Table 1 A comparative study of Anti-IL5 trials in Asthma

Leckie [16] 2000

Mild atopic asthmatic

n= 24 mc, db, pc

Single dose i.v., 2.5, 10 mg/kg

• Not an inclusion criteria

• Day 29, post-allergen 10 mg/kg dosage, blood eos 0.04 × 10⁹/L compared to 0.25 × 10⁹/L placebo (P< 0.0001)

• No significant effect on AHR

Mepolizumab

FEV₁ ≥ 70%, predicted

Baseline values:

• No significant effect on late asthmatic response to allergen challenge

•Sputum eos (% mean) > 11% in all groups

• Day 29, post- allergen,10 mg/kg dosage: 0.7% sputum eos compared to 12.8% placebo ( p= 0.005)

• Blood eos (counts × 10⁹/L) > 0.2 in all groups

Bȕttner [17] 2003

Mild to moderate asthmatics

n= 19 mc, db, pc

Three monthly doses, i.v.

No Baseline count/ median n/a

• Decrease in blood eos (median values from 300 to 45 per mL, P< 0.05 vs. placebo)

• No asthma end-points were assessed

Mepolizumab

FEV₁ > 50-80%, predicted

250/750 mg

• T-cell sub-sets and T-cell cytokine levels not altered

• Decreased levels of serum ECP (median values from 15 to 5 mg.L⁻¹, P< 0.05 vs. placebo)

• No sputum data

Kips [18] 2003

Moderate-severe asthma, FEV₁ > 40-80%, predicted

n= 32 db, pc, mc

Rising single dose (0.03, 0.1 , 0.3, 1 mg/kg) i.v

• Not included in the inclusion criteria

• Dose dependently reduced circulating eos

• Significant increase in FEV₁ post 24 hours from dose range ≥ 0.3 mg/kg (p= 0.019)

Reslizumab

Baseline value:

• Significant dose reduction with 1 mg/kg for 30 days post dosing ( p=0.05)

• blood eos (counts × 10⁹/L):

• No significant changes in other clinical indices

Placebo:0.45 ± 0.16

• No significant trend in changes of sputum eos were observed between groups due to the wide variability in baseline counts between the groups

0.3 mg/kg : 0.28 ± 0.04

1.0 mg/kg : 0.25 ± 0.04

• Sputum eos (% mean)

Placebo:22.9 ± 12.5

0.3 mg/kg : 2.6 ± 0.44

1.0 mg/kg : 5.5 ± 3.92

Flood-page [19] 2003

Mild atopic asthma

n= 24 db, pc, parallel-group,

3 i.v. doses of 750 mg

• Not included in the inclusion criteria

• Blood eos: significant reduction in wk 4 and 10 (P<0.02, vs. placebo)

• Sputum eos not checked

Mepolizumab

FEV₁ ≥ 70%, predicted

Mepolizumab/ per month

12- wk follow up

Baseline value:

• No change in clinical parameters, FEV1, AHR

• Blood eos (mean × 10⁹/L):

• Bone marrow: 70% reduction in mature eos (P= 0.017)

Group: 0.27

Placebo: 0.4

• BAL fluid eos: median reduction of 79% from baseline (P= 0.4 vs. placebo) ns

Flood-page [20] 2007

Moderate persistent asthmatics

n= 362 mc, db, pc

3 i.v. doses of

• Not included in the inclusion criteria

• Blood eos: Sustained significant 80% reduction for both doses ( p< 0.001 vs. placebo)

• No significant change in clinical end-points

Mepolizumab

FEV₁ ≥ 50-80%, predicted

750/250 mg Mepolizumab per month

• Baseline blood eos for all group showed median values ≥ 0.3 × 10⁹/L

• Sputum eos significant reduction from baseline (P=0.006, 250 mg, P= 0.004, 750 mg)

• Trend for a reduction in exacerbation rate, ns

• Decrease in summary symptom score vs. placebo for 750 mg at wk 12 (P= 0.032)

8- wk follow up

Nair [21] 2009

Severe persistent asthma with Eosinophilia

n= 20

5 i.v. doses of 750 mg per month.

• Yes. Inclusion criteria - Sputum eos > 3%

• Significant reduction in blood eos after 1st dose (49.5/μl), last dose (64.5/μl) and follow up (76.3/μ) (P< 0.05) vs. placebo, no significant reduction from baseline

• Significant reduction in asthma exacerbations with drug (1) compared to placebo (12 in 10 patients), P< 0.01

Mepolizumab

db, pc, pilot study

FEV₁%,predicted value (median ± SD): 48 ± 17 (drug) 52 ± 13 (placebo)

Prednisone dosage tapered after 2^nd infusion

Baseline:

• Blood eos;

• 83.8% reduction in prednisone dose vs. placebo (P< 0.04)

Drug: 664 ± 492.5/μl; placebo:352 ± 253.7/μl

• Significant reduction in sputum eos after 1^st dose (0%), last dose (1.3%) and follow-up (0.3%) (P< 0.05) vs. placebo, no significant reduction from baseline

• FEV_{1 -} significant improvement vs. placebo, P< 0.05

• Sputum eos:

Drug group: 16.6%

• ACQ: significant improvement from baseline P= 0.01, vs. placebo

Placebo: 4%

Haldar [22] 2009

Refractory eosinophilic severe asthma

n= 61 db, pc, parallel study

12 doses of 750 mg i.v. per month

• Inclusion criteria - Sputum eos > 3%

• Blood eos: reduced by a factor of 6.6 from baseline in drug group, compared to 1.1 in placebo (P<0.001)

• Reduction in number of exacerbation over the course of 50 wks (P= 0.02)

Mepolizumab

Baseline:

• Blood eos (x 10⁹/L);

• AQLQ score increase with drug (P= 0.02, vs. placebo)

Drug:0.32 ± 0.38 placebo: 0.35 ± 0.30

• Sputum eos: reduced by a factor of 7.1 from baseline in drug group, compared to 1.9 in placebo (P=0.002)

• Sputum eos:

• No significant difference in group in AHR, FEV₁, ACQ

Drug: 6.84 ± 0.64%

Placebo:5.46 ± 0.75%

Pavord [23] 2012

Severe refractory asthma with ≥ 2 exacerbations in past year

n= 621

3 doses s.c., at 4 wks

• Yes. Inclusion criteria - Sputum eos > 3%

• Blood eos (x10⁹/L): at 52 wk, vs. placebo

• Exacerbation rates at all doses were 39-52% less than those in the placebo group (P< 0.05 vs. placebo)

Mepolizumab

db, pc, parallel study, mc

75/250/750 mg

75 mg: 0.22< 0.0001, 250 mg: 0.14 p< 0.0001

(DREAM)

52 wk

Blood eos ≥ 0.3 x10⁹/L

750 mg:0.12 p< 0.0001

Baseline:

• Sputum eos (ratio): at 52 wk

• No changes in FEV₁, ACQ, AQLQ

• Blood eos (x 10⁹/L);

75 mg : 0.68, ns

• Lowest dose of 75 mg was near to the top of the dose response curve w.r.t reduction of blood eosinophils

>0.2 , for all groups

250 mg: 0.35, ns

• Sputum eos:

750 mg :0.12, p= 0.0082

>6% for all groups

Castro [24] 2011

Poorly controlled asthma, on high dose ICS

n= 106

3.0 mg/kg sc, at baselineand at Weeks 4, 8, and 12

• Yes. Inclusion criteria - Sputum eos > 3%

• Significant reduction in blood eosinophils (P< 0.0001, vs. placebo)

• Trend in reduction of asthma exacerbations in drug group (p= 0.083, ns)

Reslizumab

db, pc, parallel study,

Baseline:

• 95.4% reduction in sputum eos compared to placebo, 38.7% (p= 0.0068)

• ACQ trend in favour of drug group (p=0.054)

• Blood eos , median (x 10³/μL);

• Significant improvement in ACQ score in patients with nasal polyps (p= 0.012)

Drug: 0.5

Placebo: 0.5

• Significant reduction in FEV₁ in drug group (p=0.002, vs. placebo)

• Sputum eos (%):

Drug: 10.7

Placebo: 8.5

Busse [25] 2010

Mild atopic asthma

n= 44 mc, safety in open-label study

Single escalating doses (0.0003-3 mg/kg, over 3 – 30 minutes)

No. this was a safety study.

• Significant decrease in eos in dose-dependent fashion from baseline to 0.01 ± 0.0 × 10³/μL, 24 hours post-dose

• Acceptable safety profile

Benralizumab (MEDI-563)

FEV₁ ≥ 80% of predicted

Baseline:

• No adverse reactions were noted.

• Blood eos:

Mean ± SD, 0.27 ± 0.2 × 10³/μL

• 94% patients on doses ≥03.mg/ml showed 0–0.1 × 10³/μL blood eos.

• ECP levels (mean)

21.4 ± 17.2 μg/L

• ECP levels were reduced from baseline to 10.3 ± 7.0 μg/L, 24 hrs post-dosing

Laviolette [26] 2013

Eosinophilic asthma

n= 27 mc, db, pc

• Cohort 1 – (i.v) 1 mg/kg single dose

• Sputum eosinophil counts of ≥2.5%

• Significant reduction in sputum eosinophils, airway eosinophil counts and 100% reduction in bone marrow and peripheral blood

• Additional clinical factors were not measured

Benralizumab

FEV₁ ≥ 65%, predicted

Baseline:

• Cohort II-100 mg, 200 mg, combined 3 monthly (s.c).

• Sputum eos (mean%)

• Airway mucosal/submucosal eos: mean reduction vs. placebo:

• Cohort 1:

Placebo : 13.9

Cohort I : (i.v.) 61.9% (ns)

Drug: 6.6

Cohort II, combined (sc): 83.1% (p= 0.0023)

• Cohort II:

• Induced sputum eos (mean% )

Placebo: 34.1

Cohort I: 4.5%, day 21 compared to 20.8% placebo

100 mg: 10.5

200 mg: 4.9

Cohort II: (combined) 0.6% at day 28, compared to 6.4% placebo

Combined: 7.4

Castro [27] 2014

Uncontrolled asthma ACQ-6 score ≥ 1.5

n= 609

• 2 mg, 20 mg, 100 mg sc for eosinophilic patients (n= 324)

• Subjects were stratified based on blood eos, Sputum eos ≥2%, FeNO > 50 ppb

• All doses reduced blood eos<50 cells/μl after the first dosage

• Significant improvement in FEV₁ and ACQ-6 in eos subtype with all doses

Benralizumab

(324 – eosinophilic, 282)

Exacerbation ≥ 2/last year

• In eosinophilic group, 100 mg sc improved annual exacerbation rate by 41% (p= 0.096) vs. placebo, deemed significant; ns in non-eosinophilic group,

• High incidence of adverse reactions in treatment arm

Phase IIb

• 100 mg sc for non-eosinophilic (n= 282)

Db, pc, dose-ranging study

• 7 doses every 4 weeks

• Subgroup analysis showed greater improvement with increased baseline blood eos (100 mg sc reduced exacerbations by 70% in patients ≥ 400 cells/μl, p= 0.002)

Ortega [28] 2014

Severe asthma

n= 576

• Cohort 1 – 75 mg i.v. (n= 191)

• Blood eos 150/μl at screening or 300/μl in previous year

• Reduction in eos by week 4 mainted through the entire study

• Rate of exacerbations reduced by 47% and 53% in s.c and i.v. groups respectively (p< 0.001, vs. placebo)

Mepolizumab

Recurrent exacerbations, with ≥2 in previous year

mc, db, pc

Phase III

• Cohort 2 – 100 mg s.c. (n= 194)

• No sputum eos were accounted

• 83% reduction in i.v. group

ICS dose ≥880 μg fluticasone propionate

• 86% recution in s.c. group (p< 0.001, vs. placebo)

• Improvement in FEV₁ for both groups (p< 0.05) and asthma scores (p< 0.001)

Every 4 weeks for 32 weeks

Bel [29] 2014

Severe eosinophilic asthma

n= 135 mc, db, pc

• 100 mg s.c. every 4 weeks for 20 weeks

• Inclusion criteria did not account sputum eos

• Drug significantly reduced blood eos by week 4 and was maintained throughout study (p< 0.001)

• Median percentage decrease in OCS from baseline - 50% in drug arm to no reduction in placebo (p= 0.007)

Mepolizumab

On 5–35 mg of daily OCS, and severe exacerbations

Phase III

• Blood eos 150/μl at screening or 300/μl in previous year

• Relative reduction of 32% in annual exacerbation rate despite lowering of OCS in drug arm (p= 0.04, vs. placebo)

• Improvement in ACQ-5 score (p= 0.004)

Corren [30] 2014

Moderate-severe asthma

n= 395 (drug)

• 3.0 mg/kg, i.v., monthly (for 16 weeks)

• Inclusion criteria doesnot include sputum eos

• Abstract does not document any reduction in blood eos

• Significant reduction in ACQ score in drug arm (p= 0.04)

Reslizumab

ACQ ≥ 1.5

n= 97 (placebo)

On medium dose ICS (~440 μg fluticasone)

db, pc, mc, Phase III

• Study population stratified by baseline blood eos ≥ or ≤ 400 cells /μl

• Only 20% of study population was eosinophilic (or ≤ 400 cells /μl)

• FEV₁ improvement for overall population by 68 ml, 270 ml for eosinophilic patients (p= 0.04 vs. placebo), ns increase of 33 ml in non-eosinophilic patients

Bjermer [31] 2014

Eosinophilic asthma

n= 311 db, pc, parallel

• 0.3 – 3.0 mg/kg, i.v., monthly (for 16 weeks)

• blood eos ≥ 400 cells /μl

• eosinophil measurement was not documented in the abstract

• overall improvement in FEV1 p ≤0.024, ACQ score (p ≤ 0.03)

Reslizumab

ACQ ≥ 1.5

• sputum eos not accounted

Phase III

• Higher dose - significant FEV₁ increase as early as 4 weeks