Update: Advances in management for severe asthma

By David C. Howard, PharmB | Medically reviewed by Sanja Jelic, MD
Published March 21, 2022

Key Takeaways

  • The Global Initiative for Asthma Strategy (GINA) released new guidelines outlining the latest evidence-based data for the treatment and prevention of asthma.

  • Add-on maintenance treatment is effective for patients with moderate-to-severe asthma whose symptoms remain uncontrolled with inhaled corticosteroids (ICS) and bronchodilator therapies.

  • Add-on biologics offer the potential to reduce morbidity and improve patient functioning.

The prevalence of asthma continues to grow in many countries—particularly among children. Despite the optimal use of inhaled corticosteroids (ICS) and long-acting β2-agonist (LABA) therapies, between 30% and 50% of patients with moderate-to-severe asthma have persistent symptoms and/or exacerbations, according to a study published in Respiratory Medicine.

The Global Initiative for Asthma Strategy (GINA) published a strategy report to help establish up-to-date, evidence-based, clinical resources for physicians. Launched in 1993 through a collaboration between the WHO and the US National Heart, Lung, and Blood Institute, GINA publishes an annual update to help clinicians sort through new evidence and approved therapies.

Below are specific updates from this year’s guidelines, as well as investigational treatments that are moving through the pipeline.

Recommendations

Approximately 3% to 10% of individuals with asthma have severe symptoms, which is characterized as asthma that is “uncontrolled despite good adherence with optimized high-dose ICS-LABA therapy and management of contributory factors or that worsens when high-dose treatment is decreased,” according to the guidelines.

In these patients, GINA guidelines recommend assessing the clinical and inflammatory phenotype, as this would be beneficial in selection of add-on maintenance treatment. 

Recommended add-on treatment options include adding tiotropium to ICS-LABA (patients ≥ 18 years of age), which provides modest improvement in lung function. Low-dose azithromycin may also reduce exacerbations. 

Add-on biologic therapies include benralizumab, dupilumab, mepolizumab, omalizumab, and reslizumab. Tezepelumab was recently approved by the FDA and is not contained in the guidelines.

Benefits of add-on biologics include substantial reductions in severe exacerbations and potential reduction in oral corticosteroid use. 

Add-on treatment response should be assessed at follow-up, and ineffective therapies should be discontinued and/or adjusted. Patients who respond to add-on therapy should be re-evaluated every 3 to 4 months. 

Multidisciplinary care for patients with severe asthma is recommended to optimize patient outcomes.

"Asthma management is not ‘one-size-fits-all’ but instead should be personalized and adjusted in a continual cycle of assessment, treatment adjustment, and review."

Authors, The Global Initiative for Asthma Strategy

Add-on biologic agents

There are several biologic agents with an indication for asthma that may be considered. 

Benralizumab is an IL-5 receptor alpha-directed cytolytic monoclonal antibody indicated for the add-on maintenance treatment of patients with severe asthma with an eosinophilic phenotype who are aged ≥ 12 years.  

Administered by subcutaneous (SC) injection, the recommended dose is 30 mg every 4 weeks for 3 doses, and once every 8 weeks thereafter. Hypersensitivity reactions (eg, anaphylaxis, angioedema, urticaria) have occurred. Adverse events (≥ 5%) include headache and pharyngitis.

Dupilumab is an IL-4 receptor alpha antagonist indicated as an add-on maintenance treatment in patients aged 6 years and older with moderate-to-severe asthma characterized by an eosinophilic phenotype or in those with oral corticosteroid-dependent asthma. 

The recommended dosage in patients ≥ 12 years is an initial loading dose of 400 mg or 600 mg SC, followed by 200 mg or 300 mg SC every 2 weeks, respectively. Dosing in patients 6 to 11 years of age is based on body weight: 100 mg SC every 2 weeks or 300 mg SC every 4 weeks for 15 to 30 kg (33 to 66 lb); 200 mg SC every 2 weeks for ≥ 30 kg. 

Adverse reactions include injection site reactions, oropharyngeal pain, and eosinophilia. Hypersensitivity reactions have occurred.

Mepolizumab is an IL-5 antagonist monoclonal antibody indicated for add-on maintenance treatment in patients aged ≥ 6 years with severe asthma and with an eosinophilic phenotype. The recommended dose in patients aged ≥ 12 years is 100 mg SC every 4 weeks; and 40 mg SC every 4 weeks in those aged 6 to 11 years. Common adverse events include headache, injection site reaction, back pain, and fatigue. Hypersensitivity reactions have occurred.

Reslizumab is an IL-5 antagonist monoclonal antibody indicated for add-on maintenance treatment of patients with severe asthma aged ≥ 18 years and with an eosinophilic phenotype. The recommended regimen is 3 mg/kg every 4 weeks by IV infusion over 20 to 50 minutes. Reslizumab may be associated with oropharyngeal pain.

Tezepelumab is a thymic stromal lymphopoietin blocker human monoclonal antibody indicated for the add-on treatment of patients aged ≥ 12 years with severe asthma. 

The recommended dosage is 210 mg SC every 4 weeks. Adverse reactions may include pharyngitis, arthralgia and back pain; hypersensitivity reactions (eg, rash, allergic conjunctivitis) can occur. 

Omalizumab is an anti-IgE antibody indicated for moderate-to-severe persistent asthma in patients aged 6 years and older with a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. 

Omalizumab may be dosed from 75 mg to 375 mg SC every 2 to 4 weeks based on serum total IgE level and body weight (kg). 

Adverse events in patients 12 years of age and older may include arthralgia, pain, fatigue, dizziness, and pruritus. Patients aged 6 to ≤ 12 years may see nasopharyngitis, headache, pyrexia, upper abdominal pain, and epistaxis.

Limitations of add-on therapies

The five biologics listed here are not indicated for the treatment or relief of acute bronchospasm or status asthmaticus. 

Omalizumab and reslizumab have black box warnings for anaphylaxis; healthcare professionals should be prepared to manage anaphylaxis associated with their administration, which could be life-threatening. 

Benralizumab and reslizumab are not indicated for other eosinophilic conditions.

Investigational agents  

Depemokimab (GSK3511294) is a humanized anti-IL-5 monoclonal antibody featuring an extended half-life. Unlike other anti-IL-5 monoclonal antibodies, the drug has improved IL-5 affinity. Depemokimab is administered SC and resulted in marked reductions (> 48%) in blood eosinophil count at 24 hours post-dose in a recent study. There were no serious adverse events. 

The pharmacokinetics of depemokimab are linear and dose-proportional; terminal half-life is 38 to 53 days, supporting less frequent dosing when compared to other anti-IL-5 agents. 

The benefit of switching to depemokimab from mepolizumab or benralizumab in patients with severe asthma with an eosinophilic phenotype who are maintained on standard of care asthma treatment is currently being evaluated in a phase 3 study.

What this means for you

Add-on maintenance treatment for patients with moderate-to-severe asthma, who remain symptomatic despite optimal ICS-LABA therapy, provides the opportunity to reduce severe exacerbations and oral corticosteroid use. These treatments can help reduce the burden of disease in such patients and improve patient functioning. The 2021 GINA guidelines provide an evidence-based, personalized approach for management of asthma at all levels of severity.

Sources

  1. Czira A, Turner M, Martin A, et al. A systematic literature review of burden of illness in adults with uncontrolled moderate/severe asthma. Respir Med. 2022;191:106670.

  2. Reddel HK, Bacharier LB, Bateman ED, et al. Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes. Am J Respir Crit Care Med. 2022;205(1):17-35.

  3. Fasenra (benralizumab) injection for subcutaneous use, prescribing information [package insert], revised February 2021. AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850.

  4. Dupixent ® (dupilumab) injection for subcutaneous use, prescribing information [package insert], revised December 2021. sanofi-aventis U.S. LLC, Bridgewater, NJ 08807; Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.

  5. Nucala (mepolizumab) injection for subcutaneous use, prescribing information [package insert], revised January 2022. GlaxoSmithKline, Research Triangle Park, NC 27709.

  6. Cinqair® (reslizumab) injection for intravenous use, prescribing information [package insert], revised February 2020. Teva Respiratory, LLC; West Chester, PA 19380.

  7. Tezspire™ (tezepelumab-ekko) injection for subcutaneous use, prescribing information [package insert], revised December 2021. Amgen Inc. and AstraZeneca AB.

  8. Xolair ® (omalizumab) injection for subcutaneous use, prescribing information [package insert], revised July 2021. Genentech USA, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080; Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936.

  9. Singh D, Fuhr R, Bird NP, et al. A phase 1 study of the long-acting anti-IL-5 monoclonal antibody GSK3511294 in patients with asthma. Br J Clin Pharmacol. 2022;88(2):702-712.

  10. ClinicalTrials.gov. A study of GSK3511294 (depemokimab) compared with mepolizumab or benralizumab in participants with severe asthma with an eosinophilic phenotype. NCT04718389.

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