NAV

Avalglucosidase alfa

Identification

Summary

Avalglucosidase alfa is a lysosomal glycogen-specific enzyme that is used to treat patients one year of age and older with late-onset Pompe disease, or lysosomal acid alpha-glucosidase (GAA) deficiency.

Brand Names
Nexviazyme
Generic Name
Avalglucosidase alfa
DrugBank Accession Number
DB16099
Background

Avalglucosidase alfa, or NeoGAA, is a drug for enzyme replacement therapy specifically designed for Pompe disease, a rare inherited neuromuscular disorder caused by the deficiency of the alpha-glucosidase (GAA) enzyme. GAA is an essential enzyme that hydrolyzes glycogen into free glucose for use in cellular functions. In Pompe disease, the GAA enzyme is missing and patients are unable to properly break down glycogen, resulting in the accumulation of glycogen within lysosomes and progressive disruption of cellular function, especially in smooth, cardiac, and skeletal muscle cells. Pompe disease is characterized by progressive muscle weakness and loss of motor function, including respiratory muscle weakness, which leads to premature death and debilitating effects on people’s lives.1 Avalglucosidase alfa is a recombinant form of GAA that restores deficient enzyme levels. First developed by Sanofi Genzyme, avalglucosidase alfa is a chemically modified version of alglucosidase alfa, where synthetic bis-phosphorylated oligosaccharides were attached to the structure to improve cellular uptake of the drug and better muscle targeting.2

On August 6, 2021, avalglucosidase alfa-ngpt was approved by the FDA under the market name Nexviazyme to treat patients one year of age and older with late-onset Pompe disease.4 Late-onset Pompe disease is associated with a range of debilitating physical symptoms, such as progressive muscle weakness, including respiratory muscle weakness, and loss of motor function.1 In clinical trials, avalglucosidase alfa improved lung function in patients with Pompe disease.4 Avalglucosidase alfa was approved by Health Canada on November 15, 2021 for the treatment of patients older than six months of age with late-onset Pompe disease.6 The EMA approved the drug on June 24, 2022.8

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Recombinant Enzymes
Protein Chemical Formula
C4490H6818N1197O1299S32
Protein Average Weight
124000.0 Da (approximate)
Sequences
>Avalglucosidase alfa protein sequence
QQGASRPGPRDAQAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYIPAKQG
LQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDVMMETE
NRLHFTIKDPANRRYEVPLETPRVHSRAPSPLYSVEFSEEPFGVIVHRQLDGRVLLNTTV
APLFFADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANLYGSHP
FYLALEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVVQQYLD
VVGYPFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSRRDFTF
NKDGFRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNETGQPL
IGKVWPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSEDGCPNN
ELENPPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIASHRALVKARGTRPF
VISRSTFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLGNTSEE
LCVRWTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYTLFHQA
HVAGETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGTWYDLQ
TVPIEALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGLTTTES
RQQPMALAVALTKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVRVTSEG
AGLQLQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSWC
References:
  1. KEGG DRUG: Avalglucosidase alfa [Link]
Download FASTA Format
Synonyms
  • Avalglucosidase alfa
  • avalglucosidase alfa-ngpt
  • Neo-recombinant human acid alpha-glucosidase
  • NeoGAA
External IDs
  • GZ-402666
  • GZ402666

Pharmacology

Indication

Avalglucosidase alfa is a hydrolytic lysosomal glycogen-specific enzyme indicated for the treatment of patients with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency).3,7,8 In the US, it is approved in patients one year of age and older. 3

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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Avalglucosidase alfa is a recombinant alpha-glucosidase (GAA) enzyme that catalyzes hydrolysis of glycogen. In clinical trials, avalglucosidase alfa reduced the levels of glycogen excreted in the urine of patients with Pompe disease, indicating that it effectively cleaved excess glycogen.3 Avalglucosidase alfa has significantly higher binding affinity for cation-independent mannose-6-phosphate receptor (CI-MPR) for cellular uptake and better muscle targeting than alglucosidase alfa. In GAA-deficient mice, avalglucosidase alfa reduced glycogen with more efficacy than alglucosidase alfa at an equivalent dose.2

Mechanism of action

Pompe disease is a genetic glycogen metabolism disorder that is also referred to as acid maltase deficiency or glycogen storage disease type II (GSD II). It is caused by mutations in the GAA gene, which encodes the lysosomal hydrolase acid α-glucosidase (GAA), an enzyme that normally catalyzes hydrolysis of glycogen to release free glucose for absorption and use for cellular functions. GAA deficiency leads to accumulation of glycogen within lysosomes and progressive disruption of cellular function, especially in smooth, cardiac, and skeletal muscle cells.1

Enzyme replacement therapy using avalglucosidase alfa aims to restore the missing GAA enzyme. Avalglucosidase alfa is a hydrolytic lysosomal glycogen-specific recombinant human GAA enzyme that is conjugated with multiple synthetic bis-mannose-6-phosphate (bis-M6P)­ tetra-mannose glycans for enhanced targeting to skeletal muscles. The M6P of avalglucosidase alfa binds to cation-independent mannose-6-phosphate receptor (CI-MPR) on the cell surface with high affinity, which allows drug uptake into cells. Avalglucosidase alfa is internalized and transported into lysosomes to undergo proteolytic cleavage. It then exerts GAA enzymatic activity to cleave glycogen.1,3

TargetActionsOrganism
NCation-independent mannose-6-phosphate receptor
ligand
Humans
Absorption

The avalglucosidase alfa-ngpt exposure increases in an approximately proportional manner with increasing doses over a range from 5 to 20 mg/kg. Following intravenous infusion of 20 mg/kg every two weeks in patients with late-onset Pompe disease, the mean ± SD plasma Cmax of avalglucosidase alfa-ngpt was 259 ± 72 µg/mL at week one and 242 ± 81 µg/mL at week 49. The mean ± SD plasma AUC of avalglucosidase alfa-ngpt was 1,290 ± 420 µg∙h/mL at week one and 1,250 ± 433 µg∙h/mL at week 49.3

Volume of distribution

The volume of distribution of avalglucosidase alfa-ngpt was 3.4 L in patients with late-onset Pompe disease. No accumulation was observed following every two weeks-dosing schedules.3

Protein binding

There is limited information on drug protein binding.

Metabolism

The metabolic pathway of avalglucosidase alfa-ngpt has not been characterized. The protein portion of avalglucosidase alfa-ngpt is expected to be metabolized into small peptides and amino acids via catabolic pathways.3

Route of elimination

There is limited information on drug elimination.

Half-life

The mean avalglucosidase alfa-ngpt plasma elimination half-life was 1.6 hours in patients with late-onset Pompe disease.3

Clearance

The mean avalglucosidase alfa-ngpt clearance was 0.9 L/hour in patients with late-onset Pompe disease.3

Adverse Effects
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Toxicity

There is limited information on the overdose profile and LD50 values of avalglucosidase alfa.

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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International/Other Brands
Nexviazyme (Sanofi Genzyme)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NexviadymeInjection, powder, for solution100 mgIntravenousSanofi B.V.2022-08-02Not applicableEU flag
NexviadymeInjection, powder, for solution100 mgIntravenousSanofi B.V.2022-08-02Not applicableEU flag
NexviadymeInjection, powder, for solution100 mgIntravenousSanofi B.V.2022-08-02Not applicableEU flag
NexviadymeInjection, powder, for solution100 mgIntravenousSanofi B.V.2022-08-02Not applicableEU flag
NexviazymePowder, for solution100 mg / vialIntravenousSanofi Aventis2022-02-09Not applicableCanada flag
Nexviazyme ngptInjection, powder, lyophilized, for solution100 mg/10mLIntravenousGenzyme Corporation2021-08-06Not applicableUS flag

Categories

ATC Codes
A16AB22 — Avalglucosidase 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
EO144CP0X9
CAS number
1802558-87-7

References

General References
  1. Xu S, Lun Y, Frascella M, Garcia A, Soska R, Nair A, Ponery AS, Schilling A, Feng J, Tuske S, Valle MCD, Martina JA, Ralston E, Gotschall R, Valenzano KJ, Puertollano R, Do HV, Raben N, Khanna R: Improved efficacy of a next-generation ERT in murine Pompe disease. JCI Insight. 2019 Mar 7;4(5). pii: 125358. doi: 10.1172/jci.insight.125358. eCollection 2019 Mar 7. [Article]
  2. Do HV, Khanna R, Gotschall R: Challenges in treating Pompe disease: an industry perspective. Ann Transl Med. 2019 Jul;7(13):291. doi: 10.21037/atm.2019.04.15. [Article]
  3. FDA Approved Drug Products: NEXVIAZYME (avalglucosidase alfa-ngpt) for injection, for intravenous use [Link]
  4. FDA Press Announcements: FDA Approves New Treatment for Pompe Disease [Link]
  5. KEGG DRUG: Avalglucosidase alfa [Link]
  6. Newswire.ca: Nexviazyme™ (avalglucosidase alfa for injection) is now approved in Canada for patients with late-onset Pompe disease (acid α-glucosidase deficiency) [Link]
  7. Health Canada Approved Drug Products: NEXVIAZYME (avalglucosidase alfa) for intravenous injection [Link]
  8. EMA Approved Drug Products: Nexviadyme (avalglucosidase alfa) Intravenous Infusion [Link]
RxNav
2565814
Wikipedia
Avalglucosidase_alfa

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentGlycogen Storage Disease Type II1
3Active Not RecruitingTreatmentGlycogen Storage Disease Type II;Pompe's Disease1
3RecruitingTreatmentGlycogen Storage Disease Type II1
2Active Not RecruitingTreatmentGlycogen Storage Disease Type II;Pompe's Disease1
2, 3CompletedTreatmentGlycogen Storage Disease Type II;Pompe's Disease1
1CompletedTreatmentAcid Maltase Deficiency (AMD) / Glycogen Storage Disease Type II (GSD II)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous100 mg
Powder, for solutionIntravenous100 mg / vial
Injection, powder, lyophilized, for solutionIntravenous100 mg/10mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Details1. Cation-independent mannose-6-phosphate receptor
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Ligand
General Function
Transporter 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
IGF2R
Uniprot ID
P11717
Uniprot Name
Cation-independent mannose-6-phosphate receptor
Molecular Weight
274372.42 Da
References
  1. FDA Approved Drug Products: NEXVIAZYME (avalglucosidase alfa-ngpt) for injection, for intravenous use [Link]

Drug created at December 15, 2020 18:05 / Updated at December 01, 2022 11:30