Authors' objectives: 1) To assess the effectiveness and safety of biologics in treatment of severe asthma with regards to patient outcomes such as asthma control (exacerbation, spirometry, symptoms, quality of life [QoL], oral corticosteroid [OCS] sparing effects, hospital admission, Emergency Department ([ED] visit etc), mortality and adverse events or complications 2) To assess the economic implication, social, ethical, and organisational aspects related to the biologics in treatment of severe asthma

Authors' results and conclusions: Part A: Systematic Review A total of 643 records were identified through the Ovid interface and PubMed while 5 were identified from other sources (references of retrieved articles). Following the removal of 594 duplicates and irrelevant titles, 53 titles were found to be potentially relevant, and abstracts were screened using the inclusion and exclusion criteria. Of these, 52 relevant abstracts were retrieved in full text. After reading, appraising, and applying the inclusion and exclusion criteria to the52full text articles, 30 full text articles were included in this report. Twenty-seven (27) articles were excluded as those primary studies were already included in systematic review and NMA / MA(n=7) narrative reviews (n = 11) and overlapped with other included studies(n = 9). The 30 full text articles which were finally selected in this review comprised of three systematic reviews with NMA, seven systematic reviews with MA, five systematic review, eleven RCTs, one observational study and three economic evaluation studies of individual biologics (dupilumab, mepolizumab and benralizumab). All studies included were published in English language between 2018 and 2024. Effectiveness Asthma exacerbations All four biologics (mepolizumab, benralizumab, dupilumab and tezepelumab) showed consistent improvement in asthma exacerbation rate (AER) as well as in annual asthma exacerbation rate (AAER) compared to placebo. The pooled analysis study showed that the biologics significantly reduced the AAER by 44%(rate ratio [95% CI 0.52 to 0.62]; I2 = 58.4%). In term of subgroup analysis based on baseline blood eosinophils count (BEC), all four biologics showed consistent greater reductions in asthma exacerbation among patients with high BEC level (≥300cells/uL) compared to low BEC count (<300 cells/uL). The pooled rate ratio was 0.38 (95% CI 0.29 to 0.49) versus 0.67 (95%CI 0.55to0.83); Psubgroup_heterogeneity = 0.001. Asthma control The most common tool reported involving all four biologics was Asthma Control Questionnaire (ACQ) score. All four biologics showed a positive effect in reducing the ACQ score when compared to placebo. Meta-analysis of mepolizumab, benralizumab, dupilumab and tezepelumab reported a reduction in the ACQ score by -0.34points (95% CI -0.46 to -0.23, I2 = 89.5%). However, the reduction did not reach the minimal clinically important difference (MCID) for the ACQ score (-0.50 points). The biologics were also found to improve the ACQ score in patients with high BEC level (≥300 cells/uL) compared to low BEC level (<300 cells/uL). Lung function Assessment of lung function in all four biologics was an improvement in forced expiratory volume in 1 second (FEV1). Studies retrieved showed that mepolizumab, benralizumab, tezepelumab and dupilumab significantly increased the FEV1 when compared to placebo. The pooled analysis of all four biologics reported 0.11L(95%CI 0.09 to 0.14); I2 = 50.1% improvement. In subgroup analysis of high (≥300 cells/uL) and low (<300 cells/uL) BEC level, all four biologics showed greater and significant improvement in high BEC level compared to low BEC level. The recent pooled result was available for benralizumab, dupilumab and tezepelumab; 0.18L (95% CI 0.14 to 0.22) versus 0.07L (95%CI 0.04to 0.10); Psubgroup_heterogeneity <0.001. Meanwhile, for mepolizumab when compared to placebo, the result was 0.1L (95%CI 0.04 to 0.15) among patients with high BEC level. Hospital admission and Emergency Department (ED) visit Reduction in hospital admission and ED visit due to exacerbation was observed in all biologics. The pooled result of mepolizumab, benralizumab and tezepelumab showed 60% reduction with rateratio0.40 [95% 0.27 to 0.60], I2 = 32%). According to network meta- analysis, reduction in hospitalisation and ED visit due to exacerbation showed no significant difference between mepolizumab, benralizumab, dupilumab and tezepelumab as the tezepelumab leads other biologic in SUCRA ranked at 95%. In subgroup analysis of BEC level, tezepelumab, dupilumab, benralizumab and mepolizumab reduced the hospitalisation and ED visit in patients with high BEC level (≥300 cells/uL) where greatest reduction was observed in tezepelumab (90% reduction). Reduction in oral corticosteroid intake (OCS) Based on the included studies, benralizumab, mepolizumab, dupilumab and tezepelumab increased the probability of OCS dose reduction to <5mg/day. In a meta-analysis of all four biologics, 74%reduction was reported with a risk ratio of 1.74 (95%CI 1.23 to 2.46); I2 = 44.1%. The results also showed high probability of the biologics to reduce more than 50% of OCS which was 68%(95%CI 1.29to2.19; I2 = 27.2%. The probability of OCS discontinuation also increased with biologics compared to placebo; the pooled rate ratio between benralizumab, dupilumab and tezepelumab was 1.63 (95%CI 1.29 to 2.19; I2 = 27.2%) and for mepolizumab the rate ratio was1.61 (95% CI 1.07 to 2.41). The reduction in OCS occurred as early as four weeks of biologics treatment. One benralizumab extension study reported on sustained reduction of OCS used in high BEC level subgroup ranging from17%to 29%withmedian dose reduction of 10mg – 15mg to 5mg – 10mg. Other Outcomes Reduction in blood eosinophils (bEos) Many studies reported that mepolizumab, benralizumab, andtezepelumab reduced blood eosinophils in severe asthma. The pooled bEos reduction reported for mepolizumab, benralizumab, and tezepelumab were -609.19 cell/uL (95% CI -793.20 to -425.68), - 518.68 cell/uL (95% CI -820.24 to -217.12), and (-151.05 cells/uL(95% CI -165.99 to -136.12), respectively. Reduction in Fractional Exhale Nitric Oxide (FeNO) level Significant reduction in FeNO level was reported in mepolizumab(- 14.23 ppb [95% CI -19.71 to -8.75], tezepelumab (-12.41 ppb [95%CI -14.28 to -10.53]) and dupilumab compared to placebo. The FeNO reduction concentration with tezepelumab was observed as earlyasweek-2 and the reduction were sustained up to 52- to 104-weeks. Reduction in Serum IgE Reduction in serum IgE was reported in dupilumab and tezepelumab compared to placebo. The extension studies of both biologics reported a sustained reduction of serum IgE up to 104-weeks; - 122.90 IU/mL (95% CI -167.80 to -78.01), p = 0.00, I2 = 9.40%reduction in tezepelumab and 80% to 90% reduction with dupilumab. SAFETY According to the included studies, a few adverse events lead to the discontinuation of biologics treatment. Different biologics showed different risk of discontinuation such as RR 1.65 (95%CI 0.79 to3.45) in benralizumab, RR 1.03 (95% CI 0.46 to 2.30) in dupilumab, RR0.65 (95% CI 0.36 to 1.16) and RR 0.68 (95% CI 0.34 to 1.35) in tezepelumab. The reasons of the discontinuation were anaphylactic reaction, malignancy, live function abnormality, asthma-related event requiring intubation, pulmonary TB, non-asthma related events, no clinical improvement, severe headache, severe arthralgia, allergic rash, and conjunctivitis, persistent eczematous (on face, trunk and upper limb) and pruritis. Death during study period showed no difference between biologics and control groups (risk ratio 0.91[95%CI 0.39 to 2.09], I2 = 0%). On the other hand, the most common adverse events reported in both biologics and placebo were nasopharyngitis, upper respiratory infection, headache, and injection-site reaction. ORGANISATIONAL One study assessed the effects of tezepelumab on healthcare utilisation (HCU) among patients with severe asthma. The study showed that, tezepelumab showed fewer asthma-related unscheduled specialist visits, fewer telephone calls with a healthcare provider, lesser ambulance transports due to asthma, and fewer home visits from a healthcare provider than placebo. SOCIAL The included studies reported that mepolizumab, benralizumab, dupilumab and tezepelumab improved quality of life (QoL) by improving the Asthma Quality of Life Questionnaire (AQLQ), and St George’s Respiratory Questionnaire (SGRQ). One dupilumab extension study assessed the quality of life among paediatric patients as well as their caregivers. The LS mean difference (LSMD) in dupilumab versus placebo showed significant improvement sinceweek-24 onwards and at week-52 the LSMD was 0.34 (95%CI 0.16to 0.52); p = 0.0002 in Paediatric Asthma Quality of Life Questionnaire Interviewer-Administered (PAQLQ(S)-IA), and0.25(95% CI 0.00 to 0.50; p = 0.0531) at week-24 and 0.47 (95%CI 0.22to 0.72; p = 0.0003) at week-52 in Paediatric Asthma Caregiver’s Quality of Life Questionnaire (PACQLQ-IA) global score. According to the checklist, the improvements was observed in individual domain scores of emotional functions, activity limitation and symptoms. ECONOMIC EVALUATIONS Overall, most of the included studies reported an ICER/QALY gained was higher than Willingness-to-Pay (WTP) threshold. According to the studies, the potential saving was related to decrease rate of hospitalisation, ED care, primary care visits and the management of clinically significant exacerbations. In economic evaluation study of mepolizumab in Singapore, the ICER/QALY was SGD335,486(US$238,195) and the ICER/LY gained was SGD208,238(US$147,846) with average of five exacerbations were avoided per patient over a lifetime. However, the ICER was above Singapore WTP threshold (SGD250,00). Meanwhile, an economic evaluation study of benralizumab in Spain reported that benralizumab was within Spain WTP (€24,000) as the ICUR obtained was €18,177/QALY with Net Monetary Benefit obtained with benralizumab was €813. Another economic evaluation was on dupilumab in Japan. The study compared dupilumab with benralizumab, mepolizumab and omalizumab where the study reported that dupilumab was cost- effective compared to benralizumab and mepolizumab but not cost- effective compared to omalizumab. One of the key drivers for this analysis was price of each biologic per vial. Part B: Economic Evaluation A cost-effectiveness analysis (CEA) from the perspective of MOH was conducted. The model indicated that adding biologics to the SoC improves QALYs but incurred higher costs. The ICERs for tezepelumab, benralizumab, mepolizumab, and dupilumab were RM759,126, RM623,901.46, RM 1,543,407, and RM 883,807 per QALY gained, respectively. All ICERs exceeded the Malaysian Willingness to Pay (WTP) or cost- effectiveness threshold of one GDP per capita per QALY gained. In addition, three scenario analyses were performed in which the provision of shorter treatment duration, the extension of dose treatment frequency and hypothetical percentage reduction of drug costs were explored. All the interventions showed reductions in the ICERs but were not cost-effective. Moreover, all drugs required more than 90% cost reduction, except for benralizumab which requires 81%cost reduction for the ICERs to be cost-effective. One-way sensitivity analysis was performed to assess key drivers that impacted the estimated ICERs the most. Health utility value for long term OCS use and drug cost were noted to show a remarkable impact on the ICERs. Meanwhile, a probabilistic sensitivity analysis was conducted to assess the robustness of model results. A Monte Carlo simulation of 1000 iterations was performed and the model results were shown to be consistent and robust. CONCLUSION Based on the above review, mepolizumab, benralizumab, dupilumaband tezepelumab significantly reduced exacerbations, ED visits and hospitalisation, improved lung function, asthma control, quality of life and reduced the use of oral corticosteroids especially among patients with high level of BEC (≥300 cells/uL). In terms of economic implications, these biologics are effective but at a higher cost as the ICER / QALY are higher than the WTP threshold.

Authors' recommendations: Biologics (mepolizumab, benralizumab, dupilumab or tezepelumab) may be used as an add-on therapy for severe asthma in patients with these criteria; high BEC level (≥300 cells/uL) and unresponsive to the optimal therapy. Taking into consideration the economic implications, effective price negotiations may improve the cost-effectiveness of this treatment.

Authors' methods: Part A Literature search was developed by the main author and an Information Specialist who searched for published articles pertaining to biologics treatment in severe asthma. The following electronic databases were searched through the Ovid interface: OvidMEDLINE® and Epub Ahead of Print, In-Process & Other NonIndexed Citations, Daily and Versions® 1946 to June 2023, EBM Reviews - Health Technology Assessment, EBM Reviews - Cochrane Database of Systematic Review, EBM Reviews - Cochrane Central Register of Controlled Trials, and EBM Reviews - NHS Economic Evaluation Database. Parallel searches were run in PubMed, USFDA and INAHTA database. Search was limited to articles in English and in human. Part B Five-health states Markov model with a four-week cycle and a lifetimehorizon was constructed and analysed using Microsoft Excel Workbook 2021. The primary outcomes included total cost and quality-adjusted life years (QALYs) gained for each intervention in consideration. An annual discount rate of three per cent was applied to both costs and outcomes estimated. The input on the treatment effects was drawn from the systematic review carried out in Section A of this report. Meanwhile, costs for drug acquisition and disease management were based on available local data. Health utility values for asthma health states and other key parameters applied to the model were sourced from previously published studies. This analysis also was based on one time of the Malaysian per capita gross domestic product (GDP) in 2022 (MYR54,863 /QALY).

Project Status: Completed

URL for project: https://www.moh.gov.my/index.php/pages/view/1747

Year Published: 2024

URL for published report: https://www2.moh.gov.my/moh/modules_resources/bookshelf/HTA_BIOLOGICS_IN_SEVERE_ASTHMA_updt_19062025/index.html

URL for additional information: https://www.moh.gov.my/moh/resources/Penerbitan/MAHTAS/HTA/ES_BIOLOGICS_IN_SEVERE_ASTHMA.pdf

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Malaysia

Organisation Name: Malaysian Health Technology Assessment

Contact Address: Malaysian Health Technology Assessment Section, Ministry of Health Malaysia, Federal Government Administrative Centre, Level 4, Block E1, Parcel E, 62590 Putrajaya Malaysia Tel: +603 8883 1229

Contact Name: htamalaysia@moh.gov.my

Contact Email: htamalaysia@moh.gov.my

Copyright: Malaysian Health Technology Assessment Section (MaHTAS)