Table 3.
Phase IIb and Phase III clinical studies with mepolizumab
| Study | Subject characteristics | Study objective | Study design | Primary outcomes | Secondary outcomes | Comments |
|---|---|---|---|---|---|---|
| Validation studies | ||||||
| Pavord et al50: (N=621) Mepolizumab for severe eosinophilic asthma: a multicentre, double- blind, placebo-controlled trial (DREAM) |
Refractory asthma “and” ≥2 severe exacerbations in previous 12 months “and” blood eosinophils >300 cells/µL “or” sputum eosinophils >3% “or” FeNO >50 ppb “or” asthma deterioration with 25% reduction in ICSs | To validate outcomes observed in the study by Haldar et al44 To evaluate dose–response with mepolizumab for clinical outcomes To evaluate the effectiveness of different markers of the eosinophilic phenotype for predicting response to mepolizumab |
13 doses over 48 weeks: 75 mg/250 mg/750 mg iv/placebo | Annualized severe exacerbation frequency: ↓39–52% across treatment arms No difference between doses |
Exacerbations requiring hospital admission and ER visits: trend to significant reduction Change in FEV1 : no effect Change in AQLQ: no effect Change in ACQ-5: no effect Change in blood and sputum eosinophils: significant reduction in blood and sputum eosinophils with all mepolizumab treatment doses Dose-dependent reductions observed Change in FeNO: no effect |
Study not powered to reliably assess the effect of mepolizumab on the number of hospital and ER episodes Multiple criteria for characterization of eosinophilic phenotype (exploratory) Modeling clearly identified that the efficacy of mepolizumab was dependent on both the baseline blood eosinophil count and number of severe exacerbations in previous 12 months |
| Ortega et al51: (N=576) Mepolizumab treatment in patients with severe eosinophilic asthma (MENSA) |
Refractory asthma “and” ≥2 exacerbations in previous 12 months “and” blood eosinophils >150 cells/µL at screening “or” blood eosinophils recorded >300 cells/µL in previous 12 months | To evaluate and compare the mepolizumab treatment response between sc and iv routes | 8 doses over 28 weeks: 100 mg sc/75 mg iv/placebo | Annualized severe exacerbation frequency: ↓47% with iv; ↓53% with sc | Change in: FEV1 ↑100 mL with iv; ↑98 mL with sc Change in SGRQ: ↓6.4 points with iv; ↓7.0 points with sc Change in ACQ-5: ↓0.42 with iv; ↓0.44 with sc |
Equivalence of clinical effectiveness between iv and sc routes Improvements in lung function and symptoms as well as severe exacerbations Comparable profile of adverse events between iv and sc routes sc route associated with injection site reaction in 9% compared with 3% in iv group |
| Bel et al52: (N=135) Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma (SIRIUS) |
Refractory asthma On maintenance OCS for ≥6 months at a dose of 5–35 mg Blood eosinophils >150 cells/µL during optimization “or” blood eosinophils recorded >300 cells/µL in previous 12 months |
To evaluate the effectiveness of mepolizumab as an oral steroid-sparing agent | 6 doses over 20 weeks: 100 mg sc/placebo | Percentage achieving dose reduction in maintenance OCS: OR of 2.39 in favor of mepolizumab to achieve a dose reduction in OCS |
Median change in OCS dose: 50% reduction in median dose of OCS achieved (mepolizumab) vs no change (placebo) Annualized severe exacerbation frequency: ↓32% (mepolizumab vs placebo) Change in ACQ-5: ↓0.52 (mepolizumab) Change in SGRQ: ↓5.8 points Change in FEV1 : ↑114 mL |
Almost half of subjects in each treatment arm had received OCS for >5 years This is the only study that demonstrates a beneficial effect of mepolizumab on asthma symptoms control OCS reduction decisions were based on symptoms rather than the eosinophil count – the eosinophil count, a better predictor of exacerbations, so OCS reduction decisions based on this end point may have achieved greater gains, as seen in the study by Nair et al45 |
Abbreviations: ACQ-5, Asthma Control Questionnaire (5-point score); AQLQ, Asthma Quality of Life Questionnaire; DREAM, Dose Ranging Efficacy And safety with Mepolizumab; ER, emergency room; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 sec; ICS, inhaled corticosteroids; iv, intravenous; MENSA, Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma; OCS, oral corticosteroid; OR, odds ratio; sc, subcutaneous; SGRQ, St. George’s Respiratory Questionnaire; SIRIUS, Steroid Reduction with Mepolizumab Study.