Targeting better control with biologic therapy.
In the United States, asthma affects 8% of adults and 7% children1. Asthma is a chronic inflammatory respiratory disease characterized by reversible airway obstruction and hyper-responsiveness with symptoms of wheeze, shortness of breath, chest tightness and cough2.
Despite optimization of standard care regimens, approximately 5-10% of patients with asthma have severe and difficult-to-treat disease requiring use of high-dose inhaled corticosteroid plus a second controller and yet oftentimes remain uncontrolled2. These patients have higher rates of morbidity, mortality and healthcare utilization 2,3.
There are various mechanisms that contribute to the inflammation seen within asthma denoted as Th-2 high and Th-2 low asthma phenotypes. Genetic susceptibility and environmental exposure to viruses, allergens, pollutants and other irritants trigger airway inflammation and in Th-2 high this results in the release of type 2 cytokines; IL-4, IL-5 and IL-13 and recruitment of mast cells, eosinophils and basophils, secretion of IgE by B-cells, bronchoconstriction and airway remodeling3,4.
While systemic corticosteroids suppress the Th-2 inflammatory response, biologic agents also known as monoclonal antibodies (mAB) offer substantial advantages as they precisely target the source of inflammation, allowing a patient’s medical regimen to be tailored to their clinical phenotype without incurring the broad effects of systemic steroids3. The goals of treatment with the addition of a biologic are reduced exacerbations, decreased need for systemic steroids, reduced asthma symptoms, improved quality of life and pulmonary function4.
There are currently five mAB approved for moderate to severe asthma with elevated Th-2 inflammatory markers (elevated serum or sputum eosinophils, elevated fractional exhaled nitric oxide, elevated total or specific IgE). Unfortunately, at the time of this article there are no currently approved mAB for Th-2 low asthma3,4.
Use of biologics raises many questions: indications for use, impact of comorbid disease and consideration of potential side effects, preference for one agent over another and how to proceed when there is no perceived benefit. Each agent has specific indications and approval considerations.
Direct head-to-head comparisons of these agents are not available, and meta-analyses yield discordant results5. Thus, the choice of which therapeutic needs to be patient-specific.
Physicians should use asthma severity, phenotype, age, biomarkers, treatment goals, comorbid conditions, safety and cost to help guide the treatment selection in a shared decision-making process with patients. This is to help optimize adherence, with special attention to patient preferences regarding safety concerns and medication administration options5. Treatment with any mAB for asthma requires that a patient’s asthma is inadequately controlled on inhaler therapies after addressing other factors of poor control such as adherence, inhaler technique and compounding comorbidity.
In considering treatment, if more than one agent is a reasonable option, patient preference regarding the method, frequency and location of drug administration should be considered. Many agents are now available as prefilled syringes, pens or autoinjectors, and thus a requirement to return to a healthcare setting for administration may not be necessary. Alternatively, many patients may not feel comfortable performing self-administration and may prefer administration in their provider’s office or at least initially until they gain the confidence of self-administration.
Types of Biologics for Asthma
Omalizumab. Omalizumab is a recombinant humanized mAB that binds to free IgE, forming a complex that inhibits IgE from binding IgE receptors on the surface of mast cells and thereby prevents the release of allergic mediators upon exposure to allergen. It is approved for treatment of moderate and severe allergic asthma with sensitivity to perineal allergen. Laboratory monitoring is not required nor should IgE levels be followed during treatment3.
Dupilumab. Dupilumab is an mAB directed against the IL-4 receptor alpha-subunit that inhibits signaling of both IL-4 and IL-13 cytokines, which promote recruitment of eosinophils, goblet cell hyperplasia and differentiation of T cells into Th-2 cells. It is approved for oral steroid dependent asthma and eosinophilic asthma.
IL-5 Targeted Therapies (Mepolizumab, Reslizumab, Benralizumab)
Il-5 causes the differentiation, migration, activation and recruitment of eosinophils. Healthy patients without asthma do not have significant airway eosinophilia in comparison to those with eosinophilic asthma. When present, eosinophils release pro-inflammatory cytokines that result in bronchoconstriction, mucus production and airway remodeling.
Treatment reduces the presence of eosinophils in the airway and subsequently mitigates these effects and improves asthma symptoms. Mepolizumab and Reslizumab bind to IL-5 and prevent it from binding the IL-5 receptor on eosinophil and basophil cell surfaces.
The drugs differ in their routes of administration and dosing. Benralizumab binds the IL-5 alpha receptor on the surface of eosinophils and basophils. In addition, it prevents IL-5 from binding, and subsequent cellular activation also induces antibody-dependent cell-mediated death.
Potential RisksÂ
All biologic agents have the potential to cause hypersensitivity reactions, although the reported rates were higher in trials for omalizumab and reslizumab5. Mepolizumab may increase the risk of herpes zoster outbreaks5. Dupilumab has been reported to cause conjunctivitis and keratitis, yet these side effects were more frequent in patients with atopic dermatitis5.
A potential for increased risk of helminth infection is possible with all anti-IL-5 agents given their effect on eosinophils5. Safety concerns should be considered when selecting therapy. Table 1 specifically outlines the considerations for each agent.
There are many new therapeutics on the horizon targeting upstream sites of Th-2 inflammation. Upon early exposure to irritants, airway epithelium releases TSLP and IL-33. By inhibiting these early mediators of Th-2 inflammation, there can be a blockade of downstream inflammatory pathways with hopeful improved clinical response for patients 3.
Table 1: Biologic Therapies Approved for Th-2 High Asthma
| Route | Frequency | Age | Target | Biomarker | Side Effects | Other Indications | |
| Omalizumab (Xolair) | SC | q2-q4 weeks | >6 yo | Blocks IgE-mediated immune stimulation | Elevated Total IgE, Elevated Specific Perennial IgE | Anaphylaxis/ Hypersensitivity | Chronic Sinusitis with Nasal Polyposis, Chronic Spontaneous Urticaria |
| Mepolizumab (Nucala) | SC | q4weeks | >6 yo | Binds IL-5; reduction in eosinophil production and survival | AEC | Herpes Zoster, Anaphylaxis/ Hypersensitivity, Parasite Infection | EGPA,
HES |
| Reslizumab (Cinquair) | IV | q4weeks | >18 yo | Binds IL-5; reduction in eosinophil production and survival | AEC | Herpes Zoster, Anaphylaxis/ Hypersensitivity, Parasite Infection | |
| Benralizumab (Fasenra) | SC | q4weeks x3, q8 weeks | >12 yo | Binds IL-5 receptor; reduction in eosinophil production and survival, activates NK to induce apoptosis of eosinophils and basophils | AEC | Herpes Zoster, Anaphylaxis/ Hypersensitivity, Parasite Infection | |
| Dupilumab (Dupixent) | SC | q2weeks | >12 yo | Binds IL-4 receptor a subunit; inhibit IL-4 & IL-13 cytokines | AEC, FeNO, Oral Steroid Dependence | Anaphylaxis/ Hypersensitivity,
Keratitis, Conjunctivitis |
Atopic Dermatitis, Chronic Sinusitis with Nasal Polyposis |
AEC: Absolute Eosinophil Count
FeNO: Fractional Exhaled Nitric Oxide
Results
Once an agent is selected, it is imperative that physicians closely monitor patients for treatment effect and safety. Follow-up assessment should include symptom control, need for rescue medication, exacerbation history, healthcare utilization and lung function as well as adverse events.
A four- to six-month trial of treatment is needed to assess the optimal effect and treatment response of biologic therapy5. For patients who do not respond with improvement after this duration of time, patient-, disease- and medication-related factors should be evaluated and remediated if possible.
The most common reason for biologic treatment failure is lack of adherence to background inhaler controller therapy, as many fail to understand that use of a biologic is adjunct to their controller regimen not in substitution5. Additionally, home administration of biologic therapy may also pose an adherence issue.
To prevent these treatment failures, patient education regarding treatment plan should be reviewed at every visit, including medication administration techniques and goals of long-term treatment. Suboptimal responders should also undergo an investigation regarding other comorbidities that may be contributing to asthma such as: obesity, obstructive sleep apnea, deconditioning and lower airway infection5.
Suboptimal dosing may also impair medication effect but can be overcome by dose modification, either from a fixed dose to weight-based or altering the route of administration (subcutaneous v. intravenous)5. Persistent suboptimal responders may require reexamination of asthma phenotype and biomarkers and ultimate transition to an alternative agent targeting a different Th-2 pathway for an improved effect5.
Biologic therapies are vital in the care of severe asthmatics as they allow physicians to provide personalized medicine specifically targeting the type of inflammation triggering disease and symptoms unique to a patient’s clinical phenotype. This is just the beginning of a revolution in asthma care. In the coming years, as new pathways are uncovered and new sources of asthmatic inflammation are identified, additional therapeutics will enter the landscape and offer further benefit for asthma patients.
References
Centers for Disease Control and Prevention, National Center for Health Statistics. Fast Stats: Asthma 2019. Available from https: www.cdc.gov/nchs/fastats/asthma.htm. Accessed June 15, 2021.
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2021. Available from: https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdfAccessed June 15, 2021.
Krings, JC., et al. Biologics for Severe Asthma: Treatment-Specific Effects Are Important in Choosing a Specific Agent. J Allergy Clin Immunol Pract. May-June 2019; 7(5):1379-1392.
Viswanathan RK., Busse WW. How to Compare The Efficacy of Biologic Agents in Asthma. Ann Allergy Asthma Immunol. Aug 2020; 1235 (2):137-149.
Pepper AN., et al. How to Assess Effectiveness of Biologics for Asthma and What Steps to Take When There is Not Benefit. J Allergy Clin Immunol Pract. March 202; 9 (3): 1081-1088.
Dr. Marissa Shams
Dr. Shams joined the Allergy/Immunology Section at the Emory Clinic in 2014. She attended the University of Georgia and Mercer University School of Medicine. She completed her Internal Medicine residency at Tulane University and received her Allergy/Immunology fellowship training at Emory University. Dr. Shams’s clinical focus has been providing comprehensive allergy and immunology care with a specific interest in allergic skin disease, allergic disease in the elderly, asthma and immunodeficiency.
