NAV

Cipaglucosidase alfa

Identification

Summary

Cipaglucosidase alfa is a recombinant human acid alpha-glucosidase used to treat late-onset Pompe disease in adults.

Brand Names
Pombiliti
Generic Name
Cipaglucosidase alfa
DrugBank Accession Number
DB16708
Background

Cipaglucosidase alfa (ATB200) is a novel recombinant human acid alpha-glucosidase (GAA) investigated for the treatment of patients with Pompe disease, a rare inherited metabolic disorder characterized by a deficiency in GAA.1 Other types of enzyme replacement therapy for the treatment of Pompe disease include alglucosidase alfa and avalglucosidase alfa. Cipaglucosidase alfa is conjugated with mannose-6-phosphate (M6P) N-glycans that bind to the cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, one of the main affected tissues in Pompe disease. Compared to alglucosidase alfa, cipaglucosidase alfa has a higher M6P content.1,2

In December 2022, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended cipaglucosidase alfa be granted marketing authorization for the treatment of Pompe disease,6 and the EMA fully approved the drug on March 27, 2023.4 Cipaglucosidase alfa is coadministered with miglustat, a small-molecule pharmacological chaperone that stabilizes the conformation of the enzyme.1,2 In September 2023, the FDA also approved cipaglucosidase alfa for similar indications.9

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Recombinant Enzymes
Protein Chemical Formula
C4489H6796N1197O1298S32
Protein Average Weight
99400.0 Da (approximate)
Sequences
>Cipaglucosidase alfa sequence
QQGASRPGPRDAQAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYIPAKQG
LQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDVMMETE
NRLHFTIKDPANRRYEVPLETPHVHSRAPSPLYSVEFSEEPFGVIVRRQLDGRVLLNTTV
APLFFADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANLYGSHP
FYLALEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVVQQYLD
VVGYPFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSRRDFTF
NKDGFRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNETGQPL
IGKVWPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSEDGCPNN
ELENPPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIASHRALVKARGTRPF
VISRSTFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLGNTSEE
LCVRWTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYTLFHQA
HVAGETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGTWYDLQ
TVPVEALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGLTTTES
RQQPMALAVALTKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVRVTSEG
AGLQLQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSWC
References:
  1. KEGG DRUG: Cipaglucosidase alfa [Link]
Download FASTA Format
Synonyms
  • Cipaglucosidase alfa
  • Recombinant human acid alpha-glucosidase optimized for high expression of mannose 6-phosphate
External IDs
  • AT GAA
  • ATB-200
  • ATB200
  • WHO 11346
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Pharmacology

Indication

In Europe and the US, cipaglucosidase alfa is a long-term enzyme replacement therapy used in combination with the enzyme stabilizer miglustat for the treatment of adults with late-onset Pompe disease, also known as acid α-glucosidase (GAA) deficiency.7,8

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatLate-onset pompe diseaseRegimen in combination with: Miglustat (DB00419)•••••••••••••••••••• ••••••••• •• ••••••• •••••• ••••••••••• •••••••• ••••• ••• •••••••••••
Used in combination to treatLate-onset pompe diseaseRegimen in combination with: Miglustat (DB00419)••••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Cipaglucosidase alfa is a long-term enzyme replacement therapy that aims to break down glycogen and attenuate tissue damage in late-onset Pompe disease. Clinical studies demonstrate improved walking distance and stabilization of pulmonary function following the treatment with cipaglucosidase alfa.4,5

While cipaglucosidase alfa is reported to exhibit better cellular uptake and lysosomal trafficking compared to other existing replacement therapies, one study reported that cipaglucosidase alfa plus miglustat did not achieve statistical superiority to alglucosidase alfa plus placebo for improving 6-min walk distance in patients with late-onset Pompe disease.3

Mechanism of action

Pompe disease, also known as glycogen storage disease type II (GSD II), is a rare inherited disorder caused by alpha-glucosidase (GAA) gene mutations. In normal conditions, GAA hydrolyzes glycogen and releases free glucose units in lysosomes. However, patients with Pompe disease have a GAA deficiency, and glycogen accumulates within lysosomes, impairing the function of smooth, cardiac, and skeletal muscle cells and causing tissue damage. Cipaglucosidase alfa is a recombinant form of GAA conjugated with mannose-6-phosphate (M6P) N-glycans. Attributing to M6P, cipaglucosidase alfa has a high affinity for the cation-independent mannose-6-phosphate receptor (CI-MPR), a receptor responsible for the transport of GAA to lysosomes.1,2 Upon binding to CI-MPR, cipaglucosidase alfa is internalized by the lysosomes and undergoes proteolytic cleavage and N-glycan trimming to form the mature and active form of the GAA enzyme to cleave glycogen.4 Cipaglucosidase alfa is coadministered with miglustat, which stabilizes the conformation of the enzyme.1,2

TargetActionsOrganism
ACation-independent mannose-6-phosphate receptor
ligand
Humans
AAlpha glucosidase (GAA)
gene replacement
Humans
Absorption

In enzyme replacement therapy-experienced subjects with late-onset Pompe disease, the peak concentrations were reached at approximately the end of the four-hour duration of an intravenous infusion and declined biphasically to 24 hours from the start of infusion.7

The Cmax and AUC following the administration of cipaglucosidase alfa 20 mg/kg in combination with miglustat 260 mg were 345 mcg/mL and 1812 mcgh/mL, respectively. The Cmax and AUC following the administration of cipaglucosidase alfa 20 mg/kg alone were 325 mcg/mL and 1410 mcgh/mL.7

Volume of distribution

The mean volume of distribution of cipaglucosidase alfa ranged from 2.0 to 4.7 L. The distribution half-life was increased by 48% following the use of both cipaglucosidase alfa and miglustat. Cipaglucosidase alfa does not cross the blood-brain barrier.7

Protein binding

Cipaglucosidase alfa is not expected to bind to plasma proteins.7

Metabolism

The metabolic pathway of cipaglucosidase alfa has not been characterized. Cipaglucosidase alfa is expected to be metabolized into small peptides and amino acids in the liver by proteolytic hydrolysis.7,8

Route of elimination

Hepatic elimination is the main route of elimination.7

Half-life

The mean terminal elimination half-life for cipaglucosidase alfa ranged from 1.6 to 2.6 hours.7

Clearance

Coadministration of cipaglucosidase alfa and miglustat led to a 27% reduction in plasma clearance.7

Adverse Effects
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Toxicity

There is limited information regarding the acute toxicity and overdose of cipaglucosidase alfa. No doses of cipaglucosidase alfa greater than 20 mg/kg body weight have been studied.7

Based on findings from animal reproduction studies, cipaglucosidase alfa in combination with Opfolda may cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. In a rabbit embryo-fetal development study, great vessel and cardiac malformations were increased in the offspring of pregnant rabbits treated with cipaglucosidase alfa in combination with miglustat at 16-fold and 3-fold, respectively, the maximum recommended human dose (MRHD) of cipaglucosidase alfa and Opfolda based on plasma AUC exposure. A No Observed Adverse Effect Level (NOAEL) was not identified for the combination. In a pre-and post-natal development study in rats, increases in pup mortality were seen following maternal treatment with cipaglucosidase alfa (400 mg/kg) in combination with miglustat, or with cipaglucosidase alfa (400 mg/kg) alone. The NOAEL for cipaglucosidase alfa-atga alone is 150 mg/kg (5-fold the cipaglucosidase alfa MRHD margin). A NOAEL for the combination was not identified. Margins at the lowest observed adverse effect level (LOAEL), relative to exposures at the MRHD of cipaglucosidase alfa and Opfolda were 21- and 4-fold, respectively, based on plasma AUC exposure.8

Studies in animals to evaluate the carcinogenic, mutagenic, or genotoxic potential of cipaglucosidase alfa have not been conducted.8

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
PombilitiInjection, powder, for solution105 mgIntravenousAmicus Therapeutics Europe Limited2023-05-16Not applicableEU flag
PombilitiInjection, powder, for solution105 mgIntravenousAmicus Therapeutics Europe Limited2023-05-16Not applicableEU flag
PombilitiInjection, powder, for solution105 mgIntravenousAmicus Therapeutics Europe Limited2023-05-16Not applicableEU flag
Pombiliti AtgaInjection, powder, lyophilized, for solution105 mg/1IntravenousAmicus Therapeutics US, LLC2023-10-11Not applicableUS flag

Categories

ATC Codes
A16AB23 — Cipaglucosidase 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
4SED7F4BSG
CAS number
2359727-71-0

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. Schoser B, Roberts M, Byrne BJ, Sitaraman S, Jiang H, Laforet P, Toscano A, Castelli J, Diaz-Manera J, Goldman M, van der Ploeg AT, Bratkovic D, Kuchipudi S, Mozaffar T, Kishnani PS: Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial. Lancet Neurol. 2021 Dec;20(12):1027-1037. doi: 10.1016/S1474-4422(21)00331-8. [Article]
  4. Blair HA: Cipaglucosidase Alfa: First Approval. Drugs. 2023 Jun;83(8):739-745. doi: 10.1007/s40265-023-01886-5. [Article]
  5. van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ, Herson S, Kishnani PS, Laforet P, Lake SL, Lange DJ, Leshner RT, Mayhew JE, Morgan C, Nozaki K, Park DJ, Pestronk A, Rosenbloom B, Skrinar A, van Capelle CI, van der Beek NA, Wasserstein M, Zivkovic SA: A randomized study of alglucosidase alfa in late-onset Pompe's disease. N Engl J Med. 2010 Apr 15;362(15):1396-406. doi: 10.1056/NEJMoa0909859. [Article]
  6. EMA Summary of Opinion: Pombiliti (cipaglucosidase alfa) [Link]
  7. EMA Approved Drug Products: Pombiliti (cipaglucosidase alfa) Intravenous Infusion [Link]
  8. FDA Approved Drug Products: POMBILITI (cipaglucosidase alfa-atga) for injection, for intravenous use [Link]
  9. Amicus Therapeutics Announces FDA Approval and Launch of New Treatment for Pompe Disease [Link]
RxNav
2667433
Wikipedia
Cipaglucosidase_alfa

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentLate-onset Pompe Disease1
3CompletedTreatmentLate-onset Pompe Disease1
3RecruitingTreatmentGlycogen Storage Disease Type II Infantile Onset1
3RecruitingTreatmentLate-onset Pompe Disease1
1, 2Active Not RecruitingTreatmentGlycogen Storage Disease Type II1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous105 mg
Injection, powder, lyophilized, for solutionIntravenous105 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Details1. Cation-independent mannose-6-phosphate receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
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. 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. Blair HA: Cipaglucosidase Alfa: First Approval. Drugs. 2023 Jun;83(8):739-745. doi: 10.1007/s40265-023-01886-5. [Article]
  3. Amicus Therapeutics: Mechanism of action, plasma total GAA protein PK profiles and PK/PD relationships differ between cipaglucosidase alfa/miglustat and alglucosidase alfa in patients with late-onset Pompe disease (poster presentation, 18th Annual WorldSymposium, 2022) [Link]
Details2. Alpha glucosidase (GAA)
Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Gene replacement
References
  1. FDA Approved Drug Products: POMBILITI (cipaglucosidase alfa-atga) for injection, for intravenous use [Link]

Drug created at July 19, 2021 21:26 / Updated at December 15, 2023 23:52