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

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.

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.

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 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

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.

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.

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.

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.

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.

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.

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.

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.