Safety, Tolerability, and Pharmacokinetics of Benralizumab: A Phase 1, Randomized, Single-Blind Study of Healthy Chinese Participants

Figures & data

Table 1 Demographics and Baseline Subject Characteristics (Safety Analysis Set)

Characteristics	Benralizumab 10 mg (N=12)	Benralizumab 30 mg (N=12)	Benralizumab 100 mg (N=12)	Total (N=36)
Mean age (SD), years	25.8 (4.7)	24.8 (6.1)	27.2 (7.2)	25.9 (6.0)
Female, n (%)	5 (41.7)	6 (50.0)	3 (25.0)	14 (38.9)
Chinese, n (%)	12 (100)	12 (100)	12 (100)	36 (100)
Mean weight (SD), kg	59.9 (7.1)	59.4 (6.3)	61.9 (6.6)	60.4 (6.6)
Mean BMI (SD), kg/m^2	21.4 (1.5)	21.6 (1.6)	21.1 (1.5)	21.4 (1.5)
Smoking status, n (%)
Never	10 (83.3)	10 (83.3)	11 (91.7)	31 (86.1)
Current	1 (8.3)	0	0	1 (2.8)
Former	1 (8.3)	2 (16.7)	1 (8.3)	4 (11.1)
Nicotine consumption (pack years), Mean (SD)^a	1.0 (1.4)	2.0 (2.8)	1.0 (NC)	1.4 (1.7)

Notes: ^aNicotine consumption (pack years) was summarized for current/former smokers only. Nicotine consumption was rounded down to zero on the electronic case report form if the subject smoked less than 1 pack year.

Abbreviations: BMI, body mass index; N, number of participants in treatment group; n, number of participants; SD, standard deviation; NC, not calculable.

Figure 1 Study flow design.

Table 2 Summary of Adverse Events Reported During the On-Study Period (Safety Analysis Set)

	Benralizumab 10 mg (N=12)	Benralizumab 30 mg (N=12)	Benralizumab 100 mg (N=12)	Total (N=36)
AE category, n (%) ^[#]
Any AE	3 (25.0) [4]	5 (41.7) [6]	2 (16.7) [3]	10 (27.8) [13]
Any drug-related AE	0	1^a (8.3)	0	1^a (2.8)
Any SAE (including AE with death outcome)	0	0	1^b (8.3)	1^b (2.8)
Any drug-related SAE	0	0	0	0
Any AE leading to withdrawal from study	0	0	0	0
Any AE with death outcome	0	0	0	0
AE by system organ class and preferred term	n (%)	n (%)	n (%)	n (%)
General disorders and administration site conditions	2 (16.7)	4 (30.0)	1 (8.3)	7 (19.4)
Influenza like illness	2 (16.7)	3 (25.0)	1 (8.3)	6 (16.7)
Injection site swelling	0	1 (8.3)	0	1 (2.8)
Injury, poisoning and procedural complications	0	1 (8.3)	1 (8.3)	2 (5.6)
Cervical vertebral fracture	0	0	1 (8.3)	1 (2.8)
Lip injury	0	1 (8.3)	0	1 (2.8)
Skin and subcutaneous tissue disorders	1 (8.3)	0	1 (8.3)	2 (5.6)
Eczema	1 (8.3)	0	0	1 (2.8)
Rash	0	0	1 (8.3)	1 (2.8)
Gastrointestinal disorders	0	1 (8.3)	0	1 (2.8)
Nausea	0	1 (8.3)	0	1 (2.8)
Infections and infestations	1 (8.3)	0	0	1 (2.8)
Bronchitis	1 (8.3)	0	0	1 (2.8)

Notes: ^aOne participant reported a mild event of injection site swelling, this resolved within 3 days; ^bOne participant reported an SAE of cervical vertebral fracture 52 days from the single injection of benralizumab (including the day of dosing). The event was severe, assessed as not related to benralizumab by the Investigator, and did not lead to withdrawal from the study. MedDRA version 22.0. AEs during the on-study period were defined as occurring from the injection of benralizumab to the date of study completion or date of withdrawal from the study. ^#Number of events, multiple events in the same category are counted multiple times in that category.

Abbreviations: AE, adverse event; n, number of participants with at least 1 event, participants with multiple events in the same category were counted only once in that category; SAE, serious adverse event.

Figure 2 Blood eosinophil count over the study ^†period (safety analysis set). ^†Day 0 was pre-dose. Baseline (Day 0) was defined as the last non-missing measurement prior to the injection of study treatment. Error bars show minimum and maximum eosinophil counts.

Figure 3 Geometric mean serum concentration-time profile of benralizumab following single SC dose administration on Day 1 (semi-log scale) (PK analysis set). Nominal sampling elapsed time (ie time difference between nominal sampling time and dosing time) is used for mean summary plots. Pre-dose time equals to zero. Samples collected outside the protocol-defined window were excluded from summary statistics. Vertical line represents the Geometric mean ± SD=exp{mean (individual log-transformed values) ± SD (individual log-transformed values)}.

Abbreviations: PK, pharmacokinetic; SC, subcutaneous; SD, standard deviation.

Table 3 Pharmacokinetic Parameters of Benralizumab Following Single SC Dose Administration on Day 1 (PK Analysis Set)

Variable (Units)	Benralizumab 10 mg (N=12^a)	Benralizumab 30 mg (N=12^a)	Benralizumab 100 mg (N=12^a)
Cmax (ng/mL)	648.5 (38.6)	1879.6 (28.7)	6532.4 (38.2)
tmax (day)	9.5 (4, 15)	7.0 (5, 12)	7.0 (3, 12)
AUC0-t (day*ng/mL)	23,314.8 (36.2)	67,069.2 (27.3)	222,021.2 (24.3)
AUC0-∞ (day*ng/mL)	24,583.8 (32.8)	69,791.6 (28.8)	231,158.3 (24.7)
CL/F (mL/day)	406.8 (32.8)	429.9 (28.8)	432.6 (24.7)
Vz/F (L)	8.9 (42.4)	8.9 (34.5)	9.6 (39.1)
t1/2 (day)	15.1 (23.5)	14.4 (30.1)	15.4 (39.4)

Notes: Data are Geometric mean (CV%), except t_max which is Median (Min, Max). ^a12 participants included in all groups. Two participants did not have PK assessments beyond Day 30 and Day 33, respectively, and therefore were excluded from the calculations of AUC_0-t, AUC_0-∞, t_1/2, CL/F, Vz/F.

Abbreviations: AUC_0-∞, area under the concentration–time curve from 0 to infinity; AUC_0-t, area under the concentration–time curve from 0 to the last measurable time point; CL/F, apparent clearance; C_max, maximum observed concentration; CV%, coefficient of variation expressed in percentage; N, number of participants in treatment group; n, number of participants included in analysis; PK, pharmacokinetic; t_1/2, time for concentration to decrease by 50%; t_max, time to maximum observed concentration; V_z/F, apparent volume of distribution at terminal phase.

Table 4 Anti-Drug Antibody Response (Safety Analysis Set)

	Benralizumab 10 mg (N=12)	Benralizumab 30 mg (N=12)	Benralizumab 100 mg (N=12)	Total (N=36)
Any ADA result at baseline and at least 1 post-baseline ADA assessment, n	12	12	12	36
ADA positive at any visit, at baseline and/or post-baseline (ADA prevalence), m (%)	1 (8.3)	2 (16.7)	2 (16.7)	5 (13.9)
nAb positive at any time, m (%)	1 (8.3)	2 (16.7)	2 (16.7)	5 (13.9)
ADA positive at baseline only, m (%)	0	0	0	0
ADA positive at both baseline and at least 1 post-baselinemeasurement, m (%)	0	0	0	0
Treatment-emergent ADA positive (ADA incidence), m (%)^a	1 (8.3)	2 (16.7)	2 (16.7)	5 (13.9)
Treatment-induced ADA positive, m (%)^b	1 (8.3)	2 (16.7)	2 (16.7)	5 (13.9)
Treatment-boosted ADA positive, m (%)^c	0	0	0	0
Persistently positive ADA, m (%)^d	1 (8.3)	2 (16.7)	2 (16.7)	5 (13.9)
Transiently positive ADA, m (%)^e	0	0	0	0

Notes: ^aTreatment-emergent ADA positive was defined as either treatment-induced ADA positive or treatment-boosted ADA positive. The percentage is known as ADA incidence. ^bTreatment-induced ADA positive was defined as ADA negative at baseline and positive at post-baseline. ^cTreatment-boosted ADA positive was defined as baseline ADA titre that was boosted greater than 4-fold following drug administration. ^dPersistently positive ADA was defined as having ≥2 post-baseline assessments (with ≥16 weeks between first and last positive) or an ADA positive result at the last available assessment. ^eTransiently positive ADA was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive.

Abbreviations: ADA, anti-drug antibody; m, number of participants with a positive result in each category; nAb, neutralizing antibodies; N, number of participants at each dose level; n, number of participants with ADA results available in each category; % in each category is calculated using n as denominator and m as numerator.

Figure 4 Individual serum concentration of benralizumab following single SC dose administration by ADA status; (A) benralizumab 10mg, (B) benralizumab 30mg, (C) benralizumab 100mg (semi-log scale). Red crosses indicate the time point when the sample was ADA positive; for one participant in the 30 mg group who tested ADA positive in the Day 57 and Day 84 samples, the benralizumab serum concentration was <LLOQ at Day 84 and is not shown in the plot. Actual sampling elapsed time (ie time difference between actual sampling time and dosing time) is used for individual plots. After the first quantifiable concentration, any <LLOQ serum concentrations is regarded as missing.

Abbreviations: ADA, anti-drug antibody; LLOQ, lower limit of quantification; SC, subcutaneous.