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-4 Antagonist Therapy

IL-4 is a key cytokine in the early stages of the immune-mediated inflammatory cascade following immunogen activation due to its regulatory role in facilitating B-cell isotype switching from IgM to IgE production. IL-4 is also involved in eosinophil chemotaxis and in the development of effector T-cell responses from undifferentiated T-helper cells to memory-specific Th2 cells.^[79,80] Once activated, Th2 cells are primed to secrete cytokines, such as IL-3, IL-4, IL-5, IL-13 and granulocyte-macrophage colony-stimulating factor, which initiate and perpetuate the immune-mediated inflammatory airway responses that are characteristic of allergic asthma and are thought to underpin the pathophysiology of the variable airway dysfunction that is the hallmark of the condition.^[81,82,83]

Inhibiting the biological actions of IL-4 in asthma should, at least theoretically, result in a decrease in airway inflammation, and, thus, would appear to be a promising therapeutic target in the treatment of asthma and related diseases.^[84] In addition, blockade of IL-4 offers the potential additional benefit for attenuating IgE production and the subsequent IgE-mediated airway inflammation.^[85] To this end, a humanized anti-IL-4 mAb (pasolizumab) that binds IL-4 and prevents the interaction of IL-4 with the α-chain of the IL-4 receptor (IL-4R) was developed and tested on cynomolgus monkeys. Although it was found to be well tolerated, the compound had no measurable effect on serum IgE levels.^[85] Based on these disappointing clinical results, the proposed human clinical trials that were planned with this anti-IL-4 mAb have been discontinued.^[86] However, another human mAb reported to block the action of IL-4 and IL-13 is currently under development by Amgen (CA, USA; AMG-317), with a Phase II clinical trial in participants with moderate-to-severe asthma currently underway.^[203]

A second approach of IL-4 antagonism has been to generate a soluble recombinant human IL-4 receptor (consisting of the extracellular portion of human IL-4R-α) to bind and inactivate free circulating IL-4.^[87,88] It was hoped that this might result in some clinical benefit in the treatment of asthma and related diseases, and two initial studies indicated that treatment with the compound altrakincept prevented worsening of asthma symptoms and the fall in FEV₁ that was observed in the placebo-treated control group ( Table 4 ).^[87,88] However, despite these initial promising results, a subsequent Phase III RCT has failed to confirm these earlier observations.

A third approach, involving IL-4 antagonism as a potential treatment for asthma and other related allergic diseases, is to use a variant form of IL-4 called pitrakinra. This IL-4 cytokine has two functional mutations, which result in a molecule that potently inhibits binding of IL-4 and IL-13 to the IL-4R-α complex on the cell-surface membrane. Early studies in cynomolgus monkeys treated with this compound by either subcutaneous injection or nebulization confirmed that this treatment protected monkeys from allergen-induced airway eosinophilia and AHR.^[89] To date, there have been two independent randomized, double-blind, placebo-controlled Phase IIa clinical trials in patients with atopic asthma treated with either pitrakinra or placebo.^[89] In the first trial, patients were randomized to receive either pitrakinra or placebo by once-daily subcutaneous injection. In the second trial, patients were randomized to receive either pitrakinra or placebo by twice-daily nebulization. Inhaled allergen challenge was carried out before treatment and after 4 weeks of treatment. The primary study end point for the first study was maximum percentage decrease in FEV₁ over a 4-10-h period following allergen challenge, whereas in the second study, the end point was the average percentage decrease in FEV₁ over a 4-10-h period following allergen challenge. The first trial found a small but not significant attenuation of the allergen-induced FEV₁ decrease in favor of pitrakinra, and there were fewer asthma-related adverse events in the pitrakinra-treated group compared with the placebo-treated group. The second trial showed a more substantial effect of twice-daily nebulized pitrakinra in significantly protecting against an allergen-induced late asthmatic response (p = 0.0001).

Overall, the results of therapies targeting IL-4 have been disappointing to date, which might reflect redundancies with IL-13 in the immune-mediated inflammatory pathways. The available clinical evidence suggests that there is no role for the use of either the anti-IL-4 mAb pasolizumab or the soluble recombinant human IL-4 receptor altrakincept for the treatment of asthma. However, following the initial beneficial results observed with twice-daily nebulized pitrakinra in attenuating allergen-induced airway responses,^[89] further clinical studies into the clinical efficacy of this compound are warranted.^[90]

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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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