Dr. RENJU S RAVI

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.

Symptoms

ASTHMA

Breathlessness

Chest tightness

Cough

Expiratory wheezing

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

ANTICHOLINERGICS

Ipratropium

Tiotropium

Oxitropium

METHYLXANTHINES

Theophylline

Theobromine

Aminophylline

MAST CELL STABILISERS

Na cromoglycate

Nedocromil

Ketotifen

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

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