From DREAM to REALITI-A and beyond: Mepolizumab for the treatment of eosinophil-driven diseases.

Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil-reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin-5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add-on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real-world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI-A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases.

Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial.

BACKGROUND: Anti-IL-5 therapy is a potential treatment for patients with hypereosinophilic syndrome (HES), although its clinical efficacy is unclear. OBJECTIVE: We sought to investigate the clinical efficacy and safety of mepolizumab versus placebo in patients with HES. METHODS: This randomized, multicenter, double-blind, placebo-controlled, phase III trial was conducted across 39 centers in 13 countries. Eligible patients had FIP1L1-PDGFRA-negative HES, experienced 2 or more flares (worsening of HES-related symptoms or blood eosinophil count requiring therapeutic escalation) in the previous 12 months, and had a screening blood eosinophil count greater than or equal to 1000 cells/µL. Patients were randomized (1:1) to subcutaneous mepolizumab (300 mg) or placebo every 4 weeks for 32 weeks, plus existing HES therapy. The primary outcome was the proportion of patients with 1 or more flares (worsening of HES-related symptoms necessitating therapy escalation or ≥2 courses of blinded rescue oral corticosteroids) during the study; in addition, patients who withdrew early from the study were counted as having a flare. Safety end points were also assessed. RESULTS: The proportion of patients experiencing 1 or more flares/withdrawing from the study was 50% lower with mepolizumab versus placebo (15 of 54 [28%] vs 30 of 54 [56%]; P = .002). Logistic regression analysis was consistent with the primary analysis (odds ratio, 0.28; 95% CI, 0.12-0.64; P = .003). Similar proportions of patients in the mepolizumab and placebo groups experienced on-treatment adverse events (48 of 54 [89%] vs 47 of 54 [87%]). CONCLUSIONS: Compared with placebo, mepolizumab significantly reduced the occurrence of flares in patients with HES, with no new safety signals identified.

Prevalence of Eosinophilic Granulomatosis With Polyangiitis and Associated Health Care Utilization Among Patients With Concomitant Asthma in US Commercial Claims Database.

OBJECTIVE: To estimate the prevalence and associated disease burden of eosinophilic granulomatosis with polyangiitis (EGPA) in patients with asthma from a US claims database. METHODS: Two cohorts were defined using enrollees (aged ≥18 years) from the Optum deidentified Clinformatics Datamart claims database 2010-2014, based on validated EGPA case definitions with varying specificity: EGPA 1 (main cohort; more specific; patients with 2 codes [in any combination] within 12 months of each other for eosinophilia, vasculitis, or mononeuritis multiplex) and EGPA 2 (sensitivity analysis cohort; less specific; patients with 2 codes of above conditions and/or neurologic symptoms within 12 months of each other). Patients had 3 or more asthma medications in the 12-month baseline before index date (date of the second code). Eosinophilic granulomatosis with polyangiitis prevalence, asthma severity during the baseline period, oral corticosteroid (OCS) use, and health care utilization during the 12-month follow-up period were determined. RESULTS: Overall, 88 and 604 patients were included in main cohort EGPA 1 and sensitivity analysis cohort EGPA 2, respectively; corresponding annual EGPA prevalence rates were 3.2 to 5.9 and 23.4 to 30.7 cases/million patients. Approximately 75% of patients were prescribed OCS and ~30% experienced 1 or more hospitalization; 75% in EGPA 1 and 52% in EGPA 2 with 1 or more non-OCS prescription in the 90 days before index date had severe asthma. CONCLUSIONS: Eosinophilic granulomatosis with polyangiitis prevalence estimates varied based on specificity of the case definition but were generally consistent with previous country-specific estimates. Despite differences in prevalence, both cohorts displayed a generally similar, high burden of OCS use and health care utilization, highlighting the substantial disease burden among patients with EGPA and the need for specific treatments.

Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis is an eosinophilic vasculitis. Mepolizumab, an anti-interleukin-5 monoclonal antibody, reduces blood eosinophil counts and may have value in the treatment of eosinophilic granulomatosis with polyangiitis. METHODS: In this multicenter, double-blind, parallel-group, phase 3 trial, we randomly assigned participants with relapsing or refractory eosinophilic granulomatosis with polyangiitis who had received treatment for at least 4 weeks and were taking a stable prednisolone or prednisone dose to receive 300 mg of mepolizumab or placebo, administered subcutaneously every 4 weeks, plus standard care, for 52 weeks. The two primary end points were the accrued weeks of remission over a 52-week period, according to categorical quantification, and the proportion of participants in remission at both week 36 and week 48. Secondary end points included the time to first relapse and the average daily glucocorticoid dose (during weeks 48 through 52). The annualized relapse rate and safety were assessed. RESULTS: A total of 136 participants underwent randomization, with 68 participants assigned to receive mepolizumab and 68 to receive placebo. Mepolizumab treatment led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P<0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P<0.001). Remission did not occur in 47% of the participants in the mepolizumab group versus 81% of those in the placebo group. The annualized relapse rate was 1.14 in the mepolizumab group, as compared with 2.27 in the placebo group (rate ratio, 0.50; 95% CI, 0.36 to 0.70; P<0.001). A total of 44% of the participants in the mepolizumab group, as compared with 7% of those in the placebo group, had an average daily dose of prednisolone or prednisone of 4.0 mg or less per day during weeks 48 through 52 (odds ratio, 0.20; 95% CI, 0.09 to 0.41; P<0.001). The safety profile of mepolizumab was similar to that observed in previous studies. CONCLUSIONS: In participants with eosinophilic granulomatosis with polyangiitis, mepolizumab resulted in significantly more weeks in remission and a higher proportion of participants in remission than did placebo, thus allowing for reduced glucocorticoid use. Even so, only approximately half the participants treated with mepolizumab had protocol-defined remission. (Funded by GlaxoSmithKline and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT02020889 .).

Pharmacogenetic investigation of efficacy response to mepolizumab in eosinophilic granulomatosis with polyangiitis.

Treatment of patients with the rare disease eosinophilic granulomatosis with polyangiitis (EGPA) with mepolizumab, a monoclonal antibody to interleukin-5 (IL-5) that reduces blood eosinophil counts, as an add-on therapy to glucocorticoid treatment, results in more accrued weeks in remission, reductions in glucocorticoid use and reductions in relapse rate. However, treatment response varies across a continuum. Therefore, to investigate if large genetic effects could identify responders, the impact of genetic variants on efficacy in EGPA subjects taking mepolizumab and glucocorticoids was assessed in this post hoc study. Using linear regression and a negative binomial model, genetic variant association with three endpoints (accrued duration of remission, average oral glucocorticoid dose, and frequency of relapse) was tested in 61 EGPA subjects dosed with mepolizumab from MIRRA, a phase 3 trial. Candidate gene and genome-wide approaches were used. The candidate gene analysis was designed to investigate drug target effects with eight gene regions selected that were focused on the intersection of the glucocorticoid response (steroidal response) and IL-5 response mechanisms and recognizing potential overlap between EGPA and severe eosinophilic asthma diseases for which mepolizumab is used. The sample size was insufficient to enable testing of rare variants for effects. No genetic variant from either the candidate gene analysis or the GWAS associated with any endpoint. Thresholds to declare significance were p < 0.0008 (candidate variant) and p < 2.5 × 10-8 (genome-wide) analyses. Large genetic effects on mepolizumab-treatment response were not identified which could help differentiate responders from non-responders.

Long-term safety and pharmacodynamics of mepolizumab in children with severe asthma with an eosinophilic phenotype.

BACKGROUND: Mepolizumab is approved for patients with severe asthma with an eosinophilic phenotype aged 12 or more (United States) or 6 or more (European Union) years, but its long-term use in children aged 6 to 11 years has not yet been assessed. OBJECTIVE: We sought to assess the long-term safety, efficacy, and pharmacodynamics of mepolizumab in children aged 6 to 11 years with severe asthma with an eosinophilic phenotype. METHODS: In this open-label, uncontrolled, repeat-dose extension study (NCT02377427), children aged 6 to 11 years with severe asthma with an eosinophilic phenotype (blood eosinophil counts ≥150 cells/µL at screening or ≥300 cells/µL in the previous year) received a body weight-dependent dose of subcutaneous mepolizumab of 40 mg (<40 kg) or 100 mg (≥40 kg) over 52 weeks. End points included the incidence of adverse events (AEs) and immunogenicity (primary), absolute blood eosinophil counts (cells per microliter; secondary), and annualized exacerbation rates and asthma control questionnaire/childhood asthma control test scores (exploratory). RESULTS: Over 52 weeks, 30 children received mepolizumab; 27 (90%) and 7 (23%) experienced on-treatment AEs and serious AEs, respectively. No serious AEs were treatment related. There were no fatal AEs. No specific patterns of AEs were evident, and no anti-drug antibody or neutralizing antibody responses were reported. Compared with baseline values, mepolizumab treatment reduced blood eosinophil counts and asthma exacerbations and improved asthma control across all treatment groups. CONCLUSION: Long-term safety, pharmacodynamic, and efficacy data from this study support a positive benefit-risk profile for mepolizumab in children with severe asthma with an eosinophilic phenotype and were similar to data in studies in adults and adolescents.

Evaluation of clinical benefit from treatment with mepolizumab for patients with eosinophilic granulomatosis with polyangiitis.

BACKGROUND: In a recent phase III trial (NCT02020889) 53% of mepolizumab-treated versus 19% of placebo-treated patients with eosinophilic granulomatosis with polyangiitis (EGPA) achieved protocol-defined remission. OBJECTIVE: We sought to investigate post hoc the clinical benefit of mepolizumab in patients with EGPA using a comprehensive definition of benefit encompassing remission, oral glucocorticoid (OGC) dose reduction, and EGPA relapses. METHODS: The randomized, placebo-controlled, double-blind, parallel-group trial recruited patients with relapsing/refractory EGPA receiving stable OGCs (prednisolone/prednisone, ≥7.5-50 mg/d) for 4 or more weeks. Patients received 300 mg of subcutaneous mepolizumab or placebo every 4 weeks for 52 weeks. Clinical benefit was defined post hoc as follows: remission at any time (2 definitions used), 50% or greater OGC dose reduction during weeks 48 to 52, or no EGPA relapses. The 2 remission definitions were Birmingham Vasculitis Activity Score of 0 plus OGC dose of 4 mg/d or less (remission 1/clinical benefit 1) or 7.5 mg/d or less (remission 2/clinical benefit 2). Clinical benefit was assessed in all patients and among subgroups with a baseline blood eosinophil count of less than 150 cells/µL, baseline OGC dosage of greater than 20 mg/d, or weight of greater than 85 kg. RESULTS: With mepolizumab versus placebo, 78% versus 32% of patients experienced clinical benefit 1, and 87% versus 53% of patients experienced clinical benefit 2 (both P < .001). Significantly more patients experienced clinical benefit 1 with mepolizumab versus placebo in the blood eosinophil count less than 150 cells/µL subgroup (72% vs 43%, P = .033) and weight greater than 85 kg subgroup (68% vs 23%, P = .005); in the OGC greater than 20 mg/d subgroup, results were not significant but favored mepolizumab (60% vs 36%, P = .395). CONCLUSION: When a comprehensive definition of clinical benefit was applied to data from a randomized controlled trial, 78% to 87% of patients with EGPA experienced benefit with mepolizumab.

Randomized, dose-ranging study of a fluticasone propionate multidose dry powder inhaler in adolescents and adults with uncontrolled asthma not previously treated with inhaled corticosteroids.

OBJECTIVE: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) eliminates the need to coordinate actuation with inhalation. To characterize dose response, efficacy, and safety of fluticasone propionate (Fp) MDPI, a dose-ranging study was conducted with placebo and active comparators. METHODS: This 12-week, double-blind, parallel-group study randomized patients aged ≥12 years with uncontrolled persistent asthma not previously treated with inhaled corticosteroid therapy (N = 622) to twice-daily treatment with Fp MDPI (12.5, 25, 50, or 100 µg), placebo MDPI, or open-label Fp dry powder inhaler (DPI) 100 µg. The primary efficacy endpoint was change from baseline over 12 weeks in trough (morning pre-dose and pre-rescue bronchodilator) forced expiratory volume in 1 second (FEV1). Blood samples were collected from a patient subset to evaluate pharmacokinetics. Adverse events were monitored. RESULTS: Fp MDPI 25, 50, and 100 µg significantly improved change from baseline in trough FEV1 over 12 weeks compared with placebo (p < 0.01). There were no substantial differences in FEV1 change from baseline over 12 weeks between any Fp MDPI dose and Fp DPI 100 µg. Maximum observed concentration (Cmax) of Fp increased with increasing Fp MDPI doses; time of Cmax was similar across doses and treatments. Systemic exposures for Fp MDPI 25 and 50 µg were lower than that for Fp DPI 100 µg. The safety profile of Fp MDPI was consistent with that of Fp DPI. CONCLUSIONS: In this study, Fp MDPI 25 and 50 µg provided comparable efficacy and safety to Fp DPI 100 µg, with lower systemic exposure.

Safety, efficacy, and dose response of fluticasone propionate delivered via the novel MDPI in patients with severe asthma: A randomized, controlled, dose-ranging study.

OBJECTIVE: Evaluate fluticasone propionate (Fp) using a novel, inhalation-driven, multidose dry powder inhaler (MDPI) in patients with severe persistent asthma, versus placebo MDPI and Fp dry powder inhaler (DPI). METHODS: Patients with persistent asthma despite use of high-dose inhaled corticosteroids were randomized to Fp MDPI 50, 100, 200, or 400 mcg; Fp DPI 250 mcg; or placebo MDPI twice daily for 12 weeks. The primary outcome measure was change from baseline in trough forced expiratory volume in 1 second (FEV1) over the 12-week period, compared with placebo; secondary measures included change from baseline in peak expiratory flow (PEF), rescue inhaler use, and time to withdrawal due to meeting stopping criteria. Safety included adverse events and laboratory evaluations. RESULTS: Six hundred forty patients were randomized; 459 (72%) completed the study. Numerical dose-related improvements in FEV1 were observed in all Fp MDPI groups over 12 weeks but were not significantly greater versus placebo. Increases in morning PEF (baseline to week 12) were substantially greater than placebo in all Fp MDPI groups. The Fp MDPI and Fp DPI groups had substantial reductions in rescue inhaler use from baseline to end point versus placebo (p ≤ 0.05). Efficacy was comparable between Fp MDPI and Fp DPI. No new safety signals were detected; the safety profile of Fp MDPI was similar to that of Fp DPI. CONCLUSIONS: Clinical benefit observed with Fp MDPI in patients with persistent asthma was comparable to Fp DPI. Safety was reassuring with no unexpected findings. These results support further evaluation of Fp MDPI in asthma. (ClinicalTrials.gov identifier NCT01576718; EudraCT number 2010-023601-35).

Dose-ranging study of salmeterol using a novel fluticasone propionate/salmeterol multidose dry powder inhaler in patients with persistent asthma.

BACKGROUND: New inhalation devices with improved lung delivery may allow the use of lower salmeterol doses for treatment of asthma. OBJECTIVE: To determine the dose of salmeterol administered from a novel fluticasone propionate/salmeterol (FS) inhalation-driven, multidose dry powder inhaler (MDPI), which provides comparable efficacy and safety to FS dry powder inhaler (DPI). METHODS: This double-blind, six-period crossover, dose-ranging study randomized 72 patients (ages ≥12 years; with persistent asthma and predose maximum forced expiratory volume in 1 second [FEV1] of 40-85% of the predicted normal) to treatment sequences (one dose per treatment), which consisted of FS MDPI 100/6.25, 100/12.5, 100/25, 100/50 µg; fluticasone propionate (Fp) MDPI 100 µg; and open-label FS DPI 100/50 µg. The primary efficacy variable was the baseline-adjusted FEV1 area under the curve over 12 hours after the dose (AUC0-12). Pharmacokinetics and tolerability were also assessed. RESULTS: FEV1 AUC0-12 was significantly higher with all FS MDPI doses and FS DPI versus Fp MDPI (p < 0.0001), and with FS MDPI 100/50 µg versus FS DPI (least squares [LS] mean, 57.88 mL; p = 0.0017). FEV1 AUC0-12 trended toward higher efficacy with FS MDPI 100/25 µg (LS mean, 34.14 mL; p = 0.0624) and was comparable with FS MDPI 100/12.5 µg (LS mean, 3.42 mL; p = 0.8503) versus FS DPI. Salmeterol area under the plasma concentration-versus-time curve from time 0 to the time of the last measurable concentration (AUC0-t) for FS MDPI 100/12.5 µg and 100/25 µg was lower versus FS DPI 100/50 µg; AUC0-t for FS MDPI 100/50 µg was higher than FS DPI 100/50 µg. All FS MDPI doses were generally well tolerated. CONCLUSION: All FS MDPI doses produced greater efficacy versus Fp MDPI. FS MDPI 100/12.5 µg demonstrated similar efficacy to FS DPI 100/50 µg with less salmeterol exposure. Clinicaltrials.gov NCT02139644, NCT02175771, and NCT02141854.

Pharmacokinetics of fluticasone propionate multidose, inhalation-driven, novel, dry powder inhaler versus a prevailing dry powder inhaler and a metered-dose inhaler.

BACKGROUND: A novel inhalation-driven multidose dry powder inhaler (MDPI) that eliminates the need for the patient to coordinate device actuation with inhalation has been developed for delivery of inhaled asthma medications. OBJECTIVE: To characterize the pharmacokinetics of single-dose fluticasone propionate (Fp) MDPI compared with single doses of Fp dry powder inhaler (DPI) and a metered-dose inhaler (MDI) in healthy subjects. METHODS: This was a single-center, open-label, randomized, three-period crossover, single-dose pilot study in healthy adults ages 18 to 45 years. Eligible subjects (N = 18) were randomized to one of six treatment sequences that contained three treatment arms: Fp MDPI 400 µg/inhalation × two inhalations (800 µg total dose); Fp DPI 250 µg/inhalation × four (1000 µg total dose); and Fp MDI 220 µg/inhalation × four (880 µg total dose). Pharmacokinetics (area under concentration-versus-time curve [AUC], maximum plasma concentration [Cmax], time to Cmax [tmax], and elimination half-life [t½]), safety, and tolerability were assessed for each treatment. RESULTS: Plasma Fp concentration-versus-time curves were comparable across treatments. Geometric mean AUC0-t and Cmax for Fp MDPI 800 µg were 19% and 18% higher, respectively, compared with Fp DPI 1000 µg, and 47% and 82% higher, respectively, compared with Fp MDI 880 µg. Median tmax (60.0-60.6 minutes) and median t1/2 (9.1-9.8 hours) were comparable across the three treatments. Single-dose Fp was well tolerated, with no new safety issues noted. CONCLUSION: Single-dose administration of Fp MDPI 800 µg produced systemic exposure comparable with those for Fp DPI 1000 µg and Fp MDI 880 µg.

Mepolizumab has clinical benefits including oral corticosteroid sparing irrespective of baseline EGPA characteristics.

Background: The Mepolizumab in Relapsing or Refractory EGPA (MIRRA) trial (GSK ID: 115921/NCT02020889) demonstrated that mepolizumab increased remission time and reduced oral corticosteroid (OCS) use compared with placebo in patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA). The present analysis investigated the impact of baseline characteristics on clinical outcomes and characterised the OCS-sparing effect of mepolizumab. Methods: In a phase 3, randomised controlled trial for patients with EGPA (MIRRA), patients received standard of care plus mepolizumab 300 mg or placebo every 4 weeks for 52 weeks. The accrued duration of remission, the proportion of patients in remission at weeks 36 and 48, and the proportion of patients with clinical benefit (remission, OCS or relapse-related) were assessed according to baseline EGPA characteristic subgroups (post hoc). Mepolizumab-related OCS-sparing benefits were also quantified. Results: Accrued duration of remission and the proportion of patients in remission at weeks 36 and 48 were greater with mepolizumab than placebo across the baseline subgroups of refractory disease, immunosuppressant use, EGPA duration, relapse number and OCS use ≤20 mg·day-1. The proportion of patients with clinical benefit was greater with mepolizumab versus placebo (range 76-81% versus 25-39%), irrespective of immunosuppressant use or EGPA duration. Patients treated with mepolizumab versus placebo accrued significantly more weeks on OCS ≤4 mg·day-1 (OR 5.06, 95% CI 2.47-10.38) and had a mean of 1423.1 mg less per-patient OCS exposure over 52 weeks. Conclusions: Mepolizumab treatment provided benefits to patients with EGPA across varying baseline clinical characteristics and can be considered an OCS-sparing treatment in EGPA.

HES and EGPA: Two Sides of the Same Coin.

Elevated eosinophil counts are implicated in multiple diseases, from relatively prevalent organ-specific disorders such as severe eosinophilic asthma, to rare multisystem disorders such as hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA). Patients with these multisystem diseases, often associated with markedly elevated eosinophil counts, have a substantial risk of morbidity and mortality due to delayed diagnosis or inadequate treatment. A thorough workup of symptomatic patients presenting with elevated eosinophil counts is essential, although in some cases the differential diagnosis may remain difficult because of overlapping presentations between HES and EGPA. Notably, first- and second-line treatment options and response to therapy may differ for specific HES and EGPA variants. Oral corticosteroids are the first line of treatment for HES and EGPA, except when HES is the result of specific mutations driving clonal eosinophilia that are amenable to targeted treatment with a kinase inhibitor. Cytotoxic or immunomodulatory agents may be required for those with severe disease. Novel eosinophil-depleting therapies, such as those targeting interleukin 5 or its receptor, have shown great promise in reducing blood eosinophil counts, and reducing disease flares and relapses in patients with HES and EGPA. Such therapies could reduce the side effects associated with long-term oral corticosteroids or immunosuppressant use. This review provides a pragmatic guide to approaching the diagnosis and clinical management of patients with systemic hypereosinophilic disorders. We highlight practical considerations for clinicians and present cases from real-world clinical practice to show the complexity and challenges associated with diagnosing and treating patients with HES and EGPA.

Mepolizumab therapy improves the most bothersome symptoms in patients with hypereosinophilic syndrome.

Background: Hypereosinophilic syndrome (HES) is characterized by persistent elevated blood and/or tissue eosinophil levels and eosinophil-mediated organ damage. Presentation is highly heterogenous; patients may experience symptoms affecting multiple organ systems. Objectives: To assess the effects of mepolizumab, which targets interleukin-5, on HES-related symptom burden, based on HES daily symptoms (HES-DS) questionnaire data collected during the Phase III (ClinicalTrials.gov ID: NCT02836496) study of mepolizumab in patients with HES. Methods: Each of the six HES-related symptoms were rated (0-10) daily by patients, recalling worst symptom experience in the prior 24 hours; change from baseline at Week 32 was also calculated for mepolizumab versus placebo. Results: Mepolizumab versus placebo reduced HES-related symptom burden severity in patients with HES at Week 32. Improvements in the median change from baseline scores were seen across all symptom groups except skin for patients treated with mepolizumab; greatest improvement from baseline was observed for breathing symptoms. Conclusion: These data highlight the considerable symptom burden associated with HES and further support the clinical benefits of mepolizumab treatment for these patients.

Clinical Benefit of Mepolizumab in Eosinophilic Granulomatosis With Polyangiitis for Patients With and Without a Vasculitic Phenotype.

OBJECTIVE: To evaluate mepolizumab's efficacy in eosinophilic granulomatosis with polyangiitis (EGPA) with and without a vasculitic phenotype. METHODS: The MIRRA study (NCT02020889/GSK ID: 115921) included adults with relapsing/refractory EGPA and 4 or more weeks of stable oral glucocorticoids (OG). Patients received mepolizumab (300 mg subcutaneously every 4 weeks) or placebo, plus standard of care for 52 weeks. This post hoc analysis assessed EGPA vasculitic phenotype using antineutrophil cytoplasmic antibody (ANCA) history, baseline Birmingham Vasculitis Activity Score (BVAS), and Vasculitis Damage Index (VDI) score. Coprimary endpoints included accrued remission over 52 weeks and proportion in remission at Week 36 and Week 48. Remission was defined as a BVAS equal to 0 and an OG dose of 4 or more mg/day of a prednisone equivalent. Types of relapses (vasculitis, asthma, and sino-nasal) and EGPA vasculitic characteristics (by study remission status) were also assessed. RESULTS: A total of 136 patients were included (n = 68, mepolizumab and placebo). Irrespective of history of ANCA positivity status, baseline BVAS, or baseline VDI, the accrued remission duration and the proportion of patients in remission at Weeks 36 and 48 were greater with mepolizumab compared with placebo. With mepolizumab, remission at both Week 36 and Week 48 was achieved by 54% of patients with and 27% of patients without a history of ANCA positivity compared with 0% and 4%, respectively (placebo); 45% of patients with a BVAS of 0 and 22% of patients with BVAS of greater than 0 compared with 5% and 2%, respectively (placebo); and 29% of patients with a VDI score of less than 5 and 37% of patients with a VDI score of 5 or more compared with 6% and 0%, respectively (placebo). Mepolizumab reduced all types of relapses as compared with placebo. Baseline vasculitic characteristics (neuropathy, glomerulonephritis, alveolar hemorrhage, palpable purpura, and ANCA positivity) were generally similar among patients with and without remission. CONCLUSION: Mepolizumab is associated with clinical benefits for patients with and without a vasculitic EGPA phenotype.

Association Between Baseline Therapy and Flare Reduction in Mepolizumab-Treated Patients With Hypereosinophilic Syndrome.

Background: Current standard-of-care treatments for hypereosinophilic syndrome (HES) include oral corticosteroids (OCS) and immunosuppressive/cytotoxic (IS/CT) therapies. The anti-IL-5 monoclonal antibody mepolizumab has also recently been approved for patients with this disease. The objective of this analysis was to assess the relationship between baseline therapy and flare reduction in patients with HES treated with mepolizumab, using data from the Phase III 200622 study (NCT02836496). Methods: In the double-blind, parallel-group 200622 study, eligible patients were ≥12 years old and had HES for ≥6 months, ≥2 flares in the previous 12 months, blood eosinophils ≥1000 cells/µL at screening and ≥4 weeks' stable HES therapy. Patients were randomised (1:1) to receive mepolizumab 300 mg subcutaneously or placebo every 4 weeks for 32 weeks plus their existing HES therapy. This post hoc, descriptive analysis assessed the effect of baseline HES therapy [IS/CT (± OCS), OCS No IS/CT, and No IS/CT/OCS] on the proportion of patients with ≥1 flare during the study period, the annualised rate of flares, time to first flare, and the proportion of patients with ≥1 flare during Weeks 20─32, with mepolizumab versus placebo. Results: Mepolizumab treatment was associated with a decrease in the proportion of patients who experienced ≥1 flare during the study period in all baseline therapy groups versus placebo (32-96% reduction). Similarly, the probability of a flare was lower with mepolizumab (14.3-31.4%) than placebo (35.7-74.1%) in all baseline therapy groups, as was the annualised flare rate (0.22-0.68 vs 1.14-1.62). The proportion of patients who experienced ≥1 flare during Weeks 20-32 was reduced with mepolizumab versus placebo for all baseline therapy groups (55-85% reduction). For all endpoints, the greatest effect of mepolizumab treatment was seen in the IS/CT (± OCS) group. Conclusions: Patients with poorly controlled HES are likely to achieve clinical benefit with mepolizumab in terms of flare reduction, regardless of their baseline therapy. Clinical Trial Registration: (https://clinicaltrials.gov/ct2/show/NCT02836496).

Characterization of disease flares and impact of mepolizumab in patients with hypereosinophilic syndrome.

In patients with hypereosinophilic syndrome (HES), mepolizumab reduces the incidence of HES-related clinical signs and symptoms (flares). However, reports characterizing flare manifestations are limited. The double-blind, parallel-group 200622 trial (NCT02836496) enrolled patients ≥12 years old with HES for ≥6 months, ≥2 flares in the previous year, and screening blood eosinophil count ≥1000 cells/µL. Patients maintained ≥4 weeks stable HES therapy, before randomization (1:1) to 4-weekly subcutaneous mepolizumab (300 mg) or placebo, plus baseline HES therapy, for 32 weeks. This post hoc analysis investigated flare manifestations and duration by re-examining the Core Assessments form and narrative recorded for each flare during the study. Flare symptoms were retrospectively categorized into constitutional, dermatological, respiratory, nasal, gastrointestinal, neurologic and other. The most frequently reported flare symptoms were constitutional (94% of flares), dermatological (82% of flares) and respiratory (72% of flares); flares reported in patients receiving mepolizumab compared with placebo were generally similar in terms of the frequency of symptoms reported. Mepolizumab was associated with a shorter median (range) duration of flares (10.0 [4, 126] days) versus placebo (26.0 [1, 154] days). In patients with HES, flares were associated with symptoms linked to multiple organ systems highlighting the challenges faced for treating flares. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02836496, identifier NCT02836496.

Mepolizumab Reduces Hypereosinophilic Syndrome Flares Irrespective of Blood Eosinophil Count and Interleukin-5.

BACKGROUND: Mepolizumab, an anti-interleukin-5 (IL-5) antibody, reduces disease flares in patients with hypereosinophilic syndrome (HES). Factors predicting treatment response are unknown. OBJECTIVE: To assess mepolizumab efficacy by baseline blood eosinophil count (BEC) and serum IL-5 level in patients with HES. METHODS: This post hoc analysis used data from the phase III study assessing mepolizumab in patients with HES (NCT02836496). Patients 12 years old or older, with HES for 6 or more months, 2 or more flares in the previous year, and BEC ≥1,000 cells/µL at screening were randomized (1:1) to 4-weekly subcutaneous mepolizumab (300 mg) or placebo, plus baseline HES therapy, for 32 weeks. The proportion of patients experiencing 1 or more flares (wk 32), annualized flare rate, and proportion of patients with change from baseline in Brief Fatigue Inventory (BFI) item 3 (wk 32), were analyzed by baseline BEC (<1500/≥1500 to <2500/≥2500 cells/µL). Flare outcomes were assessed by baseline serum IL-5 (<7.81/≥7.81 pg/mL). RESULTS: Across baseline BEC subgroups, mepolizumab reduced the proportion of patients experiencing 1 or more flares by 63% to 90% and flare rate by 58% to 84% (treatment-by-eosinophil interaction P = .76 and P = .90, respectively); patients had improved BFI item 3 score with mepolizumab versus placebo (cells/µL: <1,500: 54% vs 37%; ≥1,500 to <2,500: 47% vs 31%; ≥2,500: 61% vs 0%; treatment-by-eosinophil interaction P = .42). Most patients had undetectable baseline serum IL-5 levels; among these, mepolizumab versus placebo reduced the proportion of patients with 1 or more flares (77%) and flare rate (67%). CONCLUSIONS: Mepolizumab was efficacious in the patients with HES studied, irrespective of baseline BEC. Undetectable IL-5 levels should not preclude mepolizumab treatment.

Clinical Profile and Treatment in Hypereosinophilic Syndrome Variants: A Pragmatic Review.

BACKGROUND: Hypereosinophilic syndrome (HES) is a group of rare hematologic disorders leading to eosinophil-driven tissue damage and dysfunction. Better understanding of HES variants may facilitate improved patient management. OBJECTIVE: To describe disease characteristics, treatment, and outcomes of patients with idiopathic (I-HES), myeloproliferative (M-HES), lymphocytic (L-HES), and chronic eosinophilic leukemia, not otherwise specified (CEL-NOS) among HES case reports and aggregate data where available. METHODS: Relevant articles published between January 1, 2000, and March 20, 2020, were retrieved via PubMed; those reporting secondary, associated/reactive, overlap/single-organ, or familial HES were excluded. RESULTS: Of 188 articles included, 171 contained data on 347 separate HES cases (152 I-HES, 121 M-HES, 62 L-HES, 12 CEL-NOS). Based on individual data, mean age at diagnosis was 43 to 48 years for patients with all HES variants. Males accounted for 90% to 91% of M-HES/CEL-NOS and 55% to 65% of I-HES/L-HES cases. Cardiac symptoms were frequently observed for all HES variants (13%-22% of patients). Respiratory symptoms (I-HES), splenomegaly (M-HES and CEL-NOS), and skin conditions (L-HES) were also frequently observed. Bone marrow, heart, lung, spleen, liver, skin, and lymph nodes were commonly involved. Most patients with I-HES, L-HES, and CEL-NOS received corticosteroids (65%-85%), whereas most with M-HES received imatinib (81%); those with CEL-NOS also received interferon alpha (42%). CONCLUSIONS: Collective analysis of HES case reports supports and extends current understanding of HES variants, highlighting differences in signs and symptoms, organ involvement, and treatment approaches. Improved characterization of HES variants may facilitate the development of novel treatments.