Pegunigalsidase alfa

Identification

Summary

Pegunigalsidase alfa is a recombinant form of human α-galactosidase-A indicated for long-term enzyme replacement therapy in patients with Fabry disease.

Generic Name
Pegunigalsidase alfa
DrugBank Accession Number
DB14992
Background

Pegunigalsidase alfa (PRX-102) is a recombinant form of human α-galactosidase-A indicated for long-term enzyme replacement therapy in patients with Fabry disease, a rare genetic disorder characterized by the deficiency of alpha-galactosidase A.2,5 Unlike other forms of recombinant alpha-galactosidase A, such as agalsidase alfa and agalsidase beta, pegunigalsidase alfa uses a plant cell-based protein expression system, leading to a different glycosylation pattern. While agalsidase alfa and agalsidase beta enter lysosomes via the mannose-6-phosphate (M6P) receptor, pegunigalsidase alfa carries no M6P on its glycans and does not depend on the M6P receptor during cellular uptake. Furthermore, the pegylation of pegunigalsidase alfa promotes higher stability and a longer half-life, allowing it to reach target organs with a lower dose and frequency of administration.1,2

In May 2023, the EMA granted marketing authorization to pegunigalsidase alfa in the European Union (EU) for the treatment of adult patients with Fabry disease.5,6 Later on, the FDA approved pegunigalsidase alfa for the treatment of adult patients with Fabry disease that same month.7,8

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Recombinant Enzymes
Protein Chemical Formula
C2060H3130N552O601S27
Protein Average Weight
116000.0 Da (homodimer with two pegylated subunits)
Sequences
>Pegunigalsidase alfa
GLDNGLARTPTMGWLHWERFMCNLDCQEEPDSCISEKLFMEMAELMVSEGWKDAGYEYLC
IDDCWMAPQRDSEGRLQADPQRFPHGIRQLANYVHSKGLKLGIYADVGNKTCAGFPGSFG
YYDIDAQTFADWGVDLLKFDGCYCDSLENLADGYKHMSLALNRTGRSIVYSCEWPLYMWP
FQKPNYTEIRQYCNHWRNFADIDDSWKSIKSILDWTSFNQERIVDVAGPGGWNDPDMLVI
GNFGLSWNQQVTQMALWAIMAAPLFMSNDLRHISPQAKALLQDKDVIAINQDPLGKQGYQ
LRQGDNFEVWERPLSGLAWAVAMINRQEIGGPRSYTIAVASLGKGVACNPACFITQLLPV
KRKLGFYEWTSRLRSHINPTGTVLLQLENTMQMSLKDLLSEKDEL
References:
  1. EMA Assessment Report: Elfabrio (pegunigalsidase alfa) solution for infusion [Link]
Download FASTA Format
Synonyms
  • Pegunigalsidase alfa
External IDs
  • PRX-102

Pharmacology

Indication

Pegunigalsidase alfa is indicated for long-term enzyme replacement therapy in adult patients with a confirmed diagnosis of Fabry disease (deficiency of alpha-galactosidase).5,7

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofFabry's disease••••••••••••••••••••••••••
Treatment ofFabry's disease•••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

In patients with Fabry disease, the use of pegunigalsidase alfa led to a mean decrease in peritubular capillary globotriaosylceramide (GB3) content of 67.8% ± 8.9% after 6 months. At the 6-months time point, most patients had their GB3 levels reduced by more than half.4 The use of pegunigalsidase alfa is associated with infusion-related reactions, hypersensitivity reactions and immunogenicity. The use of enzyme replacement therapies such as pegunigalsidase alfa may lead to depositions of immune complexes as a manifestation of immunological response. During the clinical development of pegunigalsidase alfa, a single case of glomerulonephritis membranoproliferative was reported. This led to a temporary decline in renal function, which improved upon the discontinuation of pegunigalsidase alfa.5

Mechanism of action

Fabry disease is an X-linked recessive disorder caused by mutations in the GLA gene that lead to the loss of function of α-galactosidase A. This α-galactosidase A deficiency leads to the accumulation of globotriaosylceramide (GB3) and other neutral glycosphingolipids throughout the body, including the heart, kidney, nervous system, vascular endothelium and smooth muscle. This accumulation of GB3 is characterized by chronic pain, ocular opacities, liver and kidney impairment, skin lesions, vascular deterioration and cardiac deficiencies.1,2,3

Pegunigalsidase alfa is a pegylated recombinant form of human α-galactosidase-A, with an amino acid sequence similar to the human enzyme that replaces α-galactosidase-A. It promotes the hydrolysis of the terminal α-galactosyl moieties of oligosaccharides and polysaccharides in the lysosome, reducing the amount of GB3 accumulated in patients with Fabry disease.5 The deacylated form of GB3, globotriaosylsphingosine (lyso-GB3), also plays a role in the development of Fabry disease, and the use of pegunigalsidase alfa decreases the accumulation of this metabolite as well.2,5

TargetActionsOrganism
AGlobotriaosylceramide
metabolizer
ligand
Humans
Absorption

The pharmacokinetic profile of pegunigalsidase alfa at 0.2, 1, and 2 mg/kg administered every two weeks was evaluated in adult patients with Fabry disease. At these dose levels, the AUC0-∞ of pegunigalsidase alfa increased with increasing doses on day one and throughout the study. Also, the mean values for dose-normalized AUC0-2wk were for all doses, suggesting that pegunigalsidase alfa follows a linear dose-proportional pharmacokinetic profile.5

In enzyme replacement therapy-naïve patients with Fabry disease given an intravenous infusion of 1 mg/kg of pegunigalsidase alfa every two weeks, the Cmax went from 11.1 μg/mL on day 1 to 17.3 μg/mL on week 52, and the AUCinf went from 391 μg·h/mL on day 1 to 1428 μg·h/mL on week 52. In enzyme replacement therapy-experienced patients with Fabry disease given the same dose, the Cmax ranged from 21.2 to 23.3 μg/mL, and the AUCtau ranged from 958 to 1074 μg·h/mL.7

Volume of distribution

In enzyme replacement therapy-naïve patients with Fabry disease given an intravenous infusion of 1 mg/kg of pegunigalsidase alfa every two weeks, the volume of distribution was 321 mL/kg on day 1, 271 mL/kg on week 13, 226 mL/kg on week 26, and 186 mL/kg on week 52.7

Protein binding

Not available.

Metabolism

As a recombinant protein, pegunigalsidase alfa is expected to be metabolized through peptide hydrolysis. Therefore, impaired liver function is not expected to have a clinically significant effect on the pharmacokinetics of pegunigalsidase alfa. Based on its metabolism, pegunigalsidase alfa is an unlikely target of cytochrome P450 enzymes.5

Route of elimination

Pegunigalsidase alfa has a molecular weight of approximately 116 kDa, which is twice the cut-off value for glomerular filtration. Because of this, filtration and/or proteolytic degradation in kidneys is unlikely.5

Half-life

Pegunigalsidase alfa given in two-week intervals has a plasma half-life that ranges from 53 to 134 hours across dose groups and visit day.5

Clearance

Patients treated with 1 and 2 mg/kg of pegunigalsidase alfa every two weeks had a higher half-life and AUC with increasing duration of treatment, as well as lower clearance and elimination volume of distribution, suggesting a saturated clearance.5

In enzyme replacement therapy-naïve patients with Fabry disease given an intravenous infusion of 1 mg/kg of pegunigalsidase alfa every two weeks, clearance was 2.9 mL/h/kg on day 1, 2.3 mL/h/kg on week 13, 1.6 mL/h/kg on week 26, and 1.1 mL/h/kg on week 52.7

Adverse Effects
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Toxicity

During clinical studies, no cases of pegunigalsidase alfa overdose were reported. No specific signs and symptoms were identified with the maximum dose of pegunigalsidase alfa used (2 mg/kg body weight every two weeks). Infusion-related reactions and pain in extremities were the most commonly reported adverse reactions. If an overdose is suspected, seek emergency medical attention.5

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.
Not Available
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ElfabrioInjection, solution, concentrate2 mg/mLIntravenousChiesi Farmaceutici S.P.A2023-05-10Not applicableEU flag
ElfabrioInjection, solution, concentrate5 mg/2.5mLIntravenousChiesi USA, Inc.2024-02-07Not applicableUS flag
ElfabrioInjection, solution, concentrate2 mg/mLIntravenousChiesi Farmaceutici S.P.A2023-05-10Not applicableEU flag
ElfabrioInjection, solution, concentrate20 mg/10mLIntravenousChiesi USA, Inc.2023-05-23Not applicableUS flag
ElfabrioInjection, solution, concentrate2 mg/mLIntravenousChiesi Farmaceutici S.P.A2023-05-10Not applicableEU flag

Categories

ATC Codes
A16AB20 — Pegunigalsidase 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
  • Humans and other mammals

Chemical Identifiers

UNII
8M7V7Q6537
CAS number
1644392-61-9

References

Synthesis Reference

Shulman, A., et al. (2012). Nucleic acid construct for expression of alpha-galactosidase in plants and plant cells (WO 2012/098537 A1). World Intellectual Property Organization. https://patentimages.storage.googleapis.com/2c/14/4c/4f9fd78e7edb77/AU2011356137A1.pdf

General References
  1. Kizhner T, Azulay Y, Hainrichson M, Tekoah Y, Arvatz G, Shulman A, Ruderfer I, Aviezer D, Shaaltiel Y: Characterization of a chemically modified plant cell culture expressed human alpha-Galactosidase-A enzyme for treatment of Fabry disease. Mol Genet Metab. 2015 Feb;114(2):259-67. doi: 10.1016/j.ymgme.2014.08.002. Epub 2014 Aug 10. [Article]
  2. Ruderfer I, Shulman A, Kizhner T, Azulay Y, Nataf Y, Tekoah Y, Shaaltiel Y: Development and Analytical Characterization of Pegunigalsidase Alfa, a Chemically Cross-Linked Plant Recombinant Human alpha-Galactosidase-A for Treatment of Fabry Disease. Bioconjug Chem. 2018 May 16;29(5):1630-1639. doi: 10.1021/acs.bioconjchem.8b00133. Epub 2018 May 3. [Article]
  3. Azevedo O, Gago MF, Miltenberger-Miltenyi G, Sousa N, Cunha D: Fabry Disease Therapy: State-of-the-Art and Current Challenges. Int J Mol Sci. 2020 Dec 28;22(1):206. doi: 10.3390/ijms22010206. [Article]
  4. Schiffmann R, Goker-Alpan O, Holida M, Giraldo P, Barisoni L, Colvin RB, Jennette CJ, Maegawa G, Boyadjiev SA, Gonzalez D, Nicholls K, Tuffaha A, Atta MG, Rup B, Charney MR, Paz A, Szlaifer M, Alon S, Brill-Almon E, Chertkoff R, Hughes D: Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1-year Phase 1/2 clinical trial. J Inherit Metab Dis. 2019 May;42(3):534-544. doi: 10.1002/jimd.12080. Epub 2019 Apr 8. [Article]
  5. EMA Summary of Product Characteristics: Elfabrio (pegunigalsidase alfa) solution for infusion (May 2023) [Link]
  6. LABIOTECH: Fabry disease treatment gets EU marketing authorization [Link]
  7. FDA Approved Drug Products: ELFABRIO (pegunigalsidase alfa-iwxj) injection for intravenous use (May 2023) [Link]
  8. BioSpace: Chiesi Global Rare Diseases and Protalix BioTherapeutics Announce FDA Approval of ELFABRIO (pegunigalsidase alfa-iwxj) for the Treatment of Fabry Disease [Link]
RxNav
2637446
Wikipedia
Pegunigalsidase_alfa

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentFabry's Disease2
3CompletedTreatmentFabry's Disease3
3WithdrawnTreatmentFabry's Disease1
2, 3RecruitingTreatmentFabry's Disease1
1, 2CompletedTreatmentFabry's Disease3

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solution, concentrateIntravenous2 mg/ml
Injection, solution, concentrateIntravenous20 mg/10mL
Injection, solution, concentrateIntravenous5 mg/2.5mL
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
Yes
Actions
Metabolizer
Ligand
Curator comments
Pegunigalsidase alfa catalyses the hydrolysis of globotriaosylceramide (GB3).
References
  1. Kizhner T, Azulay Y, Hainrichson M, Tekoah Y, Arvatz G, Shulman A, Ruderfer I, Aviezer D, Shaaltiel Y: Characterization of a chemically modified plant cell culture expressed human alpha-Galactosidase-A enzyme for treatment of Fabry disease. Mol Genet Metab. 2015 Feb;114(2):259-67. doi: 10.1016/j.ymgme.2014.08.002. Epub 2014 Aug 10. [Article]
  2. EMA Summary of Product Characteristics: Elfabrio (pegunigalsidase alfa) solution for infusion (May 2023) [Link]

Drug created at May 20, 2019 14:40 / Updated at May 19, 2023 23:20