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Biologics For Severe Asthma: A Review of Dupilumab (Dupixent)

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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)

52 weeks

Mean age: 48y

63% Female

Mean duration of asthma: 21 years

81% never smoked

Pre-dose FEV1 at baseline: 1.78

Randomized 2:2:1:1 to

  • Dupilumab 200mg every 2 weeks (loading dose 400mg)
  • Dupilumab 300mg every 2 weeks (loading dose 600mg)
  • Matched-volume placebos 
Annualized rate of severe asthma exacerbations: 

  • 0.46 (dupilumab 200mg) vs 0.87 (matched placebo)
  • 0.52 (dupilumab 300mg) vs 0.97 (matched placebo)  

Least square (LS) mean change from baseline to Week 12 in FEV1 before bronchodilator use: 

  •  0.32L (dupilumab 200mg) vs 0.18L (matched placebo)
  • 0.34L (dupilumab 300mg) vs 0.21L (matched placebo) 
  • AE incidence was similar across all intervention groups: 81% (in combined dupilumab groups) vs 83.1% (in combined placebo groups)
  • Serious AEs occurred in 8.2% (dupilumab) vs 8.4% (placebo) – most frequent serious AE was pneumonia
  • The most frequent AEs and occurring at higher rates in dupilumab groups was injection-site reaction
  • Increased blood eosinophil levels were associated with symptoms in 4 patients who received dupilumab and 2 of these events were reported as serious; a total of 7 eosinophilic events in dupilumab groups resulted in permanent discontinuation of the intervention
LIBERTY ASTHMA VENTURE

N=210 (adults 12 years or older)

24 weeks 

Mean age: 51y

61% Female

Mean duration of asthma: 20y

81% never smoked

Pre-dose FEV1 at baseline: 1.58 

Randomized 1:1: 

  • Dupilumab 300mg every 2 weeks (loading dose 600mg) 
  • Placebo

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

  • AE incidence was similar in the 2 groups; 62% (dupilumab) vs 64% (placebo)
  • The most frequent AEs were viral URTI, bronchitis, sinusitis, influenza, laboratory measure of eosinophilia
  • Eosinophil count of more than 3000 cells per cubic millimetre occurred in 13% (dupilumab) vs 1% (placebo) – there were no clinical consequences or associated AEs

Cost-efficacy considerations

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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