Type 2 inflammation biomarkers and their association with response to dupilumab in COPD (BOREAS): an analysis of a randomised, placebo-controlled, phase 3 trial

Abstract

Background: A raised blood eosinophil count (≥300 cells per μL), a marker of type 2 inflammation, can identify patients with chronic obstructive pulmonary disease (COPD) with higher exacerbation risk. Dupilumab reduced exacerbations in patients with COPD and type 2 inflammation in the BOREAS trial. In this post-hoc analysis, we evaluated the predictive value and longitudinal changes in type 2 inflammatory biomarkers in patients with COPD and type 2 inflammation from the BOREAS trial who received dupilumab treatment.

Methods: BOREAS, a phase 3, multicentre, double-blind, randomised trial was conducted at 275 sites in 24 countries and included patients with COPD and type 2 inflammation (screening blood eosinophils ≥300 cells per μL). Patients were randomly assigned (1:1) to receive 300 mg of dupilumab every 2 weeks for 52 weeks or matching placebo. Randomisation was stratified by country and inhaled corticosteroid dose at baseline. This post-hoc analysis assessed blood eosinophil counts, fractional exhaled nitric oxide (FeNO), serum eotaxin-3, total plasma immunoglobulin E (IgE), and serum pulmonary and activation-regulated chemokine (PARC) concentrations in the safety population. The study was registered at ClinicalTrials.gov, NCT03930732 and is complete.

Findings: BOREAS was conducted between April 15, 2019, and May 2, 2023, and included 939 patients with COPD and type 2 inflammation. 468 patients were randomly assigned to receive 300 mg of dupilumab every 2 weeks for 52 weeks and 471 were randomly assigned to receive matching placebo. 319 (34%) participants were female and 620 (66%) were male. 657 (70%) were former smokers and 282 (30%) were current smokers. At week 52, greater median percentage reductions were observed in dupilumab versus placebo for most biomarkers (total IgE: -22·5% [IQR -30·4 to -16·5] vs -0·9% [-6·5 to 4·8]; FeNO: -28·6% [-57·1 to 0] vs -6·9% [-35·7 to 25·0]; eotaxin-3: -8·8% [-15·6 to -2·9] vs -0·4% [-5·6 to 5·0]; and PARC: -14·4% [-29·2 to 2·1] vs -0·8% [-13·9 to 17·2]). Reductions were similar across treatment groups by blood eosinophil counts. Exacerbation risk overall was reduced, with a greater magnitude of reduction in those with higher baseline blood eosinophil count (p=0·0056) and baseline FeNO (p=0·043).

Interpretation: Patients with COPD and type 2 inflammation who were given dupilumab showed reduced type 2 inflammatory biomarkers, with elevated blood eosinophil count and FeNO predicting greater treatment response. These findings support biomarker-driven treatment strategies to optimise therapy.

Funding: Sanofi and Regeneron Pharmaceuticals.