Pegvaliase

Identification

Name
Pegvaliase
Accession Number
DB12839
Type
Small Molecule
Groups
Approved, Investigational
Description

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].

Structure
Thumb
Synonyms
  • PEG-PAL
  • pegvaliase-pqpz
  • Phenylase
  • rAvPAL-PEG
External IDs
BMN 165 / BMN-165
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
PalynziqInjection, solution2.5 mg/0.5mLSubcutaneousBiomarin International Limited2018-05-24Not applicableUs
PalynziqInjection, solution20 mg/1mLSubcutaneousBiomarin International Limited2018-05-24Not applicableUs
PalynziqInjection, solution10 mg/0.5mLSubcutaneousBiomarin International Limited2018-05-24Not applicableUs
Categories
Not Available
UNII
N6UAH27EUV
CAS number
1585984-95-7
Weight
Average: 318.414
Monoisotopic: 318.215472074
Chemical Formula
C15H30N2O5
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

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.

Associated Conditions
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].

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.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

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. [PubMed:29653686]
  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. [PubMed:29628378]
  3. FDA Press Announcements: FDA approves a new treatment for PKU, a rare and serious genetic disease [Link]
External Links
PubChem Compound
86278362
PubChem Substance
347829004
ChemSpider
58172730
Wikipedia
Pegvaliase
FDA label
Download (1.21 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentPhenylketonuria (PKU)1
2Active Not RecruitingTreatmentPhenylketonuria (PKU)1
2CompletedTreatmentPhenylketonuria (PKU)3
3Active Not RecruitingTreatmentPhenylketonuria (PKU)2
3CompletedTreatmentPhenylketonuria (PKU)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous10 mg/0.5mL
Injection, solutionSubcutaneous2.5 mg/0.5mL
Injection, solutionSubcutaneous20 mg/1mL
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

Taxonomy

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
L-alpha-amino acid / Medium-chain fatty acid / Amino fatty acid / Fatty amide / N-acyl-amine / Fatty acyl / Fatty acid / Carboxamide group / Amino acid / Secondary carboxylic acid amide
show 15 more
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
Not Available

Drug created on October 20, 2016 18:37 / Updated on October 01, 2018 15:21