Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases

Jennifer D Hamilton, Sivan Harel, Brian N Swanson, William Brian, Zhen Chen, Megan S Rice, Nikhil Amin, Marius Ardeleanu, Allen Radin, Brad Shumel, Marcella Ruddy, Naimish Patel, Gianluca Pirozzi, Leda Mannent, Neil M H Graham, Jennifer D Hamilton, Sivan Harel, Brian N Swanson, William Brian, Zhen Chen, Megan S Rice, Nikhil Amin, Marius Ardeleanu, Allen Radin, Brad Shumel, Marcella Ruddy, Naimish Patel, Gianluca Pirozzi, Leda Mannent, Neil M H Graham

Abstract

Background: Type 2 inflammation is common in numerous atopic/allergic diseases and can be identified by elevated biomarker levels. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation.

Objective: Assessment of dupilumab effect on type 2 inflammatory biomarkers in atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic esophagitis (EoE).

Methods: Data were extracted from three randomized placebo-controlled trials of dupilumab in AD (NCT02277743, N = 671; NCT02277769, N = 708; NCT02260986, N = 740); and one each in asthma (NCT02414854, N = 1902); CRSwNP (NCT02898454, N = 448); and EoE (NCT02379052, N = 47). Biomarkers assessed were serum thymus and activation-regulated chemokine (TARC), plasma eotaxin-3, serum total immunoglobulin E (IgE), serum periostin and blood eosinophil count.

Results: Dupilumab versus placebo significantly suppressed most type 2 inflammatory biomarker levels across all studies/indications where data were assessed. Reductions in serum TARC, plasma eotaxin-3 and serum periostin occurred rapidly, whereas reductions in serum total IgE were more gradual. Across diseases, at the end of treatment, median percentage change from baseline in TARC levels ranged from -24.8% to -88.6% (placebo +2.6% to -53.6%); -38.2% to -51.5% (placebo +8.3% to -0.16%) in eotaxin-3; -24.8% to -76.7% (placebo +8.3% to -4.4%) in total IgE; and -13.6% to -41.1% (placebo +10.1% to -6.94%) in periostin levels. Blood eosinophil responses to dupilumab varied by disease, with minimal changes in AD in the SOLO studies (median percentage change from baseline to end of treatment: 0% [95% CI: -15.8, 0]); transient increases followed by decreases to below-baseline levels in asthma (-14.6% [-20.0, -7.7]) and CRSwNP (-29.4% [-40.0, -16.3]); and significant decreases in EoE (-50.0% [-50.0, -33.3]).

Conclusion and clinical relevance: Dupilumab reduced levels of type 2 biomarkers across clinical studies in patients with AD, asthma, CRSwNP and EoE.

Keywords: asthma; atopic dermatitis; chronic rhinosinusitis with nasal polyposis; dupilumab; eosinophilic esophagitis.

Conflict of interest statement

JDH, SH, ZC, NA, MA, AR, BS and MR are employees and shareholders of Regeneron Pharmaceuticals, Inc. NMHG is a prior employee and shareholder of Regeneron Pharmaceuticals, Inc. WB, MSR, NP and LM are employees and may hold stock and/or stock options in Sanofi. BG and GP are prior employees and may hold stock and/or stock options in Sanofi.

© 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
The roles of biomarkers in type 2 inflammation. DC, dendritic cell; IL, interleukin; ECP, eosinophil cationic protein; iNOS, inducible nitric oxide synthase; PARC, pulmonary and activation‐regulated chemokine; TARC, thymus and activation‐regulated chemokine
FIGURE 2
FIGURE 2
The effect of dupilumab on concentrations of serum TARC (pg/mL). *p < .05; **p < .01, ***p < .001 vs matched placebo. p‐values represent differences between dupilumab and placebo in change from baseline (A and C) or percentage change from baseline (B and D) and were analysed using a rank ANCOVA model. CHRONOS, SOLO‐1 and SOLO‐2 included the corresponding baseline values as covariates and the treatment, geographic region, baseline Investigator Global Assessment (IGA) strata and study identifier as fixed factors. EoE PoC included the corresponding baseline values as covariates and the treatment, baseline Straumann Dysphagia Instrument (SDI) strata and study identifier as fixed factors. QUEST included the corresponding baseline value, age, sex, geographic region (pooled country), baseline eosinophil strata and baseline inhaled corticosteroid dose level as covariates. SINUS‐52 included the corresponding baseline value, age, geographic region, asthma/nonsteroidal anti‐inflammatory drugs–exacerbated respiratory disease (NSAID‐ERD) status and prior surgery history as covariates. AD, atopic dermatitis; ANCOVA, analysis of covariance; CI, confidence interval; CRSwNP, chronic rhinosinusitis with nasal polyps; EoE, eosinophilic esophagitis; PoC, proof of concept; qw, weekly; q2w, every 2 weeks; TARC, thymus and activation‐regulated chemokine
FIGURE 3
FIGURE 3
The effect of dupilumab on concentrations of plasma eotaxin‐3 (pg/mL). ***p < .001 vs matched placebo. p‐values represent differences between dupilumab and placebo in change from baseline (A) or percentage change from baseline (B) and were analysed using a rank ANCOVA model. QUEST included the corresponding baseline value, age, sex, geographic region (pooled country), baseline eosinophil strata and baseline inhaled corticosteroid dose level as covariates. SINUS‐52 included the corresponding baseline value, age, geographic region (pooled country), asthma/NSAID‐ERD status and prior surgery history as covariates. ANCOVA, analysis of covariance; CI, confidence interval; CRSwNP, chronic rhinosinusitis with nasal polyps; NSAID‐ERD, nonsteroidal anti‐inflammatory drugs–exacerbated respiratory disease; q2w, every 2 weeks
FIGURE 4
FIGURE 4
The effect of dupilumab on concentrations of serum total IgE (IU/mL). *p < .05; **p < .01, ***p < .001 vs matched placebo. P‐values represent differences between dupilumab and placebo in change from baseline (A and C) or percentage change from baseline (B and D) and were analysed using a rank ANCOVA model. CHRONOS, SOLO‐1 and SOLO‐2 included the corresponding baseline values as covariates and the treatment, geographic region, baseline IGA strata and study identifier as fixed factors. EoE PoC included the corresponding baseline values as covariates and the treatment, baseline SDI strata and study identifier as fixed factors. QUEST included the corresponding baseline value, age, sex, geographic region (pooled country), baseline eosinophil strata and baseline inhaled corticosteroid dose level as covariates. SINUS‐52 included the corresponding baseline value, age, geographic region (pooled country), asthma/NSAID‐ERD status and prior surgery history as covariates. AD, atopic dermatitis; CI, confidence interval; CRSwNP, chronic rhinosinusitis with nasal polyps; EoE, eosinophilic esophagitis; NSAID‐ERD, nonsteroidal anti‐inflammatory drugs–exacerbated respiratory disease; PoC, proof of concept; qw, weekly; q2w, every 2 weeks; SDI, Straumann Dysphagia Instrument
FIGURE 5
FIGURE 5
The effect of dupilumab on concentrations of serum periostin (ng/mL). *p < .05; **p < .01; ***p < .001 vs matched placebo. p‐values represent differences between dupilumab and placebo in change from baseline (A and C) or percentage change from baseline (B and D) and were analysed using a rank ANCOVA model. EoE PoC included the corresponding baseline values as covariates and the treatment, baseline SDI strata and study identifier as fixed factors. QUEST included the corresponding baseline value, age, sex, geographic region (pooled country), baseline eosinophil strata and baseline inhaled corticosteroid dose level as covariates. SINUS‐52 included the corresponding baseline value, age, geographic region (pooled country), asthma/NSAID‐ERD status and prior surgery history as covariates. ANCOVA, analysis of covariance; CI, confidence interval; CRSwNP, chronic rhinosinusitis with nasal polyps; EoE, eosinophilic esophagitis; NSAID‐ERD, nonsteroidal anti‐inflammatory drugs–exacerbated respiratory disease; PoC, proof of concept; qw, weekly; q2w, every 2 weeks; SDI, Straumann Dysphagia Instrument
FIGURE 6
FIGURE 6
The effect of dupilumab on concentrations of blood eosinophils (Giga/L). *p < .05; **p < .01; ***p < .001 vs matched placebo. p‐values represent differences between dupilumab and placebo in change from baseline (A and C) or percentage change from baseline (B and D) and were analysed using a rank ANCOVA model. CHRONOS, SOLO‐1 and SOLO‐2 included the corresponding baseline values as covariates and the treatment, geographic region, baseline IGA strata and study identifier as fixed factors. EoE PoC included the corresponding baseline values as covariates and the treatment, baseline SDI strata and study identifier as fixed factors. QUEST included the corresponding baseline value, age, sex, geographic region (pooled country), baseline eosinophil strata and baseline inhaled corticosteroid dose level as covariates. SINUS‐52 included the corresponding baseline value, age, geographic region (pooled country), asthma/NSAID‐ERD status and prior surgery history as covariates. AD, atopic dermatitis; ANCOVA, analysis of covariance; CI, confidence interval; CRSwNP, chronic rhinosinusitis with nasal polyps; EoE, eosinophilic esophagitis; NSAID‐ERD, nonsteroidal anti‐inflammatory drugs–exacerbated respiratory disease; PoC, proof of concept; qw, weekly; q2w, every 2 weeks; SDI, Straumann Dysphagia Instrument

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