The Lancet Respiratory Medicine JANUARY 01, 2022

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

Wechsler ME, Ford LB, Maspero JF, et al.

Bottom Line

The TRAVERSE open-label extension study demonstrated that long-term dupilumab treatment in patients with moderate-to-severe asthma maintained low exacerbation rates and sustained lung function improvements over 96 weeks with a consistent safety profile.

Key Findings

1. Treatment-emergent adverse events (TEAEs) occurred in 76.3% to 94.7% of patients, which was consistent with safety profiles observed in the parent studies.

2. The most frequent TEAEs were nasopharyngitis (17.5-25.9%), injection-site erythema (2.2-23.4%), and bronchitis (9.3-19.0%).

3. In non-oral-corticosteroid-dependent asthma patients, the unadjusted annualized severe exacerbation rate (AER) remained very low, ranging from 0.277 to 0.327 across prior treatment groups.

4. Improvements in pre-bronchodilator FEV1 were sustained to week 96, with mean changes from parent study baseline ranging from 0.22 L (SD 0.44) to 0.33 L (0.44).

5. Patients rolling over from the parent study placebo arm to dupilumab experienced rapid improvements in AER and FEV1, matching the sustained control seen in the dupilumab-to-dupilumab cohort.

Study Design

Design

Open-Label Extension

Open-Label

Sample

2,282

Patients

Duration

96 wk

Median

Setting

Multicenter, global

Population Adults and adolescents (aged 12 years and older) with moderate-to-severe asthma who had successfully completed a prior dupilumab clinical trial.

Intervention Dupilumab 300 mg administered subcutaneously every 2 weeks for up to 96 weeks.

Comparator None (single-arm extension); outcomes were descriptively compared to parent study baseline or the placebo arm crossover.

Outcome Incidence and event rates of treatment-emergent adverse events (TEAEs).

Study Limitations

• The open-label, single-arm design of the extension introduces potential subjective bias for efficacy outcomes like symptom control and quality of life scores.

• The lack of a long-term concurrent placebo control group limits definitive causal attribution for all long-term outcomes.

• Enrolling only patients who successfully completed a prior dupilumab parent trial introduces selection and survivor bias.

• While follow-up reached up to 148 weeks cumulatively, this still does not fully capture lifetime safety for a chronic disease requiring potentially indefinite biologic therapy.

Clinical Significance

TRAVERSE confirms the durability and safety of dupilumab in moderate-to-severe asthma over nearly 3 years of cumulative therapy. This reassures clinicians that the significant reductions in severe exacerbations and improvements in lung function observed in phase 3 trials are maintained long-term without new or compounding safety signals.

Historical Context

Dupilumab, a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13, significantly altered the management of Type 2 inflammatory asthma based on pivotal 52-week trials like QUEST and VENTURE. Because severe asthma requires chronic maintenance therapy, defining the multi-year trajectory of efficacy, sustained suppression of Type 2 inflammation, and long-term adverse events was essential. TRAVERSE filled this gap, setting a benchmark for evaluating long-term biologic therapy in severe asthma.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Dupilumab targets the IL-4R alpha subunit, inhibiting both IL-4 and IL-13 signaling. Based on the pathophysiology of Type 2 asthma, how does the blockade of these specific cytokines explain the downstream reduction in Fractional exhaled Nitric Oxide (FeNO) and IgE levels seen in patients in the TRAVERSE study?

Key Response

IL-4 drives B-cell isotype switching to IgE, while IL-13 directly stimulates airway epithelial cells to upregulate inducible nitric oxide synthase (iNOS), leading to increased FeNO. Blocking the shared IL-4R alpha receptor blunts both pathways, which are key inflammatory drivers of Type 2 asthma.

Resident

In prescribing dupilumab for moderate-to-severe asthma based on long-term data from trials like TRAVERSE, what baseline biomarkers predict a robust clinical response, and what specific paradoxical laboratory abnormality must be monitored during the initial months of therapy?

Key Response

Baseline peripheral eosinophils (greater than 150-300 cells/mcL) and FeNO (greater than 25 ppb) predict better efficacy. Clinicians must monitor for transient peripheral blood eosinophilia, a paradoxical effect caused by dupilumab blocking IL-4/IL-13-mediated eosinophil tissue migration without inhibiting IL-5-driven bone marrow eosinophil production.

Fellow

The TRAVERSE study included patients from the VENTURE trial who had oral corticosteroid (OCS)-dependent asthma. How does long-term dupilumab therapy impact the clinical management of OCS tapering, and what are the risks of unmasking other conditions during this process?

Key Response

As dupilumab enables profound OCS tapering, patients may suffer from adrenal insufficiency due to prolonged prior hypothalamic-pituitary-adrenal axis suppression, requiring slow tapers and endocrine testing. Additionally, systemic steroid withdrawal can unmask underlying eosinophilic granulomatosis with polyangiitis (EGPA) or severe nasal polyposis that were previously suppressed.

Attending

The sustained FEV1 improvements over 96 weeks in the TRAVERSE trial suggest potential prevention of long-term airway remodeling. As an attending physician, how does this long-term disease modification data challenge the traditional step-up paradigm of asthma management regarding the timing of biologic initiation?

Key Response

Current paradigms reserve biologics for severe, refractory cases after maximizing inhaled therapies. However, long-term data showing sustained lung function preservation suggests that earlier biologic intervention might alter the natural history of irreversible airway remodeling in Type 2 asthma, weighing the benefits of early disease modification against drug costs and continuous administration.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The TRAVERSE trial is an open-label extension (OLE) without a long-term placebo control. How does the 'survivor effect' (attrition bias) intrinsic to OLE study designs potentially confound the long-term exacerbation rates and safety profile reported in this 96-week follow-up?

Key Response

In OLEs, patients who experienced adverse events or lacked efficacy in the parent trial often drop out before or during the extension phase. This leaves a 'survivor' cohort enriched with treatment responders who tolerate the drug well, which can artificially inflate long-term efficacy metrics and underestimate the true incidence of adverse events.

Journal Editor

Given the open-label nature of TRAVERSE, subjective endpoints such as the Asthma Control Questionnaire (ACQ) are highly susceptible to placebo or Hawthorne effects. As a reviewer, what methodological safeguards and statistical analyses would you require the authors to provide to ensure the validity of the reported sustained efficacy?

Key Response

A rigorous review would require authors to emphasize objective endpoints (e.g., severe exacerbations, FEV1) over subjective scores, use mixed-effects models for repeated measures (MMRM) to handle missing data, and perform sensitivity analyses (like tipping point analyses) to ensure that non-random dropouts did not heavily skew the subjective efficacy outcomes.

Guideline Committee

Based on the TRAVERSE 96-week safety and efficacy data, how should GINA guidelines structure long-term monitoring recommendations for patients on dupilumab, and does this data support upgrading the level of evidence for its use in long-term prevention of exacerbations?

Key Response

GINA guidelines currently recommend dupilumab for severe Type 2 asthma. The TRAVERSE data provides critical long-term evidence to support sustained use, transitioning short-term efficacy data to long-term management recommendations (Evidence Level B for long-term due to OLE design). It also necessitates specific guideline additions regarding routine CBC monitoring for transient eosinophilia during the first 6 months of therapy.

Clinical Landscape

Noteworthy Related Trials

2014

MENSA Trial

n = 576 · NEJM

Tested

Mepolizumab 75mg IV or 100mg SC every 4 weeks

Population

Patients with severe eosinophilic asthma

Comparator

Placebo

Endpoint

Rate of clinically significant asthma exacerbations

Key result: Mepolizumab significantly reduced asthma exacerbations and improved asthma control in patients with severe eosinophilic asthma.

2018

LIBERTY ASTHMA QUEST

n = 1,902 · NEJM

Tested

Dupilumab 200mg or 300mg every 2 weeks

Population

Patients with uncontrolled moderate-to-severe asthma

Comparator

Placebo

Endpoint

Annualized rate of severe asthma exacerbations

Key result: Dupilumab significantly reduced the rate of severe asthma exacerbations and improved lung function, particularly in patients with elevated type 2 biomarkers.

2018

LIBERTY ASTHMA VENTURE

n = 210 · NEJM

Tested

Dupilumab 300mg every 2 weeks

Population

Patients with oral glucocorticoid-dependent severe asthma

Comparator

Placebo

Endpoint

Percentage reduction in oral glucocorticoid dose

Key result: Dupilumab significantly reduced oral glucocorticoid use while simultaneously decreasing exacerbation rates and improving lung function.

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