Pegvaliase (Palynziq) is an enzyme substitution therapy designed to manage phenylketonuria (PKU). This genetic disorder makes it difficult for the body to process phenylalanine. Phenylalanine is naturally found in many protein-containing foods and some artificial sweeteners.
Individuals with PKU lack a functional enzyme, phenylalanine hydroxylase (PAH), which is normally responsible for breaking down phenylalanine. Without this enzyme, phenylalanine accumulates in the blood and can become toxic to the brain, potentially leading to neurological and neuropsychiatric challenges if left unmanaged. Pegvaliase helps reduce elevated phenylalanine concentrations.
Mechanism of Action
Pegvaliase is a modified enzyme, specifically a PEGylated recombinant phenylalanine ammonia-lyase (PAL), derived from the bacterium Anabaena variabilis. This enzyme acts as a functional substitute for the deficient phenylalanine hydroxylase (PAH) in individuals with PKU. It works by circulating in the bloodstream and directly breaking down phenylalanine.
The PAL enzyme catalyzes the conversion of phenylalanine into two different substances: ammonia and trans-cinnamic acid. These new compounds are then further processed by the liver and eventually cleared from the body, with trans-cinnamic acid being metabolized into hippuric acid, which is excreted in the urine. This process lowers circulating phenylalanine levels, preventing harmful accumulation.
The “PEGylated” aspect refers to the attachment of polyethylene glycol molecules to the PAL enzyme. This modification serves a dual purpose: it enhances the enzyme’s stability within the body, allowing it to remain active for longer periods, and it also helps to reduce the likelihood of an immune response against the therapeutic enzyme. PEGylation thus contributes to sustained phenylalanine reduction.
Indications for Use
Pegvaliase is approved for use in adult patients diagnosed with phenylketonuria. It is for those whose blood phenylalanine concentrations remain uncontrolled despite existing management strategies, generally defined as greater than 600 micromol/L. This medication is for individuals who have not achieved adequate phenylalanine control through conventional methods, such as a phenylalanine-restricted diet or sapropterin.
Administration and Monitoring
Pegvaliase is administered as a subcutaneous injection, meaning it is given under the skin. Patients can learn to self-administer the daily injections following proper training from a healthcare provider. The therapy begins with a low dose that is gradually increased over a period of several weeks or months, a process known as dose titration.
The initial dose of pegvaliase must be given under the direct supervision of a healthcare provider who is prepared to manage potential allergic reactions. The dosage is carefully individualized based on how well the patient tolerates the treatment, their blood phenylalanine levels, and their dietary protein intake.
Regular monitoring through blood tests is an important part of treatment with pegvaliase. Blood phenylalanine concentrations are typically checked every four weeks until a stable maintenance dose is determined. Once a maintenance dose is established, ongoing periodic monitoring of phenylalanine levels helps healthcare providers assess the patient’s response and tolerability, allowing for adjustments to the dose or dietary intake as needed.
Potential Adverse Reactions
Common adverse reactions include injection site reactions (redness, itching, swelling), joint pain (arthralgia), and headaches. Some individuals may also experience fatigue, nausea, vomiting, or diarrhea.
Anaphylaxis, a severe, potentially life-threatening allergic reaction, is a concern with pegvaliase. Anaphylaxis can occur at any point during treatment and requires immediate medical attention.
Symptoms include:
- Fainting or dizziness
- Sudden confusion
- Difficulty breathing or wheezing
- Chest discomfort, fast heart rate
- Swelling of face, lips, eyes, or tongue
- Throat tightness
- Flushing, rash, itching, or hives
To mitigate the risk of anaphylaxis, strict safety protocols are in place. The very first dose of pegvaliase must be administered under the supervision of a healthcare provider equipped to manage severe allergic reactions, and patients are observed for at least 60 minutes after this initial injection. Patients are also required to have an auto-injectable epinephrine device available at all times while on pegvaliase therapy. Healthcare providers instruct patients and their caregivers on how to recognize the signs of anaphylaxis and how to properly administer the epinephrine auto-injector.