Omalizumab

1. OMALIZUMAB Dr. RENJU S RAVI

2. O verview Introduction Bronchial asthma – Definition, Symptoms, Classification Pathophysiology Approaches to treatment Role of IgE in asthma Omalizumab – MOA Pharmacokinetics/ Pharmacodynamics Adverse effects Indications/Contraindications Interactions Other monoclonal antibodies in asthma therapy

3. BRONCHIAL ASTHMA Chronic inflammatory condition of airways resulting in episodic airflow obstruction due to bronchial hyper responsiveness.

4. Symptoms ASTHMA Breathlessness Chest tightness C ough Expiratory wheezing

5. CLASSIFICATION Mild intermittent asthma Mild persistent asthma Moderate persistent asthma Severe persistent asthma

6. PATHOPHYSIOLOGY Early asthmatic response Histamine, LT-C,D,E Pg bronchospasm Allergen exposure Late asthmatic response Bronchial hyper reactivity and Inflammation β 2 agonist Theophylline LT antagonist Glucocorticoids

7. APPROACHES TO TREATMENT BRONCHODILATORS - Sympathomimetic agents Methylxanthines Anticholinergics MEDIATOR RELEASE INHIBITORS Mast cell stabilizers Lipoxygenase Inhibitors MEDIATOR ANTAGONISTS Leukotriene antagonists CORTICOSTEROIDS ANTI IgE ANTIBODY

8. SELECTIVE β 2 AGONISTS SHORT ACTING SALBUTAMOL TERBUTALINE REMITEROL FENOTEROL LONG ACTING SALMETEROL FORMOTEROL BAMBUTEROL

9. ANTICHOLINERGICS Ipratropium Tiotropium Oxitropium

10. METHYLXANTHINES Theophylline Theobromine Aminophylline

11. MAST CELL STABILISERS Na cromoglycate Nedocromil Ketotifen

12. LT MODULATORS Lipoxygenase inhibitors - Zileuton LTD 4 receptor antagonist - Zafirleukast,Monteleukast, Pranleukast,Iralukast

13. CORTICOSTEROIDS ORAL - Prednisolone, Methyl prednisolone PARENTRAL - Methyl prednisolone, Hydrocortisone INHALATIONAL - Beclomethasone, Fluticasone, Budisonide, Triamcinolone, Flunisolide

14. MONOCLONAL ANTIBODY Omalizumab MISCELLANEOUS – PDE4 inhibitors, CRth2 antagonists, Endothelin antagonists, NO synthase inhibitors, Chemokine receptor antagonists, Protease inhibitors etc…

15. Anti-IgE Therapy Most asthmatic patients have elevated circulating IgE concentrations when levels are adjusted for age IgE is produced by B lymphocytes

16. OMALIZUMAB Omalizumab is a recombinant humanized antibody of IgG 1 k subclass targeted against IgE. Approved by FDA on June 2003 for moderate to severe asthma.

17. 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.

18. 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

19. 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

20. 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

21. 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 (FEV 1 < 80% ) Body weight between 20-150 Kg and total IgE 30-1500 IU/m l

22. Trials are in progress for - Peanut allergy, Latex allergy - Atopic dermatits Chronic idiopathic urticaria… CONTRAINDICATIONS : H ypersensitivity reaction

23. 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.

24. Other MONOCLONAL ANTIBODIES In Asthma Therapy Mepolizumab Anti TNF- α MAb AntiTGF - β MAb − Fresolimumab Pitrakinra I nfliximab Golimumab

25. 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 eosinophilic asthma, mepolizumab had no effect on other physiological and clinical factors.

26. 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

27. Anti-TGF beta MAb Neutralisation of TGF- b1 with specific antibody had no significant effect on airway inflammation and eosinophilia It suppressed pulmonary fibrosis.

28. 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.

29. 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.

30. Other potential Mabs in Asthma therapy A Mab against TIM- 1 ( Tcell Immunoglobulin Mucin gene) 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.

31. 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

32. 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

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