Biologics For Severe Asthma: A Review of Dupilumab (Dupixent)
Asthma is one of the most common chronic respiratory conditions treated in the primary care setting in Singapore. Critically, it is estimated that 20% of patients with asthma have uncontrolled, moderate-to-severe disease with recurrent exacerbations and persistent symptoms despite maximal standard-of-care controller therapy. An alternative approach is therefore required, and advancements in the understanding of asthma’s immunopathogenesis have led to the development of biological targets on mediators like interleukin (IL) that play a vital role in T-helper 2 cell (Th2) inflammation. Dupilumab, an IL-4 receptor alpha antagonist (IL-4Rα), is a fully human monoclonal antibody that inhibits IL-4 and IL-13 cytokine-induced inflammatory responses, including the release of proinflammatory cytokines, chemokines, nitric oxide and immunoglobulin E (IgE).
It is approved by the Singapore’s Health Sciences Authority (HSA) for use in adults and adolescents 12 years and older as an add-on maintenance treatment for severe asthma with type 2 (Th2) inflammation characterized by elevated blood eosinophils and/or elevated fractional exhaled nitric oxide (FeNO). It is also indicated as maintenance therapy for oral corticosteroid-dependent asthma. Type 2 inflammation plays a major role in multiple related diseases, and dupilumab is also indicated for the treatment of moderate-to-severe atopic dermatitis.
Dupilumab is available in Singapore as 100mg, 200mg and 300mg pre-filled syringes containing the drug solution for injection. It is administered subcutaneously at an initial dose of 400mg, followed by 200mg every other week for the treatment of asthma. A higher regimen of 600mg initially followed by 300mg every other week is recommended for patients with oral corticosteroid (OCS)-dependent asthma.
Efficacy and safety: dupilumab’s asthma development program
Dupilumab’s asthma development program recruited a total of 2,888 adults and adolescent patients with moderate-to-severe asthma across 3 randomized placebo-controlled multi-centre trials of 24 to 52 weeks. A summary of the key Phase 3 randomized controlled trials (QUEST and VENTURE) is included in the table below.
- In Phase 2b (NCT01854047) and Phase 3 LIBERTY ASTHMA QUEST (NCT02414854), add-on dupilumab 200/ 300 mg every 2 weeks reduced severe exacerbations, improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) and quality of life measures. Severe asthma exacerbation was defined as deterioration of asthma requiring systemic corticosteroids for at least 3 days or hospitalisation or emergency room visit due to asthma that required systemic corticosteroids.
- The Phase 3 LIBERTY ASTHMA VENTURE (NCT02528214) enrolled participants with oral corticosteroid (OCS) dependent asthma receiving high-dose ICS plus up to two additional controllers. Dupilumab 300mg every 2 weeks as an add-on therapy significantly reduced OCS use in patients with OCS-dependent severe asthma, while decreasing the rate of severe exacerbations and increasing the FEV1.
- In early 2022, results from the TRAVERSE study, a 96-week multinational, multi-centre, single-arm, open-label extension study in patients who participated in previous dupilumab studies, were reported. Dupilumab demonstrated the ability to sustain OCS dosage reduction from the parent study, while maintaining a low exacerbation rate and improved lung function. Further improvements were also seen in the 5-item Asthma Control Questionnaire scores, and safety findings remained consistent with the drug’s safety profile.
|Study||Intervention vs. Comparator||Primary Efficacy Outcome||Safety Findings|
|LIBERTY ASTHMA QUEST
N=1,902 (107 adolescents; 1,795 adults)
Mean age: 48y
Mean duration of asthma: 21 years
81% never smoked
Pre-dose FEV1 at baseline: 1.78
|Randomized 2:2:1:1 to
||Annualized rate of severe asthma exacerbations:
Least square (LS) mean change from baseline to Week 12 in FEV1 before bronchodilator use:
|LIBERTY ASTHMA VENTURE
N=210 (adults 12 years or older)
Mean age: 51y
Mean duration of asthma: 20y
81% never smoked
Pre-dose FEV1 at baseline: 1.58
Intervention period consisted of a 4-week induction period where OCS was continued; followed by a 16-week period where OCS dose was reduced every 4 weeks according to a protocol-prespecified algorithm; then a 4-week maintenance period where patients continued the OCS dose established at Week 20
|LS mean % reduction in OCS dose from baseline to Week 24 while asthma control was maintained:
-70.1% (dupilumab) vs -41.9% (placebo); P<0.001
In summary, adding dupilumab to background therapy was generally well tolerated and reduced the rate of severe asthma exacerbations, improving lung function and health-related quality of life (HR-QOL), where specified. Further, dupilumab use enabled OCS doses to be reduced without impacting asthma control. The drug also displayed efficacy across various patient subgroups, although those with heightened type 2 immune activity, including elevated eosinophils and FeNO produced more prominent treatment benefit. Its cost-efficacy or utility however, remains uncertain in the local context, in the absence of a locally-adapted evaluation.
Patients with severe or uncontrolled asthma are at an increased risk for illness, especially exacerbations, and require considerable health care resources. In Singapore, the total annual cost of adult asthma was estimated to be SGD 1.74 billion, with 42% attributed to the uncontrolled group, and mainly contributed by high medical costs and lost productivity. There is thus a pressing unmet need to provide therapies that balance cost, efficacy and access for the payer and the patient alike.
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