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Mepolizumab efficacy in patients with severe eosinophilic asthma receiving different controller therapies

Open AccessPublished:July 04, 2017DOI:https://doi.org/10.1016/j.jaci.2017.06.010
      To the Editor:
      Severe asthma is a heterogeneous disease that can require multiple treatments to help maintain control of symptoms and exacerbations.

      Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. Available at: http://www.ginasthma.org. Accessed June 2017.

      Severe eosinophilic asthma is characterized by increased eosinophilic inflammation, recurrent exacerbations, and poor disease control.
      • Chung K.F.
      • Wenzel S.E.
      • Brozek J.L.
      • Bush A.
      • Castro M.
      • Sterk P.J.
      • et al.
      International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.
      Standard of care for patients with severe eosinophilic asthma includes the use of inhaled corticosteroids (ICSs) and long-acting beta 2 agonists (LABAs) with the option of a number of further add-on treatments to maintain or improve asthma control.

      Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. Available at: http://www.ginasthma.org. Accessed June 2017.

      Consequently, patients with severe asthma who are at steps 4 and 5 of treatment according to the Global Initiative for Asthma (GINA) guidelines

      Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. Available at: http://www.ginasthma.org. Accessed June 2017.

      may have a considerable treatment burden, potentially requiring 3 or 4 controller therapies in the form of inhalers, oral medications, or monthly injections. Mepolizumab is an anti–IL-5 mAb add-on therapy that has recently been added to step 5 of the GINA guidelines for patients with severe eosinophilic asthma.

      Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. Available at: http://www.ginasthma.org. Accessed June 2017.

      Although mepolizumab has been previously shown to reduce exacerbation frequency and the corticosteroid dose in patients with severe eosinophilic asthma compared with placebo when added to standard of care,
      • Pavord I.D.
      • Korn S.
      • Howarth P.
      • Bleecker E.R.
      • Buhl R.
      • Keene O.N.
      • et al.
      Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.
      • Ortega H.G.
      • Liu M.C.
      • Pavord I.D.
      • Brusselle G.G.
      • FitzGerald J.M.
      • Chetta A.
      • et al.
      Mepolizumab treatment in patients with severe eosinophilic asthma.
      • Bel E.H.
      • Wenzel S.E.
      • Thompson P.J.
      • Prazma C.M.
      • Keene O.N.
      • Yancey S.W.
      • et al.
      Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma.
      the influence of the background controller therapy has not been examined. Through this post hoc analysis of the Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA) study (NCT01691521), we aimed to determine whether the efficacy of mepolizumab was affected by the number or type of background controller therapies taken by patients.
      The MENSA study, a 32-week, randomized, double-blind study (N = 576), assessed mepolizumab efficacy in patients with severe eosinophilic asthma as an add-on therapy to standard of care (ICSs plus ≥1 controller therapy). In these patients, MENSA showed that mepolizumab was efficacious at reducing exacerbation rates compared with placebo.
      • Ortega H.G.
      • Liu M.C.
      • Pavord I.D.
      • Brusselle G.G.
      • FitzGerald J.M.
      • Chetta A.
      • et al.
      Mepolizumab treatment in patients with severe eosinophilic asthma.
      In MENSA, patients with severe eosinophilic asthma, aged 12 years or older, with a history of 2 or more exacerbations in the previous year received 75 mg intravenous or 100 mg subcutaneous (SC) mepolizumab or placebo every 4 weeks. Patients were allowed uninterrupted concurrent use of a broad range of asthma treatments (background therapy), with the exception of other biologics (eg, omalizumab). Clinically significant exacerbations were defined as those requiring administration of systemic corticosteroids for 3 or more days (needing a ≥2-fold increase in dose for those patients already on maintenance oral corticosteroids), and/or an emergency room visit/hospitalization.
      • Ortega H.G.
      • Liu M.C.
      • Pavord I.D.
      • Brusselle G.G.
      • FitzGerald J.M.
      • Chetta A.
      • et al.
      Mepolizumab treatment in patients with severe eosinophilic asthma.
      In this post hoc analysis of MENSA, we assessed the annualized rate of clinically significant exacerbations in patients receiving mepolizumab or placebo according to the number (ICS plus 1, 2, or ≥3 controllers) and type (ICS, LABA, tiotropium, or other [leukotriene receptor antagonists, xanthine, or nedocromil/cromolyn sodium]) of background controller therapies using negative binomial regression models with adjustment for covariates. Because of comparable bioequivalence and efficacy, mepolizumab doses (100 mg SC/75 mg intravenous) were pooled in this analysis. Data were available for 561 patients for this analysis. Analyses of exacerbation rates, lung function, and blood eosinophil counts by number and type of background therapy for the 100 mg SC dose only and the pooled mepolizumab doses are available in the Appendix in this article's Online Repository at www.jacionline.org.
      As might be expected, exacerbation rates in the placebo group were highest in patients on the greatest number of controller therapies (Fig 1; see Fig E1 in this article's Online Repository at www.jacionline.org), potentially reflecting the higher disease burden and more severe asthma symptoms in these patients. Clinically relevant reductions in exacerbation rates were seen with mepolizumab relative to placebo in patients with severe eosinophilic asthma irrespective of the number of controller therapies (Fig 1 and Fig E1). Furthermore, although reductions in exacerbation rates with mepolizumab versus placebo were identified in all groups, the largest reduction was seen in the ICS + 3 or more controller therapy subgroup, in which patients were likely to have the greatest burden of disease. This highlights that mepolizumab may be an effective treatment option for even the most difficult to treat patients with severe eosinophilic asthma.
      Figure thumbnail gr1
      Fig 1Reductions in exacerbation rate according to the number of standard of care asthma controller therapies taken in addition to mepolizumab or placebo. RR, Rate ratio. 95% CIs shown in parentheses after RR; number of patients presented at the bottom of each bar.
      In addition to the number of controller therapies, we assessed whether the type of background controller therapy (ICS, LABA, tiotropium, or other) affected the efficacy of mepolizumab. Because tiotropium, a long-acting anticholinergic bronchodilator add-on therapy, has been recently added to steps 4 and 5 of the GINA guidelines for patients with a history of asthma exacerbations, it was included in the analysis.
      • Reddel H.K.
      • Bateman E.D.
      • Becker A.
      • Boulet L.P.
      • Cruz A.A.
      • Drazen J.M.
      • et al.
      A summary of the new GINA strategy: a roadmap to asthma control.
      In all assessed combinations of concomitant controller medication types, we observed clinically relevant reductions in exacerbation rates with mepolizumab added to standard of care relative to placebo. For patients receiving ICS, LABA, and tiotropium in combination (inhaled triple therapy), mepolizumab reduced exacerbation rates by 65% to 70% relative to placebo and by 56% to 62% if an additional controller was taken (Fig 2; see Fig E2 in this article's Online Repository at www.jacionline.org). One limitation of this analysis is that the number of patients in each subgroup was low; however, reductions in exacerbation rates reported for patients receiving other therapy combinations were comparable, ranging from 47% to 52% and from 47% to 60% (see Fig 2 and Fig E2, respectively). This demonstrates that mepolizumab was effective in reducing exacerbation rates compared with placebo in patients with severe eosinophilic asthma, irrespective of the type of controller therapies taken by these patients, whether they are ICS, LABA, tiotropium, other controllers, or a combination of these therapies.
      Figure thumbnail gr2
      Fig 2Reductions in exacerbation rate according to the type of standard of care asthma controller therapies taken in addition to mepolizumab or placebo. RR, Rate ratio; TIO, tiotropium. 95% CIs shown in parentheses after RR; number of patients presented at the bottom of each bar; other could be 1 or more of leukotriene receptor antagonists, xanthine, or nedocromil/cromolyn sodium; 5 patients did not report a LABA controller and therefore are not included in Fig 2.
      Overall, our analysis has shown that mepolizumab reduced exacerbation rates compared with placebo in patients with severe eosinophilic asthma on low or high numbers of controller therapies. This suggests that mepolizumab can be a beneficial add-on therapy to reduce the rate of exacerbations even if a combination of numerous other therapies has not been effective in these patients. Furthermore, results for those receiving the licensed 100 mg SC dose were consistent with the results found when pooling the mepolizumab doses (Figs E1 and E2). Results presented here demonstrate that mepolizumab was effective even in patients who are currently receiving maximal therapy with combinations of ICS, LABA, tiotropium, and other controllers. This may be due to the targeted mechanism of action of mepolizumab, which reduces blood and sputum eosinophil counts through the neutralization of IL-5,
      • Pavord I.D.
      • Korn S.
      • Howarth P.
      • Bleecker E.R.
      • Buhl R.
      • Keene O.N.
      • et al.
      Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.
      • Ortega H.G.
      • Liu M.C.
      • Pavord I.D.
      • Brusselle G.G.
      • FitzGerald J.M.
      • Chetta A.
      • et al.
      Mepolizumab treatment in patients with severe eosinophilic asthma.
      • Bel E.H.
      • Wenzel S.E.
      • Thompson P.J.
      • Prazma C.M.
      • Keene O.N.
      • Yancey S.W.
      • et al.
      Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma.
      specifically addressing the eosinophilic inflammation in the target population of patients with severe eosinophilic asthma and a history of 2 or more exacerbations in the past year despite maximal therapy. Of note, baseline blood eosinophil counts were comparable across all the subgroups studied and were reduced and remained low at Week 32 irrespective of the number and type of controllers used (see Table E2 in this article's Online Repository at www.jacionline.org).
      The results from this post hoc analysis indicate that add-on treatment with mepolizumab demonstrates benefits for patients with severe eosinophilic asthma across a broad range of therapeutic backgrounds.
      Editorial support (in the form of writing assistance, including development of the initial draft, assembling tables and figures, collating authors comments, grammatical editing, and referencing) was provided by Elizabeth Hutchinson, PhD, CMPP, at Fishawack Indicia Ltd, UK, and was funded by GSK.

      Appendix

      Figure thumbnail fx1
      Fig E1Reductions in exacerbation rate according to the number of standard of care asthma controller therapies taken in addition to 100 mg SC mepolizumab or placebo. RR, Rate ratio. Reductions presented as RR (95% CI); patient numbers are presented at the bottom of each bar.
      Figure thumbnail fx2
      Fig E2Reductions in exacerbation rate according to the type of standard of care asthma controller therapies taken in addition to 100 mg SC mepolizumab or placebo. RR, Rate ratio; TIO, tiotropium. Reductions presented as RR (95% CI); patient numbers are presented at the bottom of each bar; other could be 1 or more of leukotriene receptor antagonists, xanthine, or nedocromil/cromolyn sodium; 5 patients did not report a LABA controller and, therefore, are not included in Fig E2.
      Table E1Prebronchodilator FEV1 (mL) at baseline and Week 32 in patients on different numbers and types of background standard of care asthma controller therapies taken in addition to placebo or mepolizumab
      Analysis according to:FEV1 (mL), mean ± SD
      PlaceboMepolizumab 100 mg SCMepolizumab (all doses)
      BaselineWeek 32BaselineWeek 32BaselineWeek 32
      Background controller number
       ICS + 1n = 76

      1819 ± 573.5
      n = 69

      1888 ± 617.5
      n = 72

      1809 ± 640.1
      n = 71

      2015 ± 689.3
      n = 147

      1864 ± 676.8
      n = 143

      2027 ± 718.3
       ICS + 2n = 63

      1953 ± 683.8
      n = 60

      2004 ± 611.9
      n = 72

      1743 ± 674.5
      n = 65

      1977 ± 794.8
      n = 133

      1772 ± 659.5
      n = 120

      2025 ± 757.7
       ICS + ≥3n = 47

      1740 ± 588.7
      n = 45

      1908 ± 619.8
      n = 46

      1625 ± 675.4
      n = 45

      1838 ± 701.0
      n = 95

      1703 ± 714.2
      n = 88

      1894 ± 738.6
      Background controller type
       ICS + LABA alonen = 74

      1818 ± 581.3
      n = 67

      1889 ± 626.4
      n = 74

      1812 ± 640.8
      n = 73

      2049 ± 712.8
      n = 151

      1888 ± 700.0
      n = 148

      2069 ± 748.3
       ICS + LABA + another (not TIO)n = 82

      1945 ± 685.2
      n = 78

      2007 ± 618.7
      n = 86

      1762 ± 691.6
      n = 80

      1937 ± 750.3
      n = 163

      1757 ± 651.5
      n = 147

      1975 ± 749.2
       ICS + LABA + TIO alonen = 11

      1547 ± 511.5
      n = 11

      1672 ± 434.0
      n = 13

      1621 ± 607.3
      n = 12

      1779 ± 582.0
      n = 17

      1580 ± 641.6
      n = 16

      1848 ± 621.6
       ICS + LABA + TIO + anothern = 16

      1654 ± 459.3
      n = 15

      1955 ± 694.9
      n = 17

      1402 ± 573.3
      n = 16

      1774 ± 811.5
      n = 42

      1662 ± 729.6
      n = 39

      1839 ± 686.1
      Other could be 1 or more of leukotriene receptor antagonists, xanthine, or nedocromil/cromolyn sodium; 5 patients did not report a LABA controller and, therefore, are not included when summarizing by background controller type.
      TIO, Tiotropium.
      Table E2Blood eosinophil count (cells/μL) at baseline and Week 32 in patients on different numbers and types of background standard of care asthma controller therapies taken in addition to placebo or mepolizumab
      Analysis according to:Eosinophil count (cells/μL), geometric mean ± SD logs
      PlaceboMepolizumab 100 mg SCMepolizumab (all doses)
      BaselineWeek 32BaselineWeek 32BaselineWeek 32
      Background controller number
       ICS + 1n = 76

      320 ± 0.849
      n = 66

      290 ± 0.871
      n = 71

      270 ± 0.920
      n = 71

      50 ± 0.865
      n = 145

      290 ± 0.885
      n = 139

      50 ± 0.918
       ICS + 2n = 63

      290 ± 0.851
      n = 60

      290 ± 0.880
      n = 71

      280 ± 1.071
      n = 64

      40 ± 0.917
      n = 131

      270 ± 1.071
      n = 119

      50 ± 0.928
       ICS + ≥3n = 46

      350 ± 1.026
      n = 42

      200 ± 1.091
      n = 46

      360 ± 1.144
      n = 45

      30 ± 1.043
      n = 94

      310 ± 1.104
      n = 88

      30 ± 0.945
      Background controller type
       ICS + LABA alonen = 74

      320 ± 0.854
      n = 65

      290 ± 0.877
      n = 73

      280 ± 0.915
      n = 72

      50 ± 0.859
      n = 149

      290 ± 0.886
      n = 143

      50 ± 0.902
       ICS + LABA + another (not TIO)n = 81

      290 ± 0.931
      n = 76

      260 ± 1.021
      n = 86

      310 ± 0.941
      n = 80

      40 ± 0.884
      n = 161

      290 ± 1.028
      n = 147

      40 ± 0.943
       ICS + LABA + TIO alonen = 11

      320 ± 0.836
      n = 11

      240 ± 0.737
      n = 12

      190 ± 1.454
      n = 12

      60 ± 1.089
      n = 16

      200 ± 1.279
      n = 16

      50 ± 0.982
       ICS + LABA + TIO + anothern = 16

      460 ± 0.966
      n = 14

      250 ± 1.046
      n = 17

      390 ± 1.538
      n = 16

      40 ± 1.306
      n = 42

      310 ± 1.243
      n = 39

      40 ± 0.988
      Other could be 1 or more of leukotriene receptor antagonists, xanthine, or nedocromil/cromolyn sodium; 5 patients did not report a LABA controller and therefore are not included when summarizing by background controller type.
      TIO, Tiotropium.

      References

      1. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. Available at: http://www.ginasthma.org. Accessed June 2017.

        • Chung K.F.
        • Wenzel S.E.
        • Brozek J.L.
        • Bush A.
        • Castro M.
        • Sterk P.J.
        • et al.
        International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.
        Eur Respir J. 2014; 43: 343-373
        • Pavord I.D.
        • Korn S.
        • Howarth P.
        • Bleecker E.R.
        • Buhl R.
        • Keene O.N.
        • et al.
        Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.
        Lancet. 2012; 380: 651-659
        • Ortega H.G.
        • Liu M.C.
        • Pavord I.D.
        • Brusselle G.G.
        • FitzGerald J.M.
        • Chetta A.
        • et al.
        Mepolizumab treatment in patients with severe eosinophilic asthma.
        N Engl J Med. 2014; 371: 1198-1207
        • Bel E.H.
        • Wenzel S.E.
        • Thompson P.J.
        • Prazma C.M.
        • Keene O.N.
        • Yancey S.W.
        • et al.
        Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma.
        N Engl J Med. 2014; 371: 1189-1197
        • Reddel H.K.
        • Bateman E.D.
        • Becker A.
        • Boulet L.P.
        • Cruz A.A.
        • Drazen J.M.
        • et al.
        A summary of the new GINA strategy: a roadmap to asthma control.
        Eur Respir J. 2015; 46: 622-639