Horizon Scanning Centre May 2014 Mepolizumab for severe refractory eosinophilic asthma first line SUMMARY NIHR HSC ID: 1643 This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information. Mepolizumab is intended to be used for the treatment of patients with severe refractory eosinophilic asthma that are on step 5 of the BTS/SIGN guidelines. If licensed, mepolizumab will offer an additional treatment option which targets the immune cells involved in airway inflammation. Mepolizumab is an anti-interleukin-5 humanised IgG 1 monoclonal antibody. Interleukin-5 stimulates the production, activation and maturation of eosinophils, a type of white blood cell involved in the body s defences. Mepolizumab causes a sustained reduction in the numbers of circulating eosinophils and may be effective in conditions characterised by eosinophilia, including eosinophilic asthma, where eosinophils accumulate in lung tissue producing airway inflammation, which is closely related to the risk of severe asthma exacerbations. Reduction in eosinophils may therefore lower the risk of severe asthma exacerbations and improve patient quality of life. Mepolizumab does not currently have marketing authorisation in the EU for any indication. 5.4 million people in the UK are receiving treatment for asthma; the equivalent of 1 in 12 adults or 1 in 11 children. The Health Survey for England (2010) estimated the lifetime prevalence of diagnosed asthma to be 17% in women and 16% in men. Approximately 5% of asthma sufferers are described as therapy resistant and are unable to get good control of their asthma despite using high levels of anti-asthma medicines. Mortality from asthma is rare in England and Wales, with 1,099 asthma-related deaths reported in 2012. The management of asthma aims to control the disease while minimising adverse reactions to treatment. The SIGN/British Thoracic Society (BTS) guideline recommends a stepwise approach where treatment is started at the step most appropriate to the initial severity of the asthma with the aim of achieving early control of symptoms and optimising respiratory function. Control is maintained by stepping up treatment as necessary and stepping down when control is good within the 5 steps. Mepolizumab in addition to standard care is currently in two phase III trials comparing its effect against placebo on asthma exacerbations, the need for oral corticosteroids, and the frequency of adverse events. These trials are expected to complete in the first half of 2016. This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Centre, University of Birmingham Email: nihrhsc@contacts.bham.ac.uk Web: http://www.hsc.nihr.ac.uk
TARGET GROUP Eosinophilic asthma: refractory; severe; first line; step 5 of the BTS/SIGN guidelines. TECHNOLOGY DESCRIPTION Mepolizumab (SB-240563) is an anti-interleukin-5 humanised IgG 1 monoclonal antibody. Interleukin-5 stimulates the production, activation and maturation of eosinophils, a type of white blood cell involved in the body s defence against parasites, allergic responses, tissue inflammation and immunity. Mepolizumab causes a sustained reduction in the numbers of circulating eosinophils and may be effective in conditions characterised by eosinophilia. In eosinophilic asthma, eosinophils accumulate in lung tissue producing airway inflammation, which is closely related to the risk of severe asthma exacerbations 1. A reduction in eosinophils may therefore lower the risk of severe asthma exacerbations and improve patient quality of life. In the phase III clinical trial mepolizumab is administered subcutaneously (SC) every 4 weeks at 100mg in addition to standard asthma care. Mepolizumab does not currently have Marketing Authorisation in the EU for any indication. Mepolizumab is also in phase III clinical trials for relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA/Churg-Strauss syndrome) and for severe chronic obstructive pulmonary disease. Mepolizumab is also in phase II clinical trials for severe bilateral nasal polyposis. INNOVATION and/or ADVANTAGES If licensed, mepolizumab will offer an additional treatment option which targets the immune cells involved in airway inflammation. DEVELOPER GlaxoSmithKline. AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. PATIENT GROUP BACKGROUND Asthma is a chronic disorder of the airways caused primarily by inflammation and constriction of the smooth muscle in airway walls (bronchoconstriction) 2. It is characterised by airflow obstruction and increased responsiveness of the airways to various stimuli 1. Symptoms include recurring episodes of wheezing, breathlessness, chest tightness, sputum production and coughing (particularly at night) 3, and vary in frequency and severity from 2
intermittent and mild, to frequent and severe 2. Allergic and non-allergic forms of asthma are described, although their inflammatory response to stimuli is the same a. In general, allergic asthma results from excess immunoglobulin E (IgE) produced in response to environmental allergens such as house dust mites, pollen and moulds. Non-allergic asthma can be triggered by factors such as anxiety, stress, exercise, cold air, smoke and infection 3. Eosinophilic asthma is characterised by high expression of Th2 cytokines, interleukin-5 and interleukin-13, and is generally responsive to inhaled corticosteroid (ICS) treatment in patients with milder asthma; however in some patients with severe asthma the eosinophilic inflammation persists despite high doses of ICS and systemic corticosteroids. Asthma usually develops in childhood but may start at any age. There is no cure for asthma, although patients may experience long periods of remission. Poorly controlled asthma can have a significant impact on the quality of life of the affected person and their family, with symptoms leading to fatigue and absence from school or work, though there may be variation in an individual s perception of the symptoms and how they adapt to the condition over time 2,4. Psychological problems, which can include stress, anxiety and depression, are up to 6 times more common in asthma sufferers than in the general population, and are particularly common in people with severe and difficult-to-control asthma 3. Clinical measures such as lung function may not correlate well with an individual s quality of life, but if asthma is well controlled, near maximal scores on quality of life instruments can be achieved 2. The diagnosis of asthma is a clinical one; there is no standardised definition of the type, severity or frequency of symptoms, nor of the findings on investigation 5. However, Asthma UK defines severe asthma as including those with therapy-resistant severe asthma and those who are not therapy-resistant but who have poorly managed difficult asthma 6. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: NHS England. 2013/14 NHS Standard Contract For Respiratory: Severe Asthma (Adult). A14/S/b. NHS England. 2013/14 NHS Standard Contract For Paediatric Medicine: Respiratory. E03/S/g. An outcome strategy for chronic obstructive pulmonary disease (COPD) and asthma in England (2011). CLINICAL NEED and BURDEN OF DISEASE 5.4 million people in the UK are receiving treatment for asthma; the equivalent of 1 in 12 adults or 1 in 11 children 7. Of these, it is estimated that 3.0 million are female and 2.4 million are male. The Health Survey for England (2010) estimated the lifetime prevalence of diagnosed asthma to be 17% in women and 16% in men 8. Approximately 5% of asthma sufferers are described as therapy resistant and are unable to get good control of their asthma despite using high levels of anti-asthma medicines 6. In 2012-13, there were 64,240 hospital admissions for asthma (ICD-10 J45) in England, resulting in 148,987 bed days and 84,689 finished consultant episodes 9. Mortality from asthma is rare in England and Wales, with 1,099 asthma-related deaths (316 males, 783 females) reported in 2012 10. However, expert opinion suggests that it still accounts for nearly three potentially preventable deaths, sometimes in young persons, every day 11. a Expert personal opinion. 3
In 2013, there were 18,832,830 inhaled corticosteroid b prescription items dispensed in the community in England 12. Due to the lack of a standard definition for severe asthma the population likely to be eligible to receive mepolizumab could not be estimated from available routine published sources. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal. Omalizumab for treating severe persistent allergic asthma (review of technology appraisal guidance 133 and 201) (TA278). April 2013. NICE technology appraisal. Inhaled corticosteroids for the treatment of chronic asthma in children aged 12 years and over (TA138). March 2008. NICE technology appraisal. Omalizumab for severe persistent allergic asthma (TA133). November 2007. NICE quality standard. Quality standard for asthma (QS25). February 2013. NICE diagnostics guidance. Measuring fractional exhaled nitric oxide concentration in asthma: NIOX MINO, NIOX VERO and NObreath (DG12). April 2014. NICE interventional procedure guidance. Bronchial thermoplasty for severe asthma (IPG419). January 2012. NICE Clinical Knowledge Summaries: Asthma. June 2011. Other Guidance Scottish Intercollegiate Guidelines Network and British Thoracic Society. British guideline on the management of asthma: A national clinical guide. May 2008 (revised January 2012) 13. Scottish Intercollegiate Guidelines Network. Managing asthma in adults: a booklet for patients and their families and carers. December 2011 14. NHS quality improvement (Scotland) service guidance. Asthma services for children and young people: clinical standards. March 2007 15. CURRENT TREATMENT OPTIONS The management of asthma aims to control the disease while minimising adverse reactions to treatment; good control is characterised by no daytime symptoms, no night-time awakening due to asthma, normal lung function, no need for rescue medication, no exacerbations, and no limitations on activity including exercise 3,4. The SIGN/British Thoracic Society (BTS) guideline recommends a stepwise approach to treatment 13. Treatment is started at the step most appropriate to the initial severity of the asthma with the aim of achieving early control of symptoms and optimising respiratory function. Control is maintained by stepping up treatment as necessary and stepping down when control is good 3,4. b Based on BNF therapeutic class corticosteroids (respiratory). 4
The following stepwise and additive approach is recommended 13 : Step 1 - inhaled short-acting beta 2 -agonist. Step 2 - inhaled corticosteroid (ICS) 200-800µg/day (adults) or other preventer drug if inhaled steroid cannot be used. Step 3 - inhaled long-acting beta 2 -agonist (LABA). Benefit from LABA but inadequate control increase ICS dose to 800µg/day (adults). No response to LABA - stop use and increase ICS dose to 800µg/day (adults). Control still inadequate - consider leukotriene receptor agonist or modified release theophylline. Step 4 - increase ICS up to 2,000µg/day (adults) or addition of a fourth drug, e.g. leukotriene receptor antagonist, modified release theophylline, beta-2 agonist tablet (adults). Step 5 - daily oral, corticosteroids (lowest dose) and ICS at 2,000µg/day (adults). Consider other treatments to minimise the use of oral corticosteroids. NICE guidelines also recommend the use of omalizumab for severe persistent allergic IgEmediated asthma 3. Expert opinion 11 suggests that step 5 in the stepwise approach is the most difficult to manage, where the main aim of treatment is to control asthma using the lowest possible doses of medication. Other essential steps to treat asthma include: identification and elimination of disease triggers, identification and management of co-morbidities, regular scrutiny of inhaler technique and the provision of action plans and emergency passports c. EFFICACY and SAFETY A meta-analysis 16 of seven randomised placebo-controlled trials d which investigated the efficacy of mepolizumab in patients with eosinophilic asthma found that mepolizumab was associated with significantly decreased exacerbation risk compared to placebo (odds ratio 0.30, 95%CI 0.13 to 0.67, p=0.004) and significant improvement in scores on the Asthma Quality of Life Questionnaire (AQLQ) (mean difference from placebo 0.26, 95%CI 0.03 to 0.49, p=0.03). No significant differences in lung function measures between mepolizumab and placebo groups were observed, including FEV 1, PEF, or histamine PC 20. Trial Sponsor Status Source of information Location Design Participants Schedule NCT01842607, MEA115661, EudraCT Number: 2012-001644-21; mepolizumab in addition to standard care; phase III extension. GlaxoSmithKline. Ongoing. Trial registry 17. EU (incl UK), USA, Canada and other countries. Uncontrolled, single arm. n=660 (planned); aged 12 yrs; severe, refractory asthma being treated with a controller medication for 12 weeks; history of eosinophilic inflammation; completion of treatment during MEA115588 (NCT01691521) or MEA115575 (NCT01691508) studies; not current smoker; without hypersensitivity to study medication, significant change in health status, a study related SAE, significant laboratory/clinical abnormality, or significant new illness. Mepolizumab 100mg administered SC every 4 weeks for 12 mths, in addition to standard care. c Expert personal opinion d Including trials NCT01000506 and NCT00292877 5
Follow-up Primary outcome/s Secondary outcome/s Expected reporting date Active treatment for 12 mths, follow-up 64 weeks. Adverse events (AEs), including local site reactions; withdrawals due to AEs; hospitalisations due to AEs (including asthma exacerbations); 12-lead ECG; vital signs; clinical laboratory measurements. Frequency of positive anti-mepolizumab binding antibodies and neutralising antibodies; annualised rate of exacerbations; asthma control questionnaire score (ACQ); Forced Expiratory Volume in 1 second (FEV1) measured by clinic spirometry; withdrawals due to lack of efficacy. Study completion date reported as April 2016. Trial NCT01691859, MEA115666, EudraCT Number: 2012-001643-51; mepolizumab in addition to standard care; phase III extension. DREAM, NCT01000506, MEA112997, EudraCT Number: 2009-014415-12; mepolizumab vs placebo; phase IIb/III. NCT01691521, MEA115588, EudraCT Number: 2012-001251-40; mepolizumab vs placebo, both in addition to standard care; phase III. Sponsor GlaxoSmithKline. GlaxoSmithKline. GlaxoSmithKline. Status Ongoing. Published. Completed but unpublished. Source of Trial registry 18. Publication 19, trial Trial registry 21. information registry 20. Location EU (incl UK), USA, Canada and other countries. EU (incl UK), USA, Canada and other countries. EU (incl UK), USA, Canada and other countries. Design Uncontrolled, single arm. Randomised, placebocontrolled. Randomised, placebocontrolled. Participants n=362 (screened) 347 (dosed) e ; aged 18 yrs; MEA112997 (NCT01000506) study participation (receiving at least 2 doses); positive risk:benefit ratio if subject received mepolizumab in prior study; treated with a controller medication for 12 weeks; not received omalizumab in past 130 days; not current smoker; without hypersensitivity to study medication, significant change in health status, a study related SAE, significant laboratory/clinical abnormality, or significant new illness. n=621; aged 12-74 yrs; severe refractory asthma; minimum weight 45kg; high dose ICS (i.e. 880mg/day fluticasone propionate or equivalent daily) for 12 mths; use of additional controller medication for 12 mths; persistent airflow obstruction (prebronchodilator FEV1<80% predicted at visit 1 or peak flow diurnal variability of >20% on 3 or more days during run-in); airway inflammation likely to be eosinophilic in nature (demonstrated by: peripheral blood eosinophils 300/mL, sputum eosinophils 3%, exhaled nitric oxide 50ppb or prompt deterioration of asthma control following a 25% reduction in regular maintenance dose of inhaled or oral corticosteroids); history of n=580 (planned); aged 12 yrs; severe, uncontrolled refractory asthma; minimum weight 45kg; requirement for high dose ICS 12 mths with or without maintenance oral corticosteroids; current treatment with an additional controller medication for 3 mths or a documented failure within 12 mths of an additional controller medication used for 3 mths; prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma (elevated peripheral blood eosinophil count 300 cell/µl in previous 12 mths or elevated peripheral blood eosinophil count of 150 cells/µl at visit 1 related to asthma); prebronchodilator FEV1<80% (in subjects 18 yrs), prebronchodilator FEV1<90% e Reported by the company. 6
Schedule Mepolizumab 100mg administered SC every 4 weeks in addition to standard care. 2 exacerbations in previous 12 mths; QTc<450msec or QTc<480msec for patients with bundle branch block; normal liver function tests. Patients excluded if current smoker, past smoking history >10 pack-year history, parasitic infection in 6 mths before study. Randomised to mepolizumab 750mg IV every 4 weeks; or mepolizumab 250mg IV every 4 weeks; or mepolizumab 75mg IV every 4 weeks; or placebo saline IV; all in addition to high doses of standard asthma medication. or FEV1:FVC ratio <0.8 (in subjects 12-17 yrs); history of 2 exacerbations requiring treatment with systemic corticosteroids. Patients excluded if current smoker, past smoking history >10 pack-year history, presence of other clinically important lung condition, liver disease, severe or clinically significant cardiovascular disease, other eosinophilic disease, QTc(F) 450msec or QTc(F) 480msec for subjects with bundle branch block, immunodeficiency, received omalizumab within 130 days. Randomised to mepolizumab 75mg IV and placebo SC every 4 weeks for 28 weeks; or mepolizumab 100mg SC and placebo IV every 4 weeks for 28 weeks; or matching placebo IV and placebo SC every 4 weeks for 28 weeks. Follow-up Primary outcome/s Secondary outcome/s Active treatment until marketed (approximately 30-60 mths) f, follow-up 12 weeks after final dose. AEs ECG parameters (QTcF and QT); clinical laboratory tests; vital signs; annualised rate of exacerbations; ACQ score; forced vital capacity (FVC); FEV1; immunogenicity (positive neutralising antibody); withdrawals due to lack of efficacy or AEs; hospitalisations due to AEs (including asthma exacerbations); frequency of immune reactions. Active treatment for 52 weeks (13 infusions), follow-up 8 and 24 weeks. Clinically significant asthma exacerbations. Time to first clinically significant asthma exacerbation requiring oral or systemic corticosteroids, hospitalisation and or emergency department (ED) visit; frequency of exacerbations requiring hospitalisation or ED visit; time to first exacerbation requiring hospitalisation or ED visit; frequency of investigator-defined exacerbations; time to first investigator-defined exacerbation; mean change in clinic pre-bronchodilator FEV1; mean change in post- bronchodilator FEV1; Active treatment for 32 weeks, follow-up 40 weeks. Clinically significant asthma exacerbations. Frequency of clinically significant exacerbations requiring hospitalisation or ED visits; lung function; quality of life (St George s respiratory questionnaire). f Reported by the company. 7
mean change in ACQ score. Key results - Compared with placebo, reduction in number of clinically significant exacerbations per patient per year, 48% (95% CI 31-61%) in the 75mg arm, 39% (95% CI 19-54) in the 250mg arm, and 52% (95% CI 36-64%) in the 750mg arm. Adverse effects (AEs) Expected reporting date - For the placebo, 75mg, 250mg, 750mg arms respectively, the most frequently reported AEs included: headache (17%, 21%, 21%, 21%); nasopharyngitis (15%, 22%, 22%, 19%); drugrelated adverse events included; infusion-related reaction (6%, 5%, 8%, 12%) and hypersensitivity (2%, 0%, <1%, 1%). Study completion date reported as June 2016. Compared with placebo, both treatment arms showed statistically significant reductions in the number of clinically significant exacerbations (75mg IV group, 47% reduction, p<0.001; 100mg SC group, 53% reduction, p<0.001) f. The most common AEs reported across the groups included: nasopharyngitis, headache, upper respiratory tract infection and asthma. For mepolizumab 75mg IV, mepolizumab 100mg and placebo respectively: frequency of AEs was, 84%, 78%, and 83%; frequency of serious AEs was 7%, 8%, and 14%. - Study completion date reported as January 2014. Trial NCT01691508, MEA115575, EudraCT Number: 2012-001497-29; mepolizumab vs placebo; phase III. NCT00292877, RP#02/2115, SB- 240563/046, 9427-F2453-21C; mepolizumab vs placebo, both in addition to prednisolone; phase II. Sponsor GlaxoSmithKline. St.Joseph s Healthcare Hamilton. Status Completed but unpublished. Published. Source of Trial registry 22. Publication 23, trial registry 24. information Location EU (incl UK), USA, Canada, Australia Canada. and Mexico. Design Randomised, placebo-controlled. Randomised, placebo-controlled. f Reported by the company. 8
Participants Schedule Follow-up Primary outcome/s n=135 (planned); aged 12 yrs; severe, refractory asthma; requirement for regular treatment with maintenance systemic corticosteroids within 6 mths and stable oral corticosteroid dose for 4 weeks prior to visit 1; requirement for regular treatment with high dose ICS within 6 mths (in subjects 18 yrs, dose 880µg/day fluticasone propionate or equivalent; in subjects aged 12 to 17 ICS dose 440µg/day or equivalent or highest approved maintenance dose of ICS/LABA combination preparations); current treatment with an additional controller medication for 3 mths or a documented failure within 12 mths of an additional controller medication used for 3 mths; prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma (elevated peripheral blood eosinophil count 300 cell/µl in previous 12 mths or elevated peripheral blood eosinophil count of 150 cells/µl at visit 1 related to asthma); persistent airway obstruction (pre-bronchodilator FEV1<80% predicted); airway reversibility, hyperresponsiveness or airway variability. Patients excluded if current smoker, past smoking >10 pack-year history, presence of other clinically important lung condition, liver disease, severe or clinically significant cardiovascular disease, other concurrent medical conditions, any eosinophilic disease; QTc(F) 450msec or QTc(F) 480msec for subjects with bundle branch block, immunodeficiency, received omaluzumab within 130 days. Randomised to mepolizumab 100mg SC every 4 weeks for 20 weeks; or placebo SC administered every 4 weeks for 20 weeks. Active treatment for 20 weeks, follow-up 32 weeks. Reduction of oral corticosteroid (OCS) dose during weeks 20 to 24. n=20; aged 18 70 yrs; asthma requiring treatment with oral prednisolone in addition to high dose ICS; sputum eosinophilia; abnormal FEV1 after withholding bronchodilators, before and after inhaled salbutamol (200mg) and methacholine PC20; same corticosteroid dose for 4 weeks. Patients excluded if exposure to a relevant seasonal environmental allergen known to worsen asthma during study period, respiratory tract infection within 4 weeks, or clinical exacerbation requiring increased prednisolone treatment within 4 weeks. Randomised to mepolizumab 750mg IV in weeks 2, 6,10,14 and 18; or matching IV placebo; both with prednisolone, tailing dose reduced by 5mg at weeks 6,10,14,18 and 22. Active treatment for 18 weeks, follow-up for 8 weeks up to week 26. Asthma exacerbations, mean reduction in the dose of prednisone as a percentage of maximum possible reduction (as measured by the Juniper ACQ). 9
Secondary outcome/s Key results Adverse effects (AEs) Expected reporting date 50% reduction in daily OCS dose; 5.0mg reduction in daily OCS dose; total reduction of OCS dose; median percentage reduction in OCS dose; safety (measured using AEs, clinical chemistry, haematological parameters, blood glucose, body weight, glycosylated haemoglobin and vital signs); AEs associated with chronic OCS use; mean and maximum change in QTc(F) and QTc(B). Compared to placebo, mepolizumab 100mg SC group had greater reductions in maintenance OCS (p=0.008) f. AEs were reportedly similar across treatment groups. The most common reported AEs in the two treatment groups were headache, nasopharyngitis, bronchitis, sinusitis, fatigue and asthma. Frequency of AEs was 92% in the placebo and 84% in the mepolizumab treatment group. Frequency of serious AEs was 18% in the placebo group and 1% in the mepolizumab group. Study completion date reported as December 2013. Study phase I - reduction in blood and sputum eosinophils. Study phase II - time to exacerbation; reduction in blood and sputum eosinophils; FEV1 change; symptom score. Study phase III reduction in blood and sputum eosinophils; FEV1 change; symptom score. A statistically significant difference was reported in the number of exacerbations (p=0.008), median time to exacerbation (p=0.003) and mean reduction in prednisolone dose between the mepolizumab group (±SD) (83.8±33.4%) and the placebo group (47.7±40.5%) (p=0.04). Few AEs were noted: in the mepolizumab group one patient reported progressive shortness of breath and another reported aches and tiredness when prednisolone dose was reduced to 2.5mg. - ESTIMATED COST and IMPACT COST The cost of mepolizumab is not yet known. The cost of selected inhaled corticosteroids and other treatments for asthma include: Drug Dose Unit cost 25, Beclometasone dipropionate 200-400µg twice daily adjusted to 800µg as necessary. 250µg/metered inhalation (100- dose unit): 12.31. Budesonide 100-400µg twice daily. 100µg/metered inhalation (100- dose unit): 5.90. Ciclesonide 160µg daily as a single dose. 160µg/metered inhalation (60- dose unit): 19.31. Fluticasone propionate (Flixotide; Accuhaler) Mometasone fuorate (Asmanex; Twisthaler) 50-200µg twice daily. 400µg as a single dose in the evening or in 2 divided doses. 100µg/blister with Accuhaler: 8.93. 200µg/metered inhalation (30- dose unit): 15.70. f Reported by the company. 10
Omalizumab (Xolair) Subcutaneous injection. Dose determined by baseline IgE (IU/ml), measured before the start of treatment, and body weight (kg). The maximum recommended dose is 600mg every two weeks 26. A 0.5mL, 150mg/mL (75mg) prefilled syringe costs 128.07. IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Other: patients are likely to have to attend specialist centres to receive treatment f. Reduced symptoms or disability No impact identified Impact on Health and Social Care Services Increased use of existing services Re-organisation of existing services Other: patients are likely to have to attend specialist centres to receive treatment f but may also have less unplanned use of services, i.e. through A & E. Decreased use of existing services Need for new services None identified Impact on Costs and Other Resource Use Increased drug treatment costs Other increase in costs: patients are likely to have to attend specialist centres to receive treatment, necessitating day ward bed or chair facilities and appropriate expertise of staff f. Other: uncertain unit cost compared to existing treatments. Reduced drug treatment costs Other reduction in costs: None identified Other Issues Clinical uncertainty or other research question identified: Expert opinion suggests that it is unclear how mepolizumab reduces the acute exacerbations of asthma reported in trials. Studies showing its efficacy, which appears to be limited specifically to reduction of exacerbations perhaps in the face of reduced oral corticosteroid therapy with attendant improvement in quality of life, have been arbitrarily limited to patients above a threshold of blood and sputum eosinophilia. While this may theoretically be appropriate, the lack of comparison with low eosinophil groups inevitably casts doubt on whether this is a mandatory prerequisite for response to mepolizumab which should be incorporated into guidelines f. Expert opinion also notes that the most recent Lancet study suggests that even the lowest effective dosage used (75mg monthly) may be unnecessarily high f. None identified f Expert personal opinion. f Expert personal opinion 11
REFERENCES 1 Asthma and Allergy Foundation of America. Eosinophilic Asthma. http://www.aafa.org/display.cfm?id=8&sub=17&cont=801 Accessed 7 May 2014. 2 National Institute for Health and Clinical Excellence. Inhaled corticosteroids for the treatment of chronic asthma in children aged 12 years and over. Technology appraisal TA138. London: NICE; March 2008. 3 National Institute for Health and Care Excellence. Omalizumab for treating severe persistent allergic asthma (review of technology appraisal guidance 133 and 201). Technology appraisal TA278. London: NICE; April 2013. 4 National Institute for Health and Clinical Excellence. Inhaled corticosteroids for the treatment of chronic asthma in children under the age of 12 years and over. Technology appraisal TA131. London: NICE; November 2007. 5 National Institute for Health and Clinical Excellence. Guidance on the use of inhaler systems (devices) in children under the age of 5 years with chronic asthma. Technology appraisal TA10. London: NICE; August 2000. 6 Asthma UK. Severe Asthma. www.asthma.org.uk/ Accessed 30 March 2014. 7 NHS Choices. Asthma; Introduction. http://www.nhs.uk/conditions/asthma/pages/introduction.aspx Accessed 30 March 2014. 8 The Health Survey for England. Respiratory Health: Summary of key findings. Leeds: The NHS Information Centre. 2010. 9 Health and Social Care Information Centre. Hospital episode statistics, admitted patient care, England 2012-13: Diagnosis. www.hscic.gov.uk 10 Office for National Statistics. Mortality statistics: Deaths registered in England and Wales (Series DR), 2012. Mortality statistics: Deaths registered in 2012 (Series DR) Table 5. http://www.ons.gov.uk 11 Horizon Scanning Centre. Mastinib for severe asthma. September 2012. 12 Health and Social Care Information Centre. Prescription cost analysis, England 2013 [NS]. Prescription cost analysis - England 2013: Data. www.hscic.gov.uk 13 Scottish Intercollegiate Guidelines Network and British Thoracic Society. British guideline on the management of asthma: A national clinical guide. Edinburgh: SIGN; May 2008 (revised January 2012). 14 Scottish Intercollegiate Guidelines Network. Managing asthma in adults: a booklet for patients and their families and carers. Edinburgh: SIGN; December 2011. 15 NHS Quality Improvement Scotland. Asthma services for children and young people: clinical standards March 2007. 16 Liu Y, Zhang S, Li D et al. Efficacy of anti-interleukin-5 therapy with mepolizumab in patients with asthma: A meta-analysis of randomized placebo-controlled trials. PLOS ONE 2013;8(3):e59872. 17 ClinicalTrials.gov. A study to determine long-term safety of mepolizumab in asthmatic subjects. http://clinicaltrials.gov/ct2/show/study/nct01842607 Accessed 30 March 2014. 18 ClinicalTrials.gov. MEA112997 Open-label long term extension safety study of mepolizumab in asthmatic subjects. http://www.clinicaltrials.gov/ct2/show/nct01691859 Accessed 1 May 2014. 19 Pavord ID, Korn S, Howarth P et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651-659. 20 ClinicalTrials.gov. Dose ranging efficacy and safety with mepolizumab in severe asthma (DREAM). http://www.clinicaltrials.gov/ct2/show/study/nct01000506 Accessed 1 May 2014. 21 ClinicalTrials.gov. Efficacy and safety study of mepolizumab adjunctive therapy in subjects with severe uncontrolled refractory asthma. http://clinicaltrials.gov/ct2/show/nct01691521 Accessed 6 May 2014. 22 ClinicalTrials.gov. Mepolizumab steroid-sparing study in subjects with severe refractory asthma. http://www.clinicaltrials.gov/ct2/show/nct01691508 Accessed 6 May 2014. 23 Nair P, Pizzichini MM, Kjarsgaard M et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. New England Journal of Medicine 2009;360:985-93. 24 ClinicalTrials.gov. The Prednisone-sparing Effect of Anti-IL-5 Antibody (SB-240563). http://clinicaltrials.gov/ct2/show/nct00292877 Accessed 7 May 2014. 25 British National Formulary (BNF). http://www.bnf.org/bnf/index.htm Accessed 7 May 2014. 12
26 The electronic Medicines Compendium (emc). Summary of Product Characteristics, Xolair. Novartis Pharmaceuticals UK Ltd. Accessed 7 May 2014. 13