Benralizumab for Severe Eosinophilic Asthma

DEFINITION OF ASTHMA

Asthma is a complex clinical syndrome of chronic airway inflammation characterized by recurrent and reversible airway obstruction. Inflammation also leads to hyperactivity, which causes the airway to narrow in response to various stimuli.^1,2

BACKGROUND

Asthma affects approximately 8% to 10% of the US population, or about 25 million Americans (1 in 13) who have the condition. This equates to 7.6% of adults and 8.4% of children. Asthma occurrence rates have been increasing since the early 1980s in all age, sex, and racial groups. It is more common in women than men, but children have the highest prevalence. Asthma is the leading chronic disease in children; there are approximately 6 million individuals under the age of 18 currently with the condition.²

PATHOPHYSIOLOGY

Inflammation in asthma happens in the breathing tubes and is even present when a person with asthma is not having an attack and is breathing well. This underlying inflammation causes swollen airways and excess mucus, which dramatically reduces the size of the airway, making it difficult for air to pass through.^1,3

CURRENT TREATMENT OPTIONS

Current treatment options for asthma include relievers, preventers, and controllers. Relievers, such as albuterol (Ventolin), are short-acting β agonists that open airways by relaxing the tight muscles. These treatments work within minutes to give quick relief from coughing, wheezing, or shortness of breath. These medications should only be used when necessary.

Preventers, such as beclomethasone (Qvar), are corticosteroids that reduce swelling and mucus in the airways. These medications work slowly and must be taken daily to work efficiently. Controllers, such as salmeterol (Serevent Discus), are long-acting beta agonists that relieve the symptoms of asthma by opening the airways and keeping them open for 12 hours. They are commonly used in conjunction with inhaled corticosteroids.²

TREATMENT OF EOSINOPHILIC ASTHMA

Benralizumab (Fasenra) is indicated as an add-on therapy for patients with severe eosinophilic asthma. Eosinophilic asthma is a subtype of severe asthma marked by high levels of white blood cells known as eosinophils, which are part of the immune system and help the body fight off infection. However, high levels of eosinophils can cause inflammation in the airways, affecting the sinuses and nasal passages, and lower airways. In general, as the level of eosinophils increases, inflammation and other symptoms of asthma become more severe.⁴

According to the CDC, 15% of all asthma patients are diagnosed with severe asthma. Eosinophilic asthma is the leading cause, affecting approximately 50% to 60% of all people diagnosed with severe asthma. This form of asthma most often develops in people between the ages of 25 and 35 years. Although other forms of asthma are triggered by allergic responses to environmental factors, such as pollen or pet hair, eosinophilic asthma does not develop in this way.

High levels of eosinophils can develop when the body is fighting off a parasitic infection, but scientists have not yet determined what causes these levels to spike in cases of eosinophilic asthma. The disease can run in families, therefore, researchers are exploring the possibility of a genetic connection; however, no direct genetic link has been found with eosinophilic asthma, as of yet. With no identified cause, this condition can be difficult to treat and may have detrimental effects on an individual’s quality of life.

The goals of therapy include reducing eosinophils in the airways and controlling a person’s breathing, preventing chronic symptoms such as coughing, difficulty breathing, or shortness of breath, and maintaining the patient’s normal daily activities, such as exercising, attending school, or working, to preserve their quality of life.^2,5

Patients who have eosinophilic asthma respond to typical asthma therapies, including inhaled and/or oral corticosteroids, but other patients may have symptoms that are resistant to these first-line therapies. Along with the use of first-line therapy options for asthma, biological therapies that target eosinophils may also be prescribed to treat eosinophilic asthma.

Mepolizumab (Nucala) is a humanized monoclonal antibody that recognizes and blocks interleukin-5 (IL-5), a signaling protein that is part of the immune system. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Eosinophils are cells associated with inflammation and an important component in the pathogenesis of asthma. Mepolizumab is approved for use in the United States and is used in combination with other asthma medications to treat patients 12 years or older who have eosinophilic asthma.

Reslizumab (Cinqair) is another anti-IL-5 monoclonal antibody approved for use in the United States as an add-on treatment for patients aged 18 years or older who have eosinophilic asthma.

On November 14, 2017, the FDA approved benralizumab (Fasenra) for severe eosinophilic asthma.^2,5

MECHANISM OF ACTION

Benralizumab, a humanized monoclonal antibody (IgG1, kappa), works as an IL-5 receptor antagonist. Benralizumab reduces the production and survival of eosinophils by inhibiting IL-5 signaling.³

DOSAGE AND ADMINISTRATION

This medication comes in a subcutaneous (SC) injection in which 30 mg are administrated every 4 weeks for the first 3 doses, then just once every 8 weeks thereafter.⁶

WARNINGS AND PRECAUTIONS

Common adverse reactions that can develop with benralizumab are local injection-site reactions, immunologic or hypersensitivity reactions (3%), headaches (8%), pharyngitis (5%), and fevers (3%). While on this medication, it is important to consult patients to recognize the signs of anaphylaxis or hypersensitivity reactions. Patients should schedule routine peak flow or pulmonary function tests to assess efficacy of therapy. They should also monitor for any signs of infection and report these symptoms if they become bothersome. Benralizumab should not be used to treat acute asthma, acute bronchospasm, or status asthmaticus.⁶

CLINICAL STUDIES

The 2 pivotal trials for benralizumab, SIROCCO and CALIMA, were randomized, double-blind, placebo-controlled trials designed to evaluate the efficacy and safety of SC administration of benralizumab (fixed 30-mg dose) for up to 56 weeks in exacerbation-prone patients age 12 years or older. A total of 2510 patients received standard-of-care medicine and were randomly assigned to receive benralizumab 30 mg every 4 weeks, benralizumab 30 mg every 4 weeks for the first 3 doses followed by 30 mg every 8 weeks, or placebo administered via SC injection using an accessorized prefilled syringe.

Results showed that SC injections of benralizumab every 4 or 8 weeks reduced asthma exacerbations, improved lung function evidenced by increased FEV1 values, improved symptom control, and depleted blood eosinophils in patients with counts greater than 300 cells/μL. Moreover, the researchers found that dosing benralizumab every 8 weeks appeared to be more effective than administering the drug every 4 weeks. Importantly, administering the drug every 8 weeks decreased the medication burden on the patient.^7,8

The ZONDA trial evaluated whether the administration of Fasenra could reduce the need for oral glucocorticoid therapy in patients with persistent eosinophilia. The trial included 369 patients of whom 220 of were randomized into 3 groups. The first experimental group received SC injections of benralizumab every 4 weeks, the second experimental group received SC injections of benralizumab every 8 weeks, and the control group received placebo injections.

The researchers also decreased oral glucocorticoid doses taken by all 3 groups to a minimal level needed to control asthma. Annual asthma exacerbation rates, lung function, symptoms, and safety were also assessed during this trial. Results showed that in both experimental groups taking benralizumab, the final median oral glucocorticoid doses were 75% lower than those at baseline.

In the placebo group, the final median oral glucocorticoid dose was 25% lower than those at baseline. Participants taking benralizumab were more than 4 times as likely to experience a reduction of oral glucocorticoid dose as those receiving placebo. In the cohort administered benralizumab every 4 weeks, the annual incidence of asthma exacerbations dropped 55% compared with the control group.

In the cohort taking benralizumab every 8 weeks, the annual incidence of asthma exacerbations dropped 70% compared with the control group. The frequency of adverse events was similar in those taking benralizumab and those taking placebo, which suggests it is likely safe.^5,7,8

In terms of the major benefits of benralizumab, the maintenance dosing frequency of every 8 weeks is more advantageous compared with the required monthly doses of Nucala and Cinqair. According to the SIROCCO and CALIMA trials, dosing benralizumab every 8 weeks appeared to be more effective than administering the drug every 4 weeks. Importantly, administering the drug every 8 weeks decreased the medication burden on the patient and possibly improved adherence.

The ZONDA trial indicated that 75% of patients on benralizumab reduced their use of oral corticosteroid use, which has been linked to potentially serious adverse effects, such as diabetes, osteoporosis, cardiovascular disease, and immunosuppression if used chronically.

Like mepolizumab (Xolair), benralizumab is administered by SC injections while reslizumab requires an intravenous infusion. These key factors could potentially affect the patient’s willingness and accessibility to treatment. Although the drug prices vary based on several factors, according to some estimates, mepolizumab costs approximately $32,500 per year and reslizumab costs about the same. Finally, because benralizumab can be administered less frequently than these other biologics, the price would also be lower.^7,8

Although many patients with eosinophilic asthma usually benefit from treatment with inhaled corticosteroids, some subjects expressing severe airway inflammation from eosinophilic asthma cannot be adequately controlled by inhaled or even systemic corticosteroids. This is where IL-5 antagonists come into play as add on therapy for these specific patient populations.

Benralizumab can potentially be more effective than the other anti-IL-5 monoclonal antibodies mentioned earlier in inducing eosinophil depletion, which correlates with a decreased rate of asthma exacerbations and relevant improvements in symptom score, lung function, and quality of life. An additional positive feature of benralizumab is its medication profile, its proven efficacy even when administered every 8 weeks, which can be advantageous for improving adherence to treatment. Trials thus far show promising efficacy and safety profile data, arising from many pre-marketing clinical studies. On top of that, benralizumab may have the potential to reduce or eliminate the need for corticosteroid use.

About the Author

Andrea Szabados is a 4^th year Doctor of Pharmacy candidate at Concordia University Wisconsin School of Pharmacy in Mequon, WI. Her goal as future pharmacist is to further expand her knowledge about specialty medications and actively get involved in the treatment of complex, chronic, and rare conditions managed by specialty medications.

References

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2. Carr TF, Zeki AA, Kraft M. Eosinophilic and non-eosinophilic asthma. Am J Respir Crit Care Med. 2018; 197(1):22—37. [PMC free article] [PubMed]

3. Pelaia G, Vatrella A, Busceti MT, et al. Cellular mechanisms underlying eosinophilic and neutrophilic airway inflammation in asthma. Mediators Inflamm. 2015; 2015:879783. [PMC free article] [PubMed]

4. Saco TV et al. Benralizumab for the treatment of asthma. Expert Review of Clinical Pharmacology. Expert Review of Clinical Immunology. 2017; 13(5):405-413. http://www.tandfonline.com/doi/full/10.1080/1744666X.2017.1316194.

5. Nair P et al. Oral Glucocorticoid—Sparing Effect of Benralizumab in Severe Asthma. The New England Journal of Medicine. 2017; 376:2448-58. https://doi.org/10.1056/NEJMoa1703501.

6. Fasenra (Benralizumab) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2018.

7. Goldman M et al. The association between blood eosinophil count and benralizumab efficacy for patients with severe, uncontrolled asthma: subanalyses of the Phase III SIROCCO and CALIMA studies. Current Medical Research and Opinion. 2017; 33:1605-1613. https://doi.org/10.1080/03007995.2017.1347091.

8. Liu T, Wang F, Wang G, Mao H. Efficacy and safety of benralizumab in patients with eosinophilic asthma: a meta-analysis of randomized placebo-controlled trials. Front Med. 2017 Oct; 30. Epub. [PubMed] 9. Khorasanizadeh M, Eskian M, Assa’ad CA, Rezaei N. Efficacy and safety of benralizumab, a monoclonal antibody against IL-5Rα, in uncontrolled severe asthma. Int Rev Immunol. 2016; 35(4):294—311. [PubMed]