A Phase 2 interventional study of KZR-616 and Placebo in Polymyositis and Dermatomyositis, sponsored by Kezar Life Sciences, Inc.. Completed at 14 sites in 3 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-11-19.
Sponsored by Kezar Life Sciences, Inc. · Phase 2, Interventional, and Treatment
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.
Must have their data reviewed by an adjudication committee to confirm eligibility unless at least 1 of the following is present:
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:
Exclusion Criteria:
Any of the following laboratory values at Screening:
* 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
Drug: KZR-616 · Drug: 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
Drug: KZR-616 · Drug: Placebo
Subcutaneous 30 mg weekly for 2 weeks, then 45 mg weekly for 14 weeks
Also known as: zetomipzomib
Subcutaneous injection for 16 weeks
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)
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)
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)
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)
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)
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)
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
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
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
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
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
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
| Milestone | Zetomipzomib First, Then Placebo (Arm A) | Placebo First, Then Zetomipzomib (Arm B) |
|---|---|---|
| Started | 13 | 12 |
| Completed | 10 | 12 |
| Not completed | 3 | 0 |
| Milestone | Zetomipzomib First, Then Placebo (Arm A) | Placebo First, Then Zetomipzomib (Arm B) |
|---|---|---|
| Started | 10 | 12 |
| Completed | 8 | 12 |
| Not completed | 2 | 0 |
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.
| score on a scale | Arm A: Period 1 (Zetomipzomib) | Arm B: Period 1 (Placebo) | Arm A: Period 2 (Placebo) | Arm B: Period 2 (Zetomipzomib) |
|---|---|---|---|---|
| Mean Change in the Total Improvement Score (TIS) From Start to End of Zetomipzomib (KZR-616) Treatment Period | 25.5 ± 18.6 | 25.0 ± 19.9 | 33.1 ± 17.6 | 33.5 ± 22.9 |
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.
| participants | Arm A: Period 1 (Zetomipzomib) | Arm B: Period 1 (Placebo) | Arm A: Period 2 (Placebo) | Arm B: Period 2 (Zetomipzomib) |
|---|---|---|---|---|
| Minimal (TIS ≥ 20) | 6 | 7 | 1 | 6 |
| Moderate (TIS ≥ 40) | 2 | 2 | 1 | 2 |
| Major (TIS ≥ 60) | 0 | 1 | 0 | 1 |
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).
| participants | Arm A: Period 1 (Zetomipzomib) | Arm B: Period 1 (Placebo) | Arm A: Period 2 (Placebo) | Arm B: Period 2 (Zetomipzomib) |
|---|---|---|---|---|
| Number of Patients Meeting the International Myositis Assessment and Clinical Studies Group (IMACS) Definition of Improvement (DOI) | 1 | 1 | 1 | 3 |
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
| percent change | Arm A: Period 1 (Zetomipzomib) | Arm B: Period 1 (Placebo) | Arm A: Period 2 (Placebo) | Arm B: Period 2 (Zetomipzomib) |
|---|---|---|---|---|
| Physician Global Assessment (MDGA) | -32.5 ± 35.1 | -22.1 ± 36.8 | 81.7 ± 204.3 | -4.5 ± 58.6 |
| Patient Global Assessments of Disease Activity (PtGADA) | -23.1 ± 35.1 | -21.7 ± 49.8 | 48.6 ± 121.4 | 64.4 ± 163.8 |
| Manual Muscle Testing-8 Muscle Groups (MMT-8) | 6.7 ± 8.6 | 5.6 ± 6.1 | 0.2 ± 4.6 | 1.5 ± 7.1 |
| Health Assessment Questionnaire-Disability Index (HAQ-DI) | -28.2 ± 34.4 | 1.2 ± 80.5 | 19.2 ± 51.2 | -8.8 ± 60.4 |
| The Extramuscular Global Assessment of the Myositis Disease Activity Assessment Tool (MDAAT) | -14.6 ± 75.2 | -14.7 ± 68.7 | 0.8 ± 69.4 | -34.8 ± 47.5 |
| Muscle enzymes (clinical laboratory assessments) | -19.8 ± 24.1 | 8.7 ± 44.2 | -3.9 ± 42.6 | -8.3 ± 50.6 |
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.
| score on a scale | Arm A: Period 1 (Zetomipzomib) | Arm B: Period 1 (Placebo) | Arm A: Period 2 (Placebo) | Arm B: Period 2 (Zetomipzomib) |
|---|---|---|---|---|
| Activity Score | -2.2 ± 5.3 | -1.2 ± 13.5 | -4.4 ± 5.2 | -0.2 ± 16.1 |
| Damage Score | 0.0 ± 0.7 | -0.8 ± 2.1 | -0.2 ± 0.8 | -1.7 ± 3.1 |
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.
| score on a scale | Arm A: Period 1 (Zetomipzomib) | Arm B: Period 1 (Placebo) | Arm A: Period 2 (Placebo) | Arm B: Period 2 (Zetomipzomib) |
|---|---|---|---|---|
| Mean Change in PP-NRS From Start to End of Zetomipzomib (KZR-616) Treatment | -1.8 ± 1.3 | -2.0 ± 4.2 | -2.0 ± 1.9 | -3.5 ± 3.5 |
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.
| ng/mL | Zetomipzomib (Arm A: Period 1) | Zetomipzomib (Arm B: Period 2) |
|---|---|---|
| PK of Zetomipzomib [KZR-616] (Cmax) | 57.5 ± 78.9 | 82.3 ± 42.5 |
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.
| hours | Zetomipzomib (Arm A: Period 1) | Zetomipzomib (Arm B: Period 2) |
|---|---|---|
| PK of Zetomipzomib [KZR-616] (Tmax) | 0.50 (0.25 to 0.53) | 0.50 (0.25 to 0.55) |
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.
| ng*h/mL | Zetomipzomib (Arm A: Period 1) | Zetomipzomib (Arm B: Period 2) |
|---|---|---|
| PK of Zetomipzomib [KZR-616] (AUC) | 120 ± 59.0 | 156 ± 40.4 |
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.
| ng/mL | Zetomipzomib (Arm A: Period 1) | Zetomipzomib (Arm B: Period 2) |
|---|---|---|
| PK of KZR-59587 (Cmax) | 48.2 ± 58.5 | 58.5 ± 46.4 |
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.
| hours | Zetomipzomib (Arm A: Period 1) | Zetomipzomib (Arm B: Period 2) |
|---|---|---|
| PK of KZR-59587 (Tmax) | 2.50 (0.52 to 4.02) | 3.92 (0.98 to 4.55) |
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.
| ng*h/mL | Zetomipzomib (Arm A: Period 1) | Zetomipzomib (Arm B: Period 2) |
|---|---|---|
| PK of KZR-59587 (AUC) | 150 ± 59.2 | 176 ± 53.3 |
Collected over Up to 40 weeks. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Arm A: Period 1 (Zetomipzomib) | 0/13 (0%) | 1/13 (7.7%) | 12/13 (92.3%) |
| Arm A: Period 2 (Placebo) | 0/10 (0%) | 0/10 (0%) | 8/10 (80%) |
| Arm B: Period 1 (Placebo) | 0/12 (0%) | 1/12 (8.3%) | 7/12 (58.3%) |
| Arm B: Period 2 (Zetomipzomib) | 0/12 (0%) | 1/12 (8.3%) | 10/12 (83.3%) |
| Event | Arm A: Period 1 (Zetomipzomib) | Arm A: Period 2 (Placebo) | Arm B: Period 1 (Placebo) | Arm B: Period 2 (Zetomipzomib) |
|---|---|---|---|---|
| Retinal detachmentEye disorders | 0/13 | 0/10 | 0/12 | 1/12 |
| COVID-19 pneumoniaInfections and infestations | 0/13 | 0/10 | 1/12 | 0/12 |
| FallInjury, poisoning and procedural complications | 1/13 | 0/10 | 0/12 | 0/12 |
| SyncopeNervous system disorders | 1/13 | 0/10 | 0/12 | 0/12 |
| Event | Arm A: Period 1 (Zetomipzomib) | Arm A: Period 2 (Placebo) | Arm B: Period 1 (Placebo) | Arm B: Period 2 (Zetomipzomib) |
|---|---|---|---|---|
| Injection site reactionGeneral disorders | 3/13 | 0/10 | 2/12 | 6/12 |
| Injection site painGeneral disorders | 6/13 | 0/10 | 1/12 | 2/12 |
| FatigueGeneral disorders | 5/13 | 0/10 | 0/12 | 1/12 |
| Injection site erythemaGeneral disorders | 5/13 | 0/10 | 0/12 | 2/12 |
| PainGeneral disorders | 4/13 | 0/10 | 0/12 | 0/12 |
| HeadacheNervous system disorders | 4/13 | 0/10 | 1/12 | 0/12 |
| Urinary tract infectionInfections and infestations | 2/13 | 0/10 | 3/12 | 1/12 |
| PruritusSkin and subcutaneous tissue disorders | 3/13 | 0/10 | 1/12 | 3/12 |
| NauseaGastrointestinal disorders | 3/13 | 1/10 | 1/12 | 0/12 |
| RashSkin and subcutaneous tissue disorders | 3/13 | 0/10 | 0/12 | 0/12 |
| Age, Continuous(years) | Zetomipzomib First, Then Placebo (Arm A) | Placebo First, Then Zetomipzomib (Arm B) | Total |
|---|---|---|---|
| Mean | 49.2 ± 10.7 | 54.3 ± 16.4 | 51.6 ± 13.7 |
| Sex: Female, Male(Participants) | Zetomipzomib First, Then Placebo (Arm A) | Placebo First, Then Zetomipzomib (Arm B) | Total |
|---|---|---|---|
| Female | 10 | 8 | 18 |
| Male | 3 | 4 | 7 |
| Ethnicity (NIH/OMB)(Participants) | Zetomipzomib First, Then Placebo (Arm A) | Placebo First, Then Zetomipzomib (Arm B) | Total |
|---|---|---|---|
| Hispanic or Latino | 3 | 3 | 6 |
| Not Hispanic or Latino | 10 | 9 | 19 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Zetomipzomib First, Then Placebo (Arm A) | Placebo First, Then Zetomipzomib (Arm B) | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 3 | 0 | 3 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 1 | 1 | 2 |
| White | 5 | 10 | 15 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 4 | 1 | 5 |
| Physician Global Assessment (MDGA)(score on a scale) | Zetomipzomib First, Then Placebo (Arm A) | Placebo First, Then Zetomipzomib (Arm B) | Total |
|---|---|---|---|
| Mean | 5.1 ± 1.3 | 4.9 ± 1.6 | 5.0 ± 1.4 |
| Patient Global Assessment of Disease Activity (PtGADA)(score on a scale) | Zetomipzomib First, Then Placebo (Arm A) | Placebo First, Then Zetomipzomib (Arm B) | Total |
|---|---|---|---|
| Mean | 68.8 ± 20.5 | 58.6 ± 18.9 | 63.9 ± 20.0 |
| Manual Muscle Testing-8 Muscle Groups (MMT-8)(score on a scale) | Zetomipzomib First, Then Placebo (Arm A) | Placebo First, Then Zetomipzomib (Arm B) | Total |
|---|---|---|---|
| Mean | 124.2 ± 9.5 | 127.7 ± 6.5 | 125.9 ± 8.2 |
| Health Assessment Questionnaire - Disability (HAQ-DI)(score on a scale) | Zetomipzomib First, Then Placebo (Arm A) | Placebo First, Then Zetomipzomib (Arm B) | Total |
|---|---|---|---|
| Mean | 1.7 ± 0.9 | 1.2 ± 0.7 | 1.5 ± 0.8 |
2 further baseline measures are reported on the registry.
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Kezar Life Sciences, Inc.