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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 subcutaneous injection. Pegvaliase-pqpz is a homotetrameric protein composed of recombinant phenylalanine ammonia lyase (rAvPAL) conjugated to N-hydroxysuccinimide (NHS)-methoxypolyethylene glycol (PEG).4 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
- Biotech
- Groups
- Approved, Investigational
- 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.4
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Uncontrolled phenylketonuria •••••••••••• ••••• ••••••••• Management of Uncontrolled phenylketonuria •••••••••••• ••••••••• - Contraindications & Blackbox Warnings
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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.
Target Actions Organism APhenylalanine-4-hydroxylase modulatorHumans - 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 4. The time to reach Cmax (Tmax) was approximately 8 hours 4.
- 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 4.
- 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 4.
- 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 4.
- 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 4.
- 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 4. 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. - Food Interactions
- 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 Solution 20 mg / mL Subcutaneous Biomarin International Limited 2022-08-26 Not applicable Canada 
Palynziq Injection, solution 20 mg/1mL Subcutaneous BioMarin Pharmaceutical Inc. 2018-05-24 Not applicable US 
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 2022-08-26 Not applicable Canada Palynziq Injection, solution 10 mg/0.5mL Subcutaneous BioMarin Pharmaceutical Inc. 2018-05-24 Not applicable US
Categories
- ATC Codes
- A16AB19 — Pegvaliase
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- N6UAH27EUV
- CAS number
- 1585984-95-7
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]
- FDA Approved Drug Products: PALYNZIQ (pegvaliase-pqpz) injection for subcutaneous use [Link]
- Health Canada Approved Drug Products: PALYNZIQ (pegvaliase-pqpz) injection for subcutaneous use [Link]
- External Links
- Human Metabolome Database
- HMDB0304893
- PubChem Compound
- 86278362
- PubChem Substance
- 347829004
- ChemSpider
- 58172730
- 2046360
- Wikipedia
- Pegvaliase
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available Phenylketonuria (PKU) 1 somestatus stop reason just information to hide Not Available Enrolling by Invitation Not Available Phenylketonuria (PKU) 1 somestatus stop reason just information to hide Not Available Recruiting Not Available Maternal Phenylketonuria 1 somestatus stop reason just information to hide Not Available Recruiting Not Available Phenylketonuria (PKU) 3 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Phenylketonuria (PKU) 1 somestatus stop reason just information to hide
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
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Modulator
- General Function
- Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine
- Specific Function
- iron ion binding
- Gene Name
- PAH
- Uniprot ID
- P00439
- Uniprot Name
- Phenylalanine-4-hydroxylase
- Molecular Weight
- 51861.565 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Drug created at October 21, 2016 00:37 / Updated at August 26, 2024 19:24