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    Pegvaliase

    FINISHED DOSAGE FORMULATIONS

    DIGITAL CONTENT

    GLOBAL SALES INFORMATION

    PharmaCompass
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    2D Structure
    Also known as: Ravpal-peg, Peg-pal, Pegvaliase-pqpz, 1585984-95-7, Pegvaliase [inn], Unii-n6uah27euv
    Molecular Formula
    C15H30N2O5
    Molecular Weight
    318.41  g/mol
    InChI Key
    NPOCDVAOUKODSQ-ZDUSSCGKSA-N
    Pegvaliase is a recombinant phenylalanine ammonia lyase (PAL) enzyme derived from Anabaena variabilis that converts phenylalanine to ammonia and trans-cinnamic acid. 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) and affects about 1 in 10,000 to 15,000 people in the United States. 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. Individuals with PKU also need to be under a strictly restricted diet as Phe is present in foods and products with high-intensity sweeteners. 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 mol/L to 3690 mol/L. 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 [DB00360], that are ineffective to many patients due to long-term adherence issues or inadequate Phe-lowering effects. The presence of a PEG moiety in pegvaliase-pqpz allows a reduced immune response and improved pharmacodynamic stability.
    1 2D Structure

    2D Structure

    2 Identification
    2.1 Computed Descriptors
    2.1.1 IUPAC Name
    (2S)-2-amino-6-[6-(2-methoxyethoxy)hexanoylamino]hexanoic acid
    2.1.2 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
    2.1.3 InChI Key
    NPOCDVAOUKODSQ-ZDUSSCGKSA-N
    2.1.4 Canonical SMILES
    COCCOCCCCCC(=O)NCCCCC(C(=O)O)N
    2.1.5 Isomeric SMILES
    COCCOCCCCCC(=O)NCCCC[C@@H](C(=O)O)N
    2.2 Synonyms
    2.2.1 MeSH Synonyms

    1. Bmn-165

    2. Palynziq

    3. Pegvaliase-pqpz

    2.2.2 Depositor-Supplied Synonyms

    1. Ravpal-peg

    2. Peg-pal

    3. Pegvaliase-pqpz

    4. 1585984-95-7

    5. Pegvaliase [inn]

    6. Unii-n6uah27euv

    7. Phenylase

    8. Bmn 165

    9. N6uah27euv

    10. Dtxsid501336362

    11. Db12839

    2.3 Create Date
    2014-11-22
    3 Chemical and Physical Properties
    Molecular Weight 318.41 g/mol
    Molecular Formula C15H30N2O5
    XLogP3-2.3
    Hydrogen Bond Donor Count3
    Hydrogen Bond Acceptor Count6
    Rotatable Bond Count15
    Exact Mass318.21547206 g/mol
    Monoisotopic Mass318.21547206 g/mol
    Topological Polar Surface Area111 Ų
    Heavy Atom Count22
    Formal Charge0
    Complexity300
    Isotope Atom Count0
    Defined Atom Stereocenter Count1
    Undefined Atom Stereocenter Count0
    Defined Bond Stereocenter Count0
    Undefined Bond Stereocenter Count0
    Covalently Bonded Unit Count1
    4 Drug and Medication Information
    4.1 Drug 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.

    FDA Label

    Palynziq is indicated for the treatment of patients with phenylketonuria (PKU) aged 16 years and older who have inadequate blood phenylalanine control (blood phenylalanine levels greater than 600 micromol/l) despite prior management with available treatment options.

    Treatment of hyperphenylalaninaemia

    5 Pharmacology and Biochemistry
    5.1 Pharmacology

    In a phase 3 clinical trial of adult patients with phenylketonuria and blood phenylalanine concentrations greater than 600 mol/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.

    5.2 FDA Pharmacological Classification
    5.2.1 Pharmacological Classes
    Phenylalanine Metabolizing Enzyme [EPC]; Phenylalanine Ammonia-Lyase [CS]
    5.3 ATC Code

    A16AB19

    A - Alimentary tract and metabolism

    A16 - Other alimentary tract and metabolism products

    A16A - Other alimentary tract and metabolism products

    A16AB - Enzymes

    A16AB19 - Pegvaliase

    5.4 Absorption, Distribution and Excretion

    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. The time to reach Cmax (Tmax) was approximately 8 hours.

    Route of Elimination

    Human elimination pathway of pegvaliase has not been studied.

    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.

    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.

    5.5 Metabolism/Metabolites

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

    5.6 Biological 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.

    5.7 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. Formed conversion products are metabolized in the liver and later excreted in the urine.