Impact of baseline patient characteristics on dupilumab efficacy in type 2 asthma

Severe asthma affects an estimated 5–10% of the total asthma patient population [1]. Various demographic factors, such as sex, age, obesity and age of onset, have been associated with asthma disease severity [2, 3], and the efficacy of asthma treatments has previously been found to vary depending on patient demographics [4, 5].

Short abstract

Dupilumab treatment versus placebo improved exacerbation rate and lung function outcomes in patients with uncontrolled moderate-to-severe asthma and high type 2 biomarkers at baseline, regardless of baseline characteristics in the phase 3 QUEST study https://bit.ly/3yR7MlD

To the Editor:

Severe asthma affects an estimated 5–10% of the total asthma patient population [1]. Various demographic factors, such as sex, age, obesity and age of onset, have been associated with asthma disease severity [2, 3], and the efficacy of asthma treatments has previously been found to vary depending on patient demographics [4, 5].

Approximately 50% of asthma patients are affected by type 2 inflammatory asthma, characterised by increased production of interleukin (IL)-4, IL-5 and IL-13 [6]. Dupilumab, a fully human VelocImmune-derived monoclonal antibody [7, 8], blocks the shared receptor component for IL-4 and IL-13, key and central drivers of type 2 inflammation in multiple diseases [9]. In the European Union, dupilumab is indicated as an add-on maintenance treatment in patients aged ≥12 years with severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised fractional exhaled nitric oxide (F_eNO) that is inadequately controlled with high-dose inhaled corticosteroids (ICS) plus another medicinal product for maintenance treatment [10–12]. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), add-on dupilumab 200 mg or 300 mg every 2 weeks, versus placebo, significantly reduced severe asthma exacerbations, improved pre-bronchodilator forced expiratory volume in 1 s (FEV₁), and was generally well tolerated in the overall population of patients with uncontrolled, moderate-to-severe asthma. Treatment effects were greater in patients with elevated type 2 biomarkers at baseline (blood eosinophils or F_eNO) [11].

In this non-prespecified post hoc analysis of the phase 3 QUEST study, we assessed efficacy of dupilumab in the population of patients with elevated baseline type 2 biomarker levels (blood eosinophils ≥150 cells·µL⁻¹ and/or F_eNO ≥20 ppb), and stratified them into subgroups by demographic and disease characteristics at baseline (gender, geographical region, body mass index, age, age at asthma onset, medication use, pre-bronchodilator FEV₁, number of severe asthma exacerbations in the year before study start, smoking history, blood eosinophil levels, F_eNO levels) to evaluate whether the response to dupilumab was affected by these characteristics. Patients were randomised 2:2:1:1 to receive add-on subcutaneous dupilumab 200 mg or 300 mg or matched-volume placebo every 2 weeks for 52 weeks. Injections were administered during patient study visits until week 12 and could be administered by patients and/or caregivers later. Full details of the study design and methodology have been reported previously [11]. Annualised rate of severe exacerbations during the 52-week treatment period was analysed using negative binomial regression models, with the total number of events occurring during the observation period as the response variable; and treatment group, age, region, baseline eosinophil strata, baseline ICS dose level, number of severe exacerbation events within 1 year prior to the study, subgroup (demographic or disease characteristic if different than the aforementioned) and treatment by subgroup interaction as covariates. Least squares mean change from baseline in pre-bronchodilator FEV₁ at week 12 was assessed using mixed-effects models with repeated measures. The model included change from baseline in pre-bronchodilator FEV₁ values up to week 12 as response variable; and treatment group, age, patient sex and height, region, baseline eosinophil strata, baseline ICS dose level, visit, treatment-by-visit interaction, baseline pre-bronchodilator FEV₁ value, baseline-by-visit interaction, subgroup (demographic or disease characteristic if different than the aforementioned covariates), subgroup-by-treatment interaction, and subgroup-by-treatment-by-visit interaction as covariates.

Of the 1902 patients randomised in the study, 1584 (dupilumab: 1040; placebo: 544) had baseline blood eosinophils ≥150 cells·µL⁻¹ or F_eNO ≥20 ppb. Among these patients, demographic and disease characteristics at study initiation were comparable between treatment groups.

Dupilumab versus placebo reduced the annualised rate of severe exacerbations, irrespective of demographic or disease characteristics at baseline (figure 1a). In general, efficacy of dupilumab was comparable between demographic and disease characteristic subgroups. Dupilumab efficacy was greater in patients with >1 exacerbation in the year prior to study initiation (p=0.0164), and age at asthma onset >18 years (p=0.0010). Dupilumab had a greater treatment effect in patients with higher baseline blood eosinophil concentrations (p=0.0036) and F_eNO levels (p=0.0200) in line with previous observations [11].

FIGURE 1.

a) Adjusted annualised severe exacerbation rate. b) Least squares (LS) mean difference in the change in pre-bronchodilator forced expiratory volume in 1 s (FEV₁) from baseline at week 12 between dupilumab and placebo by baseline patient demographic and disease characteristic subgroup. BMI: body mass index; F_eNO: fractional exhaled nitric oxide; ICS: inhaled corticosteroids; LABA: long-acting β2-agonists; ppb: parts per billion.

In this post hoc analysis, dupilumab improved pre-bronchodilator FEV₁ 12 weeks after treatment initiation in all demographic and disease characteristic subgroups examined (figure 1b). No significant treatment-by-subgroup interactions were detected, with the exception of baseline blood eosinophil concentration (p=0.0002) and F_eNO levels (p<0.0001), suggesting a comparable treatment benefit for all patients, irrespective of their demographic or disease characteristics.

Our findings suggest that in this population of patients with elevated type 2 biomarkers at baseline, dupilumab reduced the annualised rate of severe exacerbations and improved pre-bronchodilator FEV₁ consistently across most patient demographic and disease characteristics at baseline. This included patients with differing gender, geographical region, body mass index, age, age at asthma onset, medication use, pre-bronchodilator FEV₁, number of severe asthma exacerbations in the year before study start, smoking history, blood eosinophil levels, and F_eNO levels. Previous studies have found the efficacy of some asthma treatments to vary depending on patient demographics, for example age and age of asthma onset, with limited efficacy observed in patients with asthma onset <18 years [4, 5]. Although patients with differing age at asthma onset and exacerbation history showed variations in the degree to which the exacerbation rate was reduced, dupilumab was efficacious in reducing severe exacerbations versus placebo in all demographic and disease characteristic subgroups evaluated, including those in whom asthma started before age 18 years. Benefits of dupilumab on patient lung function were not impacted by demographic and disease characteristics. Taken together, these findings add to the body of knowledge guiding treatment decisions for asthma patients. Current EAACI guidelines recommend the use of dupilumab as an add-on treatment for adult and adolescent patients with severe uncontrolled asthma with a type 2 phenotype [13–15]. This analysis supports these recommendations, demonstrating that dupilumab treatment is efficacious in all patients with moderate-to-severe, type 2 asthma, regardless of demographics or disease characteristics.

In conclusion, the response to dupilumab treatment in patients with uncontrolled, moderate-to-severe, type 2 asthma was unaffected by patient demographic or disease characteristics at baseline.

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