Biologic Therapy for Asthma
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Transcript of 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
Holgate ST & Polosa R.Treatment strategies for allergy and asthma. Nature Reviews Immunology 8, 218-230 (March 2008)
Pathobiology of asthma
Pathobiology of asthma
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
Holgate ST & Polosa R.Treatment strategies for allergy and asthma. Nature Reviews Immunology 8, 218-230 (March 2008)
Biological drugs in asthma treatment
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
Biological drugs in asthma treatment
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
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
Omalizumab:clinical use
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 for AsthmaRobert C. Strunk, M.D., and Gordon R. Bloomberg, M.D.N Engl J Med 2006; 354:2689-2695
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 for AsthmaRobert C. Strunk, M.D., and Gordon R. Bloomberg, M.D.N Engl J Med 2006; 354:2689-2695
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.
Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma
N Engl J Med 2014;371:1198-207.
Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma
N Engl J Med 2014;371:1198-207.
Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma
N Engl J Med 2014;371:1198-207.
Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma
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
Th17 Targeting: Anti-IL17
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.
Th17 Targeting: Anti-IL17
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, con- trolled 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.