Mepolizumab

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
Db06612
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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
AInterleukin-5
antagonist
Humans
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.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Mepolizumab.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Mepolizumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Mepolizumab.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Mepolizumab.
AducanumabThe risk or severity of adverse effects can be increased when Mepolizumab is combined with Aducanumab.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Mepolizumab.
AlefaceptThe risk or severity of adverse effects can be increased when Alefacept is combined with Mepolizumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Mepolizumab.
AlirocumabThe risk or severity of adverse effects can be increased when Mepolizumab is combined with Alirocumab.
AltretamineThe risk or severity of adverse effects can be increased when Altretamine is combined with Mepolizumab.
Interactions
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Food Interactions
No interactions found.

Products

Products
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International/Other Brands
Bosatria (GlaxoSmithKline)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NucalaInjection100 mgSubcutaneousGlaxo Smith Kline Trading Services2020-12-16Not applicableEU flag
NucalaInjection, powder, for solution100 mgSubcutaneousGlaxo Smith Kline Trading Services2020-12-16Not applicableEU flag
NucalaInjection, powder, for solution100 mg/1mLSubcutaneousGlaxoSmithKline LLC2015-11-04Not applicableUS flag
NucalaSolution100 mg / mLSubcutaneousGlaxosmithkline Inc2019-12-10Not applicableCanada flag
NucalaInjection, solution100 mgSubcutaneousGlaxo Smith Kline Trading Services2020-12-16Not applicableEU flag
NucalaInjection, powder, for solution100 mgSubcutaneousGlaxo Smith Kline Trading Services2020-12-16Not applicableEU flag
NucalaInjection, powder, for solution100 mg/1mLSubcutaneousGlaxoSmithKline Manufacturing SpA2015-11-042017-12-12US flag
NucalaInjection, solution100 mgSubcutaneousGlaxo Smith Kline Trading Services2020-12-16Not applicableEU flag
NucalaPowder, for solution100 mg / vialSubcutaneousGlaxosmithkline Inc2016-03-14Not applicableCanada flag
NucalaInjection, solution100 mg/1mLSubcutaneousGlaxoSmithKline LLC2019-06-06Not applicableUS flag

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
  1. 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]
  2. Curtis C, Ogbogu P: Hypereosinophilic Syndrome. Clin Rev Allergy Immunol. 2016 Apr;50(2):240-51. doi: 10.1007/s12016-015-8506-7. [Article]
  3. 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]
  4. Bakakos A, Loukides S, Bakakos P: Severe Eosinophilic Asthma. J Clin Med. 2019 Sep 2;8(9). pii: jcm8091375. doi: 10.3390/jcm8091375. [Article]
  5. 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]
  6. FDA Approved Drug Products: Nucala (mepolizumab) injection [Link]
  7. GlaxoSmithKline: NUCALA safety data sheet [Link]
KEGG Drug
D04923
PubChem Substance
347910353
RxNav
1720597
Drugs.com
Drugs.com Drug Page
Wikipedia
Mepolizumab
AHFS Codes
  • 92:44.00 — Immunosuppressive Agents
FDA label
Download (3.56 MB)
MSDS
Download (86.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAsthma2
4Not Yet RecruitingTreatmentAsthma1
4Not Yet RecruitingTreatmentAsthma / Chronic Cough (CC) / Eosinophilic Bronchitis1
4RecruitingTreatmentAsthma / Eosinophilic Asthma1
4RecruitingTreatmentEosinophilic Asthma1
4RecruitingTreatmentSevere Asthma1
3Active Not RecruitingTreatmentAllergic granulomatous angiitis / Churg-Strauss Syndrome1
3CompletedTreatmentAllergic granulomatous angiitis / Churg-Strauss Syndrome1
3CompletedTreatmentAsthma10
3CompletedTreatmentBronchitis / Chronic Airways Limitation / Chronic Obstructive Pulmonary Disease (COPD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionSubcutaneous100 mg
Injection, powder, for solutionParenteral; Subcutaneous
Injection, powder, for solutionSubcutaneous100 mg/1mL
Injection, solutionSubcutaneous
Injection, solutionSubcutaneous100 mg/1mL
Injection, solutionSubcutaneous100 mg
Powder, for solutionSubcutaneous100 mg / vial
SolutionSubcutaneous100 mg / mL
Injection, powder, lyophilized, for solutionSubcutaneous
Injection, powder, for solutionSubcutaneous100 mg
Injection, powder, for solutionSubcutaneous
Injection, powder, for solution100 mg/1vial
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US20100086547No2007-04-302027-04-30US flag

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Interleukin-5 receptor binding
Specific Function
Factor that induces terminal differentiation of late-developing B-cells to immunoglobulin secreting cells.
Gene Name
IL5
Uniprot ID
P05113
Uniprot Name
Interleukin-5
Molecular Weight
15237.695 Da
References
  1. 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]
  2. 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]
  3. FDA Approved Drug Products: Nucala (mepolizumab) injection [Link]

Drug created on March 19, 2008 16:41 / Updated on June 22, 2021 09:25