Trial Outcomes & Findings for Pharmacodynamic Biomarkers to Support Biosimilar Development: Interleukin-5 Antagonists (NCT NCT04183192)

Last Updated: 2024-04-22

Results Overview

The values and variability of AUEC for eosinophils at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab. AUEC was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Calculations were performed using non-compartmental analysis packages available in R software.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

72 participants

Primary outcome timeframe

Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I.

Results posted on

2024-04-22

Participant Flow

Participant milestones

Participant milestones
Measure	Arm A: Mepolizumab Low Dose Single dose of mepolizumab 3 mg SC Mepolizumab: Mepolizumab 3 mg administered SC	Arm B: Mepolizumab Low Intermediate Dose Single dose of mepolizumab 6 mg SC Mepolizumab: Mepolizumab 6 mg administered SC	Arm C: Mepolizumab High Intermediate Dose Single dose of mepolizumab 12 mg SC Mepolizumab: Mepolizumab 12 mg administered SC	Arm D: Mepolizumab High Dose Single dose of mepolizumab 24 mg SC Mepolizumab: Mepolizumab 24 mg administered SC	Arm E: Reslizumab Low Dose Single dose of reslizumab 0.1 mg/kg IV Reslizumab: Reslizumab 0.1 mg/kg administered IV	Arm F: Reslizumab Intermediate Low Dose Single dose of reslizumab 0.2 mg/kg IV Reslizumab: Reslizumab 0.2 mg/kg administered IV	Arm G: Reslizumab High Intermediate Dose Single dose of reslizumab 0.4 mg/kg IV Reslizumab: Reslizumab 0.4 mg/kg administered IV	Arm H: Reslizumab High Dose Single dose of reslizumab 0.8 mg/kg IV Reslizumab: Reslizumab 0.8 mg/kg administered IV	Arm I: Placebo Single dose of placebo Placebo: Placebo (administered either IV or SC)
Overall Study STARTED	8	8	8	8	8	8	8	8	8
Overall Study COMPLETED	7	8	7	8	8	8	8	8	8
Overall Study NOT COMPLETED	1	0	1	0	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Pharmacodynamic Biomarkers to Support Biosimilar Development: Interleukin-5 Antagonists

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A: Mepolizumab Low Dose n=8 Participants Single dose of mepolizumab 3 mg SC Mepolizumab: Mepolizumab 3 mg administered SC	Arm B: Mepolizumab Low Intermediate Dose n=8 Participants Single dose of mepolizumab 6 mg SC Mepolizumab: Mepolizumab 6 mg administered SC	Arm C: Mepolizumab High Intermediate Dose n=8 Participants Single dose of mepolizumab 12 mg SC Mepolizumab: Mepolizumab 12 mg administered SC	Arm D: Mepolizumab High Dose n=8 Participants Single dose of mepolizumab 24 mg SC Mepolizumab: Mepolizumab 24 mg administered SC	Arm E: Reslizumab Low Dose n=8 Participants Single dose of reslizumab 0.1 mg/kg IV Reslizumab: Reslizumab 0.1 mg/kg administered IV	Arm F: Reslizumab Intermediate Low Dose n=8 Participants Single dose of reslizumab 0.2 mg/kg IV Reslizumab: Reslizumab 0.2 mg/kg administered IV	Arm G: Reslizumab High Intermediate Dose n=8 Participants Single dose of reslizumab 0.4 mg/kg IV Reslizumab: Reslizumab 0.4 mg/kg administered IV	Arm H: Reslizumab High Dose n=8 Participants Single dose of reslizumab 0.8 mg/kg IV Reslizumab: Reslizumab 0.8 mg/kg administered IV	Arm I: Placebo n=8 Participants Single dose of placebo Placebo: Placebo (administered either IV or SC)	Total n=72 Participants Total of all reporting groups
Age, Continuous	32 years n=5 Participants	29 years n=7 Participants	33 years n=5 Participants	39 years n=4 Participants	46 years n=21 Participants	36 years n=8 Participants	45 years n=8 Participants	49 years n=24 Participants	40 years n=42 Participants	39 years n=42 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants	2 Participants n=21 Participants	2 Participants n=8 Participants	2 Participants n=8 Participants	2 Participants n=24 Participants	2 Participants n=42 Participants	21 Participants n=42 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	6 Participants n=7 Participants	5 Participants n=5 Participants	5 Participants n=4 Participants	6 Participants n=21 Participants	6 Participants n=8 Participants	6 Participants n=8 Participants	6 Participants n=24 Participants	6 Participants n=42 Participants	51 Participants n=42 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	2 Participants n=8 Participants	1 Participants n=8 Participants	1 Participants n=24 Participants	1 Participants n=42 Participants	9 Participants n=42 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	8 Participants n=7 Participants	7 Participants n=5 Participants	7 Participants n=4 Participants	8 Participants n=21 Participants	6 Participants n=8 Participants	7 Participants n=8 Participants	7 Participants n=24 Participants	7 Participants n=42 Participants	63 Participants n=42 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	2 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants	2 Participants n=42 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants	2 Participants n=42 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants	4 Participants n=4 Participants	5 Participants n=21 Participants	3 Participants n=8 Participants	3 Participants n=8 Participants	2 Participants n=24 Participants	3 Participants n=42 Participants	33 Participants n=42 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants	3 Participants n=21 Participants	2 Participants n=8 Participants	3 Participants n=8 Participants	6 Participants n=24 Participants	5 Participants n=42 Participants	33 Participants n=42 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	2 Participants n=8 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants	2 Participants n=42 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=24 Participants	0 Participants n=42 Participants	0 Participants n=42 Participants
Region of Enrollment United States	8 participants n=5 Participants	8 participants n=7 Participants	8 participants n=5 Participants	8 participants n=4 Participants	8 participants n=21 Participants	8 participants n=8 Participants	8 participants n=8 Participants	8 participants n=24 Participants	8 participants n=42 Participants	72 participants n=42 Participants
Body Weight	73 kg n=5 Participants	71 kg n=7 Participants	72 kg n=5 Participants	79 kg n=4 Participants	75 kg n=21 Participants	80 kg n=8 Participants	78 kg n=8 Participants	72 kg n=24 Participants	82 kg n=42 Participants	77 kg n=42 Participants
Body Mass Index	25.3 kg/m^2 n=5 Participants	23.7 kg/m^2 n=7 Participants	26.7 kg/m^2 n=5 Participants	24.8 kg/m^2 n=4 Participants	23.9 kg/m^2 n=21 Participants	27.5 kg/m^2 n=8 Participants	26.2 kg/m^2 n=8 Participants	23.8 kg/m^2 n=24 Participants	27.5 kg/m^2 n=42 Participants	25.6 kg/m^2 n=42 Participants

PRIMARY outcome

Timeframe: Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I.

Population: Analysis population includes all subjects who did not discontinue before the end of study.

Outcome measures

Outcome measures
Measure	Arm A: Mepolizumab Low Dose n=7 Participants Single dose of mepolizumab 3 mg SC Mepolizumab: Mepolizumab 3 mg administered SC	Arm B: Mepolizumab Low Intermediate Dose n=8 Participants Single dose of mepolizumab 6 mg SC Mepolizumab: Mepolizumab 6 mg administered SC	Arm C: Mepolizumab High Intermediate Dose n=7 Participants Single dose of mepolizumab 12 mg SC Mepolizumab: Mepolizumab 12 mg administered SC	Arm D: Mepolizumab High Dose n=7 Participants Single dose of mepolizumab 24 mg SC Mepolizumab: Mepolizumab 24 mg administered SC	Arm E: Reslizumab Low Dose n=8 Participants Single dose of reslizumab 0.1 mg/kg IV Reslizumab: Reslizumab 0.1 mg/kg administered IV	Arm F: Reslizumab Intermediate Low Dose n=8 Participants Single dose of reslizumab 0.2 mg/kg IV Reslizumab: Reslizumab 0.2 mg/kg administered IV	Arm G: Reslizumab High Intermediate Dose n=8 Participants Single dose of reslizumab 0.4 mg/kg IV Reslizumab: Reslizumab 0.4 mg/kg administered IV	Arm H: Reslizumab High Dose n=8 Participants Single dose of reslizumab 0.8 mg/kg IV Reslizumab: Reslizumab 0.8 mg/kg administered IV	Arm I: Placebo n=8 Participants Single dose of placebo Placebo: Placebo (administered either IV or SC)
Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab	-1804 Percentage change from baseline * day Standard Deviation 1425	-195 Percentage change from baseline * day Standard Deviation 1568	-1456 Percentage change from baseline * day Standard Deviation 1951	-1428 Percentage change from baseline * day Standard Deviation 2442	-1748 Percentage change from baseline * day Standard Deviation 1888	-1075 Percentage change from baseline * day Standard Deviation 1312	-3313 Percentage change from baseline * day Standard Deviation 4506	-2905 Percentage change from baseline * day Standard Deviation 1423	-1409 Percentage change from baseline * day Standard Deviation 3410

PRIMARY outcome

Population: Analysis population includes all subjects who did not discontinue before the end of study.

The values and variability of maximal change from baseline for eosinophils at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab. Values are percentage change from baseline.

Outcome measures

Outcome measures
Measure	Arm A: Mepolizumab Low Dose n=7 Participants Single dose of mepolizumab 3 mg SC Mepolizumab: Mepolizumab 3 mg administered SC	Arm B: Mepolizumab Low Intermediate Dose n=8 Participants Single dose of mepolizumab 6 mg SC Mepolizumab: Mepolizumab 6 mg administered SC	Arm C: Mepolizumab High Intermediate Dose n=7 Participants Single dose of mepolizumab 12 mg SC Mepolizumab: Mepolizumab 12 mg administered SC	Arm D: Mepolizumab High Dose n=7 Participants Single dose of mepolizumab 24 mg SC Mepolizumab: Mepolizumab 24 mg administered SC	Arm E: Reslizumab Low Dose n=8 Participants Single dose of reslizumab 0.1 mg/kg IV Reslizumab: Reslizumab 0.1 mg/kg administered IV	Arm F: Reslizumab Intermediate Low Dose n=8 Participants Single dose of reslizumab 0.2 mg/kg IV Reslizumab: Reslizumab 0.2 mg/kg administered IV	Arm G: Reslizumab High Intermediate Dose n=8 Participants Single dose of reslizumab 0.4 mg/kg IV Reslizumab: Reslizumab 0.4 mg/kg administered IV	Arm H: Reslizumab High Dose n=8 Participants Single dose of reslizumab 0.8 mg/kg IV Reslizumab: Reslizumab 0.8 mg/kg administered IV	Arm I: Placebo n=8 Participants Single dose of placebo Placebo: Placebo (administered either IV or SC)
Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab	-72 Percentage change from baseline Standard Deviation 73	-63 Percentage change from baseline Standard Deviation 14	-82 Percentage change from baseline Standard Deviation 23	-85 Percentage change from baseline Standard Deviation 14	-79 Percentage change from baseline Standard Deviation 9	-67 Percentage change from baseline Standard Deviation 27	-75 Percentage change from baseline Standard Deviation 25	-77 Percentage change from baseline Standard Deviation 25	-41 Percentage change from baseline Standard Deviation 15

SECONDARY outcome

Timeframe: 0 (pre-dose), 1, 4, 12, 24, hours post-dose; once daily from Day 3 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, and H.

Population: Analysis population includes all subjects who did not discontinue before the end of study.

The values and variability of Cmax at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab.

Outcome measures

Outcome measures
Measure	Arm A: Mepolizumab Low Dose n=7 Participants Single dose of mepolizumab 3 mg SC Mepolizumab: Mepolizumab 3 mg administered SC	Arm B: Mepolizumab Low Intermediate Dose n=8 Participants Single dose of mepolizumab 6 mg SC Mepolizumab: Mepolizumab 6 mg administered SC	Arm C: Mepolizumab High Intermediate Dose n=7 Participants Single dose of mepolizumab 12 mg SC Mepolizumab: Mepolizumab 12 mg administered SC	Arm D: Mepolizumab High Dose n=8 Participants Single dose of mepolizumab 24 mg SC Mepolizumab: Mepolizumab 24 mg administered SC	Arm E: Reslizumab Low Dose n=5 Participants Single dose of reslizumab 0.1 mg/kg IV Reslizumab: Reslizumab 0.1 mg/kg administered IV	Arm F: Reslizumab Intermediate Low Dose n=8 Participants Single dose of reslizumab 0.2 mg/kg IV Reslizumab: Reslizumab 0.2 mg/kg administered IV	Arm G: Reslizumab High Intermediate Dose n=8 Participants Single dose of reslizumab 0.4 mg/kg IV Reslizumab: Reslizumab 0.4 mg/kg administered IV	Arm H: Reslizumab High Dose n=8 Participants Single dose of reslizumab 0.8 mg/kg IV Reslizumab: Reslizumab 0.8 mg/kg administered IV	Arm I: Placebo Single dose of placebo Placebo: Placebo (administered either IV or SC)
Maximum Concentration (Cmax) for Mepolizumab and Reslizumab	0.36 μg/mL Geometric Coefficient of Variation 74	0.53 μg/mL Geometric Coefficient of Variation 54	1.21 μg/mL Geometric Coefficient of Variation 23	2.05 μg/mL Geometric Coefficient of Variation 27	3.1 μg/mL Geometric Coefficient of Variation 10	5.2 μg/mL Geometric Coefficient of Variation 35	12.3 μg/mL Geometric Coefficient of Variation 26	18.7 μg/mL Geometric Coefficient of Variation 20	—

SECONDARY outcome

Population: Analysis population includes all subjects who did not discontinue before the end of study.

The values and variability of AUC at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab.

Outcome measures

Outcome measures
Measure	Arm A: Mepolizumab Low Dose n=7 Participants Single dose of mepolizumab 3 mg SC Mepolizumab: Mepolizumab 3 mg administered SC	Arm B: Mepolizumab Low Intermediate Dose n=8 Participants Single dose of mepolizumab 6 mg SC Mepolizumab: Mepolizumab 6 mg administered SC	Arm C: Mepolizumab High Intermediate Dose n=7 Participants Single dose of mepolizumab 12 mg SC Mepolizumab: Mepolizumab 12 mg administered SC	Arm D: Mepolizumab High Dose n=8 Participants Single dose of mepolizumab 24 mg SC Mepolizumab: Mepolizumab 24 mg administered SC	Arm E: Reslizumab Low Dose n=5 Participants Single dose of reslizumab 0.1 mg/kg IV Reslizumab: Reslizumab 0.1 mg/kg administered IV	Arm F: Reslizumab Intermediate Low Dose n=8 Participants Single dose of reslizumab 0.2 mg/kg IV Reslizumab: Reslizumab 0.2 mg/kg administered IV	Arm G: Reslizumab High Intermediate Dose n=8 Participants Single dose of reslizumab 0.4 mg/kg IV Reslizumab: Reslizumab 0.4 mg/kg administered IV	Arm H: Reslizumab High Dose n=8 Participants Single dose of reslizumab 0.8 mg/kg IV Reslizumab: Reslizumab 0.8 mg/kg administered IV	Arm I: Placebo Single dose of placebo Placebo: Placebo (administered either IV or SC)
Area Under the Curve (AUC) for Mepolizumab and Reslizumab	17.6 μg/mL*day Geometric Coefficient of Variation 73	21.7 μg/mL*day Geometric Coefficient of Variation 153	38.1 μg/mL*day Geometric Coefficient of Variation 21	61.8 μg/mL*day Geometric Coefficient of Variation 46	150 μg/mL*day Geometric Coefficient of Variation 109	152 μg/mL*day Geometric Coefficient of Variation 239	450 μg/mL*day Geometric Coefficient of Variation 72	420 μg/mL*day Geometric Coefficient of Variation 70	—

SECONDARY outcome

Population: Analysis population for each group was limited to those subjects administered mepolizumab or placebo (the mepolizumab group) or administered reslizumab or placebo (reslizumab group) who completed the study. Results from subjects administered placebo were used in all analyses.

The model parameter (Emax, units percentage change from baseline \* day) from an Emax model for eosinophil area under the effect curve versus dose were calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab or reslizumab with placebo data. AUEC (units of percentage change from baseline \* day) was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.

Outcome measures

Outcome measures
Measure	Arm A: Mepolizumab Low Dose n=38 Participants Single dose of mepolizumab 3 mg SC Mepolizumab: Mepolizumab 3 mg administered SC	Arm B: Mepolizumab Low Intermediate Dose n=40 Participants Single dose of mepolizumab 6 mg SC Mepolizumab: Mepolizumab 6 mg administered SC	Arm C: Mepolizumab High Intermediate Dose Single dose of mepolizumab 12 mg SC Mepolizumab: Mepolizumab 12 mg administered SC	Arm D: Mepolizumab High Dose Single dose of mepolizumab 24 mg SC Mepolizumab: Mepolizumab 24 mg administered SC	Arm E: Reslizumab Low Dose Single dose of reslizumab 0.1 mg/kg IV Reslizumab: Reslizumab 0.1 mg/kg administered IV	Arm F: Reslizumab Intermediate Low Dose Single dose of reslizumab 0.2 mg/kg IV Reslizumab: Reslizumab 0.2 mg/kg administered IV	Arm G: Reslizumab High Intermediate Dose Single dose of reslizumab 0.4 mg/kg IV Reslizumab: Reslizumab 0.4 mg/kg administered IV	Arm H: Reslizumab High Dose Single dose of reslizumab 0.8 mg/kg IV Reslizumab: Reslizumab 0.8 mg/kg administered IV	Arm I: Placebo Single dose of placebo Placebo: Placebo (administered either IV or SC)
Pharmacodynamic Model Parameters (Maximum Effect [Emax]) for Eosinophil Area Under the Effect Curve Versus Dose Emax Models for Mepolizumab or Reslizumab	10840 Percentage change from baseline * day Interval 6571.0 to 31670.0	10446 Percentage change from baseline * day Interval 4138.0 to 22373.0	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, and until Day 123 post-dose for Arms C, D, and I.

Population: Analysis population for each group was limited to those subjects administered mepolizumab or placebo (the mepolizumab group) who completed the study. Results from subjects administered placebo were used in all analyses.

The model parameter (ED50, units mg) from an Emax model for eosinophil area under the effect curve versus dose were calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab with placebo data. AUEC (units of percentage change from baseline \* day) was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.

Outcome measures

Outcome measures
Measure	Arm A: Mepolizumab Low Dose n=38 Participants Single dose of mepolizumab 3 mg SC Mepolizumab: Mepolizumab 3 mg administered SC	Arm B: Mepolizumab Low Intermediate Dose Single dose of mepolizumab 6 mg SC Mepolizumab: Mepolizumab 6 mg administered SC	Arm C: Mepolizumab High Intermediate Dose Single dose of mepolizumab 12 mg SC Mepolizumab: Mepolizumab 12 mg administered SC	Arm D: Mepolizumab High Dose Single dose of mepolizumab 24 mg SC Mepolizumab: Mepolizumab 24 mg administered SC	Arm E: Reslizumab Low Dose Single dose of reslizumab 0.1 mg/kg IV Reslizumab: Reslizumab 0.1 mg/kg administered IV	Arm F: Reslizumab Intermediate Low Dose Single dose of reslizumab 0.2 mg/kg IV Reslizumab: Reslizumab 0.2 mg/kg administered IV	Arm G: Reslizumab High Intermediate Dose Single dose of reslizumab 0.4 mg/kg IV Reslizumab: Reslizumab 0.4 mg/kg administered IV	Arm H: Reslizumab High Dose Single dose of reslizumab 0.8 mg/kg IV Reslizumab: Reslizumab 0.8 mg/kg administered IV	Arm I: Placebo Single dose of placebo Placebo: Placebo (administered either IV or SC)
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Area Under the Effect Curve Versus Dose Emax Model for Mepolizumab	31.3 mg Interval 8.6 to 400.0	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms E, F and until Day 123 post-dose for Arms G, H, and I.

Population: Analysis population for each group was limited to those subjects administered reslizumab or placebo (reslizumab group) who completed the study. Results from subjects administered placebo were used in all analyses.

The model parameter (ED50, units mg/kg) from an Emax model for eosinophil area under the effect curve versus dose were calculated after combining data from low, intermediate low, intermediate high, and high doses of reslizumab with placebo data. AUEC (units of percentage change from baseline \* day) was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.

Outcome measures

Outcome measures
Measure	Arm A: Mepolizumab Low Dose n=40 Participants Single dose of mepolizumab 3 mg SC Mepolizumab: Mepolizumab 3 mg administered SC	Arm B: Mepolizumab Low Intermediate Dose Single dose of mepolizumab 6 mg SC Mepolizumab: Mepolizumab 6 mg administered SC	Arm C: Mepolizumab High Intermediate Dose Single dose of mepolizumab 12 mg SC Mepolizumab: Mepolizumab 12 mg administered SC	Arm D: Mepolizumab High Dose Single dose of mepolizumab 24 mg SC Mepolizumab: Mepolizumab 24 mg administered SC	Arm E: Reslizumab Low Dose Single dose of reslizumab 0.1 mg/kg IV Reslizumab: Reslizumab 0.1 mg/kg administered IV	Arm F: Reslizumab Intermediate Low Dose Single dose of reslizumab 0.2 mg/kg IV Reslizumab: Reslizumab 0.2 mg/kg administered IV	Arm G: Reslizumab High Intermediate Dose Single dose of reslizumab 0.4 mg/kg IV Reslizumab: Reslizumab 0.4 mg/kg administered IV	Arm H: Reslizumab High Dose Single dose of reslizumab 0.8 mg/kg IV Reslizumab: Reslizumab 0.8 mg/kg administered IV	Arm I: Placebo Single dose of placebo Placebo: Placebo (administered either IV or SC)
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Area Under the Effect Curve Versus Dose Emax Model for Reslizumab	0.31 mg/kg Interval 0.01 to 1.2	—	—	—	—	—	—	—	—

SECONDARY outcome

Population: Analysis population for each group was limited to those subjects administered mepolizumab or placebo (the mepolizumab group) or administered reslizumab or placebo (reslizumab) who completed the study. Results from subjects administered placebo were used in all analyses.

The model parameter (Emax, units percentage change from baseline) from an Emax model for eosinophil maximum change from baseline versus dose was calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab or reslizumab with placebo data. Maximum change from baseline (units of percentage change from baseline) was calculated as percentage change from baseline and considered all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.

Outcome measures

Outcome measures
Measure	Arm A: Mepolizumab Low Dose n=38 Participants Single dose of mepolizumab 3 mg SC Mepolizumab: Mepolizumab 3 mg administered SC	Arm B: Mepolizumab Low Intermediate Dose n=40 Participants Single dose of mepolizumab 6 mg SC Mepolizumab: Mepolizumab 6 mg administered SC	Arm C: Mepolizumab High Intermediate Dose Single dose of mepolizumab 12 mg SC Mepolizumab: Mepolizumab 12 mg administered SC	Arm D: Mepolizumab High Dose Single dose of mepolizumab 24 mg SC Mepolizumab: Mepolizumab 24 mg administered SC	Arm E: Reslizumab Low Dose Single dose of reslizumab 0.1 mg/kg IV Reslizumab: Reslizumab 0.1 mg/kg administered IV	Arm F: Reslizumab Intermediate Low Dose Single dose of reslizumab 0.2 mg/kg IV Reslizumab: Reslizumab 0.2 mg/kg administered IV	Arm G: Reslizumab High Intermediate Dose Single dose of reslizumab 0.4 mg/kg IV Reslizumab: Reslizumab 0.4 mg/kg administered IV	Arm H: Reslizumab High Dose Single dose of reslizumab 0.8 mg/kg IV Reslizumab: Reslizumab 0.8 mg/kg administered IV	Arm I: Placebo Single dose of placebo Placebo: Placebo (administered either IV or SC)
Pharmacodynamic Model Parameters (Maximum Effect [Emax]) for Eosinophil Maximum Change From Baseline Versus Dose Emax Models With Mepolizumab or Reslizumab	85 Percentage change from baseline Interval 78.0 to 92.0	86 Percentage change from baseline Interval 77.0 to 95.0	—	—	—	—	—	—	—

SECONDARY outcome

The model parameter (ED50, units mg) from an Emax model for eosinophil maximum change from baseline versus dose was calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab with placebo data. Maximum change from baseline (units of percentage change from baseline) was calculated as percentage change from baseline and considered all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.

Outcome measures

Outcome measures
Measure	Arm A: Mepolizumab Low Dose n=38 Participants Single dose of mepolizumab 3 mg SC Mepolizumab: Mepolizumab 3 mg administered SC	Arm B: Mepolizumab Low Intermediate Dose Single dose of mepolizumab 6 mg SC Mepolizumab: Mepolizumab 6 mg administered SC	Arm C: Mepolizumab High Intermediate Dose Single dose of mepolizumab 12 mg SC Mepolizumab: Mepolizumab 12 mg administered SC	Arm D: Mepolizumab High Dose Single dose of mepolizumab 24 mg SC Mepolizumab: Mepolizumab 24 mg administered SC	Arm E: Reslizumab Low Dose Single dose of reslizumab 0.1 mg/kg IV Reslizumab: Reslizumab 0.1 mg/kg administered IV	Arm F: Reslizumab Intermediate Low Dose Single dose of reslizumab 0.2 mg/kg IV Reslizumab: Reslizumab 0.2 mg/kg administered IV	Arm G: Reslizumab High Intermediate Dose Single dose of reslizumab 0.4 mg/kg IV Reslizumab: Reslizumab 0.4 mg/kg administered IV	Arm H: Reslizumab High Dose Single dose of reslizumab 0.8 mg/kg IV Reslizumab: Reslizumab 0.8 mg/kg administered IV	Arm I: Placebo Single dose of placebo Placebo: Placebo (administered either IV or SC)
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Maximum Change From Baseline Curve Versus Dose Emax Model Mepolizumab	3.8 mg Interval 2.0 to 6.4	—	—	—	—	—	—	—	—

SECONDARY outcome

Population: Analysis population for each group was limited to those subjects administered reslizumab or placebo (reslizumab) who completed the study. Results from subjects administered placebo were used in all analyses.

The model parameter (ED50, units mg/kg) from an Emax model for eosinophil maximum change from baseline versus dose was calculated after combining data from low, intermediate low, intermediate high, and high doses of reslizumab with placebo data. Maximum change from baseline (units of percentage change from baseline) was calculated as percentage change from baseline and considered all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.