Type 2 asthma in children managed by dupilumab, despite atopic comorbidities

A post-hoc analysis of the phase 3 Liberty Asthma VOYAGE trial reported that dupilumab reduced severe asthma exacerbation rates and also improved overall lung function in children with moderate-to-severe asthma, independent of the presence of atopic comorbidities, including chronic rhinosinusitis, nasal polyps, or eosinophilic oesophagitis. A second presentation identified FeNO as a prognostic factor in the Liberty Asthma QUEST trial.

The Liberty Asthma VOYAGE trial (NCT02948959) evaluated the efficacy of dupilumab, a monoclonal antibody that blocks 2 primary drivers of type 2 inflammation (IL-4 and IL-13), every 2 weeks compared with placebo in children aged 6 to 11 years with uncontrolled, persistent asthma, and reported positive effects on severe asthma exacerbations in December 2021 [1]. A new post-hoc analysis of the Liberty Asthma VOYAGE trial took a look at the effect of dupilumab on comorbid atopic disorders and type 2 inflammation in that cohort [2].

For the current post-hoc analysis, presented by Prof. Theresa Guilbert (University of Cincinnati, OH, USA), 408 participants treated with dupilumab 100/200 mg or placebo were stratified by their burden of comorbid disease, into groups without any comorbid disease (dupilumab n=33; placebo n=28), with 1 comorbid phenotype (dupilumab n=91; placebo n=41), or with >1 ongoing comorbid disease (dupilumab n=149; placebo n=66). Participants were evaluated for a 52-week treatment period. Comorbid diseases were self-reported at baseline and included atopic dermatitis, allergic conjunctivitis, allergic rhinitis, chronic rhinosinusitis (i.e. chronic rhinitis or chronic sinusitis), nasal polyposis, eosinophilic oesophagitis, food allergy, and hives. Participants were assessed via the annualised rate of severe asthma exacerbations and lung function, measured by change from baseline in percentage predicted prebronchodilator forced expiratory volume in 1 second (FEV₁pp).

The results indicated that severe asthma exacerbations were reduced among participants treated with dupilumab compared with those treated with placebo, irrespective of whether they presented with no comorbid disease (relative risk [RR] 0.284; 95% CI 0.072–1.117; D-71.6%; P=0.07), 1 ongoing comorbid disease (RR 0.980; 95% CI 0.438–2.194; D-2%; P=0.96), or >1 comorbid disease (RR 0.315; 95% CI 0.207–0.479; D -68.5%; P<0.0001). At 12 weeks, lung function improved most in patients with >1 atopic comorbidity treated with dupilumab; pre-bronchodilator FEV₁pp after 12 weeks was significantly improved by dupilumab treatment (1 comorbid disease: least square mean difference [LSMD] 5.37; 95% CI -0.18 to 10.93; P=0.058; >1 comorbid disease: LSMD 5.34; 95% CI 1.58–9.11; P=0.006), although no difference were observed in changes from baseline in pre-bronchodilator FEV₁pp among patients with no atopic comorbidities (LSMD -0.96; 95% CI -9.04 to 7.11; P=0.812). However, even for patients without any comorbid type 2 phenotype, after 52 weeks, dupilumab was associated with improvement in the change from baseline in pre-bronchodilator FEV₁pp for all patients compared with placebo: no comorbidities (LSMD 7.86; 95% CI 0.21–15.51; P=0.044), 1 comorbid disease (LSMD 5.87; 95% CI -0.64 to 12.38; P=0.077), and >1 comorbid disease (LSMD 7.26; 95% CI 3.17–11.36; P<0.001).

Prof. Guilbert concluded that dupilumab reduced severe exacerbation rates and by the end of treatment, had improved the percentage predicted pre-bronchodilator FEV₁ in children aged 6 to 11 years with uncontrolled, moderate-to-severe asthma, in patients with or without atopic comorbidities.

In a related talk, Prof. Ian Pavord (University of Oxford, UK) and colleagues used data from the Liberty Asthma QUEST study (NCT02414854) in order to identify biomarkers that may predict risk of lung function decline and response to dupilumab [3]. Multivariate regression analysis identified covariates that predicted lung function decline in placebo and dupilumab arms, with patients stratified by baseline exhaled nitric oxide (FeNO) levels and blood eosinophil levels.

Lung function decline at 52 weeks was similar between dupilumab and placebo across blood eosinophil levels; however, lung function decline difference increased in populations with higher baseline FeNO (see Figure).

Figure: Rate of lung function decline consistently increased in patients with higher baseline FeNO levels [3]



Because dupilumab attenuated lung function decline in patients with moderate-to-severe asthma, and patients with higher baseline FeNO levels demonstrated greater loss of lung function in placebo patients, Prof. Pavord pointed to a potential prognostic role of FeNO in identifying patients at risk of lung function decline. Furthermore, greater attenuation of loss of lung function after 1 year of dupilumab treatment indicated the potential predictive role of FeNO for dupilumab response. However, future, prospective studies are needed to validate FeNO as a biomarker.

1. Bacharier LB, et al. N Engl J Med 2021;385(24):2230–2240.
2. Guilbert TW, et al. Efficacy of dupilumab in pediatric patients with uncontrolled, moderate-to-severe asthma with and without ongoing atopic comorbid disease: LIBERTY ASTHMA VOYAGE Study. Session A2, ATS International Conference 2022, San Francisco, CA, USA, 13–18 May.
3. Pavord I, et al. FeNO as a potential prognostic and predictive marker of lung function decline in patients with uncontrolled, moderate-to-severe asthma: LIBERTY ASTHMA QUEST. Session B93, ATS International Conference 2022, San Francisco, CA, USA, 13–18 May.

 

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Posted on 18 July 2022