Clinic Rev Allerg Immunol DOI 10.1007/s12016-014-8444-9
Biological Modulators in Eosinophilic Diseases Panida Sriaroon & Mark Ballow
# Springer Science+Business Media New York 2014
Abstract Eosinophils can regulate local and systemic inflammation, and their presence in higher numbers appears to play an important role in the pathology of various atopic and inflammatory diseases. Eosinophil maturation, recruitment, and survival depend on several cytokine regulators, including interleukin (IL)-5, IL-4, and IL-13 as well as growth factors such as GM-CSF. Over the last decade, the approach to treating eosinophilic diseases has changed greatly. A number of biologic modulators have been developed to target eosinophilic inflammatory pathways, and their usage has resulted in variable clinical improvement in the treatment of eosinophilicassociated conditions. Novel targeted therapies that are safe and effective for treating these disorders are being investigated. This review summarizes the clinical use of biologic agents that have been studied in clinical trials or approved for treating eosinophilic diseases. Keywords Eosinophils . Eosinophilic diseases . Biologics . Monoclonal antibodies . Asthma . Hypereosinophilic syndrome . Eosinophilic granulomatosis with polyangiitis . Churg-Strauss syndrome . Nasal polyposis . Eosinophilic esophagitis Abbreviations mAb Monoclonal antibody HES Hypereosinophilic syndrome CHR Complete hematologic response CMR Complete molecular response CSS Churg-Strauss syndrome EGPA Eosinophilic granulomatosis with polyangiitis NP Nasal polyposis P. Sriaroon (*) : M. Ballow Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of South Florida, 140 7th ave S, CRI 4008, St. Petersburg, FL 33701, USA e-mail: [email protected]
EOE CRTH2
Eosinophilic esophagitis Chemoattractant receptor homologous molecule expressed on Th2 cells
Introduction Eosinophils are derived from common myeloid progenitors in the bone marrow, and they undergo maturation and proliferation in the peripheral circulation. The development and survival of eosinophils depend largely on transcription factors and several cytokines, particularly interleukin (IL)-3 and IL-5, and granulocyte-macrophage colony-stimulating factor (GMCSF) [1]. Of these cytokines, IL-5 is the most lineage specific and serves as a major eosinophil regulator [2]. In eosinophilrelated disorders, the immune responses and inflammation occur in tissues after eosinophil activation that results in the release of either preformed or newly produced mediators, including cytotoxic cationic granule proteins, lipid mediators, growth factors, proinflammatory cytokines and chemokines (Table 1). Eosinophils express an array of cell-surface receptors (Fig. 1) [3]. Some of these regulatory cytokines and eosinophil surface molecules are unique to eosinophils and have been actively studied as potential therapeutic targets for eosinophilic diseases. Peripheral eosinophilia can be associated with various conditions, including parasitic infection, allergies, drug reactions, metabolic diseases, some hematologic malignancies, and proliferative disorders. In most cases, treatments are typically geared toward managing the underlying condition. By contrast, rare disorders such as hypereosinophilic syndrome (HES), Churg-Strauss syndrome (CSS), and eosinophilic gastrointestinal disorders (EGID) can present with chronic eosinophilia in blood, tissue, or both without an identifiable cause. In more common diseases such as asthma and nasal polyposis (NP), eosinophilic inflammation in tissues is found in subsets of patients. These eosinophilic-associated conditions may lead
Clinic Rev Allerg Immunol Table 1 Eosinophil-derived mediators
Cationic granule proteins Lipid mediators Growth factors
IL interleukin, GM-CSF granulocyte-macrophage colonystimulating factor, RANTES regulated on activation normal T cell expressed and secreted, MIP macrophage inflammatory protein, MCP monocyte chemoattractant protein
Cytokines Chemokines Others
Major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN) Leukotrienes (LTC4), prostaglandins (PGE1 and PGE2), 15-hydroxyeicosatetraenoic acid (HETE), and platelet-activating factor (PAF) Transforming growth factor (TGF)-α/β, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), and stem cell factor (SCF) IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-11, IL-12, IL-13, IL-16, IL-18, GM-CSF, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α CCL5 (RANTES), CCL11 (eotaxin), CXCL8 (IL-8), CCL3 (MIP-1α), CCL7 (MCP-3), and CCL13 (MCP-4) Charcot-Leyden crystal protein (CLC; galectin-10), enzymes (acid phosphatase, arylsulfatase, collagenase, and metalloproteases), and reactive oxygen species
to significant morbidity and mortality and usually require long-term therapy. Corticosteroids remain the most effective form of first-line treatment to reduce blood and tissue eosinophilia. Corticosteroid therapy inhibits pro-survival signals induced by IL-3, IL5, and GM-CSF and directly induces apoptosis thus promoting eosinophil clearance [4]. Prolonged systemic corticosteroid use is often problematic due to its unfavorable adverse effect profile. Other treatment options for chronic eosinophilic diseases such as HES and CSS are often limited due to lack of efficacy or poor tolerability. Therefore, there is a significant
need for new therapies in individuals who fail standard treatment. Recent advances in our understanding of the pathophysiologic mechanisms of the eosinophilic-associated conditions have led to the new concept of endotype-specific therapy. As a result, several promising novel therapeutic agents have been designed and investigated. The tyrosine kinase inhibitor, imatinib, has transformed the treatment of HES and some hematologic disorders, but only in patients with specific genetic rearrangements. Therapy targeting IL-5 has been studied in human clinical trials for the treatment of asthma, HES, CSS, NP, and EGID. As discussed below, anti-IL-5 monoclonal
Fig. 1 Eosinophil surface markers. IL interleukin, TNF-α tumor necrosis factor-α, IFN-γ interferon-γ, CR complement receptor, CCR chemokine receptor, CXCR chemokine receptor, CRTH2 chemoattractant receptor homologous molecule expressed on Th2 cells, CysLT cysteinyl-
leukotriene, PAFR platelet-activating factor receptor, LTB4R leukotriene B4 receptor, LIR3 leukocyte immunoglobulin-like receptor 3, KIR2DL3 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail 3, Siglec sialic acid-binding immunoglobulin-type lectin
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antibody (mAb) treatments have been shown to dramatically reduce blood eosinophilia in these diseases but the reduction of tissue eosinophil counts and clinical benefits vary depending on the disorder and patient selection. In this review, we provide an overview of biologic agents that have been studied in human clinical trials or approved for eosinophil-related diseases, as described in Table 2. Novel agents in development are also discussed briefly.
Asthma Asthma is classically defined by chronic episodic bronchospasm and variable airflow obstruction due to airway inflammation and nonspecific bronchial hyper-responsiveness. Approximately, one third to one half of adult patients with asthma have elevated eosinophil counts in the airway [47], also termed eosinophilic asthma. There is a correlation between blood [48], sputum [49, 50], and bronchoalveolar lavage fluid eosinophilia [48] and asthma severity. Traditional therapy for asthma includes inhaled corticosteroids (ICS), β2-receptor agonists, leukotriene receptor antagonists, and anticholinergic agents. However, complete symptom control is not achieved in a large subgroup of asthmatics [51–54], and there are a substantial number of patients with moderate-to-severe uncontrolled asthma who require additional therapy. Research has provided evidence that asthma represents a heterogeneous condition that is characterized by multiple phenotypes. Attempts have been made to categorize these phenotypes based on molecular characteristics, biomarkers, and cellular phenotyping rather than using only clinical or physiologic profiles [55]. New treatment approaches for asthma have focused on phenotype-directed management rather than a universal strategy, especially in individuals with more severe disease.
Anti-IgE Therapy Omalizumab Omalizumab (Xolair) is a recombinant DNA-derived humanized anti-IgE IgG1 mAb. The drug has been approved in the USA since 2003 for the treatment of moderate-to-severe persistent allergic asthma in patients ≥12 years old whose symptoms are not adequately controlled with ICS. Until now, omalizumab has been the only approved biologic for the treatment of asthma. In March 2014, the US Food and Drug Administration (FDA) approved omalizumab for the treatment of chronic idiopathic urticaria in patients 12 years and older. Omalizumab selectively binds the Cε3 domain in heavy chain of circulating free IgE, regardless of IgE specificity, and prevents its binding to the high-affinity IgE receptor (FCεRI) on mast cells, basophils, and dendritic cells, as well as a low-
affinity IgE receptor (FCεRIIB) expressed on eosinophils, macrophages, and lymphocytes. In asthma patients, this action results in markedly attenuated activation of IgE, which leads to decreased secretion of mediators, cytokines and chemokines from inflammatory cells, decreased sputum and bronchial eosinophilia [56, 57], and consequently, interruption of the allergic cascade of asthma [58]. Omalizumab does not cross-link or bind to receptor-bound IgE on the cell surface [58]. The significant effects of omalizumab that were discovered during clinical trials include the reduction of the free IgE levels [59], and the downregulation of FcεRI expression on basophils, mast cells, and dendritic cells [60, 61], making those cells much less sensitive to the allergen stimulation. Omalizumab also has demonstrated benefits in management of several other atopic conditions such as oral food desensitization [62, 63], allergen immunotherapy [64–67], venom immunotherapy [68], and NP [40] and has been investigated in the treatment of allergic rhinitis [69], atopic dermatitis [70], as well as allergic bronchopulmonary aspergillosis in patients with cystic fibrosis [71, 72]. Omalizumab has demonstrated therapeutic efficacy as an add-on treatment in several large clinical trials of allergic asthma. The drug improves asthma symptoms [6, 7] and quality of life [8, 9], decreases asthma exacerbations [5–10], reduces ICS dosage requirements [6, 8], rescues bronchodilator use [6–8], and decreases emergency room visits and hospitalizations [5, 9]. The EXTRA study, a large longitudinal randomized, double-blind, placebo-controlled (RDBPC) multicenter study, evaluated the efficacy and safety of omalizumab treatment during the 48-week treatment period in 850 subjects with poorly controlled severe asthma [7]. The treatment group had significant improvements in the rate of asthma exacerbations (25 % decrease, P=0.006), bronchodilator use, asthma symptoms, and asthma-related quality of life scores compared with the placebo group. Biomarker analysis reported in the follow-up study [73] showed that the reduction in asthma exacerbation frequency was greater in subgroups with high levels of fractional exhaled nitric oxide (FeNO) (53 vs 16 % with placebo), blood eosinophil counts (32 vs 9 % with placebo), and serum periostin (30 vs 3 % with placebo), when compared with the low-biomarker subgroups. The results of this study suggest the potential use of biomarkers in identifying subsets of patients who may respond better to omalizumab treatment. Studies have shown that omalizumab can effectively lower free serum IgE levels by 96–99 %, suppress new IgE production [11], and reduce airway inflammation [74–76], although its effect on airway remodeling remains unclear. In addition, no correlation was found between free serum IgE levels and clinical response [77]. Measurement of total IgE is needed at baseline to determine appropriate dosing but is not required during omalizumab treatment. This is because omalizumab forms a complex with IgE, which can potentially lead to a
IL-5Rα IL-4Rα IL-4Rα IL-4Rα IL-13 IL-13 IL-13 IL-13 CCR3/βc CCR3 CRTH2 D-prostanoid/CRTH2 TLR9 FIP1L1-PDGFRA
IL-5 IL-5 IL-5Rα CD52
Benralizumab (Medi-563) Pitrakinra (Aerovant) AMG 317 Dupilumab
Lebrikizumab
Tralokinumab Anrukinzumab (IMA-638)
GSK679586 TPI ASM8
GW766994 OC000459
AMG 853 QbG10
Imatinib mesylate (Gleevec)
Mepolizumab Reslizumab
Benralizumab Alemtuzumab (Campath)
Mepolizumab
Omalizumab Mepolizumab
EGPA (CSS)
NP and asthma NP
IgE IL-5
IL-5
FDA- and EMA-approved
IL-5
Reslizumab (Cinquil)
HES
Phase I/II Phase II
IL-5
Mepolizumab (Bosatria)
Phase II Phase II
Phase III
Phase II Case series
Phase III Phase I/II
Phase II Phase II
Phase I/II Phase II
Phase I/II Phase II
Phase II/III
Phase III Phase II Phase II Phase II/III
Phase III
Phase III
FDA and EMA approved
IgE
Omalizumab (Xolair)
Development
Asthma
Target
Drug
Disease
Table 2 Biologic modulators in eosinophilic diseases
Steroid-sparing; decreases peripheral blood eosinophilia [34, 35] Improves symptoms; decreases peripheral blood eosinophilia; rebound eosinophilia and symptom recurrence after cessation (data from small case reports) [36] Study ongoing Improves symptoms; complete or partial hematologic response but most with relapse after cessation (data from retrospective analysis) [37] Steroid sparing; decreases peripheral blood eosinophilia; symptom recurrence after cessation (data from small case series) [38, 39] Decreases polyp scores; improves nasal and asthma symptoms and QOL scores [40] Decreases polyp scores [41]
No clinical benefit as add-on therapy in severe refractory asthma [26] Reduces allergen-induced early-phase asthmatic response; reduces allergen-induced sputum eosinophilia [27] No clinical benefit as add-on therapy in eosinophilic asthma [28] Improves FEV1 particularly in subgroup with peripheral eosinophilia; improves asthma control; reduces exacerbations [29] No clinical benefit as add-on therapy in poorly controlled asthma [30] Improves asthma symptoms; steroid-sparing [31]; recent larger trial terminated early (Clinicaltrials.gov NCT01673672) Improves HES-related symptoms; reduces peripheral eosinophilia and serum tryptase; induces CHR in PDGFRA-positive myeloproliferative variant HES [32, 33]; molecular remission in most patients [33]
Reduces exacerbations and asthma symptoms; reduces ICS and rescue medication use; improves quality of life; reduces hospitalizations and emergency room visits [5–10]; reduces free serum IgE levels and FcεRI on mast cells and dendritic cells [11] Reduces exacerbations; steroid-sparing [12–14]; reduces sputum and blood eosinophils [14, 15] Improves FEV1; trend toward improved asthma control and decreased exacerbations [16] reduces sputum and blood eosinophils [16, 17] Reduces blood eosinophils; reduces bone marrow eosinophils and eosinophil precursors [18] Reduces allergen-induced late-phase asthmatic response [19] No significant clinical efficacy [20] Reduces exacerbations; improves asthma symptoms and FEV1; no reduction in blood or sputum eosinophils [21] Improves FEV1 particularly in high-periostin subgroup in one study [22]; no improvement of FEV1 in another study [23] No improvement in asthma control; trend toward improved FEV1 [24] Reduces allergen-induced early- and late-phase asthmatic response [25]
Outcome
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Ig immunoglobulin, FDA The US Food and Drug Administration, EMA The European Medicines Agency, IL interleukin, ICS inhaled corticosteroids, FEV1 forced expiratory volume in 1 s, CCR3 chemokine receptor 3, βc common β subunit of IL-3, IL-5, and GM-CSF receptors, CRTH2 chemoattractant receptor homologous molecule expressed on Th2 cells, TLR9 Toll-like receptor 9, HES hypereosinophilic syndrome, FIP1L1-PDGFRA FIP1-like 1-platelet-derived growth factor receptor-alpha fusion gene, CHR complete hematologic response, EGPA eosinophilic granulomatosis with polyangiitis, CSS Churg-Strauss syndrome, NP nasal polyposis, QOL quality of life, EoE eosinophilic esophagitis
IL-5 Reslizumab
EoE
Phase II/III
Decreases polyp scores [42] Study ongoing Trend toward improving symptoms [43]; symptom improvement correlates with reduction in esophageal mast cell counts [44]; decreases esophageal eosinophil and mast cell counts [43–45] Symptom improved in all groups including placebo; decreases esophageal eosinophil counts [46] IL-5 IL-4Rα IL-5 Reslizumab Dupilumab Mepolizumab
Phase I Phase II Phase II
Target Drug Disease
Table 2 (continued)
Development
Outcome
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falsely elevated total serum IgE level. Measurement of unbound IgE in patients receiving omalizumab treatment is not routinely needed. Omalizumab has been shown to modulate sputum, bronchial, as well as peripheral eosinophilia [6, 10, 56]. In a meta-analysis, reduction in blood eosinophil counts was associated with improved clinical outcomes, including a decrease in asthma exacerbations requiring corticosteroid bursts [78]. The antieosinophilic property of omalizumab is presently being investigated. Although approved for the treatment of asthma, the use of omalizumab in other eosinophilic diseases remains investigational. The dosing of omalizumab in allergic asthma is based on body weight and pretreatment serum IgE level. In the USA, the eligibility criteria for omalizumab treatment in allergic asthma include a baseline total serum IgE level ranging between 30 and 700 IU/mL. Patients with nonallergic asthma and those with higher IgE levels are not to be treated with omalizumab. However, anecdotal evidence exists to support the use of omalizumab in patients with nonallergic asthma [40]. Subjects with very high serum IgE levels are excluded from treatment because it is unlikely that there would be sufficient antibody to effectively bind to all the IgE [79]. The drug is administered by subcutaneous injection monthly, or every 2 weeks for higher dosages, and patients should receive at least 0.016 mg/kg/IgE (IU/mL) every 4 weeks. Dosage adjustment is not required based on age. The duration of omalizumab treatment is generally at the discretion of the treating physician. More data are needed to determine the clinically measurable biomarkers that could predict a good response and the optimum duration of treatment. Due to high cost, a trial of treatment over 4 months is often recommended to identify good responders. Bousquet et al. evaluated 400 patients receiving standard asthma therapy or standard therapy and omalizumab by using the global evaluation of treatment effectiveness scale, and found that clinical assessment at 16 weeks is an effective predictor of persistency of response at 32 weeks for the majority of patients [80]. Despite the high cost of omalizumab vs other standard asthma medications, add-on omalizumab appears to be cost effective in reducing healthcare costs in industrialized countries [81], particularly costs related to symptomatic drug use, hospitalizations, emergency room visits, and unscheduled physician’s visits in patients with severe persistent asthma. Omalizumab has a favorable safety and tolerability profile [82]. In a systematic review of eight placebo-controlled trials (n=3,429) [83], omalizumab was generally well tolerated with the most common side effects being local injection-site reactions (19.9 vs 13.2 % placebo; P=0.002), including injectionsite pain, bruising, swelling, erythema, and pruritus. Other adverse events include nasopharyngitis, headache, and upper respiratory tract infection. A pooled analysis of
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data from nearly 1,000 six- to eleven-year-old children found similar results [84]. Data from the eXpeRience registry showed that 6.9 % (64 of 925) of real-world omalizumab-treated patients reported at least one serious adverse event during the treatment periods up to 2 years [85]. Anaphylaxis occurred infrequently in patients receiving omalizumab injections (approximately 0.09– 0.14 %) [82, 86]. Sixty-one percent of anaphylaxis events happened within the first 2 h after the first three injections, and 14 % occurred within 30 min after the fourth or later injection [87]. In 2007, the Omalizumab Joint Task Force from the American Academy and College of Allergy, Asthma & Immunology recommended a waiting period after injection and that patients receiving omalizumab carry an epinephrine autoinjector for 24 h after receiving the treatment. Postmarketing reports confirmed episodes of anaphylaxis, and in 2011 the Task Force confirmed its ongoing support for the 2007 recommendation [88]. Previous pooled data from phase I to III trials in 2003 showed higher incidence of malignancy in omalizumabtreated subjects (0.5 %) compared with controls (0.2 %) [89] and consequently a malignancy warning is included in the package insert although the biological plausibility of a mechanism by which the drug could cause malignancy has not been established. Data from two recent studies did not suggest an association between omalizumab therapy and risk of malignancy [90, 91]. In a pooled analysis of 67 phases I to IV clinical trials of omalizumab, 32 were RDBPC studies and malignancies were identified in 14 of 4,254 omalizumab-treated patients and 11 in 3,178 placebotreated patients with a rate ratio of 0.73 [90]. The primary malignancies reported in patients enrolled in those trials included a wide range of histologic types and occurred in varying organ systems. The EXCELS study, which is a prospective phase IV postmarketing 5year registry of 7,000 omalizumab-treated and nonomalizumab-treated patients, found similar malignancy rates in both groups [91]. The rate ratio was 0.84 (95 % confidence interval (CI), 0.62–1.13) for all malignancies including nonmelanoma skin cancer (NMSC) and 0.98 (95 % CI, 0.71–1.36) for all malignancies excluding NMSC. Reported malignancies were mostly solid tumors, including skin, breast, and prostate cancer. Compelling evidence demonstrates that omalizumab is effective and safe as an add-on therapy in children 6 years and older with moderate-to-severe persistent allergic asthma [84, 92, 93]. The adverse events are similar to those previously reported in adults [84]. In the European Union, omalizumab is approved for use in children over 6 years of age while the US FDA does not recommend the drug in children aged 6–11, reasoning that the reduction in exacerbations was modest and was not sufficient to justify the high treatment cost [94].
Anti-IL-5 Therapy IL-5 regulates the differentiation, maturation, activation, tissue recruitment, and survival of eosinophils [95]. Activation of the IL-5 receptor-α (IL-5Rα) on the surface of eosinophils induces the recruitment and survival of these cells. Inhibition of IL-5 has been shown to lower blood and sputum eosinophil levels [17, 96] with some promising clinical efficacy in selected asthma subgroups. In addition to asthma, anti-IL-5 mAbs have also been investigated for the treatment of other eosinophil-associated conditions such as hypereosinophilic diseases, CSS, and EoE [34–36, 38, 39, 43, 45, 46]. The antibodies target eosinophils either by preventing circulating IL-5 binding to IL-5Rα on the surface of eosinophils (mepolizumab and reslizumab) or by blocking IL-5Rα (benralizumab). Mepolizumab Mepolizumab (Bosatria) is a humanized murine IgG1 mAb against free IL-5. The antibody neutralizes IL-5 by inhibiting binding of IL-5 to the α chain of the IL-5 receptor expressed on eosinophils [97]. Mepolizumab has been investigated for the treatment of asthma, atopic dermatitis, HES, EoE, and NP and is now being investigated in a phase III study for severe asthma with eosinophilic inflammation and CSS. In earlier studies of asthma in which patients were not recruited on the basis of eosinophilic inflammation in the airways, mepolizumab resulted in definite reductions in blood and sputum eosinophils but failed to show improvement in asthma symptoms, measures of bronchial hyper-responsiveness, pulmonary function, or exacerbation frequency [15, 96]. However, its demonstrated efficacy in improving skin manifestations [97, 98] and a precipitous reduction in tissue and blood eosinophil counts [97] in patients with HES encouraged the continued effort to study mepolizumab in asthma and other eosinophilic diseases. Two small proof-of-concept studies of mepolizumab in asthma by Haldar et al. and Nair et al. that were targeted specifically at patients with asthma with persistent eosinophilic airway inflammation yielded the same conclusion despite using different outcome measures [12, 13]. In these trials, mepolizumab exhibited benefits as a prednisone-sparing agent, reduced the frequency of asthma exacerbation, and improved quality of life in subjects with severe refractory eosinophilic asthma. In a larger RDBPC Dose-Ranging Efficacy and Safety with Mepolizumab in Severe Asthma (DREAM) trial of 621 patients from 81 multinational centers, subjects with severe, exacerbation-prone asthma with sputum eosinophil counts ≥3 %, FeNO ≥50 ppb, and peripheral eosinophilia were randomized to three different doses of mepolizumab or placebo for over 1 year [14]. All treatment groups had fewer asthma exacerbations (reduced by
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approximately 50 %), visits to emergency departments, hospital admissions, and lower blood and sputum eosinophil counts; however, no significant changes in forced expiratory volume in 1 s (FEV1) or asthma symptoms were observed. Response to mepolizumab correlated with baseline blood eosinophil counts but not atopy history or serum IgE levels. These studies support the significance of asthma phenotyping and provide further compelling evidence for mepolizumab as an effective and safe treatment in subgroups with severe asthma and active eosinophilic inflammation, particularly those with frequent exacerbations. Despite promising effects in selected patients, as evidenced by remarkable improvement in exacerbation frequency, clinical use of mepolizumab is cautioned by some due to the rarity of eosinophilic-related asthma and its limited effectiveness in improving asthma symptoms and lung function [99, 100]. This marked dissociation between the clinical and functional measurements and the exacerbations suggests that different underlying pathological mechanisms exist and mepolizumab therapy may only suppress inflammation mediated by eosinophils [99, 101]. The observations of an increase in plasma IL-5 levels and IL-5Rα expression by blood eosinophils after mepolizumab treatment in a variety of eosinophilic diseases led to concerns that there could, theoretically, be a rebound worsening of tissue inflammation when anti-IL-5 therapy is discontinued [102]. A follow-up unblinded, prospective, observational study by Haldar et al. examined the clinical and biological markers after cessation of mepolizumab therapy in refractory eosinophilic asthma [103]. Soon after stopping the 12-month treatment, sputum and blood eosinophil counts expanded and reached baseline levels within 6 months. Similarly, the frequency of asthma exacerbation increased significantly after stopping mepolizumab and by 12 months was not significantly different in the mepolizumab vs placebo group. The authors suggested that the increase in symptoms after treatment withdrawal may, in part, represent regression to the mean symptom scores due to lower levels in the treatment group at the end of study period and were unlikely to be due to a rebound phenomenon. Reslizumab Reslizumab (Cinquil, formerly SCH55700) is a humanized IgG4 anti-IL-5 mAb. With high affinity to human IL-5, the antibody binds to and neutralizes circulating IL-5 by preventing its binding to eosinophils. Reslizumab has been studied in several randomized controlled clinical trials in asthma [16, 17], NP [42], EoE [46], as well as small openlabel studies in HES [36] and EGID with peripheral eosinophilia [104]. In a small pilot RDBPC dose-ranging study of a single intravenous dose reslizumab in patients with poorly controlled asthma, no significant changes in FEV 1 or
symptom score were observed in the treatment group despite the profound decrease in blood eosinophil counts which occurred in a dose-dependent fashion [17]. Post hoc analysis demonstrated a significant increase in FEV1 in patients with baseline sputum eosinophils >3 % who received 1.0 mg/kg reslizumab vs placebo; this treatment effect was not detected in subjects with lower baseline sputum eosinophil counts. This finding prompted further trials of reslizumab in diseases characterized by tissue eosinophilia, such as eosinophilic asthma, NP, and EoE. A more recent phase II RDBPC multicenter trial investigated the use of reslizumab (3 mg/kg once each month for 4 months) in patients with poorly controlled eosinophilic asthma, some with NP [16]. The drug resulted in a statistically significant yet small improvement in FEV1 when compared with placebo after 15 weeks and there was a trend toward improved asthma control as measured by an asthma control questionnaire (ACQ) score. Reslizumab profoundly reduced sputum and blood eosinophils counts. There was also a trend toward decreased exacerbations in the reslizumab group, but exacerbations were infrequent in both arms, likely due to the short duration of the study. Greater clinical benefit was observed in patients with concomitant NP although the direct effect of reslizumab on nasal polyps was not studied. The most frequently reported adverse events were nasopharyngitis, fatigue, and pharyngolaryngeal pain. During a short duration of follow-up (3 weeks after the last dose), rebound eosinophilia was not observed. This study has added to the literature the importance of defining a distinct patient population in which the anti-IL-5 therapy has the most potential benefit. However, a larger and longer duration study is needed. Benralizumab Benralizumab (MEDI-563) is a humanized, afucosylated, IgG1 mAb that binds specifically to the α-subunit of the human IL-5Rα on eosinophils and basophils [105], resulting in inhibition of IL-5-mediated receptor activation. Afucosylation significantly augments the binding affinity of benralizumab to the FcγRIIIa, the main activating Fcγ receptor expressed on natural killer cells, macrophages, and neutrophils, causing enhanced antibody-dependent cellular cytotoxicity (ADCC) functions that mediate eosinophil apotosis [106]. It has been suggested that benralizumab might have a greater clinical efficacy than either mepolizumab or reslizumab for several reasons. First, the eosinophil depletion from benralizumab occurs through highly efficient ADCC rather than through passive removal of IL-5 by means of IL5 neutralization and inhibition. Therefore, benralizumab may deplete eosinophils with relatively low levels of IL-5Rα expression including those that are independent on IL-5 as a survival factor [107]. Second, benralizumab has been shown to reduce airway eosinophilic infiltration in addition to
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depleting sputum and blood eosinophils [18], which has not been observed after other anti-IL-5 mAb therapies. In the initial phase I open study of benralizumab in patients with mild atopic asthma, striking, dose-dependent reductions in blood eosinophil counts were observed within 24 h of administration of a single intravenous dose of each of the seven doses administered [108]. Eosinopenia persisted more than 12 weeks in the highest dose group. In addition, there was a transient reduction in white blood cell counts in all dose cohorts, with more than half the patients having a marked decrease to
Biological Modulators in Eosinophilic Diseases Panida Sriaroon & Mark Ballow
# Springer Science+Business Media New York 2014
Abstract Eosinophils can regulate local and systemic inflammation, and their presence in higher numbers appears to play an important role in the pathology of various atopic and inflammatory diseases. Eosinophil maturation, recruitment, and survival depend on several cytokine regulators, including interleukin (IL)-5, IL-4, and IL-13 as well as growth factors such as GM-CSF. Over the last decade, the approach to treating eosinophilic diseases has changed greatly. A number of biologic modulators have been developed to target eosinophilic inflammatory pathways, and their usage has resulted in variable clinical improvement in the treatment of eosinophilicassociated conditions. Novel targeted therapies that are safe and effective for treating these disorders are being investigated. This review summarizes the clinical use of biologic agents that have been studied in clinical trials or approved for treating eosinophilic diseases. Keywords Eosinophils . Eosinophilic diseases . Biologics . Monoclonal antibodies . Asthma . Hypereosinophilic syndrome . Eosinophilic granulomatosis with polyangiitis . Churg-Strauss syndrome . Nasal polyposis . Eosinophilic esophagitis Abbreviations mAb Monoclonal antibody HES Hypereosinophilic syndrome CHR Complete hematologic response CMR Complete molecular response CSS Churg-Strauss syndrome EGPA Eosinophilic granulomatosis with polyangiitis NP Nasal polyposis P. Sriaroon (*) : M. Ballow Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of South Florida, 140 7th ave S, CRI 4008, St. Petersburg, FL 33701, USA e-mail: [email protected]
EOE CRTH2
Eosinophilic esophagitis Chemoattractant receptor homologous molecule expressed on Th2 cells
Introduction Eosinophils are derived from common myeloid progenitors in the bone marrow, and they undergo maturation and proliferation in the peripheral circulation. The development and survival of eosinophils depend largely on transcription factors and several cytokines, particularly interleukin (IL)-3 and IL-5, and granulocyte-macrophage colony-stimulating factor (GMCSF) [1]. Of these cytokines, IL-5 is the most lineage specific and serves as a major eosinophil regulator [2]. In eosinophilrelated disorders, the immune responses and inflammation occur in tissues after eosinophil activation that results in the release of either preformed or newly produced mediators, including cytotoxic cationic granule proteins, lipid mediators, growth factors, proinflammatory cytokines and chemokines (Table 1). Eosinophils express an array of cell-surface receptors (Fig. 1) [3]. Some of these regulatory cytokines and eosinophil surface molecules are unique to eosinophils and have been actively studied as potential therapeutic targets for eosinophilic diseases. Peripheral eosinophilia can be associated with various conditions, including parasitic infection, allergies, drug reactions, metabolic diseases, some hematologic malignancies, and proliferative disorders. In most cases, treatments are typically geared toward managing the underlying condition. By contrast, rare disorders such as hypereosinophilic syndrome (HES), Churg-Strauss syndrome (CSS), and eosinophilic gastrointestinal disorders (EGID) can present with chronic eosinophilia in blood, tissue, or both without an identifiable cause. In more common diseases such as asthma and nasal polyposis (NP), eosinophilic inflammation in tissues is found in subsets of patients. These eosinophilic-associated conditions may lead
Clinic Rev Allerg Immunol Table 1 Eosinophil-derived mediators
Cationic granule proteins Lipid mediators Growth factors
IL interleukin, GM-CSF granulocyte-macrophage colonystimulating factor, RANTES regulated on activation normal T cell expressed and secreted, MIP macrophage inflammatory protein, MCP monocyte chemoattractant protein
Cytokines Chemokines Others
Major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN) Leukotrienes (LTC4), prostaglandins (PGE1 and PGE2), 15-hydroxyeicosatetraenoic acid (HETE), and platelet-activating factor (PAF) Transforming growth factor (TGF)-α/β, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), and stem cell factor (SCF) IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-11, IL-12, IL-13, IL-16, IL-18, GM-CSF, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α CCL5 (RANTES), CCL11 (eotaxin), CXCL8 (IL-8), CCL3 (MIP-1α), CCL7 (MCP-3), and CCL13 (MCP-4) Charcot-Leyden crystal protein (CLC; galectin-10), enzymes (acid phosphatase, arylsulfatase, collagenase, and metalloproteases), and reactive oxygen species
to significant morbidity and mortality and usually require long-term therapy. Corticosteroids remain the most effective form of first-line treatment to reduce blood and tissue eosinophilia. Corticosteroid therapy inhibits pro-survival signals induced by IL-3, IL5, and GM-CSF and directly induces apoptosis thus promoting eosinophil clearance [4]. Prolonged systemic corticosteroid use is often problematic due to its unfavorable adverse effect profile. Other treatment options for chronic eosinophilic diseases such as HES and CSS are often limited due to lack of efficacy or poor tolerability. Therefore, there is a significant
need for new therapies in individuals who fail standard treatment. Recent advances in our understanding of the pathophysiologic mechanisms of the eosinophilic-associated conditions have led to the new concept of endotype-specific therapy. As a result, several promising novel therapeutic agents have been designed and investigated. The tyrosine kinase inhibitor, imatinib, has transformed the treatment of HES and some hematologic disorders, but only in patients with specific genetic rearrangements. Therapy targeting IL-5 has been studied in human clinical trials for the treatment of asthma, HES, CSS, NP, and EGID. As discussed below, anti-IL-5 monoclonal
Fig. 1 Eosinophil surface markers. IL interleukin, TNF-α tumor necrosis factor-α, IFN-γ interferon-γ, CR complement receptor, CCR chemokine receptor, CXCR chemokine receptor, CRTH2 chemoattractant receptor homologous molecule expressed on Th2 cells, CysLT cysteinyl-
leukotriene, PAFR platelet-activating factor receptor, LTB4R leukotriene B4 receptor, LIR3 leukocyte immunoglobulin-like receptor 3, KIR2DL3 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail 3, Siglec sialic acid-binding immunoglobulin-type lectin
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antibody (mAb) treatments have been shown to dramatically reduce blood eosinophilia in these diseases but the reduction of tissue eosinophil counts and clinical benefits vary depending on the disorder and patient selection. In this review, we provide an overview of biologic agents that have been studied in human clinical trials or approved for eosinophil-related diseases, as described in Table 2. Novel agents in development are also discussed briefly.
Asthma Asthma is classically defined by chronic episodic bronchospasm and variable airflow obstruction due to airway inflammation and nonspecific bronchial hyper-responsiveness. Approximately, one third to one half of adult patients with asthma have elevated eosinophil counts in the airway [47], also termed eosinophilic asthma. There is a correlation between blood [48], sputum [49, 50], and bronchoalveolar lavage fluid eosinophilia [48] and asthma severity. Traditional therapy for asthma includes inhaled corticosteroids (ICS), β2-receptor agonists, leukotriene receptor antagonists, and anticholinergic agents. However, complete symptom control is not achieved in a large subgroup of asthmatics [51–54], and there are a substantial number of patients with moderate-to-severe uncontrolled asthma who require additional therapy. Research has provided evidence that asthma represents a heterogeneous condition that is characterized by multiple phenotypes. Attempts have been made to categorize these phenotypes based on molecular characteristics, biomarkers, and cellular phenotyping rather than using only clinical or physiologic profiles [55]. New treatment approaches for asthma have focused on phenotype-directed management rather than a universal strategy, especially in individuals with more severe disease.
Anti-IgE Therapy Omalizumab Omalizumab (Xolair) is a recombinant DNA-derived humanized anti-IgE IgG1 mAb. The drug has been approved in the USA since 2003 for the treatment of moderate-to-severe persistent allergic asthma in patients ≥12 years old whose symptoms are not adequately controlled with ICS. Until now, omalizumab has been the only approved biologic for the treatment of asthma. In March 2014, the US Food and Drug Administration (FDA) approved omalizumab for the treatment of chronic idiopathic urticaria in patients 12 years and older. Omalizumab selectively binds the Cε3 domain in heavy chain of circulating free IgE, regardless of IgE specificity, and prevents its binding to the high-affinity IgE receptor (FCεRI) on mast cells, basophils, and dendritic cells, as well as a low-
affinity IgE receptor (FCεRIIB) expressed on eosinophils, macrophages, and lymphocytes. In asthma patients, this action results in markedly attenuated activation of IgE, which leads to decreased secretion of mediators, cytokines and chemokines from inflammatory cells, decreased sputum and bronchial eosinophilia [56, 57], and consequently, interruption of the allergic cascade of asthma [58]. Omalizumab does not cross-link or bind to receptor-bound IgE on the cell surface [58]. The significant effects of omalizumab that were discovered during clinical trials include the reduction of the free IgE levels [59], and the downregulation of FcεRI expression on basophils, mast cells, and dendritic cells [60, 61], making those cells much less sensitive to the allergen stimulation. Omalizumab also has demonstrated benefits in management of several other atopic conditions such as oral food desensitization [62, 63], allergen immunotherapy [64–67], venom immunotherapy [68], and NP [40] and has been investigated in the treatment of allergic rhinitis [69], atopic dermatitis [70], as well as allergic bronchopulmonary aspergillosis in patients with cystic fibrosis [71, 72]. Omalizumab has demonstrated therapeutic efficacy as an add-on treatment in several large clinical trials of allergic asthma. The drug improves asthma symptoms [6, 7] and quality of life [8, 9], decreases asthma exacerbations [5–10], reduces ICS dosage requirements [6, 8], rescues bronchodilator use [6–8], and decreases emergency room visits and hospitalizations [5, 9]. The EXTRA study, a large longitudinal randomized, double-blind, placebo-controlled (RDBPC) multicenter study, evaluated the efficacy and safety of omalizumab treatment during the 48-week treatment period in 850 subjects with poorly controlled severe asthma [7]. The treatment group had significant improvements in the rate of asthma exacerbations (25 % decrease, P=0.006), bronchodilator use, asthma symptoms, and asthma-related quality of life scores compared with the placebo group. Biomarker analysis reported in the follow-up study [73] showed that the reduction in asthma exacerbation frequency was greater in subgroups with high levels of fractional exhaled nitric oxide (FeNO) (53 vs 16 % with placebo), blood eosinophil counts (32 vs 9 % with placebo), and serum periostin (30 vs 3 % with placebo), when compared with the low-biomarker subgroups. The results of this study suggest the potential use of biomarkers in identifying subsets of patients who may respond better to omalizumab treatment. Studies have shown that omalizumab can effectively lower free serum IgE levels by 96–99 %, suppress new IgE production [11], and reduce airway inflammation [74–76], although its effect on airway remodeling remains unclear. In addition, no correlation was found between free serum IgE levels and clinical response [77]. Measurement of total IgE is needed at baseline to determine appropriate dosing but is not required during omalizumab treatment. This is because omalizumab forms a complex with IgE, which can potentially lead to a
IL-5Rα IL-4Rα IL-4Rα IL-4Rα IL-13 IL-13 IL-13 IL-13 CCR3/βc CCR3 CRTH2 D-prostanoid/CRTH2 TLR9 FIP1L1-PDGFRA
IL-5 IL-5 IL-5Rα CD52
Benralizumab (Medi-563) Pitrakinra (Aerovant) AMG 317 Dupilumab
Lebrikizumab
Tralokinumab Anrukinzumab (IMA-638)
GSK679586 TPI ASM8
GW766994 OC000459
AMG 853 QbG10
Imatinib mesylate (Gleevec)
Mepolizumab Reslizumab
Benralizumab Alemtuzumab (Campath)
Mepolizumab
Omalizumab Mepolizumab
EGPA (CSS)
NP and asthma NP
IgE IL-5
IL-5
FDA- and EMA-approved
IL-5
Reslizumab (Cinquil)
HES
Phase I/II Phase II
IL-5
Mepolizumab (Bosatria)
Phase II Phase II
Phase III
Phase II Case series
Phase III Phase I/II
Phase II Phase II
Phase I/II Phase II
Phase I/II Phase II
Phase II/III
Phase III Phase II Phase II Phase II/III
Phase III
Phase III
FDA and EMA approved
IgE
Omalizumab (Xolair)
Development
Asthma
Target
Drug
Disease
Table 2 Biologic modulators in eosinophilic diseases
Steroid-sparing; decreases peripheral blood eosinophilia [34, 35] Improves symptoms; decreases peripheral blood eosinophilia; rebound eosinophilia and symptom recurrence after cessation (data from small case reports) [36] Study ongoing Improves symptoms; complete or partial hematologic response but most with relapse after cessation (data from retrospective analysis) [37] Steroid sparing; decreases peripheral blood eosinophilia; symptom recurrence after cessation (data from small case series) [38, 39] Decreases polyp scores; improves nasal and asthma symptoms and QOL scores [40] Decreases polyp scores [41]
No clinical benefit as add-on therapy in severe refractory asthma [26] Reduces allergen-induced early-phase asthmatic response; reduces allergen-induced sputum eosinophilia [27] No clinical benefit as add-on therapy in eosinophilic asthma [28] Improves FEV1 particularly in subgroup with peripheral eosinophilia; improves asthma control; reduces exacerbations [29] No clinical benefit as add-on therapy in poorly controlled asthma [30] Improves asthma symptoms; steroid-sparing [31]; recent larger trial terminated early (Clinicaltrials.gov NCT01673672) Improves HES-related symptoms; reduces peripheral eosinophilia and serum tryptase; induces CHR in PDGFRA-positive myeloproliferative variant HES [32, 33]; molecular remission in most patients [33]
Reduces exacerbations and asthma symptoms; reduces ICS and rescue medication use; improves quality of life; reduces hospitalizations and emergency room visits [5–10]; reduces free serum IgE levels and FcεRI on mast cells and dendritic cells [11] Reduces exacerbations; steroid-sparing [12–14]; reduces sputum and blood eosinophils [14, 15] Improves FEV1; trend toward improved asthma control and decreased exacerbations [16] reduces sputum and blood eosinophils [16, 17] Reduces blood eosinophils; reduces bone marrow eosinophils and eosinophil precursors [18] Reduces allergen-induced late-phase asthmatic response [19] No significant clinical efficacy [20] Reduces exacerbations; improves asthma symptoms and FEV1; no reduction in blood or sputum eosinophils [21] Improves FEV1 particularly in high-periostin subgroup in one study [22]; no improvement of FEV1 in another study [23] No improvement in asthma control; trend toward improved FEV1 [24] Reduces allergen-induced early- and late-phase asthmatic response [25]
Outcome
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Ig immunoglobulin, FDA The US Food and Drug Administration, EMA The European Medicines Agency, IL interleukin, ICS inhaled corticosteroids, FEV1 forced expiratory volume in 1 s, CCR3 chemokine receptor 3, βc common β subunit of IL-3, IL-5, and GM-CSF receptors, CRTH2 chemoattractant receptor homologous molecule expressed on Th2 cells, TLR9 Toll-like receptor 9, HES hypereosinophilic syndrome, FIP1L1-PDGFRA FIP1-like 1-platelet-derived growth factor receptor-alpha fusion gene, CHR complete hematologic response, EGPA eosinophilic granulomatosis with polyangiitis, CSS Churg-Strauss syndrome, NP nasal polyposis, QOL quality of life, EoE eosinophilic esophagitis
IL-5 Reslizumab
EoE
Phase II/III
Decreases polyp scores [42] Study ongoing Trend toward improving symptoms [43]; symptom improvement correlates with reduction in esophageal mast cell counts [44]; decreases esophageal eosinophil and mast cell counts [43–45] Symptom improved in all groups including placebo; decreases esophageal eosinophil counts [46] IL-5 IL-4Rα IL-5 Reslizumab Dupilumab Mepolizumab
Phase I Phase II Phase II
Target Drug Disease
Table 2 (continued)
Development
Outcome
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falsely elevated total serum IgE level. Measurement of unbound IgE in patients receiving omalizumab treatment is not routinely needed. Omalizumab has been shown to modulate sputum, bronchial, as well as peripheral eosinophilia [6, 10, 56]. In a meta-analysis, reduction in blood eosinophil counts was associated with improved clinical outcomes, including a decrease in asthma exacerbations requiring corticosteroid bursts [78]. The antieosinophilic property of omalizumab is presently being investigated. Although approved for the treatment of asthma, the use of omalizumab in other eosinophilic diseases remains investigational. The dosing of omalizumab in allergic asthma is based on body weight and pretreatment serum IgE level. In the USA, the eligibility criteria for omalizumab treatment in allergic asthma include a baseline total serum IgE level ranging between 30 and 700 IU/mL. Patients with nonallergic asthma and those with higher IgE levels are not to be treated with omalizumab. However, anecdotal evidence exists to support the use of omalizumab in patients with nonallergic asthma [40]. Subjects with very high serum IgE levels are excluded from treatment because it is unlikely that there would be sufficient antibody to effectively bind to all the IgE [79]. The drug is administered by subcutaneous injection monthly, or every 2 weeks for higher dosages, and patients should receive at least 0.016 mg/kg/IgE (IU/mL) every 4 weeks. Dosage adjustment is not required based on age. The duration of omalizumab treatment is generally at the discretion of the treating physician. More data are needed to determine the clinically measurable biomarkers that could predict a good response and the optimum duration of treatment. Due to high cost, a trial of treatment over 4 months is often recommended to identify good responders. Bousquet et al. evaluated 400 patients receiving standard asthma therapy or standard therapy and omalizumab by using the global evaluation of treatment effectiveness scale, and found that clinical assessment at 16 weeks is an effective predictor of persistency of response at 32 weeks for the majority of patients [80]. Despite the high cost of omalizumab vs other standard asthma medications, add-on omalizumab appears to be cost effective in reducing healthcare costs in industrialized countries [81], particularly costs related to symptomatic drug use, hospitalizations, emergency room visits, and unscheduled physician’s visits in patients with severe persistent asthma. Omalizumab has a favorable safety and tolerability profile [82]. In a systematic review of eight placebo-controlled trials (n=3,429) [83], omalizumab was generally well tolerated with the most common side effects being local injection-site reactions (19.9 vs 13.2 % placebo; P=0.002), including injectionsite pain, bruising, swelling, erythema, and pruritus. Other adverse events include nasopharyngitis, headache, and upper respiratory tract infection. A pooled analysis of
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data from nearly 1,000 six- to eleven-year-old children found similar results [84]. Data from the eXpeRience registry showed that 6.9 % (64 of 925) of real-world omalizumab-treated patients reported at least one serious adverse event during the treatment periods up to 2 years [85]. Anaphylaxis occurred infrequently in patients receiving omalizumab injections (approximately 0.09– 0.14 %) [82, 86]. Sixty-one percent of anaphylaxis events happened within the first 2 h after the first three injections, and 14 % occurred within 30 min after the fourth or later injection [87]. In 2007, the Omalizumab Joint Task Force from the American Academy and College of Allergy, Asthma & Immunology recommended a waiting period after injection and that patients receiving omalizumab carry an epinephrine autoinjector for 24 h after receiving the treatment. Postmarketing reports confirmed episodes of anaphylaxis, and in 2011 the Task Force confirmed its ongoing support for the 2007 recommendation [88]. Previous pooled data from phase I to III trials in 2003 showed higher incidence of malignancy in omalizumabtreated subjects (0.5 %) compared with controls (0.2 %) [89] and consequently a malignancy warning is included in the package insert although the biological plausibility of a mechanism by which the drug could cause malignancy has not been established. Data from two recent studies did not suggest an association between omalizumab therapy and risk of malignancy [90, 91]. In a pooled analysis of 67 phases I to IV clinical trials of omalizumab, 32 were RDBPC studies and malignancies were identified in 14 of 4,254 omalizumab-treated patients and 11 in 3,178 placebotreated patients with a rate ratio of 0.73 [90]. The primary malignancies reported in patients enrolled in those trials included a wide range of histologic types and occurred in varying organ systems. The EXCELS study, which is a prospective phase IV postmarketing 5year registry of 7,000 omalizumab-treated and nonomalizumab-treated patients, found similar malignancy rates in both groups [91]. The rate ratio was 0.84 (95 % confidence interval (CI), 0.62–1.13) for all malignancies including nonmelanoma skin cancer (NMSC) and 0.98 (95 % CI, 0.71–1.36) for all malignancies excluding NMSC. Reported malignancies were mostly solid tumors, including skin, breast, and prostate cancer. Compelling evidence demonstrates that omalizumab is effective and safe as an add-on therapy in children 6 years and older with moderate-to-severe persistent allergic asthma [84, 92, 93]. The adverse events are similar to those previously reported in adults [84]. In the European Union, omalizumab is approved for use in children over 6 years of age while the US FDA does not recommend the drug in children aged 6–11, reasoning that the reduction in exacerbations was modest and was not sufficient to justify the high treatment cost [94].
Anti-IL-5 Therapy IL-5 regulates the differentiation, maturation, activation, tissue recruitment, and survival of eosinophils [95]. Activation of the IL-5 receptor-α (IL-5Rα) on the surface of eosinophils induces the recruitment and survival of these cells. Inhibition of IL-5 has been shown to lower blood and sputum eosinophil levels [17, 96] with some promising clinical efficacy in selected asthma subgroups. In addition to asthma, anti-IL-5 mAbs have also been investigated for the treatment of other eosinophil-associated conditions such as hypereosinophilic diseases, CSS, and EoE [34–36, 38, 39, 43, 45, 46]. The antibodies target eosinophils either by preventing circulating IL-5 binding to IL-5Rα on the surface of eosinophils (mepolizumab and reslizumab) or by blocking IL-5Rα (benralizumab). Mepolizumab Mepolizumab (Bosatria) is a humanized murine IgG1 mAb against free IL-5. The antibody neutralizes IL-5 by inhibiting binding of IL-5 to the α chain of the IL-5 receptor expressed on eosinophils [97]. Mepolizumab has been investigated for the treatment of asthma, atopic dermatitis, HES, EoE, and NP and is now being investigated in a phase III study for severe asthma with eosinophilic inflammation and CSS. In earlier studies of asthma in which patients were not recruited on the basis of eosinophilic inflammation in the airways, mepolizumab resulted in definite reductions in blood and sputum eosinophils but failed to show improvement in asthma symptoms, measures of bronchial hyper-responsiveness, pulmonary function, or exacerbation frequency [15, 96]. However, its demonstrated efficacy in improving skin manifestations [97, 98] and a precipitous reduction in tissue and blood eosinophil counts [97] in patients with HES encouraged the continued effort to study mepolizumab in asthma and other eosinophilic diseases. Two small proof-of-concept studies of mepolizumab in asthma by Haldar et al. and Nair et al. that were targeted specifically at patients with asthma with persistent eosinophilic airway inflammation yielded the same conclusion despite using different outcome measures [12, 13]. In these trials, mepolizumab exhibited benefits as a prednisone-sparing agent, reduced the frequency of asthma exacerbation, and improved quality of life in subjects with severe refractory eosinophilic asthma. In a larger RDBPC Dose-Ranging Efficacy and Safety with Mepolizumab in Severe Asthma (DREAM) trial of 621 patients from 81 multinational centers, subjects with severe, exacerbation-prone asthma with sputum eosinophil counts ≥3 %, FeNO ≥50 ppb, and peripheral eosinophilia were randomized to three different doses of mepolizumab or placebo for over 1 year [14]. All treatment groups had fewer asthma exacerbations (reduced by
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approximately 50 %), visits to emergency departments, hospital admissions, and lower blood and sputum eosinophil counts; however, no significant changes in forced expiratory volume in 1 s (FEV1) or asthma symptoms were observed. Response to mepolizumab correlated with baseline blood eosinophil counts but not atopy history or serum IgE levels. These studies support the significance of asthma phenotyping and provide further compelling evidence for mepolizumab as an effective and safe treatment in subgroups with severe asthma and active eosinophilic inflammation, particularly those with frequent exacerbations. Despite promising effects in selected patients, as evidenced by remarkable improvement in exacerbation frequency, clinical use of mepolizumab is cautioned by some due to the rarity of eosinophilic-related asthma and its limited effectiveness in improving asthma symptoms and lung function [99, 100]. This marked dissociation between the clinical and functional measurements and the exacerbations suggests that different underlying pathological mechanisms exist and mepolizumab therapy may only suppress inflammation mediated by eosinophils [99, 101]. The observations of an increase in plasma IL-5 levels and IL-5Rα expression by blood eosinophils after mepolizumab treatment in a variety of eosinophilic diseases led to concerns that there could, theoretically, be a rebound worsening of tissue inflammation when anti-IL-5 therapy is discontinued [102]. A follow-up unblinded, prospective, observational study by Haldar et al. examined the clinical and biological markers after cessation of mepolizumab therapy in refractory eosinophilic asthma [103]. Soon after stopping the 12-month treatment, sputum and blood eosinophil counts expanded and reached baseline levels within 6 months. Similarly, the frequency of asthma exacerbation increased significantly after stopping mepolizumab and by 12 months was not significantly different in the mepolizumab vs placebo group. The authors suggested that the increase in symptoms after treatment withdrawal may, in part, represent regression to the mean symptom scores due to lower levels in the treatment group at the end of study period and were unlikely to be due to a rebound phenomenon. Reslizumab Reslizumab (Cinquil, formerly SCH55700) is a humanized IgG4 anti-IL-5 mAb. With high affinity to human IL-5, the antibody binds to and neutralizes circulating IL-5 by preventing its binding to eosinophils. Reslizumab has been studied in several randomized controlled clinical trials in asthma [16, 17], NP [42], EoE [46], as well as small openlabel studies in HES [36] and EGID with peripheral eosinophilia [104]. In a small pilot RDBPC dose-ranging study of a single intravenous dose reslizumab in patients with poorly controlled asthma, no significant changes in FEV 1 or
symptom score were observed in the treatment group despite the profound decrease in blood eosinophil counts which occurred in a dose-dependent fashion [17]. Post hoc analysis demonstrated a significant increase in FEV1 in patients with baseline sputum eosinophils >3 % who received 1.0 mg/kg reslizumab vs placebo; this treatment effect was not detected in subjects with lower baseline sputum eosinophil counts. This finding prompted further trials of reslizumab in diseases characterized by tissue eosinophilia, such as eosinophilic asthma, NP, and EoE. A more recent phase II RDBPC multicenter trial investigated the use of reslizumab (3 mg/kg once each month for 4 months) in patients with poorly controlled eosinophilic asthma, some with NP [16]. The drug resulted in a statistically significant yet small improvement in FEV1 when compared with placebo after 15 weeks and there was a trend toward improved asthma control as measured by an asthma control questionnaire (ACQ) score. Reslizumab profoundly reduced sputum and blood eosinophils counts. There was also a trend toward decreased exacerbations in the reslizumab group, but exacerbations were infrequent in both arms, likely due to the short duration of the study. Greater clinical benefit was observed in patients with concomitant NP although the direct effect of reslizumab on nasal polyps was not studied. The most frequently reported adverse events were nasopharyngitis, fatigue, and pharyngolaryngeal pain. During a short duration of follow-up (3 weeks after the last dose), rebound eosinophilia was not observed. This study has added to the literature the importance of defining a distinct patient population in which the anti-IL-5 therapy has the most potential benefit. However, a larger and longer duration study is needed. Benralizumab Benralizumab (MEDI-563) is a humanized, afucosylated, IgG1 mAb that binds specifically to the α-subunit of the human IL-5Rα on eosinophils and basophils [105], resulting in inhibition of IL-5-mediated receptor activation. Afucosylation significantly augments the binding affinity of benralizumab to the FcγRIIIa, the main activating Fcγ receptor expressed on natural killer cells, macrophages, and neutrophils, causing enhanced antibody-dependent cellular cytotoxicity (ADCC) functions that mediate eosinophil apotosis [106]. It has been suggested that benralizumab might have a greater clinical efficacy than either mepolizumab or reslizumab for several reasons. First, the eosinophil depletion from benralizumab occurs through highly efficient ADCC rather than through passive removal of IL-5 by means of IL5 neutralization and inhibition. Therefore, benralizumab may deplete eosinophils with relatively low levels of IL-5Rα expression including those that are independent on IL-5 as a survival factor [107]. Second, benralizumab has been shown to reduce airway eosinophilic infiltration in addition to
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depleting sputum and blood eosinophils [18], which has not been observed after other anti-IL-5 mAb therapies. In the initial phase I open study of benralizumab in patients with mild atopic asthma, striking, dose-dependent reductions in blood eosinophil counts were observed within 24 h of administration of a single intravenous dose of each of the seven doses administered [108]. Eosinopenia persisted more than 12 weeks in the highest dose group. In addition, there was a transient reduction in white blood cell counts in all dose cohorts, with more than half the patients having a marked decrease to
