Background

The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived “alarmin.” Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics.

 

Objectives

This study evaluated astegolimab efficacy and safety in patients with severe asthma.

 

Methods

This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured ∼30 patients who were eosinophil-high (≥300 cells/μL) and ∼95 patients who were eosinophil-low (<300 cells/μL) per arm.

 

Results

Overall, adjusted AER reductions relative to placebo were 43% (P = .005), 22% (P = .18), and 37% (P = .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P = .002), 14% (P = .48), and 35% (P = .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups.

 

Conclusions

Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.
 
Severe asthma affects 8% to 10% of the 300 million people worldwide who have asthma, a chronic inflammatory airway disorder., Inhaled corticosteroids (ICSs) and long-acting β-agonist controllers effectively treat most patients, but others remain poorly controlled.,, , , , , Exacerbations, elicited by various triggers (respiratory viral infections, allergens, indoor and outdoor pollutants, other environmental irritants, and exercise), occur most frequently in patients with advanced disease and indicate poor control. Frequent or severe exacerbations affect patient quality of life, drive increased utilization of health care resources, and adversely affect workplace productivity, with severe asthmatics accounting for the majority of asthma health care expenditures. Exacerbation-reducing treatments are needed to improve asthma control and quality of life.
Recent asthma treatments target and treat patients with certain biomarker profiles. , , , , ,  Treatment effectiveness appears limited to patient subgroups with markers of type 2 (T2) inflammation (high blood eosinophil levels, serum IgE allergen test positivity, and nitric oxide levels), who compose only about one-half of severe asthmatics. Post hoc analyses of omalizumab (anti-IgE) and mepolizumab (anti-IL-5) phase 3 studies indicate that baseline blood eosinophil count is directly related to exacerbation rate reduction., , These results highlight the diminishing clinical benefit for patients with low blood eosinophil counts and the need for broader treatments that effectively target both patients who are T2-high and patients who are T2-low.
 
IL-33, an IL-1-class molecule, is an epithelial-derived alarmin released in response to tissue injury. Inhaled allergens and respiratory viruses, common asthma exacerbation triggers, potently induce IL-33 synthesis and release. , ,  IL-33 binds its receptor (ST2; IL-1 receptor-like 1) on parenchymal and inflammatory cells and can activate TH1 and TH2 cells depending on the cytokine milieu.Following activation by IL-33, inflammatory and resident airway cells release cytokines such as TNF-α, IFN-γ, IL-5, IL-6, IL-9, and IL-13. Both genetic and biologic evidence implicate IL-33 in asthma susceptibility and severity. , , Astegolimab is a human IgG2 mAb that blocks IL-33 signaling by targeting ST2, the IL-33 receptor. Because cell types involved in both T2-high and T2-low asthma express ST2 (eg, innate lymphoid cells, T cells, eosinophils, mast cells, dendritic cells, macrophages, and endothelial cells), , this novel strategy to block inflammation downstream of IL-33 may benefit patients who have asthma with or without high eosinophils. Phase 1 clinical studies in healthy volunteers showed no adverse events (AEs) leading to treatment discontinuation or serious AEs (SAEs) after single or multiple subcutaneous (2.1-560 mg) or intravenous doses (210-700 mg) (unpublished data).
 
This phase 2b study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) evaluated multiple subcutaneous doses of astegolimab for efficacy, safety, and pharmacokinetics in patients with severe asthma. The primary efficacy endpoint was the reduction in asthma exacerbations versus placebo. Secondary endpoints included time to first asthma exacerbation, prebronchodilator FEV1, and patient-reported outcomes. Additionally, exacerbation rates were compared between subgroups defined by baseline blood eosinophil levels.

Methods

Trial design and oversight

This phase 2b, randomized, placebo-controlled, double-blind, multicenter study compared astegolimab with placebo as add-on therapy in patients with severe asthma receiving medium- or high-dose ICS therapy and an additional controller medication. Patients were recruited at 132 sites (see this article’s Online Repository available at www.jacionline.org) across 15 countries. The 70-week study consisted of 2 to 4 weeks of screening, a 2-week single-blind placebo run-in period, a 52-week double-blind treatment period, and a 16-week follow-up (see Fig E1, A in this article’s Online Repository at www.jacionline.org). Background asthma-control medications were maintained at stable doses and short-acting rescue therapy was continued throughout the study as needed.
Genentech, Inc, developed the protocol and conducted the study in full conformance with the International Council for Harmonisation (of Technical Requirements for Registration of Pharmaceuticals for Human Use E6 guideline for Good Clinical Practice), the principles of the Declaration of Helsinki, or the laws/regulations of the country where the research occurred, whichever provided better protection to the individual. The study complied with requirements of the International Council for Harmonisation E2A guideline. Patients provided written, informed consent before study procedures.

 Patients

Eligible patients for the run-in were 18 to 75 years old, current nonsmokers, with documented physician-diagnosed asthma (see full eligibility criteria and Table E1 in this article’s Online Repository at www.jacionline.org). The following criteria were required: on stable ICS therapy at a total daily dose of ≥500 μg fluticasone propionate equivalent and ≥1 additional allowed controller medication with no anticipated changes in controller dosing regimens throughout the study; morning prebronchodilator FEV1 of 40% to 80% of predicted; postbronchodilator FEV1 reversibility of ≥12%; 5-item Asthma Control Questionnaire score ≥1.5, and nighttime awakening ≥1 time/week or short-acting rescue therapy >2 days/week; documented history of ≥1 asthma exacerbation within 12 months before screening; and demonstrated compliance with required use of the eDiary, defined as documenting asthma medication use and answering questions related to asthma symptoms and asthma-related nighttime awakenings, on at least 5 of 7 days during each of 2 consecutive weeks during the screening period.
For randomization into the double-blind treatment period, patients must have demonstrated clinical stability of asthma defined as follows: no changes in controller medications during run-in, morning prebronchodilator FEV1 of 40% to 80% of predicted at randomization visit, no absolute change of ≥15% in morning prebronchodilator FEV1 or an absolute change in fractional exhaled nitric oxide (Feno) ≥20 parts per billion and ≥40% relative change between screening and randomization visits.

 Randomization and blinding

Patients were randomized 1:1:1:1 to 70-mg, 210-mg, or 490-mg doses of astegolimab or placebo administered subcutaneously every 4 weeks. An interactive voice/web-based response system randomized patients, stratifying by screening blood eosinophil status (<150, ≥150 to <300, ≥300 cells/μL), number of documented asthma exacerbations in the previous 12 months (1-2, ≥3), total daily ICS dose (<1000 μg or ≥1000 μg fluticasone propionate or equivalent), and country. Enrollment caps were utilized to ensure adequate power for efficacy and biomarker subgroup analyses using blood eosinophil status (≥300, <300 cells/μL), with randomization designed to assign approximately 30 patients who were eosinophil-high and approximately 95 patients who were eosinophil-low to each arm.
Patients, study site personnel, and other sponsor agents remained blinded to individual treatment assignments. An independent data monitoring committee reviewed unblinded safety data throughout the study.

 Outcomes and assessments

The primary efficacy endpoint was the reduction over placebo in the asthma exacerbation rate (AER) after 52 weeks of treatment. Asthma exacerbation was defined as new or increased asthma symptoms (wheezing, coughing, dyspnea, chest tightness, and/or nighttime awakenings) resulting in one or both of the following: hospitalization or emergency department visit with administration of systemic corticosteroids, or treatment with systemic corticosteroids for ≥3 days or a long-acting depot corticosteroid preparation with a therapeutic effectiveness of ≥3 days.
Secondary efficacy endpoints included the time to the first asthma exacerbation during the 52-week treatment period and changes from baseline in prebronchodilator FEV1, Asthma Quality of Life Questionnaire score, 5-item Asthma Control Questionnaire score, short-acting rescue therapy use, nighttime awakenings, and asthma daily symptom severity.
Primary endpoint assessment by eosinophil subgroups and changes in biomarkers (blood eosinophils and Feno) were also explored. Safety assessments included incidence and severity of AEs, changes in vital signs, electrocardiograms, clinical laboratory results, and incidence of anti-drug antibodies. See the Online Repository for details of pharmacokinetics assessments, asthma assessments, and laboratory measures.

 Statistical methods

Efficacy analyses were conducted on a modified intention-to-treat population, including all patients who received ≥1 dose of study drug, with patients grouped according to the treatment assigned at randomization. For robust control of type I error in multiple testing, a fixed-sequence procedure comparing from highest to lowest astegolimab dose with placebo within each endpoint was used. Nominal P values are reported.
The primary efficacy outcome of AER was estimated for each arm using Poisson regression with overdispersion that included covariates of treatment arm, baseline blood eosinophil level, number of exacerbations in the prior year, total daily ICS dose, and country. All patients in the modified intention-to-treat population were included in the primary efficacy analysis.

A total of 502 patients were randomized to receive 1 of 3 doses of astegolimab or placebo. This sample size provided approximately 80% power to detect a 40% reduction in AER between one astegolimab group and the placebo group, assuming 0.63 exacerbations per patient per year in the placebo arm, a 15% dropout rate, and a 2-sided significance level (⍺) of 0.05.

 See the Online Repository for sample size calculation for analyses based on blood eosinophil status.

SAS software (SAS Institute, Cary, NC) and R (R Core Team, 2017, Vienna, Austria) were used to perform the analyses. Statistical methods for secondary endpoints, safety, pharmacokinetics, and anti-drug antibodies analyses are described in the Online Repository.

Results

 Patient disposition and baseline characteristics

The ZENYATTA study was conducted from September 20, 2016, through July 26, 2019. Overall, 1437 patients were screened, and 502 were randomized and received ≥1 dose of astegolimab or placebo: 122, 126, 127, and 127 patients were assigned to the 490-mg, 210-mg, 70-mg dose astegolimab groups, and placebo, respectively. A total of 468 patients completed the double-blind treatment period, and 455 patients completed the entire study treatment (Fig E1B).

All 4 treatment groups were well matched by baseline asthma characteristics and demographics (Table I). The majority of patients were female (66.1%) and White (84.1%), median age was 53 years (range 18-75 years), and median body mass index was 27.94 kg/m2 (range 18.4-37.0 kg/m2). Per the eligibility criteria, all patients used daily ICS therapy; of those, 56.4% used a daily dose of >1000 μg fluticasone propionate equivalent. Most patients (94.4%) had 1 to 2 asthma exacerbations in the prior year; 5.6% had ≥3.

Table IBaseline demographic and clinical characteristics
 Placebo Q4WAstegolimabAll patients
70-mg dose Q4W210-mg dose Q4W490-mg dose Q4W
(n = 127)(n = 127)(n = 126)(n = 122)(N = 502)
Age (y)51.4 ± 12.252.4 ± 11.952.5 ± 12.051.4 ± 12.051.9 ± 12.0
Sex, female82 (64.6)81 (63.8)90 (71.4)79 (64.8)332 (66.1)
Race     
 American Indian or Alaska native5 (3.9)5 (3.9)8 (6.3)4 (3.3)22 (4.4)
 Asian6 (4.7)4 (3.1)4 (3.2)9 (7.4)23 (4.6)
 Black8 (6.3)9 (7.1)6 (4.8)6 (4.9)29 (5.8)
 White107 (84.3)105 (82.7)108 (85.7)102 (83.6)422 (84.1)
 Multiple1 (0.8)4 (3.1)01 (0.8)6 (1.2)
Ethnicity, Hispanic or Latino18 (14.2)19 (15.0)15 (11.9)14 (11.5)66 (13.1)
Weight (kg)79.5 ± 13.879.4 ± 15.479.1 ± 13.878.8 ± 14.2879.2 ± 14.3
BMI (kg/m2)28.3 ± 4.228.0 ± 4.428.4 ± 4.027.9 ± 4.228.1 ± 4.2
BMI >30 kg/m247 (37)48 (37.8)49 (38.9)38 (31.1)182 (36.3)
Region     
 North America35 (27.6)31 (24.4)22 (17.5)30 (24.6)118 (23.5)
 Latin America15 (11.8)15 (11.8)15 (11.9)14 (11.5)59 (11.8)
 Eastern Europe71 (55.9)69 (54.3)75 (59.5)68 (55.7)283 (56.4)
 Western Europe/rest of world6 (4.7)12 (9.4)14 (11.1)10 (8.2)42 (8.4)

Daily ICS dose

     
 <1000 μg57 (44.9)54 (42.5)55 (43.7)53 (43.4)219 (43.6)
 ≥1000 μg70 (55.1)73 (57.5)71 (56.3)69 (56.6)283 (56.4)

Asthma exacerbations in prior year

     
 1-2120 (94.5)120 (94.5)120 (95.2)114 (93.4)474 (94.4)
 ≥37 (5.5)7 (5.5)6 (4.8)8 (6.6)28 (5.6)
Pre-bronchodilator FEV1     
 mL1796.3 ± 554.31774.4 ± 481.41807.2 ± 569.41805.4 ± 428.61795.7 ± 510.9
 Percentage of predicted normal value54.6 ± 10.454.6 ± 9.457.6 ± 10.855.4 ± 10.255.6 ± 10.3
AQLQ score4.2 ± 1.04.2 ± 0.94.4 ± 1.04.2 ± 0.94.3 ± 0.9
ACQ-5 score2.8 ± 0.82.7 ± 0.72.8 ± 0.92.8 ± 0.82.8 ± 0.8
Blood eosinophils (cells/μL) at screening262.0 ± 251.4260.2 ± 260.9218.0 ± 193.6246.1 ± 188.0246.7 ± 226.4

Blood eosinophils (cells/μL) at screening

     
 <15043 (33.9)43 (33.9)46 (36.5)41 (33.6)173 (34.5)
 ≥150 to <30052 (40.9)53 (41.7)51 (40.5)50 (41.0)206 (41.0)
 ≥30032 (25.2)31 (24.4)29 (23.0)31 (25.4)123 (24.5)
Feno (ppb)30.1 ± 25.727.5 ± 23.827.9 ± 23.229.1 ± 24.128.7 ± 24.2
ACQ-5, Asthma Control Questionnaire-5; AQLQ, Asthma Quality-of-Life Questionnaire; BMI, body mass index; Feno, fractional exhaled nitric oxide; Q4W, every 4 weeks.
Values are mean ± SD or n (%).
∗ Daily ICS dose, asthma exacerbations, and blood eosinophils were used as stratification factors for randomization

 Primary efficacy endpoint

During the 52-week treatment period, patients experienced a total of 266 asthma exacerbations. The percentage of patients having an asthma exacerbation was 31.1%, 37.3%, and 33.1% in the 490-mg, 210-mg, and 70-mg dose astegolimab groups, respectively, compared with 42.5% in the placebo group. Adjusted annualized AERs were 0.42, 0.58, and 0.47 in the 490-mg, 210-mg, and 70-mg dose astegolimab groups, respectively, and 0.74 in the placebo group (Table II; unadjusted AERs and relative reductions are shown in Fig 1A). Compared with placebo, the relative reduction in AER (adjusted) was 43% in the 490-mg dose astegolimab group (P = .0049) (Table II), which met testing criteria for statistical significance. Adjusted AER reductions were 21.9% in the 210-mg dose astegolimab group (P = .1838) and 36.9% in the 70-mg group (P = .0144). In the prespecified exploratory subgroup analysis of patients who were eosinophil-low (<300 cells/μL), we observed AER reductions over placebo of 54% (P = .0016) and 35% (P = .0473) at the 490-mg and 70-mg doses, respectively (Fig 1B). In the eosinophil-high subgroup (≥300 cells/μL), none of the astegolimab dose groups showed a significant improvement over placebo (Table II). Exploratory analyses of eosinophil subgroups (<150, ≥150 cells/μL) also showed reductions in the AER (Fig 1BTable II) in astegolimab-treated groups.

Table IIAnnualized adjusted AERs and percentage rate reductions in the overall population and in patients stratified by eosinophil subgroups
Eosinophils (cells/μL)Placebo70-mg astegolimab dose210-mg astegolimab dose490-mg astegolimab dose
nAERnAERPercent rate reduction (95% CI)

Rate reduction

P value

nAERPercent rate reduction (95% CI)

Rate reduction

P value

nAERPercent rate reduction (95% CI)

Rate reduction

P value

Overall1270.741270.4736.9 (9 to 56).01441260.5821.9 (−12 to 46).18381220.4243 (16 to 61).0049
<300960.71950.4734.9 (1 to 57).0473990.6213.5 (−30 to 42).4843920.3353.6 (25 to 71).0016
≥300310.83320.5039.9 (−29 to 72).1891260.4348.4 (−27 to 79).1490290.7510.2 (−85 to 56).7718
<150410.69440.5125.4 (−46 to 62).3929470.74−7.4 (−100 to 42).8216420.3745.9 (−11 to 74).0953
≥150860.78830.4542.1 (9 to 63).0172780.4936.6 (−1 to 60).0571790.4541.5 (7 to 63).02
Rates and rate reductions were adjusted for baseline blood eosinophil level, number of exacerbations in the prior year, total daily ICS dose, and country.
Figure thumbnail gr1
Fig 1Annualized AERs in the (A) overall population and in (B) patients stratified by baseline eosinophil levels (Eos; cells/μL). Bars show unadjusted rates by treatment groups. Gray arrows indicate unadjusted percentage rate reductions.

 Secondary efficacy endpoints

Compared with placebo, the 490-mg dose astegolimab group showed a longer time to the first asthma exacerbation (Fig 2A). Additionally, the risk of having an asthma exacerbation was lower in each of the astegolimab groups: 490 mg (hazard ratio, 0.63; 95% CI, 0.42 to 0.96; P = .0326); 210 mg (hazard ratio, 0.84; 95% CI, 0.56 to 1.24; P = .3784); and 70 mg (hazard ratio, 0.70; 95% CI, 0.47 to 1.05; P = .0842).

Figure thumbnail gr2
Fig 2Secondary outcomes. A, Cumulative number of patients with asthma exacerbations over the treatment period. B, Absolute change in FEV1 from baseline to week 54.
None of the astegolimab dose groups showed a significant benefit over placebo in absolute change in prebronchodilator FEV1 at week 54 (Fig 2B). Overall, FEV1 tended to be higher in the 490 mg dose astegolimab group, with the greatest numerical difference (128 mL) occurring at week 50 between the 490-mg astegolimab and placebo groups (Fig 2B). FEV1 improvement appeared to be higher in patients with blood eosinophil levels <150 cells/μL (see Fig E2 in this article’s Online Repository at www.jacionline.org).

The percentage of patients showing an improvement in the Standardized Asthma Quality-of-Life Questionnaire score after 52 weeks was nominally greater in the 490-mg dose astegolimab group over placebo (13.6%; odds ratio, 1.79; 95% CI, 1.01 to 3.18; P = .0463). Astegolimab treatment did not demonstrate significant improvements over placebo in other patient-reported outcomes (Table III).

Table IIISecondary efficacy endpoints from patient-reported outcomes, mITT population
Secondary endpointPlacebo (n = 127)70-mg astegolimab dose (n = 127)210-mg astegolimab dose (n = 126)490-mg astegolimab dose (n = 122)
Achievement of improvement AQLQ(S) score (increase of ≥0.5 points from baseline to week 54)

n

Adjusted rates for responder (Δ), %

Odds ratio (95% CI)

P value

116

55.3

116

64.8 (9.5)

1.49 (0.85 to 2.60)

.1657

115

61.3 (6.0)

1.28 (0.73 to 2.24)

.3866

112

68.9 (13.6)

1.79 (1.01 to 3.18)

.0463

Achievement of improvement in ACQ-5 score at week 54 (decrease of ≥0.5 points from baseline to week 54)

n

Adjusted rates for responder (Δ), %

Odds ratio (95% CI)

P value

117

66.4

116

65.7 (−0.7)

0.97 (0.55 to 1.70)

.9118

116

72.3 (5.9)

1.32 (0.74 to 2.35)

.3468

113

64.6 (−1.8)

0.92 (0.53 to 1.62)

.7832

Absolute change in patient-reported use of short-acting rescue therapy from baseline to week 54

n

Adjusted mean

Δ (95% CI)

P value

107

0

106

0

0 (0 to 0)

.2112

102

0

0 (0 to 0)

.9345

99

0

0 (0 to 0)

.2009

Proportion of weeks without patient-reported asthma-related nighttime awakenings from baseline through week 54

n

Adjusted mean, %

Δ (95% CI), %

P value

127

0.4

126

0.4

−0.0 (0.1 to 0.1)

.8259

126

0.3

−0.1 (−0.1 to 0.0)

.2459

122

0.3

−0.0 (−0.1 to 0.0)

.2972

Absolute change in patient-reported daytime asthma symptom severity as measured by the ADSD from baseline to week 54

n

Adjusted mean

Δ (95% CI)

P value

97

−1

95

−2

0 (−1 to 0)

.1308

96

−1

0 (0 to 0)

.8332

94

−1

0 (−1 to 0)

.3314

ADSD, Asthma Daily Symptom Diary; mITT, modified intention-to-treat; Δ, difference from placebo.
∗ Number of patients with data at week 54 for each endpoint.

 Biomarkers

In all astegolimab treatment groups, we observed substantial and consistent decreases in blood eosinophil counts throughout the 52-week treatment period (Fig 3A). However, there were no significant differences in Feno levels between astegolimab-treated groups relative to placebo (Fig 3B).

Figure thumbnail gr3
Fig 3Mean change from baseline in (A) blood eosinophils and (B) Fenoppb, Parts per billion.

 Safety

During the treatment period, a similar proportion of patients across all cohorts experienced ≥1 AE, regardless of causality (Table IV). The most common AEs (>5% in any treatment group) were asthma symptoms, nasopharyngitis, upper respiratory tract infection, headache, and injection site reaction. Injection site reaction was the most common drug-related AE and was reported more frequently in astegolimab groups (n = 25, 5.0%) than in the placebo group (n = 5, 0.8%). All injection site reactions were nonserious and mild or moderate in severity. A slightly higher number of AEs in the system organ class of nervous system disorders was reported in the highest (490-mg) and lowest (70-mg) dose astegolimab treatment groups (14.8% and 13.4%, respectively) compared with the placebo and 210-mg dose astegolimab groups (6.3% and 7.9%, respectively), mainly due to a higher prevalence of patients reporting AEs of headache or migraine.

Table IVOverview of AEs and AEs occurring in ≥5% of any treatment group
 Placebo Q4WAstegolimabAll patients
70-mg dose Q4W210-mg dose Q4W490-mg dose Q4W
(n = 127)(n = 127)(n = 126)(n = 122)(N = 502)
Total no. of patients with ≥1AE98 (77.2)90 (70.9)91 (72.2)88 (72.1)367 (73.1)
Total no. of AEs3483963514391534
Total no. of deaths001 (0.8)1 (0.8)2 (0.4)
Total no. of subjects withdrawn from study due to an AE00000
Total no. of subjects with ≥1SAE8 (6.3)14 (11.0)9 (7.1)6 (4.9)37 (7.4)
Total no. of subjects with a related AE4 (3.1)15 (11.8)7 (5.6)10 (8.2)36 (7.2)
AEs occurring in ≥5% of any cohort
 Asthma60 (47.2)45 (35.4)56 (44.4)41 (33.6)202 (40.2)
 Nasopharyngitis14 (11.0)12 (9.4)21 (16.7)17 (13.9)64 (12.7)
 Upper respiratory tract infection12 (9.4)9 (7.1)8 (6.3)6 (4.9)35 (7.0)
 Headache6 (4.7)8 (6.3)7 (5.6)14 (11.5)35 (7.0)
 Injection site reaction1 (0.8)10 (7.9)8 (6.3)6 (4.9)25 (5.0)
 Back pain7 (5.5)6 (4.7)5 (4.0)4 (3.3)22 (4.4)
 Rhinitis7 (5.5)7 (5.5)3 (2.4)2 (1.6)19 (3.8)
 Sinusitis3 (2.4)7 (5.5)3 (2.4)6 (4.9)19 (3.8)
 Arthralgia2 (1.6)7 (5.5)4 (3.2)4 (3.3)17 (3.4)
Data are no. (%) of subjects with an AE or number of AEs. AEs were coded with the Medical Dictionary for Regulatory Activities (MedDRA), version 22.0.
Fifty SAEs were reported for 37 patients (7.4%) during the treatment period (see Table E2 in this article’s Online Repository at www.jacionline.org). The number of patients reporting SAEs was comparable across all study groups. The most common SAE among all patients was asthma exacerbation (1.8%), followed by pneumonia (0.6%); other SAEs occurred in 2 patients each (0.4%). One SAE of moderate livedo reticularis (70-mg dose) was reported 2 days after the second dose, leading to discontinuation of astegolimab. This SAE was considered as related to astegolimab and was evaluated as a suspected unexpected serious adverse reaction (see Narrative in this article’s Online Repository at www.jacionline.org). Two patients (0.4%) reported anaphylaxis and hypersensitivity reactions: 1 severe SAE of anaphylactic reaction (placebo) and 1 moderate hypersensitivity related to astegolimab (490-mg dose). Overall, 233 patients (46.4%) reported infections. The number of infections was comparable across all study groups (placebo, 65 [51.2%]; 70-mg dose, 55 [43.3%]; 210-mg dose, 58 [46.0%]; 490-mg dose, 55 [45.1%]). The most frequently reported infection (12.7% incidence) was nasopharyngitis.
Two deaths, unrelated to study drug, were reported: 1 patient died following an SAE of asthma exacerbation (210-mg dose group); another patient’s death (490-mg dose group) was unexplained (see Narrative in the Online Repository). No clinically meaningful changes in laboratory parameters, vital signs, or electrocardiograms occurred, and these changes raised no safety concerns.

 Pharmacokinetics and immunogenicity

Astegolimab pharmacokinetics were approximately dose proportional (see Fig E3 in this article’s Online Repository at www.jacionline.org). Anti-drug antibodies positivity was low (7.3% of all patients), comparable between astegolimab groups, and did not appear to affect astegolimab pharmacokinetics, efficacy, or safety (see Table E3 in this article’s Online Repository at www.jacionline.org).

Discussion

ZENYATTA is the first study to examine the effect of IL-33 pathway inhibition on asthma exacerbations. The study met the primary endpoint of AER reduction over placebo at 490-mg doses of astegolimab every 4 weeks, the highest dosage tested. At this dosage, astegolimab also showed a nominally significant increase in the time to the first asthma exacerbation. Overall, all doses of astegolimab were safe and well tolerated, with similar AE rates and intensity (mostly mild to moderate) between placebo and treatment arms. Two deaths that occurred (1 following an SAE of asthma exacerbation and 1 unexplained death in a patient lost to follow-up) were deemed unrelated to study drug. While no clear dose-response relationship was observed between the doses of astegolimab tested and AER, only the 490-mg dose astegolimab group showed a nominally significant improvement in Asthma Quality of Life Questionnaire and a trend of increased FEV1 over placebo.

Multiple pathways lead to asthma disease pathology and exacerbations. Drugs targeting these pathways have demonstrated the importance of eosinophils and T2 cytokines. ,  However, recent studies in severe asthma identified T2-low asthma as a distinct subtype characterized by increased severity and remodeling and poorer response to anti-inflammatory treatment.

 While understanding of T2-low asthma mechanisms lags far behind that of T2-high asthma pathways, dysregulated innate immune responses (ie, T2 innate lymphoid cells), neutrophils, the inflammasome, IL-17, and alarmins such as IL-33 may be important., In ZENYATTA, enrollment of patients who were eosinophil-low was enriched to ensure that the trial was powered to evaluate AER reductions in this subgroup with the highest unmet need. Reductions in AER and improvements in lung function in patients who were eosinophil-low were observed with astegolimab treatment, suggesting that in this subgroup, IL-33-dependent pathways are pathogenic and linked to these outcomes.
Further work is needed to explore IL-33-dependent pathways active in patients who are eosinophil-low, but current evidence indicates that IL-33 release, in response to irritants such as viral infections and cigarette smoke, can contribute to nonspecific tissue damage. , Because the environment regulates IL-33 bioactivity, different cellular populations in the lung (epithelium, mesenchymal cells, smooth muscle, and macrophages) can produce IL-33, and ST2 is expressed by cell types that are not exclusive to T2-high inflammation (eg, mast cells, neurons, endothelial cells, macrophages, neutrophils, and lymphocytes), IL-33 can therefore act upstream, directly activating immune and nonimmune cells to promote inflammation.  Its direct effect on mast cells is particularly intriguing, given that patients with asthma exhibit elevated mast cell density within airway smooth muscle, regardless of eosinophil levels, and mast cells are implicated in regulation of airway hypercontractility. , , Additionally, IL-33 activation of neutrophils and natural killer cells may contribute to pathologies following fungal or bacterial infections or toxin exposure. IL-33 may also regulate eosinophil biology through direct effects on eosinophil progenitor maturation, and we observe decreases in blood eosinophils with astegolimab treatment. These properties position IL-33 as a central mediator of airway inflammation, which is shaped by the nature of the insult to the lung tissue. While these data support a unique role for IL-33 in T2-low inflammation, they also highlight the existence of redundant mechanisms regulating T2-high inflammation. ,  In our study, the effects of IL-33 pathway inhibition were not as pronounced in the eosinophil-high population, and furthermore, Feno levels (an airway biomarker that is reduced after IL-4/IL-13 pathway blockade in asthma ) were unchanged.
Based on the accepted definition, asthma exacerbations are recognized to be infrequent events, complicating their utility as an endpoint in severe asthma trials and leading to the more recent development of composite endpoints such as CompEx.  A CompEx event is defined as the first occurrence of either a diary event or an asthma exacerbation. Of note, while this study was powered to test the effect of each of the astegolimab treatment arms in reducing the rate of asthma exacerbations over placebo, it was not powered to determine differences in treatment effect within astegolimab treatment arms, which would have required a larger sample size. Given these limitations, the differences in exacerbation rate reduction at the 210-mg dose may be due to chance findings or endpoint variability, rather than reflecting a true difference in treatment effect between the 70-mg dose arm and the 210-mg dose arm. Our study was also limited by the lower than expected observed AER in the placebo arm for the eosinophil-high subgroup (0.83 instead of 1.00). This led to reduced power for detecting a significant change in the eosinophil-high subgroup and might explain the lack of significant clinical improvement in that subgroup despite a reduction in blood eosinophils. Nevertheless, we note that this underpowering would not explain the consistent lack of FEV1 change in the eosinophil-high subgroup.

In conclusion, this first clinical evaluation of IL-33/ST2 pathway blockade on exacerbation frequency in patients with low blood eosinophils (<300 cells/μL) reveals a beneficial effect of astegolimab in a population with a significant unmet medical need. These data highlight IL-33’s pathogenic role in inflammation driven by non-T2 pathways and suggest astegolimab may be beneficial in other airway diseases where T2 inflammation is not the predominant mode of tissue damage. Further studies are needed to investigate astegolimab in these other conditions and elucidate the molecular mechanisms of pathogenic IL-33 activity.

Fuente: ASTHMA AND LOWER AIRWAY DISEASE| VOLUME 148, ISSUE 3P790-798, SEPTEMBER 01, 2021
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