Mepolizumab
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Identification
- Summary
Mepolizumab is a fully-humanized monoclonal IgG1 kappa anti-IL-5 antibody used in conjunction with other therapies to treat severe asthma, eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndrome.
- Brand Names
- Nucala
- Generic Name
- Mepolizumab
- DrugBank Accession Number
- DB06612
- Background
Eosinophils are involved in inflammatory immune responses, and prolonged hypereosinophilia (typically defined as absolute eosinophil levels of 1500/mm3 or more) is associated with a spectrum of diseases, including severe asthma, eosinophilic granulomatosis with polyangiitis (EGPA), and hypereosinophilic syndrome (HES). The pathogenesis of eosinophilia is complex, but IL-5 is recognized as a key cytokine involved in the differentiation, recruitment, activation, and prolonged survival of eosinophils in peripheral tissue. Activated eosinophils further stimulate an inflammatory response and also induce tissue lesions and promote fibrosis, all of which contribute to the multifactorial symptomatology of hypereosinophilic diseases.1,2,3,4,5,6
Mepolizumab is a fully-humanized recombinant IgG1 kappa monoclonal antibody directed against IL-5 produced in Chinese hamster ovary cells. Mepolizumab was first approved by the FDA on November 4, 2015, as an add-on therapy for severe asthma and marketed under the brand name Nucala by GlaxoSmithKline. This indication was subsequently expanded to cover EGPA on December 12, 2017, and HES on September 25, 2020.6
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Monoclonal antibody (mAb) - Protein Structure
- Protein Chemical Formula
- Not Available
- Protein Average Weight
- 149000.0 Da
- Sequences
- Not Available
- Synonyms
- Mepolizumab
- External IDs
- SB 240563
- SB-240563
Pharmacology
- Indication
Mepolizumab is an anti-IL-5 IgG1 kappa monoclonal antibody indicated as an add-on maintenance treatment in patients aged six years and older with severe eosinophilic asthma and as a treatment in adult patients for eosinophilic granulomatosis with polyangiitis (EGPA). Mepolizumab is also indicated for the treatment of hypereosinophilic syndrome (HES) in patients aged 12 and older in whom eosinophilia is present for at least six months without an identifiable non-hematologic secondary cause.6
Mepolizumab is additionally indicated as an add-on maintenance treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in patients ≥18 years old with inadequate response to nasal corticosteroids.6
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Adjunct therapy in management of Chronic rhinosinusitis phenotype with nasal polyps (crswnp) •••••••••••• ••••• •••••••••• •••••••• •• ••••• ••••••••••••••• ••••••••• Treatment of Eosinophilic granulomatosis with polyangiitis •••••••••••• ••••• ••••••••• Treatment of Hypereosinophilic syndromes •••••••••••• ••••••••••••••••• ••••••• •• ••••• ••• ••••••• •• •••••••••••• ••••••••••••••• ••••••••• ••••• ••••••••• Adjunct therapy in management of Severe eosinophilic asthma •••••••••••• ••••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Mepolizumab is a monoclonal antibody that acts through interleukin-5 (IL-5) antagonism to reduce blood eosinophil levels, generally in the range of 60-90% of baseline depending on dose, which in turn offers therapeutic benefit in the specific conditions for which mepolizumab is indicated. Mepolizumab has a relatively long half-life of between 16 and 22 days, which allows for long-lasting therapeutic benefit and a four-week dosing schedule. Despite a good demonstrated safety profile, mepolizumab use does act to depress part of the immune system and may be associated with increased infections, such as with herpes zoster virus; pre-existing helminth infections should be treated before starting mepolizumab therapy. Inhaled and oral corticosteroids should not be discontinued after starting mepolizumab but may be tapered as appropriate. Mepolizumab should not be used to treat acute bronchospasms or status asthmatics. Finally, hypersensitivity reactions, including anaphylaxis, have been reported in patients; mepolizumab should be discontinued in patients with suspected or confirmed hypersensitivity.6
- Mechanism of action
Hypereosinophilia is typically considered as an absolute eosinophil count of 1500/mm3 or higher and is associated with aberrant immune responses in several conditions, including severe asthma, eosinophilic granulomatosis with polyangiitis, and the variable spectrum of hypereosinophilic syndrome (HES).1,2 Eosinophils are involved in the inflammatory response by secretion of molecules such as MBP, leukotrienes, matrix metalloproteinases, transforming growth factor-β, nitric oxide, and other reactive oxygen species.3,4 Interleukin-5 (IL-5) is the primary cytokine associated with the differentiation of bone marrow progenitor cells into mature inflammatory neutrophils and the subsequent migration, activation, and prolonged survival of activated neutrophils. In concert with other cells, including lymphocytes, neutrophils, mast cells, and macrophages, which themselves can secrete additional pro-inflammatory molecules, high concentrations of neutrophils are associated with tissue damage and fibrosis, leading to the symptoms of eosinophilic diseases.1,2,3,4,5
Typically, eosinophils arise from both CD34+ and dual CD34+, IL-5 receptor-positive (IL-5R+) progenitor cells, which is in part mediated by the cytokines IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF).4 Although there exists a population of eosinophils that are insensitive to IL-5 levels, the main population of inflammatory eosinophils proliferates and migrates into the tissue in response to IL-5.4 Mepolizumab is a fully-humanized monoclonal IgG1 kappa antibody that binds IL-5 with a dissociation constant of 100 pM, preventing IL-5 from binding to and subsequently activating IL-5R+ cells.6 This reduction lowers circulating blood eosinophil levels and therefore exerts a beneficial effect in eosinophilic disease; the exact mechanistic nature of mepolizumab action has not been definitively determined.1,2,3,4,5,6 Not all patients will benefit from mepolizumab treatment, such as those with milder asthma or those with a sub-type of HES that is independent of IL-5 signalling.1,4
Target Actions Organism AInterleukin-5 antagonistregulatorHumans - Absorption
Mepolizumab is administered subcutaneously and has a bioavailability of approximately 80% based on a 100 mg dose given to both adult and adolescent subjects with asthma. With the recommended four-week dosing schedule, there is an approximately two-fold accumulation of mepolizumab at steady-state.6
- Volume of distribution
Mepolizumab has a population central volume of distribution of 3.6 L (for a 70 kg individual) in adult asthma patients.6
- Protein binding
Not Available
- Metabolism
As a monoclonal antibody, mepolizumab is subject to proteolytic degradation at sites distributed throughout the body.6
- Route of elimination
Not Available
- Half-life
Mepolizumab has a mean terminal half-life of between 16 and 22 days.6
- Clearance
Mepolizumab has an estimated apparent population systemic clearance of 0.28 L/day (for a 70-kg individual) in adult and adolescent subjects.6
- Adverse Effects
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- Toxicity
Toxicity information regarding mepolizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as newly established or worsening chronic infections, including those caused by helminths, and generalized immune depression. Symptomatic and supportive measures are recommended.6
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- 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 Integrate drug-drug
interactions in your softwareAbatacept The risk or severity of adverse effects can be increased when Abatacept is combined with Mepolizumab. Abciximab The risk or severity of adverse effects can be increased when Abciximab is combined with Mepolizumab. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Mepolizumab. Adenovirus type 7 vaccine live The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Mepolizumab. Aducanumab The risk or severity of adverse effects can be increased when Mepolizumab is combined with Aducanumab. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- International/Other Brands
- Bosatria (GlaxoSmithKline)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Nucala Powder, for solution 100 mg / vial Subcutaneous Glaxosmithkline Inc 2016-03-14 2023-12-06 Canada Nucala Injection, solution 100 mg Subcutaneous Glaxo Smith Kline Trading Services 2022-05-04 Not applicable EU Nucala Injection, powder, for solution 100 mg/1mL Subcutaneous GlaxoSmithKline LLC 2015-11-04 Not applicable US Nucala Injection, solution 100 mg Subcutaneous Glaxo Smith Kline Trading Services 2020-12-16 Not applicable EU Nucala Injection, powder, for solution 100 mg Subcutaneous Glaxo Smith Kline Trading Services 2020-12-16 Not applicable EU
Categories
- ATC Codes
- R03DX09 — Mepolizumab
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- Not Available
- Kingdom
- Organic Compounds
- Super Class
- Organic Acids
- Class
- Carboxylic Acids and Derivatives
- Sub Class
- Amino Acids, Peptides, and Analogues
- Direct Parent
- Peptides
- Alternative Parents
- Not Available
- Substituents
- Not Available
- Molecular Framework
- Not Available
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 90Z2UF0E52
- CAS number
- 196078-29-2
References
- Synthesis Reference
Robert S. Ames, Edward Robert Appelbaum, Irwin M. Chaiken, Richard M. Cook, Mitchell Stuart Gross, Stephen Dudley Holmes, Lynette Jane McMillan, Timothy Wayne Theisen, "Recombinant il-5 antagonists useful in treatment of il-5 mediated disorders." Patent WO1996021000A2, issued July 11, 1996.
- General References
- Kuang FL, Fay MP, Ware J, Wetzler L, Holland-Thomas N, Brown T, Ortega H, Steinfeld J, Khoury P, Klion AD: Long-Term Clinical Outcomes of High-Dose Mepolizumab Treatment for Hypereosinophilic Syndrome. J Allergy Clin Immunol Pract. 2018 Sep - Oct;6(5):1518-1527.e5. doi: 10.1016/j.jaip.2018.04.033. Epub 2018 May 8. [Article]
- Curtis C, Ogbogu P: Hypereosinophilic Syndrome. Clin Rev Allergy Immunol. 2016 Apr;50(2):240-51. doi: 10.1007/s12016-015-8506-7. [Article]
- Caminati M, Menzella F, Guidolin L, Senna G: Targeting eosinophils: severe asthma and beyond. Drugs Context. 2019 Jul 23;8:212587. doi: 10.7573/dic.212587. eCollection 2019. [Article]
- Bakakos A, Loukides S, Bakakos P: Severe Eosinophilic Asthma. J Clin Med. 2019 Sep 2;8(9). pii: jcm8091375. doi: 10.3390/jcm8091375. [Article]
- Rothenberg ME, Klion AD, Roufosse FE, Kahn JE, Weller PF, Simon HU, Schwartz LB, Rosenwasser LJ, Ring J, Griffin EF, Haig AE, Frewer PI, Parkin JM, Gleich GJ: Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008 Mar 20;358(12):1215-28. doi: 10.1056/NEJMoa070812. Epub 2008 Mar 16. [Article]
- FDA Approved Drug Products: Nucala (mepolizumab) for subcutaneous injection [Link]
- GlaxoSmithKline: NUCALA safety data sheet [Link]
- External Links
- KEGG Drug
- D04923
- PubChem Substance
- 347910353
- 1720597
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Mepolizumab
- FDA label
- Download (3.56 MB)
- MSDS
- Download (86.4 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Active Not Recruiting Not Available Asthma in Children 1 somestatus stop reason just information to hide Not Available Active Not Recruiting Not Available Coronavirus Disease 2019 (COVID‑19) / Eosinophilic Asthma / Late-Onset Asthma / Severe Asthma 1 somestatus stop reason just information to hide Not Available Completed Not Available Asthma 2 somestatus stop reason just information to hide Not Available Completed Not Available Asthma Severe Persistent Uncontrolled 1 somestatus stop reason just information to hide Not Available Completed Not Available Eosinophilic Asthma 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection Subcutaneous 100 mg Injection, powder, for solution Subcutaneous 100 mg/1mL Injection, powder, for solution Subcutaneous 100 MG Injection, solution Parenteral; Subcutaneous 100 MG Injection, solution Parenteral; Subcutaneous 40 mg Injection, solution Subcutaneous 100 mg Injection, solution Subcutaneous 100 mg/1mL Injection, solution Subcutaneous 40 mg Injection, solution Subcutaneous 40 mg/0.4mL Powder, for solution Subcutaneous 100 mg / vial Solution Subcutaneous 100 mg / mL Solution Subcutaneous 40 mg / 0.4 mL Solution Subcutaneous 40.000 mg Solution Subcutaneous 100 mg/ml Injection, powder, lyophilized, for solution Subcutaneous 100 mg Injection, solution Subcutaneous 100 mg/ml Solution Subcutaneous 100 mg Injection, powder, for solution Subcutaneous 100 mg/1vial - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US20100086547 No 2007-04-30 2027-04-30 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- AntagonistRegulator
- General Function
- Homodimeric cytokine expressed predominantly by T-lymphocytes and NK cells that plays an important role in the survival, differentiation, and chemotaxis of eosinophils (PubMed:2653458, PubMed:9010276). Acts also on activated and resting B-cells to induce immunoglobulin production, growth, and differentiation (By similarity). Mechanistically, exerts its biological effects through a receptor composed of IL5RA subunit and the cytokine receptor common subunit beta/CSF2RB (PubMed:1495999, PubMed:22528658). Binding to the receptor leads to activation of various kinases including LYN, SYK and JAK2 and thereby propagates signals through the RAS-MAPK and JAK-STAT5 pathways respectively (PubMed:7613138)
- Specific Function
- cytokine activity
- Gene Name
- IL5
- Uniprot ID
- P05113
- Uniprot Name
- Interleukin-5
- Molecular Weight
- 15237.695 Da
References
- Basavaraju KP, Wong T: Eosinophilic oesophagitis: a common cause of dysphagia in young adults? Int J Clin Pract. 2008 Jul;62(7):1096-107. doi: 10.1111/j.1742-1241.2008.01782.x. [Article]
- Garrett JK, Jameson SC, Thomson B, Collins MH, Wagoner LE, Freese DK, Beck LA, Boyce JA, Filipovich AH, Villanueva JM, Sutton SA, Assa'ad AH, Rothenberg ME: Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol. 2004 Jan;113(1):115-9. Epub 2003 Dec 12. [Article]
- Agarwal A, Spath D, Sherris DA, Kita H, Ponikau JU: Therapeutic Antibodies for Nasal Polyposis Treatment: Where Are We Headed? Clin Rev Allergy Immunol. 2020 Oct;59(2):141-149. doi: 10.1007/s12016-019-08734-z. [Article]
- FDA Approved Drug Products: Nucala (mepolizumab) for subcutaneous injection [Link]
Drug created at March 19, 2008 16:41 / Updated at June 03, 2022 07:24