2 hours post-dose.
PK of Zetomipzomib [KZR-616] (Tmax)	Up to 5 hours	This is the time to maximum observed plasma concentration (tmax) observed after administration of the first dose of KZR-616 (either Week 0 or Week 16). The PK parameters were calculated using all timepoints at which the concentration was measured, ie. predose and 30 minutes, and 4 hours postdose, with an additional sample obtained at 0.25, 1, or 2 hours postdose.
PK of Zetomipzomib [KZR-616] (AUC)	Up to 5 hours	This is the area under the curve (AUC) from predose through 4 hour postdose observed after administration of the first dose of KZR-616 (either Week 0 or Week 16). The PK parameters were calculated using all timepoints at which the concentration was measured, ie. predose and 30 minutes, and 4 hours postdose, with an additional sample obtained at 0.25, 1, or 2 hours postdose.
PK of KZR-59587 (Cmax)	Up to 5 hours	This is the maximum observed plasma concentration of KZR-59587 (Cmax) observed after administration of the first dose of KZR-616 (either Week 0 or Week 16). The pharmacokinetic (PK) parameters were calculated using all timepoints at which the concentration was measured, ie. pre-dose and 30 minutes, and 4 hours post-dose, with an additional sample obtained at 0.25, 1, or 2 hours post-dose.
PK of KZR-59587 (Tmax)	Up to 5 hours	This is the time to maximum observed plasma concentration of KZR-59587 (tmax) observed after administration of the first dose of KZR-616 (either Week 0 or Week 16). The PK parameters were calculated using all timepoints at which the concentration was measured, ie. predose and 30 minutes, and 4 hours postdose, with an additional sample obtained at 0.25, 1, or 2 hours postdose.
PK of KZR-59587 (AUC)	Up to 5 hours	This is the area under the curve of KZR-59587 (AUC) from predose through 4 hour postdose observed after administration of the first dose of KZR-616 (either Week 0 or Week 16). The PK parameters were calculated using all timepoints at which the concentration was measured, ie. predose and 30 minutes, and 4 hours postdose, with an additional sample obtained at 0.25, 1, or 2 hours postdose.

Trial Locations

Locations (1)

KZR Research Site; 🇩🇪 Göttingen, Germany