Cerliponase alfa

Identification

Summary

Cerliponase alfa is an enzyme replacement therapy used to treat neuronal ceroid lipofuscinosis type 2 (CLN2) disease, also known as tripeptidyl peptidase 1 (TPP1) deficiency.

Brand Names
Brineura
Generic Name
Cerliponase alfa
DrugBank Accession Number
DB13173
Background

Cerliponase alfa is an enzyme replacement treatment for a specific form of Batten disease. It was the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency. Intraventricular administration of the drug allows significant uptake into the brain. Cerliponase alfa was approved in April, 2017 (as Brineura).

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Recombinant Enzymes
Protein Chemical Formula
Not Available
Protein Average Weight
59.0 Da (glycosylated)
Sequences
>Cerliponase alfa Sequence
SYSPEPDQRRTLPPGWVSLGRADPEEELSLTFALRQQNVERLSELVQAVSDPSSPQYGKY
LTLENVADLVRPSPLTLHTVQKWLLAAGAQKCHSVITQDFLTCWLSIRQAELLLPGAEFH
HYVGGPTETHVVRSPHPYQLPQALAPHVDFVGGLHRFPPTSSLRQRPEPQVTGTVGLHLG
VTPSVIRKRYNLTSQDVGSGTSNNSQACAQFLEQYFHDSDLAQFMRLFGGNFAHQASVAR
VVGQQGRGRAGIEASLDVQYLMSAGANISTWVYSSPGRHEGQEPFLQWLMLLSNESALPH
VHTVSYGDDEDSLSSAYIQRVNTELMKAAARGLTLLFASGDSGAGCWSVSGRHQFRPTFP
ASSPYVTTVGGTSFQEPFLITNEIVDYISGGGFSNVFPRPSYQEEAVTKFLSSSPHLPPS
SYFNASGRAYPDVAALSDGYWVVSNRVPIPWVSGTSASTPVFGGILSLINEHRILSGRPP
LGFLNPRLYQQHGAGLFDVTRGCHESCLDEEVEGQGFCSGPGWDPVTGWGTPNFPALLKT
LLNP
Download FASTA Format
Synonyms
  • Cerliponase alfa
  • Immature cell growth-inhibiting gene 1 protein
  • Immature human tripeptidyl-peptidase 1
  • Immature lysosomal pepstatin-insensitive protease
  • Immature tripeptidyl-peptidase I
External IDs
  • BMN 190
  • BMN-190

Pharmacology

Indication

Cerliponase alfa is a treatment for late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease to decelerate the progressive motor function decline in patients 3 years of age and older. CLN2 disease is a form of Batten disease, a rare inherited neurodegenerative disorder and is associated with seizures, ataxia, rapid loss of language and motor functions, blindness, and early death 4. It is caused by the lack the lysosomal enzyme tripeptidyl peptidase-1 (TPP1) and subsequent accumulation of lysosomal storage materials normally metabolized by this enzyme in the central nervous system.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Cerliponase alfa contains the active substance tripeptidyl peptidase-1 (rhTPP1), a recombinant human lysosomal exopeptidase which cleaves the N-terminal of tripeptides with a broad substrate specificity. Cerliponase alfa slows the progressive decline in motor function caused by abnormal motor signalling in the brain by restoring the normal levels and activity of TPP1.

Mechanism of action

The mature form of enzyme contains 5 consensus N-glycosylation sites with high mannose, phosphorylated high mannose and complex glycosylation structures. It is taken up by LINCL fibroblasts and translocated to the lysosomes through the Cation Independent Mannose-6-Phosphate Receptor (CI-MPR, also known as M6P/IGF2 receptor). Cerliponase alfa is activated in the lysosome under low pH conditions and the activated proteolytic form of rhTPP1 cleaves tripeptides from the N-terminus of stored proteins.

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

Refer to FDA Label

Volume of distribution

The estimated CSF volume of distribution of cerliponase alfa following intraventricular infusion of 300mg of Brineura (median Vss = 245 mL) exceeds the typical CSF volume (100 mL) Label.

Protein binding

Not Available

Metabolism

Predicted to be metabolized through peptide hydrolysis.

Route of elimination

Not Available

Half-life

Refer to FDA Label

Clearance

Refer to FDA Label

Adverse Effects
Medicalerrors
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Toxicity

No data from carcinogenicity, genotoxicity, and fertility studies. Unwanted effects of cerliponase alfa treatment include pyrexia, ECG abnormalities, decreased CSF protein, seizure and hypersensitivity.

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

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BrineuraKit150 mg/5mLIntraventricularBioMarin Pharmaceutical Inc.2017-04-27Not applicableUS flag
BrineuraSolution150 mg / 5 mLIntracerebralBiomarin International Limited2019-03-18Not applicableCanada flag
BrineuraInjection, solution150 mgIntracerebralBiomarin International Limited2020-12-23Not applicableEU flag

Categories

ATC Codes
A16AB17 — Cerliponase 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
X8R2D92QP1
CAS number
151662-36-1

References

General References
  1. Guhaniyogi J, Sohar I, Das K, Stock AM, Lobel P: Crystal structure and autoactivation pathway of the precursor form of human tripeptidyl-peptidase 1, the enzyme deficient in late infantile ceroid lipofuscinosis. J Biol Chem. 2009 Feb 6;284(6):3985-97. doi: 10.1074/jbc.M806943200. Epub 2008 Nov 26. [Article]
  2. Zhang Y, Chen LY, Han X, Xie W, Kim H, Yang D, Liu D, Songyang Z: Phosphorylation of TPP1 regulates cell cycle-dependent telomerase recruitment. Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5457-62. doi: 10.1073/pnas.1217733110. Epub 2013 Mar 18. [Article]
  3. Pal A, Kraetzner R, Gruene T, Grapp M, Schreiber K, Gronborg M, Urlaub H, Becker S, Asif AR, Gartner J, Sheldrick GM, Steinfeld R: Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis. J Biol Chem. 2009 Feb 6;284(6):3976-84. doi: 10.1074/jbc.M806947200. Epub 2008 Nov 26. [Article]
  4. Intracerebroventricular Cerliponase Alfa (BMN 190) in Children with CLN2 Disease: Interim Results from a Phase 1/2, Open-Label, Dose-Escalation Study [Link]
KEGG Drug
D10813
PubChem Substance
347911440
RxNav
1922436
ChEMBL
CHEMBL3544921
Wikipedia
Cerliponase_alfa
FDA label
Download (793 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentCLN2 Disease / CLN2 Disorder / Jansky-Bielschowsky Disease / Juvenile Neuronal Ceroid Lipofuscinosis / Late-Infantile Neuronal Ceroid Lipofuscinosis Type 21
1, 2CompletedTreatmentCLN2 Disease / CLN2 Disorder / Jansky-Bielschowsky Disease / Juvenile Neuronal Ceroid Lipofuscinosis / Late-Infantile Neuronal Ceroid Lipofuscinosis Type 21
1, 2CompletedTreatmentCLN2 Disease / Jansky-Bielschowsky Disease / Juvenile Neuronal Ceroid Lipofuscinosis / Late-Infantile Neuronal Ceroid Lipofuscinosis Type 21
Not AvailableApproved for MarketingNot AvailableCLN2 Disease1
Not AvailableRecruitingNot AvailableLate-Infantile Neuronal Ceroid Lipofuscinosis Type 21

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntracerebral
Injection, solutionIntracerebral150 mg
KitIntraventricular150 mg/5mL
SolutionIntracerebral150 mg / 5 mL
SolutionIntracerebral30 mg
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. Meng Y, Sohar I, Wang L, Sleat DE, Lobel P: Systemic administration of tripeptidyl peptidase I in a mouse model of late infantile neuronal ceroid lipofuscinosis: effect of glycan modification. PLoS One. 2012;7(7):e40509. doi: 10.1371/journal.pone.0040509. Epub 2012 Jul 6. [Article]

Drug created on April 28, 2017 19:55 / Updated on July 29, 2021 06:27