FDA Approves PALYNZIQ (pegvaliase-pqpz) to Reduce Blood Phenylalanine Concentrations in Adult Patients with Phenylketonuria who have Uncontrolled Blood Phenylalanine Concentrations

FDA Approves PALYNZIQ (pegvaliase-pqpz) to Reduce Blood Phenylalanine Concentrations in Adult Patients with Phenylketonuria who have Uncontrolled Blood Phenylalanine Concentrations

On May 24, 2018, the U.S. Food and Drug Administration (FDA) approved PALYNZIQ (pegvaliase-pqpz), a phenylalanine metabolizing enzyme, to reduce blood phenylalanine concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations > 600 micromol/L on existing management. 

Treatment with PALYNZIQ should be managed by a healthcare provider experienced in the management of PKU. The approved recommended subcutaneous dosage of PALYNZIQ includes the following induction, titration, and maintenance regimens. Additional information regarding dosage and administration can be found in the full prescribing information linked below.

• Induction: The recommended initial dosage is 2.5 mg once weekly for 4 weeks. 
• Titration: Titrate the dosage in a step-wise manner, based on tolerability, over at least 5 weeks, to achieve a dosage of 20 mg once daily. 
• Maintenance: Maintain the 20 mg once daily dosage for at least 24 weeks. The dosage may be increased to a maximum of 40 mg once daily in patients who have not achieved a response with 20 mg once daily continuous treatment for at least 24 weeks. Use the lowest effective and tolerated dosage of PALYNZIQ.

Obtain blood phenylalanine concentration before initiating treatment and every 4 weeks until a maintenance dose is established. Assess patient’s tolerability, blood phenylalanine concentration, and dietary protein and phenylalanine intake throughout treatment. 

Anaphylaxis: Anaphylaxis has been reported after administration of PALYNZIQ and may occur at any time during treatment. Administer the initial dose under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe patients for at least 60 minutes following injection. Prescribe auto injectable epinephrine to all patients receiving PALYNZIQ and instruct patients to carry auto injectable epinephrine with them at all times during PALYNZIQ treatment. Prior to the first dose, instruct the patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer auto injectable epinephrine, and to seek immediate medical care upon its use. Because of the risk of anaphylaxis, PALYNZIQ is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Additional information regarding the boxed warning can be found in the full prescribing information linked below.

Other Hypersensitivity Reactions: Consider premedication with an H1-receptor antagonist, H2-receptor antagonist, or antipyretic prior to PALYNZIQ administration based upon individual patient tolerability.

Dose Reduction for Low Phenylalanine Concentrations: For blood phenylalanine concentrations < 30 micromol/L during titration or maintenance treatment, the dosage of PALYNZIQ may be reduced and/or dietary protein and phenylalanine intake may be modified to maintain blood phenylalanine concentrations within a clinically acceptable range and > 30 micromol/L. 

Discontinuation: Discontinue PALYNZIQ in patients who have not achieved a response (≥ 20% reduction in blood phenylalanine concentration from pre-treatment baseline or a blood phenylalanine concentration ≤ 600 micromol/L) after 16 weeks of continuous treatment with the maximum dosage of 40 mg once daily.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD) 

• MOA: Pegvaliase-pqpz is a PEGylated phenylalanine ammonia lyase enzyme that substitutes for the deficient phenylalanine hydroxylase enzyme activity in patients with PKU and reduces blood phenylalanine concentrations.
• General PK: Pegvaliase pqpz PK exhibit high variability due to the heterogeneity of patient immune responses. Higher antibody titers correlated with higher apparent clearance of pegvaliase pqpz. Plasma pegvaliase pqpz concentrations were low to not measurable during induction and titration treatment. 
• Steady State Exposure: The mean ± SD plasma trough pegvaliase pqpz concentrations for 20 and 40 mg once daily dosages were 11.2 ± 9.0 mg/L and 10.4 ± 12.7 mg/L, respectively, and peak concentrations were 14.0 ± 16.3 mg/L and 16.7 ± 19.5 mg/L, respectively. 
• Absorption: The median T_max was approximately 8 hours. 
• Distribution: The mean ± SD apparent volume of distribution for 20 and 40 mg once daily dosages was 26.4 ± 64.8 L and 22.2 ± 19.7 L, respectively.
• Elimination: The mean ± SD half-life for 20 and 40 mg once daily dosages was 47 ± 42 hours and 60 ± 45 hours, respectively, and apparent clearance was 0.39 ± 0.87 L/h and 1.25 ± 2.46 L/h, respectively. 
• Metabolism: The metabolism of phenylalanine ammonia lyase is expected to occur via catabolic pathways and be degraded into small peptides and amino acids.
• Excretion: The route of elimination of pegvaliase pqpz has not been studied in humans.
• PD: PALYNZIQ reduced blood phenylalanine concentrations from pre-treatment baseline. The reduction of blood phenylalanine concentrations diminished with decreased pegvaliase pqpz plasma concentrations. 
• Immunogenicity: All patients treated with PALYNZIQ developed a sustained total anti-drug antibody (TAb) response and anti-phenylalanine ammonia lyase (PAL) IgM antibodies were detected in all patients. The majority (≥ 88%) of patients treated with PALYNZIQ developed anti-PAL IgG antibodies, anti-PEG IgM and IgG antibodies, and neutralizing antibodies (NAb).  The highest frequency of hypersensitivity reactions occurred within the first 6 months of PALYNZIQ treatment when mean circulating immune complex (CIC) concentrations were at their highest and mean complement C3 and C4 concentrations were at their lowest. Higher antibody responses for all antibody analytes, including NAb, were associated with lower mean trough pegvaliase-pqpz concentrations and with higher blood phenylalanine concentrations. Additional information regarding immunogenicity can be found in the full prescribing information linked below.

Drug Interactions

Other PEGylated Products: Hypersensitivity reactions were observed following concomitant injections of medroxyprogesterone acetate suspension (a formulation containing PEG 3350) with PALYNZIQ. The clinical effect of concomitant treatment with different PEGylated products is unknown. Monitor for hypersensitivity reactions, including anaphylaxis, with concomitant treatment. 

Efficacy and Safety

Safety and tolerability of PALYNZIQ was demonstrated in adult patients with PKU who received PALYNZIQ in an induction/titration/maintenance regimen in two clinical trials. Efficacy of PALYNZIQ was demonstrated in patients with PKU who were previously-treated with PALYNZIQ 20 mg/day or 40 mg/day and entered a randomized withdrawal period following 13 weeks of continued treatment. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (at least 20% in either the induction/titration or maintenance treatment phase) include injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus, nausea, abdominal pain, oropharyngeal pain, vomiting, cough, diarrhea, and fatigue.

Full prescribing information is available at https://go.usa.gov/xQVFG. 

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