Treatment Of Severe Eosinophilic Asthma Research Articles

Effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid-dependent asthma: results from two phase 3, randomised, double-blind, placebo-controlled trials

Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2). Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per μL or more (including no more than 30% patients with an eosinophil count <400 cells/μL), and at least a medium dose of inhaled corticosteroids with one or more additional asthma controllers. Patients in study 2 had severe asthma, a blood eosinophil count of 300 cells per μL or more, daily maintenance oral corticosteroid (prednisone 5-40 mg, or equivalent), and high-dose inhaled corticosteroids plus another controller. Patients were randomly assigned (1:1) to subcutaneous reslizumab (110 mg) or placebo once every 4 weeks for 52 weeks in study 1 and 24 weeks in study 2. Patients and investigators were masked to treatment assignment. Primary efficacy outcomes were frequency of exacerbations during 52 weeks in study 1 and categorised percentage reduction in daily oral corticosteroid dose from baseline to weeks 20-24 in study 2. Primary efficacy analyses were by intention to treat, and safety analyses included all patients who received at least one dose of study treatment. These studies are registered with ClinicalTrials.gov, NCT02452190 (study 1) and NCT02501629 (study 2). Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56-1·12; p=0·19). Subcutaneous reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per μL or more (0·64, 95% CI 0·43-0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the reslizumab group vs the placebo group, 1·23, 95% CI 0·70-2·16; p=0·47). The frequency of adverse events and serious adverse events with reslizumab were similar to those with placebo in both studies. Fixed-dose (110 mg) subcutaneous reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/μL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous reslizumab are required to achieve maximal efficacy. Teva Branded Pharmaceutical Products R&D.

Predictors of the enhanced response to mepolizumab treatment for severe eosinophilic asthma: A retrospective, long-term study

Mepolizumab significantly reduces the number of annual exacerbations (AEs) and the maintenance dose of systemic corticosteroids (CSs) in patients with severe eosinophilic asthma (SEA). However, there are few studies based on real life with a long-term observational period in Japan. Between July 2016 and December 2019, 24 Japanese patients received mepolizumab at Jikei University Hospital for at least 12 months. We retrospectively evaluated these characteristics, AEs and CS doses. To elucidate the predictors of the enhanced responders, we performed multivariate logistic regression analysis. After introduction, asthma symptoms improved and were maintained for over a year. The number of AEs and CS doses significantly decreased. In the subgroup analysis, the younger than 65 years-old, body mass index (BMI) < 25 kg/m2, eosinophilic chronic rhinosinusitis, or eosinophil count ≥ 400/mm3 exhibited effective reductions in either AEs or CS doses with mepolizumab treatment. The percentage change in the AEs (≤ −75%) was significantly decreased in the patients with a BMI < 25 using multivariate logistic regression analysis (odds ratio 31, 95% confidence interval: 1.4–700, P = 0.03). In real-life, BMI < 25 could be a predictor for reductions in AEs with mepolizumab treatment in the patients with SEA.Abbreviations IL, interleukin; CS, corticosteroid; SEA, severe eosinophilic asthma; BMI, body mass index; ECRS, eosinophilic chronic rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyps

Mepolizumab: Real World Evidence Study for the Treatment of Severe Eosinophilic Asthma in Greece

Mepolizumab: Real World Evidence Study for the Treatment of Severe Eosinophilic Asthma in Greece

Efficacy and safety of mepolizumab in a real-world cohort of patients with severe eosinophilic asthma

Background The interleukin 5 (IL-5) pathway is an important component in the pathophysiology of severe eosinophilic asthma. Mepolizumab is a monoclonal antibody that targets the IL-5 pathway. Clinical trials showed efficacy of Mepolizumab in patients with severe eosinophilic asthma. However, reports on experience with treatment in a real-world cohort are limited. Objectives Evaluation of the efficacy and safety of Mepolizumab for treatment of severe eosinophilic asthma in a real-world cohort of patients. Methods A clinical prospective observational trial included all patients >18 years treated with Mepolizumab between March 2016 to March 2019 at Rabin Medical Center. The composite primary outcome measures evaluated: increase in FEV1 by≥ 200 ml and/or decrease in exacerbation rate of ≥50% and/or cessation of oral corticosteroids (OCS) treatment or ≥50% decrease in dosage. Also evaluated: blood eosinophil count, adverse events and quality of life. Results Of 61 patients, 50 (82.0%) achieved the primary outcome. The number of patients who suffered from frequent exacerbations decreased from 52 (85.2%) to 8 (13.1%) (p < 0.001). Twenty-two patients (68%) stopped OCS treatment or received >50% reduced dosage (p < 0.001). Mean FEV1 increased from 1.72 ± 0.78 liters to 1.87 ± 0.85 liters (p = 0.043). Response to therapy was seen within six months. Forty-nine patients (80%) reported an improvement in quality of life (p < 0.001). Only minor adverse events were reported. Conclusion Treatment with mepolizumab was well tolerated and significantly lowered the exacerbation rate and OCS dependence in a real-world cohort of severe eosinophilic asthma patients. Response to therapy was within six months and treatment effect was sustained over time.

Targeted Therapy for Severe Asthma in Children and Adolescents: Current and Future Perspectives.

Severe asthma in children remains a significant issue. It places a heavy burden on affected individuals and society as a whole in terms of high morbidity, mortality, consumption of healthcare resources, and side effects from high-dose corticosteroid therapy. New, targeted biologic therapies for asthma have emerged as effective add-on options, complementing our expanding understanding of asthma phenotypes/endotypes and the underlying immunopathology of the disease spectrum. They include omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab. Omalizumab represents the first available therapeutic option for allergic asthma in patients as young as 6years of age. Its efficacy and safety have been established by several randomized controlled trials specifically conducted in pediatric patients, leading to its final registration > 10years ago. Three new interleukin (IL)-5 targeted agents, mepolizumab, reslizumab, and benralizumab, have been approved for the treatment of severe eosinophilic asthma starting from 6years of age, and varying by country. More recently, dupilumab, a targeted agent against the IL-4 receptor α-chain, was approved for patients ≥12years of age in the United States after pivotal trials were completed. The late-stage clinical testing of these targeted agents has mostly involved patients aged 12years and up, and the application of those data to younger children can be inappropriate and carry risk. The efficacy and safety of these newer biologics in children should be supported by adequate research within this targeted age group. In this review, we will present the most recent evidence on these five biological therapies for severe asthma and will discuss dosage and administration, their efficacy, safety, and future prospects, with a focus on the pediatric age group, defined as age < 18years.

Proportion of Severe Asthma Patients Eligible for Mepolizumab Therapy by Age and Age of Onset of Asthma

Mepolizumab is an anti-IL-5 antibody approved for the treatment of severe eosinophilic asthma. However, the prevalence of patients with severe asthma eligible for mepolizumab remains unknown, especially among children. To determine, in a population of patients with severe asthma from a tertiary referral center, the proportion of patients with an eosinophilic phenotype who would be eligible for mepolizumab, when stratified for the age of onset of asthma, and the prevalence of phenotypic features that favor mepolizumab therapy. An extensive database of 245 adults and children referred for severe asthma was used. The prevalence of severe asthma was estimated by using the European Respiratory Society/American Thoracic Society criteria. Patients with an eosinophilic uncontrolled phenotype qualified for mepolizumab. In our cohort, 216 (88%) had severe asthma. Based on blood eosinophils of either greater than or equal to 150 cells/μL or greater than or equal to 300 cells/μL, 61%/41% had an eosinophilic phenotype, while 49%/34% were eligible for mepolizumab therapy. A greater percentage of adults (60%/47% of adults with asthma onset in adulthood [AoA] and 48%/26% adults with childhood-onset asthma [<18 years, CoA]) were eligible compared with children (33%/24%), for eosinophil counts of ≥150 and ≥300 cells/μL, respectively; P < .05. Compared with adults, children had a similar number of exacerbations while having better lung function (P < .05). Among adults, those with AoA were older, were more likely to have nasal polyps (28% vs 5%; P < .05), and had higher blood eosinophil counts (272 vs 150 cells/μL; P < .05) compared with those with CoA, with no difference in lung function noted between the 2 groups. Subjects showing greater than or equal to 500 eosinophils/μL, a strong indicator for mepolizumab therapy, had more nasal polyps, higher inhaled steroid dose, lower lung function, and AoA predominance than did those with less than 500 eosinophils/μL (P < .05). A smaller percentage of children with severe asthma were eligible for mepolizumab compared with their adult peers. Severe AoA has distinct phenotypic features that favor treatment with mepolizumab, including greater eosinophilia and nasal polyposis, in contrast to CoA, which appears to have fewer features of type 2 mucosal inflammation.

Cost-Effectiveness Analysis of Treatment for Severe Eosinophilic Asthma in Adults: Mepolizumab and Omalizumab

Objective: Based on the cost-effectiveness analysis (CEA) to determine economic and clinical consequences of using mepolizumab instead of omalizumab in adults with severe eosinophilic asthma, when omalizumab is administered once every 2 weeks or mepolizumab is administered once every 4 weeks. Methods: Effectiveness and safety analysis was conducted based on the published network meta-analysis, because head-to-head clinical trials of omalizumab versus mepolizumab were not identified during targeted scientific literature search. Direct medical costs were calculated using information from the register of manufacturers` maximum selling prices for vital and essential drugs (VED), instructions for medical use, the unit cost of healthcare services. Results: Effectiveness and safety of the compared drugs were determined based on the results of the network meta-analysis. Frequency of clinically significant asthma exacerbations (risk ratio = 0,19; 95% CI: 0,02–2,32) and withdrawals due to adverse events (risk ratio = 0,05; 95% CI: 0,002–0,95). Therefore, despite the tendency to mepolisumab benefits, it was concluded that there are no statistically significant differences in the effectiveness and safety of the compared drugs due to the insufficient statistical power of the result. Direct medical costs were 870130 rubles and 1852063 rubles for mepolizumab and omalizumab respectively. Saving of direct medical costs for mepolizumab treatment was 959170 rubles per patient per year or 52%. Conclusion: treatment with mepolizumab versus omalizumab in patients with severe eosinophilic asthma, when omalizumab is administered once every 2 weeks or mepolizumab is administered once every 4 weeks, leads to saving of direct medical costs for drug treatment.

Benralizumab: A New Approach for the Treatment of Severe Eosinophilic Asthma.

Eosinophilic asthma is the most common phenotype of severe asthma. It is characterized by abnormal production and release of type 2 cytokines from T helper type 2 (TH2) lymphocytes and type 2 innate lymphoid cells, such as IL-5. This leads to a persistent increase and activation of eosinophils in blood and the airways despite treatment with high-dose inhaled corticosteroids. Eosinophil differentiation, survival, and activation are preferentially regulated by IL-5, a cytokine that binds to the IL-5 receptor (IL-5R), which is located on the surface of eosinophils or basophils and plays a critical role in the pathogenesis and severity of asthma. Benralizumab is a monoclonal antibody that binds to IL-5R via its Fab domain, blocking the binding of IL-5 to its receptor and resulting in inhibition of eosinophil differentiation and maturation in bone marrow. In addition, this antibody is able to bind through its afucosylated Fc domain to the RIIIa region of the Fcy receptor on NK cells, macrophages, and neutrophils, thus strongly inducing antibody-dependent, cell-mediated cytotoxicity in both circulating and tissue-resident eosinophils. This double function of benralizumab induces almost complete fast and maintained depletion of eosinophils that is much greater than that induced by other monoclonal antibodies targeting the IL-5 pathway, such as mepolizumab and reslizumab. This review focuses on benralizumab as an alternative to other agents targeting the IL-5 pathway in the treatment of eosinophilic asthma.

Genetically engineered drugs for treatment of bronchial asthma: recent achievements

Current population of patients with asthma is characterized by increasing resistance to standard pharmacotherapeutic agents such as inhaled corticosteroids, antileukotriene agents and anti-IgE antibodies. These findings were confirmed by international statistic data and indicate insufficient efficacy of the treatment. Asthma phenotyping encompassing a role of certain biomarkers for bronchial inflammation could contribute to achieving better response to treatment. Genetically engineered drugs could directly impact on mediators and modulators involved in the inflammation and bronchoconstriction. This is one of the most promising directions of the modern pharmacotherapy, particularly considering severe and difficult-to-treat asthma. A comparative analysis of efficacy and safety of currently available genetically engineered drug groups (monoclonal anti-IgE antibodies, monoclonal antibodies against interleukin (IL)-4/IL-13 and IL-5, and prostaglandin D2 receptor antagonists) was performed by the authors of this article on the basis of results of randomized controlled clinical trials (RCT). According to RCT results, omalizumab is still the leading genetically engineered drug. Moreover, evidence of efficacy and safety of novel agents has been published that allowed implementation these drugs in the routine clinical practice for treatment of severe eosinophilic asthma.

Benralizumab, an add-on treatment for severe eosinophilic asthma: evaluation of exacerbations, emergency department visits, lung function, and oral corticosteroid use.

There are now multiple monoclonal antibodies targeting different inflammatory pathways of severe asthma. Benralizumab is a recently approved monoclonal antibody indicated for the treatment of severe eosinophilic asthma by targeting a subunit of the IL-5 receptor. Treatment with benralizumab results in significant reductions of blood and tissue eosinophils. Early studies report that this therapy has an adequate safety profile, and this was confirmed in later trials. Phase III studies have shown that benralizumab is effective in reducing the rate of exacerbations and improving asthma symptoms and quality of life in patients with severe eosinophilic asthma. Additionally, treatment with benralizumab has resulted in important reductions in the use of chronic oral corticosteroids. In this review, we evaluate the evidence up to date on the efficacy of benralizumab in severe eosinophilic asthma and explore the implications of this therapy in the ever-growing landscape of therapies for severe asthma.

Benralizumab for the treatment of severe eosinophilic asthma

Benralizumab (Fasenra) is a new anti‐interleukin‐5 monoclonal antibody therapy for the management of severe uncontrolled eosinophilic asthma. This article discusses its properties, clinical trial efficacy and adverse effects.

Tralokinumab unsuccessful for management of severe, uncontrolled asthma

In the past decade, substantial efforts have been made to develop therapies based on biologics, particularly those targeting type 2 immune cytokines such as interleukins 4, 5, and 13, and as a result of these efforts, anti-interleukin-5 and anti-interleukin-5 receptor-α antibodies for the treatment of severe eosinophilic asthma are now available. 1 Chung KF Targeting the interleukin pathway in the treatment of asthma. Lancet. 2015; 386: 1086-1096 Summary Full Text Full Text PDF PubMed Scopus (190) Google Scholar Interleukin 13—a cytokine produced by T-helper 2 lymphocytes, type-2 innate lymphoid cells, mast cells, and eosinophils—has been implicated in the pathogenesis of asthma with its ability to induce goblet cell hyperplasia, lung eosinophilia, and bronchial hyper-responsiveness, in addition to its contribution to airway wall remodelling. 2 Hirose K Iwata A Tamachi T Nakajima H Allergic airway inflammation: key players beyond the Th2 cell pathway. Immunol Rev. 2017; 278: 145-161 Crossref PubMed Scopus (85) Google Scholar It is therefore not surprising that interleukin 13 has been considered as another target for the treatment of asthma associated with type 2 inflammation. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trialsTralokinumab reduced AAER in participants with severe asthma with baseline FENO 37 ppb or higher in STRATOS 1, but not in STRATOS 2. These inconsistent effects on AAER do not support a key role for interleukin 13 in severe asthma exacerbations. Full-Text PDF Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trialTralokinumab did not significantly affect eosinophilic inflammation in bronchial submucosa, blood, or sputum compared with placebo, but did reduce FENO and IgE concentrations. These results suggest interleukin 13 is not crucial for eosinophilic airway inflammation control in moderate-to-severe asthma. Full-Text PDF

Biologics and chronic obstructive pulmonary disease

The presence of airway inflammation in patients with chronic obstructive pulmonary disease (COPD) provides a rationale for biological agents targeting specific inflammatory pathways. This approach has been strikingly effective in patients with other chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, and asthma. However, there are important and unresolved challenges in COPD, including our incomplete understanding of heterogeneity of the lower airway inflammatory response and how these contribute to the clinical expression of disease. As a result, progress has been slow, and there have been many failures. One notable exception is the targeting of eosinophilic airway inflammation with anti-IL-5, which has an acknowledged and important role in the treatment of severe eosinophilic asthma. Recent phase III studies have shown a reduction in exacerbations of around 20% in patients with COPD and clear evidence of a blood eosinophil count-dependent beneficial effect. The demonstration of clinical efficacy linked to a clinically accessible biomarker raises the possibility of precision biomarker-directed use of biological agents in patients with COPD. The hope is that this will be anexemplar for the future development of biological agentsinpatients with COPD.

Mepolizumab in the treatment of severe eosinophilic asthma: Results from a physician in the field

Mepolizumab in the treatment of severe eosinophilic asthma: Results from a physician in the field

Reslizumab for Treating Asthma with Elevated Blood Eosinophils Inadequately Controlled by Inhaled Corticosteroids: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) process, the manufacturer of reslizumab (Teva) submitted evidence for its clinical and cost effectiveness for the treatment of eosinophilic asthma inadequately controlled by inhaled corticosteroids. NICE commissioned Southampton Health Technology Assessments Centre (SHTAC) as an independent Evidence Review Group (ERG) to provide a critique of the manufacturer's submitted evidence. Reslizumab is compared with best standard of care and omalizumab, for a small 'overlap' population of patients who have both eosinophilic and IgE-mediated severe asthma. This paper provides a summary of the ERG's review of the manufacturer's submission, and summarises the NICE Appraisal Committee's subsequent guidance (issued in August 2017). The ERG considered that there were limitations in the approach proposed by the manufacturer for the exacerbation rate and the utility for severe exacerbation. The company amended their initial analysis, following comments from the ERG and the NICE committee, whereby the incremental cost effectiveness ratio was £29,870 per QALY gained for reslizumab compared with best standard care. The NICE Appraisal Committee (AC) concluded that reslizumab was recommended as an option for the treatment of severe eosinophilic asthma that is inadequately controlled in adults despite maintenance therapy with high-dose inhaled corticosteroids plus another drug, only if (1) the blood eosinophil count has been recorded as 400 cells per microlitre or more and (2) the patient has had three or more asthma exacerbations in the past 12months, and (3) the company provides reslizumab with the discount agreed in the patient access scheme.

Reslizumab in the treatment of severe eosinophilic asthma:an update.

A marked heterogeneity is exhibited by asthma both clinically and at the molecular level with different phenotypes driven by diverse mechanistic pathways that require specifically targeted treatments. Biologics aimed at IL-4/13, IL-5 or IgE are proven or potentially effective treatments for patients with difficult to treat eosinophilic asthma. Importantly, it is now widely accepted that biologic-based therapies give significant clinical improvements in those patient populations where asthma phenotypes are taken into account. Such asthma phenotypes have been identified by reproducible and straightforward discriminatory biomarkers. This short review discusses recent studies of the effectiveness of the anti-IL-5 reslizumab in relation to the use of simple reproducible biomarkers in eosinophilic asthma.

Benralizumab: First Global Approval.

Kyowa Hakko Kirin, AstraZeneca and subsidiaries are developing benralizumab (Fasenra™)-a humanised anti-interleukin-5 receptor alpha chain (IL-5Rα) monoclonal antibody-as a treatment of severe eosinophilic asthma and chronic obstructive pulmonary disease (COPD). Eosinophilia is a characteristic of certain asthma and COPD phenotypes and depletion of eosinophils has demonstrated therapeutic benefit. Benralizumab was recently approved by the US FDA as add-on maintenance therapy for patients with severe asthma who have an eosinophilic phenotype. This article summarizes the milestones in the development of benralizumab leading to this first approval for the treatment of severe eosinophilic asthma.

Evaluation of Potential Continuation Rules for Mepolizumab Treatment of Severe Eosinophilic Asthma

Mepolizumab significantly reduces exacerbations in patients with severe eosinophilic asthma. The early identification of patients likely to receive long-term benefit from treatment could ensure effective resource allocation. To assess potential continuation rules for mepolizumab in addition to initiation criteria defined as 2 or more exacerbations in the previous year and blood eosinophil counts of 150 cells/μL or more at initiation or 300 cells/μL or more in the previous year. This post hoc analysis included data from 2 randomized, double-blind, placebo-controlled studies (NCT01000506 and NCT01691521) of mepolizumab in patients with severe eosinophilic asthma (N= 1,192). Rules based on blood eosinophils, physician-rated response to treatment, FEV1, Asthma Control Questionnaire (ACQ-5) score, and exacerbation reduction were assessed at week 16. To assess these rules, 2 key metrics accounting for the effects observed in the placebo arm were developed. Patients not meeting continuation rules based on physician-rated response, FEV1, and the ACQ-5 score still derived long-term benefit from mepolizumab. Nearly all patients failing to reduce blood eosinophils had counts of 150 cells/μL or less at baseline. For exacerbations, assessment after 16 weeks was potentially premature for predicting future exacerbations. There was no evidence of a reliable physician-rated response, ACQ-5 score, or lung function-based continuation rule. The added value of changes in blood eosinophils at week 16 over baseline was marginal. Initiation criteria for mepolizumab treatment provide the best method for assessing patient benefit from mepolizumab treatment, and treatment continuation should be reviewed on the basis of a predefined reduction in long-term exacerbation frequency and/or oral corticosteroid dose.

Severe eosinophilic asthma: from the pathogenic role of interleukin-5 to the therapeutic action of mepolizumab.

Mepolizumab is an anti-interleukin-5 (IL-5) humanized monoclonal antibody that has been recently approved as an add-on biological treatment for severe eosinophilic asthma, by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Moreover, mepolizumab is also currently included within the step 5 of the Global Initiative for Asthma guidelines, as an add-on therapy for severe uncontrolled asthma. The relevant therapeutic benefits detectable in patients with refractory eosinophilic asthma receiving mepolizumab depend on the pivotal pathogenic role played by IL-5 in these subjects. Indeed, IL-5 is the key cytokine responsible for maturation, activation, proliferation, and survival of eosinophils. Therefore, IL-5 represents a strategic molecular target for anti-eosinophilic treatments. By selectively inhibiting the biological actions of IL-5, mepolizumab provides a valuable therapeutic option for patients with severe eosinophilic asthma, refractory to standard treatments including inhaled and even systemic corticosteroids. In particular, the very important advantages linked to the use of mepolizumab in these difficult-to-treat asthmatic individuals have been well documented by several different trials performed worldwide.

Mepolizumab for Treating Severe Eosinophilic Asthma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the company (GlaxoSmithKline) that manufactures mepolizumab (Nucala®) to submit evidence on the clinical and cost effectiveness of mepolizumab for the treatment of severe eosinophilic asthma. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). The ERG produced a review of the evidence for the clinical and cost effectiveness of mepolizumab as add-on to standard of care (SoC) compared with SoC and omalizumab, based upon the company's submission to NICE. The clinical-effectiveness evidence in the company's submission was based predominantly on three randomised controlled trials (DREAM, MENSA and SIRIUS) comparing add-on mepolizumab with placebo plus SoC. The relevant population was defined in terms of degree of asthma severity (four or more exacerbations in the previous year and/or dependency on maintenance oral corticosteroids [mOCS]) and degree of eosinophilia (a blood eosinophil count of≥300 cells/µl in the previous year) based on post hoc subgroup analyses of the pivotal trials. Other subpopulations were considered throughout the appraisal, defined by different eosinophil measurements, number of exacerbations and dependency (or lack thereof) on mOCS. Statistically significant reductions in clinically significant exacerbations were observed in patients receiving mepolizumab compared with SoC meta-analysed across MENSA and DREAM in the modified intention-to-treat (ITT) population (rate ratio [RR] 0.51; 95% confidence interval [CI] 0.42-0.62) as well as in the relevant population (RR 0.47; 95% CI 0.36-0.62). In terms of quality of life, differences on the St. George's Respiratory Questionnaire in MENSA for add-on subcutaneous mepolizumab 100mg vs. placebo were 7 and 7.5 units in the modified ITT and relevant populations, respectively. A number of issues in the clinical evidence base warrant caution in its interpretation. The ERG noted that the definition of SoC used in the trials differed from that in clinical practice, where patients with severe uncontrolled asthma start treatment with a mOCS. The company's economic post-consultation analysis incorporating a confidential patient access scheme (PAS) estimated that the incremental cost-effectiveness ratio (ICER) for add-on mepolizumab compared with SoC was £27,418 per quality-adjusted life-year (QALY) gained in the relevant population if patients stopped mepolizumab after 1year unless (1) the number of exacerbations decreased at least 50% or (2) a reduction in corticosteroids dose was achieved whilst maintaining asthma control. The ERG applied an age adjustment to all utilities and corrected the post-continuation assessment utilities, which resulted in an ICER for add-on mepolizumab compared with SoC of £29,163 per QALY gained. The ERG noted that this ICER was not robust for patients who continued treatment due to a corticosteroid dose reduction where exacerbations had decreased by less than 50%, because corticosteroid dose reduction was not allowed in the main trial in which the evidence was gathered (MENSA). The NICE appraisal committee (AC) concluded that add-on mepolizumab could be recommended as an option for treating severe refractory eosinophilic asthma in adults for the relevant population when the stopping rule suggested by the company was applied. The AC also concluded that the comparison between mepolizumab and omalizumab was not clinically relevant or methodologically robust.