Long-term Safety and Clinical Benefit of Mepolizumab in Patients With the Most Severe Eosinophilic Asthma: the COSMEX Study

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In selected patients with the most severe forms of severe eosinophilic asthma who had previously shown clinical benefit with mepolizumab, long-term treatment with mepolizumab throughout COSMEX and previous lead–in studies was well tolerated and provided sustained and consistent reductions in exacerbation rate, with sustained improvements in ACQ-5 score and FEV1 over a period of up to 4.5 years. Furthermore, the reduction in OCS dose initially achieved during SIRIUS was also sustained, with additional patients no longer requiring OCS treatment following continued mepolizumab treatment across the SIRIUS, COSMOS, and COSMEX studies. This study extends our knowledge of the long-term safety and efficacy of mepolizumab in a population of patients with the most severe forms of eosinophilic asthma.

The type and frequency of the AEs, including fatal events and events of special interest, reported in this study were broadly consistent with those reported in other mepolizumab clinical studies,11x11Ortega, H.G., Liu, M.C., Pavord, I.D. et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;
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,12x12Bel, E.H., Wenzel, S.E., Thompson, P.J. et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;
371: 1189–1197
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,13x13Lugogo, N., Domingo, C., Chanez, P. et al. Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin Ther. 2016;
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,14x14Pavord, I.D., Korn, S., Howarth, P. et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;
380: 651–659
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,15x15Chupp, G.L., Bradford, E.S., Albers, F.C. 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;
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and no new safety concerns were identified. Immunogenicity incidence was low and consistent with previous mepolizumab studies in severe eosinophilic asthma, and no patients tested positive for neutralizing antibodies 11x11Ortega, H.G., Liu, M.C., Pavord, I.D. et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;
371: 1198–1207
Google ScholarSee all References
,12x12Bel, E.H., Wenzel, S.E., Thompson, P.J. et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;
371: 1189–1197
Google ScholarSee all References
,13x13Lugogo, N., Domingo, C., Chanez, P. et al. Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin Ther. 2016;
38: 2058–2070 ()
Google ScholarSee all References
,14x14Pavord, I.D., Korn, S., Howarth, P. et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;
380: 651–659
Google ScholarSee all References
,15x15Chupp, G.L., Bradford, E.S., Albers, F.C. 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
Google ScholarSee all References
.

The primary efficacy endpoint for this study was the annualized exacerbation rate, which was estimated at 0.93 event/year, consistent with findings from the COSMOS and COLUMBA (Open-label Long Term Extension Safety Study of Mepolizumab in Asthmatic Subjects; MEA115666/NCT01691859) mepolizumab studies in which rates of 0.93 and 0.68 event/year, respectively, were reported.13x13Lugogo, N., Domingo, C., Chanez, P. et al. Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin Ther. 2016;
38: 2058–2070 ()
Google ScholarSee all References
,16x16Khatri, S., Moore, W., Gibson, P.G. et al. Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma. J Allergy Clin Immunol. 2019;
143: 1742–1751 ()
Google ScholarSee all References
In addition, those patients with continuous study participation since MENSA reported a sustained reduction in exacerbation rate with mepolizumab. Patients with ≥188 weeks of continuous enrollment across MENSA, COSMOS, and COSMEX presented an annualized exacerbation rate of ∼5 events/year in the 12 months before MENSA, which was reduced by mepolizumab to ∼1 event/year across studies. There were limited changes in efficacy parameters (ACQ-5 and FEV1) in COSMEX, demonstrating the persistence of clinical benefit in responsive patients treated continuously with mepolizumab with no sign of loss of efficacy. The withdrawal rate due to a lack of efficacy was very low, further supporting the durability of mepolizumab. Furthermore, we observed that long-term mepolizumab treatment provided a sustained OCS reduction and no evidence of tolerance to mepolizumab after long-term administration, with blood eosinophil levels remaining low and stable.

Although most patients enrolled in COSMEX had minimal gaps between successive clinical studies, a small proportion experienced a prolonged interruption in mepolizumab treatment (>12 weeks between COSMOS and COSMEX doses). These patients showed a worsening in lung function (FEV1) and asthma control (ACQ-5 score) and an increase in blood eosinophil count at baseline compared with patients who had maintained continuous therapy. These data are consistent with the long-term COLUMBA safety study, in which the cessation of mepolizumab led to increases in blood eosinophil levels and frequency of exacerbations approaching pretreatment levels.16x16Khatri, S., Moore, W., Gibson, P.G. et al. Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma. J Allergy Clin Immunol. 2019;
143: 1742–1751 ()
Google ScholarSee all References

The current study has several limitations. Regarding the study design, the lack of a placebo-controlled arm means it is difficult to make robust clinical interpretations regarding any treatment-related outcomes. Patient recruitment to this extension study was also biased toward those who responded to mepolizumab, and those without AEs leading to discontinuation from the previous studies, which may have positively affected long-term mepolizumab safety and efficacy. Approximately 370 of the 651 patients from COSMOS were eligible for continued mepolizumab treatment within COSMEX when assessed against the life-threatening/seriously debilitating and clinical benefit eligibility criteria, with the majority (92%) of eligible patients entering this extension study. Subsequently, the percentage of patients enrolled into COSMEX from the COSMOS trial was ∼50%, and into COSMOS from the MENSA and SIRIUS trials was ∼90%. These proportions are noteworthy because, owing to the nature of the studies, each subsequent study favored patients who responded to mepolizumab; however, these criteria for continued treatment are consistent with those of clinical practice. The use of background asthma therapies was also not systematically checked during this study; instead, it was at the investigator’s discretion whether to reduce or change background therapies. This approach may have influenced the results to some extent, and in particular, any changes in bronchodilator therapy may have affected the results on lung function. Owing to the attrition of patients during this study, later-stage efficacy endpoints should also be interpreted with caution because the results are based on fewer patients compared with the first 2 years of the COSMEX study.

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