omalizumab
TRANSCRIPT
Overview Introduction Bronchial asthma – Definition, Symptoms, Classification
PathophysiologyApproaches to treatment
Role of IgE in asthma Omalizumab – MOA
Pharmacokinetics/PharmacodynamicsAdverse effectsIndications/ContraindicationsInteractions
Other monoclonal antibodies in asthma therapy
BRONCHIAL ASTHMA
Chronic inflammatory condition of airways resulting in episodic airflow obstruction due to bronchial hyper responsiveness.
CLASSIFICATION
Mild intermittent asthma
Mild persistent asthma
Moderate persistent asthma
Severe persistent asthma
PATHOPHYSIOLOGY
Early asthmatic response
Histamine,LT-C,D,E
Pg
bronchospasm
Allergen exposureLate
asthmatic response
Bronchial hyper reactivity andInflammation
β2 agonistTheophyllineLT antagonist
Glucocorticoids
APPROACHES TO TREATMENT
• BRONCHODILATORS- Sympathomimetic agents
Methylxanthines
Anticholinergics
• MEDIATOR RELEASE INHIBITORS
Mast cell stabilizers
Lipoxygenase Inhibitors
• MEDIATOR ANTAGONISTS
Leukotriene antagonists
CORTICOSTEROIDS
ANTI IgE ANTIBODY
SELECTIVE β2 AGONISTS
SHORT ACTING
SALBUTAMOL
TERBUTALINE
REMITEROL
FENOTEROL
LONG ACTING
SALMETEROL
FORMOTEROL
BAMBUTEROL
LT MODULATORS
Lipoxygenase inhibitors - Zileuton
LTD 4 receptor antagonist
- Zafirleukast,Monteleukast,
Pranleukast,Iralukast
CORTICOSTEROIDS
ORAL - Prednisolone, Methyl prednisolone
PARENTRAL - Methyl prednisolone, Hydrocortisone
INHALATIONAL - Beclomethasone, Fluticasone, Budisonide, Triamcinolone, Flunisolide
MONOCLONAL ANTIBODY
• Omalizumab
• MISCELLANEOUS – PDE4 inhibitors, CRth2 antagonists, Endothelin antagonists, NO synthase inhibitors, Chemokine receptor antagonists, Protease inhibitors etc…
Anti-IgE Therapy
Most asthmatic patients have elevated circulating IgE concentrations when levels are adjusted for age
IgE is produced by B lymphocytes
OMALIZUMAB
Omalizumab is a recombinant humanized antibody of IgG1k subclass targeted against IgE.
Approved by FDA on June 2003 for moderate to severe asthma.
Omalizumab MOA
1) inhibits the binding of IgE to mast cells and basophils.
2) inhibits the activation of IgE already bound to mast cells and thus prevent their degranulation.
3) down-regulates Fc€R-1 receptor present on mast
cells and basophils.
Omalizumab Slowly absorbed, Bioavailability = 60 % Peak serum concentration is reached in 7 to 8 days
Volume of Distribution = 78 +/- 32ml/kg
Elimination of Omalizumab - IgE complexes occur in liver and reticuloendothelial system and primarily excreted via hepatic degradation.
Elimination half-life is 26 days
A/E – Injection site reactions, headache, URTI, parasitosis,anaphylaxis, malignancy
Omalizumab Indications – Moderate to severe allergic asthma
Pts with severe concomitant allergic rhinitis
Considered as an add-on therapy to reduce or discontinue treatment with oral corticosteroids .
Reduce asthma exacerbations.
Can’t be used as a rescue medication
Omalizumab Dose of 150 to 375 mg subcutaneously every 2 to 4 weeks
Dose determined by levels of serum IgE
Should be treated for a minimum of 12 weeks
Pregnancy - Category B
Lactation - caution should be exercised
PATIENT’S SELECTION FOR OMALIZUMAB THERAPY
Multiple documented severe asthma exacerbations.
Symptomatic despite high dose ICS and LABA therapy.
Frequent daytime symptoms or night-time awakenings.
Reduced lung function (FEV1 < 80%)
Body weight between 20-150 Kg and total IgE 30-1500 IU/ml
Trials are in progress for
- Peanut allergy, Latex allergy
- Atopic dermatits
Chronic idiopathic urticaria…
CONTRAINDICATIONS: Hypersensitivity reaction
INTERACTIONS:
Can be safely used in conjunction with inhaled corticosteroids, inhaled beta agonists and oral antihistamines.
No formal drug interaction studies have been performed with omalizumab.
Other MONOCLONAL ANTIBODIES In Asthma Therapy Mepolizumab
Anti TNF-α MAb
AntiTGF-β MAb − Fresolimumab
Pitrakinra
Infliximab
Golimumab
MEPOLIZUMAB (Anti IL -5Ab) IL -5 -- cytokine in eosinophil function at sites of
allergic inflammation.
Recent studies confirm that in patients with eosinophilic asthma, mepolizumab therapy had some clinical benefit.
However, many patients with asthma do not have eosinophilia, and even in patients with eosinophilicasthma, mepolizumab had no effect on other physiological and clinical factors.
Anti TNF- alpha in Asthma Therapy Infliximab - occurrence of neutralizing antibodies
against is a common event,
may compromise drug efficacy.
Incidence of anti-TNF induced tuberculosis in treated patients.
Studies with golimumab did not demonstrate a favorable risk– benefit profile
Anti-TGF beta MAb Neutralisation of TGF-b1 with specific antibody had
no significant effect on airway inflammation and eosinophilia
It suppressed pulmonary fibrosis.
PITRAKINRA A mutated interleukin- -4
binds to IL -4Rα and blocks the effects of both IL- 4 and IL- 13.
A phase II trial in mild to moderate asthmatics showed that inhaled pitrakinra reduced the late phase decline in lung function.
Other potential Mabs in Asthma therapy
A phase 1 study evaluating the pharmacokinetics, safety and tolerability of a human IL -13 antibody (CAT- 354) revealed an acceptable safety profile.
Specific inhibition of tissue kallikrein 1 with a human monoclonal antibody(DX- 2300 ) revealed a potential in vitro and in vivo role in airway diseases.
Other potential Mabs in Asthma therapy
A Mab against TIM- 1 (Tcell Immunoglobulin Mucingene) protein influenced activated T cells and blocked the development of disease in a humanized mouse model of allergic asthma suggesting that it may provide potent therapeutic benefit in asthma.
Limitations of Use of MAbs in Asthma
Expense
Parenteral administration
Adverse effects
Host anti-drug responses limiting ongoing therapy
Limitations in current concepts of molecular pathogenesis of disease
Omalizumab is the only monoclonal
antibody to date that has been found to be effective and approved by both the FDA and European Medicines Agency (EMEA) for the treatment of difficult allergic asthma.
Bousquet J,et al. Expert Opin Biol Ther 2012;8(12):1921- 8