Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): an open-label extension study

Summary

Background

Clinical trials have shown treatment benefits of dupilumab in patients with uncontrolled asthma for up to 1 year. This study aimed to evaluate the long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma, as data for extended treatment with dupilumab beyond 1 year are not available.

Methods

TRAVERSE was an open-label extension study in 362 hospitals and clinical centres across 27 countries that assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in adults and adolescents (aged 12–84 years) with moderate-to-severe or oral-corticosteroid-dependent severe asthma who had completed a previous dupilumab asthma study (phase 2A EXPEDITION, phase 2B DRI [P2b], phase 3 QUEST, or VENTURE). The primary endpoint was the number and percentage of patients with any treatment-emergent adverse events. Secondary endpoints included annualised exacerbation rate (AER) over the treatment period and change from parent study baseline in pre-bronchodilator FEV₁, the five-item asthma control questionnaire (ACQ-5), the asthma quality of life questionnaire (AQLQ), type 2 biomarkers (blood eosinophils and serum total IgE), and anti-drug antibodies (ADAs). Statistical analyses were descriptive. We report safety in all enrolled patients, and efficacy in patients with non-oral-corticosteroid-dependent asthma and in subgroups, including patients with a type 2 inflammatory phenotype who received 148 weeks of treatment. This study is registered with ClinicalTrials.gov, NCT02134028.

Findings

Between Aug 5, 2014, and Oct 11, 2019, of 2302 patients assessed for eligibility, 2282 adults and adolescents were enrolled (median age 50 years, 62·1% female and 37·9% male). Safety during TRAVERSE was consistent with the known dupilumab safety profile. The proportion of patients reporting treatment-emergent adverse events throughout the study duration was similar to that observed in the parent studies and ranged from 76·3% to 94·7%. The most frequently reported treatment-emergent adverse events were nasopharyngitis (17·5–25·9%), injection-site erythema (2·2–23·4%), and bronchitis (9·3–19·0%). Serious asthma exacerbations (0·5–3·6%) and pneumonia (0·7–2·7%) were the most frequently reported serious adverse events. There were four treatment-emergent adverse events leading to death. Efficacy during TRAVERSE was also consistent with the results of parent studies. In patients who were non-oral-corticosteroid-dependent, AER remained low (0·277–0·327) across parent study and treatment groups, pre-bronchodilator FEV₁ improvements were sustained to the end of treatment at week 96 (mean changes from parent study baseline ranged from 0·22 L [SD 0·44] to 0·33 L [0·44] across parent study and treatment groups), and improvements in ACQ-5 and AQLQ scores were sustained to the last timepoint assessed at week 48. Rapid improvements were observed in pre-bronchodilator FEV₁ and sustained improvements were seen in all outcome measures for patients given dupilumab who previously received placebo in parent studies; further improvements in AER, asthma control, and health-related quality of life were observed in patients who continued receiving dupilumab. Blood eosinophils and serum total IgE decreased progressively. ADA status had no effect on safety or efficacy. In the subgroup of patients with a type 2 inflammatory phenotype followed-up for 148 weeks, AER decreased progressively, and initial lung function improvements were sustained over 148 weeks.

Interpretation

Data show that safety and efficacy of dupilumab in adult and adolescent patients with moderate-to-severe asthma are sustained when treatment is extended up to 148 weeks. These findings therefore support the long-term use of dupilumab in this patient population.

Funding

Sanofi and Regeneron Pharmaceuticals.

Introduction

Asthma is a chronic lung condition characterised by episodic breathing difficulties, exacerbations, and airflow obstruction. Long-term uncontrolled asthma with associated inflammation increases the risk of exacerbations and leads to lung function deterioration.1, 2, 3, 4 Approximately 80% of patients with asthma have type 2 inflammation-driven disease, characterised by elevated biomarkers including blood eosinophils, fractional exhaled nitric oxide (FeNO), and serum periostin.5, 6, 7, 8, 9 Interleukin (IL)-4 and IL-13 are key and central drivers of type 2 inflammation, and upregulation of these cytokines constitutes an important component of asthma.10, 11 Dupilumab, a fully human VelocImmune-derived12, 13 monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13.¹⁰ In phase 2B DRI (P2b; NCT01854047)¹⁴ and phase 3 LIBERTY ASTHMA QUEST studies (QUEST; NCT02414854),¹⁵ add-on dupilumab 200 mg and 300 mg every 2 weeks versus placebo reduced annualised exacerbation rate (AER) and improved pre-bronchodilator FEV₁ in patients with non-oral corticosteroid (OCS)-dependent, uncontrolled, moderate-to-severe asthma. In the phase 3 LIBERTY ASTHMA VENTURE study (VENTURE; NCT02528214)¹⁶ in patients with OCS-dependent severe asthma, add-on dupilumab 300 mg every 2 weeks versus placebo reduced daily OCS dose while reducing AER and improving pre-bronchodilator FEV₁.

Research in context

Evidence before this study

We searched PubMed on May 4, 2021, for previous studies that assessed the long-term safety and efficacy of dupilumab using multiple search terms including “dupilumab,” “anti-interleukin-4,” “anti-interleukin-13,” “safety,” “efficacy,” “open-label,” “asthma,” and “long-term.” No language or time restrictions were applied. Our searches revealed studies showing long-term safety and efficacy data for dupilumab in patients with atopic dermatitis, and long-term open-label extension studies of mepolizumab, benralizumab, omalizumab, and reslizumab in patients with asthma, lasting from approximately 1·0 year to 4·5 years. No long-term studies investigating the safety or efficacy of dupilumab in patients with asthma were identified.

Added value of this study

To our knowledge, this study is the first assessment of the long-term safety and efficacy of dupilumab in patients with asthma. To date, safety and efficacy data have been assessed in randomised controlled trials of up to 1 year in duration. The current study is an open-label extension that enrolled patients from phase 2A, phase 2B, and phase 3 studies assessing dupilumab in patients with both oral-corticosteroid-dependent and non-oral-corticosteroid-dependent asthma. We found that the safety profile was acceptable and consistent with that observed in the parent studies, and improvements in exacerbation rates, lung function, asthma control, and quality of life were sustained or improved further over the extended treatment period.

Implications of all the available evidence

This study provides a robust assessment of the safety and efficacy of dupilumab in 2282 patients with asthma up to 148 weeks, and complements the long-term safety profile of dupilumab previously reported in patients with atopic dermatitis. These findings support the long-term use of dupilumab in patients with uncontrolled moderate-to-severe asthma.

Although these studies show the safety and efficacy of dupilumab up to 1 year, the longer-term effects of dupilumab treatment in patients with asthma have not been assessed. This open-label extension study, LIBERTY ASTHMA TRAVERSE (TRAVERSE), aimed to evaluate the long-term safety and efficacy of dupilumab in patients who had participated in previous dupilumab asthma studies, P2b,¹⁴ phase 3 QUEST,¹⁵ phase 3 VENTURE,¹⁶ and the translational phase 2A EXPEDITION study (NCT02573233). This analysis presents safety data in all patients enrolled in TRAVERSE and efficacy data in patients with non-OCS-dependent asthma from P2b¹⁴ and QUEST.¹⁵