Clinical Review Innovative Therapies for Severe

Maj Anna Christensen, MD, USAF; and Michael Ott, MD

Severe asthma therapies have progressed to include many options that have improved the quality of life for patients.

ore than 39.5 million peo- severity and age group.3 The Inter- mation, therefore, quantifying airway ple in the U.S. have been national European Respiratory So- inflammation.6-8 diagnosed with asthma, ciety (ERS) and American Thoracic There has been some variability and about 3,400 deaths Society (ATS) task force report was in the evidence supporting the use of M 5 occur annually due to asthma com- updated in 2014. The Global Initia- fractional exhaled NO (FeNO) lev- plications.1 Although the prevalence tive for Asthma (GINA) report, up- els as a diagnostic tool. Some stud- of atopy and asthma have increased dated in 2016, now includes several ies have suggested that FeNO is also over the past few decades in west- of the advances in asthma care for elevated in other nonasthma condi- ern countries, control and outcomes those patients refractory to standard tions, such as eosinophilic bronchi- are improving.2 Use of asthma pro- treatments. tis, atopy, and allergic rhinitis. Also, tocols and early recognition by the FeNO levels have been shown to be primary care provider (PCP) are ASTHMA THERAPIES variably influenced by smoking, bron- among the main reasons for trends In this review, the authors cover choconstriction, and viral respiratory toward decreased hospitalization therapies for severe asthma that are infections.9 However, FeNO levels and fewer asthma-related deaths.3,4 becoming more important for PCPs > 50 ppb correlated most strongly In addition to the mainstay of to consider, including exhaled nitric with eosinophilic asthma and steroid treatments, including trigger avoid- oxide (NO) levels, the use of tiotro- responsiveness.9 ance, inhaled corticosteroids (ICS), pium for asthma, the applicability of Fractional exhaled NO tests now and rescue bronchodilators, new biologic agents, the use of allergen can be performed in the PCP of- therapies have been developed to immunotherapy, and the usefulness fice with NIOX VERO (Chicago, supplement the treatment of severe of . This review also cov- IL), a small, relatively inexpensive persistent asthma, which constitutes ers therapy, bronchial device. Although the 2016 GINA about 5% to 10% of asthma cases. Se- thermoplasty, and a discussion of long- guidelines and the 2015 ERS/ATS vere asthma is defined as asthma that acting beta-agonist (LABA) therapy. guidelines do not offer specific rec- is unresponsive to baseline therapy.5 ommendations for use and do not Three sets of guidelines and rec- Fractional Exhaled Nitric Oxide support withholding ICS based on ommendations exist to provide Nitric oxide is present in the exhaled FeNO test results, guidelines for structure to asthma treatment deci- breath and is elevated in those with FeNO use do exist. In 2011, ATS sion making. The Expert Panel Re- eosinophilic asthma.6 The role of NO published a specific set of FeNO port-3 (EPR-3) was created by the in asthma pathology is complex, in- interpretive guidelines for office- National Education and Prevention volving proinflammatory qualities based use.9 When performed in Program (NAEPP) and was last pub- that contribute to airway hyperre- conjunction with standard testing, lished in 2007. The NAEPP favors a sponsiveness (AHR) and as a weak FeNO levels can provide valuable stepwise approach, based on asthma mediator of smooth muscle relax- clinically relevant information, such ation. In exhaled air, NO correlates as (1) detection of eosinophilic air- Maj Christensen and Dr. Ott are physicians at with up-regulation of NO synthase way inflammation; (2) determin- Eglin Air Force Hospital in Valparasio, Florida. (NOS), which occurs with inflam- ing the likelihood of corticosteroid

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Table 1. FeNO Interpretation9

Diagnosis Monitoring

Levels Symptoms Present Symptoms Present Symptoms Absent

FeNO < 25 ppb Eosinophilic airway inflammation unlikelya Check alternative diagnoses, unlikely Adequate ICS dose (< 20 ppb for patients < 12 y) Unlikely to benefit from ICSa to benefit from increase in ICS Consider taper

FeNO 25-50 ppb Be cautious, evaluate clinical symptoms Inadequate ICS dose, consider Adequate ICS dose (20-35 ppb for patients < 12 y) and FENO over timeb steroid resistance or poor adherence Persistent allergen exposure

FeNO > 50 ppb Eosinophilic airway inflammation presenta Inadequate ICS dose, steroid ICS taper may result (> 35 ppb for patients < 12 y) Likely to benefit from ICSa resistance or poor adherence; in relapse increased risk for exacerbation Poor adherence or Persistent allergen response technique

Abbreviations: FeNO, fraction of exhaled nitric oxide; ICS, inhaled corticosteroid; PPB, parts per billion. aStrong recommendation, moderate quality of evidence. bStrong recommendation, low quality of evidence. responsiveness; (3) monitoring of The FDA approved the addition exertional dyspnea and exercise tol- airway inflammation to determine of tiotropium for treating asthma erance. On day 42 of a randomized, the need for steroids; and (4) un- in September 2015 for patients double-blinded, placebo-controlled, masking of otherwise unsuspected aged ≥ 12 years. The use of tiotro- parallel-group study of 187 patients, nonadherence to corticosteroid pium is supported by both the ERS/ vital capacity and inspiratory capac- therapy (Table 1). ASTS and GINA 2016 guidelines. ity were noted to be increased with The recommended and approved decreases in residual volume and Tiotropium as an Adjunct Treatment dose of tiotropium for asthma is functional residual capacity. Exercise Tiotropium is a long-acting inhaled 2.5 µg daily (the recommended endurance times increased by 105 ± . A sentinel 1984 study dose for COPD treatment is 5 µg).12 40 sec (21%).16 This effect has not by Gross and Skorodin demonstrated A recent phase 3 study compared been studied yet in a population of that parasympathetic activity is the 2.5 µg vs 5 µg dosing with ICS but patients with asthma; however, the dominant reversible component in no LABA in adolescents, noting sig- same principles may hold true. patients with chronic obstructive pul- nificant improvement with the 2.5 µg monary disease (COPD), including dose.13 Adding tiotropium to ICS + BIOLOGIC AGENTS emphysema.10 In addition, all achiev- LABA in patients with severe symp- Recent asthma research has been fo- able bronchodilation was obtained tomatic asthma has been associated cused on disrupting the inflamma- with an inhaled anticholinergic com- with positive results in initial studies tory cascade. Both GINA and ERS/ pared with that of separate or simul- by Kersjens and colleagues.14 Even ATS divide asthma into allergic taneous administration of adrenergics. as early as 2010, the use of tiotro- vs nonallergic endotypes. Allergic Sympathetic neural pathways are pium was shown to produce statis- asthma usually is manifested by spu- sparse in human lungs and have their tically significant improvement in tum eosinophilia and high serum endings on the cells of the cholinergic morning peak expiratory flow (PEF), eosinophil counts, whereas other postganglionic fibers, because sym- with a mean difference of 25.8 L/min endotypes include -sensitive pathetic terminals on airway smooth (n = 210, P < .001).15 and exercise-induced asthmas that muscle cells are rare or nonexistent.11 Tiotropium also has been shown to present with a neutrophilic predomi- Therefore, sympathetic modulation or provide a sustained reduction in lung nance. Nonallergic asthma is more activation of beta cells could change hyperinflation for those with COPD, severe typically and has been linked the parasympathetic tone.11 thus providing an improvement in to steroid resistance.17 Many different

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Table 2. Biologic Agents for the Treatment of Severe Asthma20,23,26,30,34-39

Treatment (Brand) Mechanism of Action Type of Antibody Approved for Use (y)

Omalizumab (Xolair) Antibody that creates inert IgE complexes and stops Humanized MAB Yes (2003) complement activation

Mepolizumab (Nucala) Binds directly to IL-5 and prevents eosinophil activation Humanized MAB Yes (2015)

Reslizumab (Cinqair) Binds directly to IL-5 and prevents eosinophil activation Humanized MAB Yes (2016)

Dupilumab Binds to the IL-4Rα subunit of the IL-4 receptor, blocks Human MAB No, but received FDA “break- Th2 activation through therapy” designation

Fevipiprant D2 , blocks migration of N/A No Th2 cells, cytokines, prevents eosinophil activation

Benralizumab Anti-IL-5 receptor, block eosinophil activation Humanized MAB No

Abbreviations: IG, immunoglobulin; IL, interleuken; MAB, monoclonal antibody, Th2, T helper type 2. phenotypes have been identified, the newer completely human MABs. analysis of more than 10,000 patients but the main categories include eo- forms small, biologically did not support any relationship with sinophilic, neutrophilic, mixed, and inert IgE+ anti-IgE complexes that malignancy.27,28 A higher incidence paucigranulocytic.18 cannot activate the complement cas- of cardiovascular and cerebrovascu- Mast cells, bronchial epithelium, cade. The serum free IgE level is de- lar AEs has been observed, and the and macrophages are involved in creased.20 Approved in 2003 for those FDA issued a safety announcement asthma progression. Targeting the aged ≤ 12 years, its use is restricted regarding this finding.29 cytokines produced by these pathways to patients with severe asthma, al- Both ERS/ATS and GINA 2016 can be achieved through direct and in- lergic sensitization (positive allergen recommended that a therapeutic direct modulation. Interleukin (IL)-13 skin testing), and an elevated serum trial of omalizumab should be per- is central to development of AHR, and IgE level (30-700 IU/mL). It is ad- formed in all patients with severe its effect is mediated through bind- ministered subcutaneously every 2 to confirmed IgE dependent allergic ing to its receptor and IL-4 receptor 4 weeks, based on body weight and asthma.4,5 If there is no response in α complexes.19 Patients with severe serum IgE levels. 4 months, it is unlikely that further asthma with an eosinophilic pheno- For those with baseline eosinophil administration would be beneficial. type can benefit with the use of the counts > 300 µL, addition of omali- new biologics, which decrease the zumab most likely has been shown to Mepolizumab amount of eosinophilia in lung tissue improve quality of life (QOL) and re- Interleukin-5 is a key cytokine in the by blocking specific receptors for IL-5. duce exacerbations, the use of rescue eosinophil life pathway. There are re- , ICS dosages, and ED ceptors for IL-5 on eosinophils, baso- Omalizumab visits.21-26 The most dangerous ad- phils, and β cells.30 Mepolizumab is Omalizumab, an anti-immunoglobu- verse effect (AE) was found to be an an anti-IL-5 antibody for those with lin E (IgE) antibody, has been shown anaphylaxis rate of 0.09%, most fre- refractory eosinophilic asthma and a to be helpful in treating patients with quently occurring in the first 2 hours history of continued exacerbations. allergic asthma. Omalizumab is a 95% after the first dose. Therefore, the pa- It has beneficial effects in the man- humanized IgE monoclonal antibody tient must be monitored for 2 hours agement of persistent airways eosino- (MAB) that binds to the IgE molecule after the first dose and 30 minutes philia among corticosteroid-resistant at the fc region and prevents IgE from after subsequent doses. Epinephrine subjects. In a 2009 study, rates of binding to cell-surface receptors. In a injection also should be prescribed. exacerbations at 50 weeks were sig- humanized MAB, only the hypervari- Although a 5-year prospective co- nificantly lower than with placebo able regions are from mouse origin vs hort study and retrospective pooled (2.0 vs 3.4 mean exacerbations per

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subject, 95% confidence interval Other Biologic Therapies therapy compared with placebo dem- [CI], 0.32-0.92; P = .002) as were eo- Many biologics are being developed onstrated improvements in bronchial sinophil counts in blood and sputum as medical researchers continue to hyperresponsiveness and decreased (P < .001 and P = .002 respec- understand more of the mechanisms use.41 Expert Panel Re- tively.31 A 2014 randomized, double- and pathways that contribute to al- port-3 guidelines recommend con- blind trial by Ortega and colleagues lergic disease (Table 2). Dupilumab sideration of immunotherapy for demonstrated reduction in rate of is an IL-4 inhibitor designated as a mild-to-moderate asthma.5 While asthma exacerbations (primary “breakthrough therapy” in 2014 by ERS/ATS guidelines for severe asthma outcome) to 47% (95% CI, 29-61) the FDA. This biologic blocks the do not address allergen immunother- among patients receiving IV dosing downstream signaling events induced apy, GINA guidelines incorporate it and 53% (95% CI, 37-65) in the oral by IL-4 and IL-13 by binding to a as Evidence A for treating modifiable mepolizumab group (P < .001 for subunit of the IL-4 receptor in the risk factors to reduce exacerbations, both groups, n = 576).32 complexes. It has been found benefi- although the efficacy is limited.6 In addition, there is significant cial for those with high blood eosino- data to show that even if the patient phil counts and moderate-to-severe Roflumilast did not respond to omalizumab, he asthma and decreased asthma exac- Roflumilast is a selective PDE4 in- or she might still respond to mepo- erbations when LABA and ICS were hibitor that has shown an anti- lizumab. Data were collected from withdrawn.36,37 inflammatory effect in COPD. 2 randomized, double-blind, pla- Fevipiprant is a Studies evaluating the reversibility cebo-controlled studies with rate of inhibitor that blocks T-helper type and prevention of airway remodel- exacerbation and percentage reduc- 2 (Th2) cell migration and subse- ing showed good promise in mouse tion in oral corticosteroid dose as quent bronchoconstriction and cy- models.42 Data from 8 placebo- the primary outcomes. In one of the tokine effects with decreased IL-4, controlled, double-blind, phase studies (n = 576), the subjects were IL-5, and IL-13. Although sputum 1, 2, and 3 studies conducted at noted to have prior omalizumab use eosinophil percentage was noted to 14 sites in Europe, North Amer- but still decreased exacerbation rate be decreased in a study involving ica, and South Africa from 1997 by 57%.33 61 patients randomized to treatment to 2005 showed reduced sputum for 12 weeks, asthma QOL question- eosinophil and neutrophil counts, Reslizumab naires and prebronchodilator spirom- consistent with findings during Reslizumab also is an FDA-approved etry did not change.38,39 COPD treatment. However, forced anti-IL-5 antibody. It binds directly to Benralizumab is an anti-IL-5 re- expiratory volume in one second

IL-5 and prevents it from binding to ceptor antibody that has been more (FEV1) and PEF values were un- eosinophils.34 For adults with severe effective in reduction of airway and changed, suggesting that there was eosinophilic asthma and refractory blood eosinophils levels compared no acute bronchodilatory effect exacerbations, the goal of reslizumab with that of mepolizumab (unde- with roflumilast therapy.43 Roflu- therapy is to reduce eosinophil matu- tectable vs 52% reduction), within milast is not addressed in the 2016 ration, recruitment, and activation. 24 hours of IV dosing. In contrast, GINA guidelines and at this time Reslizumab is delivered in a weight- the anti-IL-5 antibodies take about does not have a role in the treat- based IV dose (3 mg/kg) every 4 weeks to decrease eosinophil levels ment of severe asthma. 4 weeks. The FDA has issued a in blood and sputum.34 There have boxed warning for a 0.3% anaphy- been no documented AEs aside from laxis rate.35 The most common AEs nasopharyngitis and injection site reac- After the activation of mast cells are elevated creatinine kinase, mus- tions and no safety concerns to date. It and eosinophils, leukotrienes are culoskeletal pain, and oropharyn- is currently undergoing phase 3 trials.40 generated by 5-lipoxygenase from geal pain. Use of reslizumab resulted and create bron- in greater reduction in sputum eo- IMMUNOTHERAPIES choconstriction, vasodilation, sinophils, improvements in airway Allergen immunotherapy is rec- increased mucus production, in- function, and a trend toward greater ommended for mild-to-moderate creased recruitment of eosinophils, asthma control compared with that asthma. A 2010 Cochrane Review and decreased ciliary motility. Some of placebo.34 found that subcutaneous immuno- studies have encouraged adding

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leukotriene receptor blockers (both Some earlier studies reported that ized controlled study (n = 32, 15 ran- and ) to a small number of subjects had an domly assigned to BT) that showed 44,45 ICS therapy and to therapy for increase in transaminases that re- improved prebronchodilator FEV1 patients with aspirin-intolerant solved when they discontinued the in patients with severe, symptomatic 46,47 asthma or allergic asthma. medication. Therefore, it is recom- asthma and baseline FEV1 of 62% to However, other studies have mended to check baseline laboratory 66% with half the patients requir- shown them to be of limited ben- results every 2 to 3 months.54,55 Nei- ing oral corticosteroids (percentage efit.48,49 A recent Cochrane Review ther GINA nor ERS/ATS guidelines predicted; 14.9 ± 17.4 vs -0.9 ± 22.3; of 18 randomized-controlled tri- address the use of . P =.04).57 Quality of life scores were als with 7,208 adults and children also significantly improved. At 5 years compared ICS + leukotriene re- BRONCHIAL THERMOPLASTY (14 BT patients were followed), the ceptor antagonist (LTRA) vs ICS + With asthma there is marked hyper- frequency of hospitalizations and ED LABA.50 The ICS + LABA resulted in trophy and hyperplasia that occurs visits decreased.59 greater improvements in lung func- in the airway smooth muscle. The The 2010 AIR2 study was a ran- tion, symptoms score, and rates of airway of the patient with asthma domized, double blind, sham- exacerbations.50 also is lined with cells that promote controlled study (n = 288) developed Most recommendations recog- inflammation. Thermal energy is to address the limitations of the 2 pre- nize the limitations of antileukotri- used to perform controlled destruc- vious studies. It excluded the severest ene medications and agree that they tion of the inflammatory lining asthma cases, and its blinded nature are an adjunct rather than primary and pathologic hyperplasia. Three was created with sham bronchoscopy therapy. The GINA 2016 guide- sequential bronchoscopies are per- to eliminate possible placebo effect. lines support the use of LTRAs in formed 3 weeks apart to treat the The study questionnaires showed im- mild asthma, stating that although right lower lobe, left lower lobe, proved QOL overall (79% vs 64%); LTRAs are less effective than ICS and bilateral upper lobes. The right however, there was a definite placebo (Evidence A), they may be appro- middle lobe is not treated due to its effect noted.60 Decreased frequency priate for initial controller treatment smaller diameter. Each bronchos- of severe exacerbations as well as for some patients who are unable or copy takes about 30 to 60 minutes. ED visits and days lost from work unwilling to use ICS or for patients Patients are given perioperative or school also were documented as with concurrent allergic rhinitis steroids.56 secondary endpoints. At 5 years, de- (Evidence B).51,52 Three large phase 3 clinical trials creased frequency of severe exacer- Zileuton is a different type of an- have evaluated the efficacy of bron- bations and ED visits continued in tileukotriene. It inhibits leukotrienes chial thermoplasty (BT). The AIR the control group (85% consented to B4, C4, D4, and E4 by inhibition of (Asthma Intervention Research) trial follow-up).61 Importantly, despite the 5-lipoxygenase, interfering with leu- in 2007 was a randomized controlled placebo effect in QOL scores, there kotriene formation. It is approved study of 112 patients with moderate were no improvements in exacerba- for patients aged ≥ 12 years and is or severe asthma that showed im- tion rates or hospitalizations in those more expensive than montelukast proved exacerbation rates, symptom- receiving sham bronchoscopy at the or zafirlukast. Most studies support- free days and QOL scores (1.3 ± 1.0 1-year mark.61 ing its use were conducted in pa- vs 0.6 ± 1.1; P = .003), but no differ- Although more longitudinal stud- tients with mild-to-moderate asthma ence in prebronchodilator FEV1 or ies need to be planned, including on β-agonist therapy only. A 1988 AHR.57 There was a significant reduc- evaluation of those with the most study showed that zileuton therapy tion in the rate of mild exacerbations severe asthma, there seems to be a 57 improved FEV1, reduced nasal symp- and increase in morning PEF rates. sustained improvement in patients. toms, and decreased bronchial re- Findings at 5 years showed improved Those who have received BT gen- sponsiveness to inhaled aspirin and AHR but no difference in frequency erally are found to have reduced histamine.53 All but 1 study patient of need for oral corticosteroids and airway smooth muscle with lower were on ICS or oral corticosteroids. frequency of hospital or emergency concentration of key inflamma- Zileuton was noted to be effective department (ED) visits.58 tory cytokines on follow-up bron- for patients with aspirin-intolerant The Research in Severe Asthma choscopy. However, variability in asthma. (RISA) clinical trial was a random- response has been documented.56

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There has been no documented dete- NAEPP (EPR-3) and ERS/ATS Author disclosures rioration in pulmonary function with recommend stepwise increases in The authors report no actual or poten- BT, and no significant structural ab- the dose of ICS in combination with tial conflicts of interest with regard to normalities have been seen on high- a LABA. The GINA guidelines rec- this article. resolution computed tomography.56,58 ommend controller therapy to in- Both GINA 2016 and ERS/ATS sup- clude combination IHS and LABA Disclaimer port the use of BT in the context of but with the consideration of higher The opinions expressed herein are those adults with severe asthma, calling for doses of ICS than are routinely rec- of the authors and do not necessarily more long-term studies to address ommended for general use. reflect those of Federal Practitioner, delayed benefits and safety. Frontline Medical Communications Inhaler and Inhaler Combinations Inc., the U.S. Government, or any of its LABA INHALERS Many different inhalers of ICS alone agencies. This article may discuss un- A multicenter, double-blind, 26-week and ICS/LABA combinations exist labeled or investigational use of certain study of 11,693 patients random- on the market today. There are dif- drugs. Please review the complete pre- ized to ICS + LABA (/ ferences in delivery that affect patient scribing information for specific drugs ) vs ICS (budesonide) preference but these differences have or drug combinations—including indi- alone has shown no increased AEs not been found to improve delivery. cations, contraindications, warnings, in either arm. The study found that Small particle ICS therapy could pos- and adverse effects—before administer- treatment with budesonide/for- sibly correlate with improved deliv- ing pharmacologic therapy to patients. moterol was associated with lower ery to the small airways.65 There are risk of asthma exacerbations than 3 preparations of inhaled steroids REFERENCES 1. Centers for Disease Control and Prevention. using budesonide alone (16.5%; that fit in to this group, including Asthma facts: CDC’s national asthma control pro- P = .002).62 beclomethasone, , and gram grantees. https://www.cdc.gov/asthma/pdfs /asthma_facts_program_grantees.pdf. Published The safety of adding a LABA to . Other inhaled steroid July 2013. Accessed November 9, 2017. fluticasone also has been evaluated formulations include budesonide, 2. Wilson DH, Adams RJ, Tucker G, Appleton S, Tay- lor AW, Ruffin RE. Trends in asthma prevalence and recently. 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