ars.els-cdn.com · Web view0.37 (0.47) NR Placebo 16 1.65 (0.58) 246 0.24 (0.47) NR CALIMA a, FitzGerald 20164(high ICS) Benralizumab 30 mg q4w to q8w 16 1.76 (0.62) 239 0.31 (0.50)

Supplementary Appendix

Pairwise indirect treatment comparison of dupilumab versus other biologics in patients with uncontrolled persistent asthma

1

Supplementary information

Table E1. Details of studies identified by the SLR and included in the analysis.

Study name, author year

Dosage of interest

Treatment duration,weeks

ITT population, N

Severe exacerbations in previous year, n

Included in ITC, N

Outcomes used in the ITC

Uncontrolled persistent asthma trials

Dupilumab

QUEST, Castro 20151

CSR data200 mg, 300 mg q2w 52 1,902 ≥ 1

Compared with mepolizumab: 406 (21.3%)Compared with reslizumab:556 (29.2%)Compared with benralizumab: 439 (23.1%)Compared with omalizumab: 762 (40.0%)Full ITT scenario: 1,902

Ex, F: Wks 12, 24F%: Wks 24, 52

DRI, Asthma phase 2b (DRI), Wenzel 20162

CSR data

300 mg q2w 24 All Tx arms: 776Tx arms of interest: 465

≥ 1 Compared with mepolizumab: 112 (24.1%)Compared with reslizumab: 128 (27.5%)Compared

Ex, F: Wks 12, 24F%: Wks 24

2


Dosage of interest


ITT population, N


Included in ITC, N


with benralizumab: 100 (21.5%)Compared with omalizumab: 210 (45.2%)Full ITT scenario: 465*

MepolizumabMUSCA, Chupp 20173 100 mg q4w 20 551 ≥ 2 551 Ex, F: Wks 12,

24

MENSA, Ortega 20144

75 mg, 100 mg q4w 32

All Tx arms: 576 ≥ 2 576 Ex, F: Wk 24

DREAM, Pavord 20125 75 mg q4w 52

All Tx arms: 621Tx arms of interest: 308

≥ 2 308* Ex, F: Wks 12, 24

ReslizumabBREATH (study 3081),

Bjermer 20166

3 mg/kg q4w 16 315 NR 211 F: Wk 16

BREATH (study 3082),

Castro 20151

3 mg/kg q4w 52 489 ≥ 1 489 Ex, F: Wks 12, 24


Castro 20151

3 mg/kg q4w 52 464 ≥ 1 464 Ex, F: Wks 12, 24

3


Dosage of interest


ITT population, N


Included in ITC, N



Corren 20167

3 mg/kg q4w 16 496 NR 496 F: Wk 16

Castro 20118 3 mg/kg q4w 12 106 NR 106 Ex, F: Wk 12

Benralizumab

SIROCCO, Bleecker 20169

30 mg q8w 48All Tx arms: 1,204Tx arms of interest: 805

≥ 2 805* Ex, F: Wks 12, 24

SIROCCO, Bleecker 20169 (≥ 300 EOS subgroup)

30 mg q8w 48

All Tx arms: 1,204Tx arms of interest: 805Patients with ≥ 300 EOS and high dose ICS: 534

≥ 2 534* Ex, F: Wks 12, 24

CALIMA, FitzGerald 201610

30 mg q8w 56All Tx arms: 1,306Tx arms of interest: 881

≥ 2 881* Ex, F: Wks 12, 24

CALIMA, FitzGerald 201610 (≥ 300 EOS subgroup)

30 mg q8w 56All Tx arms: 728Tx arms of interest: 487

≥ 2 487* Ex, F: Wks 12, 24

OmalizumabEXTRA, Hanania 201311

150–375 mg 48 848 ≥ 1 848 Ex, F%: Wks 24, 52

EXTRA, 150–375 mg 48 848 ≥ 1 414 Ex, F%: Wks

4


Dosage of interest


ITT population, N


Included in ITC, N


Hanania 201311

(≥ 260 EOS subgroup)

24, 52

INNOVATE, Humbert 200512

150–375 mg 28 482 ≥ 2 482 Ex

INNOVATE, Manga 201613


150–375 mg 28 482 ≥ 2 245 Ex

* Not all treatment arms were included, as not all dosages/routes of administration were approved/recommended.CSR, clinical study report; EOS, eosinophil; Ex, exacerbation; ITC, indirect treatment comparison; ITT, intent-to-treat; F, forced expiratory volume in 1 second (FEV1); F%, % predicted FEV1; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks; q8w, every 8 weeks; SLR, systematic literature review; Tx, treatment; Wk, Week.

Table E1 references

1. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3:355-66.

2. Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388:31-44.

3. Chupp GL, Bradford ES, Albers FC, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5:390-400.

4. Ortega HG, Liu MC, Pavord ID, et al.; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-207.5. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380:651-9.6. Bjermer L, Lemiere C, Maspero J, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest.

2016;150:789-98.

5

7. Corren J, Weinstein S, Janka L, Zangrilli J, Garin M. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016;150:799-810.

8. Castro M, Mathur S, Hargreave F, et al; Res-5-0010 Study Group. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184:1125-32.

9. Bleecker ER, FitzGerald JM, Chanez P, et al; SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-27.

10. FitzGerald JM, Bleecker ER, Nair P, et al; CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388:2128-41.

11. Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187:804-11.

12. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60:309-16.

13. Manga V, Humbert M, Djukanovic R, et al. Blood eosinophils and serum IgE predict response to omalizumab in patients with severe allergic asthma: Innovate trial post-hoc analysis. J Allergy Clin Immunol. 2016;137 Suppl:AB16.

6

Table E2. Definitions of severe exacerbations for each of the studies.Study Drug Definition of Exacerbations Hospitalization

ComponentER Component

OCS Component Exacerbation Reporting Time Points

Dupilumab A severe exacerbation event was defined as a deterioration of asthma requiring either the use of systemic corticosteroids for ≥3 days or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids.

Yes ER visit Systemic use for ≥3 days

Annualized rate (52-week follow-up)

Mepolizumab Clinically significant exacerbations were defined as worsening of asthma such that the treating physician elected to administer systemic glucocorticoids for at least 3 days or the patient visited an emergency department or was hospitalized.


Rate (32 weeks)

Reslizumab Clinical asthma exacerbations were defined as worsening of asthma that resulted in use of systemic corticosteroids in patients not already receiving treatment, or a two-times increase in the dose of either inhaled corticosteroids or systemic corticosteroids for 3 or more days, or the need for asthma-related emergency treatment (emergency room visit, hospital admission, or unscheduled physician’s office visit for nebulizer or other urgent treatment).


Rate (52 weeks)

Benralizumab An exacerbation was defined as a worsening of asthma that led to one of the following: (1) use of systemic corticosteroids, or temporary increase in a stable oral corticosteroid background dosage, for at least 3 days or a single injectable dose of corticosteroids; (2) emergency department or visit to an urgent care center (< 24 hours) because of asthma that needed systemic corticosteroids; or (3) inpatient hospital stay (>= 24 hours) because of asthma.

Yes ER or urgent care visit

Systemic use or temporary increase in stable OCS use for ≥3 days or a single injectable dose

Annualized rate (48-week follow-up)

Omalizumab An exacerbation with worsening asthma symptoms requiring treatment with systemic corticosteroids for ≥3 days; for patients receiving long-term OCS, an exacerbation was a ≥20 mg in the average daily dose of oral prednisone (or a comparable dose of another systemic corticosteroid).EXTRA/INNOVATE: clinically significant exacerbations, which was defined as worsening of asthma symptoms requiring treatment with systemic corticosteroids.

Not defined Not defined Systemic use for ≥3 days or ≥20 mg increase in the average daily dose of oral prednisone (or a comparable dose of another systemic corticosteroid)

Rate [HR; p-values] (48-week)

7

Table E3. Baseline characteristics of dupilumab subgroups: (A) compared with benralizumab; (B) compared with mepolizumab; (C) compared with reslizumab; and (d) dupilumab’s allergic and eosinophilic population compared with omalizumab’s eosinophilic subgroup.

(A)

ITT population or subgroup Trial N % total ITT

population

ICS/LABA baseline dose,μg/day

Blood EOS level at baseline, cells/µL

Previous exacerbations (prior year)

Age, years

Predicted FEV1 reversibility, %

InclusionMean baseline ICS (SD)

Inclusion Median (range) Inclusion Mean baseline (SD) Inclusion Mean

baseline (SD) Median

Compared with benralizumab

QUEST 439 439/1,902 (23.1%) Medium/high 803 (313) ≥ 300 560 (300–4,330) ≥ 2 3.3 (2.3) ≥ 12 47.9 (14.6) 21.0

Asthma phase 2b study (DRI)

100 100/465 (21.5%)* Medium/high NR ≥ 300 480 (300–2,060) ≥ 2 3.8 (2.9) ≥ 18 48.3 (13.4) NR

Subgroup ≥ 300

EOS (high ICS) (benralizumab)

SIROCCO 534 534/1,204(44.4%)a Medium/high 908 (NR) ≥ 300 500 (300–3,100) ≥ 2 3.0 (1.8) 12–75 48.1 (14.7) 20.5

Subgroup ≥ 300 EOS (high ICS) (benralizumab)b

CALIMA 487 487/1,306(37.3%)* Medium/highb 966 (NR) ≥ 300 505 (300–4,494) ≥ 2 2.8 (1.5) 12–75 49.0 (13.6) 20

Subgroup ≥ 300 EOS (medium ICS) (benralizumab)†

CALIMA 96 96/1,306(7.4%)a Medium/highb NR ≥ 300 NR ≥ 2 NR 12–75 NR NR

a Not all treatment arms from the trial are included since not all dosages/routes of administration were approved.bFor severe exacerbations, data based on treatment doses of interest were included for subgroups ≥ 300 EOS and high-dose ICS and ≥ 300 EOS and medium-dose ICS. For CFB in FEV1, data were available and included for subgroup ≥ 300 EOS and high-dose ICS. For CALIMA, no baseline characteristics were reported for the medium-dose ICS subgroups.CFB, change from baseline; EOS, eosinophil; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; ITT, intent-to-treat; LABA, long-acting 2-agonist; NR, not

reported; SD, standard deviation.

8

(B)

ITT population or subgroup Trial N % total ITT

population

ICS/LABA baseline dose, μg/day



Age, years



Inclusion Geometric mean baseline

Inclusion

Mean baseline (SD)

InclusionMean baseline (SD)

Mean (SD)

Compared with mepolizumab

QUEST 406 406/1,902 (21.3%) High 1,009 (221) ≥ 150 405a ≥ 2 3.2 (2.0) ≥ 12 49.6 (13.4) 26.5 (19.5)


112 112/465 (24.1%)b High NR ≥ 150 366a ≥ 2 3.8 (2.9) ≥ 12 50.8 (12.0) NR

ITT(mepolizumab)

MENSA 576 100%

Medium/high (< 18 years); high (≥ 18 years)

NR ≥ 150c 296a ≥ 2 3.6 (2.6) 12–82 50.0 (NR) 27 (21.5)

MUSCA 551 100%

Medium/high (< 18 years); high (≥ 18 years)

NR ≥ 150c 330a ≥ 2 2.8 (1.7) ≥ 12 50.9 (13.5) 21.3 (22.4)

DREAM 308 308/616 (50%)b High NR

≥ 300 or sputum-EOS ≥ 3% or FeNO ≥ 50 ppb

265a ≥ 2 3.7 (3.5) 12–74 48.3 (11.1) ~ 28d (NR)

The mean baseline values were derived by taking a weighted average of the study arms included in the ITC analysis.Allergic: total IgE 30–700 IU/mL and ≥ 1 perennial aeroallergen-specific IgE ≥ 0.35 kU/L.

9

a Geometric means presented for dupilumab trials to align with baseline data reported in mepolizumab trials.b Not all treatment arms from the trial are included since not all dosages/routes of administration were approved or were bioequivalent.c Baseline EOS ≥ 150 at screening or ≥ 300 cells/µL in the prior year.d Pulmonary-Allergy Drug Advisory Committee June 11, 2015 [BLA 125-526], Slide 7 (p. 16): Study 97.EOS, eosinophil; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; ITT, intent-to-treat; LABA, long-acting 2-agonist; NR, not reported; SD, standard deviation.

10

(C)

ITT population or subgroup

Trial N % total ITT population



Previous exacerbations

(prior year)

Age, years



Inclusion

Mean baseline (SD) Inclusion

Mean baseline (SD)

InclusionMean baseline (SD) Mean (SD)

Compared with reslizumab

QUEST 556 556/1,902 (29.2%) Medium/high 768 (294) ≥ 400

738 (417)≥ 1 2.3 (2.1) ≥ 18 49.8 (13.3) 25.6 (19.8)


128 128/465 (27.5%)a Medium/high

NR% with high ICS: 57%

≥ 400682 (381)

≥ 1 2.4 (2.2) ≥ 18 48.2 (13.0) NR

ITT(reslizumab)

BREATH (study 3082) 489 100% Medium/high 836 (412) ≥ 400 660 (681) ≥ 1 2.0 (2.0) 12–75 48.5 (14.1) 26.2 (16.8)

BREATH (study 3083) 464 100% Medium/high 807 (459) ≥ 400 649 (563) ≥ 1 2.0 (1.7) 12–75 48.0 (13.7) 28.4 (20.3)

BREATH (study 3081) 211 67%a Medium/high 785 (NR) ≥ 400 597 (NR) NR NR 12–75 43.6 (NR) 25.8 (NR)

Castro 20111 106 100% High NR Sputum-EOS ≥ 3% 500 (NR) NR NR 18–75 45.4 (12.8) NR

Subgroup ≥ 400 EOS (reslizumab)

BREATH (study 3084) 96 19% Medium/high NR ≥ 400 NR NR NR NR NR NR

The mean baseline values were derived by taking a weighted average of the study arms included in the ITC analysis.aNot all treatment arms from the trial are included since not all dosages/routes of administration were approved.

11

EOS, eosinophil; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; ITC, indirect treatment comparison; ITT, intent-to-treat; LABA , long-acting 2-agonist; NR, not reported; SD, standard deviation.

(D)

ITT population or subgroup

Trial N % total ITT population


IgE level at baseline, IU/mL


Age, years


Inclusion Mean baseline ICS (SD) Inclusion

Mean baseline (SD) Inclusion

Mean baseline (SD)

InclusionMean baseline (SD)

Mean (SD]

Dupilumab’s allergic and eosinophilic subgroupa

QUEST 300300/1,902(15.8%)

Medium/high 757 (314) 30–700 290 (176) ≥ 1b 2.0 (1.7) ≥ 12 44.4 (14.8) 26.5 (19.7]


8484/465(18.1%)b Medium/high NR 30–700 298 (175) ≥ 1 2.3 (2.0) ≥ 12 45.2 (13.1) NR

Omalizumab’s eosinophilic subgroup

INNOVATE, Manga 20162

(EOS > 300)

245 245/482 (50.8%) High NR 30–700 NR ≥ 2 NR 12–75 NR NR

EXTRA, Hanania 20133

(EOS > 260)

414 414/848 (48.8%) High NR 30–700 196 (140) ≥ 1 2.0 (2.0) 12–75 44.0 (15.0) NR

The mean baseline values were derived by taking a weighted average of the study arms included in the ITC analysis. a Dupilumab’s allergic and eosinophilic subgroup: medium/high ICS, total IgE 30–700 IU/mL and ≥ 1 positive perennial aeroallergen-specific IgE (≥ 0.35 kU/L), and EOS ≥ 300.b Not all treatment arms from the trial are included since not all dosages/routes of administration were approved.EOS, eosinophil; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; IgE, immunoglobulin E; ITT, intent-to-treat; LABA, long-acting 2-agonist; NR, not reported; SD, standard deviation.

12

Table E3 references

1. Castro M, Mathur S, Hargreave F, et al; Res-5-0010 Study Group. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184:1125-32.

2. Manga V, Humbert M, Djukanovic R, et al. Blood eosinophils and serum IgE predict response to omalizumab in patients with severe allergic asthma: Innovate trial post-hoc analysis. J Allergy Clin Immunol. 2016;137 Suppl:AB16.


13

Table E4. Severe exacerbation rates by individual dupilumab subgroups and comparator arms: (A) dupilumab and benralizumab; (B) dupilumab and mepolizumab; (C) dupilumab and reslizumab; and (D) dupilumab allergic and eosinophilic subgroup and omalizumab’s eosinophilic subgroup.

(A)

Trial Treatment Follow-up, weeks N Person-years Rate

(95% CI)Rate ratio (95% CI)

QUEST, Castro 20151

Dupilumab 200 mg q2w 52 140 136.6 0.40 (0.29–0.55) 0.25 (0.16–0.38)

Placebo 52 77 71.4 1.58 (1.17–2.13) Reference armDupilumab 300 mg q2w 52 144 130.2 0.38 (0.27–0.52) 0.26 (0.17–0.40)

Placebo 52 78 74.0 1.43 (1.07–1.93) Reference arm

Asthma phase 2b study (DRI), Wenzel 20162

Dupilumab 200 mg q2w 24 30 12.6 0.50 (0.18–1.34) 0.37 (0.12–1.19)

Dupilumab 300 mg q2w 24 36 15.5 0.26 (0.09–0.80) 0.20 (0.06–0.69)


SIROCCOa, Bleecker 20163

(high ICS)

Benralizumab 30 mg q4w to q8w

48 267 246.5 0.65 (0.53–0.80) 0.49 (0.37–0.64)


CALIMAa, FitzGerald 20164

(high ICS)


56 239 257.4 0.66 (0.54–0.82) 0.72 (0.54–0.95)

Placebo 56 248 267.1 0.93 (0.77–1.12) Reference armCALIMAa, FitzGerald 20164

(medium ICS)


56 49 52.8 0.27 (NR) 0.48 (0.22–1.03)

Rate ratios presented by study were adjusted for patient-level covariates in a negative binomial model.Person-years were calculated, when not reported, by the number of patients randomized multiplied by the number of years of follow-up, except the dupilumab trials.a Data from SIROCCO3 and CALIMA4 were not available for the full ITT population; therefore, data for a subgroup of patients with baseline EOS ≥ 300 were included.CI, confidence interval; EOS, eosinophil; ITT, intent-to-treat; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks; q8w, every 8 weeks.

14

(B)

Trial Treatment Follow-up, weeks Person-years N Rate (95% CI) Rate ratio

(95% CI)

QUEST, Castro 20151

Dupilumab 200 mg q2w 52 119.4 124 0.57 (0.41–0.79) 0.33 (0.21–0.50)

Placebo 52 66.4 75 1.75 (1.26–2.44) Reference armDupilumab 300 mg q2w 52 116.2 130 0.52 (0.37–0.72) 0.38 (0.24–0.59)

Placebo 52 72.3 77 1.36 (0.98–1.89) Reference arm


Dupilumab 200 mg q2w 24 13.7 33 0.56 (0.20–1.57) 0.47 (0.15–1.46)

Dupilumab 300 mg q2w 24 18.6 42 0.55 (0.23–1.31) 0.46 (0.16–1.27)


MENSA, Ortega 20145

Mepolizumab 100 mg q4w SC 32 119.4 194 0.81 (NR) NR

Mepolizumab 75 mg q4w IV 32 117.5 191 0.93 (NR) NR

Placebo 32 117.5 191 1.75 (NR) NR

MUSCA, Chupp 20176

Mepolizumab 100 mg q4w 24 126.5 274 0.51 (NR) 0.42 (0.31–0.56)

Placebo 24 127.8 277 1.21 (NR) Reference armDREAM, Pavord 20127

Mepolizumab 75 mg q4w IV 52 153.0 153 1.24 (1.00–1.48) 0.52 (0.39–0.69)

Placebo 52 155.0 155 2.40 (2.18–2.62) Reference armPerson-years were calculated, when not reported, by the number of patients randomized multiplied by the number of years of follow-up, except the dupilumab trials. CI, confidence interval; IV, intravenous; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks; SC, subcutaneous.

15

(C)

Trial Treatment Follow-up, weeks N Person-years Rate

(95% CI)Rate ratio(95% CI)

QUEST, Castro 20151

Dupilumab 200 mg q2w 52 17

7 164.7 0.35 (0.26–0.49) 0.27 (0.17–0.42)

Placebo 52 101 92.8 1.31 (0.96–

1.77) Reference arm

Dupilumab 300 mg q2w 52 17

9 159.6 0.40 (0.30–0.55) 0.33 (0.22–0.51)



Dupilumab 200 mg q2w 24 46 20.0 0.39 (0.16–

0.97) 0.29 (0.10–0.82)

Dupilumab 300 mg q2w 24 37 15.5 0.12 (0.03–

0.56) 0.09 (0.02–0.44)


BREATH (study 3082/3083 pooleda), Castro 20151

Reslizumab 3 mg/kg q4w 52 47

7 477.0 0.84 (NR) 0.46 (0.37–0.58)

Placebo 52 476 476.0 1.81 (NR) Reference arm

Rate ratios presented by study were adjusted for patient-level covariates in a negative binomial model. Person-years were calculated, when not reported, by the number of patients randomized multiplied by the number of years of follow-up, except the dupilumab trials. a Castro 20151 reported pooled patients baseline and outcome for 2 BREATH trials, which were used in the ITC as 1 data input.CI, confidence interval; ITC, indirect treatment comparison; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks.

16

(D)

Trial Treatment Follow-up,weeks Person-years N Rate (95% CI) Rate ratio (95%

CI)

QUEST, Castro 20151

Dupilumab 200 mg q2w 52 88.1 89 0.45 (0.30–

0.68) 0.57 (0.33–0.99)


Dupilumab 300 mg q2w 52 97.8 101 0.45 (0.31–

0.67) 0.43 (0.24–0.76)



Dupilumab 200 mg q2w 24 9.2 20 0.57 (0.17–

1.85) 0.58 (0.16–2.19)

Dupilumab 300 mg q2w 24 14.8 33 0.31 (0.10–

0.91) 0.31 (0.09–1.14)


INNOVATE, Manga 20168 (baseline EOS ≥ 300 cells/µL)

Omalizumab 150–375 mg q4w/q2w 28 NR NR NR 0.61 (0.38–0.98a)

Placebo 28 NR NR NR Reference armEXTRA, Hanania 20139

(baseline EOS ≥ 260 cells/µL)

Omalizumab 150–375 mg q4w/q2w 48 197.5 214 0.7 (NR) 0.68 (0.52–0.89)

Placebo 48 184.6 200 1.03 (NR) Reference armPerson-years were calculated when not reported, by the number of patients randomized multiplied by the number of years of follow-up, except the dupilumab trials. Allergic: total IgE 30–700 IU/mL and ≥ 1 perennial aeroallergen-specific IgE ≥ 0.35 kU/L.a Calculated from p value.CI, confidence interval; EOS, eosinophils; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks.

17

Table E4 references



3. Bleecker ER, FitzGerald JM, Chanez P, et al; SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-27.


5. Ortega HG, Liu MC, Pavord ID, et al.; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-207.6. Chupp GL, Bradford ES, Albers FC, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic

asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5:390-400.7. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380:651-9.8. Manga V, Humbert M, Djukanovic R, et al. Blood eosinophils and serum IgE predict response to omalizumab in patients with severe allergic asthma: innovate trial post-hoc

analysis. J Allergy Clin Immunol. 2016;137 Suppl:AB16.9. Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med.

2013;187:804-11.

18

Table E5. Change in FEV1 (L) from baseline by individual treatment arms: (A) dupilumab and benralizumab at 12 weeks; (B) dupilumab and benralizumab at 24 weeks; (C) dupilumab and mepolizumab at 12 weeks; (D) dupilumab and mepolizumab at 24 weeks; (E) dupilumab and reslizumab at 12 weeks; (F) dupilumab and reslizumab at 24 weeks; and (G) and (H) dupilumab allergic and eosinophilic subgroup and omalizumab’s eosinophilic subgroup at Week 24 and Week 52, respectively.

(A)

Trial Treatment

Follow-up, weeks

Baseline mean (SD) N CFB, mean (SD) MD (95% CI)

QUEST, Castro 20151

Dupilumab 200 mg q2w 12 1.75 (0.67) 138 0.49 (0.47) 0.23 (0.12–0.35)

Placebo 12 1.78 (0.64) 74 0.26 (0.43) Reference armDupilumab 300 mg q2w 12 1.66 (0.52) 139 0.52 (0.47) 0.23 (0.11–0.34)

Placebo 12 1.62 (0.44) 77 0.29 (0.44) Reference arm


Dupilumab 200 mg q2w 12 1.69 (0.45) 27 0.48 (0.47) 0.25 (0.02–0.49)

Dupilumab 300 mg q2w 12 1.62 (0.40) 33 0.51 (0.46) 0.29 (0.06–0.51)



(high ICS)


16 1.67 (0.58) 250 0.37 (0.47) NR

Placebo 16 1.65 (0.58) 246 0.24 (0.47) NRCALIMAa, FitzGerald 20164

(high ICS)


16 1.76 (0.62) 239 0.31 (0.50) NR

Placebo 16 1.82 (0.65) 248 0.21 (0.50) NRQUEST pooled placebo data: N = 155; baseline mean: 1.70 (SD: 0.55), CFB mean: 0.27 (SD: 0.03), MD dupilumab 300 mg vs placebo: 0.24 (95% CI: 0.15–0.34),MD dupilumab 200 mg vs placebo: 0.21 (95% CI: 0.12–0.31).a FEV1 change from baseline from SIROCCO3 and CALIMA4 were only available for the subgroup patients with high-dose ICS and baseline EOS ≥ 300; therefore, data for the subgroup of patients were included.CFB, change from baseline; CI, confidence interval; EOS, eosinophil; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; MD, mean difference; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks; q8w, every 8 weeks; SD, standard deviation.

19

(B)

Trial Treatment Follow-up, weeks


QUEST, Castro 20151

Dupilumab 200 mg q2w 24 1.75 (0.67) 140 0.51 (0.47) 0.26 (0.14–0.38)




Dupilumab 200 mg q2w 24 1.69 (0.45) 27 0.45 (0.42) 0.29 (0.07–0.51)

Dupilumab 300 mg q2w 24 1.62 (0.40) 33 0.46 (0.40) 0.30 (0.09–0.50)



(high ICS)


24 1.67 (0.58) 251 0.38 (0.48) NR

Placebo 24 1.65 (0.58) 247 0.26 (0.47) Reference armCALIMAa, FitzGerald 20164

(high ICS)


24 1.76 (0.62) 239 0.31 (0.50) NR

Placebo 24 1.82 (0.65) 248 0.20 (0.50) NRQUEST pooled placebo data: N = 155; baseline mean: 1.70 (SD: 0.55), CFB mean: 0.30 (SD: 0.04), MD dupilumab 300 mg vs placebo: 0.21 (95% CI: 0.11–0.30), MD dupilumab 200 mg vs placebo: 0.21 (95% CI: 0.12–0.31).a FEV1 change from baseline from SIROCCO3 and CALIMA4 were only available for the subgroup patients with high-dose ICS and baseline EOS ≥ 300; therefore, data for the subgroup of patients were included.CFB, change from baseline; CI, confidence interval; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; MD, mean difference; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks; q8w, every 8 weeks; SD, standard deviation.

20

(C)

Trial Treatment

Follow-up, weeks


QUEST, Castro 20151

Dupilumab 200 mg q2w

12 1.70 (0.56) 123 0.33 (0.44) 0.09 (−0.02 to 0.20)

Placebo 12 1.76 (0.54) 71 0.24 (0.42) Reference armDupilumab 300 mg q2w

12 1.63 (0.51) 125 0.43 (0.45) 0.13 (0.02–0.24)

Placebo 12 1.60 (0.45) 76 0.30 (0.44) Reference armAsthma phase 2b study (DRI), Wenzel 20162/Haldar 20095


12 1.63 (0.46) 29 0.28 (0.38) 0.21 (0.02–0.40)


12 1.69 (0.50) 40 0.31 (0.38) 0.24 (0.07–0.42)


MUSCA, Chupp 20176

Mepolizumab 100 mg q4w

12 1.80 (0.60) 274 0.17 (0.50) NR

Placebo 12 1.70 (0.60) 277 0.05 (0.33) NRDREAM, Pavord 20127

Mepolizumab 75 mg q4w IV

12 1.90 (0.65) 154 0.12 (NR) NR

Placebo 12 1.81 (0.64) 159 0.13 (NR) NRQUEST pooled placebo data: N = 152; baseline mean: 1.67 (SD: 0.57), CFB mean: 0.27 (SD: 0.03), MD dupilumab 300 mg vs placebo: 0.16 (95% CI: 0.07–0.25), MD dupilumab 200 mg vs placebo: 0.06 (95% CI: −0.03 to 0.15).CFB, change from baseline; CI, confidence interval; IV, intravenous; MD, mean difference; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks; SD, standard deviation.

21

(D)


Baseline mean (SD) N CFB, mean

(SD)MD(95% CI)

QUEST, Castro 20151

Dupilumab 200 mg q2w 24 1.70 (0.56) 123 0.34 (0.44) 0.14 (0.02–0.26)

Placebo 24 1.76 (0.54) 68 0.20 (0.41) Reference armDupilumab 300 mg q2w 24 1.63 (0.51) 123 0.40 (0.44) 0.11 (−0.01 to

0.23)Placebo 24 1.60 (0.45) 69 0.29 (0.42) Reference arm


Dupilumab 200 mg q2w 24 1.63 (0.46) 29 0.24 (0.38) 0.23 (0.07–0.40)

Dupilumab 300 mg q2w 24 1.69 (0.50) 40 0.27 (0.38) 0.27 (0.11–0.42)


MENSA, Ortega 20148

Mepolizumab 100 mg q4w 32 1.73 (0.66) 194 0.18 (0.42) 0.10 (0.01–0.18)

Mepolizumab 75 mg q4w IV 32 1.86 (0.70) 191 0.19 (0.03) 0.10 (0.01–019)


MUSCA, Chupp 20176

Mepolizumab 100 mg q4w 24 1.89 (0.60) 264 0.18 (0.49) 0.12 (0.05–0.19)


DREAM, Pavord 20127

Mepolizumab 75 mg q4w IV 24 1.90 (0.65) 154 0.13 (NR) NR

Placebo 24 1.81 (0.64) 159 0.12 (NR) Reference armQUEST pooled placebo data: N = 152; baseline mean: 1.68 (SD: 0.5), CFB mean: 0.25 (SD: 0.04), MD dupilumab 300 mg vs placebo: 0.15 (95% CI: 0.05–0.25), MD dupilumab 200 mg vs placebo: 0.10 (95% CI: 0.00–0.20).CFB, change from baseline; CI, confidence interval; IV, intravenous; MD, mean difference; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks; SD, standard deviation.

22

(E)

Trial TreatmentFollow-up, weeks

Baseline mean (SD) CFB, N CFB, mean (SD) MD (95% CI)

QUEST, Castro 20151

Dupilumab 200 mg q2w 12 1.76 (0.61) 172 0.45 (0.39) 0.23 (0.13–0.32)Placebo 12 1.65 (0.61) 99 0.22 (0.40) Reference armDupilumab 300 mg q2w 12 1.67 (0.56) 171 0.51 (0.39) 0.27 (0.17–0.37)Placebo 12 1.69 (0.52) 96 0.24 (0.39) Reference arm

Asthma phase 2b study (DRI), Wenzel 20162/Haldar 20095

Dupilumab 200 mg q2w 12 1.81 (0.57) 43 0.43 (0.46) 0.24 (0.05–0.42)Dupilumab 300 mg q2w 12 1.82 (0.53) 33 0.41 (0.46) 0.21 (0.02–0.41)Placebo 12 1.85 (0.68) 43 0.20 (0.46) Reference arm

BREATH (study 3081), Bjermer 20169

Reslizumab 3 mg/kg q4w 12 2.20 (NR) 106 0.30 (0.62) NRPlacebo 12 2.22 (NR) 105 0.17 (0.61) NR

BREATH (study 3082), Castro 20151

Reslizumab 3 mg/kg q4w 12 1.89 (0.73) 245 0.27 (0.50) 0.17 (NR)Placebo 12 1.93 (0.80) 244 0.10 (0.60) Reference arm

BREATH (study 3083), Castro 20151

Reslizumab 3 mg/kg q4w 12 2.13 (0.78) 232 0.19 (0.60) NRPlacebo 12 2.00 (0.67) 232 0.13 (0.70) Reference arm

BREATH (study 3084), Corren 201610 (EOS ≥ 400)

Reslizumab 3 mg/kg q4w 16 2.22 (0.81) 77 0.27 (0.49) 0.27 (0.01–0.53)


Castro 201111Reslizumab 3 mg/kg q4w 15 2.08 (0.61) 52 0.18 (0.40) NRPlacebo 15 2.26 (0.75) 52 –0.08 (0.40) 0.24 (0.09–NR)

QUEST pooled placebo data: N = 200; baseline mean: 1.67 (SD: 0.57), CFB mean: 0.23 (SD: 0.03), MD dupilumab 300 mg vs placebo: 0.28 (95% CI: 0.20–0.36), MD dupilumab 200 mg vs placebo: 0.28 (95% CI: 0.20–0.36).CFB, change from baseline; CI, confidence interval; MD, mean difference; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks; SD, standard deviation.

23

(F)



(SD) MD (95% CI)

QUEST, Castro 20151

Dupilumab 200 mg q2w 24 1.76 (0.61) 167 0.48 (0.39) 0.27 (0.17–0.37)




Dupilumab 200 mg q2w 24 1.81 (0.57) 43 0.39 (0.39) 0.23 (0.06–0.41)

Dupilumab 300 mg q2w 24 1.82 (0.53) 33 0.45 (0.40) 0.29 (0.10–0.48)

Placebo 24 1.85 (0.68) 41 0.16 (0.45) Reference armBREATH (study 3082),Castro 20151

Reslizumab 3 mg/kg q4w 24 1.89 (0.73) 245 0.25 (0.50) 0.14 (NR)

Placebo 24 1.93 (0.80) 244 0.12 (0.50) Reference armBREATH (study 3083), Castro 20151

Reslizumab 3 mg/kg q4w 24 2.13 (0.78) 232 0.21 (0.70) NR

Placebo 24 2.00 (0.67) 232 0.15 (0.70) Reference armQUEST pooled placebo data: N = 200; baseline mean: 1.67 (SD: 0.57), CFB mean: 0.24 (SD: 0.03), MD dupilumab 300 mg vs placebo: 0.26 (95% CI: 0.17–0.34), MD dupilumab 200 mg vs placebo. CFB, change from baseline; CI, confidence interval; MD, mean difference; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks; SD, standard deviation.

24

(G)



(SD) MD (95% CI)

QUEST, Castro 20151

Dupilumab 200 mg q2w 24 57.96 (14.58) 97 13.01 (12.71) 7.71 (3.41–12.01)




Dupilumab 200 mg q2w 24 58.15 (11.24) 18 12.67 (13.75) 5.09 (−2.76 to

12.93)Dupilumab 300 mg q2w 24 59.58 (11.08) 31 13.82 (13.98) 6.24 (−0.58 to

13.05)Placebo 24 60.90 (11.23) 29 7.59 (13.79) Reference arm

EXTRA, Hanania 201312


Omalizumab 150–375 mg q4w/q2w 24 NR 214 12.00 (12.71a) NR

Placebo 24 NR 200 9.03 (12.71a) NRAllergic: total IgE 30–700 IU/mL and ≥ 1 perennial aeroallergen-specific IgE ≥ 0.35 kU/L.a Imputed SD as the median of SD for CFB from 3 other trials. CFB, change from baseline; CI, confidence interval; EOS, eosinophil; MD, mean difference; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks; SD, standard deviation.

25

(H)



(SD) MD (95% CI)

QUEST, Castro 20151

Dupilumab 200 mg q2w 52 57.96 (14.58) 73 14.12 (11.96) 9.20 (4.63–13.78)


Placebo 52 55.50 (14.66) 49 7.20 (11.97) Reference armEXTRA, Hanania 201312


Omalizumab 150–375 mg q4w/q2w 48 NR 214 11.77 (12.14) NR

Placebo 48 NR 200 10.97 (12.14) NRAllergic: total IgE 30–700 IU/mL and ≥ 1 perennial aeroallergen-specific IgE ≥ 0.35 kU/L.CFB, change from baseline; CI, confidence interval; EOS, eosinophil; MD, mean difference; NR, not reported; q2w, every 2 weeks; q4w, every 4 weeks; SD, standard deviation.

Table E5 references



3. Bleecker ER, FitzGerald JM, Chanez P, et al.; SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-27.


5. Haldar P, Brightling CE, Hargadon B, al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973-84.6. Chupp GL, Bradford ES, Albers FC, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic

asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5:390-400.7. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380:651-

9.8. Ortega HG, Liu MC, Pavord ID, et al.; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-207.9. Bjermer L, Lemiere C, Maspero J, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest.

2016;150:789-98.

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10. Corren J, Weinstein S, Janka L, Zangrilli J, Garin M. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016;150:799-810.

11. Castro M, Mathur S, Hargreave F, et al.; Res-5-0010 Study Group. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184:1125-32.


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Documents

ars.els-cdn.com · Web view0.37 (0.47) NR Placebo 16 1.65 (0.58) 246 0.24 (0.47) NR CALIMA a, FitzGerald 20164(high ICS) Benralizumab 30 mg q4w to q8w 16 1.76 (0.62) 239 0.31 (0.50)