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
Structure for Pegvaliase (DB12839)
- 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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- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- 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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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.
Drug Interaction Integrate drug-drug
interactions in your softwareAntihemophilic factor (recombinant), PEGylated The therapeutic efficacy of Pegvaliase can be decreased when used in combination with Antihemophilic factor (recombinant), PEGylated. Certolizumab pegol The therapeutic efficacy of Pegvaliase can be decreased when used in combination with Certolizumab pegol. Damoctocog alfa pegol The therapeutic efficacy of Damoctocog alfa pegol can be decreased when used in combination with Pegvaliase. Elapegademase The therapeutic efficacy of Elapegademase can be decreased when used in combination with Pegvaliase. Lipegfilgrastim The therapeutic efficacy of Lipegfilgrastim can be decreased when used in combination with Pegvaliase. Methoxy polyethylene glycol-epoetin beta The therapeutic efficacy of Pegvaliase can be decreased when used in combination with Methoxy polyethylene glycol-epoetin beta. Nonacog beta pegol The therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with Pegvaliase. Pegademase The therapeutic efficacy of Pegvaliase can be decreased when used in combination with Pegademase. Pegaptanib The therapeutic efficacy of Pegvaliase can be decreased when used in combination with Pegaptanib. Pegaspargase The therapeutic efficacy of Pegvaliase can be decreased when used in combination with Pegaspargase. 
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- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Palynziq Injection, solution 10 mg Subcutaneous Biomarin International Limited 2021-03-17 Not applicable EU 
Palynziq Solution 10 mg / 0.5 mL Subcutaneous Biomarin International Limited Not applicable Not applicable Canada 
Palynziq Injection, solution 20 mg/1mL Subcutaneous BioMarin Pharmaceutical Inc. 2018-05-24 Not applicable US 
Palynziq Injection, solution 20 mg Subcutaneous Biomarin International Limited 2021-03-17 Not applicable EU Palynziq Injection, solution 2.5 mg Subcutaneous Biomarin International Limited 2021-03-17 Not applicable EU Palynziq Injection, solution 10 mg/0.5mL Subcutaneous BioMarin Pharmaceutical Inc. 2018-05-24 Not applicable US Palynziq Injection, solution 20 mg Subcutaneous Biomarin International Limited 2021-03-17 Not applicable EU Palynziq Solution 2.5 mg / 0.5 mL Subcutaneous Biomarin International Limited Not applicable Not applicable Canada Palynziq Solution 20 mg / mL Subcutaneous Biomarin International Limited Not applicable Not applicable Canada Palynziq Injection, solution 2.5 mg/0.5mL Subcutaneous BioMarin Pharmaceutical Inc. 2018-05-24 Not applicable US
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
- 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]
- 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]
- 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
- 2046360
- Wikipedia
- Pegvaliase
- FDA label
- Download (1.21 MB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Phenylketonuria (PKU) 3 3 Not Yet Recruiting Treatment Phenylketonuria (PKU) 1 2 Completed Treatment Phenylketonuria (PKU) 4 1 Completed Treatment Phenylketonuria (PKU) 1 Not Available Completed Not Available Phenylketonuria (PKU) 1 Not Available Enrolling by Invitation Not Available Phenylketonuria (PKU) 1 Not Available Recruiting Not Available Phenylketonuria (PKU) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Parenteral; Subcutaneous 10 MG Injection, solution Parenteral; Subcutaneous 2.5 MG Injection, solution Parenteral; Subcutaneous 20 MG Injection, solution Subcutaneous 10 mg/0.5mL Injection, solution Subcutaneous 10 mg Injection, solution Subcutaneous 2.5 mg/0.5mL Injection, solution Subcutaneous 2.5 mg Injection, solution Subcutaneous 20 mg/1mL Injection, solution Subcutaneous 20 mg Solution Subcutaneous 10 mg / 0.5 mL Solution Subcutaneous 2.5 mg / 0.5 mL Solution Subcutaneous 20 mg / mL - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.63 mg/mL ALOGPS logP -1.3 ALOGPS logP -2 ChemAxon logS -2.7 ALOGPS pKa (Strongest Acidic) 2.24 ChemAxon pKa (Strongest Basic) 9.53 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 6 ChemAxon Hydrogen Donor Count 3 ChemAxon Polar Surface Area 110.88 Å2 ChemAxon Rotatable Bond Count 15 ChemAxon Refractivity 83.41 m3·mol-1 ChemAxon Polarizability 36.89 Å3 ChemAxon Number of Rings 0 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Drug created at October 21, 2016 00:37 / Updated at February 21, 2021 18:54