Dermatomyositis, Polymyositis
Conditions
Keywords
Myositis, Idiopathic inflammatory myopathies, Polymyositis, Dermatomyositis, Musculoskeletal Diseases, Muscular Diseases
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.
Interventions
DRUGKZR-616
Subcutaneous 30 mg weekly for 2 weeks, then 45 mg weekly for 14 weeks
DRUGPlacebo
Subcutaneous injection for 16 weeks
Sponsors
Kezar Life Sciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Czechia, Germany, United States
Participant flow
Pre-assignment details
This study had a cross-over design. There was a 32-week double-blind Treatment Period divided into two 16-week treatment periods. Participants enrolled at the end of Treatment Period 2 were allowed to join an optional open-label extension study, KZR-616-003E (NCT04628936).
Participants by arm
| Arm | Count |
|---|---|
| Zetomipzomib First, Then Placebo (Arm A) * Treatment Period 1: Zetomipzomib 30 mg SC weekly for 2 weeks, then 45 mg SC weekly for 14 weeks
* Treatment Period 2: Placebo SC weekly for 16 weeks | 13 |
| Placebo First, Then Zetomipzomib (Arm B) * Treatment Period 1: Placebo SC weekly for 16 weeks
* Treatment Period 2: Zetomipzomib 30 mg SC weekly for 2 weeks, then 45 mg SC weekly for 14 weeks | 12 |
| Total | 25 |
Baseline characteristics
| Characteristic | Zetomipzomib First, Then Placebo (Arm A) | Placebo First, Then Zetomipzomib (Arm B) | Total |
|---|---|---|---|
| Age, Continuous | 49.2 years STANDARD_DEVIATION 10.7 | 54.3 years STANDARD_DEVIATION 16.4 | 51.6 years STANDARD_DEVIATION 13.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 9 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Health Assessment Questionnaire - Disability (HAQ-DI) | 1.7 score on a scale STANDARD_DEVIATION 0.9 | 1.2 score on a scale STANDARD_DEVIATION 0.7 | 1.5 score on a scale STANDARD_DEVIATION 0.8 |
| Manual Muscle Testing-8 Muscle Groups (MMT-8) | 124.2 score on a scale STANDARD_DEVIATION 9.5 | 127.7 score on a scale STANDARD_DEVIATION 6.5 | 125.9 score on a scale STANDARD_DEVIATION 8.2 |
| Muscle Enzymes | 2752.7 U/L STANDARD_DEVIATION 4521.1 | 2070.4 U/L STANDARD_DEVIATION 3108.2 | 2425.2 U/L STANDARD_DEVIATION 3843.1 |
| Patient Global Assessment of Disease Activity (PtGADA) | 68.8 score on a scale STANDARD_DEVIATION 20.5 | 58.6 score on a scale STANDARD_DEVIATION 18.9 | 63.9 score on a scale STANDARD_DEVIATION 20 |
| Physician Global Assessment (MDGA) | 5.1 score on a scale STANDARD_DEVIATION 1.3 | 4.9 score on a scale STANDARD_DEVIATION 1.6 | 5.0 score on a scale STANDARD_DEVIATION 1.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) White | 5 Participants | 10 Participants | 15 Participants |
| Sex: Female, Male Female | 10 Participants | 8 Participants | 18 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants |
| The Extramuscular Global Assessment of the Myositis Disease Activity Assessment Tool (MDAAT) | 2.3 score on a scale STANDARD_DEVIATION 1.9 | 2.8 score on a scale STANDARD_DEVIATION 2.4 | 2.5 score on a scale STANDARD_DEVIATION 2.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 10 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 12 / 13 | 8 / 10 | 7 / 12 | 10 / 12 |
| serious Total, serious adverse events | 1 / 13 | 0 / 10 | 1 / 12 | 1 / 12 |
Outcome results
Primary
Mean Change in the Total Improvement Score (TIS) From Start to End of Zetomipzomib (KZR-616) Treatment Period
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.
Time frame: 16 weeks in each Treatment Period (32 weeks total)
Population: For the first 16 weeks, analysis was done for Treatment Period 1. For the second 16 weeks, analysis was done for Treatment Period 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | Mean Change in the Total Improvement Score (TIS) From Start to End of Zetomipzomib (KZR-616) Treatment Period | 25.5 score on a scale | Standard Deviation 18.6 |
| Arm B: Period 1 (Placebo) | Mean Change in the Total Improvement Score (TIS) From Start to End of Zetomipzomib (KZR-616) Treatment Period | 25.0 score on a scale | Standard Deviation 19.9 |
| Arm A: Period 2 (Placebo) | Mean Change in the Total Improvement Score (TIS) From Start to End of Zetomipzomib (KZR-616) Treatment Period | 33.1 score on a scale | Standard Deviation 17.6 |
| Arm B: Period 2 (Zetomipzomib) | Mean Change in the Total Improvement Score (TIS) From Start to End of Zetomipzomib (KZR-616) Treatment Period | 33.5 score on a scale | Standard Deviation 22.9 |
Secondary
Mean Change in CDASI From Start to End of Zetomipzomib (KZR-616) Treatment
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.
Time frame: 16 weeks in each Treatment Period (32 weeks total)
Population: This measure was only performed for patients with DM.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | Mean Change in CDASI From Start to End of Zetomipzomib (KZR-616) Treatment | Activity Score | -2.2 score on a scale | Standard Deviation 5.3 |
| Arm A: Period 1 (Zetomipzomib) | Mean Change in CDASI From Start to End of Zetomipzomib (KZR-616) Treatment | Damage Score | 0.0 score on a scale | Standard Deviation 0.7 |
| Arm B: Period 1 (Placebo) | Mean Change in CDASI From Start to End of Zetomipzomib (KZR-616) Treatment | Damage Score | -0.8 score on a scale | Standard Deviation 2.1 |
| Arm B: Period 1 (Placebo) | Mean Change in CDASI From Start to End of Zetomipzomib (KZR-616) Treatment | Activity Score | -1.2 score on a scale | Standard Deviation 13.5 |
| Arm A: Period 2 (Placebo) | Mean Change in CDASI From Start to End of Zetomipzomib (KZR-616) Treatment | Activity Score | -4.4 score on a scale | Standard Deviation 5.2 |
| Arm A: Period 2 (Placebo) | Mean Change in CDASI From Start to End of Zetomipzomib (KZR-616) Treatment | Damage Score | -0.2 score on a scale | Standard Deviation 0.8 |
| Arm B: Period 2 (Zetomipzomib) | Mean Change in CDASI From Start to End of Zetomipzomib (KZR-616) Treatment | Activity Score | -0.2 score on a scale | Standard Deviation 16.1 |
| Arm B: Period 2 (Zetomipzomib) | Mean Change in CDASI From Start to End of Zetomipzomib (KZR-616) Treatment | Damage Score | -1.7 score on a scale | Standard Deviation 3.1 |
Secondary
Mean Change in PP-NRS From Start to End of Zetomipzomib (KZR-616) Treatment
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.
Time frame: 16 weeks in each Treatment Period (32 weeks total)
Population: This measure was only performed for patients with DM.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | Mean Change in PP-NRS From Start to End of Zetomipzomib (KZR-616) Treatment | -1.8 score on a scale | Standard Deviation 1.3 |
| Arm B: Period 1 (Placebo) | Mean Change in PP-NRS From Start to End of Zetomipzomib (KZR-616) Treatment | -2.0 score on a scale | Standard Deviation 4.2 |
| Arm A: Period 2 (Placebo) | Mean Change in PP-NRS From Start to End of Zetomipzomib (KZR-616) Treatment | -2.0 score on a scale | Standard Deviation 1.9 |
| Arm B: Period 2 (Zetomipzomib) | Mean Change in PP-NRS From Start to End of Zetomipzomib (KZR-616) Treatment | -3.5 score on a scale | Standard Deviation 3.5 |
Secondary
Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs
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
Time frame: 16 weeks in each Treatment Period (32 weeks total)
Population: Some values were not collected for participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Physician Global Assessment (MDGA) | -32.5 percent change | Standard Deviation 35.1 |
| Arm A: Period 1 (Zetomipzomib) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Patient Global Assessments of Disease Activity (PtGADA) | -23.1 percent change | Standard Deviation 35.1 |
| Arm A: Period 1 (Zetomipzomib) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Manual Muscle Testing-8 Muscle Groups (MMT-8) | 6.7 percent change | Standard Deviation 8.6 |
| Arm A: Period 1 (Zetomipzomib) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Health Assessment Questionnaire-Disability Index (HAQ-DI) | -28.2 percent change | Standard Deviation 34.4 |
| Arm A: Period 1 (Zetomipzomib) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | The Extramuscular Global Assessment of the Myositis Disease Activity Assessment Tool (MDAAT) | -14.6 percent change | Standard Deviation 75.2 |
| Arm A: Period 1 (Zetomipzomib) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Muscle enzymes (clinical laboratory assessments) | -19.8 percent change | Standard Deviation 24.1 |
| Arm B: Period 1 (Placebo) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Muscle enzymes (clinical laboratory assessments) | 8.7 percent change | Standard Deviation 44.2 |
| Arm B: Period 1 (Placebo) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Health Assessment Questionnaire-Disability Index (HAQ-DI) | 1.2 percent change | Standard Deviation 80.5 |
| Arm B: Period 1 (Placebo) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Physician Global Assessment (MDGA) | -22.1 percent change | Standard Deviation 36.8 |
| Arm B: Period 1 (Placebo) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Manual Muscle Testing-8 Muscle Groups (MMT-8) | 5.6 percent change | Standard Deviation 6.1 |
| Arm B: Period 1 (Placebo) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Patient Global Assessments of Disease Activity (PtGADA) | -21.7 percent change | Standard Deviation 49.8 |
| Arm B: Period 1 (Placebo) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | The Extramuscular Global Assessment of the Myositis Disease Activity Assessment Tool (MDAAT) | -14.7 percent change | Standard Deviation 68.7 |
| Arm A: Period 2 (Placebo) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Patient Global Assessments of Disease Activity (PtGADA) | 48.6 percent change | Standard Deviation 121.4 |
| Arm A: Period 2 (Placebo) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Manual Muscle Testing-8 Muscle Groups (MMT-8) | 0.2 percent change | Standard Deviation 4.6 |
| Arm A: Period 2 (Placebo) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Health Assessment Questionnaire-Disability Index (HAQ-DI) | 19.2 percent change | Standard Deviation 51.2 |
| Arm A: Period 2 (Placebo) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Muscle enzymes (clinical laboratory assessments) | -3.9 percent change | Standard Deviation 42.6 |
| Arm A: Period 2 (Placebo) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | The Extramuscular Global Assessment of the Myositis Disease Activity Assessment Tool (MDAAT) | 0.8 percent change | Standard Deviation 69.4 |
| Arm A: Period 2 (Placebo) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Physician Global Assessment (MDGA) | 81.7 percent change | Standard Deviation 204.3 |
| Arm B: Period 2 (Zetomipzomib) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | The Extramuscular Global Assessment of the Myositis Disease Activity Assessment Tool (MDAAT) | -34.8 percent change | Standard Deviation 47.5 |
| Arm B: Period 2 (Zetomipzomib) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Muscle enzymes (clinical laboratory assessments) | -8.3 percent change | Standard Deviation 50.6 |
| Arm B: Period 2 (Zetomipzomib) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Patient Global Assessments of Disease Activity (PtGADA) | 64.4 percent change | Standard Deviation 163.8 |
| Arm B: Period 2 (Zetomipzomib) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Health Assessment Questionnaire-Disability Index (HAQ-DI) | -8.8 percent change | Standard Deviation 60.4 |
| Arm B: Period 2 (Zetomipzomib) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Physician Global Assessment (MDGA) | -4.5 percent change | Standard Deviation 58.6 |
| Arm B: Period 2 (Zetomipzomib) | Mean Percent Change From Baseline From Start to End of Treatment in the IMACS Individual CSAMs | Manual Muscle Testing-8 Muscle Groups (MMT-8) | 1.5 percent change | Standard Deviation 7.1 |
Secondary
Number of Patients Meeting the International Myositis Assessment and Clinical Studies Group (IMACS) Definition of Improvement (DOI)
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).
Time frame: 16 weeks in each Treatment Period (32 weeks total)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | Number of Patients Meeting the International Myositis Assessment and Clinical Studies Group (IMACS) Definition of Improvement (DOI) | 1 participants |
| Arm B: Period 1 (Placebo) | Number of Patients Meeting the International Myositis Assessment and Clinical Studies Group (IMACS) Definition of Improvement (DOI) | 1 participants |
| Arm A: Period 2 (Placebo) | Number of Patients Meeting the International Myositis Assessment and Clinical Studies Group (IMACS) Definition of Improvement (DOI) | 1 participants |
| Arm B: Period 2 (Zetomipzomib) | Number of Patients Meeting the International Myositis Assessment and Clinical Studies Group (IMACS) Definition of Improvement (DOI) | 3 participants |
Secondary
PK of KZR-59587 (AUC)
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.
Time frame: Up to 5 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | PK of KZR-59587 (AUC) | 150 ng*h/mL | Geometric Coefficient of Variation 59.2 |
| Arm B: Period 1 (Placebo) | PK of KZR-59587 (AUC) | 176 ng*h/mL | Geometric Coefficient of Variation 53.3 |
Secondary
PK of KZR-59587 (Cmax)
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.
Time frame: Up to 5 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | PK of KZR-59587 (Cmax) | 48.2 ng/mL | Geometric Coefficient of Variation 58.5 |
| Arm B: Period 1 (Placebo) | PK of KZR-59587 (Cmax) | 58.5 ng/mL | Geometric Coefficient of Variation 46.4 |
Secondary
PK of KZR-59587 (Tmax)
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.
Time frame: Up to 5 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | PK of KZR-59587 (Tmax) | 2.50 hours |
| Arm B: Period 1 (Placebo) | PK of KZR-59587 (Tmax) | 3.92 hours |
Secondary
PK of Zetomipzomib [KZR-616] (AUC)
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.
Time frame: Up to 5 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | PK of Zetomipzomib [KZR-616] (AUC) | 120 ng*h/mL | Geometric Coefficient of Variation 59 |
| Arm B: Period 1 (Placebo) | PK of Zetomipzomib [KZR-616] (AUC) | 156 ng*h/mL | Geometric Coefficient of Variation 40.4 |
Secondary
PK of Zetomipzomib [KZR-616] (Cmax)
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.
Time frame: Up to 5 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | PK of Zetomipzomib [KZR-616] (Cmax) | 57.5 ng/mL | Geometric Coefficient of Variation 78.9 |
| Arm B: Period 1 (Placebo) | PK of Zetomipzomib [KZR-616] (Cmax) | 82.3 ng/mL | Geometric Coefficient of Variation 42.5 |
Secondary
PK of Zetomipzomib [KZR-616] (Tmax)
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.
Time frame: Up to 5 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | PK of Zetomipzomib [KZR-616] (Tmax) | 0.50 hours |
| Arm B: Period 1 (Placebo) | PK of Zetomipzomib [KZR-616] (Tmax) | 0.50 hours |
Secondary
Proportion of Patients With TIS Response
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.
Time frame: 16 weeks in each Treatment Period (32 weeks total)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | Proportion of Patients With TIS Response | Major (TIS ≥ 60) | 0 participants |
| Arm A: Period 1 (Zetomipzomib) | Proportion of Patients With TIS Response | Moderate (TIS ≥ 40) | 2 participants |
| Arm A: Period 1 (Zetomipzomib) | Proportion of Patients With TIS Response | Minimal (TIS ≥ 20) | 6 participants |
| Arm B: Period 1 (Placebo) | Proportion of Patients With TIS Response | Moderate (TIS ≥ 40) | 2 participants |
| Arm B: Period 1 (Placebo) | Proportion of Patients With TIS Response | Minimal (TIS ≥ 20) | 7 participants |
| Arm B: Period 1 (Placebo) | Proportion of Patients With TIS Response | Major (TIS ≥ 60) | 1 participants |
| Arm A: Period 2 (Placebo) | Proportion of Patients With TIS Response | Minimal (TIS ≥ 20) | 1 participants |
| Arm A: Period 2 (Placebo) | Proportion of Patients With TIS Response | Major (TIS ≥ 60) | 0 participants |
| Arm A: Period 2 (Placebo) | Proportion of Patients With TIS Response | Moderate (TIS ≥ 40) | 1 participants |
| Arm B: Period 2 (Zetomipzomib) | Proportion of Patients With TIS Response | Moderate (TIS ≥ 40) | 2 participants |
| Arm B: Period 2 (Zetomipzomib) | Proportion of Patients With TIS Response | Minimal (TIS ≥ 20) | 6 participants |
| Arm B: Period 2 (Zetomipzomib) | Proportion of Patients With TIS Response | Major (TIS ≥ 60) | 1 participants |