Severe Refractory Eosinophilic Asthma Research Articles

Economic evaluation and budgetary burden of mepolizumab in severe refractory eosinophilic asthma

ObjectiveMepolizumab is indicated as an additional treatment of severe refractory eosinophilic asthma. The observed differences in population subgroups according to plasma eosinophil count, the existence of patients with high levels of immunoglobulin E who are candidates of omalizumab and mepolizumab, as well as mepolizumab's economic impact, lead to make efficient economic studies for clinical decision making. The aim was to analyze mepolizumab's cost-efficacy and budget impact. MethodCost comparison and the use of mepolizumab's budgetary impact was performed, from the Spanish National Health System's perspective. Among the assessed alternatives, inhaled systemic corticosteroids, plus long acting beta agonist (β2) and/or oral systemic corticosteroids in patients with non immunoglobulin E-mediated severe allergic asthma, and said treatment along with omalizumab in patients with immunoglobulin E mediated eosinophilic allergic asthma were included. Its efficacy was evaluated through avoided clinically relevant exacerbations. The direct costs associated with exacerbation were assessed. ResultsMepolizumab's long run average incremental cost regarding omalizumab's is 797 euros per patient a year. Considering omalizumab's alternative discounted price, including mepolizumab for patients with immunoglobulin E mediated eosinophilic allergic asthma would increase public spending from 2.3 to 4.6 million euros. Given omalizumab's notified price, the gradual introduction of mepolizumab in the Spanish National Health System would save 3.6 million euros in three years. For non immunoglobulin E-mediated severe asthma patients, the avoided cost/exacerbation by introducing mepolizumab is 15,085 euros, assuming a gradual market penetration of mepolizumab. In patients with ≥ 500 eosinophils/µL, this cost decreases to 7,767 euros per avoided exacerbation with a budgetary impact of 183.2 million euros in three years with a progressive penetration of mepolizumab. ConclusionsThe cost comparison between mepolizumab and omalizumab in immunoglobulin E mediated eosinophilic asthma patients suggests a use of the lower cost drug, promoting price competition. Additionally, prioritizing its use among non immunoglobulin E-mediated severe refractory eosinophilic asthma patients and ≥ 500 eosinophils/µL plasma level patients, would improve its efficiency as well as reducing its budgetary impact.

Effectiveness of Switching to Benralizumab in Severe Refractory Eosinophilic Asthma.

PurposeBenralizumab is a monoclonal antibody that targets the α subunit of the IL-5 receptor. Clinical trials have demonstrated the efficacy of this agent with respect to lung function and symptom control in patients with refractory eosinophilic asthma. However, few studies have evaluated the efficacy of benralizumab after switching previous treatment with other monoclonal antibodies.Patients and MethodsWe performed a multicenter retrospective study under conditions of daily clinical practice. The study population comprised consecutively included patients with severe refractory eosinophilic asthma whose initial treatment with omalizumab or mepolizumab was switched to benralizumab. Patients were evaluated at 4 and 12 months after starting treatment with benralizumab. We analyzed asthma control, number of severe exacerbations, corticosteroid cycles, visits to the emergency department, and hospital admissions, as well as lung function. Similarly, we evaluated the response to treatment according to previously established criteria.ResultsWe evaluated 40 patients who switched from omalizumab (n=16) or mepolizumab (n=24) to benralizumab. The reasons for switching were lack of response in 30 cases, adverse effects in 9, and patient request in 1. Switching was followed by a significant decrease in the number of exacerbations, visits to the emergency department, and corticosteroid cycles, as well as improved ACT both at 4 and 12 months. However, no significant improvement in lung function was observed. Asthma control (including complete response and control) was achieved in 55% of patients (n=22) at 12 months. Specifically, a complete response was achieved in 30% of patients at 12 months (66.7% switching from omalizumab and 33.3% from mepolizumab).ConclusionPatients diagnosed with severe refractory eosinophilic asthma who experience a partial response with omalizumab or mepolizumab could benefit from switching to benralizumab. This approach can reduce the number of exacerbations, visits to the emergency department, and corticosteroid cycles and improve control of asthma.

Increasing utility of FeNO as a biomarker of type-2 inflammation in severe asthma

Since the discovery that nitric oxide (NO) can be measured in the exhaled breath and that the fractional exhaled NO (FeNO) is increased in asthma, FeNO has been recognised as a biomarker of type 2 inflammation in the airways, reflecting the effect of type 2-associated cytokines, interleukin (IL)-4 and IL-13, that play an important role in bronchial hyperresponsiveness, mucus secretion and goblet cell hyperplasia, and T-helper type 2 polarisation, and also in allergic and eosinophilic inflammation. Since 2011, FeNO, which remains a convenient measurement for patients as young as 5 years, has been recommended for use in the diagnosis of eosinophilic airway inflammation as a supportive adjunct towards the diagnosis of asthma and in assessing corticosteroid responsiveness. 1 Dweik RA Sorkness RL Wenzel S et al. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med. 2010; 181: 1033-1041 Crossref PubMed Scopus (220) Google Scholar Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysisIn uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations. Full-Text PDF The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational studyExacerbations on mepolizumab are two distinct entities, which can largely be differentiated using FeNO: non-eosinophilic events are driven by infection with a low FeNO and high C-reactive protein concentration, whereas eosinophilic exacerbations are FeNO high. The results of the MEX study challenge the routine use of oral corticosteroids for the treatment of all asthma exacerbation events on mepolizumab, as well as the switching of biological therapies for treatment failure without profiling the inflammatory phenotype of ongoing asthma exacerbations. Full-Text PDF

The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational study

Clinical trials with mepolizumab, a humanised monoclonal antibody against interleukin-5, show a 50% reduction in severe asthma exacerbations in people with severe eosinophilic asthma. Exacerbations in patients treated with mepolizumab seem to be different to exacerbations in those given placebo, as patients treated with mepolizumab report fewer symptoms, have a lower sputum eosinophil count, and smaller fall in peak expiratory flow. We aimed to investigate the inflammatory phenotype and physiological characteristics of exacerbation events in patients with severe eosinophilic asthma who were treated with mepolizumab. This multicentre, prospective, observational cohort study was carried out at four UK specialist severe asthma centres. Participants were aged 18-80 years, with severe eosinophilic asthma (Global Initiative for Asthma steps 4 and 5), and were eligible for mepolizumab therapy. All participants received mepolizumab 100 mg subcutaneously every 4 weeks, had a scheduled study visit when stable on mepolizumab (≥3 months on treatment), and measured daily peak flow and completed symptoms diaries throughout the course of the study. Participants attended their study centre for unscheduled exacerbation assessment when symptoms worsened outside of their normal daily variation and before commencing rescue treatment. If a participant was unable to attend their study centre for exacerbation or had initiated rescue treatment before the study visit, clinical details of the missed exacerbation were collected by clinical staff. In this exploratory study, the endpoint was 100 clinical assessments at exacerbation completed across all sites for participants on mepolizumab before initiation of rescue treatment. Characteristics of those who had exacerbations on mepolizumab were compared with those who did not, peak flow and symptoms diaries were compared for assessed versus missed exacerbations, and exacerbation phenotypes defined by sputum eosinophil cell count were compared. The utility of fractional exhaled nitric oxide (FeNO) and C-reactive protein in determining exacerbation phenotype on mepolizumab treatment were also assessed. This study is registered with ClinicalTrials.gov, NCT03324230. Between Nov 30, 2017, and May 29, 2019, 145 participants were enrolled and treated with mepolizumab, five were excluded from the analysis. 172 exacerbations occurred, with 96 (56%) assessed before commencing rescue treatment. Compared with patients who did not exacerbate, patients who exacerbated had a higher exacerbation rate and more emergency department attendances in the year before commencing mepolizumab. The change in peak expiratory flow at nadir in the assessed exacerbation group was mean -40·5 L/min (SD 76·3) versus mean -37·0 L/min (93·0; p=0·84) in the missed exacerbation group, and there was no difference in reported symptom burden. When comparing exacerbations with a high sputum eosinophil count (≥2%; SEHIGH) with exacerbations with a low sputum eosinophil count (<2%; SELOW), the SEHIGH exacerbations were FeNO high (median difference 33 parts per billion [ppb; 95% CI 8 to 87]; p=0·0004), with lower FEV1 percent predicted (mean difference -15·9% [-27·0 to -4·8]; p=0·0075), lower FEV1 to forced vital capacity ratio (mean difference -10·3 [-17·0 to -3·6]; p=0·0043), and higher blood eosinophil counts (median difference 40 cells per μL [20 to 70]; p=0·0009). By contrast, SELOW exacerbations had higher C-reactive protein concentrations (median difference 12·7 mg/L [3·5 to 18·5]; p<0·0001), higher sputum neutrophil counts (median difference 52·7% [34·5 to 59·2]; p<0·0001), and were more likely to be treated with antibiotics (p=0·031). FeNO (≤20 or ≥50 ppb) was the most useful discriminator of inflammatory phenotype at exacerbation. The most common adverse event was hospital admission due to asthma exacerbation (17 [50%] of 34 events), none of the adverse events were study procedure related. Exacerbations on mepolizumab are two distinct entities, which can largely be differentiated using FeNO: non-eosinophilic events are driven by infection with a low FeNO and high C-reactive protein concentration, whereas eosinophilic exacerbations are FeNO high. The results of the MEX study challenge the routine use of oral corticosteroids for the treatment of all asthma exacerbation events on mepolizumab, as well as the switching of biological therapies for treatment failure without profiling the inflammatory phenotype of ongoing asthma exacerbations. The results highlight clinically available tools to enable profiling of these residual exacerbations in patients treated with mepolizumab. UK Medical Research council.

Significant improvement in lung function and asthma control after benralizumab treatment for severe refractory eosinophilic asthma

Severe eosinophilic asthma is a complex disease and much effort has been made to fully understand its mechanisms. Bronchial remodeling and loss of lung function are important features in asthma, however their key aspects are not completely clear, especially the impact that biological drugs may have on them. One of the key cytokines involved in the pathophysiology of eosinophilic asthma is interleukin-5 (IL-5), which plays a very important role together with other type 2 cytokines and chemokines in the development, transmigration and persistence of eosinophils into airways, such as eotaxin-2 and 3, thymic stromal lymphopoietin (TSLP), IL-33, as well as IL-4 and IL-13. Several monoclonal antibodies have been developed against this cytokine (mepolizumab, reslizumab) or its receptor (benralizumab). Data on the improvement of respiratory function in patients who undergo benralizumab treatment are scarce and partly conflicting. Real-life studies may play a crucial role in clarifying this important aspect.The aim of this retrospective observational real-world study was to evaluate the effect of benralizumab on lung function improvement, exacerbation rate, oral corticosteroids (OCS) reduction and asthma control questionnaire (ACQ) score before and after six months of treatment with benralizumab in a cohort of 20 consecutive patients with severe refractory asthma (SRA) treated at the Pneumology Unit of Local Health Authority, Reggio Emilia, Italy.Add-on therapy with benralizumab allowed to completely suspend OCS in 19 out of 20 patients. Notably, the number of moderate/severe exacerbations dropped significantly (p < 0,0001); as well as an improvement in ACQ score (p < 0,0001). The most relevant data concern respiratory function: the average pre-bronchodilator FEV1 increased by 21.3% (+680 ml) compared to baseline (p = 0,0006). Moreover, the improvement in morning PEF (+66,6 l/min) confirmed the benefit of benralizumab (p = 0,02). The improvement in respiratory function was significantly higher in patients with blood eosinophilia greater than 500 cells/μL and chronic rhinosinusitis with nasal polyps (CRSwNP).This study underlies a noticeable improvement in respiratory function, much higher than what has been observed in literature so far. This aspect, together with the others aforementioned, should be considered when choosing a treatment option in the context of precision medicine.

Real-life effectiveness of mepolizumab in patients with severe refractory eosinophilic asthma and multiple comorbidities

BackgroundData on mepolizumab in patients with severe eosinophilic asthma (EA) and comorbidities are needed to assess whether randomized controlled trial results are applicable in the real world. ObjectiveTo evaluate real-life effectiveness and the presence/absence of predictors of treatment response in patients with one or more comorbidities (nasal polyps, allergic rhinitis, gastro-esophageal reflux disease, nonallergic rhinitis with eosinophilia syndrome, obesity, bronchiectasis) who received mepolizumab (MEPO) for the treatment of severe EA. MethodsWe performed a single-center retrospective study in patients with severe asthma and presence of comorbidities treated with mepolizumab at the respiratory outpatient clinic, Policlinico-Vittorio Emanuele, Catania, Italy. Health records of 31 severe asthmatic patients were retrieved and analyzed. Asthma control test (ACT) score, blood eosinophil count, forced expiratory volume in 1 s (FEV1), FEV1% of predicted and FEV1/FVC (Forced Vital Capacity) ratio, oral corticosteroid (OCS) dosage, and exacerbations were recorded at baseline (T0), after 3 (T1), 6 (T3), 9 (T6), and 12 months (T12). Clinical response was defined when 3 of these 4 criteria were fulfilled: i) 30% exacerbation decrease; ii) 80% blood eosinophilia reduction; iii) 3 point ACT increase; iv) FEV1 increase ≥200 mL. Results83.87% of patients were classified as responsive to MEPO treatment. Substantial depletion of the blood eosinophils (>80%) was found in 87.1% of patients, FEV1 > 200 mL was seen in 54.84% of patients, a 3-point ACT improvement from baseline was recorded in 80.65% 25 of patients and a 30% reduction of exacerbations rates was seen in 96.77% of patients. Moreover, the majority 38.71% of patients met 3/4 parameters after 12 months. Neither the comorbidities nor other characteristics (sex, BMI, age, smoking) influenced treatment response. ConclusionsMEPO in patients with severe EA is effective regardless of the presence of comorbidities.

Case Report: Acute effect of benralizumab on asthma exacerbation without concomitant corticosteroid use

Background: Monoclonal antibodies are a relatively new therapeutic option for patients with severe refractory asthma, which can be used as an add-on to maintenance therapy, reducing the need for systemic corticosteroid usage, improving asthma symptom control and reducing exacerbations. We report a case of a patient with severe refractory eosinophilic asthma, reluctant to take systemic steroids, who was successfully treated with benralizumab alone during an acute asthma attack. Case presentation: A 59-year-old Caucasian woman with a history of allergic asthma since childhood showed a progressive decline in lung function with difficult to control symptoms and an increased number of hospitalizations despite maximal maintenance treatment, and was diagnosed with severe refractory asthma. She was reluctant to take systemic corticosteroids during exacerbations due to severe urinary retention; therefore, she started omalizumab with a partial reduction of symptoms and exacerbations over time. During a follow-up visit, she showed signs of acute exacerbation and she was switched to benralizumab during her acute phase with a rapid, dramatic amelioration of respiratory symptoms and pulmonary function, without concomitant systemic corticosteroid administration. During the treatment and at follow-up after one month, good tolerance and no side effects were observed. Conclusions: The use of benralizumab seems to be feasible, rapid, and safe in treating acute exacerbation of severe eosinophilic asthma without the use of systemic corticosteroids.

Real-life experience with benralizumab during 6 months

BackgroundBenralizumab is a monoclonal antibody that binds to the human interleukin-5 (IL-5) receptor (IL-5R), thereby preventing IL-5 from binding to its receptor and inhibiting differentiation and maturation of eosinophils in the bone marrow. Because of its recent marketing approval, sufficient real-life evidence is lacking to confirm the efficacy and safety data from clinical trials. The purpose of this study was to evaluate the efficacy and safety of benralizumab for the treatment of severe refractory eosinophilic asthma in a real-world cohort of patients.MethodsThis was a cross-sectional multicentre study of consecutive patients with severe refractory eosinophilic asthma who received treatment with benralizumab during at least 6 months. Patient follow-up was performed in specialised severe asthma units.ResultsA total of 42 patients were enrolled and treated with benralizumab. Asthma control, as measured by the asthma control test (ACT), improved in all patients both at 3 months of treatment compared with baseline (13.9 ± 4 vs 20.1 ± 3.7, p < 0.001) and at 6 months of treatment compared with the results obtained at 3 months (20.1 ± 3.7 vs 21 ± 2.7, p = 0.037). Similarly, the number of emergency department visits decreased both at 3 months compared with baseline (1 [IR:0.7] vs 0 [IR:0.75], p < 0.001) and at 6 months compared with the results at 3 months (0 [IR:0.75] vs 0 [IR:0], p = 0.012). Reductions in the number of oral corticosteroid cycles, percentage of corticosteroid-dependent patients, and mean daily dose of oral or inhaled corticosteroid were also evidenced. Finally, mean lung function improvement was 291 mL (p < 0.001), and FEV1% improved both at 3 months compared with baseline (64.4 ± 9.3 vs 73.1 ± 9.1, p < 0.001) and at 6 months compared to 3 months (73.1 ± 9.1 vs 76.1 ± 12, p = 0.002). Side effects were mild and did not lead to treatment discontinuation.ConclusionsThis study confirms the efficacy and safety of benralizumab in a real-life setting with improved asthma control and lung function, and a reduced oral and inhaled corticosteroid use as well as fewer emergency department visits. In addition to a rapid initial improvement, it appears that patients continue to improve during the first 6 months of treatment.

Mepolizumab prefilled syringe and autoinjector: a profile of their use in severe eosinophilic asthma

Mepolizumab (Nucala®), a monoclonal antibody that targets interleukin-5, has a well-established efficacy and tolerability profile as an add-on treatment for patients with severe eosinophilic asthma. Mepolizumab was first available in a lyophilized formulation that required reconstitution and administration by a healthcare professional. More recently, a comparable liquid formulation of mepolizumab has been developed for administration via a prefilled single-use syringe or autoinjector, thereby allowing administration of the drug by patients/caregivers at home, which increases patient convenience. The mepolizumab prefilled syringe and autoinjector are approved for use in patients aged ≥ 12 years with severe eosinophilic asthma in the USA and those with severe refractory eosinophilic asthma in the EU. In usability studies, most patients and their caregivers successfully administered mepolizumab using the prefilled syringe or autoinjector. Patients generally found the devices easy to use, showed high levels of patient satisfaction and preferred self-administration over assisted administration.

Effectiveness and safety of mepolizumab in severe refractory eosinophilic asthma: results in clinical practice.

BackgroundAsthma is an inflammatory disease of the airways with symptoms that vary over time and intensity, sometimes leading to disability or even death. Eosinophilic asthma accounts for 25% of cases of severe asthma. It is mediated by eosinophils regulated by interleukin-5 (IL-5), the target of mepolizumab, which has been recently licensed as an add-on treatment of severe refractory eosinophilic asthma. The aim of this study was to evaluate the effectiveness and safety of mepolizumab in clinical practice.MethodsA multicentre, retrospective, and descriptive study covering a year was conducted in a province of Spain with more than 500,000 inhabitants. Every patient prescribed with mepolizumab since its introduction into the hospital was included in the study. Clinical parameters were collected from the pharmacists’ counselling reports from electronic prescription software and electronic patient records. Effectiveness was assessed as a decrease in the exacerbation frequency and/or a reduction in the use of oral corticosteroids (OCS) compared to the previous year.ResultsA total of 25 patients were studied, but only 23 could be evaluated by the cut-off date. A decrease in the exacerbation frequency was observed in 19 (82.6%) patients, 11 of them without any exacerbation during the treatment. A relative reduction of 87% in the exacerbation rate per year was obtained. A total of 15 patients were on regular OCS – 9 patients (60%) reduced their average dose, whilst 4 (26.7%) patients completely abandoned OCS. Safety was evaluated based on reported adverse effects. Adverse events were observed in 12 patients, the most common being headache, arthralgia, and dizziness/nausea.ConclusionMepolizumab has been shown to be effective based on the high decrease in the exacerbation frequency and reduced use of OCS. Reported adverse effects were mostly mild and appeared in half of the patients; some of the adverse events had not been previously described in pivotal trials.

Efficacy and steroid-sparing effect of benralizumab: has it an advantage over its competitors?

Severe refractory asthma is characterized by a higher risk of asthma-related symptoms, morbidities, and exacerbations. This disease also determines much greater healthcare costs and deterioration in health-related quality of life (HR-QoL). Another concern, which is currently much discussed, is the high percentage of patients needing regular use of oral corticosteroids (OCS), which can lead to several systemic side effects. Airway eosinophilia is present in the majority of asthmatic patients, and elevated levels of blood and sputum eosinophils are associated with worse control of asthma. Regarding severe refractory eosinophilic asthma, interleukin-5 (IL-5) plays a fundamental role in the inflammatory response, due to the profound effect on eosinophils biology. The advent of the biological therapies provided an effective strategy, even if the increased number of molecules with different targets raised the challenge of choosing the right therapy and avoid overlapping. When considering severe refractory eosinophilic asthma and anti-IL-5 treatments, it is not easy to define which drug to choose between mepolizumab, reslizumab, and benralizumab.In this article, we carried out an indirect comparison among literature data, especially between OCS reduction studies (ZONDA-SIRIUS) and pivotal studies (SIROCCO-MENSA), evaluating whether the clinical efficacy and the steroid-sparing effect of benralizumab may represent an advantage over other compounds. This data could help the clinician in the decision process of treatment choice, within the different available therapeutic options for eosinophilic refractory severe asthma.

Comparing biologicals and small molecule drug therapies for chronic respiratory diseases: An EAACI Taskforce on Immunopharmacology position paper.

Chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), together with their comorbidities, bear a significant burden on public health. Increased appreciation of molecular networks underlying inflammatory airway disease needs to be translated into new therapies for distinct phenotypes not controlled by current treatment regimens. On the other hand, development of new safe and effective therapies for such respiratory diseases is an arduous and expensive process. Antibody-based (biological) therapies are successful in treating certain respiratory conditions not controlled by standard therapies such as severe allergic and refractory eosinophilic severe asthma, while in other inflammatory respiratory diseases, such as COPD, biologicals are having a more limited impact. Small molecule drug (SMD)-based therapies represent an active field in pharmaceutical research and development. SMDs expand biologicals' therapeutic targets by reaching the intracellular compartment by delivery as either an oral or topically based formulation, offering both convenience and lower costs. Aim of this review was to compare and contrast the distinct pharmacological properties and clinical applications of SMDs- and antibody-based treatment strategies, their limitations and challenges, in order to highlight how they should be integrated for their optimal utilization and to fill the critical gaps in current treatment for these chronic inflammatory respiratory diseases.

PRS55 - COST-EFFECTIVENESS OF MEPOLIZUMAB IN SEVERE EOSINOPHILIC ASTHMA PATIENTS IN FRANCE

To assess the cost-effectiveness of mepolizumab in severe eosinophilic asthma (SEA) patients in France. Mepolizumab is indicated as an add-on treatment for severe refractory eosinophilic asthma in adult patients. A cost-utility model was developed and adapted to the French setting and the all payers perspective. Mepolizumab combined to standard therapy was compared to standard therapy (SoC) alone in the base case analysis, and to omalizumab combined to SoC in a scenario analysis. The lifetime markovian model considered four health states and three undercurrent events. The model parameters sources were a multicentre randomized controlled trial, a French cohort and literature. Results are defined as cost per quality-adjusted life year (QALY) gained. Over a lifetime horizon, mepolizumab reduced the number of exacerbations compared to standard therapy (15.2 versus 19.6 exacerbations, respectively) which induced a lower mortality, and a better life expectancy for patients treated with mepolizumab in combination with standard therapy (13.9 years) as compared to standard therapy alone (12.7 years). Improvement in health conditions and lower exacerbation and mortality rates translated in terms of better quality of life and higher QALYs for mepolizumab (10.3 versus 9.3 QALYs). The incremental cost-utility ratio (ICUR) of mepolizumab combined to standard therapy versus standard therapy alone is of €105,610 per QALY gained. Versus omalizumab, mepolizumab is dominant. Mepolizumab is a non-dominant strategy compared to the standard therapy alone, and a dominant strategy compared to add-on omalizumab and standard therapy. (Funding: GSK (HO-15-16522))

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.

Medications and Recent Patents for Status Asthmaticus in Children.

Status asthmaticus is an acute exacerbation of asthma that is persistent and intractable and remains unresponsive to initial treatment with bronchodilators and systemic corticosteroids and that the condition can result in hypoxemia, hypercarbia, and secondary respiratory failure. To review treatment and recent patents on management of status asthmaticus. A PubMed search was completed in Clinical Queries using the key term "status asthmaticus". The search included meta-analyses, randomized controlled trials, clinical trials, reviews and pertinent references. Patents were searched using the key term status "asthmaticus" from www.google.com/patents, www.uspto.gov, and www.freepatentsonline.com. Supplemental oxygen should be given to maintain an oxygen saturation of ≥ 92% in room air. Mainstay of pharmacologic treatment of status asthmaticus includes short-acting, β2 agonists such as salbutamol (albuterol) administered by metered-dose inhaler with spacer or, preferably, by nebulizer and oral corticosteroids. There is no advantage to intravenous corticosteroids unless the child cannot tolerate oral corticosteroids (e.g., protracted vomiting), or unable to take oral corticosteroid (e.g., intubated or unconscious). Inhaled ipratropium bromide and intravenous magnesium sulfate should be considered in children with severe asthma exacerbations not responsive to conventional therapy. Subcutaneous and intramuscular β2 agonists such as terbutaline and epinephrine may be considered for children with severe asthma exacerbation who have poor air entry, are uncooperative with nebulized therapy, or have poor response to nebulized therapy. Monoclonal anti-IgE antibody (omalizumab) and humanized monoclonal antibodies targeting interleukin pathway have shown great promise in severe refractory eosinophilic asthma. Failing therapeutic interventions necessitate non-invasive or invasive ventilation support. Severe exhaustion, deteriorating consciousness, poor air entry, worsening hypoxemia, hypercapnia, and cardiopulmonary arrest are indications for mechanical ventilation and intubation. For chronic treatment of asthma, inhaled corticosteroids, bronchodilator, and oral montelukasts are the mainstay. Some formulations of herbal medicine are efficacious but evidence of other modalities of complementary and alternative medicine are generally lacking. This review also discusses recent patents related to the management of asthma. These recent patents describe a few immunomodulating medications useful for the treatment of chronic severe asthma. There have been no recent patents for the management of status asthmaticus. Inhaled bronchodilators and systematic corticosteroids are the mainstay of therapy in the management of severe and status asthmaticus.

Mepolizumab for severe refractory eosinophilic asthma: evidence to date and clinical potential

Severe asthma is characterized by major impairment of quality of life, poor symptom control and frequent exacerbations. Inflammatory, clinical and causative factors identify different phenotypes and endotypes of asthma. In the last few years, new treatment options have allowed for targeted treatments according to the different phenotypes of the disease. To accurately select a specific treatment for each asthmatic variant, the identification of appropriate biomarkers is required. Eosinophilic asthma is a distinct phenotype characterized by thickening of the basement membrane and corticosteroid responsiveness. This review reports the latest evidence on an anti-IL-5 monoclonal antibody, mepolizumab, a new and promising biological agent recently approved by the FDA specifically for the treatment of severe eosinophilic refractory asthma.

The use of biological agents for the treatment of fungal asthma and allergic bronchopulmonary aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is a virulent manifestation of the Th2 asthma endotype that includes asthma with fungal sensitization, raising the feasibility of biological therapies targeting Th2 pathway molecules or cells. The first molecule amenable to clinical intervention with a biological was IgE. Omalizumab, a humanized monoclonal antibody (Mab), targets the same epitope on the IgE CH3 region that binds to and crosslinks high-affinity receptors on mast cells and basophils, thereby initiating the allergic inflammatory cascade. Omalizumab is licensed for allergic asthma and has been beneficial in uncontrolled studies of ABPA, reducing exacerbations and steroid requirements. Trials of several Mabs directed against the Th2 cytokine IL-5 show clinical benefit in patients with a severe refractory eosinophilic asthma phenotype, while a Mab against IL-13 is effective in asthma patients with a Th2-high endotype. Immunodulation is also feasible with small molecule biologicals, such as antisense oligodeoxynucleotides and cholecalciferol. Controlled trials of Th2-inhibiting biologicals in patients with ABPA and severe asthma with fungal sensitization appear warranted.