Dupilumab (Dupixent®) – first-in-class, PBS-listed IL-4 receptor alpha biologic (targeting IL-4 and IL-13) for uncontrolled severe asthma

Wednesday, 16 Jun 2021


An estimated 2.7 million Australians have asthma and in 3–10% of cases, this is considered to be severe.1,2 From 1 April 2021, the first-in-class biologic targeting IL-4 and IL-13, dupilumab, became available on the PBS for the treatment of uncontrolled severe asthma in eligible patients.3 To better understand what this means for the management of severe asthma in Australia, the limbic spoke with Professor Jo Douglass, Professor of Medicine, Melbourne Medical School and the Director of Research at the Royal Melbourne Hospital.

The Global Initiative for Asthma (GINA) guidelines define severe asthma as a subset of difficult-to-treat asthma whereby asthma is uncontrolled despite adherence to maximal optimised therapy and treatment of contributory factors, or whereby asthma worsens when high-dose treatment is decreased.4 Patients with severe asthma experience a heavy burden of symptoms and medication side effects and often experience frightening, unpredictable exacerbations, which can greatly impact quality of life.4 

The newly PBS-listed dual inhibitor of interleukin-4 (IL-4) and interleukin-13 (IL-13), dupilumab, provides a treatment for patients with uncontrolled severe eosinophilic or allergic asthma.3 According to Professor Douglass, an investigator in the Phase III studies assessing dupilumab, “The patients I treated with dupilumab in the clinical trials often experienced a great improvement in symptoms. Overall, when the biologics work well in asthma, they can be life changing.”

Dupilumab – anti-IL-4Rα (targeting IL-4 and IL-13) biologic therapy for the treatment of severe asthma5

Clinicians traditionally treat asthma to a specific phenotype, but most patients with severe disease have a mixture of phenotypes.6

As explained by Professor Douglass, “Prior to dupilumab, there was a need to make a choice if a patient had predominantly allergic asthma or predominantly eosinophilic asthma and prescribe accordingly – and that created some uncertainty. Dupilumab is indicated for both those phenotypes so it will be very useful in that regard.”

Dupilumab directly targets two cytokines responsible for type 2 inflammation – IL-4 and IL-13.5 This means that dupilumab can be used to treat patients with severe uncontrolled asthma, regardless of whether they have allergic or eosinophilic asthma, or a mixture of both.5

According to Professor Douglass, “Type 2 asthma is an inflammatory phenotype that is common to both primary eosinophilic asthma and allergic asthma, and unlike the other currently available biologics that are indicated for only one of the pathways, dupilumab targets both the allergic and eosinophilic pathways.”

How effective is dupilumab in treating severe uncontrolled asthma? 

Dupilumab may provide Australians with severe uncontrolled asthma the opportunity for improved lung function, reduced rates of exacerbation and less reliance on oral corticosteroids.7-9

Professor Douglass explains, “Patients will often notice improvement in lung function after the first dose and in the clinical trials that was certainly the case with improvements seen as early as two weeks, with some additional benefits accruing over the first six months. Patients would be expected to show benefit associated with oral corticosteroid reduction by 12 weeks.”

Indeed, clinical trial results showed that dupilumab significantly improved lung function as early as two weeks, regardless of the patient’s dependence on oral corticosteroids, with lung function improvements maintained throughout the duration of the 52-week study.7

Dupilumab also reduced the rate of severe asthma exacerbations up to 70% (compared to placebo, DRI12544, duration 24 weeks)8 and up to 48% compared to placebo, (QUEST, duration 52 weeks7), with greater reductions in the rate of severe exacerbations in patients with higher baseline biomarker levels of type 2 inflammation, such as eosinophils and fraction of exhaled nitric oxide (FeNO).8

Dupilumab also reduced the dose of oral corticosteroids required by patients with steroid-dependent asthma by 28% (compared to placebo) over 24 weeks. At this time point, more than half (52%) of patients treated with dupilumab no longer used oral corticosteroids (compared with 29% in the placebo group).9 According to Professor Douglass, “This is an important endpoint because long-term corticosteroid use is associated with multiple side effects, including osteoporosis, diabetes and weight gain.”

Based on these trial results, she concluded that, “This is another effective biologic for severe asthma and we know from other biologics that are available on the PBS for asthma that many individuals find them life changing. On the other hand, there are some patients who have not had such remarkable benefit and they still have Type 2 inflammation – and these patients may well benefit from dupilumab.”

Dupilumab safety profile

Professor Douglass highlighted that “People are often concerned that biologics are broadly immunosuppressive and that patients will suffer from infections, but that is not seen with asthma biologics, including in trials of dupilumab. There were injection site reactions with dupilumab in almost 17% of patients, but they were mild and transient. So the drug has a good safety profile overall.”

One side effect that was observed was a mean initial increase in baseline eosinophil count in patients treated with dupilumab compared to placebo.5 Eosinophil counts declined to near baseline levels by week 52 of treatment.7 Most of the observed elevations in eosinophil counts were laboratory findings without clinical consequences or associated adverse events.7

Which patients can access dupilumab on the PBS?

Professor Douglass explained that, “Like all the biologics, there are several eligibility requirements that must be met for PBS supply. The good thing is that the majority of criteria remain the same. The key difference is that dupilumab is the only biologic that is indicated for either eosinophilic or allergic asthma.”

“To be eligible for dupilumab 300 mg, patients need to have severe uncontrolled asthma with a history of exacerbation in the previous 12 months and they must have been receiving regular oral corticosteroid therapy during the last 6 months with a stable daily dose of 5 to 35 mg/day of prednisolone or equivalent over the 4 weeks prior to treatment initiation.

To be eligible for dupilumab 200 mg, patients need to have been treated with oral corticosteroids – either daily oral corticosteroids for at least 6 weeks OR a cumulative dose of oral corticosteroids of at least 500 mg prednisolone equivalent in the previous 12 months, unless contraindicated or not tolerated.

“For patients to be eligible for either 200 mg or 300 mg, they also need to have Type 2 inflammation demonstrated by raised blood immunoglobulin E of 30 IU/mL or greater and evidence of sensitisation to a specific allergen OR the presence of raised eosinophil count greater than or equal to 150 cells per microlitre while receiving treatment with oral corticosteroids in the last 12 months OR 300 cells per microlitre in the last 12 months.

They also have to have evidence of asthma demonstrated by reversible airflow obstruction on spirometry, evidence of positive airway challenge or reversibility demonstrated on peak flow reading.

Finally, patients have to be seen and assessed by a specialist – either a respiratory physician, clinical immunologist, allergist or general physician experienced in the management of severe asthma – and seen by that physician for six months OR assessed by an asthma multi-disciplinary team.”

For full PBS criteria, please visit www.pbs.gov.au

Conclusions

Professor Douglass concluded, “In patients with uncontrolled severe asthma who are initiating a biologic and meet the criteria of either allergic or eosinophilic asthma, dupilumab may be a suitable choice to try to achieve good asthma control with improvement in lung function as well as preventing exacerbations. Dupilumab has been shown to have a well-tolerated safety and efficacy profile in those with uncontrolled severe eosinophilic or allergic asthma* so it is exciting to have this therapy available on the PBS.”

*Dupixent 200 mg and 300 mg has been found to be generally well-tolerated up to 52 weeks in clinical trials, with safety data for the 300 mg dose up to 96 weeks consistent with the parent study.5

Before prescribing, please refer to the full product information for Dupixent, available here or by contacting 1800 818 806.

This article was sponsored by Sanofi Genzyme, who reviewed the article for technical accuracy. The article is based on published studies and expert opinion, independent of Sanofi.

References:

  1. Australian Institute of Health and Welfare (AIHW). Asthma. Available at: https://www.aihw.gov.au/reports/chronic-respiratory-conditions/asthma/contents/asthma. Accessed May 2021. 
  2. Severe Asthma Toolkit. Available at: https://toolkit.severeasthma.org.au/severe-asthma/overview/. Accessed May 2021.
  3. Pharmaceutical Benefits Scheme. Available at: www.pbs.gov.au. Accessed April 2021.
  4. Global Initiative for Asthma Difficult-to-Treat and Severe Asthma in adolescent and adult patients Diagnosis and Management. A GINA Pocket Guide for Health Professionals. V2.0 April 2019.
  5. Dupixent® (dupilumab) Australian Product Information. 1 April 2021 
  6. Tran TN, et al. Overlap of atopic, eosinophilic, and TH2-high asthma phenotypes in a general population with current asthma. Ann Allergy Asthma Immunol 2016; 116 (1): 37-42
  7. Castro M, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma N Engl J Med. 2018;378:2486–2496.
  8. Wenzel S, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016;388:31–44.
  9. Rabe KF, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma N Engl J Med 2018;378:2475–2485;

© Sanofi Australia and New Zealand. Talavera Corporate Centre, Building D, 12-24 Talavera Road, Macquarie Park, NSW 2113 MAT-AU-2100819 First issued May 2021

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