Identification

Summary

Pegvaliase is an enzyme used to treat phenylketonuria in patients with phenylalanine levels that are too high on current treatment.

Brand Names
Palynziq
Generic Name
Pegvaliase
DrugBank Accession Number
DB12839
Background

Pegvaliase is a recombinant phenylalanine ammonia lyase (PAL) enzyme derived from Anabaena variabilis that converts phenylalanine to ammonia and trans-cinnamic acid 1. Both the U.S. Food and Drug Administration and European Medicines Agency approved pegvaliase-pqpz in May 2018 for the treatment of adult patients with phenylketonuria (PKU). Phenylketonuria is a rare autosomal recessive disorder that is characterized by deficiency of the enzyme phenylalanine hydroxylase (PAH) 1 and affects about 1 in 10,000 to 15,000 people in the United States 3. PAH deficiency and inability to break down an amino acid phenylalanine (Phe) leads to elevated blood phenylalanine concentrations and accumulation of neurotoxic Phe in the brain, causing chronic intellectual, neurodevelopmental and psychiatric disabilities if untreated 1. Individuals with PKU also need to be under a strictly restricted diet as Phe is present in foods and products with high-intensity sweeteners 3. The primary goal of lifelong treatment of PKU, as recommended by the American College of Medical Genetics and Genomics (ACMG) guidelines, is to maintain blood Phe concentration in the range of 120 µmol/L to 3690 µmol/L 2. Pegvaliase-pqpz, or PEGylated pegvaliase, is used as a novel enzyme substitution therapy and is marketed as Palynziq for subcutanoues injection. It is advantageous over currently available management therapies for PKU, such as Sapropterin, that are ineffective to many patients due to long-term adherence issues or inadequate Phe-lowering effects 1. The presence of a PEG moiety in pegvaliase-pqpz allows a reduced immune response and improved pharmacodynamic stability 1.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 318.414
Monoisotopic: 318.215472074
Chemical Formula
C15H30N2O5
Synonyms
  • PEG-PAL
  • Pegvaliase
  • pegvaliase-pqpz
  • Phenylase
  • rAvPAL-PEG
External IDs
  • BMN 165
  • BMN-165

Pharmacology

Indication

Pegvaliase is indicated for the management of phenylketonuria (PKU) in adult patients who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management.

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

In a phase 3 clinical trial of adult patients with phenylketonuria and blood phenylalanine concentrations greater than 600 µmol/L on existing management therapies, subcutaneous administration of pegvaliase resulted in significantly reduced blood phenylalanine concentrations in most patients compared to their pre-treatment baseline levels within 24 months in addition to improved neuropsychiatric symptoms 1,2.

Mechanism of action

Pegvaliase is a phenylalanine ammonia lyase (PAL) enzyme that temporarily restores the levels of deficient enzyme and reduces blood phenylalanine concentrations by converting phenylalanine to ammonia and trans-cinnamic acid 1. Formed conversion products are metabolized in the liver and later excreted in the urine 2.

Absorption

At steady state during maintenance treatment with pegvaliase 20 mg and 40 mg subcutaneously once daily, the mean ± SD (range) peak plasma concentration (Cmax) was 14.0 ± 16.3 (0.26 to 68.5) mg/L and 16.7 ± 19.5 (0.24 to 63.8) mg/L, respectively Label. The time to reach Cmax (Tmax) was approximately 8 hours Label.

Volume of distribution

The mean ± SD (range) apparent volume of distribution at steady state was 26.4 ± 64.8 (1.8 to 241) L and 22.2 ± 19.7 (3.1 to 49.5) L after once-daily subcutaneous administration of 20 mg and 40 mg pegvaliase, respectively Label.

Protein binding

No protein binding has been reported.

Metabolism

It is expected that pegvaliase undergoes the catabolic pathway to be degraded into small peptides and amino acids Label.

Route of elimination

Human elimination pathway of pegvaliase has not been studied.

Half-life

Following once-daily subcutaneous administration of 20 mg and 40 mg pegvaliase, the mean ± SD (range) half-life at steady state was 47 ± 42 (14 to 132) hours and 60 ± 45 (14 to 127) hours, respectively Label.

Clearance

At steady state following once-daily subcutaneous administration of 20 mg and 40 mg pegvaliase, the mean ± SD (range) apparent clearance was 0.39 ± 0.87 L/h and 1.25 ± 2.46 L/h, respectively Label.

Adverse Effects
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Toxicity

No LD50 value has been reported for pegvaliase. A subcutaneous dose of 20 mg/kg/day of pegvaliase-pqpz produced impaired fertility in female rats leading to decreases in corpora lutea, implantations, and litter size, in association with toxic effects including decreased weight, ovarian weight, and food consumption Label. The carcinogenic and genototoxic potential have not been studied.

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.
DrugInteraction
Antihemophilic factor (recombinant), PEGylatedThe therapeutic efficacy of Pegvaliase can be decreased when used in combination with Antihemophilic factor (recombinant), PEGylated.
Certolizumab pegolThe therapeutic efficacy of Pegvaliase can be decreased when used in combination with Certolizumab pegol.
Damoctocog alfa pegolThe therapeutic efficacy of Damoctocog alfa pegol can be decreased when used in combination with Pegvaliase.
ElapegademaseThe therapeutic efficacy of Elapegademase can be decreased when used in combination with Pegvaliase.
LipegfilgrastimThe therapeutic efficacy of Lipegfilgrastim can be decreased when used in combination with Pegvaliase.
Methoxy polyethylene glycol-epoetin betaThe therapeutic efficacy of Pegvaliase can be decreased when used in combination with Methoxy polyethylene glycol-epoetin beta.
Nonacog beta pegolThe therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with Pegvaliase.
PegademaseThe therapeutic efficacy of Pegvaliase can be decreased when used in combination with Pegademase.
PegaptanibThe therapeutic efficacy of Pegvaliase can be decreased when used in combination with Pegaptanib.
PegaspargaseThe therapeutic efficacy of Pegvaliase can be decreased when used in combination with Pegaspargase.
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PalynziqInjection, solution10 mgSubcutaneousBiomarin International Limited2021-03-17Not applicableEU flag
PalynziqSolution10 mg / 0.5 mLSubcutaneousBiomarin International LimitedNot applicableNot applicableCanada flag
PalynziqInjection, solution20 mg/1mLSubcutaneousBioMarin Pharmaceutical Inc.2018-05-24Not applicableUS flag
PalynziqInjection, solution20 mgSubcutaneousBiomarin International Limited2021-03-17Not applicableEU flag
PalynziqInjection, solution2.5 mgSubcutaneousBiomarin International Limited2021-03-17Not applicableEU flag
PalynziqInjection, solution10 mg/0.5mLSubcutaneousBioMarin Pharmaceutical Inc.2018-05-24Not applicableUS flag
PalynziqInjection, solution20 mgSubcutaneousBiomarin International Limited2021-03-17Not applicableEU flag
PalynziqSolution2.5 mg / 0.5 mLSubcutaneousBiomarin International LimitedNot applicableNot applicableCanada flag
PalynziqSolution20 mg / mLSubcutaneousBiomarin International LimitedNot applicableNot applicableCanada flag
PalynziqInjection, solution2.5 mg/0.5mLSubcutaneousBioMarin Pharmaceutical Inc.2018-05-24Not applicableUS flag

Categories

ATC Codes
A16AB19 — Pegvaliase
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as l-alpha-amino acids. These are alpha amino acids which have the L-configuration of the alpha-carbon atom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
L-alpha-amino acids
Alternative Parents
Medium-chain fatty acids / Amino fatty acids / N-acyl amines / Secondary carboxylic acid amides / Amino acids / Monocarboxylic acids and derivatives / Dialkyl ethers / Carboxylic acids / Organic oxides / Monoalkylamines
show 2 more
Substituents
Aliphatic acyclic compound / Amine / Amino acid / Amino fatty acid / Carbonyl group / Carboxamide group / Carboxylic acid / Dialkyl ether / Ether / Fatty acid
show 15 more
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
N6UAH27EUV
CAS number
1585984-95-7
InChI Key
NPOCDVAOUKODSQ-ZDUSSCGKSA-N
InChI
InChI=1S/C15H30N2O5/c1-21-11-12-22-10-6-2-3-8-14(18)17-9-5-4-7-13(16)15(19)20/h13H,2-12,16H2,1H3,(H,17,18)(H,19,20)/t13-/m0/s1
IUPAC Name
(2S)-2-amino-6-[6-(2-methoxyethoxy)hexanamido]hexanoic acid
SMILES
COCCOCCCCCC(=O)NCCCC[C@H](N)C(O)=O

References

General References
  1. Thomas J, Levy H, Amato S, Vockley J, Zori R, Dimmock D, Harding CO, Bilder DA, Weng HH, Olbertz J, Merilainen M, Jiang J, Larimore K, Gupta S, Gu Z, Northrup H: Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM). Mol Genet Metab. 2018 May;124(1):27-38. doi: 10.1016/j.ymgme.2018.03.006. Epub 2018 Mar 31. [Article]
  2. Harding CO, Amato RS, Stuy M, Longo N, Burton BK, Posner J, Weng HH, Merilainen M, Gu Z, Jiang J, Vockley J: Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial. Mol Genet Metab. 2018 May;124(1):20-26. doi: 10.1016/j.ymgme.2018.03.003. Epub 2018 Mar 18. [Article]
  3. FDA Press Announcements: FDA approves a new treatment for PKU, a rare and serious genetic disease [Link]
PubChem Compound
86278362
PubChem Substance
347829004
ChemSpider
58172730
RxNav
2046360
Wikipedia
Pegvaliase
FDA label
Download (1.21 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentPhenylketonuria (PKU)3
3Not Yet RecruitingTreatmentPhenylketonuria (PKU)1
2CompletedTreatmentPhenylketonuria (PKU)4
1CompletedTreatmentPhenylketonuria (PKU)1
Not AvailableCompletedNot AvailablePhenylketonuria (PKU)1
Not AvailableEnrolling by InvitationNot AvailablePhenylketonuria (PKU)1
Not AvailableRecruitingNot AvailablePhenylketonuria (PKU)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionParenteral; Subcutaneous10 MG
Injection, solutionParenteral; Subcutaneous2.5 MG
Injection, solutionParenteral; Subcutaneous20 MG
Injection, solutionSubcutaneous10 mg/0.5mL
Injection, solutionSubcutaneous10 mg
Injection, solutionSubcutaneous2.5 mg/0.5mL
Injection, solutionSubcutaneous2.5 mg
Injection, solutionSubcutaneous20 mg/1mL
Injection, solutionSubcutaneous20 mg
SolutionSubcutaneous10 mg / 0.5 mL
SolutionSubcutaneous2.5 mg / 0.5 mL
SolutionSubcutaneous20 mg / mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.63 mg/mLALOGPS
logP-1.3ALOGPS
logP-2ChemAxon
logS-2.7ALOGPS
pKa (Strongest Acidic)2.24ChemAxon
pKa (Strongest Basic)9.53ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area110.88 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity83.41 m3·mol-1ChemAxon
Polarizability36.89 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Drug created at October 21, 2016 00:37 / Updated at February 21, 2021 18:54