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Randomized Controlled Trial
. 2022 Jan 6;59(1):2100396.
doi: 10.1183/13993003.00396-2021. Print 2022 Jan.

Stopping versus continuing long-term mepolizumab treatment in severe eosinophilic asthma (COMET study)

Wendy C Moore  1 , Oliver Kornmann  2 , Marc Humbert  3   4   5 , Claude Poirier  6 , Elisabeth H Bel  7 , Norihiro Kaneko  8 , Steven G Smith  9 , Neil Martin  10   11 , Martyn J Gilson  12 , Robert G Price  13 , Eric S Bradford  9 , Mark C Liu  14
Affiliations
Randomized Controlled Trial

Stopping versus continuing long-term mepolizumab treatment in severe eosinophilic asthma (COMET study)

Wendy C Moore et al. Eur Respir J. .

Abstract

Background: The long-term efficacy and safety of mepolizumab for treatment of severe eosinophilic asthma are well established. Here, we examine the clinical impact of stopping mepolizumab after long-term use.

Methods: COMET (NCT02555371) was a randomised, double-blind, placebo-controlled, parallel-group, multicentre study. Patients who had completed COLUMBA (NCT01691859) or COSMEX (NCT02135692) and received continuous mepolizumab treatment for ≥3 years were randomised 1:1 to stop (switch to placebo) or continue subcutaneous mepolizumab 100 mg every 4 weeks for 52 weeks. Primary end-point: time to first clinically significant exacerbation; secondary end-points: time to first exacerbation requiring hospitalisation/emergency department visit, time to decrease in asthma control (≥0.5-point increase in Asthma Control Questionnaire-5 score from COMET baseline) and blood eosinophil count ratio to COMET baseline. Safety was assessed.

Results: Patients stopping (n=151) versus continuing (n=144) mepolizumab had significantly shorter times to first clinically significant exacerbation (hazard ratio 1.61, 95% CI 1.17-2.22; p=0.004) and decrease in asthma control (hazard ratio 1.52, 95% CI 1.13-2.02; p=0.005), and higher blood eosinophil counts at week 52 (270 versus 40 cells·µL-1; ratio (stopping versus continuing) 6.19, 95% CI 4.89-7.83; p<0.001). Differences in efficacy outcomes between groups were observed when assessed from week 12 (16 weeks after last mepolizumab dose). Exacerbations requiring hospitalisation/emergency department visit were rare. Adverse events in patients continuing mepolizumab were consistent with previous studies. For patients who stopped mepolizumab, the safety profile was consistent with other eosinophilic asthma populations.

Conclusion: Patients who stopped mepolizumab had an increase in exacerbations and reduced asthma control versus those who continued.

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Conflict of interest statement

Conflict of interest: W.C. Moore reports that the study and writing support was funded by GlaxoSmithKline; and has received funding for clinical research and personal fees for participation in advisory boards from GSK, AstraZeneca and Sanofi Regeneron, outside the submitted work. Conflict of interest: O. Kornmann reports that the study and writing support was funded by GlaxoSmithKline; and has received personal fees from AstraZeneca, GSK, Novartis, Boehringer Ingelheim, Sanofi Aventis, and Roche, outside the submitted work. Conflict of interest: M. Humbert reports that the study and writing support was funded by GlaxoSmithKline; and has received personal fees for consultancy services and speaking at conferences, and participation in clinical research projects with AstraZeneca, GSK, Novartis, Roche, Sanofi Regeneron and TEVA; and has a research grant from GSK, outside the submitted work. Conflict of interest: C. Poirier reports that the study and writing support was funded by GlaxoSmithKline; and has received personal fees from GSK, Novartis, Sanofi, and Boehringer Ingelheim, outside the submitted work. Conflict of interest: E.H. Bel reports that the study and writing support was funded by GlaxoSmithKline; and grants from GSK and Teva, personal fees from AstraZeneca, GSK, Novartis, Sanofi/Regeneron, Sterna Biologicals and Chiesi, outside the submitted work. Conflict of interest: N. Kaneko reports that the study and writing support was funded by GlaxoSmithKline. Conflict of interest: S.G. Smith reports that the study and writing support was funded by GlaxoSmithKline; and is an employee of GSK and owns stocks/shares. Conflict of interest: N. Martin reports that the study and writing support was funded by GlaxoSmithKline; and is an employee of GSK and owns stocks/shares. Conflict of interest: M.J. Gilson reports that the study and writing support was funded by GlaxoSmithKline; and is an employee of GSK and owns stocks/shares. Conflict of interest: R.G. Price reports that the study and writing support was funded by GlaxoSmithKline; and is an employee of GSK and owns stocks/shares. Conflict of interest: E.S. Bradford reports that the study and writing support was funded by GlaxoSmithKline; and was an employee at GSK at the time of the study. Conflict of interest: M.C. Liu reports that the study and writing support was funded by GlaxoSmithKline; and has received grants for clinical trials from Boehringer Ingelheim, GSK, MedImmune, Mereo BioPharm, and Gossamer Bio, outside the submitted work.

Figures

FIGURE 1
FIGURE 1
Study design and description of the individual study parts.
FIGURE 2
FIGURE 2
Kaplan–Meier cumulative incidence curve for time to first a) clinically significant exacerbation; and b) decrease in asthma control, defined as an increase from baseline in Asthma Control Questionnaire-5 score of ≥0.5 units [15], and the associated hazard ratios (stopping/continuing mepolizumab) (on-treatment; Part C; blinded treatment). Week 0 represents 4 weeks following the last dose of open-label mepolizumab. Shaded areas represent 95% confidence intervals. Arrows indicate that the difference between groups was seen from week 12 onwards (16 weeks after the last dose of open-label mepolizumab).
FIGURE 3
FIGURE 3
a) Mean change from baseline (start of double-blind treatment in COMET) in Asthma Control Questionnaire (ACQ)-5 score; b) ratio to baseline in blood eosinophil count; c) mean change from baseline in St George's Respiratory Questionnaire (SGRQ) total score; and d) mean change from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV1) (on-treatment; part C; blinded treatment). Week 0 represents 4 weeks following the last dose of open-label mepolizumab. Data are presented as least squares means (95% CI). Patient numbers at each given time point are shown below each graph. Higher scores on the ACQ-5 indicate worse control (range 0–6); a change of 0.5 points is the minimal clinically important difference [15]. Higher scores on the SGRQ indicate a worse function (range 0–100); a change of 4 points is the minimal clinically important difference [16].
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