Managing Severe Asthma: Key Considerations When Recommending Therapy

Asthma is a heterogeneous disease commonly characterized by airway hyper-reactivity, respiratory symptoms, airflow obstruction, and underlying inflammation.^1,2 Symptoms such as wheezing, shortness of breath, chest tightness and cough often vary over time and in intensity. In the United States, over 17 million adults and approximately 7 million children have been diagnosed with asthma.³ An estimated 5-10% of the adult asthma population is believed to have severe asthma,⁴ which is associated with a significant symptom burden, increased hospitalizations, and higher mortality. Accordingly, severe asthma accounts for approximately 60% of the costs associated with this disease.^5,6

Asthma severity is generally associated with the level of treatment required to maintain good symptom control and prevent future acute exacerbations.² “Severe asthma” is a retrospective label generally referring to a subset of patients who require daily use of a medium-to-high dose inhaled corticosteroid (ICS) plus another controller therapy (eg a long-acting bronchodilator, leukotriene modifier, etc), or when regular use of an oral corticosteroid is needed to maintain control.⁶ Asthma is also considered severe when it remains uncontrolled despite proper use and adherence to this level of therapy.⁷

Symptom burden (eg daily symptoms, nocturnal symptoms, reliever use, and activity limitation) and the risk of adverse asthma outcomes (eg persistent airflow limitation, exacerbations, and medication adverse effects) are 2 domains to consider when assessing asthma control.² Patients with poorly controlled symptoms, including those who experience frequent exacerbations (≥2 per year) or a severe exacerbation requiring hospitalization (≥1 per year) should be referred to a specialist and may require additional treatment with an asthma biologic.⁶ Prior to escalating therapy, it is important to evaluate potential contributing factors of suboptimal control such as poor adherence to controller therapy, inappropriate inhalation technique, complicating comorbidities, and persistent exposure to allergens and other asthma triggers despite targeted mitigation strategies.^1,2,6 The Global Initiative for Asthma (GINA) and the European Respiratory Society/American Thoracic Society (ERS/ATS) Task Force on severe asthma have suggested reserving the label of “severe asthma” for patients with uncontrolled asthma despite proper adherence to treatment and other measures to control precipitating factors and complicating comorbidities.^6,8 Patients with uncontrolled asthma due to these modifiable factors are considered to be “difficult-to-treat” and interventions should be directed toward addressing these factors prior to increasing therapy.^2,6,8

In recent years, several novel biologic therapies aimed toward the underlying pathophysiology of asthma have been approved. Asthma phenotypes or clusters of observable characteristics and related biomarkers, which help explain underlying mechanisms of the disease (ie endotypes) have been identified to better personalize therapy.^5,9 Approximately 50-70% of patients with asthma exhibit type 2 airway inflammation, which often includes allergic asthma, eosinophilic asthma, and exercise-induced bronchoconstriction (EIB).¹⁰ Type 2 inflammation generally involves the activation of pro-inflammatory cytokines such as interleukin-4 (IL-4), interleukin-5 (IL-5) and interleukin-13 (IL-13), which in turn, signal the production of immunoglobulin E (IgE) along with the activation and recruitment of mast cells, eosinophils, and other effector cells.¹¹

A total of 5 asthma biologics have been approved by the FDA to date, all of which target various mediators associated with type 2 inflammation. Collectively, asthma biologics have been shown to significantly reduce the frequency of asthma exacerbations and oral corticosteroid use in patients with severe asthma.^{6, 12-16} Therapeutic selection is generally based on asthma phenotype and predominant immuno-inflammatory endotype.⁹ Omalizumab (Xolair) is an anti-IgE antibody indicated for moderate to severe persistent asthma in patients 6 years of age and older with a positive skin test or in vitro reactivity to a perennial aeroallergen.¹² Dosing is based on body weight (kg) and total serum IgE level (IU/mL), measured before the start of treatment. Mepolizumab (Nucala), reslizumab (Cinqair), and benralizumab (Fasenra) interfere with IL-5 activity and are add-on maintenance treatment options for patients with severe eosinophilic asthma.^13-15 Mepolizumab and reslizumab are humanized monoclonal antibodies directed toward IL-5, while benralizumab is a monoclonal antibody that targets the IL-5 alpha receptor found on the surface of eosinophils resulting in rapid apoptosis and cell elimination within 24 hours.^4,13-15 Although, it is important to note that the relationship between pharmacologic properties of these agents and clinical efficacy has not been established.

Finally, dupilumab (Dupixent) is an IL-4 receptor alpha antagonist that affects IL-4 and IL-13 signaling and is indicated for patients 12 years of age and older with moderate-to-severe eosinophilic asthma or in those with oral corticosteroid dependent asthma.¹⁶ Therapy may be further tailored based on cost, route of administration, dosing frequency, and patient characteristics (Table 1).^4,6 For instance, dupilumab, mepolizumab, and benralizumab pre-filled syringes may be administered by the patient or caregiver at home once appropriately trained by a health care professional.^13,15,16

Dosing frequency and coverage should be considered and may impact patient convenience and cost.

Table 1: Biologic agents for severe asthma therapy^12-16

_{a. Approved for home use by patient or caregiver following proper trainingb. Determine dose (mg) and dosing frequency by serum total IgE level (IU/mL) measured before treatment, and by body weight (kg).c. 12+ years: 100 mg subcutaneously once every 4 weeks; 6-11 years 40 mg subcutaneously once every 4 weeksd. 18+ years: 3 mg/kg administered by intravenous infusion over 20-50 minutese. Pricing Based on AWP — Redbook Online. Thomson Reuters, 2019 [cited 2019 Sept 20]}

The potential benefits of biologic therapy should be weighed against the high cost, possible adverse reactions, and areas in need of further research.⁹ The most frequently reported adverse reactions reported among asthma biologics include headache, fatigue, and injection site reactions.^12-16 Hypersensitivity reactions have been reported rarely and these agents should be avoided in patients with active parasitic (helminth) infections.^12-16 There are no formal recommendations on how to guide therapeutic decisions when multiple biomarkers are elevated. Moreover, additional discriminatory biomarkers with evidence-based reference ranges are needed to better predict optimal response to treatment. Finally, no head-to-head clinical trials have been performed to determine whether certain asthma biologics are safe and efficacious when combined.⁴ The GINA group recommends an initial trial of at least 4 months before modifying therapy, but no formal recommendations regarding duration of therapy currently exists.⁶ Further long-term safety studies are needed.

In conclusion, advancements in the understanding of asthma pathophysiology has led to the discovery of defined asthma phenotypes and targeted interventions involving novel biologic therapies. The treatment of severe asthma involves a stepwise approach that requires full understanding of the patient’s medical history, asthma phenotype, and history of response to prior therapy. Barriers to achieving optimal asthma control should be addressed before escalating or modifying treatment.

References

1. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma. Expert Panel Report 3, Publication No. 08-5846. Bethesda, MD: US Department of Health and Human Services; Oct 2007. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/

2. GINA report. Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA): Updated 2019. www.ginasthma.org. Accessed June 18, 2019.

3. Asthma Stats - Uncontrolled Asthma among Persons with Current Asthma | CDC. Uncontrolled Asthma among Persons with Current Asthma. https://www.cdc.gov/asthma/asthma_stats/uncontrolled_asthma.htm. Accessed June 30, 2019.

4. Manka LA, Wechsler ME. Selecting the right biologic for your patients with severe asthma. Ann Allergy Asthma Immunol1 2018;21:406-413

5. Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med 2017;377:965-76.

6. Global Initiative for Asthma. Pocket guide for diagnosis and management of difficult-to-treat and severe asthma in adolescent and adult patients. April 2019.

7. Severe Asthma. American Academy of Allergy, Asthma, and Immunology Reviewed 7/29/19. https://www.aaaai.org/conditions-and-treatments/library/asthma-library/severe-asthma. Accessed September 11, 2019.

8. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43:343

9. Wechsler ME. Current and Emerging Biologic Therapies for Asthma and COPD. Respir Care

2018;63(6):699-707.

10. Canonica GW, Diamant Z, Dahlén SE. Type 2 Inflammation and the Evolving Profile of Uncontrolled Persistent Asthma. EMJ. 2018;3[4]:24-33. Link https://www.emjreviews.com/respiratory/symposium/type-2-inflammation-and-the-evolving-profile-of-uncontrolled-persistent-asthma/

11. Kim H, Ellis AK, Fischer D, et al. Asthma biomarkers in the age of biologics. Allergy Asthma Clin Immunol. 2017;13:48

12. Xolair (omalizumab)[package insert] San Francisco, CA; Genetech Inc; Revised May 2019 https://www.gene.com/download/pdf/xolair_prescribing.pdf. Accessed July 9, 2019.

13. Nucala (mepolizumab) [package insert] Philadelphia, PA; GlaxoSmithKline; Revised June 2019. https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Nucala/pdf/NUCALA-PI-PIL.PDF. Accessed July 9, 2019

14. Cinqair (reslizumab) [package insert]. Frazer, PA; TEVA ; Published May, 2016. .https://www.cinqair.com/globalassets/cinqair/prescribinginformation.pdf. Accessed July 9, 2019

15. Fasenra (benralizumab) [package insert]. Wilmington, DE; AstraZeneca Pharmaceuticals; Revised October, 2019. https://www.azpicentral.com/fasenra/fasenra.pdf#page=1. Accessed November 8, 2019

16. Dupixent (dupilumab) [package insert] Tarrytown, NY; Regeneron Pharmaceuticals.https://www.regeneron.com/sites/default/files/Dupixent_FPI.pdf. Accessed July 9, 2019.

17. Sriaroon P, Casale TB. The challenge of choosing the correct biologic for the correct asthma patient. Ann Allergy Asthma Immunol 121 (2018) 385-386