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Pegvaliase

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6 FDF Dossiers, 3 FDA Orange Book, 3 Canada

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3 FDA Orange Book
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1 US Medicaid Prescriptions, 6 Annual Reports

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1 US Medicaid Prescriptions
6 Annual Reports

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Chemistry

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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

Pegvaliase

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 Formula	C₁₅H₃₀N₂O₅
Molecular Weight	318.41 g/mol
XLogP3	-2.3
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	15
Exact Mass	318.21547206 g/mol
Monoisotopic Mass	318.21547206 g/mol
Topological Polar Surface Area	111 Å²
Heavy Atom Count	22
Formal Charge	0
Complexity	300
Isotope Atom Count	0
Defined Atom Stereocenter Count	1
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

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.

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