The clinical benefit of mepolizumab replacing omalizumab in uncontrolled severe eosinophilic asthma

Abstract Background Mepolizumab and omalizumab are treatments for distinct but overlapping severe asthma phenotypes. Objective To assess if patients eligible for both biologics but not optimally controlled with omalizumab experience improved asthma control when switched directly to mepolizumab. Methods OSMO was a multicenter, open‐label, single‐arm, 32‐week trial in patients with ≥2 asthma exacerbations in the year prior to enrollment, despite receiving high‐dose inhaled corticosteroids and other controller(s), plus omalizumab (≥4 months). At baseline, patients with blood eosinophil counts ≥150 cells/µL (or ≥300 cells/µL in the prior year) and an Asthma Control Questionnaire (ACQ)‐5 score ≥1.5 discontinued omalizumab and immediately commenced mepolizumab 100 mg subcutaneously every 4 weeks. Endpoints included change from baseline in ACQ‐5 score (primary), St George's Respiratory Questionnaire (SGRQ) score and the proportions of ACQ‐5 and SGRQ responders, all at Week 32, and the annualized exacerbation rate over the study period. Results At Week 32 (intent‐to‐treat population [n = 145]), the least squares (LS) mean changes (standard error [SE]) in ACQ‐5 and SGRQ total scores were −1.45 (0.107) and −19.0 (1.64) points; with 77% and 79% of patients achieving the minimum clinically important differences (ACQ‐5: ≥0.5 points; SGRQ: ≥4 points), respectively. The annualized rate of clinically significant exacerbations was 1.18 events/year, a 64% reduction from 3.26 events/year during the previous year. Safety and immunogenicity profiles were consistent with previous trials. Conclusion After directly switching from omalizumab to mepolizumab, patients with uncontrolled severe eosinophilic asthma experienced clinically significant improvements in asthma control, health status, and exacerbation rate, with no tolerability issues reported.


| INTRODUC TI ON
Asthma is a heterogenous condition that affects approximately 235 million people worldwide. 1 Although most patients with asthma are able to manage their symptoms and enjoy a good quality of life, 5%-10% of patients suffer from severe asthma. 2 Severe asthma is associated with significant morbidity and mortality, 3 and accounts for approximately 50% of asthma care costs. 4 Patients with severe asthma typically require regular treatment with high-dose inhaled corticosteroids (ICS), plus an additional controller or systemic corticosteroids (SCS) to prevent their disease from becoming uncontrolled. 2 Despite this therapy, a subset of patients continue to have uncontrolled disease.
Severe asthma comprises different phenotypes driven by distinct pathophysiological processes. 5 However, some severe asthma phenotypes overlap in terms of clinical and physiological characteristics, biomarker expression, and treatment response. 2,5 In clinical practice, severe allergic asthma and severe eosinophilic asthma are recognized as distinct, but potentially overlapping phenotypes of severe asthma. 6 Severe allergic asthma is characterized by an early age of onset, high levels of serum immunoglobulin E (IgE), high fractional exhaled nitric oxide (FeNO), clinically relevant sensitization to common aeroallergens and eosinophilic inflammation; severe eosinophilic asthma is characterized by a later age of onset, peripheral eosinophilia, high FeNO, and frequent exacerbations. 2,5 Due to the unmet clinical need within these severe asthma populations, novel biologic therapies that target the immunologic mediators of disease have been developed. 4 Omalizumab is an anti-IgE antibody indicated for use in patients with moderate-to-severe allergic asthma. 7 The humanized monoclonal antibody binds to the FcεRI binding domain of free circulating IgE, inhibits binding of IgE to its receptors, and decreases free IgE levels in serum. 8 In patients with severe asthma, omalizumab treatment decreases exacerbations, improves asthma control and improves patient quality of life. [9][10][11] Omalizumab is recommended by the Global Initiative for Asthma (GINA) as a potential Step 5 treatment for patients with severe allergic asthma. 12 However, in some patients, symptoms remain Conclusion: After directly switching from omalizumab to mepolizumab, patients with uncontrolled severe eosinophilic asthma experienced clinically significant improvements in asthma control, health status, and exacerbation rate, with no tolerability issues reported.

K E Y W O R D S
ACQ-5, asthma control, mepolizumab, omalizumab, severe eosinophilic asthma G R A P H I C A L A B S T R A C T Minimal clinically important difference for improvement in asthma control questionnaire-5 and St. George's Respiratory Questionnaire total scores was achieved by 77% and 79% of patients, respectively. Annualized rate of clinically significant exacerbations was reduced from 3.26 to 1.18 events/year. Safety and immunogenicity profiles of mepolizumab were consistent with previous placebo-controlled trials in severe eosinophilic asthma.
uncontrolled despite omalizumab therapy. The European Respiratory Society/American Thoracic Society guidelines note that if symptoms do not improve within 4 months of initiating omalizumab treatment, further administration is unlikely to be beneficial. 2 Mepolizumab is an anti-interleukin (IL)-5 humanized monoclonal antibody indicated for use in severe eosinophilic asthma. 13 By binding with high affinity to free IL-5, mepolizumab blocks the interaction between IL-5 and the eosinophil cell surface receptor IL5Rα, preventing IL-5-driven eosinophil proliferation, survival and differentiation. 14 Mepolizumab effectively decreases peripheral blood eosinophil counts and exacerbations, [15][16][17] reduces oral glucocorticoid dependence, 15 and improves lung function and health-related quality of life in patients with severe eosinophilic asthma. 16,18 Mepolizumab is also recommended by GINA as a potential Step 5 treatment for patients with severe eosinophilic asthma. 12 Omalizumab has been available for clinical use since 2003. 7 As such, some patients with severe asthma who are eligible for both biologics have been receiving omalizumab. 18,19 The primary objective of this study was to identify patients with severe eosinophilic asthma being treated with omalizumab whose disease was not optimally controlled, and to evaluate, in a pragmatic setting, any improvement in asthma control following a switch from omalizumab to mepolizumab without a washout period.

| Study design and treatment
OSMO (Omalizumab Switch to MepOlizumab study) was an open-label, single-arm, multicenter trial in patients with severe eosinophilic asthma not optimally controlled by omalizumab treatment (NCT02654145).
Details of study locations are provided in the Appendix S1. The single-arm study design was chosen in order to focus on the switch from omalizumab to mepolizumab in a manner that reflects clinical practice.
Following a prescreening phase, which occurred over a 2-week period, patients attended a screening visit (Visit 1) to assess eligibility for the study. Eligible patients entered a 1-4 weeks run-in period, during which their continued eligibility was assessed. All maintenance therapy, including omalizumab, was continued throughout the run-in period. At the baseline study visit (Visit 2), patients discontinued omalizumab treatment and switched to mepolizumab 100 mg subcutaneously every 4 weeks for 32 weeks (final dose Week 28). With the exception of omalizumab, patients continued their maintenance therapies in unchanged dosages throughout the study period.

| Patients
Eligible patients were ≥12 years of age (or ≥18 years of age where local regulations restricted enrollment to adults), had a physician's diagnosis of asthma for ≥2 years according to National Heart, Lung and Blood Institute or GINA guidelines, 20

| Endpoints and assessments
The primary endpoint was mean change from baseline at Week 32 in ACQ-5 score. The ACQ-5 score has a range of 0-6 with higher scores indicating worse asthma control. The minimum clinically important difference (MCID) in ACQ-5 score has been established as 0.5 points. 22 Secondary endpoints were mean change from baseline at Week 32 in St George's Respiratory Questionnaire (SGRQ) score, frequency of clinically significant asthma exacerbations over the 32-week study period (Appendix S1), and ratio to baseline at Week 32 of blood eosinophil count. SGRQ scores range from 0 to 100, with higher scores indicating worse health status (MCID = 4-point change in score). 23 Additional endpoints included the percentage of patients achieving ≥0.5-point reduction from baseline in ACQ-5 score, the percentage of patients achieving ≥4-point reduction from baseline in SGRQ total score, and mean change from baseline in pre-and postbronchodilator FEV 1 , all at Week 32. We also assessed the frequency of exacerbations requiring an emergency room (ER) visit or hospitalization over the 32-week study period, patient-and clinician-rated response to therapy, and the mean change from baseline in Treatment Satisfaction Questionnaire for Medication (TSQM-9). The TSQM-9 Overall Satisfaction Scale score has a range of 0-100, with higher scores indicating greater satisfaction. Levels of inflammatory biomarkers were also assessed (Appendix S1).
Safety endpoints were the frequency of adverse events (AEs), serious AEs (SAEs) and AEs of special interest (AESIs; Appendix S1).
AEs were recorded on a worksheet by patients and documented by study staff at each visit. Immunogenicity endpoints included the presence of anti-drug antibodies (ADAs), defined as any antibody isotype directed against mepolizumab; binding assays were performed at baseline and Weeks 12, 28, and 32. Samples testing positive for ADAs were further tested for the presence of neutralizing antibodies.

| Statistical analysis
The intent-to-treat (ITT) population, defined as all patients who were enrolled in the study and received ≥1 dose of mepolizumab, formed the primary analysis population. To take into account a possible "placebo effect" or "Hawthorne effect" due to clinical trial participation, the primary endpoint data were also compared to two "historical placebo" estimates produced from meta-analyses of previous studies of mepolizumab in patients with severe eosinophilic asthma.
The first, a meta-analysis of DREAM (NCT01000506) 17  We estimated that a sample size of 120 would provide 90% power to declare statistical significance over the historical "placebo effect" of −0.55 mean improvement from baseline in ACQ-5 score at a two-sided significance level of 5%. These estimates were made based on a residual standard deviation (SD) of 0.96 and assumed 15% of patients would withdraw from the study prematurely. Post hoc subgroup analyses were additionally conducted in patients who were or were not receiving maintenance OCS at baseline, and in patients who experienced ≥2 exacerbations during the ontreatment period. All statistical analyses were performed using SAS version 9.4 (SAS Institute).
F I G U R E 1 Overview of study design and patient flow. One patient failed two inclusion/exclusion criteria at screening *Fourteen patients (10%) received mepolizumab and were included in the ITT population despite having failed ≥ 1 eligibility criterion, see Table S1 for details. There were two patients that discontinued treatment with mepolizumab due to adverse events (urticaria and ECG QT prolonged) but who were not withdrawn and completed the study. ECG, electrocardiogram; ITT, intent-to-treat

| Patient population
The study was conducted from March 17, 2016, to May 31, 2017.
Overall, 206 patients currently receiving omalizumab were enrolled in the study, of whom 145 were switched to mepolizumab and were included in the ITT population. Seven patients (5%) withdrew from the study and two additional patients (1%) withdrew from the investigational product (mepolizumab) due to AEs but completed the study (Figure 1). Demographic and baseline clinical characteristics are summarized in Table 1. Patients in the ITT population had an average age of 53.6 years and 59% were women. Overall, 52% and 48% of patients previously received omalizumab every 2 weeks and every 4 weeks, respectively, with a median (range) prior omalizumab treatment duration of 29.6 (4, 161) months (Table 1).

| Primary endpoint
Patient ACQ-5 scores improved substantially over the study period, There was an early response in asthma control, with 103 patients (71%) achieving an improvement (reduction) in ACQ-5 score of ≥0.5 points by Week 8. This improvement was maintained over the study period, with 111 patients (77%) meeting the MCID in ACQ-5 score at Week 32 ( Figure 2B).

| Secondary endpoints
The LS mean (SE) SGRQ total score improved from 56. Sixty patients (41%) experienced a total of 104 clinically significant exacerbations during the 32-week study period, of whom 15 patients required an ER visit/hospitalization and 9 patients required hospitalization. During the study period, the annualized rates of clinically significant exacerbations and exacerbations requiring an ER visit/hospitalization were reduced by 64% and 69%, respectively, compared with the year prior to study enrollment ( Table 2). The cumulative incidence for time to first clinically significant exacerbation is shown in Figure S1.
In the subgroup of patients who experienced ≥2 exacerbations during the on-treatment period (n = 24), the mean (SD) number of exacerbations during the 12 months prior to screening was 4.3 (3.61) compared with 3.3 (2.65) in the overall study population. Other disease characteristics were similar to those in the overall ITT population (Table S2). Despite experiencing ≥2 exacerbations during mepolizumab treatment, 6/24 (25%) patients in this subgroup still experienced a ≥10% reduction in exacerbation rate while on treatment compared with the 12 months prior to the study (Table S3).
As observed in previous studies, blood eosinophil counts de-

| Additional endpoints
Prebronchodilator  Figure S2B). Both these results exceeded the MCID in FEV 1 of 100 mL. Patient-and clinician-rated responses to therapy supported the improvements seen in clinical outcomes (Appendix S1).
In subgroup analyses, improvements from baseline were seen in ACQ-5 score, SGRQ total score, and prebronchodilator FEV 1 at Week 32 both in patients who required maintenance OCS use at baseline and in those who did not (Table S4). Additionally, compared with the year prior to study enrollment, the annualized rate of clinically significant exacerbations was reduced during the study period by 51% in patients who required maintenance OCS use at baseline and by 69% in patients who did not (Table S4).

| D ISCUSS I ON
Patients with severe eosinophilic asthma not optimally controlled by omalizumab experienced a clinically significant benefit in asthma control following a direct switch from omalizumab to mepolizumab.
Over the study period, the adjusted LS mean change in ACQ-5 score was substantially greater than the MCID of 0.5 points, demonstrat- Despite switching patients from one biologic to another without a washout period, the safety and immunogenicity profiles of mepolizumab during this study were similar to previous clinical trials in patients with severe eosinophilic asthma. 28 Omalizumab has previously been reported to reduce peripheral blood eosinophil counts in patients with severe asthma, 29 and to have greater efficacy in terms of exacerbation reduction in patients with blood eosinophil counts ≥260 cells/µL 30 or ≥300 cells/µL, 31,32 as compared with patients with lower blood eosinophil counts.
Interestingly, the present study assessed patients whose asthma   of patients in the ITT population experienced a clinically significant improvement in asthma control in response to mepolizumab.
The principal limitation of this study was the single-arm design without a randomized control group. This limitation was partly addressed using historical placebo control estimates, generated by metaanalyses of previous clinical trials of mepolizumab in patients with severe eosinophilic asthma. The clinical trials used in these meta-analyses were of similar length and had comparable inclusion and exclusion criteria; therefore, the "placebo estimates" were based on patients of similar clinical status and disposition. In particular, the meta-analysis of MENSA/MUSCA only included patients who had previously received omalizumab therapy. Secondly, this was a 32-week, rather than 12month study. Thirty-two weeks is shorter than the ideal time frame for assessment of exacerbation rates; however, this limitation was partly mitigated through recruitment of patients across seasons, reducing seasonality confounding. Furthermore, although clinical conditions may vary when comparing exacerbation rates pre-and poststudy, objective measures such as FEV 1 and blood eosinophil counts showed the same trend as exacerbation rates over this time frame. Thirdly, as patients were receiving omalizumab treatment prior to entering the study, the initial indications for prescribing omalizumab were not known for all patients, and therefore could have been incorrect in a subset. Nonetheless, it is thought that these patients were likely to have been identified as suitable for omalizumab treatment according to the product label and, as such, would have been diagnosed with allergic asthma and received the appropriate dose of omalizumab based on their IgE levels. Indeed, one of the study inclusion criteria stated that study patients must have been receiving omalizumab based on weight and IgE levels. As patients were not required to washout prior to the switch to mepolizumab, baseline measurements of atopy were not collected as these would have been confounded by current omalizumab treatment. Finally, to justify the study treatment, this study was conducted in a subgroup of patients eligible for both omalizumab and mepolizumab who had uncontrolled disease. Consequently, the results of this study are not necessarily generalizable to the entire overlapping population of patients eligible for both biologics.
In conclusion, this open-label study provides evidence that patients with severe asthma who are eligible for both biologics and not optimally controlled with omalizumab could be effectively switched to mepolizumab to improve their asthma control. Patients experienced statistically significant and clinically meaningful improvements in asthma control (measured by ACQ-5), quality of life (measured by SGRQ), and asthma exacerbations, following the switch from omalizumab to mepolizumab without a standard washout. No tolerability issues were observed. This pragmatic study reflects expected clinical practice and provides practical guidance to clinicians for the treatment of patients with severe eosinophilic asthma. form of writing assistance, including development of the initial draft from the study report, assembling tables and figures, collating authors comments, grammatical editing and referencing) was provided by Natasha Dean, MSc, and Susan Parker, PhD, at Fishawack Indicia Ltd, UK, and was funded by Glaxo Smith Kline (GSK).

DATA S H A R I N G
Anonymized individual participant data and study documents can be requested for further research from www.clini calst udyda tareq uest. com.