Identification

Summary

Agalsidase alfa is a recombinant human alpha-galactosidase indicated to treat Fabry disease, a genetic deficiency in the enzyme leading to buildup of globotriaosylceramide.

Brand Names
Replagal
Generic Name
Agalsidase alfa
DrugBank Accession Number
DB15874
Background

Agalsidase alfa is a recombinant human α-galactosidase A similar to agalsidase beta. While patients generally do not experience a clinically significant difference in outcomes between the two drugs, some patients may experience greater benefit with agalsidase beta.1,2 Use of agalsidase beta has decreased in Europe, in favor of agalsidase alfa, after a contamination event in 2009.6

Agalsidase alfa was granted EMA approval on 3 August 2001.8

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Recombinant Enzymes
Protein Structure
Protein Chemical Formula
C2029H3080N544O587S27
Protein Average Weight
45351.6 Da
Sequences
>Agalsidase alfa sequence
LDNGLARTPTMGWLHWERFMCNLDCQEEPDSCISEKLFMEMAELMVSEGWKDAGYEYLCI
DDCWMAPQRDSEGRLQADPQRFPHGIRQLANYVHSKGLKLGIYADVGNKTCAGFPGSFGY
YDIDAQTFADWGVDLLKFDGCYCDSLENLADGYKHMSLALNRTGRSIVYSCEWPLYMWPF
QKPNYTEIRQYCNHWRNFADIDDSWKSIKSILDWTSFNQERIVDVAGPGGWNDPDMLVIG
NFGLSWNQQVTQMALWAIMAAPLFMSNDLRHISPQAKALLQDKDVIAINQDPLGKQGYQL
RQGDNFEVWERPLSGLAWAVAMINRQEIGGPRSYTIAVASLGKGVACNPACFITQLLPVK
RKLGFYEWTSRLRSHINPTGTVLLQLENTMQMSLKDLL
References:
  1. NCBI: Galactosidase Alpha Gene [Link]
Download FASTA Format
Synonyms
  • Agalsidase alfa
  • Agalsidase alfa (genetical recombination)
  • Agalsidase alpha
  • alpha-D-galactopyranosidase
  • alpha-D-galactosidase
  • alpha-D-galactosidase enzyme
  • alpha-D-galactoside galactohydrolase
  • alpha-galactisidase
  • alpha-galactosidase A
  • Recombinant alpha-galactosidase A
External IDs
  • DRX-005B
  • DRX005B
  • EC 3.2.1.22

Pharmacology

Indication

Agalsidase alfa is indicated in the treatment of Fabry disease.7

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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Agalsidase alfa is a recombinant human α-galactosidase A used as enzyme replacement therapy in the treatment of Fabry disease.7 It has a long duration of action and a wide therapeutic index.7 Patients should be counselled regarding the risk of infusion related reactions and hypersensitivity.7

Mechanism of action

α-galactosidase A is uptaken by cells via the mannose 6 phosphate receptor.3 Agalsidase alfa hydrolyzes globotriaosylceramide and other glycosphingolipids that would normally be hydrolyzed by endogenous α-galactosidase A.7 Preventing the accumulation of glycosphingolipids prevents or reduces the severity of manifestations of Fabry disease such as renal failure, cardiomyopathy, or cerebrovascular events.7

TargetActionsOrganism
UGlobotriaosylceramide
metabolizer
ligand
Humans
Absorption

A dose of agalsidase alfa in non end stage renal disease patients reaches a Cmax of 3710 ± 855 U/mL with an AUC of 256,958 ± 63,499 min*U/mL.5

Volume of distribution

The volume of distribution at steady state in non end stage renal disease patients was approximately 17% of body weight regardless of sex.5,7

Protein binding

Agalsidase alfa is not expected to be protein bound in circulation.7

Metabolism

Data regarding the metabolism of agalsidase alfa is not readily available.7 However, protein drugs are expected to be degraded by proteases and other catalytic enzymes to smaller peptides and amino acids.4

Route of elimination

After nonspecific proteolysis, the amino acids from protein drugs are reused for protein synthesis or further broken down and eliminated by the kidneys.4

Half-life

The elimination half life was 108 ± 17 minutes for males and 89 ± 28 minutes for females.7

Clearance

The clearance for doses of 0.007-0.2 mg/kg were 2.66 mL/min/kg for males and 2.10 mL/min/kg for females.7

Adverse Effects
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Toxicity

Data regarding overdoses of agalsidase alfa are not readily available.7 Patients experiencing an overdose of agalsidase alfa may experience an increased incidence and severity of adverse effects. Overdose can be managed through the use of symptomatic and supportive measures.

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
Agalsidase betaThe therapeutic efficacy of Agalsidase beta can be decreased when used in combination with Agalsidase alfa.
AmiodaroneThe therapeutic efficacy of Agalsidase alfa can be decreased when used in combination with Amiodarone.
ChloroquineThe therapeutic efficacy of Agalsidase alfa can be decreased when used in combination with Chloroquine.
GentamicinThe therapeutic efficacy of Agalsidase alfa can be decreased when used in combination with Gentamicin.
MonobenzoneThe therapeutic efficacy of Agalsidase alfa can be decreased when used in combination with Monobenzone.
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ReplagalInjection, solution, concentrate1 mg/mlIntravenousTakeda Pharmaceuticals International Ag Ireland Branch2016-09-08Not applicableEU flag
ReplagalInjection, solution, concentrate1 mg/mlIntravenousTakeda Pharmaceuticals International Ag Ireland Branch2016-09-08Not applicableEU flag
ReplagalSolution1 mg / mLIntravenousTakeda2004-03-18Not applicableCanada flag
ReplagalInjection, solution, concentrate1 mg/mlIntravenousTakeda Pharmaceuticals International Ag Ireland Branch2016-09-08Not applicableEU flag

Categories

ATC Codes
A16AB03 — Agalsidase alfa
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
Not Available

Chemical Identifiers

UNII
2HLC17MX9G
CAS number
Not Available

References

General References
  1. Germain DP, Elliott PM, Falissard B, Fomin VV, Hilz MJ, Jovanovic A, Kantola I, Linhart A, Mignani R, Namdar M, Nowak A, Oliveira JP, Pieroni M, Viana-Baptista M, Wanner C, Spada M: The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts. Mol Genet Metab Rep. 2019 Feb 6;19:100454. doi: 10.1016/j.ymgmr.2019.100454. eCollection 2019 Jun. [Article]
  2. Wilcox WR, Feldt-Rasmussen U, Martins AM, Ortiz A, Lemay RM, Jovanovic A, Germain DP, Varas C, Nicholls K, Weidemann F, Hopkin RJ: Improvement of Fabry Disease-Related Gastrointestinal Symptoms in a Significant Proportion of Female Patients Treated with Agalsidase Beta: Data from the Fabry Registry. JIMD Rep. 2018;38:45-51. doi: 10.1007/8904_2017_28. Epub 2017 May 17. [Article]
  3. Prabakaran T, Nielsen R, Satchell SC, Mathieson PW, Feldt-Rasmussen U, Sorensen SS, Christensen EI: Mannose 6-phosphate receptor and sortilin mediated endocytosis of alpha-galactosidase A in kidney endothelial cells. PLoS One. 2012;7(6):e39975. doi: 10.1371/journal.pone.0039975. Epub 2012 Jun 29. [Article]
  4. Katsila T, Siskos AP, Tamvakopoulos C: Peptide and protein drugs: the study of their metabolism and catabolism by mass spectrometry. Mass Spectrom Rev. 2012 Jan-Feb;31(1):110-33. doi: 10.1002/mas.20340. Epub 2011 Jun 22. [Article]
  5. Pastores GM, Boyd E, Crandall K, Whelan A, Piersall L, Barnett N: Safety and pharmacokinetics of agalsidase alfa in patients with Fabry disease and end-stage renal disease. Nephrol Dial Transplant. 2007 Jul;22(7):1920-5. doi: 10.1093/ndt/gfm096. Epub 2007 Mar 29. [Article]
  6. Pisani A, Riccio E, Sabbatini M: Agalsidase alfa and agalsidase beta in the treatment of Fabry disease: does the dose really matter? Genet Med. 2015 Jan;17(1):21-3. doi: 10.1038/gim.2014.79. Epub 2014 Jul 10. [Article]
  7. EMA Summary of Product Characteristics: Replagal Agalsidase Alfa Intravenous Injection [Link]
  8. EMA: Replagal Authorization Details [Link]
RxNav
259351
Wikipedia
Alpha-galactosidase

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentFabry's Disease2
4RecruitingTreatmentFabry's Disease1
4Unknown StatusTreatmentFabry's Disease1
4WithdrawnTreatmentFabry's Disease1
3CompletedTreatmentFabry's Disease4
3RecruitingTreatmentFabry's Disease3
2CompletedOtherFabry's Disease1
2CompletedTreatmentFabry's Disease7
1CompletedBasic ScienceFabry's Disease1
1CompletedTreatmentFabry's Disease2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solution, concentrateIntravenous1 MG/ML
SolutionIntravenous1 mg / mL
Solution, concentrateIntravenous3.5 mg
SolutionIntravenous1.0 mg/mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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1. Globotriaosylceramide
Kind
Group
Organism
Humans
Pharmacological action
Unknown
Actions
Metabolizer
Ligand
References
  1. Schaefer RM, Tylki-Szymanska A, Hilz MJ: Enzyme replacement therapy for Fabry disease: a systematic review of available evidence. Drugs. 2009 Nov 12;69(16):2179-205. doi: 10.2165/11318300-000000000-00000. [Article]
  2. El Dib RP, Pastores GM: Enzyme replacement therapy for Anderson-Fabry disease. Cochrane Database Syst Rev. 2010 May 12;(5):CD006663. doi: 10.1002/14651858.CD006663.pub2. [Article]
  3. Lim-Melia ER, Kronn DF: Current enzyme replacement therapy for the treatment of lysosomal storage diseases. Pediatr Ann. 2009 Aug;38(8):448-55. [Article]
  4. EMA Summary of Product Characteristics: Replagal Agalsidase Alfa Intravenous Injection [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Transmembrane signaling receptor activity
Specific Function
Transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate r...
Gene Name
M6PR
Uniprot ID
P20645
Uniprot Name
Cation-dependent mannose-6-phosphate receptor
Molecular Weight
30993.06 Da
References
  1. EMA Summary of Product Characteristics: Replagal Agalsidase Alfa Intravenous Injection [Link]

Drug created at September 22, 2020 14:49 / Updated at November 29, 2022 21:14