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28 Journal of Managed Care Medicine | Vol. 23, No. 1 | www.namcp.org

Summary There are new therapeutic approaches for severe asthma that improve outcomes, including exacerbations and oral steroid dependence. The patient selection for bio- logics is evolving, but it typically involves being uncontrolled on triple therapy and having biomarkers of eosinophilic asthma.

Key Points • Severe asthma is difficult to control. • Biologic therapies targeting underlying pathology for eosinophilic asthma are available. • Biologic agents reduce exacerbations and, for some of the agents, reduce oral steroid dependence. • Reducing steroid dependence is especially important because of the long-term adverse event risk.

SEVERE ASTHMA IS A SUBSET OF DIFFICULT to treat asthma patients. These patients remain un- controlled despite high-dose inhaled corticoste- roids combined with long-acting beta agonists (LABAs), montelukast, theophylline or systemic steroids (Exhibit 1).1

The goal of asthma management is disease con- trol. Asthma control is defined by current clinical condition (symptoms, short-acting beta agonist use, night waking, activity limitation, and lung func- tion) and features associated with future risk (exac- erbations in past year, ever admitted to critical care for asthma, accelerated decline in lung function, and adverse events of treatment).2,3 Consistently con- trolled asthma is important because lack of control increases risk of future asthma exacerbations, which are a key risk outcome and cost driver in asthma management.4 In one trial, those with exacerbations

had 3.5-fold increase in costs compared to those without exacerbations.5

Much has been learned about the pathophysiology of severe asthma in the past 20 years. Most patients with severe asthma have type 2 inflammation driving their lung disease. T helper two (Th2) cells mainly se- crete the prototypical cytokines interleukin four (IL- 4), IL-5 and IL-13, and stimulate type 2 immunity, which is characterized by high antibody titers and eosinophilia.6,7 Airway eosinophils have been shown to drive type 2 inflammation and correlate with re- duced lung function (FEV

1 ) in asthma and asthma

exacerbations.8 Type 2 inflammatory responses in the lungs often start in childhood and are driven by in- teraction between epithelial cells in the lung and en- vironmental stimuli — such as viral respiratory tract infections or exposures to oxidants, such as cigarette smoke or other airborne pollutants. Activated airway

Exploring New Pathways and Emerging Data for Better Control and Management in the Personalized Treatment of Severe Asthma

David I. Bernstein, MD For a CME/CEU version of this article, please go to www.namcp.org/home/education, and then click the activity title.

www.namcp.org | Vol. 23, No. 1 | Journal of Managed Care Medicine 29

epithelial cells produce IL-25, IL-33 or thymic stro- mal lymphopoietin (TSLP), which initiates a patho- genic cascade of Th2 cell proliferation.

Exhibit 2 details the most important clinical phe- notypes of severe uncontrolled asthma.7 Most pa- tients with severe asthma have eosinophilic asthma, which is either allergic or non-allergic. Eosinophil levels and exhaled nitric oxide (FeNO) are bio- markers of eosinophilic asthma. Eosinophil levels correlate with decline in lung function and risk of future disease exacerbations, and FeNO levels are an indirect marker of eosinophilic inflammation. A rarer form of severe asthma is neutrophilic asthma, which is not responsive to steroids.

Asthma management uses a control-based asth- ma management cycle.3 This cycle begins with as- sessment (accurate diagnosis, symptoms, and risk factors). Treatment with pharmacologic therapy and environmental controls is initiated and then treatment response is assessed. The cycle is a loop where response to therapy is assessed at each visit and therapy is adjusted as appropriate to achieve disease control.

Inhaled corticosteroids (ICS), which have long been the mainstay controller medication for asthma, suppress type 2 inflammation.6 Regular use of ICS leads to a reduced risk of exacerbations and death from asthma.9 A significant barrier to optimal asth- ma control has been underutilization of ICS.10 Un- derutilization can be under-prescribing and patient nonadherence. Unfortunately, the majority of pa- tients with severe asthma are not adherent with their prescribed ICS; most are only taking 50 percent of the prescribed dose.

Health literacy has been shown to impact asthma controller medication adherence.11 In an Asthma in America survey, only about one in three (34%) pa- tients said that the underlying cause of asthma could be treated; half (50%) thought it was possible to treat only symptoms; the rest (16%) were not sure.

The percentage who were aware that the underlying cause can be treated corresponded to the assump- tions of the general public, suggesting that asthma patients are no better informed about their condi- tion than individuals without asthma.10

Some possible adherence solutions are patient education to improve health literacy and review- ing inhaler device technique. Newer options on the horizon are adherence tracking devices on in- halers which can transmit data to providers. The first will be for rescue albuterol inhalers. Frequent use of a rescue inhaler is a marker of uncontrolled asthma. FeNO levels can also be used as a marker of adherence. The cleverest solution may be the use of on-demand rescue albuterol in combina- tion with ICS or a low-dose inhaled budesonide/ formoterol combination. This approach is now recommended by the Global Initiative for Asthma guidelines instead of prescribing rescue albuterol alone for mild asthma.3

Achieving control with severe asthma requires optimizing medication therapy, treating comorbid conditions which can exacerbate the disease, and modifying environmental risk factors. Optimizing medications requires addressing that the patient is on appropriate medication, adding medications if control is not achieved, and ensuring medication adherence. Environmental risk factors include aero- allergen sensitization (i.e., animals, dust mites), oc- cupational exposures, traffic pollutants (e.g., fine particulate matter), indoor pollutants, and tobacco smoke. Environmental controls such as mattress en- casings are effective for preventing asthma emergen- cy room visits and hospitalizations.12

Clinicians should assess asthma control after ad- dressing medications, comorbid conditions, ad- herence, and environmental factors. If the patient has a good response to ICS, therapy is continued and monitored. If there is a poor response, thera- py is added in a stepwise manner (Exhibit 3).3 For

Exhibit 1: Asthma Definitions (ATS/ERS Guidelines)1

Difficult to Treat Asthma

• Uncontrolled asthma despite high-dose inhaled corticosteroids or other controllers.

OR

• Requires such treatment to remain controlled.

Severe Asthma

• Subset of difficult to treat asthma patients

• Remain uncontrolled despite high-dose inhaled steroids combined with: - Long-acting beta agonist (LABA) montelukast, theophylline or systemic steroids for prior 6 months.

30 Journal of Managed Care Medicine | Vol. 23, No. 1 | www.namcp.org

Exhibit 2: Severe Uncontrolled Asthma – Clinical Phenotypes7

Allergic-eosinophilic Nonallergic-eosinophilic Neutrophilic

Frequency Very common Very common Uncommon

Causes Indoor and outdoor aeroaller- gens, occupational causes

Aspirin exacerbated (AERD) or no ASA sensitivity Idio- pathic

Infections, smoke, pollutants, irritants, occupational agents

Biomarkers Blood eosinophils ≥ 300 FeNO ≥ 20 ppb

Blood eosinophils ≥ 300 FeNO ≥ 40 ppb ↑ Sputum eosinophils

≥ 40-60% sputum neutro- phils

Clinical Features Onset in childhood, associ- ated with allergic rhinitis, atopic dermatitis, asthma exacerbations.

Onset in adulthood, chronic rhinosinusitis, nasal polyps and obstruction, asthma exacerbations.

Poor response to inhaled cor- ticosteroids, purulent mucus, reduced lung function

ASA = aspirin FeNO = exhaled nitric oxide

the severe asthma patient who is not controlled on high-dose ICS, LABAs, long-acting antimuscarin- ics (LAMAs), and oral steroids daily or periodically, inflammatory phenotype-based biologics should be considered. The goals of adding biologic therapy are to achieve asthma control, reduce exacerbations, and reduce oral steroid requirements.

Five monoclonal antibodies have been FDA ap- proved for treating severe asthma: omalizumab (Xolair®, anti-IgE), mepolizumab (Nucala®, binds IL-5), reslizumab (Cinqair®, binds IL-5), benrali- zumab (Fasenra®, blocks IL-5α receptor), and du- pilumab (Dupixent®, inhibits IL-13 and IL-4 com- mon receptor). Omalizumab was the first agent approved, and it binds free IgE to prevent mast cell activation. It is indicated for the allergic asthma phenotype with elevated IgE levels. Treatment with omalizumab produced a 25 percent reduction in the rate of asthma exacerbations in severe patients un- controlled on ICS/LABA.13 It has no consistent oral steroid sparing effect and works better in patients with high peripheral eosinophils (≥300) or high ex- haled nitric oxide (≥20 ppb).

The anti-IL-5 agents are FDA approved for add- on therapy of severe asthma with an eosinophilic phenotype. Importantly, the anti-IL-5 agents lack efficacy for non-eosinophilic asthma. Mepolizumab and benralizumab produce about a 50 percent re- duction in exacerbations and 50 percent reduction in oral corticosteroid use (Exhibit 4).7,14,15 Resli- zumab produces a 50 percent reduction in exacer- bations, but data in oral steroid-dependent patients are not yet available. A disadvantage of reslizumab is administration by intravenous infusion, unlike the other two which are subcutaneous injections that

patients can do at home.16

Dupilumab treatment produces increases in forced expiratory volume (FEV

1 ) and a 50 percent

reduction in exacerbations, and is oral steroid spar- ing. In steroid-dependent patients, there was a 28 percent decrease in oral prednisone dose versus pla- cebo with a 59 percent decrease in exacerbations.17 A disadvantage of dupilumab is every two-week dosing compared with longer dosing intervals for the anti-IL-5 agents. An advantage of dupilumab is that this agent appears to work in patients with lower eosinophil levels.

Biologics appear to have the most promising ef- fects in eosinophilic (type 2 inflammation) asthma. More data are available on using in oral steroid de- pendent asthma for mepolizumab, benralizumab, and dupilumab. The biologics likely have a major impact on hospitalizations and death, but this data still needs to be determined.

Some questions with using the biologics in severe asthma remain. At this time, there are no compara- tive data between biologics; therefore, whether one is better than another is unknown. Optimal patient selection for biologics is not yet known but is typi- cally based on evidence of eosinophilic asthma that

Exhibit 3: Pharmacologic Approach to Asthma3

1. Optimize LABA-inhaled corticosteroids 2. Add leukotriene antagonist 3. Add long-acting antimuscarinic (LAMA) 4. Add oral steroids (e.g., low-dose prednisone) 5. Consider biologic agent (monoclonal antibody)

www.namcp.org | Vol. 23, No. 1 | Journal of Managed Care Medicine 31

is uncontrolled on triple therapy or is steroid de- pendent. Additional biologics are on the horizon. Agents in development for severe asthma include anti-TSLP, anti-IL 33 (regulates T2 and non-T2 inflammation), anti-IL25, and prostaglandin DP2 (PGD2) receptor antagonists.

Conclusion Severe asthma is difficult to control, but there are now therapies targeting underlying pathology for eosinophilic asthma. These biologic agents have been shown to reduce exacerbations and, for some of the agents, reduce steroid dependence. Reducing steroid dependence is especially important because of the long-term adverse event risk.

David I. Bernstein, MD is a Professor of Medicine in the Division of

Immunology, Allergy and Rheumatology at the University of Cincinnati,

Cincinnati, OH.

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Exhibit 4: Anti IL-5 Monoclonal Antibodies for Eosinophilic Asthma7

Mepolizumab (binds IL-5) Benralizumab (binds IL5 receptor) Reslizumab (anti IL-5 cytokine)

Subcutaneous 100 mg monthly Ages ≥ 12 Studied in those with blood eosinophils ≥150, 53% ↓ exacerbation rate 50% ↓ oral steroid versus placebo Reduces blood eosinophils FEV1 improved by 100 ml Works best in those with ≥ 300 eosinophils and two or more exacerbations annually Safety: herpes zoster, anaphylaxis

Subcutaneous 30 mg q 8 weeks (q4 for first 3 doses) Ages ≥12 Studied in those with blood eo- sionophils ≥300 50% ↓ exacerbation rates 50% ↓ oral steroids versus placebo Safety: anaphylaxis 3%

Intravenous dosing by weight (3 mg/kg) monthly Studied in uncontrolled asthmatic on medium-high inhaled steroids with ≥400 eosinophils and ≥1 exacerba- tion/year No data in oral steroid dependent patients 50% to 60% reduction in exacerba- tions versus placebo FEV1 improved by 100 ml Safety: rare anaphylaxis

IL = interleukin; FEV1 = forced expiratory volume in 1 second

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