Pegvaliase, sold under the brand name Palynziq, is an injectable enzyme substitution therapy approved to manage Phenylketonuria (PKU). This medication is indicated for patients whose blood phenylalanine (Phe) concentrations remain uncontrolled, typically defined as levels greater than 600 micromoles per liter, despite previous management efforts. It functions by providing an exogenous enzyme to metabolize the excess amino acid, reducing its concentration in the bloodstream.
Understanding Phenylketonuria
Phenylketonuria is a rare, inherited metabolic disorder caused by a genetic mutation affecting the PAH gene. This gene provides instructions for making the enzyme phenylalanine hydroxylase (PAH), which is primarily produced in the liver. PAH is responsible for converting the amino acid phenylalanine, obtained from dietary protein, into tyrosine.
A deficiency or absence of functional PAH activity prevents the body from properly processing phenylalanine. As a result, Phe accumulates to abnormally high, potentially toxic concentrations in the blood and brain. This buildup is neurotoxic and can lead to progressive, irreversible complications if not managed from an early age.
For decades, the standard management for PKU has been a severely restrictive, lifelong diet that limits the intake of natural protein, necessitating specialized medical foods. Despite this challenging regimen, many adults with PKU struggle to maintain blood Phe levels within the recommended therapeutic range. Uncontrolled levels are associated with neurocognitive issues, including problems with executive function, and various psychiatric symptoms.
The Mechanism of Enzyme Replacement Therapy
Pegvaliase functions as a substitute for the deficient PAH enzyme. The drug is a pegylated form of phenylalanine ammonia lyase (PAL), a non-human enzyme derived from the bacterium Anabaena variabilis. This recombinant enzyme provides an alternative pathway for Phe catabolism that is independent of the PAH enzyme.
The PAL enzyme catalyzes the breakdown of phenylalanine into two non-toxic compounds: trans-cinnamic acid and ammonia. The attachment of polyethylene glycol (PEG) molecules, known as pegylation, stabilizes the enzyme and prolongs its circulation time. This modification also helps to reduce the body’s immune response against the foreign protein.
Once the phenylalanine is converted, the trans-cinnamic acid is further metabolized in the liver into hippuric acid, which is then excreted in the urine. This mechanism effectively lowers the concentration of Phe in the systemic circulation, reducing the risk of neurotoxicity. The action of Pegvaliase differs from other therapies, such as sapropterin, which works by acting as a cofactor to enhance any residual PAH activity.
Dosage and Titration Protocol
Pegvaliase is administered via subcutaneous injection, which can be self-administered at home following appropriate training. The treatment follows a dosing strategy consisting of induction, titration, and maintenance phases. This protocol is designed to maximize patient tolerability and minimize immune-mediated reactions.
The induction phase begins with a very low dose, typically 2.5 milligrams (mg) once per week for four weeks. The subsequent titration phase involves a gradual increase in the frequency and amount of the dose over several weeks or months. This progressive escalation is customized based on individual patient tolerability and the measured reduction in blood Phe levels.
The goal of the titration process is to establish a stable, effective maintenance dose, often 20 mg or 40 mg administered once daily. Some patients may require an increase up to the maximum approved dose of 60 mg daily to achieve therapeutic control. The maintenance dose is individualized to ensure the patient sustains blood phenylalanine concentrations at or below the target of 600 micromol/L. Monitoring of blood Phe levels is necessary throughout treatment, and the dosage may be adjusted downward if concentrations fall below 30 micromol/L, a condition known as hypophenylalaninemia.
Managing Safety and Adverse Reactions
The safety profile of Pegvaliase requires careful management due to the potential for serious adverse reactions, primarily anaphylaxis. Anaphylaxis is a severe, life-threatening allergic reaction that can occur at any time during treatment. Because of this risk, the drug is only available through a restricted distribution system known as a Risk Evaluation and Mitigation Strategy (REMS) program.
The REMS program mandates that both the prescribing healthcare provider and the dispensing pharmacy be certified. Patients must be educated on the signs and symptoms of anaphylaxis and are required to carry an epinephrine auto-injector at all times. The initial dose, and any dose following a period of interruption or anaphylaxis, must be administered under the supervision of a healthcare provider equipped to manage allergic emergencies.
Beyond anaphylaxis, common adverse reactions include injection site reactions, such as redness, pain, or swelling. Other frequently reported side effects are:
- Arthralgia (joint pain)
- Generalized skin reactions lasting two weeks or more
- Hypersensitivity reactions
Patients may receive premedication, such as antihistamines or antipyretics, to manage these immune-mediated symptoms and improve treatment adherence.