Dupilumab Improves Lung Function/Asthma Control in Allergic/Non-Allergic Asthma

Dupilumab reduced annualized severe exacerbation rates (AER) and improved lung function, asthma control, and health-related quality of life (HRQoL) in patients with and without allergic asthma, according to study findings published in The Journal of Allergy and Clinical Immunology: In Practice.

Investigators conducted a post hoc analysis of 2 clinical trials of dupilumab for uncontrolled, moderate to severe or severe oral-corticosteroid dependent asthma. In the current post hoc analysis, patients were stratified by allergic asthma status to determine whether the efficacy and outcomes achieved by dupilumab use were affected by allergic asthma status.

The 2 placebo-controlled clinical trials on which the post hoc analysis was based were: (1) a phase 2b trial (P2B; ClinicalTrials.gov Identifier: NCT01854047) of adults with uncontrolled moderate-to-severe asthma treated with medium-to-high dose inhaled corticosteroids; and (2) the phase 3 VENTURE trial (ClinicalTrials.gov Identifier: NCT02528214), a study of adults and adolescents with OCS-dependent severe asthma. Notably, investigators for the post hoc analysis specifically aimed to confirm outcomes of the previously conducted QUEST trial, which assessed the efficacy of dupilumab for adults and adolescents with persistent asthma (ClinicalTrials.gov Identifier: NCT02414854)

In the post hoc analysis, which stratified patients by their allergic asthma status, allergic asthma was defined as total serum immunolglobulin E (IgE) of at least 30 IU/mL and at least 1 perennial aeroallergen-specific IgE of at least 0.35kU/L at baseline. For patients with and without allergic asthma, the researchers assessed annualized severe exacerbation rates as well as participants’ change from baseline in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV₁), FEV₁/forced vital capacity (FVC) ratio, 5-item Asthma Control Questionnaire (ACQ-5) score, Asthma Quality of Life Questionnaire (AQLQ) global score, and levels of type 2 biomarkers. These biomarkers included total IgE, fractional inhaled nitric oxide (FeNO), and serum thymus and activation-regulated chemokine (TARC). Reduction in OCS levels was also analyzed in VENTURE trial participants.

Specific IgE levels over the 24-week treatment periods were also assessed for the following perennial allergens that had been included in both studies: Cladosporium herbarum/hormodendrum, Alternaria tenuis/alternata, cat and dog dander, Aspergillus fumigatus, Dermatophagoides farinae, Dermatophagoides pteronyssinus, oriental cockroach, and, for P2B only, German cockroach.

The post hoc analysis included 271 patients from the P2B trial with evidence of allergic asthma (dupilumab n=176; placebo n=95) and 194 patients without evidence of allergic asthma (dupilumab n=131; placebo n=63). Also included were 86 patients from the VENTURE trial with evidence of allergic asthma (dupilumab n=46; placebo n=40) and 124 patients without evidence of allergic asthma (dupilumab n=57; placebo n=67). The investigators noted that patients with allergic asthma had earlier age of asthma onset and tended to be younger than patients without evidence of allergic asthma. Atopic medical condition rates were higher in patients with allergic asthma.

In comparing patients without evidence of allergic asthma receiving placebo vs dupilumab in P2B, 48 vs 96, respectively, had baseline total IgE at least 30 IU/mL but no positive perennial allergen; 6 vs 8, respectively, had total IgE less than 30 IU/mL but at least 1 positive perennial allergen; and 9 vs 27, respectively, had total IgE less than 30 IU/mL and no positive perennial allergens.

In comparing patients without evidence of allergic asthma receiving placebo vs dupilumab in VENTURE, the investigators found that 48 vs 47, respectively, had baseline total IgE at least 30 IU/mL but no positive perennial allergen; 2 vs 0, respectively, had total IgE less than 30 IU/mL but at least 1 positive perennial allergen; and 17 vs 10, respectively, had total IgE less than 30 IU/mL and no positive perennial allergens.

Significant reductions in AERs were seen in both trials in patients with allergic asthma using dupilumab every 2 weeks (P2B: pooled 200/300 mg; VENTURE: 300 mg) vs placebo. In P2B, AERs were reduced by 60%; (risk ratio [RR], 0.38; 95% CI, 0.21-0.77; P =.0063) and in VENTURE, AERs were reduced by 72%; (RR, 0.28; 95% CI, 0.13-0.58; P =.0008). Reductions in AERs in patients without evidence of allergic asthma were 86% for P2B (RR, 0.14; 95% CI, 0.06-0.34; P <.0001) and 45% for VENTURE (RR, 0.55; 95% CI, 0.31-0.96; P =.0358).

With respect to lung function measures, patients in P2B with allergic asthma showed significantly greater early and sustained improvements in pre-BD FEV₁ (P <.01) and FEV₁/FVC (P <.05). In the VENTURE trial, participants with allergic asthma also showed improvements in these lung function measures after dupilumab treatment, but the improvements were not significant.

With respect to asthma control and HRQol, patients from both trials with allergic asthma taking dupilumab had significantly greater improvements in asthma control scores and AQLQ global scores from baseline than patients with allergic asthma in the placebo group. Improvements in these scores that were numerically greater were also seen in patients without evidence of allergic asthma from both trials.

With respect to biomarkers, investigators found dupilumab was associated with early and sustained significantly reduced total IgE levels from baseline compared with placebo in both trials, in patients with and without allergic asthma. Likewise, in patients with or without allergic asthma in both trials, significantly greater improvements in

FeNO levels were associated with dupilumab vs placebo.

OCS use was also reduced in patients with and without evidence of allergic asthma in those using dupilumab vs placebo. Notably, this analysis only involved participants in the VENTURE trial.

Post-hoc study limitations include the nature of a post hoc design, trials not designed for assessment of the subgroups analyzed, and misclassification of patients into subgroups without evidence of allergic asthma.

“Dupilumab significantly reduced AER and improved lung function and asthma control and HRQoL in patients with or without evidence of allergic asthma,” investigators concluded. “[D]upilumab suppressed both total IgE and allergen-specific IgE in patients with allergic asthma, and also reduced IgE in patients not meeting allergic asthma criteria,” the investigators added. “The observed efficacy [of dupilumab] in patients both with and without allergic asthma indicates that baseline IgE level is not a relevant biomarker when considering the suitability of dupilumab for individual patients, with key biomarkers being blood eosinophil counts and FeNO,” said study authors.

Disclosure: This research was supported by Sanofi and Regeneron Pharmaceuticals, Inc.

Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.