Figures
- FIGURE 1
Study flow chart: a three-step survey.
- FIGURE 2
Comparison of the number of available biotherapies according to gross domestic product (GDP) per capita. Results are expressed as mean±sem; data analysed by parametric unpaired t-tests.
Tables
- TABLE 1
Biologics available in severe asthma
Biologics Type Route and dosing Mechanism of action FDA–EMA recommendations Omalizumab (Xolair) Anti-IgE SC
0.016 mg·kg−1 per IU·mL−1 of IgE per month, injected every 2 to 4 weeksBinds to free IgE, thereby preventing IgE binding to its receptor
FDA approval: 2002 • Adults and children >6 years old
• IgE-mediated moderate-to-severe allergic asthma
• Uncontrolled despite a well-applied GINA step 4 treatment
• High IgE blood levels
• Sensitisation to at least one perennial allergen [31, 32]
Mepolizumab (Nucala) Anti-IL-5 SC
100 mg every 4 weeksBinds to IL-5-ligand
Prevents IL-5 from binding to its receptor
FDA approval: 2015 • High blood eosinophil count (≥150 cells·µL−1 at first administration or ≥300 cells·µL−1 in the past year)
• At least two asthma exacerbations requiring OCS in the previous year [33, 34]
Reslizumab (Cinquaero) Anti-IL-5 IV (intravenous)
3 mg·kg−1Binds to IL-5 ligand
Prevents IL-5 from binding to its receptor
FDA approval: 2016 • Adult patients
• Severe eosinophilic asthma (≥400 eosinophils·µL−1)
• At least three asthma exacerbations in the past 12 months [35, 36]
Benralizumab (Fasenra) Anti-IL-5R SC
30 mg every 4 weeks for the first three doses, then 30 mg every 8 weeksBinds to IL-5 receptor subunit α on eosinophils and basophils
Causes apoptosis of eosinophils and basophils
FDA approval: 2017 • Adults (EMA) or patients aged ≥12 years (FDA)
• Inadequately controlled severe eosinophilic asthma
• High blood eosinophilic count (≥300 blood eosinophils·µL−1) [37, 38]
Dupilumab (Dupixent) Anti-IL-4/IL-13 SC
400–600 mg for loading dose, then 200–300 mg every 2 weeksBinds to IL-4 receptor subunit α
Blocks IL-4 and IL-13 signalling pathways
FDA approval: 2018 • Moderate-to-severe asthma patients aged ≥12 years
• Eosinophilic phenotype or OCS-dependent asthma [39] (FDA)
• Type 2 inflammation with high blood eosinophils and/or elevated FENO levels [40] (EMA)
FDA: Food and Drug Administration; EMA: European Medicines Agency; SC: subcutaneous; GINA: Global Initiative for Asthma; IV: intravenous; IL: interleukin; OCS: oral corticosteroids; FENO: fractional exhaled nitric oxide.
- TABLE 2
Availability of biologics in Europe (as of April 2021)
Country Number of available biologics Omalizumab Mepolizumab Reslizumab Benralizumab Dupilumab Austria 5 1 1 1 1 1 Belgium 4 1 1 1 1 0 Croatia 4 1 1 1 1 0 Czech Republic 5 1 1 1 1 1 Denmark 5 1 1 1 1 1 Estonia 5 1 1 1 1 1 Finland 5 1 1 1 1 1 France 5 1 1 1 1 1 Germany 5 1 1 1 1 1 Greece 2 1 1 0 0 0 Hungary 5 1 1 1 1 1 Iceland 5 1 1 1 1 1 Ireland 4 1 1 1 1 0 Italy 3 1 1 0 1 0 Latvia 5 1 1 1 1 1 Lithuania 3 1 1 0 1 0 Netherlands 5 1 1 1 1 1 Poland 3 1 1 0 1 0 Portugal 5 1 1 1 1 1 Romania 2 1 0 0 1 0 Russia 5 1 1 1 1 1 Serbia 3 1 0 1 1 0 Slovenia 4 1 1 1 1 0 Spain 5 1 1 1 1 0 Sweden 5 1 1 1 1 1 Switzerland 5 1 1 1 1 Off label Turkey 2 1 1 0 0 0 UK 5 1 1 1 1 1 Of note, this table summarises the availability of biologics at the time the survey was conducted (November 2020 to April 2021). Since survey completion, dupilumab has become available in Spain, Switzerland, Croatia and Slovenia.
- TABLE 3
Inclusion criteria for severe asthma biotherapies in Europe
Biotherapy Common criteria Disparities noted between countries Additional criteria for some countries Omalizumab (n=26 countries) Severe asthma definition (ATS/ERS) (24/26)
Exacerbation rate (24/26)
• Four countries required >2 exacerbations/year
• 20 countries considered ≤2 exacerbations/year
IgE levels (25/26), with very variable threshold (majority >30 or >76 IU·mL−1)Age threshold: adults versus children for some countries
FEV1 levels: used as criterion in 13/26 countries (50%)Adherence is an absolute criterion in two countries
Non-smoking status is an absolute criterion in three countries
Questionnaire for quality of life (QOL) was used as criterion in one countryMepolizumab
(n=24 countries)Severe asthma definition (ATS/ERS) (21/24)
Exacerbation rate (24/24)
• Five countries required >2 exacerbations/year
• 19 countries considered ≤2 exacerbations/year
Blood eosinophils (24/24), with a threshold variable between 150 and 500 cells·µL−1)
Of note, one country separated maintenance OCS patients and not on maintenance OCS patients to define thresholdAge: adult versus children. This was not clearly defined as criterion in some countries
FEV1 levels: used as criterion in 5/24 countries (20.8%)Adherence is an absolute criterion in four countries
Non-smoking status is an absolute criterion in three countries
Questionnaire for QOL was used as criterion in one country
Two countries offer the possibility of inclusion if sputum eosinophils are high, even if blood eosinophils are below the fixed threshold
Cotinine level in saliva is a criterion in one countryBenralizumab (n=24 countries) Severe asthma definition (ATS/ERS) (20/24)
Exacerbation rate (22/24)
• Five countries required >2 exacerbations/year
• 17 countries considered ≤2 exacerbations/year
Blood eosinophils (24/24), with a threshold variable between 150 and 500 cells·µL−1)Age: adult versus children. This was not clearly defined as criterion in some countries
FEV1 levels: used as criterion in 6/24 countries (25%)Adherence is an absolute criterion in three countries
Non-smoking status is an absolute criterion in three countries
Questionnaire for QOL was used as criterion in one country
Two countries offer the possibility of inclusion if sputum eosinophils are high, even if blood eosinophils are below the fixed threshold
Cotinine level in saliva is a criterion in one countryReslizumab (n=16 countries) Severe asthma definition (ATS/ERS) (16/16)
Exacerbation rate (16/16)
• Seven countries required >2 exacerbations/year
• Nine countries considered ≤2 exacerbations/year
Blood eosinophils (16/16), with a threshold variable between 150 and 400 cells·µL−1)Age: adult versus children. This was not clearly defined as criterion in some countries
FEV1 levels: used as criterion in 5/16 countries (31.2%)Adherence is an absolute criterion in three countries
Non-smoking status is an absolute criterion in three countries
Questionnaires for QOL were not used
Two countries offer the possibility of inclusion if sputum eosinophils are high, even if blood eosinophils are below the fixed threshold
Three countries granted the biotherapy if patient was on OCS >50% of the year
Cotinine level in saliva was not usedDupilumab (n=11 countries) Severe asthma definition (ATS/ERS) (10/11)
Exacerbation rate (10/11)
• One country required >2 exacerbations/year
• Nine countries considered ≤2 exacerbations/year
• One country had no threshold
Blood eosinophils (11/11), with a threshold variable between 150 and 300 cells·µL−1)Age: adult versus children. This was not clearly defined as criterion in some countries
FEV1 levels: used as criterion in 1/11 countries (9.1%)
FENO levels: used in 5/11 countries (45.5%), with threshold >25 ppb for all countriesAdherence is an absolute criterion in two countries
Non-smoking status is an absolute criterion in two countries
Questionnaires for QOL were not used
Three countries granted the biotherapy if patient was on OCS >50% of the year (without needing exacerbations or high blood eosinophilic count)
Cotinine level in saliva is a criterion in one countryATS: American Thoracic Society; ERS: European Respiratory Society; FEV1: forced expiratory volume in 1 s; QOL: quality of life; OCS: oral corticosteroids; FENO: fractional exhaled nitric oxide.
- TABLE 4
Assessment of effectiveness in biologics: ranking of objective criteria
Ranking Patients on maintenance OCS Item score Patients not on maintenance OCS Item score National Leads Survey (n=28) 1 Reduction of exacerbation rate by 75% over 1 year 3.4 Reduction of exacerbation rate by 75% over 1 year 2.5 2 Reduction of chronic dose of OCS by 50% 3.4 Reduction of exacerbation rate by 50% over 1 year 2.8 3 Stopping chronic maintenance OCS 3.5 Reduction of exacerbation rate by 25% over 1 year 4.8 4 Reduction of exacerbation rate by 50% over 1 year 4.1 Reduction in ACQ by 1 at 4/6 months 5 5 Reduction of exacerbation rate by 25% over 1 year 6 Increase in AQLQ by 1 at 4/6 months 5 6 Increase in AQLQ by 1 at 4/6 months 6.1 Reduction in ACQ by 0.5 at 4/6 months 5.5 7 Reduction in ACQ by 1 at 4/6 months 6.2 Increase in AQLQ by 0.5 at 4/6 months 5.7 8 Reduction in ACQ by 0.5 at 4/6 months 6.6 Reduction of chronic dose of ICS by 50% 6.2 9 Increase in AQLQ by 0.5 at 4/6 months 6.9 Improvement of 5% predicted FEV1 7.6 10 Improvement of 5% predicted FEV1 8.5 Experts Broad Survey (n=263) 1 Reduction of exacerbation rate by 75% over 1 year 2.6 Reduction of exacerbation rate by 75% over 1 year 1.9 2 Reduction of exacerbation rate by 50% over 1 year 3.1 Reduction of exacerbation rate by 50% over 1 year 3.1 3 Stopping chronic maintenance OCS 3.5 Reduction of exacerbation rate by 25% over 1 year 4.5 4 Reduction of chronic dose of OCS by 50% 4.1 Reduction in ACQ by 1 at 4/6 months 4.6 5 Reduction in ACQ by 1 at 4/6 months 4.8 Reduction in ACQ by 0.5 at 4/6 months 5.2 6 Reduction of exacerbation rate by 25% over 1 year 5.1 Reduction of chronic dose of ICS by 50% 5.6 7 Reduction in ACQ by 0.5 at 4/6 months 6.3 Increase in AQLQ by 1 at 4/6 months 6.3 8 Increase in AQLQ by 1 at 4/6 months 7.3 Increase in AQLQ by 0.5 at 4/6 months 6.8 9 Increase in AQLQ by 0.5 at 4/6 months 8.5 Improvement of 5% predicted FEV1 7.8 10 Improvement of 5% predicted FEV1 8.9 These items are clinical efficacy criteria used in most RCTs to assess effectiveness of biologics in severe asthma. The lower the mean score of the item is, the higher its importance as effectiveness criteria is, according to participants. OCS: oral corticosteroids; AQLQ: Asthma Quality of Life Questionnaire; ACQ: Asthma Control Questionnaire; ICS: inhaled corticosteroids; FEV1: forced expiratory volume in 1 s.
