Omalizumab

Identification

Summary

Omalizumab is a monoclonal anti-immunoglobulin E antibody used in the treatment of severe asthma and chronic idiopathic urticaria.

Brand Names

Xolair

Generic Name

Omalizumab

DrugBank Accession Number

DB00043

Background

Omalizumab, manufactured by Genentech, was first FDA approved in 2003 to treat adults and children 12 years of age and older with moderate to severe persistent allergic asthma which is not controlled by inhaled steroids ⁶. Since its U.S. approval, more than 200,000 patients older than 12 with allergic asthma have been treated ⁶. In September 2018, a new prefilled syringe formulation of this drug was approved by the FDA ⁷.

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Structure

Protein Chemical Formula: C₆₄₅₀H₉₉₁₆N₁₇₁₄O₂₀₂₃S₃₈
Protein Average Weight: 149000.0 Da

Sequences

>Omalizumab heavy chain
EVQLVESGGGLVQPGGSLRLSCAVSGYSITSGYSWNWIRQAPGKGLEWVASITYDGSTNY
ADSVKGRFTISRDDSKNTFYLQMNSLRAEDTAVYYCARGSHYFGHWHFAVWGQGTLVTVS
SGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK

>Omalizumab light chain
DIQLTQSPSSLSASVGDRVTITCRASQSVDYDGDSYMNWYQQKPGKAPKLLIYAASYLES
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHEDPYTFGQGTKVEIKRTVAAPSVF
IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS
STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR

Download FASTA Format

Synonyms

Omalizumab

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Pharmacology

Indication

This drug is an anti-IgE antibody indicated for:

Moderate to severe persistent asthma in patients 6 years of age and older with a positive skin test or in vitro reactivity to a perennial aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids ^Label
Chronic idiopathic urticaria in adults and adolescents 12 years of age and older who remain symptomatic despite H1 antihistamine treatment ^Label

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Associated Conditions

Indication Type	Indication	Approval Level	Patient Characteristics	Dose Form
Management of	Chronic idiopathic urticaria	••••••••••••	••••••••••• ••••••• •• ••••••••••••• •••••••••
Management of	Moderate asthma	••••••••••••	•••••••• •••••••••••• •••••••••• •••• ••••••• •••••••••••••••	•••••••••• ••••••••
Management of	Severe asthma	••••••••••••	•••••••• •••••••••••• •••••••••• •••• ••••••• •••••••••••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Omalizumab is a recombinant, humanized, monoclonal antibody against human immunoglobulin E (IgE) which treats the symptoms of asthma and chronic idiopathic urticaria by limiting the allergic response ^Label, ³. It inhibits the binding of IgE to receptors on mast cells and basophils, blocking the IgE-mediated secretion of inflammatory mediators from these cells ¹.

Mast cell activation and the release of mediators, in response to allergen exposure and IgE, results in a cascade of events. This cascade culminates in the activation of B-lymphocytes, T-lymphocytes, eosinophils, fibroblasts, smooth muscle cells, and the endothelium. This cellular interaction, as well as the release of cytokines, chemokines and growth factors and inflammatory remodeling of the airway results in chronic asthma ².

After 4 weeks of use of this medication in patients with chronic urticaria, it was found that rescue medication use was reduced significantly and quality of life improved ⁴.

Mechanism of action

When an environmental allergen first enters the body, is taken up by antigen-presenting cells (APCs). It is then processed, and presented to T and B immune cells. This is followed by the activation of B-lymphocyte and production of allergen-specific IgE. This IgE is then released by plasma cells (converted B lymphocytes) and is therefore available to bind to IgE receptors on several other cells ³.

IgE binds to high-affinity (Fc€RI) and low-affinity (Fc€RII) receptors on multiple cells of the immune system. Following subsequent antigen exposure, cross-linking of the antigen occurs by several Fc€RI-bound IgE molecules on the surface of both basophils and mast cells. This leads to the activation of mast cells and histamine release, producing a wheal and other symptoms of urticaria ³.

The following are explanations of the mechanism of action for both indications of this drug:

Asthma

Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor (FcεRI) on the surface of both mast cells and basophils. The reduction in surface-bound IgE on FcεRI-bearing cells limits the degree of release of mediators of the typical allergic response. Treatment with omalizumab also reduces the number of FcεRI receptors on basophils in atopic patients ^Label.

Omalizumab binds to free IgE with a higher affinity than IgE itself binds to the high-affinity Fc€RI receptors found on basophils. Therefore, it decreases the availability of free IgE for binding ³. Omalizumab by itself does not bind to the Fc€RI receptors, nor does the drug bind to receptor-bound IgE. These binding characteristics allow omalizumab to neutralize the typical IgE-mediated responses without causing the degranulation of basophils or cross-linking with basophil-bound IgE ³.

Chronic Idiopathic Urticaria Omalizumab binds to IgE and decreases free IgE levels. Subsequently, IgE receptors (FcεRI) on cells are down-regulated. The mechanism by which these effects of omalizumab result in an improvement of CIU symptoms is unclear^Label.

Target	Actions	Organism
AHigh affinity immunoglobulin epsilon receptor subunit alpha	inhibitor	Humans
AHigh affinity immunoglobulin epsilon receptor subunit beta	inhibitor	Humans

Absorption

After subcutaneous administration in pharmacokinetic studies, omalizumab was absorbed with a mean absolute bioavailability of 62% ^Label. After the administration of a single subcutanous dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly. The peak serum concentrations peaked after an average of 7-8 days. In patients with CIU, the peak serum concentration was reached at a similar time after a single SC dose. The pharmacokinetics of omalizumab was linear at doses which were higher than 0.5 mg/kg. In patients with asthma, after several doses of omalizumab, areas under the serum concentration-time curve from Day 0 to Day 14 at steady state were up to 6-fold of those after one dose. In patients with CIU, omalizumab showed linear pharmacokinetics in the dose range of 75 mg to 600 mg administered as a single subcutaneous dose. After repeated dosing from 75mg-300 mg every 4 weeks, trough serum concentrations of omalizumab increased proportionally with the dose ^Label.

Volume of distribution

The apparent volume of distribution of omalizumab in patients with asthma after subcutaneous administration was 78 ± 32 mL/kg. In patients with CIU, the distribution of omalizumab was similar to that in asthmatic patients ^Label.

Protein binding

Monoclonal antibodies are usually not required to have protein binding studies.

Metabolism

Monoclonal antibodies, in general, are believed to be internalized in endothelial cells bound to the Fc receptor and rescued from metabolism by recycling. At a later time, they are degraded in the reticuloendothelial system to smaller peptides and amino acids, which can then be used for de-novo protein synthesis ⁵. Several factors may influence this process, however. These include factors related to the target antigen, antibody, and patient ⁵.

The metabolism of omalizumab is determined by its IgG1 framework, and by its specific binding to IgE. The elimination of omalizumab is dose-dependent. The reticuloendothelial system and the liver are two sites of elimination for IgG (including degradation in the liver reticuloendothelial system and endothelial cells) ⁹, ⁵. The omalizumab:IgE complexes are thought to be to cleared via interactions with Fc- gamma-Rs (Fc gamma RI, Fc gamma RII, and Fc gamma RIII) at rates that are more rapid than that of IgG clearance. The relative clearance of free omalizumab, free IgE, and complexes is summarized as: free IgE clearance > > omalizumab:IgE clearance > omalizumab clearance ⁹.

Route of elimination

Liver elimination of IgG includes degradation in the liver reticuloendothelial system (RES) and endothelial cells. Intact IgG was also shown to be excreted in bile, in pharmacokinetic studies ^Label.

Half-life

In chronic idiopathic urticaria (CIU) patients, at steady state, based on population pharmacokinetics, omalizumab serum elimination half-life averaged 24 days ^Label.

In asthmatic patients omalizumab serum elimination half-life averaged 26 days ^Label.

Clearance

In pharmacokinetic studies, the clearance of omalizumab involved IgG clearance as well as clearance by specific binding and complex formation with its target ligand, IgE ^Label, ⁹.

The apparent clearance averaging 2.4 ± 1.1 mL/kg/day was measured in asthmatic patients ^Label.

In chronic idiopathic urticaria (CIU) patients, at steady state, based on population pharmacokinetics, omalizumab apparent clearance averaged 240 mL/day (corresponding to 3.0 mL/kg/day for an 80 kg patient)^Label.

Adverse Effects

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Toxicity

Anaphylaxis

Anaphylaxis may occur rarely with this agent, either after the first dose or multiple doses ^Label, ². Anaphylaxis presenting clinically as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue, has been reported during and after this use of this drug. Therefore, close clinical monitoring should be performed during and shortly after administration ^Label.

Maximum Dosage

The maximum tolerated dosage of omalizumab has not yet been determined. Single intravenous (IV) doses of up to 4000 mg have been administered to patients without evidence of dose-limiting toxicity. The highest cumulative dose administered to patients was 44,000 mg over a 20 week time period, which was not associated with any toxicities ^Label.

The use in Pregnancy

The data with omalizumab use in pregnant women are insufficient to inform on drug-associated risk. Monoclonal antibodies, such as omalizumab, are transported across the placenta in a linear fashion as a pregnancy progresses; therefore, potential effects on a fetus are likely to be greater in frequency during the second and third trimesters ^Label.

In women with inadequately or moderately controlled asthma, the current evidence suggests that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small fetal size ^Label.

The use During Breastfeeding

There is no information regarding the presence of omalizumab in human milk, the effects on the breastfed infant, or the effects on milk production ^Label. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for omalizumab and any potential adverse effects on the breastfed child from omalizumab or from the underlying maternal condition ^Label.

Pathways

Not Available

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Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abciximab	The risk or severity of adverse effects can be increased when Omalizumab is combined with Abciximab.
Adalimumab	The risk or severity of adverse effects can be increased when Omalizumab is combined with Adalimumab.
Aducanumab	The risk or severity of adverse effects can be increased when Omalizumab is combined with Aducanumab.
Alemtuzumab	The risk or severity of adverse effects can be increased when Omalizumab is combined with Alemtuzumab.
Alirocumab	The risk or severity of adverse effects can be increased when Omalizumab is combined with Alirocumab.

Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Xolair	Solution	150 mg / mL	Subcutaneous	Novartis	2017-07-06	Not applicable
Xolair	Injection, solution	300 mg	Subcutaneous	Novartis Europharm Limited	2023-11-28	Not applicable
Xolair	Injection, solution	150 mg	Subcutaneous	Novartis Europharm Limited	2023-11-28	Not applicable
Xolair	Injection, solution	300 mg	Subcutaneous	Novartis Europharm Limited	2023-11-28	Not applicable
Xolair	Injection, solution	75 mg	Subcutaneous	Novartis Europharm Limited	2023-11-28	Not applicable

Chemical Identifiers

UNII: 2P471X1Z11
CAS number: 242138-07-4

References

General References

Jensen RK, Plum M, Tjerrild L, Jakob T, Spillner E, Andersen GR: Structure of the omalizumab Fab. Acta Crystallogr F Struct Biol Commun. 2015 Apr;71(Pt 4):419-26. doi: 10.1107/S2053230X15004100. Epub 2015 Mar 20. [Article]
Miller CW, Krishnaswamy N, Johnston C, Krishnaswamy G: Severe asthma and the omalizumab option. Clin Mol Allergy. 2008 May 20;6:4. doi: 10.1186/1476-7961-6-4. [Article]
Godse K, Mehta A, Patil S, Gautam M, Nadkarni N: Omalizumab-A Review. Indian J Dermatol. 2015 Jul-Aug;60(4):381-4. doi: 10.4103/0019-5154.160490. [Article]
Kaplan AP, Joseph K, Maykut RJ, Geba GP, Zeldin RK: Treatment of chronic autoimmune urticaria with omalizumab. J Allergy Clin Immunol. 2008 Sep;122(3):569-73. doi: 10.1016/j.jaci.2008.07.006. [Article]
Tabrizi MA, Tseng CM, Roskos LK: Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006 Jan;11(1-2):81-8. doi: 10.1016/S1359-6446(05)03638-X. [Article]
FDA Approves Genentech’s Xolair® (omalizumab) for Allergic Asthma in Children [Link]
FDA Approves Genentech's Xolair (omalizumab) Prefilled Syringe Formulation [Link]
Omalizumab properties, THPdb Database [Link]
Xolair EMA label [File]

External Links

UniProt: P01857
Genbank: J00228
PubChem Substance: 46507002
RxNav: 302379
ChEMBL: CHEMBL1201589
Therapeutic Targets Database: DAP000387
PharmGKB: PA164752253
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Omalizumab

MSDS

Download (582 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Not Available	Atopic Dermatitis	1
4	Completed	Basic Science	Asthma	1
4	Completed	Diagnostic	Asthma, Allergic	1
4	Completed	Treatment	Allergic Rhinitis (AR) / Asthma / Atopic Dermatitis	1
4	Completed	Treatment	Aspirin Sensitivity	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Genentech Inc.
Novartis AG

Dosage Forms

Form	Route	Strength
Injection	Subcutaneous	150 MG
Injection, powder, for solution	Subcutaneous	150 MG
Injection, powder, for solution	Subcutaneous	75 MG
Injection, solution	Parenteral; Subcutaneous	150 MG
Injection, solution	Parenteral; Subcutaneous	75 MG
Injection, solution	Subcutaneous	150 mg/1.2mL
Injection, solution	Subcutaneous	300 mg
Injection, solution	Subcutaneous	300 mg/2mL
Injection, solution	Subcutaneous	75 mg
Powder		150 mg/1vial
Powder, for solution	Subcutaneous	150 mg / vial
Solution	Subcutaneous	150 mg / mL
Solution	Subcutaneous	75 mg / 0.5 mL
Solution	Subcutaneous	75.000 mg
Solution	Subcutaneous	150 mg
Solution	Subcutaneous	75 mg
Injection, solution	Subcutaneous	150 mg
Injection, solution	Subcutaneous	150 mg/ml
Injection, powder, lyophilized, for solution	Subcutaneous	150 mg
Injection, powder, for solution	Subcutaneous
Injection, powder, lyophilized, for solution	Subcutaneous	75 mg
Injection, solution	Subcutaneous	150 mg/1mL
Injection, solution	Subcutaneous	75 mg/0.5mL
Injection, solution	Subcutaneous	150 mg/1.0mL

Prices

Unit description	Cost	Unit
Xolair 150 mg vial	715.42USD	vial

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
CA2113813	No	2005-04-12	2012-08-14
CA1340233	No	1998-12-15	2015-12-15

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	61 °C (FAB fragment)	http://crdd.osdd.net/raghava/thpdb/display_thppid_sub.php?details=Th1038
boiling point (°C)	Fab and Fc domains denaturates at 60 and 70 ºC respectively	Arnoldus W. et al. (2000). Biophysical Journal. Vol 78. 394-404
hydrophobicity	-0.432	Not Available
isoelectric point	6.6 - 7.2	Jin, et al. Electrophoresis. Sep;23(19):3385-91. (2002).

Targets

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Details1. High affinity immunoglobulin epsilon receptor subunit alpha

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Ige receptor activity
Specific Function: Binds to the Fc region of immunoglobulins epsilon. High affinity receptor. Responsible for initiating the allergic response. Binding of allergen to receptor-bound IgE leads to cell activation and t...
Gene Name: FCER1A
Uniprot ID: P12319
Uniprot Name: High affinity immunoglobulin epsilon receptor subunit alpha
Molecular Weight: 29595.67 Da

References

Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S: Omalizumab-induced reductions in mast cell Fce psilon RI expression and function. J Allergy Clin Immunol. 2004 Sep;114(3):527-30. [Article]
Mirkina I, Schweighoffer T, Kricek F: Inhibition of human cord blood-derived mast cell responses by anti-Fc epsilon RI mAb 15/1 versus anti-IgE Omalizumab. Immunol Lett. 2007 Apr 15;109(2):120-8. Epub 2007 Mar 1. [Article]
Godse K, Mehta A, Patil S, Gautam M, Nadkarni N: Omalizumab-A Review. Indian J Dermatol. 2015 Jul-Aug;60(4):381-4. doi: 10.4103/0019-5154.160490. [Article]

Details2. High affinity immunoglobulin epsilon receptor subunit beta

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Ige receptor activity
Specific Function: High affinity receptor that binds to the Fc region of immunoglobulins epsilon. Aggregation of FCER1 by multivalent antigens is required for the full mast cell response, including the release of pre...
Gene Name: MS4A2
Uniprot ID: Q01362
Uniprot Name: High affinity immunoglobulin epsilon receptor subunit beta
Molecular Weight: 26533.365 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
DuBuske LM: IgE, allergic diseases, and omalizumab. Curr Pharm Des. 2006;12(30):3929-44. [Article]
Raunio H, Rautio A, Gullsten H, Pelkonen O: Polymorphisms of CYP2A6 and its practical consequences. Br J Clin Pharmacol. 2001 Oct;52(4):357-63. [Article]

Drug created at June 13, 2005 13:24 / Updated at January 02, 2024 23:41

Omalizumab

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References

References