Indirect case-matched comparison of anti-IL4Rα versus anti-IL5Rα on airway hyperresponsiveness

The efficacy of biologics on airway hyperresponsiveness (AHR) has been studied before, but evidence is lacking in regard to which biologic is most effective.¹

Therefore, we performed a post-hoc case-matched analysis of two prospective single-arm open-label phase IV clinical trials investigating benralizumab (EudraCT2019-003763-22) and dupilumab (EudraCT2021-005593-25) on mannitol induced AHR in patients with uncontrolled type 2 high severe asthma. Twelve out of 21 patients from each study (n = 24 total) were case matched according to baseline PD₁₀ for appropriate comparison.

Patients taking benralizumab received a higher daily dose of inhaled corticosteroids but exhibited similar asthma control and lung function (Table 1). Dupilumab conferred greater improvements than benralizumab for mannitol PD₁₀ as geometric mean fold change (95% CI) from baseline: Dupi 3.77(2.30,6.18) p < .001 versus Benra 1.81(1.09,3.01) p < .05, amounting to a between treatment doubling difference (95% CI) of 1.06(0.09,2.02) p < .05 (Figure 1A). There was also greater attenuation for mannitol response dose ratio (RDR) as geometric mean fold change: Dupi 6.11(2.98,12.50) p < .001 versus Benra 1.77(1.00,3.15) p = .05 amounting to a between-treatment doubling difference 1.78(0.54,3.03) p < .01. Between baseline and week 12, there were no changes in fixed-dose ICS/LABA for patients taking benralizumab. In the same timeframe, the mean daily dose of extra fine BDP/FF 100/6 μg Nexthaler was reduced by 1.2 actuations using the dose counter, equating to a mean 240 μg budesonide equivalent reduction.

After 12 weeks the absolute geometric mean PD₁₀ was higher with Dupi 542 mg (437,672) versus Benra 267 mg (158,449) amounting to a geometric mean fold (95%CI) difference 2.08(1.07,4.05) p < .05. Moreover, after 12 weeks there were proportionately more patients who exhibited AHR remission with Dupi versus Benra: n = 8/12(67%) versus n = 3/12(25%) p < .05 (Figure 1B).

This is the first indirect case-matched comparison of dupilumab versus benralizumab on mannitol AHR in uncontrolled type 2 high-severe asthma. There was greater AHR attenuation with dupilumab along with a higher likelihood for inducing AHR remission. Patients who achieved AHR remission, as PD₁₀ ≥ 635 mg at 12 weeks, were censored at the maximum administered mannitol dose of 635 mg thereby underestimating the true extent of AHR improvement. Indeed, this degree of underestimation would have been amplified in terms of the relative doubling difference between treatments since more patients (67% vs. 25%) achieved AHR remission with dupilumab. Previously, some investigators have censored at twice the maximum dose of mannitol (1270 mg) to account for such underestimation.² However, by the same token censoring at 1270 mg might lead to overestimation of AHR improvement in some individuals. Hence, we believe our calculation here is more statistically robust.

Whereas anti-IL5Rα improves AHR by airway eosinophilic depletion,³ anti-IL4Rα suppresses downstream inflammatory cytokines IL4 and IL13, the latter of which regulates bronchial smooth muscle contraction and mucus plugging. IL4 and IL13 induce AHR in isolated small airways,⁴ and are involved in activating mast cells, which are key effector cells in mediating AHR.¹

We believe a strength of our study is that both trials were performed in the same center by the same staff using the same methodology and study protocol. This possibly explains why we were able to ascertain differences in AHR between treatments with a relatively small sample size, although we appreciate that the latter is a potential limitation. Notably, cases selected from both studies were matched in terms of their baseline PD₁₀ to obviate any confounding bias with regards to room for potential improvement in AHR when comparing treatments. Whilst PD₁₅ is more commonly used in clinical practice, we opted for a lower threshold as this is safer to use in severe asthma, more sensitive for detecting AHR, and serves a more robust definition for AHR remission.⁵ Although the patients were matched by baseline PD₁₀, there were no differences between treatment groups in lung function or asthma control as ACQ score despite the difference in ICS dose.

In conclusion, this case-matched indirect comparison showed dupilumab to confer greater attenuation of AHR in patients with T2 inflammation than benralizumab in patients with eosinophilic-driven disease and was more likely to confer remission of AHR in patients with severe T2 high uncontrolled asthma. This was in the context of patients taking dupilumab managing to reduce their daily ICS/LABA dose. The impact on AHR is in line with an indirect case-matched comparison, which demonstrated the superiority of dupilumab versus benralizumab on peripheral airway resistance and compliance.⁶ Further direct prospective head-to-head evaluation is now indicated to confirm our observations.

R.C. and B.L. were responsible for idea conception. R.C., K.S., C.R.W.K. and B.L. were responsible for data collection, analysis and drafting all versions of the manuscript.

Unrestricted research grants from AstraZeneca (EudraCT 2019–003763-22) and Sanofi (EudraCT 2021-005593-25) to University of Dundee.

Dr Chan reports personal fees (talks) and support attending ERS from AstraZeneca, personal fees from Vitalograph, and personal fees (talks) from Thorasys. Ms Stewart reports no conflicts of interest. Dr Kuo reports personal fees from AstraZeneca, personal fees from Chiesi, and non-financial support from GSK outside the submitted work. Dr Lipworth reports non-financial support (equipment) from GSK; grants, personal fees (consulting, talks and advisory board), other support (attending ATS and ERS) and from AstraZeneca; personal fees (talks and consulting) from Sanofi/Regeneron, personal fees (consulting, talks and advisory board) from Circassia in relation to the submitted work; grants, personal fees (consulting, talks, advisory board), other support (attending ERS) from Teva, personal fees (talks and consulting), grants and other support (attending ERS and BTS) from Chiesi, personal fees (consulting and talks) from Lupin, personal fees (consulting) from Glenmark, personal fees (consulting, talks, advisory board), other support (attending BTS) from Boehringer Ingelheim, grants and personal fees (advisory board and talks) from Mylan outside of the submitted work; and the son of BJL is presently an employee of AstraZeneca. The son of BJL is an employee of AstraZeneca.

Informed consent was obtained from all participants of this study.