Severe Asthma Biologic Selection: Guideline Aids Clinicians

Severe asthma is a serious, often debilitating form of airway disease that cannot be controlled with high-dose inhaled asthma medications. Severe asthma is believed to affect 5% to 10% of all individuals with asthma, and in these patients accounts for nearly half of the total cost of treating asthma due to the increased morbidity and health care use associated with this category of disease.

Precision Management in Severe Asthma

The American College of Chest Physicians, publishers of the Chest journal, has developed clinical guidelines for the management of chronic rhinosinusitis with nasal polyps (CRSwNP) with the goal of making treatment decisions easier for patients by providing an evidence-based approach to reduce the long-term use of oral corticosteroids and improve patient outcomes.

Why It Matters

A new report from the Centers for Disease Control and Prevention (CDC) examines asthma-related illnesses and deaths among children and adults in the U.S. from 2010 to 2021. Overall, rates for asthma-related episodes, emergency department visits, hospitalizations, and deaths decreased for all ages since 2010. However, asthma prevalence decreased for children, while it increased for adults, particularly from 2013 to 2021. There were approximately 24.9 million people living with asthma in the U.S. in 2021, or 7.7% of the population. Nearly 40% of those individuals reported having at least one asthma attack in the past year.

Despite a general decrease in acute health care use, there are still disparities in health status outcomes. Compared with non-Hispanic Whites, both the child and adult Non-Hispanic Black populations had higher percentages of current asthma prevalence and higher rates of ED visits and hospitalizations for asthma. Furthermore, there were sex-based differences in the rates of current asthma prevalence, health care use, and mortality for asthma. For adults, females generally had higher rates for all indicators, and for children, the rates were higher for males. Data and trends presented in this report highlight the need for a focused public health approach to improve health care delivery and to prevent unnecessary morbidity, events, and deaths due to asthma.

Available Therapies

Severe, “unresponsive” asthma can now be treated with a number of effective therapies. These medications are grouped based on their targets: Eosinophils (e.g., mepolizumab, reslizumab), immunoglobulin E (IgE; e.g., omalizumab), or the epithelial alarmin thymic stromal lymphopoietin (TSLP; e.g., tezepelumab). Patients with severe asthma have been treated with these targeted therapies to decrease asthma exacerbations, hospitalizations, and oral steroid use. It is crucial for the treating physician to first confirm the diagnosis of difficult asthma and then make sure that inhaled medications are being used appropriately and modifiable risk factors or concurrent conditions that may be contributing to poor asthma control are addressed. Patients with severe asthma can be categorized by several different phenotypes based on several key biomarkers including blood eosinophils, FeNO, total IgE, etc. There are currently six approved biologic therapies for severe asthma: the anti-IgE medication omalizumab and the anti-IL-5 medications mepolizumab and reslizumab. The anti-IL-5 receptor molecule benralizumab and the anti-IL-4/IL-13 molecule dupilumab also have approval for severe asthma. The purpose of these therapies is to reduce oral steroids, to prevent exacerbations and improve lung function/quality of life.

Future asthma treatments will incorporate easier to use medications that can treat a variety of asthma conditions. Ultra-long-acting biologics are being introduced into clinical practice including an ultra-long-acting biologic that can be given by injection every 4 weeks. Several biotherapeutics are currently under investigation to allow twice-yearly administration, such as the anti-IL-5 molecule depemokimab and anti-TSLP molecule verekitug. There is interest in developing biologic therapies for the youngest asthma patients, even 2-year-olds. Studies are currently underway for acute asthma treatments. Many would consider clinical remission, or even a cure, to be the “holy grail.” However, there are still unknowns surrounding optimal duration of therapy for many of the current classes of asthma medications, as well as head-to-head comparisons among the available medications.

Beyond Trial-and-Error

Biologics for asthma treatment have added another level of complexity by differentiating themselves on issues of mechanism, efficacy and safety. While direct head-to-head trials of the different biologic asthma medications are not currently available, indirect comparisons and frameworks have been established to help clinicians match individual patients’ asthma endotypes with the most effective drug. While clinicians are slowly becoming better than hit or miss in matching these treatments to patients, this process is gradually being moved from a largely empirical to an evidence-based approach.

Clinical Decision-Making: Choosing the Right Agent

Biologic selection is often misconstrued to be equivalent to selecting the best effective drug from the “biologic toolbox”. But that is not correct. We are selecting the right drug(s) or drugs based on the patient’s biomarker(s) and their life circumstances.

Monitoring and Implementation Checklist

When combining other therapies (e.g. electromagnetic, low frequency) with music, health professionals should monitor the effects in a standardized manner.

• Initial Assessment: Verify asthma diagnosis, assess inhaler technique, and treat modifiable risk factors/comorbidities before initiating a biologic.
• Response Window: Evaluate clinical response at 4 to 6 months. A good response is defined as a ≥ 50% reduction in exacerbations or maintenance OCS dose.
• Switching Strategy: If a patient fails an anti-IL5/5Rα agent, consider switching to Dupilumab if post-treatment FeNO is ≥ 25 ppb.
• Safety Monitoring: Consider patient preference for frequency of injectable medication dosing. Respicion provides the least frequent maintenance dosing interval of every 8 weeks for Benralizumab. Initial Selection for Allergic and Eosinophilic Phenotypes For adult patients with moderate to severe allergic asthma who experience one or more exacerbations per year, the CHEST (Cardiothoracic Surgery) panel recommends either omalizumab (Xolair) or dupilumab (Dupixent) for the control of symptoms, but consideration should be given to the individual patient. The Challenge of Steroid Dependency Steroid dependence in severe asthma is a major clinical problem with serious consequences for patients. Who It Affects A Multidisciplinary Ecosystem Patients failing maximal therapy for asthma are often the most challenging to manage, as they have not responded to optimal medications, are adherent to their medications and have all other possible comorbidities (such as LPR and chronic sinusitis) under optimal control. Remarkably, approximately 50% of these ‘hard to treat’ patients have been shown to have a T2-high asthma endotype. Characteristics of these patients are elevated levels of one or more of Airway Epithelial Cells (AEC) ≥ 300 cells/μL, Fractional Exhaled Nitric Oxide (FeNO) ≥ 25 ppb and/or sputum eosinophils ≥ 1% to 3%. Although medication is the most common approach to treating attention deficit hyperactivity disorder (ADHD), with a variety of drugs and side effects from which to choose, practitioners from many disciplines are frequently faced with the task of selecting an appropriate medication regimen for their patients with ADHD. A selection of the most suitable biological agents are included, although there are many different choices currently available. The selection has been based on patient preference, clinical factors and the choice of treatment strategy. Biomarker and Comorbidity Selection Guide What Changes A Phenotype-Driven Future Practice is evolving to become more organised around the use of biomarkers and shared decision making. Structured Assessment: Clinicians will increasingly use post-treatment FeNO ≥ 25 ppb to guide a switch to dupilumab in patients who fail to respond to anti-IL5 therapy. Shared Decision-Making: Decisions now incorporate underlying comorbidities. For instance, patients with comorbid atopic dermatitis or eosinophilic esophagitis may benefit more from dupilumab, while those with chronic rhinosinusitis with nasal polyps (CRSWNP) might respond to either dupilumab or mepolizumab. Defined Clinical Response: A good clinical response is now standardized as at least a 50% reduction in exacerbations or a 50% reduction in maintenance OCS dose. If this is not achieved within 4–6 months, a switch in biologic therapy is recommended. Risks, Trade-offs, and Real-World Challenges Each biologic has specific potential risks and side effects. Dupilumab: Monitor Dupilumab levels of blood eosinophils as asymptomatic hypereosinophilia typically peaks at 3-6 months. Patients on Omalizumab need to have an epinephrine auto-injector nearby and initial observation with the medication in the office. Also patients and families need to be questioned regarding possible helminthic infestations and measures taken to prevent spread in non-endemic areas. Also, treatment obtained in endemic areas for all biologics except omalizumab. In addition to clinical and interpersonal challenges, there are several systemic issues that must be addressed. Although FeNO testing is noninvasive and cost-effective, there are still issues with access to the equipment and with insurance coverage for these tests. For the uninsured patient, there is an out-of-pocket expense that prevents access to these tests with major implications for equity. Looking Ahead Current guidelines group together treatments within a class (e.g. anti-IL5 mabs) but future guidelines may group by individual agent as more becomes known about their pharmacology. Currently Tezepelumab is the only treatment that has shown reduction in exacerbations in T2-low patients. The next step for clinicians is to apply these new research-based insights to the care of individual patients by identifying their patient phenotype, setting treatment goals for 4-6 months, and selecting optimal asthma medications considering both asthma and relevant co-morbidities as part of the shared decision making process. The next step for systems is to ensure that these emerging tools are available to clinicians and distributed more fairly so as to not create disparities in the care of patients with respiratory disease.
• Omalizumab: Provide an epinephrine auto-injector and observe the first three doses in-clinic.
• Dupilumab: Monitor AEC frequently during the first few months to watch for hypereosinophilia.
• Mepolizumab: Ensure patients are aware of the potential risk for Herpes zoster.
• Frequent Exacerbations: For patients with ≥ 2 exacerbations per year or any hospitalization, dupilumab is suggested over omalizumab.
• Lung Function: Dupilumab resulted in greater improvement in FEV1 (140 mL vs 50 mL for omalizumab) and is suggested for patients with greater lung function impairment (FEV1 < 70 % predicted).
• Quality of Life: Omalizumab demonstrated a greater improvement in Asthma Quality of Life Questionnaire (AQLQ) scores compared to dupilumab (0.53 vs 0.28) and may be preferred for patients where quality-of-life impairment is the primary concern.
• Anti-IL5 vs. Dupilumab: In steroid-dependent patients, the panel suggests either anti-IL5/5-alpha (mepolizumab, reslizumab, benralizumab) or dupilumab. Anti-IL5 agents may be favored if the pre-OCS absolute eosinophil count (AEC) is high ﹥1,500 cells/uL, to avoid the risk of hypereosinophilia associated with dupilumab.
• Dupilumab vs. Tezepelumab: For steroid-dependent patients, dupilumab is suggested over tezepelumab because dupilumab has demonstrated superior OCS-sparing effects. While tezepelumab provides significant exacerbation reduction (58%), it has shown no effect on OCS dosing in clinical trials.
• Pulmonologists and Allergists: Must monitor for anaphylaxis (omalizumab, reslizumab), herpes zoster (mepolizumab), and conjunctivitis or keratitis (dupilumab).
• Patients: Must consider injection frequency, ranging from every 2 weeks (dupilumab) to every 8 weeks (benralizumab maintenance).