Use of Biologicals as Immunotherapy in Asthma and Related Diseases

Brandie L. Walker; Richard Leigh

Expert Rev Clin Immunol. 2008;4(6):743-756.

IL-13 Antagonist Therapy

IL-13 regulates inflammatory immune responses and is believed to play a key role in the pathogenesis of asthma. It is known to drive epithelial cell maturation and mucus production, promote the generation of extracellular matrix proteins and increase the contractility of airway smooth muscle cells.^[91] It is produced by Th2 cells as well as by natural killer T cells, mast cells and basophils, and is similar in activity to IL-4.^[92,93] The activity of the cytokine is mediated through binding to two different cytokine receptor chains that form a heterodimer expressed on IL-13-responsive cells: the IL-13R-α1 and the IL-4R-α chains.^[94] This receptor is activated by both IL-13 and by IL-4.^[95] In mouse models, administration of IL-13 to the lungs or targeted overexpression of IL-13 in lung tissue triggers asthma-like phenotypes, including airway eosinophilia, mucus-cell metaplasia, airway fibrosis and AHR.^{[96,97,98,99,100]}

In asthmatic individuals, IL-13 is present at increased levels in bronchial tissue and in induced sputum,^[101] and in nasal lavage fluid.^[102] In addition, both IL-13 mRNA and protein levels are further increased in bronchoalveolar lavage (BAL) fluid in asthmatic subjects following allergen challenge.^[103,104] The gene for IL-13 is located on chromosome 5q31 and this region has been linked to asthma and related phenotypes.^{[105,106,107]} In further support of the role of IL-13 in asthma, genetic polymorphisms of IL-13 have been linked with increased risk of atopic disease. Specifically, the R110Q variant of IL-13 has been linked to high serum IgE titers, as well as to increased occurrence of allergy and atopic dermatitis.^[108,109]

Human clinical studies examining the role of IL-13 antagonists in the treatment of asthma and related allergic diseases are in the early stages of development. The human anti-IL-13 IgG4 monoclonal antibody CAT-354 has been tested in a murine model of IL-13 mediated airway and esophageal inflammation. Results in this study show that if mice are pretreated with the anti-IL-13 antibody before exposure to IL-13, there is a significant reduction in airway eosinophilia and airway reactivity.^[110] The CAT-354 mAb is currently being evaluated in a double-blind placebo controlled study in patients with refractory asthma whose symptoms remain uncontrolled despite optimal treatment.^[204] A second monoclonal antibody against IL-13, termed QAX576 is also being examined in Phase I and II clinical studies to assess the safety, tolerability, pharmacokinetics and dynamics, and clinical efficacy of various intravenous dosages of QAX576 in patients with moderate allergic asthma.^[205]

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Selected Omalizumab Studies in Patients With Asthma
Author	Study type	Patient population	Duration of study	Patients (n)	Major study results	Ref.
Humbert et al. (INNOVATE study)	Double-blind, parallel group, multicenter	Severe asthma (≥ two exacerbations per year) Age 12–75 years Positive skin-prick test	28 weeks	209 in treatment group 210 in placebo group	26% decrease in clinically significant exacerbations 50% decline in severe exacerbations 44% decrease in ER visits	^[18]
Ayres et al.	Open-label, parallel group, 49 centers	Moderate-to-severe asthma for over 2 years (≥ one ER visit and ≥ one oral corticosteroid per year) Positive skin prick to two clinically relevant allergens	52 weeks	206 in treatment group (omalizumab plus best standard of care) 106 in best standard of care group	Measured in asthma-related deterioration-related incidents (course of steroid, missed school work and unscheduled physician visit) 50% decrease in treatment group 60% decrease in exacerbations	^[19]
Busse et al.	Phase III double-blind, placebo-controlled multicenter	Severe allergic asthma of at least 1 year duration (with daily ICS use) Age 12–75 years Positive skin prick to one allergen	28 weeks: week 1–16 steroid reduction phase; week 16–28 stable steroid phase	268 in omalizumab group 252 in placebo group	59% decrease in annual rate of asthma exacerbation Decrease in ICS dose in treatment group Improved daily asthma scores in treatment group	^[20]
Holgate et al.	Randomized, placebo-controlled, multicenter	Severe allergic asthma (needing ICS) Age 12–75 years Serum IgE 30–700 IU/ml Positive skin-prick test	6–10 week run-in period to switch to fluticasone 16 week stable fluticasone 16 week to decrease fluticasone	126 in omalizumab group 109 in placebo group	Greater decrease of fluticasone use with omalizumab	^[21]
Soler et al.	Double-blind, Randomized placebo-controlled, parallel group, multicenter	Moderate-to-severe asthma for at least 1 year (stable) Age 12–75 years Positive skin-prick test Serum IgE 30–700 IU/ml	28 weeks: week 0–15 steroid stable phase; week 16–28 steroid reduction phase	274 in omalizumab group 272 in placebo group	58% fewer exacerbations per patient in steroid stable phase 50% fewer exacerbations per patient in steroid reduction phase	^[22]
Holgate et al.	Meta-analysis of three studies	Moderate-to-severe allergic asthma with daily ICS use	16-week stable steroid phase and 12–16 week steroid-reduction phase. Studies 1 and 2 had additional 24-week extension phase	1412 total patients enrolled in all groups of the 3 studies. Pooled subgroup analysis of only high-risk asthma patients included 135 in omalizumab and 119 in placebo group	Annualized rate of significant asthma exacerbation episodes was decreased in high-risk group on omalizumab	^[23]
Buhl et al.	Double-blind extension to Soler et al.	Moderate-to-severe asthma for at least 1 year (stable) Age 12–75 years Positive skin-prick test Serum IgE 30–700 IU/ml	24-week extension to 28-week trial	254 in omalizumab group 229 in placebo group	Lower ongoing beclametasone use in omalizumab group Disease control sustained in more patients in treatment group	^[24]
Lanier et al.	Double-blind extension to Busse et al.	Severe allergic asthma of at least 1 year duration (with daily ICS use) Age 12–75 years Positive skin prick to one allergen	24-week extension to 28-week study	245 in omalizumab group 215 in placebo group	Continued significant decrease in exacerbation rate and sustained decrease in ICS use in treatment group	^[25]

ER = Emergency room; ICS = Inhaled corticosteroid

Selected Antihuman TNF-α Studies in Patients With Asthma
Author	Study type	Patient population	Duration of study (weeks)	Patients (n)	Major study results	Ref.
Howarth et al.	Open-label, uncontrolled, proof-of-concept of etanercept	Severe asthma Age 30–67 years	12 of etanercept	17 with severe asthma	Improved asthma symptoms, lung function and bronchial hyperresponsiveness	^[50]
Berry et al.	Double-blind, placebo-controlled, crossover pilot study	Treatment-refractory asthma (symptomatic with daily ICS)	10	Ten	Improved airway hyperresponsiveness, asthma-related Qol scores and FEV₁	^[51]
Erin et al.	Double-blind, placebo-controlled, parallel group	Moderate-to-severe asthma (treated with ICS) Asthmatics for over 1 year	12	38 (20 placebo; 18 infliximab)	No change in primary end point (lung function) Mild decrease in rate of exacerbations and decreased level of TNF-α in sputum of treatment group	^[52]
Morjaria et al.	Double-blind, randomized, placebo-controlled parallel group	Severe asthma refractory to ICS	12	39 (20 placebo; 19 etanercept)	Very small improvement in asthma control questionnaire score in treatment group No change in asthma Qol score, lung function or exacerbation rates	^[54]

FEV₁ = Forced expiratory volume in 1 s; ICS = Inhaled corticosteroid; Qol = Quality of life.

Selected Mepolizumab Studies on Human Patients With Asthma
Author	Study type	Patient population	Duration of study	Patients (n)	Major study results	Ref.
Leckie et al.	Double-blind, randomized, placebo-controlled	Mild asthma Nonsmokers Positive skin-prick test	30 days	24 (16 mepolizumab; 8 placebo)	Significant decrease in blood and sputum eosinophils No difference between groups on histamine challenge	^[75]
Flood-Page et al.	Double-blind, randomized, placebo-controlled	Mild asthma (airway hyper-responsiveness) Ages 18–55 years Nonsmokers	20 weeks	24 (11 mepolizumab; 13 placebo)	55% reduction in airway eosinophils 52% reduction in bone marrow eosinophils but no change in clinical outcomes	^[77]
Flood-Page et al.	Double-blind, multicenter, randomized, placebo-controlled	Moderate-to-persistent asthma despite ICS use		362	Decrease in blood and sputum eosinophils but no change in peak flow or other clinical outcomes	^[78]

ICS = Inhaled corticosteroid.

Selected IL-4 Studies in Patients With Asthma (Altrakincept [Soluble IL-4 Receptor] and Pitrakinra [IL-4 Variant])
Author	Study type	Patient population	Duration of study	Patients (n)	Major study results	Ref.
Borish et al.	Double-blind, placebo-controlled, Phase I/II of altrakincept	Moderate asthma for over 1 year (with ICS use) Age over 18 years, positive skin-prick test	29 days	25 (8 in placebo group; 8 in 500 µg nebulizer-dose group; 9 in 1500 µg nebulizer-dose group)	Statistically significant improvement in the FEV₁ for the higher concentration group Improved asthma symptom scores	^[87]
Borish et al.	Double-blind, randomized, placebo-controlled dose-finding study for altrakincept	Poorly controlled asthma requiring ICS	12 weeks	62 (16 in placebo group; 15 in 0.75-mg group; 16 in 1.5-mg group; 15 in 3-mg group)	Placebo group had decrease in FEV₁ not observed in 3-mg group and better asthma symptom scores were observed in 3-mg group	^[88]
Wenzel et al.	Double-blind, randomized, placebo-controlled, parallel group, Phase IIa	Atopic asthma (measured by reactive airways), Age over 18 years	1 month	56 (12 in sc. placebo group; 12 in sc. pitrakinra group; 16 in nebulizer placebo group; 16 in nebulizer pitrakinra group)	For sc. administration, no significant change was observed in FEV₁ between the groups For nebulizer group, there was a statistically significant drop in FEV₁ in placebo group compared with pitrakinra group	^[89]

FEV₁ = Forced expiratory volume in 1 s; ICS = Inhaled corticosteroid; sc. = Subcutaneous.

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