Biologic Therapy for Asthma

Biologic Therapy for Asthma

Sirinoot Palapinyo,RPh.2015, March

OutlineIntroduction

Pathobiology of asthma

Biological drugs in asthma treatment

Biological drugs or agents

Anti-Immunoglobulin E

Targeting Th2 response : IL-5, IL-4, IL-13, IL-5

Others

Introduction

IntroductionAsthma : Heterogenous, Chronic inflammation disorder of airway

Diagnosis : Symptom & Evidence of variable air flow limitation

Bronchial hyper-responsiveness(BHR)

Mucus overproduction

Airway wall remodelling

Airway narrowing (reversible)

Holgate ST & Polosa R.Treatment strategies for allergy and asthma. Nature Reviews Immunology 8, 218-230 (March 2008)

Introduction Clinical symptoms : Recurrent dyspnea,Wheezing, SOB, Cough

The Global Initiative for Asthma (GINA) guidelines

Most patients controlled asthma by current standard therapies

Combinations of inhaled corticosteroids, β2-adrenergic receptor agonists and/or oral leukotriene inhibitors, theophylline

5–10% of people with asthma the disease remains symptomatic and inadequately controlled

High risk of serious morbidity and mortality GINA,2014

IntroductionHeterogeneous phenotype disease

Allergic asthma: Children & Triggered by inhaling allergens : IgE

Non-allergic asthma : Adults & Unclear allergens

“Phenotypes OR rEndotypes” represent specific cellular patterns along with clinical characteristics within each patient

Eosinophilic, neutrophilic, mixed granulocytic, or pauci-granulocytic




Chronic airway inflammation is frequently associated with structural changes to the airway wall, referred to as tissue remodelling.

Always triggered by an immune-inflammatory response driven by T helper type 2 (Th2) lymphocytes

Th2 : Eosinophillic asthma

Th17 : Neutrophillic asthma



Biologic agent

‘‘A diagnostic, preventive, or therapeutic preparation derived or obtained from living organisms and their product, e.g. serum, vaccine, antigen, antitoxin; a compound or medicine derived from living products, rather than chemicals’’

Stedman JK, Branger E. Stedman’s medical dictionary for the health professions and nursing. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2008.

Monoclonal AntibodyConstant region : Type of Ab : IgG, IgM ect.

Variable region : Antigen binding site

Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The structure of a typical antibody molecule. Available from: http://www.ncbi.nlm.nih.gov/books/NBK27144/

Monoclonal Antibody

Purple : Human component Orange : Murine components

J.B. Bice et al. / Ann Allergy Asthma Immunol 112 (2014) 108e115


1. Anti IgE

Biological drugs in asthma treatment 2. Th2 Response

Biological drugs in asthma treatment 3. Anti-IL17

Biological drugs in asthma treatment 4.TNF-alpha

Th1->neutrophils

Anti-Immunoglobulin E

1. IgE Antibody : Omalizumab

Omalizumab

Omali-zumab : Recombinant humanised

Developed by immunizing mice with human IgE.

Recognizes IgE at the same site as the high-affinity receptor for IgE (FcεRI).

Mechanism

Omalizumab:Clinical evidence4 RCTs : Omalizumab Vs Placebo

Patients :

Had asthma for at least one year and required treatment with inhaled corticosteroids.

Had at least one positive skin test to a perennial aeroallergen (specifically, dust mites, cockroaches, or dog or cat dander)

Elevated total serum IgE level.

During each trial, ICS were initially maintained at a stable dose, followed by a phase of dose reduction to the lowest dose required for asthma control. Omalizumab for Asthma

Robert C. Strunk, M.D., and Gordon R. Bloomberg, M.D.N Engl J Med 2006; 354:2689-2695

Omalizumab:Clinical evidenceOmalizumab groups:

Significant improvements in lung function as measured by FEV1

Significantly fewer exacerbations of asthma per patient

Significantly lower percentage of patients had an exacerbation (Fewer hospitalizations, unscheduled outpatient visits and emergency hospital visits)

Dose of inhaled corticosteroids required to control symptoms was significantly less among patients treated with omalizumab than placebo.

Omalizumab for AsthmaRobert C. Strunk, M.D., and Gordon R. Bloomberg, M.D.N Engl J Med 2006; 354:2689-2695

Omalizumab:Clinical evidence

Phase III trials:

Patients receiving omalizumab had fewer asthma exacerbations,

Improvements in asthma symptoms Quality of life

Decreased requirements for both inhaled corticosteroids and rescue bronchodilators

Omalizumab:clinical use

Indication

An option for the treatment of severe persistent allergic (IgE mediated) asthma as add-on therapy to optimised standard therapy, only in adults and adolescents (6 years and older) who have been identified as having severe unstable disease

Nice, 2013


Indication

An option for the treatment of severe persistent allergic (IgE mediated) asthma as add-on therapy to optimised standard therapy, only in adults and adolescents (6 years and older) who have been identified as having severe unstable disease

Nice, 2013


The recommended dose

SC 0.016 mg / kg of body weight / IU of IgE every 2-4

This dose is based on the estimated amount of the drug that is required to reduce circulating free IgE levels to less than 10 IU/ mL

Nice, 2013

Omalizumab:clinical useThe recommended dose

SC 0.016 mg / kg of body weight / IU of IgE every 2-4 weeks

This dose is based on the estimated amount of the drug that is required to reduce circulating free IgE levels to less than 10 IU/ mL

Monitoring of total serum IgE levels during the course of therapy with omalizumab is not indicated

Total serum IgE levels will generally increase during treatment, because of the presence of circulating IgE–anti-IgE complexes


Omalizumab:clinical useEfficacy assessment : at least 12 weeks

Discontinued : Serum IgE levels & the numbers of FcεRIs increase after therapy

No report on the duration of effects after discontinuation.

If treatment is interrupted before nine months have elapsed since the last injection, treatment should be resumed at the dose initially prescribed.

Adjusted dose in the event of substantial changes in body weight


Omalizumab:safetyAnaphylaxis has been reported in at least 0.2% of cases (compared to less than 0.1% initial incidence during clinical trials), requiring administration in health care setting

Malignant neoplasm: 0.5% risk compared with 0.1% of control population within 1 year follow up

Injection site reactions

Upper respiratory tract infection

Increased risk of helminthic infections.

Churg–Strauss syndrome (rare)

Targeting Th2 response

Targeting Th2 response

Anti-IL5 (mepolizumab reslizumab and benralizumab)

Anti-IL4 (dupilumab)

Anti-IL13 (lebrikizumab)

Anti-IL9

2. IL-5 Antibody : Mepolizumab

IL-5 targeted antibodies

Mepolizumab

Eosinophilic asthma

Refractory to corticosteroid or omalizumab

Reslizumab : Patient with highest level of blood & sputum eosinophils and presence of nasal polyposis

Benralizumab : more specific on cellular target

Mepolizumab for severe eosinophilic asthma (DREAM)

A multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries

621 patients were aged 12–74 years, and had a history of recurrent severe asthma exacerbations, and had signs of eosinophilic inflammation.

Randomly assigned to receive one of three doses of IV mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo (100 mL 0·9% NaCl).

The primary outcome measure was the rate of clinically significant asthma exacerbations over 12 months

Pavord et al. Lancet 2012;380:651-59

Mepolizumab for severe eosinophilic asthma (DREAM)

The rate of clinically significant exacerbations was reduced by 39%-48% (different doses) compared with placebo

Small effects on FEV1 and QOL scores, which generally did not differ significantly from those reported with placebo

A dissociation between symptoms and risk of exacerbations probably exists in patients with severe asthma.

Pavord et al. Lancet 2012;380:651-59

Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma

Randomized, double-blind, double-dummy study

576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of 3 study groups.

Receivemepolizumab 75-mg IV or a 100-mg SC, or placebo every 4 weeks for 32 weeks.

The primary outcome: Rate of exacerbations.

Other outcomes : FEV1 and scores on the St. George’s Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5)

N Engl J Med 2014;371:1198-207.


N Engl J Med 2014;371:1198-207.


N Engl J Med 2014;371:1198-207.


N Engl J Med 2014;371:1198-207.


Summary

Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control.

Funded by GlaxoSmithKline

N Engl J Med 2014;371:1198-207.

IL-4 targeted antibodies

Th2 differentiation & expansion

B-cell —> IgE

Development mast cell & mucous metaplasia

Up-regulation of collagen & fibronectin production

Overlap Il-13

2. IL-4 /IL-13Antibody

Th17 Targeting: Anti-IL17

Th17 Targeting: Anti-IL17IL-17A and IL-17F : pro-inflammatory cytokines

Released by TH17 cells and crucially involved in neutrophilic inflammation as well as in airway remodelling

Neutralizing mAB against IL-17 lowered the numbers of neutrophils, eosinophils and lymphocytes in bronchoalveolar lavage fluid in mouse models of allergic asthma


Secukinumab (also known as AIN457) -> Phase II clinical trials

Evaluating the efficacy and safety of a fully human IL-17A-specific mAB as well as of a human IL-17R-specific mAB in patients with severe asthma that is not adequately controlled by ICS and long-acting β2-adrenergic receptor agonists.


Another potential therapeutic : Antibodies directed against the IL-17-regulating cytokine IL-23 blockade

Inhibition of antigen- dependent recruitment of neutrophils, eosinophils and lymphocytes into the airways of sensitised mice

Anti-Tumor Necrosis Factor-alpha Targeted Therapies

TNF-α and asthmaIt causes the recruitment of pro-inflammatory cells and affects airway remodeling – typical asthma symptoms

Inhaled recombinant human TNF-α has been demonstrated to cause

Decrease in FEV

Increased neutrophil and eosinophil recruitment

Brightling et al. 2008

Anti-TNF-α TreatmentsEtanercept – human fusion protein made of TNF-αR2 and the Fc region of IgG1

Subcutaneous injection

Non-selective for transmembrane TNF or soluble TNF

Doesn’t activate complement system

In a large RCT, multicenter : evaluate the efficacy and safety of this product (25 mg twice a week) in patients with moderate to severe persistent asthma,

No improvement was reported in any of the asthma parameters

http://media.pharmacologycorner.com/wp-content/uploads/2009/05/tnfmoa7.gif

Holgate ST, Noonan M, Chanez P, Busse W, Dupont L, Pavord I, et al. Efficacy/safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur Respir J. 2011;37:1352–9.

Anti-TNF-α TreatmentsInfliximab – chimeric monoclonal antibody made up of human Ig constant region, 2 mouse variable regions to TNF-α

Can trigger complement system

Non-selective for tmTNF or sol TNF

Case series suggests that infliximab may improve the condition of patients with severe steroid-refractory asthma

Risk-benefit profile, considering asthma severity, occurrence of life-threatening exacerbations and complications of long-term oral steroids.

Phase II: Reduced PEF & exacerbation

Taillé C, Poulet C, Marchand-Adam S, et al. Monoclonal Anti-TNF-α Antibodies for Severe Steroid-Dependent Asthma: A Case Series. The Open Respiratory Medicine Journal. 2013;7:21-25.

Limitations of Use of Biologics in Asthma

Expense

Parenteral administration

Adverse effects

Host anti-drug responses limiting ongoing therapy

Limitations in current concepts of molecular pathogenesis of disease

Take Home MessageAsthma is both easy &hard to treat

Accurate characterisation of asthma phenotypes is essential for development and implementation of biological treatment

The cost-effectiveness and adverse events associated with the use of each monoclonal antibody should be considered.

This could be achieved by carefully revising the existing clinical trials in light of solid evidence-based criteria.

Paediatric data on cytokine-specific monoclonal antibody therapies are still needed.

Health & Medicine

Biologic Therapy for Asthma