Head-To-Head Comparison of Biologic Efficacy in Asthma: What Have We Learned?

Abstract

We performed an in-depth appraisal of indirect head-to-head comparisons of biologics approved for asthma, including anti-IL5/5Rα (mepolizumab, benralizumab), anti-IL4Rα (dupilumab), anti-TSLP (tezepelumab) and anti-IgE (omalizumab), which was neither a systematic review nor a meta-analysis. A crude evaluation of 95% CI's for rate ratios which excluded unity revealed greater overall reductions in annualised exacerbations with dupilumab versus either mepolizumab or benralizumab and also with tezepelumab versus benralizumab. Furthermore in patients with eosinophils ≥ 300/μL exacerbation rates were lower for tezepelumab, dupilumab and mepolizumab versus benralizumab; and with eosinophils< 150/μL for tezepelumab versus dupilumab. For lung function, no overall differences in FEV1 response were observed between drugs where there was considerable heterogeneity of overlapping 95% CI's. Dupilumab was superior to benralizumab for oscillometry-derived peripheral lung resistance and compliance, as well as for attenuation of mannitol airway hyperresponsiveness. There were no differences in asthma control or quality of life scores where the effect sizes were small, along with wide overlaps in 95% CI's. There is an unmet need for prospective pragmatic randomised controlled trials to directly compare biologics, especially to assess clinical remission in both type 2 high and low asthma patients. Real-life studies might also evaluate complete remission with different biologics to include outcomes such as inhaled corticosteroid sparing, small airways dysfunction using oscillometry, abolition of airway hyperresponsiveness and to assess mucus plugging and remodelling as wall thickening with imaging.

Keywords: benralizumab; dupilumab; mepolizumab; omalizumab; tezepelumab.

FIGURE 1

Schematic diagram simplified to depict the type 2 immunology pathway in asthma. The upstream epithelial cytokine tap drips TSLP and IL33, which activate downstream T2 cytokines to fill the mucosal airway bucket with escape of IL4/5/13. The epithelial cytokines may have pathological effects in their own right aside from promoting activation of downstream T2 cytokines. IgE release may be mediated via both IL4 and IL13. The T2 cascade may be blocked either upstream by (a) anti‐TSLP as tezepelumab, (b) anti‐IL33 as itepekimab; or downstream by (c) anti‐IL5/IL5Rα, as mepolizumab or benralizumab, (d) anti‐IL4Rα as dupilumab, (e) anti‐IgE as omalizumab. Eos, eosinophils; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IL, interleukin 4/5/13/33; T2, type 2 inflammation; TSLP, thymic stromal lymphopoietin.

FIGURE 2

Schematic diagram to illustrate the interplay of various factors which may determine the efficacy of biologics in refractory severe asthma. AHR, airway hyperresponsiveness; T2, type 2 inflammation.

FIGURE 3

Forest plot showing pairwise indirect comparisons of biologics in uncontrolled asthma for reductions in overall annualised exacerbation rates (AER) shown as rate ratios (RR) and 95% confidence intervals (CI). For crude pairwise comparisons of drug A versus drug B, red circles for the RR denote a significant difference in favour of drug A where the 95% CI excludes unity. Black circles for the RR denote no significant difference between biologics where the 95% CI includes unity [43, 45, 46, 47, 48, 49, 50, 51, 52, 54, 55, 56]. Benra, benralizumab; Dupi, dupilumab; Mepo, mepolizumab; Omal; omalizumab; Teze, tezepelumab.

FIGURE 4

Forest plot showing pairwise indirect comparisons of biologics in uncontrolled asthma for reductions in annualised exacerbation rates (AER) for the subgroup of patients with baseline eosinophils (Eos) ≥ 300/μL, as rate ratios (RR) and 95% confidence intervals (CI). For crude pairwise comparisons of drug A versus drug B, red circles for the RR denote a significant difference in favour of drug A where the 95% CI excludes unity. Black circles for the RR denote no significant difference between biologics where the 95% CI includes unity [45, 46, 52, 54, 55]. Benra, benralizumab; Dupi, dupilumab; Mepo, mepolizumab; Omal, omalizumab, Teze, tezepelumab.

FIGURE 5

Forest plot showing pairwise indirect comparisons of biologics in uncontrolled asthma for reductions in use of systemic corticosteroid (SCS), as rate ratios (RR) and 95% confidence intervals (CI). For crude pairwise comparisons of drug A versus drug B, red circles for the RR indicate a significant difference in favour of drug A where the 95% CI excludes unity [48, 49]. Benra, benralizumab; Dupi, dupilumab; Mepo, mepolizumab; Omal, omalizumab.

FIGURE 6

Forest plot showing pairwise indirect comparisons of biologics in uncontrolled asthma for reductions in asthma control questionnaire (ACQ) score as mean difference and 95% confidence intervals (CI). For pairwise comparisons of drug A versus drug B, a negative value for the difference indicates a greater improvement for drug A versus drug B. Black circles for RR denote no significant difference between biologics where the 95% CI includes zero. The minimal importance difference is +/−0.5 [52, 53, 54, 56]. Benra, benralizumab; Dupi, dupilumab; Mepo, mepolizumab; Omal, omalizumab; Teze, tezepelumab.

FIGURE 7

Forest plot showing pairwise indirect comparisons of biologics in uncontrolled asthma for reductions in asthma quality of life questionnaire (AQLQ) score as mean difference and 95% confidence intervals (CI). For pairwise comparisons of drug A versus drug B, a positive value for the difference indicates greater improvement for drug A versus drug B. Black circles for RR denote no significant difference between biologics where the 95% CI includes zero. The minimal importance difference is +/−0.5 [45, 46, 54]. Benra, benralizumab; Dupi: Dupilumab, Mepo, mepolizumab; Omal, omalizumab; Teze, tezepelumab.

FIGURE 8

Forest plot showing pairwise indirect comparisons of biologics in uncontrolled asthma for overall improvements in FEV1 as mean difference and 95% confidence intervals (CI). For crude pairwise comparisons of drug A versus drug B, red circles denote a significant difference in favour of drug A where the 95% CI excludes zero, and black circles denote no significant difference between biologics where the 95% CI includes zero. The minimal importance difference for FEV1 is +/−150 mL [43, 45, 46, 47, 50, 52, 53, 54, 56]. Benra, benralizumab; Dupi, dupilumab; Mepo, mepolizumab; Omal, omalizumab; Teze, tezepelumab.

FIGURE 9

Forest plot showing pairwise indirect comparisons of biologics in uncontrolled asthma for improvements in FEV1 for the subgroup of patients with baseline eosinophils (Eos) ≥ 300/μL as mean difference and 95% confidence intervals (CI). For pairwise comparisons of drug A versus drug B, red circles denote a significant difference in favour of drug A where the 95% CI excludes zero, and black circles denote no significant difference between biologics where the 95% CI includes zero. The minimal importance difference for FEV1 is +/−150 mL [45, 46, 52, 54]. Benra, benralizumab; Dupi; dupilumab; Mepo, mepolizumab; Teze, tezepelumab.

FIGURE 10

(a, b). Forest plot showing pairwise indirect comparisons of biologics in uncontrolled asthma for (a) improvements in AX and R5–R20 as mean % difference and 95% confidence intervals (CI) and (b) improvements in airway hyperresponsiveness as mannitol PD10 or RDR as mean doubling difference and 95% CI. For pairwise comparisons of drug A versus drug B, red circles denote a significant difference in favour of drug A where the 95% CI excludes zero [72, 73]. AX, Area under reactance curve; PD10, Challenge sensitivity as provocative dose of mannitol required to induce a 10% fall in FEV1; R5–R20, Resistance heterogeneity between 5 Hz and 20 Hz; RDR, Challenge reactivity as response dose ratio  for maximal % fall in FEV1 divided by the final cumulative mannitol dose.