The association between blood eosinophil count and benralizumab efficacy for patients with severe, uncontrolled asthma: subanalyses of the Phase III SIROCCO and CALIMA studies

Figures & data

Table 1. Demographics and baseline clinical characteristics (adults).

	SIROCCO (n = 753)				CALIMA (n = 703)
	High-dosage ICS/LABA + baseline blood eosinophils ≥150 cells/μL (n = 631)		High-dosage ICS/LABA + baseline blood eosinophils <150 cells/μL (n = 122)		High-dosage ICS/LABA + baseline blood eosinophils ≥150 cells/μL (n = 615)		High-dosage ICS/LABA + baseline blood eosinophils <150 cells/μL (n = 88)
	Placebo (n = 306)	Benralizumab 30 mg Q8W (n = 325)	Placebo (n = 74)	Benralizumab 30 mg Q8W (n = 48)	Placebo (n = 315)	Benralizumab 30 mg Q8W (n = 300)	Placebo (n = 40)	Benralizumab 30 mg Q8W (n = 48)
Age [years], mean (SD)	50.8 (12.6)	49.6 (12.7)	51.6 (12.0)	48.3 (12.6)	50.6 (12.9)	51.0 (11.8)	53.3 (13.5)	52.3 (13.5)
Sex, n (%)
Male	96 (31)	114 (35)	25 (34)	19 (40)	125 (40)	119 (40)	15 (37.5)	14 (29)
Female	210 (69)	211 (65)	49 (66)	29 (60)	190 (60)	181 (60)	25 (62.5)	34 (71)
Race, n (%)
White	221 (72)	239 (74)	59 (80)	30 (62.5)	273 (87)	255 (85)	34 (85)	42 (88)
Black/African-American	12 (4)	11 (3)	3 (4)	2 (4)	11 (3)	12 (4)	0	0
Asian	41 (13)	40 (12)	8 (11)	9 (19)	31 (10)	32 (11)	6 (15)	6 (13)
Other^a	32 (10)	35 (11)	4 (5)	7 (15)	0	1 (< 1)	0	0
Ethnic group, n (%)
Hispanic or Latino	61 (20)	62 (19)	12 (16)	10 (21)	64 (20)	68 (23)	6 (15)	6 (13)
Not Hispanic or Latino	245 (80)	263 (81)	62 (84)	38 (79)	251 (80)	232 (77)	34 (85)	42 (88)
BMI [kg/m^2], mean (SD)^b	29.0 (6.8)	28.4 (5.9)	30.8 (7.5)	29.2 (5.2)	29.6 (6.4)	29.1 (6.1)	28.5 (7.6)	29.1 (7.5)
Eosinophil count [cells/μL], median (range)^b	435 (150–2,690)	400 (150–3,100)	100 (0–149)	100 (0–140)	410 (150–4,494)	440 (150–2,600)	100 (0–148)	85 (0–143)
FEV1 prebronchodilator [L], mean (SD)^b	1.600 (0.553)	1.665 (0.576)	1.664 (0.606)	1.590 (0.518)	1.759 (0.614)	1.720 (0.623)	1.474 (0.535)	1.710 (0.614)
FEV1 prebronchodilator [% predicted normal], mean (SD)^b^,^c	55.1% (14.3)	55.6% (14.3)	56.9% (15.4)	54.3% (15.1)	57.7% (14.1)	56.3% (14.3)	50.4% (15.5)	58.6% (14.1)
FEV1 [L]/FVC [L] prebronchodilator [%], mean (SD)^b	61 (13)	60 (12)	60 (12)	62 (14)	60 (12)	59 (13)	57 (14)	61 (16)
Reversibility [%], median (range)^b	22% (–8 to 154)	21% (–12 to 157)	17% (–7 to 112)	24% (–2 to 114)	19.5% (–18 to 133)	20% (–13 to 170.5)	17% (–2 to 814)	17% (–10 to 130)
ACQ-6 score, mean (SD)^d	2.90 (0.96)	2.82 (0.88)	2.85 (0.90)	2.72 (0.88)	2.71 (0.92)	2.81 (0.93)	2.92 (0.86)	2.89 (1.05)
Time since asthma diagnosis [years], median (range)	14.2 (1.1–65.2)	14.8 (1.1–66.9)	21.1 (1.6–72.4)	14.1 (1.2–58.8)	18.3 (1.3–69.9)	16.7 (1.2–64.6)	12.6 (1.2–64.9)	18.5 (1.1–57.3)
Number of exacerbations in previous 12 months, mean (SD)	3.1 (1.9)	2.9 (1.55)	2.7 (1.6)	2.4 (0.8)	2.7 (1.5)	2.7 (1.2)	2.5 (1.3)	3.1 (2.4)
Number of exacerbations in previous 12 months resulting in ED visit, mean (SD)	0.3 (0.8)	0.3 (0.9)	0.3 (0.7)	0.2 (0.7)	0.3 (1.3)	0.2 (0.6)	0.1 (0.4)	0.2 (0.5)
Number of exacerbations in previous 12 months resulting in hospitalization, mean (SD)	0.4 (0.8)	0.4 (0.85)	0.5 (0.8)	0.4 (0.8)	0.3 (0.7)	0.3 (0.6)	0.2 (0.6)	0.2 (0.5)
Total asthma symptom score, mean (SD)^b	2.72 (1.10)	2.71 (1.11)	2.66 (0.91)	2.65 (1.13)	2.67 (1.03)	2.79 (1.04)	2.92 (1.09)	2.81 (1.13)
AQLQ(S) + 12 score, mean (SD)^b^,^e	3.89 (1.01)	3.90 (0.97)	3.79 (1.01)	4.01 (1.11)	3.96 (1.03)	3.86 (1.02)	3.89 (0.89)	3.79 (0.95)
Diagnosis of allergic rhinitis, n (%)	168 (55)	175 (54)	36 (49)	31 (65)	177 (56)	154 (51)	18 (45)	20 (42)
Nasal polyps, n (%)	69 (23)	70 (22)	8 (11)	3 (6)	62 (20)	58 (19)	5 (13)	3 (6)
Maintenance OCS use, n (%)	51 (17)	62 (19)	17 (23)	6 (13)	36 (11)	29 (10)	4 (10)	9 (19)

ACQ-6, Asthma Control Questionnaire 6; AQLQ(S) + 12, Standardized Asthma Quality of Life Questionnaire for 12 years and older; BMI, body mass index; ED, emergency department; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; ICS, inhaled corticosteroids; LABA, long-acting β₂-agonist; OCS, oral corticosteroids; Q8W, every 8 weeks (first three doses every 4 weeks); SD, standard deviation.

^a Native Hawaiian or other Pacific Islander, American Indian or Alaska Native, and Other.

^b Data not available for all randomized patients.

^c Percentage predicted normal is FEV₁ expressed as a percentage of the normal value for a person of the same sex, age, and height.

^d The ACQ-6 is a 6-item questionnaire to assess daytime and night-time symptoms and rescue β-agonist use on a 0–6 scale (low numbers represent better control).

^e The AQLQ(S) + 12 is a 32-item questionnaire to assess asthma-related quality of life scored on a 1–7 scale (high numbers indicate better health-related quality of life).

Table 2. Annual exacerbation rates for patients with baseline blood eosinophil counts ≥150 and <150 cells/μL treated with benralizumab plus high-dosage ICS/LABA (adults).

	High-dosage ICS/LABA with baseline blood eosinophils ≥150 cells/μL^a				High-dosage ICS/LABA with baseline blood eosinophils <150 cells/μL^a
	SIROCCO (n = 631)		CALIMA (n = 615)		SIROCCO (n = 122)		CALIMA (n = 88)
	Placebo (n = 306)	Benralizumab 30 mg Q8W (n = 325)	Placebo (n = 315)	Benralizumab 30 mg Q8W (n = 300)	Placebo (n = 74)	Benralizumab 30 mg Q8W (n = 48)	Placebo (n = 40)	Benralizumab 30 mg Q8W (n = 48)
All exacerbations
Number of patients analyzed	306	325	315	300	74	48	40	48
Rate estimate (95% CI)	1.50 (1.27–1.76)	0.87 (0.72–1.05)	1.10 (0.94–1.28)	0.70 (0.58–0.85)	1.34 (1.00–1.79)	1.01 (0.66–1.55)	1.55 (1.06–2.28)	1.01 (0.69–1.48)
Absolute difference estimate (95% CI)	—	−0.63 (−0.91 to −0.35)	—	−0.40 (−0.61 to −0.19)	—	−0.33 (−0.91 to 0.25)	—	−0.54 (−1.23 to 0.14)
Rate ratio vs. placebo (95% CI, p-value)	—	0.58 (0.46–0.74, < 0.001)	—	0.64 (0.50–0.81, < 0.001)	—	0.76 (0.45–1.27, 0.287)	—	0.65 (0.39–1.09, 0.105)
Exacerbations associated with emergency department visits or hospitalizations
Number of patients analyzed	306	325	315	300	74	48	40	48
Rate estimate (95% CI)	0.23 (0.16–0.32)	0.12 (0.08–0.18)	NC	NC	0.16 (0.09–0.30)	0.31 (0.15–0.64)	NC	NC
Absolute difference estimate (95% CI)	—	−0.10 (−0.19 to −0.02)	—	NC	—	0.15 (−0.10 to 0.40)	—	NC
Rate ratio vs. placebo (95% CI, p-value)	—	0.54 (0.32–0.90, 0.018)	—	NC	—	1.92 (0.72–5.14, 0.192)	—	NC

CI, confidence interval; ICS, inhaled corticosteroids; ITT, intention-to-treat; LABA, long-acting β₂-agonists; NC, not calculable; Q8W, every 8 weeks (first three doses every 4 weeks).

Data are from the ITT population from the high-dosage ICS plus LABA treatment cohort from the SIROCCO and CALIMA studies.

^a Estimates were calculated by using a negative binomial model, with adjustment for treatment, region, oral corticosteroid use at time of randomization, and prior exacerbations. The estimates were weighted to account for the 2:1 randomization ratio of patients with baseline blood eosinophil counts ≥300/μL or <300/μL.

Figure 1. Change from baseline in prebronchodilator FEV₁ for patients receiving high-dosage ICS/LABA with baseline eosinophil counts (A, B) ≥ 150 cells/μL and (C, D) < 150 cells/μL for the SIROCCO (A, C) and CALIMA (B, D) studies (adults). FEV₁, forced expiratory volume in 1 s; ICS, inhaled corticosteroids; LABA, long-acting β₂-agonists; Q8W, every 8 weeks (first three doses every 4 weeks). * p < 0.05 for benralizumab Q8W vs. placebo treatment comparison.

Table 3. Change in key secondary endpoints with benralizumab plus high-dosage ICS/LABA treatment for patients with blood eosinophil counts ≥150 or <150 cells/μL (adults).

	High-dosage ICS/LABA with baseline blood eosinophils ≥150 cells/μL				High-dosage ICS/LABA with baseline blood eosinophils <150 cells/μL
	SIROCCO (n = 631)		CALIMA (n = 615)		SIROCCO (n = 122)		CALIMA (n = 88)
	Placebo (n = 306)	Benralizumab 30 mg Q8W (n = 325)	Placebo (n = 315)	Benralizumab 30 mg Q8W (n = 300)	Placebo (n = 74)	Benralizumab 30 mg Q8W (n = 48)	Placebo (n = 40)	Benralizumab 30 mg Q8W (n = 48)
FEV1 [L]^a
Number of patients analyzed	300	323	308	298	72	46	37	46
LS mean (number of patients at EOT)	0.160 (267)	0.323 (290)	0.169 (282)	0.286 (258)	0.125 (64)	0.265 (41)	0.164 (33)	0.033 (40)
LS mean difference vs. placebo (95% CI, p-value)	—	0.163 (0.087 to 0.239, <0.001)	—	0.116 (0.041 to 0.191, 0.002)	—	0.140 (−0.045 to 0.325, 0.136)	—	−0.131 (−0.306 to 0.045, 0.142)
Total asthma symptom score^a
Number of patients analyzed	306	320	314	298	73	47	40	48
LS mean (number of patients at EOT)	−0.95 (213)	−1.18 (221)	−1.08 (242)	−1.24 (227)	−0.80 (50)	−1.20 (34)	−0.84 (29)	−0.79 (37)
LS mean difference vs. placebo (95% CI, p-value)	—	−0.23 (−0.41 to −0.06, 0.009)	—	−0.16 (−0.33 to 0.01, 0.073)	—	−0.40 (−0.78 to −0.03, 0.035)	—	0.04 (−0.37 to 0.45, 0.842)

CI, confidence interval; EOT, end of treatment; FEV₁, forced expiratory volume in 1 s; ICS, inhaled corticosteroids; ITT, intention-to-treat; LABA, long-acting β₂-agonists; LS, least squares; Q8W, every 8 weeks (first three doses every 4 weeks).

Data are from the ITT population from the high-dosage ICS plus LABA treatment cohorts of the SIROCCO and CALIMA studies. Prebronchodilator FEV₁ and total asthma symptom score change are from baseline to EOT (SIROCCO: Week 48; CALIMA: Week 56).

^a Estimates were calculated by using a mixed-effects model for repeated measures analysis, with adjustment for treatment, baseline value, region, oral corticosteroid use at time of randomization, visit, and visit × treatment. The estimates were weighted to account for the 2:1 randomization ratio of patients with baseline blood eosinophil counts ≥300/μL or <300/μL.

Table 4. Change in AQLQ(S) + 12 and ACQ-6 with benralizumab plus high-dosage ICS/LABA treatment for patients with blood eosinophil counts ≥150 or <150 cells/μL (adults).

	High-dosage ICS/LABA with baseline blood eosinophils ≥150 cells/μL				High-dosage ICS/LABA with baseline blood eosinophils <150 cells/μL
	SIROCCO (n = 631)		CALIMA (n = 615)		SIROCCO (n = 122)		CALIMA (n = 88)
	Placebo (n = 306)	Benralizumab 30 mg Q8W (n = 325)	Placebo (n = 315)	Benralizumab 30 mg Q8W (n = 300)	Placebo (n = 74)	Benralizumab 30 mg Q8W (n = 48)	Placebo (n = 40)	Benralizumab 30 mg Q8W (n = 48)
AQLQ(S) + 12^a
Number of patients analyzed	294	307	305	292	70	46	39	46
LS mean (number of patients at EOT)	1.18 (204)	1.37 (226)	1.19 (245)	1.39 (221)	0.77 (53)	1.24 (34)	0.98 (29)	0.97 (34)
LS mean difference vs. placebo (95% CI, p-value)	—	0.19 (0.01 to 0.37, 0.036)	—	0.20 (0.02 to 0.38, 0.029)	—	0.46 (−0.01 to 0.94, 0.056)	—	−0.01 (−0.48 to 0.47, 0.972)
ACQ-6^a
Number of patients analyzed	305	321	314	300	73	47	40	48
LS mean (number of patients at EOT)	−1.13 (209)	−1.27 (233)	−1.08 (252)	−1.30 (226)	−0.62 (52)	−1.32 (35)	−0.84 (30)	−0.91 (35)
LS mean difference vs. placebo (95% CI, p-value)	—	−0.15 (−0.31 to 0.02, 0.084)	—	−0.22 (−0.39 to −0.06, 0.008)	—	−0.70 (−1.15 to −0.25, 0.003)	—	−0.07 (−0.56 to 0.43, 0.783)

ACQ-6, Asthma Control Questionnaire 6; AQLQ(S) + 12, Standardized Asthma Quality of Life Questionnaire for 12 years and older; CI, confidence interval; EOT, end of treatment; ICS, inhaled corticosteroids; ITT, intention-to-treat; LABA, long-acting β₂-agonist; LS, least squares; Q8W, every 8 weeks (first three doses every 4 weeks).

Data are from the ITT population from the high-dosage ICS plus LABA treatment cohort from the SIROCCO and CALIMA studies. ACQ-6 and AQLQ(S) + 12 changes are from baseline to EOT (SIROCCO: Week 48; CALIMA: Week 56).

^a Estimates were calculated by using a mixed-effects model for repeated measures analysis with adjustment for treatment, baseline value, region, oral corticosteroids, visit, and visit × treatment. The estimates were weighted to account for the 2:1 randomization ratio of patients with baseline blood eosinophil counts ≥300/μL or <300/μL.

Table 5. Adverse events, injection-site reactions, and hypersensitivity during on study period (adults).

	SIROCCO (n = 753)				CALIMA (n = 703)
	High-dosage ICS/LABA + baseline blood eosinophils ≥150 cells/μL (n = 631)		High-dosage ICS/LABA + baseline blood eosinophils <150 cells/μL (n = 122)		High-dosage ICS/LABA + baseline blood eosinophils ≥150 cells/μL (n = 615)		High-dosage ICS/LABA + baseline blood eosinophils <150 cells/μL (n = 88)
	Placebo (n = 306)	Benralizumab 30 mg Q8W (n = 325)	Placebo (n = 74)	Benralizumab 30 mg Q8W (n = 48)	Placebo (n = 315)	Benralizumab 30 mg Q8W (n = 300)	Placebo (n = 40)	Benralizumab 30 mg Q8W (n = 48)
Any AE, n (%)	238 (78)	233 (72)	62 (84)	37 (77)	248 (79)	237 (79)	33 (83)	37 (77)
Any SAE, n (%)	44 (14)	43 (13)	13 (18)	10 (21)	44 (14)	33 (11)	9 (23)	3 (6)
AEs in ≥5% of patients, n (%)^a
Asthma worsening	64 (21)	39 (12)	17 (23)	7 (15)	51 (16)	35 (12)	5 (13)	3 (6)
Nasopharyngitis	42 (14)	37 (11)	6 (8)	5 (10)	73 (23)	57 (20)	10 (25)	14 (29)
Upper respiratory tract infection	29 (10)	26 (8)	6 (8)	5 (10)	25 (8)	24 (8)	3 (8)	7 (15)
Bronchitis	25 (8)	13 (4)	4 (5)	2 (4)	42 (13)	26 (9)	4 (10)	8 (17)
Sinusitis	21 (7)	19 (6)	6 (8)	4 (8)	34 (11)	16 (6)	2 (5)	1 (2)
Influenza	20 (7)	17 (5)	3 (4)	1 (2)	15 (5)	7 (2)	1 (3)	1 (2)
Headache	17 (6)	33 (10)	1 (1)	2 (4)	28 (9)	22 (8)	1 (3)	4 (8)
Rhinitis	10 (3)	7 (2)	3 (4)	3 (6)	14 (4)	13 (5)	1 (3)	2 (4)
Back pain	10 (3)	8 (3)	4 (5)	0	11 (4)	8 (3)	3 (8)	2 (4)
Arthralgia	8 (3)	17 (5)	4 (5)	1 (2)	9 (3)	8 (3)	0	3 (6)
Hypertension	8 (3)	10 (3)	3 (4)	0	15 (5)	12 (4)	5 (13)	5 (10)
Pharyngitis	7 (2)	16 (5)	4 (5)	4 (8)	6 (2)	6 (2)	1 (3)	2 (4)
Dizziness	6 (2)	2 (1)	1 (1)	0	2 (1)	3 (1)	1 (3)	4 (8)
Urticaria	6 (2)	8 (3)	1 (1)	0	7 (2)	4 (1)	2 (5)	3 (6)
Rhinitis allergic	5 (2)	12 (4)	1 (1)	0	14 (4)	10 (3)	3 (8)	1 (2)
Gastroenteritis	4 (1)	8 (3)	2 (3)	3 (6)	8 (3)	3 (1)	1 (3)	1 (2)
Ligament sprain	4 (1)	3 (1)	1 (1)	1 (2)	2 (1)	3 (1)	0	3 (6)
Cystitis	3 (1)	0	0	3 (6)	5 (2)	3 (1)	NA	NA
Musculoskeletal pain	3 (1)	6 (2)	NA	NA	3 (1)	3 (1)	2 (5)	1 (2)
Abdominal pain upper	2 (1)	2 (1)	1 (4)	0	1 (<1)	2 (1)	1 (3)	3 (6)
Vertigo	1 (<1)	2 (1)	NA	NA	3 (1)	1 (<1)	2 (5)	0
Injection-site reactions, n (%)	5 (2)	7 (2)	0	2 (4)	6 (2)	6 (2)	1 (3)	2 (4)
Hypersensitivity adverse events	7 (2)	10 (3)	4 (5)	1 (2)	13 (4)	9 (3)	2 (5)	3 (6)

AE, adverse event; NA, not available; Q8W, every 8 weeks (first three doses every 4 weeks); SAE, serious adverse event.

^a Medical Dictionary for Regulatory Activities version 18.1.