Table S1: Outcomes of Clinical Trials in Asthmatic Patients

Table S1: Outcomes of Clinical Trials in Asthmatic Patients.

Pharmaceuticals / Reference / Patients and treatment regimen / Reported positive outcomes / Notes
Daclizumab
(mAb against IL-2Ra) / [1] / -Moderate to severe persistent asthma suboptimally controlled despite medium-to-high dose ICS (n = 115)
-IV every 2 weeks at 2 mg/ml for the first dose and at 1 mg/ml thereafter, initially as add-on to stable dose of ICS for 12 weeks and then 8 weeks during ICS tapering. / -Decreased blood eosinophils and serum eosinophil cationic protein.
-Increased FEV1 (60 ml), FEV1/FVC, FEF25-75% and evening PEF.
-Prolonged time to first exacerbation.
-Decreased daytime symptoms and rescue SABA use. / -No effect on nocturnal symptoms, morning PEF, asthma-free days and exacerbations requiring systemic corticosteroids
-Potentially serious adverse effects
Reslizumab
(mAb against IL-5) / [2] / -Severe persistent asthmatics treated with high-dose ICS and/or OCS (n = 32)
-A single IV dose of
0.03, 0.1, 0.3 or 1 mg/kg / -Decreased blood eosinophils in a dose-dependent fashion, for up to 30 days with 1 mg/kg.
-0.3 mg/kg caused a short-lived improvement in FEV1. / -No effect on sputum eosinophils,
FEV1/FVC, PEF, symptom score and physician-evaluated overall condition
-Well tolerated.
[3] / -Asthmatics with sputum eosinophils 3% poorly controlled despite high-dose ICS + another drug (n = 106)
-4 IV doses of 3.0 mg/kg at 4-week intervals / -Reduced sputum eosinophils.
-Increased FEV1 (0.18 L). / -Tended to reduce exacerbations and ACQ score.
-Common adverse effects included nasopharyngitis, fatigue and pharyngolaryngeal pain.
[4] / -Asthmatics with blood eosinophils ≥ 400/µl inadequately controlled despite at least medium-dose ICS (n = 477)
-IV doses of 3 mg/kg at 4-week intervals for 1 year / -Reduced exacerbations requiring oral corticosteroids.
-Increased FEV1 (0.22 L).
-Reduced blood eosinophils.
-Improved AQLQ, ACQ and ASUI scores. / -No effect on exacerbations requiring hospital admission or ER treatment.
-No effect on SABA use
-Adverse effects similar to placebo
[5] / -Asthmatics inadequately controlled despite at least medium dose ICS (n = 492)
-IV doses of 3 mg/kg at 4-week intervals for 16 weeks / -Decreased blood eosinophils.
-Improved ACQ-7 (0.20).
-Increased FEV1 (0.27 L) in a subgroup of patient with blood eosinophils > 400/µl. / -No effect on FEV1 in the overall population
-No effect on FVC and SABA use
-Well tolerated.
[6] / -Asthmatics with blood eosinophils ≥ 400/µl poorly controlled despite at least medium-dose ICS (n = 315)
-4 IV doses of 0.3 or 3 mg/kg at 4-week intervals / -Decreased blood eosinophils.
-Increased FEV1 (0.12 and 0.16 L at 0.3 and 3 mg/kg, respectively) and FVC (only at 3 mg/kg).
-Reduced SABA use.
-Improved ACQ-7 (0.24 and 0.36 at 0.3 and 3 mg/kg, respectively), AQLQ and ASUI scores. / -No effect on FEF25-75%
-Generally well tolerated.
Mepolizumab
(mAb against IL-5) / [7] / -Allergen challenge in mild allergic asthmatic men using SABA as needed (n = 24)
-A single IV dose of 2.5 or 10 mg/kg / -Lowered blood eosinophils and prevented blood/sputum eosinophilia post-allergen challenge. / -No effect on airway responsiveness to histamine and LAR
-No adverse events
[8] & [9] / -Mild atopic asthmatics using SABA as needed (n = 24)
-3 IV doses of 750 mg at monthly intervals / -Decreased eosinophils in the bronchial mucosa, bone marrow and blood by 55, 52 and 100%, respectively.
-Decreased the thickness x density of tenascin, lumican and procollagen III in the RBM.
-Reduced TGF-β1 expression in BALF and the number and % of eosinophils expressing TGF-β1 mRNA. / -No effect on bronchial mucosa staining of eosinophil major basic protein
-No effect on FEV1, morning PEF and histamine PC20
[10] / -Moderate persistent asthmatics treated with ICS (n = 362)
-3 IV doses of 250 or 750 mg at 4-week intervals / -Sustained reduction in blood and sputum eosinophils
-Increased PEF (250 mg group only). / -No effect on FEV1, SABA use, symptom score and exacerbations
-Well tolerated.
[11] / -Refractory eosinophilic asthmatics on high-dose ICS (n = 61)
-12 IV doses of 750 mg at monthly intervals / -Reduced blood and sputum eosinophils, exacerbations and airway wall thickness.
-Improved AQLQ scores (0.35). / -No effect on FEV1, airway responsiveness to MCh, symptom scores, FENO and sputum neutrophils
-Acceptable adverse-event profile
[12] / -Asthmatics with persistent sputum eosinophilia despite OCS and high-dose ICS (n = 20)
-5 IV doses of 750 mg at 4-week intervals / -Reduced blood and sputum eosinophils, the number of exacerbations and OCS use.
-Increased FEV1 (0.3 L), ACQ-7 score and cough score. / -Decreased the number of lymphocytes in sputum 4 weeks after the last dose.
-No effect on symptoms score
-No serious adverse events
[13] / -Severe asthmatics with eosinophilic inflammation (n = 621)
-13 IV doses of 75, 250, or 750 mg at 4-week intervals / -Reduced blood and sputum eosinophils.
-Reduced exacerbations.
-Prolonged time to first exacerbation. / -No effect on FEV1 and scores on AQLQ and ACQ-6
-Well tolerated.
[14] / -Severe asthmatics with eosinophilia despite high-dose ICS (n = 576)
-8 IV doses of 75 mg or subcutaneous doses of 100 mg at 4-week intervals / -Reduced exacerbations.
-Increased FEV1 (0.10 L) and morning PEF.
-Improved scores on ACQ-5 (IV, 0.42; subcutaneous, 0.44) and SGRQ. / -Well tolerated.
[15] & [16] / -Severe eosinophilic asthmatics treated with high-dose ICS and OCS (n = 135)
-5 subcutaneous doses of 100 mg at 4-week intervals
-OCS dose was reduced from week 4 to week 20. / -Reduced blood eosinophils and asthma exacerbations.
-Median reduction in OCS from baseline was 50%.
-Reduction of daily OCS dose ≥ 50% was observed in 54% of patients.
-Improved ACQ-5 score (0.52). / -No effect on FEV1
-Well tolerated.
Benralizumab
(mAb against IL-5Ra) / [17] / -Mild atopic asthmatics (n = 44)
-A single IV doses ranging from 0.0003 to 3 mg/kg over 3 to 30 min / -Decreased blood eosinophils in a dose-dependent fashion within 24 h after dosing, which lasted at least 8 weeks for doses 0.03 mg/kg and above.
-Reduced blood ECP levels. / -No effect on lung function, symptom scores, SABA use and FENO
-Increased creatine phosphokinase, CRP and IL-6.
-Decreased white blood cells.
[18] / -Eosinophilic asthmatics
Cohort 1 (n = 13):
-Single IV dose of 1 mg/kg
Cohort 2 (n = 14):
-3 subcutaneous doses of 100 or 200 mg at monthly intervals / -Reduced sputum eosinophils and suppressed completely bone marrow and blood eosinophils. / -No significant effect on airway eosinophils
-Well tolerated.
[19] / -Uncontrolled asthmatics treated with medium-to-high dose ICS + LABA (n = 609)
-Subcutaneous doses every 4 weeks for the first 3 doses and then every 8 weeks for 1 year at 2, 20 or 100 mg for subjects with eosinophilia and at 100 mg for subjects with no eosinophilia / -100 mg reduced exacerbations in eosinophilic asthmatics only. / -No effect on exacerbations in non-eosinophilic subjects
-No effect on FEV1, ACQ-6 score, symptoms, FENO and SABA use
Golimumab
(mAb against TNFa) / [20] / -Severe asthmatics uncontrolled despite high-dose ICS (n = 309)
-Subcutaneous doses of 50, 100 or 200 mg at 4-week intervals for 52 weeks / -No effect on exacerbations, FEV1, PEF, SABA use and scores on AQLQ and ACQ
-Serious adverse events (infections and malignancies)
-Poor risk-benefit profile led to early discontinuation of the study.
Infliximab
(mAb against TNFa) / [21] / -Moderate asthmatics symptomatic despite ICS (n = 38)
-3 IV doses of 5 mg/kg at weeks 0, 2 and 6 / -Decreased exacerbations and diurnal variation of PEF.
-Decreased levels of TNF-α, IL-1α, IL-6, CXCL10 and CXCL8, but not CCL11, in sputum. / -No effect on morning/evening PEF, FEV1, asthma symptom score, SABA use, blood and sputum eosinophils, sputum neutrophils and total blood IgE
-No serious adverse events
Etanercept
(fusion protein constituted from the constant end of IgG1 and the TNF receptor 2, acting as a TNF inhibitor) / [22] / -Symptomatic severe asthmatics treated with maximal dose ICS (n = 17)
-Subcutaneous doses of 25 mg twice weekly for 12 weeks / -Increased FEV1 (0.24 L), FVC and morning/evening PEF.
-Reduced AHR.
-Improved JACQ score. / -Proof of concept study (open-labelled and uncontrolled)
-Mild adverse events
[23] / -Patients with either mild-to-moderate asthma or refractory asthma treated with ICS (n = 30)
-Subcutaneous doses of 25 mg twice a week for 10 weeks / -Improved MCh PC20, JACQ score and post-bronchodilator FEV1 (0.32 L).
-Decreased histamine in sputum. / -No effect on FENO and sputum levels of eosinophil cationic protein, CXCL8 and cysteinyl-leukotrienes
[24] / -Severe refractory asthmatics treated with ICS and/or OCS (n = 39)
-12 subcutaneous doses of 50 mg at weekly intervals / -Improved ACQ score (0.59).
-Reduced serum CRP and sputum macrophages.
-Increased serum TNF-α and albumin. / -No effect on exacerbations, AQLQ score, FEV1, FEV1/FVC ratio, FEV25-75, morning and evening PEF, diurnal variation in PEF, AHR, and sputum IL-6, CXCL8 and IL-1β
-Non-significant increase in sputum eosinophils and neutrophils
-Mild adverse events
Pitrakinra
(antagonist of IL-4Ra) / [25] / -Allergen challenge in steroid-free atopic asthmatics using only SABA and displaying a LAR.
-Study 1 (n = 24): Subcutaneous injection of 25 mg o.d. for 4 weeks
-Study 2 (n = 32): Nebulization of 60 mg b.i.d. for 4 weeks / -Reduced LAR (inhalation only).
-Lowered pre-allergen FENO (inhalation only).
-Reduced asthma-related adverse events requiring SABA. / -No effect on EAR, airway responsiveness to either MCh or AMP, skin response to allergen, eosinophils in both sputum and blood, and IgE
-Few adverse effects
-Further genetic analyses demonstrated that the level of responsiveness to pitrakinra, in terms of reduction in LAR, is influenced by SNPs in the IL4RA gene [26].
[27] / -Stable moderate-to-severe asthma on ICS and LABA (n = 534)
-Nebulization of 1, 3 or 10 mg b.i.d. for 12 weeks
-LABA was withdrawn after week 4.
-ICS were stepped down to zero from week 6 to beginning of week 10. / -Stratifying the patients according to genotypes of IL4RA SNPs predicted the response to treatment, in terms of exacerbations, nocturnal awakenings and activities limited by asthma. / -Only genotyped non-Hispanic white subjects were analyzed (n = 407)
-No effect on exacerbation in the overall population
-Safety profile was satisfactory.
Dupilumab
(mAb against IL-4Ra) / [28] / -Persistent, moderate-to-severe asthma with elevated blood and sputum eosinophils treated with medium-to-high dose ICS and LABA (n = 52).
-Subcutaneous doses of 300 mg once weekly for 12 weeks
-LABA was withdrawn after week 4.
-ICS were stepped down to zero from week 6 to beginning of week 10. / -Reduced exacerbations (87%) and increased time to first exacerbation induced by medication withdrawal.
-Increased FEV1 (0.27 L) and morning PEF (34.6 L/min).
-Improved on ACQ-5 score (0.73), morning and evening symptom scores and SNOT-22 score.
-Reduced the use of SABA.
-Decreased FENO and serum levels of CCL17, CCL26 and IgE. / -No significant change in evening PEF, nocturnal awakenings and eosinophil levels
[29] / -Persistent asthmatics uncontrolled despite medium-to-high dose ICS + LABA (n = 769)
-Subcutaneous doses of 200 or 300 mg every 2 or 4 weeks for 24 weeks / -Incrased FEV1 by 0.10 to 0.20 L at week 12 and by 0.10 to 0.16 L at week 24.
-Reduced rates of severe exacerbations.
-Improved ACQ-5 score (0.18 to 0.35), AQLQ score, as well as morning and evening symptom scores. / -Splitting the population according to baseline blood eosinophil counts of ³ or 300/µl did not change the outcomes.
-Well tolerated but increased transiently blood eosinophils.
Altrakincept
(soluble form of IL-4Ra, acting as an IL-4 and IL-13 inhibitor) / [30] / -Moderate asthmatics requiring ICS (n = 25)
-One single nebulization of 500 or 1500 µg after ICS withdrawal / -1500 µg maintained FEV1, FEF25-75, symptoms control, SABA use and FENO. / -Well tolerated.
[31] / -ICS-dependent, moderately severe patients after ICS withdrawal (n = 62)
-Inhaled dose of 0.75, 1.5 or 3 mg at weekly intervals for 12 weeks / -3 mg prevented the decline in FEV1, as well as the increase in symptom score. / -Lower doses (0.75 and 1.5 mg) had no significant effects.
-Study discontinued because exacerbations were not different between groups.
AMG 317
(mAb against IL-4Ra) / [32] / -Moderate-to-severe asthma on ICS (n = 294)
-Subcutaneous doses of 75, 150 or 300 mg at weekly intervals for 12 weeks / -No effect on ACQ score (primary endpoint), FEV1, AQLQ score, SABA use, morning and evening PEF, % of symptom-free day, total daily symptom score and serum IgE
-Numerical decrease in number of exacerbations
-Numerical increase in time to first exacerbation
-The response to 150 and 300 mg seemed greater in patients with higher ACQ scores at baseline.
-Numerical increase in adverse events
Tralokinumab
(mAb against IL-13) / [33] / -Moderate-to-severe asthmatics uncontrolled despite controller therapies (n = 194)
-Subcutaneous doses of 150, 300 or 600 mg every 2 weeks for 12 weeks / -Decreased the use of SABA
-Evidence of greater improvement of ACQ-6 score and FEV1 in a sub-group of patients with sputum IL-13 ³ 10 ng/ml / -No effect on ACQ-6 score (primary endpoint), PEF and FEV1 (a numerical increase of 0.15 L)
-Increased total adverse events.
-Diarrhoea and urinary-related adverse events were only reported in tralokinumab group.
-Increased eosinophils in blood and sputum.