Vestronidase alfa

Identification

Name
Vestronidase alfa
Accession Number
DB12366
Description

Vestronidase alfa, or vestronidase alfa-vjbk, is a recombinant human lysosomal beta glucuronidase that is a purified enzyme produced by recombinant DNA technology in a Chinese hamster ovary cell line. The enzyme is a homotetramer consisted of 4 monomers with 629 amino acids, and holds the same amino acid sequence as human beta-glucuronidase (GUS) Label. Vestronidase alfa is an enzyme replacement therapy for the treatment of mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome, which is an inherited, rare genetic metabolic condition that targets a small subset of population. MPS VII is a progressive condition that affects most tissues and organs due to the lack of a lysosomal enzyme called beta-glucuronidase, leading to buildup of toxic metabolites. The disorder is initiated with skeletal abnormalities, including short stature, along with other pathological conditions including enlarged liver and spleen, heart valve abnormalities, and narrowed airways which can lead to lung infections and trouble breathing. Last two conditions are leading causes of fatalities in patients with MPS VII.

Some affected individuals do not survive infancy, while others may live into adolescence or adulthood and patients may experience developmental delay and progressive intellectual disability Label. In clinical trials, vestronidase alfa treatment demonstrated improvement and stabilization in motor symptoms by increasing the patients' ability to walk longer distances in comparison to treatment with placebo . Few patients also experienced improved pulmonary function.

Vestronidase alfa was FDA-approved on November 17th, 2017 under the trade name Mepsevii as an intravenous infusion for the treatment of pediatric and adult patients.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Recombinant Enzymes
Protein Chemical Formula
Not Available
Protein Average Weight
72562.0 Da (Non-glycosylated)
Sequences
Not Available
Synonyms
  • Recombinant human beta-glucuronidase
  • Vestronidase alfa-vjbk
External IDs
  • UX-003
  • UX003

Pharmacology

Indication

Indicated in pediatric and adult patients for the treatment of Mucopolysaccharidosis VII (MPS VII, Sly syndrome).

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

In all patients evaluated, MEPSEVII treatment resulted in reduction of urinary excretion of GAGs including chondroitin sulfate and dermatan sulfate, which was sustained with continued treatment Label.

Mechanism of action

Beta-glucuronidase (GUS) is a lysosomal enzyme responsible for degradation of glucuronate-containing glycosaminoglycan (GAG) 2. Resulting lysosomal storage and GAG accumulation in cells from incomplete metabolic degradation of macromolecules leads to damage to multiple tissues and organs. Vestronidase alfa serves as an exogenous source of GUS enzyme for uptake into cellular lysosomes, which is facilitated by the presence of mannose-6-phosphate (M6P) residues on the oligosaccharide chains of the recombinant enzyme. The chains allow binding of the enzyme to cell surface receptors to promote cellular uptake, and targets the lysosomes to achieve catabolism of accumulated GAGs in affected tissues Label.

Absorption

Serum exposures of vestronidase alfa increases in a dose-proportional manner, from 1 mg/kg (0.25 times the approved recommended dosage) to 2 mg/kg (0.5 times the approved recommended dosage), and 4 mg/kg (the recommended dosage). After repeated dosing of 4 mg/kg every other week in patients with MPS VII, the mean ± standard deviation of maximal concentration (Cmax) was 20.0 ± 8.1 mcg/mL (range: 6.6 to 34.9 mcg/mL). The mean ± standard deviation of area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) was 3440 ± 1430 mcg x min/mL (range: 1130 to 5820 mcg x min/mL) Label.

Volume of distribution

After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the total volume of distribution (Vss) was 260 ± 130 mL/kg (range: 97 to 598 mL/kg) Label.

Protein binding
Not Available
Metabolism

Vestronidase alfa is eliminated by nonspecific proteolytic degradation into small peptides and amino acids Label.

Route of elimination

Vestronidase alfa-vjbk is not expected to be eliminated through renal or fecal excretion. No excretion studies have been conducted Label.

Half-life

After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the elimination half-life (t1/2) was 155 ± 37 minutes (range: 51 to 213 minutes) Label.

Clearance

After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the total clearance (CL) was 1.3 ± 0.7 mL/min/kg (range: 0.6 to 3.3 mL/min/kg) Label.

Adverse Effects
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Toxicity

Treatment of vestronidase alfa with doses up to 20 mg/kg administered weekly in rats did not result in adverse effect on fertility and reproductive performance of male and female rats. Studies assessing the mutagenic or carcinogenic potential of vestronidase alfa have not been performed Label.

Affected organisms
Not Available
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
Not Available

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MepseviiInjection2 mg/1mLIntravenousUltragenyx Pharmaceutical Inc.2017-11-15Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number
    Available for Purchase

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
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    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
A16AB18 — Vestronidase 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

Chemical Identifiers

UNII
7XZ4062R17
CAS number
1638194-78-1

References

General References
  1. Basinska A, Florianczyk B: Beta-glucuronidase in physiology and disease. Ann Univ Mariae Curie Sklodowska Med. 2003;58(2):386-9. [PubMed:15323223]
  2. Naz H, Islam A, Waheed A, Sly WS, Ahmad F, Hassan I: Human beta-glucuronidase: structure, function, and application in enzyme replacement therapy. Rejuvenation Res. 2013 Oct;16(5):352-63. doi: 10.1089/rej.2013.1407. [PubMed:23777470]
PubChem Substance
347911326
RxNav
1989818
Wikipedia
Vestronidase_alfa
FDA label
Download (369 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentMPS 7 / MPS VII / Mucopolysaccharidosis / Sly Syndrome1
3CompletedTreatmentMPS VII / Mucopolysaccharidosis / Mucopolysaccharidosis VII / Sly Syndrome1
2CompletedTreatmentMPS VII / Mucopolysaccharidosis / Mucopolysaccharidosis VII / Sly Syndrome1
1Not Yet RecruitingTreatmentGaucher Disease, Type 2 / Gaucher Disease, Type 3 / MPS I / MPS II / MPS IVA / MPS VI / MPS VII / Pompe Disease Infantile-Onset / Wolman's Disease1
1, 2CompletedTreatmentMucopolysaccharidosis Type 71
Not AvailableAvailableNot AvailableMPS VII / Mucopolysaccharidosis VII / Sly Syndrome1
Not AvailableNo Longer AvailableNot AvailableMucopolysaccharidosis Type 71

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous2 mg/1mL
Injection, solution, concentrateIntravenous2 MG/ML
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Drug created on October 20, 2016 16:05 / Updated on June 12, 2020 11:42

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