Tezepelumab compared with other biologics for the treatment of severe asthma: a systematic review and indirect treatment comparison

Figures & data

Table 1. Eligibility criteria for identification of relevant studies.

Category	Inclusion criteria	Exclusion criteria
Population	Patients at least 12 years of age who have asthma that remains uncontrolled despite adherence with maximal optimized GINA step 4 or 5 treatment, including medium-to-high dose ICS and LABA^a	Mild disease severity only Other respiratory disease without asthma included Non-human studies All patients under the age of 12 years
Interventions	Tezepelumab (210 mg every 4 weeks)	None
Comparator	Approved dosages of anti-IgE, anti-IL-5 pathways, or anti-IL-4/IL-13, based on prescribing information from FDA, EMA, and/or Japan^b. Specific biologics to be included are listed here: Anti-IgE Omalizumab (75–375 mg [FDA and Japan] or 75–600 mg [EMA] every 2 or 4 weeks; dose and frequency determined by baseline IgE level and body weight [kg]) Anti-IL-5 pathways Mepolizumab (100 mg every 4 weeks) Reslizumab (3 mg/kg once every 4 weeks) Benralizumab (30 mg every 4 weeks for the first 3 doses, and once every 8 weeks thereafter) Anti-IL-4/IL-13 Dupilumab (an initial dose of 400 mg [two 200 mg injections] followed by 200 mg every other week or an initial dose of 600 mg [two 300 mg injections] followed by 300 mg every other week)	Other treatments not listed in inclusion criteria Treatments or doses not indicated/approved for the population of interest Non-pharmacological interventions
Outcomes	Efficacy, safety, and patient-reported outcomes including (but not limited to) one or more of the following: Exacerbation rate reduction Exacerbations leading to hospital/ER visits Reduction in OCS use Improvements in quality-of-life (e.g. generic measures such as EQ-5D and SF-36, and disease-specific measures such as AQLQ, SGRQ, cough assessments, and impact specific PROs) Response to treatment Discontinuation of treatment Reduction in biomarkers (e.g. blood eosinophils, IgE, FeNO)	None
Study design	RCTs reported in peer-reviewed publications, conference abstracts/posters, or gray literature Systematic reviews, meta-analyses, and network meta-analyses^c	Non-RCTs Single-arm studies Study protocols Opinion pieces, commentaries, letters, editorials, case reports Economic/cost-effectiveness evaluations Narrative reviews (i.e. non-systematic)
Location	Global	None
Language	English only^d	Non-English
Publication date	No restriction: from the inception of the databases to date of search; additionally, regular alerts will be established	None

^aThis criterion was relaxed after initial screening to permit inclusion of studies in which at least 75% of patients reported LABA use (plus at least medium-dose ICS), despite not requiring use of LABA or other controllers as part of their inclusion criteria; ^bLatest version of Japanese prescribing information (as for March 2020); ^cSystematic reviews, meta-analyses, network meta-analyses, and the bibliographies of these records were reviewed and cross-referenced with the included study lists to ensure that no primary studies were missed; ^dSearch captured all languages, but non-English citations were excluded during full-text screening.

Abbreviations: AQLQ, Asthma Quality-of-Life Questionnaire; EMA, European Medicines Agency; ER, emergency room; EQ-5D, EuroQol-5 Dimensions; FDA, Food and Drug Administration; FeNO, fractional exhaled nitric oxide; GINA, Global Initiative for Asthma; ICS, inhaled corticosteroid; IgE, immunoglobulin E; IL, interleukin; LABA, long-acting β-agonist; OCS, oral corticosteroid; PRO, patient-reported outcome; RCT, randomized controlled trial; SF-36, 36-Item Short-Form Health Survey; SGRQ, St George's Respiratory Questionnaire.

Figure 1. PRISMA flow diagram. NAVIGATOR⁶² and SOURCE⁶⁵ were additional trials to those identified through the systematic literature search. Abbreviations: CSR, clinical study report; HTA, Health Technology Assessment; MA, meta-analysis; NMA, network meta-analysis; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT, randomized controlled trial; SLR, systematic literature review.

Figure 2. Network diagram for primary NMAs of AAER overall and AAER leading to hospitalization/emergency room visit. ^aThese studies were excluded from the sensitivity analysis that restricted inclusion to blinded and placebo-controlled trials. ^bThese studies were excluded from the sensitivity analysis that restricted inclusion to phase 3 and 4 studies. In this sensitivity analysis, studies were excluded if they were not phase 3 or 4 studies, or if their source article did not report the study phase. Castro et al.⁸ reported data for two different studies (NCT01287039 and NCT01285323), so contributes two treatment arms. LIBERTY ASTHMA QUEST reported data for two different treatment arms, based on dupilumab dose. Abbreviations: AAER, annualized asthma exacerbation rate; NMA, network meta-analysis.

Table 2. Primary NMA: rate ratios for AAER overall, reported as cross-tabulation of all treatment arms in the network.

Treatment arm	Rate ratio (95% CrI)^a: row vs column
	Tezepelumab	Dupilumab 200 mg	Dupilumab 300 mg	Benralizumab	Mepolizumab	Reslizumab	Omalizumab	Placebo
Tezepelumab	–	0.84 (0.45–1.56)	0.84 (0.45–1.56)	0.63 (0.35–1.09)	0.82 (0.43–1.50)	0.82 (0.43–1.49)	0.60 (0.35–1.01)	0.37 (0.23–0.57)*
Dupilumab 200 mg	1.19 (0.64–2.22)	–	1.00 (0.58–1.71)	0.75 (0.43–1.28)	0.98 (0.52–1.77)	0.97 (0.52–1.75)	0.71 (0.42–1.18)	0.44 (0.28–0.67)*
Dupilumab 300 mg	1.19 (0.64–2.22)	1.00 (0.58–1.72)	–	0.75 (0.43–1.28)	0.98 (0.53–1.78)	0.97 (0.52–1.76)	0.72 (0.42–1.18)	0.44 (0.28–0.67)*
Benralizumab	1.59 (0.92–2.86)	1.33 (0.78–2.33)	1.33 (0.78–2.33)	–	1.32 (0.76–2.27)	1.30 (0.76–2.22)	0.96 (0.61–1.48)	0.59 (0.42–0.82)*
Mepolizumab	1.22 (0.67–2.33)	1.02 (0.56–1.92)	1.02 (0.56–1.89)	0.76 (0.44–1.32)	–	0.99 (0.54–1.81)	0.73 (0.43–1.21)	0.45 (0.29–0.69)*
Reslizumab	1.22 (0.67–2.33)	1.03 (0.57–1.92)	1.03 (0.57–1.92)	0.77 (0.45–1.32)	1.01 (0.55–1.85)	–	0.74 (0.44–1.22)	0.45 (0.30–0.69)*
Omalizumab	1.67 (0.99–2.86)	1.41 (0.85–2.38)	1.39 (0.85–2.38)	1.04 (0.68–1.64)	1.37 (0.83–2.33)	1.35 (0.82–2.27)	–	0.61 (0.46–0.82)*
Placebo	2.70 (1.75–4.35)*	2.27 (1.49–3.57)*	2.27 (1.49–3.57)*	1.69 (1.22–2.38)*	2.22 (1.45–3.45)*	2.22 (1.45–3.33)*	1.64 (1.22–2.17)*	–

Treatments are listed in descending order of the date of US FDA approval.

^aRate ratio estimates are derived from a random-effects model. *Statistical significance at 5% level.

Abbreviations: AAER, annualized asthma exacerbation rate; CrI, credible interval; FDA, Food and Drug Administration; NMA, network meta-analysis.

Table 3. Primary NMA: rate ratios for AAER leading to hospitalization/emergency room visit, reported as cross-tabulation of all treatment arms in the network.

Treatment arm	Rate ratio (95% CrI)^a: row vs column
	Tezepelumab	Dupilumab 200/300 mg	Benralizumab	Mepolizumab	Reslizumab	Omalizumab	Placebo
Tezepelumab	–	0.36 (0.07–1.59)	0.35 (0.08–1.16)	0.54 (0.13–2.00)	0.29 (0.07–1.08)	0.40 (0.10–1.55)	0.19 (0.07–0.47)*
Dupilumab 200/300 mg	2.78 (0.63–14.29)	–	1.00 (0.19–4.40)	1.52 (0.33–7.69)	0.83 (0.18–4.12)	1.15 (0.25–5.88)	0.54 (0.16–1.92)
Benralizumab	2.86 (0.86–12.50)	1.00 (0.23–5.26)	–	1.54 (0.45–6.67)	0.84 (0.24–3.56)	1.15 (0.35–5.00)	0.54 (0.23–1.53)
Mepolizumab	1.85 (0.50–7.69)	0.66 (0.13–3.04)	0.65 (0.15–2.22)	–	0.55 (0.14–2.05)	0.75 (0.20–2.91)	0.35 (0.13–0.89)*
Reslizumab	3.45 (0.93–14.29)	1.20 (0.24–5.56)	1.19 (0.28–4.17)	1.82 (0.49–7.14)	–	1.37 (0.37–5.56)	0.65 (0.25–1.63)
Omalizumab	2.50 (0.65–10.00)	0.87 (0.17–3.96)	0.87 (0.20–2.89)	1.33 (0.34–5.00)	0.73 (0.18–2.68)	–	0.47 (0.17–1.15)
Placebo	5.26 (2.13–14.29)*	1.85 (0.52–6.25)	1.85 (0.65–4.35)	2.86 (1.12–7.69)*	1.54 (0.61–4.00)	2.13 (0.87–5.88)	–

Treatments are listed in descending order of the date of US FDA approval.

^aRate ratio estimates are derived from a random-effects model. *Statistical significance at 5% level.

Abbreviations: AAER, annualized asthma exacerbation rate; CrI, credible interval; FDA, Food and Drug Administration; NMA, network meta-analysis.

Table 4. Subgroup NMA for patients with eosinophil count ≥ 300 cells/µL: rate ratios for AAER overall, reported as cross-tabulation of all treatment arms in the network.

Treatment arm	Rate ratio (95% CrI)^a: row vs column
	Tezepelumab	Dupilumab 200 mg	Dupilumab 300 mg	Benralizumab	Mepolizumab	Reslizumab	Omalizumab	Placebo
Tezepelumab	–	0.95 (0.47–1.92)	1.08 (0.54–2.27)	0.60 (0.34–1.13)	0.89 (0.42–1.95)	0.70 (0.37–1.37)	0.60 (0.29–1.30)	0.32 (0.20–0.53)*
Dupilumab 200 mg	1.05 (0.52–2.13)	–	1.12 (0.59–2.27)	0.64 (0.35–1.19)	0.94 (0.43–2.09)	0.74 (0.38–1.46)	0.64 (0.30–1.37)	0.34 (0.20–0.56)*
Dupilumab 300 mg	0.93 (0.44–1.86)	0.89 (0.44–1.70)	–	0.57 (0.30–1.04)	0.84 (0.37–1.77)	0.66 (0.32–1.27)	0.56 (0.26–1.19)	0.30 (0.17–0.50)*
Benralizumab	1.67 (0.88–2.94)	1.56 (0.84–2.86)	1.75 (0.96–3.33)	–	1.47 (0.73–2.94)	1.16 (0.66–2.04)	0.99 (0.52–1.92)	0.53 (0.37–0.75)*
Mepolizumab	1.12 (0.51–2.38)	1.06 (0.48–2.33)	1.19 (0.56–2.70)	0.68 (0.34–1.37)	–	0.79 (0.38–1.63)	0.68 (0.31–1.55)	0.36 (0.20–0.65)*
Reslizumab	1.43 (0.73–2.70)	1.35 (0.68–2.63)	1.52 (0.79–3.13)	0.86 (0.49–1.51)	1.27 (0.61–2.63)	–	0.86 (0.43–1.75)	0.46 (0.30–0.70)*
Omalizumab	1.67 (0.77–3.45)	1.56 (0.73–3.33)	1.79 (0.84–3.85)	1.01 (0.52–1.91)	1.47 (0.65–3.23)	1.16 (0.57–2.33)	–	0.53 (0.30–0.93)*
Placebo	3.13 (1.89–5.00)*	2.94 (1.79–5.00)*	3.33 (2.00–5.88)*	1.89 (1.33–2.70)*	2.78 (1.54–5.00)*	2.17 (1.43–3.33)*	1.89 (1.08–3.33)*	–

Treatments are listed in descending order of the date of US FDA approval.

^aRate ratio estimates are derived from a random-effects model. *Statistical significance at 5% level.

Abbreviations: AAER, annualized asthma exacerbation rate; CrI, credible interval; FDA, Food and Drug Administration; NMA, network meta-analysis.

Table 5. Subgroup NMA for patients with eosinophil count <300 cells/µL: rate ratios for AAER overall, reported as cross-tabulation of all treatment arms in the network.

Treatment arm	Rate ratio (95% CrI)^a: row vs column
	Tezepelumab	Dupilumab 200 mg	Dupilumab 300 mg	Benralizumab	Placebo
Tezepelumab	–	0.69 (0.12–3.32)	0.61 (0.10–2.83)	0.59 (0.10–2.62)	0.41 (0.11–1.18)
Dupilumab 200 mg	1.45 (0.30–8.33)	–	0.89 (0.22–3.54)	0.86 (0.15–4.25)	0.61 (0.18–1.84)
Dupilumab 300 mg	1.64 (0.35–10.00)	1.12 (0.28–4.55)	–	0.97 (0.18–4.92)	0.68 (0.20–2.12)
Benralizumab	1.69 (0.38–10.00)	1.16 (0.24–6.67)	1.03 (0.20–5.56)	–	0.71 (0.22–2.27)
Placebo	2.44 (0.85–9.09)	1.64 (0.54–5.56)	1.47 (0.47–5.00)	1.41 (0.44–4.55)	–

Treatments are listed in descending order of the date of US FDA approval.

^aRate ratio estimates are derived from a random-effects model. *Statistical significance at 5% level.

Abbreviations: AAER, annualized asthma exacerbation rate; CrI, credible interval; FDA, Food and Drug Administration; NMA, network meta-analysis.

Figure 3. Anchor and comparator trials used for the STC. Treatment effect of tezepelumab was simulated in the study population of each of the comparator trials. ^aCALIMA and SIROCCO were both suitable as comparator studies and had the same inclusion criteria; thus, these studies were pooled. ^bHanania et al.⁵⁵ was used for AAER overall because this study did not report results for AAER leading to hospitalization/emergency room visit. EXALT was used for AAER leading to hospitalization/emergency room visit. Abbreviations: AAER, annualized asthma exacerbation rate; STC, simulated treatment comparison.

Figure 4. Findings from the STC, rate ratios for AAER, tezepelumab versus comparators. RR reflects the effect of tezepelumab in the comparator study population. Treatment effect modifiers included in the models of each comparator and outcome can be found in Supplementary Table S20. Abbreviations: AAER, annualized asthma exacerbation rate; CI, confidence interval; N/A, not applicable; RR, rate ratio; STC, simulated treatment comparison.

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