Two-Year Integrated Efficacy And Safety Analysis Of Benralizumab In Severe Asthma

Figures & data

Figure 1 Benralizumab 2-Year Integrated Analysis Study Design.

Abbreviations: NA, not available; Q4W, every 4 weeks; Q8W, every 8 weeks (first three doses Q4W); SC, subcutaneously.

Figure 2 Trial profile for benralizumab 2-year integrated analysis. ^aIncluding patients who discontinued treatment but attended all study visits. ^bOne patient did not receive treatment and one patient did not fulfill eligibility criteria.

Abbreviations: APS, all patients set; FAS, full analysis set; Q4W, every 4 weeks; Q8W, every 8 weeks (first three doses Q4W).

Table 1 Demographics And Baseline Clinical Characteristics Of Benralizumab 2-Year Integrated Analysis Patients (FAS)^a

	SIROCCO/CALIMA Blood Eosinophil Counts ≥300 Cells/μL
	Benralizumab 30 mg Q4W (n=323)	Benralizumab 30 mg Q8W (n=318)
Age (years), mean (SD)	49.4 (13.1)	48.0 (14.5)
Age group (years), n (%)
≥12–<18	11 (3)	17 (5)
≥18–75	312 (97)	301 (95)
Sex, n (%)
Male	118 (37)	129 (41)
Female	205 (64)	189 (59)
Race, n (%)
White	245 (76)	237 (75)
Black or African-American	5 (2)	7 (2)
Asian	56 (17)	53 (17)
Other^b	17 (5)	21 (7)
Ethnic group, n (%)
Hispanic or Latino	71 (22)	64 (20)
Not Hispanic or Latino	252 (78)	254 (80)
BMI (kg/m^2), mean (SD)	28.9 (7.4)	27.8 (6.0)
Eosinophil count (cells/µL), median (range)	470 (0–2800)	460 (10–3110)
Prebronchodilator FEV1 (L), mean (SD)	1.7 (0.55)	1.7 (0.62)
Prebronchodilator FEV1 (% predicted normal), mean (SD)	57.8% (13.8)	57.4% (14.5)
Reversibility (%), median (range)	24.9% (24.5)	24.1% (22.2)
Prebronchodilator FEV1/FVC, mean (SD)	61.6 (11.4)	60.4 (12.5)
ACQ-6 score, mean (SD)	2.7 (0.9)	2.7 (0.9)
Time since asthma diagnosis (years), median (range)	14.7 (1.3–66.2)	15.4 (1.1–58.3)
Number of exacerbations in the past 12 months	2.9 (1.8)	2.7 (1.4)
2 exacerbations, n (%)	199 (62)	200 (63)
≥3 exacerbations, n (%)	124 (38)	118 (37)
Patients with ≥1 exacerbation in the past 12 months resulting in hospitalizations or ED visits, n (%)	93 (29)	98 (31)
AQLQ(S)+12 score, mean (SD)	4.0 (1.0)	3.9 (1.0)

Notes: ^aBaseline data from preceding pivotal studies. ^bNative Hawaiian or “other” Pacific Islander, American Indian or Alaska Native and other.

Abbreviations: ACQ-6, Asthma Control Questionnaire 6; AQLQ(S)+12, Asthma Quality of Life Questionnaire (standardized) for 12 years and older; BMI, body mass index; ED, emergency department; FAS, full analysis set; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; Q4W, every 4 weeks; Q8W, every 8 weeks (first three doses Q4W); SD, standard deviation.

Figure 3 Annual asthma exacerbation rate for patients in SIROCCO/CALIMA pivotal study (Full analysis set, on-treatment period, blood eosinophil counts ≥300 cells/µL^a). n values are 323/318 for patients receiving benralizumab 30 mg Q4W and Q8W, respectively. Baseline value represents exacerbation rate over the year before pivotal study entry. ^aBlood eosinophil counts at baseline of preceding pivotal studies.

Abbreviations: Q4W, every 4 weeks; Q8W, every 8 weeks (first three doses Q4W).

Table 2 Asthma Exacerbations For SIROCCO/CALIMA Pivotal Study Patients In The Benralizumab 2-Year Integrated Analysis (FAS, On-Treatment period)

	Blood Eosinophil Counts ≥300 Cells/μL^a		Blood Eosinophil Counts <300 Cells/μL^a
	Benralizumab 30 mg Q4W (n=323)	Benralizumab 30 mg Q8W (n=318)	Benralizumab 30 mg Q4W (n=165)	Benralizumab 30 mg Q8W (n=166)
All exacerbations
Patients with ≥1 exacerbation, n (%)	152 (47)	157 (49)	85 (52)	90 (54)
Crude annual rate (95% CI)	0.65 (0.59, 0.71)	0.56 (0.51, 0.62)	0.80 (0.71, 0.90)	0.68 (0.60, 0.77)
Exacerbations per patient, mean (SD)	1.3 (2.3)	1.2 (1.8)	1.6 (3.1)	1.4 (2.0)
Exacerbations leading to hospitalizations or ED visits
Patients with ≥1 exacerbation, n (%)	39 (12)	37 (12)	26 (16)	19 (11)
Crude annual rate (95% CI)	0.10 (0.08, 0.13)	0.08 (0.06, 0.11)	0.11 (0.08, 0.15)	0.08 (0.05, 0.12)
Exacerbations per patient, mean (SD)	0.2 (0.7)	0.2 (0.5)	0.2 (0.6)	0.2 (0.5)
Exacerbations leading to hospitalizations
Patients with ≥1 exacerbation, n (%)	18 (6)	19 (6)	20 (12)	12 (7)
Crude annual rate (95% CI)	0.05 (0.03, 0.07)	0.04 (0.02, 0.06)	0.08 (0.05, 0.11)	0.05 (0.03, 0.08)
Exacerbations per patient, mean (SD)	0.1 (0.5)	0.1 (0.3)	0.2 (0.4)	0.1 (0.5)

Notes: Published annual rate for the pooled SIROCCO and CALIMA placebo patients with blood eosinophil counts ≥300 cells/µL at end of the pivotal studies was 1.14. Data from FitzGerald et al.^{19 a}Eosinophil counts at baseline of preceding pivotal studies.

Abbreviations: CI, confidence interval; ED, emergency department; FAS, full analysis set; Q4W, every 4 weeks; Q8W, every 8 weeks (first three doses Q4W); SD, standard deviation.

Figure 4 Change from SIROCCO/CALIMA pivotal study baseline in (A) Lung Function (FEV₁), (B) ACQ-6, and (C) AQLQ(S)+12 with benralizumab during the 2-year integrated analysis (Full analysis set, on-treatment period, blood eosinophil counts ≥300 cells/µL^a). Error bars represent standard error. ^aBlood eosinophil counts at baseline of preceding pivotal studies.

Abbreviations: ACQ-6, Asthma Control Questionnaire 6; AQLQ(S)+12, Asthma Quality of Life Questionnaire (standardized) for 12 years and older; FEV₁, forced expiratory volume in 1 second; Q4W, every 4 weeks; Q8W, every 8 weeks (first three doses Q4W).

Table 3 Changes In Lung Function, ACQ-6, And AQLQ(S)+12 With Benralizumab During The 2-Year Integrated Analysis Period For SIROCCO/CALIMA Pivotal Study Patients (FAS, On-Treatment period)

	Blood Eosinophil Counts ≥300 Cells/μL^a		Blood Eosinophil Counts <300 Cells/μL^a
	Benralizumab 30 mg Q4W (n=323)	Benralizumab 30 mg Q8W (n=318)	Benralizumab 30 mg Q4W (n=165)	Benralizumab 30 mg Q8W (n=166)
Prebronchodilator FEV1 (L)
Baseline, mean (SD), n	1.703 (0.555), 323	1.741 (0.621), 318	1.668 (0.556), 163	1.758 (0.612), 166
Change at pivotal study EOT,^b mean (SD), n	0.328 (0.449), 313	0.343 (0.507), 305	0.158 (0.433), 158	0.174 (0.421), 165
Change at extension Week 56, mean (SD), n	0.310 (0.481), 279	0.364 (0.544), 273	0.128 (0.449), 139	0.134 (0.446), 143
ACQ-6
Baseline, mean (SD), n	2.73 (0.91), 323	2.74 (0.90), 318	2.75 (0.94), 165	2.76 (0.92), 166
Change at pivotal study EOT,^b mean (SD), n	−1.36 (1.16), 322	−1.44 (1.13), 315	−1.04 (1.18), 165	−1.09 (0.99), 166
Change at extension Week 56, mean (SD), n	−1.43 (1.13), 280	−1.54 (1.09), 278	−1.15 (1.08), 143	−1.16 (1.03), 144
AQLQ(S)+12
Baseline, mean (SD), n	3.96 (0.98), 314	3.90 (0.99), 307	4.01 (0.93), 161	3.96 (1.01), 163
Change at pivotal study EOT,^b mean (SD), n	1.41 (1.16), 314	1.58 (1.23), 306	1.01 (1.16), 161	1.11 (1.09), 163
Change at extension Week 56, mean (SD), n	1.48 (1.20), 271	1.69 (1.24), 267	1.12 (1.07), 139	1.28 (1.07), 141

Notes: Published least squares mean changes from baseline for the pooled SIROCCO and CALIMA placebo patients with blood eosinophil counts ≥300 cells/µL at end of the pivotal studies were 0.224 L (prebronchodilator FEV₁), −1.16 (ACQ-6), and 1.27 (AQLQ[S]+12). Data from FitzGerald et al.¹⁹ aEosinophil counts at baseline of preceding pivotal studies. ^bWeek 48 for SIROCCO and Week 56 for CALIMA.

Abbreviations: ACQ-6, Asthma Control Questionnaire 6; AQLQ(S)+12, Asthma Quality of Life Questionnaire (standardized) for 12 years and older; EOT, end of treatment; FAS, full analysis set; FEV₁, forced expiratory volume in 1 second; Q4W, every 4 weeks; Q8W, every 8 weeks (first three doses Q4W); SD, standard deviation.

Table 4 Adverse Events, Injection-Site Reactions, And Hypersensitivity For SIROCCO/CALIMA Pivotal Study Patients During The 2-Year Integrated Analysis Period (FAS, On-Treatment Period, All Patients Regardless Of Blood Eosinophil Count)

	Benralizumab 30 mg Q4W (n=518) (Exp=1049.97)^a		Benralizumab 30 mg Q8W (n=512) (Exp=1051.11)^a
	n (%)	Event Rate (per 100-Patient-Years)	n (%)	Event Rate (Per 100-Patient-Years)
Any AE	452 (87)	43.05	436 (85)	41.48
Any AE leading to treatment discontinuation	10 (2)	0.95	8 (2)	0.76
AEs in ≥5% of patients^b
Viral upper respiratory tract infection	138 (27)	13.14	137 (27)	13.03
Upper respiratory tract infection	63 (12)	6.00	67 (13)	6.37
Bronchitis	60 (12)	5.71	66 (13)	6.28
Sinusitis	33 (6)	3.14	35 (7)	3.33
Influenza	31 (6)	2.95	28 (6)	2.66
Pharyngitis	31 (6)	2.95	28 (6)	2.66
Acute sinusitis	24 (5)	2.29	34 (7)	3.23
Rhinitis	26 (5)	2.48	31 (6)	2.95
Any SAE	95 (18)	9.05	79 (15)	7.52
SAEs in ≥1% of patients
Worsening asthma	36 (7)	3.43	30 (6)	2.85
Nasal polyps	3 (1)	0.29	0 (0)	0
Pneumonia bacterial	3 (1)	0.29	2 (<1)	0.19
Pneumonia	3 (1)	0.29	1 (<1)	0.10
Influenza	3 (1)	0.29	0 (0)	0
Osteoarthritis	1 (<1)	0.10	3 (1)	0.29
SAEs associated with infections	16 (3)	1.52	17 (3)	1.62
Deaths^c	1 (<1)	0.10	2 (<1)	0.19
Injection-site reactions	27 (5)	2.57	20 (4)	1.90
Hypersensitivity AEs	30 (6)	2.86	19 (4)	1.81

Notes: ^aTotal on-treatment period (years) across all patients in the specific group. ^bAs defined in Medical Dictionary for Regulatory Activities version 20.0. ^cPatients who entered BORA. Ten deaths were reported for patients who received benralizumab in SIROCCO/CALIMA, regardless of whether they entered BORA.

Abbreviations: AE, adverse event; exp, exposure; FAS, full analysis set; Q4W, every 4 weeks; Q8W, every 8 weeks (first three doses Q4W); SAE, serious adverse event.

FitzGerald JM, Bleecker ER, Menzies-Gow A, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med. 2018;6(1):51–64. doi:10.1016/S2213-2600(17)30344-228919200

 PubMed Web of Science ®Google Scholar