Pegvaliase

12.1 Mechanism of Action Pegvaliase-pqpz is a PEGylated phenylalanine ammonia lyase (PAL) enzyme that converts phenylalanine to ammonia and trans ‑cinnamic acid. It substitutes for the deficient phenylalanine hydroxylase (PAH) enzyme activity in patients with PKU and reduces blood phenylalanine concentrations.

1 INDICATIONS AND USAGE Palynziq is indicated to reduce blood phenylalanine concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management. Palynziq is a phenylalanine (Phe)‑metabolizing enzyme indicated to reduce blood Phe concentrations in adult patients with phenylketonuria who have uncontrolled blood Phe concentrations greater than 600 micromol/L on existing management. ( 1 )

2 DOSAGE AND ADMINISTRATION Dosage ( 2.1 ) Obtain baseline blood Phe concentration before initiating treatment. The recommended initial dosage is 2.5 mg subcutaneously once weekly for 4 weeks. Titrate the dosage in a step-wise manner over at least 5 weeks based on tolerability to achieve a dosage of 20 mg once daily. See full prescribing information for titration regimen. Assess patient tolerability, blood Phe concentration, and dietary protein and Phe intake throughout treatment. Consider increasing the dosage to 40 mg once daily in patients who have been on 20 mg once daily continuously for at least 24 weeks and who have not achieved blood Phe control (blood phenylalanine concentration less than or equal to 600 micromol/L). Consider increasing the dosage to a maximum of 60 mg once daily in patients who have been on 40 mg once daily continuously for at least 16 weeks and who have not achieved blood Phe control. Discontinue Palynziq in patients who have not achieved an adequate response after 16 weeks of continuous treatment with the maximum dosage of 60 mg once daily. Reduce the dosage and/or modify dietary protein and Phe intake, as needed, to maintain blood Phe concentrations within a clinically acceptable range and above 30 micromol/L. Blood Phenylalanine Monitoring and Diet ( 2.2 ) Obtain blood Phe concentrations every 4 weeks until a maintenance dosage is established. Periodically monitor blood Phe concentrations during maintenance therapy. Counsel patients to monitor dietary protein and Phe intake, and adjust as directed by their healthcare provider. Premedication ( 2.3 , 5.1 , 5.3 ) Consider premedication for hypersensitivity reactions. Administration Instructions ( 2.4 ) Rotate injection sites. If more than one injection is needed for a single dose, the injection sites should be at least 2 inches away from each other. 2.1 Dosage Treatment with Palynziq should be managed by a healthcare provider experienced in the management of PKU. Obtain baseline blood phenylalanine concentration before initiating treatment. Induction The recommended initial induction dosage for Palynziq is 2.5 mg subcutaneously once weekly for 4 weeks. Administer the initial dose under the supervision of a healthcare provider [see Dosage and Administration ( 2.4 )]. Titration Titrate the Palynziq dosage in a step-wise manner, based on tolerability, over at least 5 weeks, to achieve a dosage of 20 mg subcutaneously once daily according to Table 1. Maintenance Therapeutic response may not be achieved until the patient is titrated to an effective maintenance dosage of Palynziq. Use the lowest effective and tolerated dosage of Palynziq. Assess patient tolerability, blood phenylalanine concentrations, and dietary protein and phenylalanine intake throughout treatment. Individualize the maintenance dosage to achieve blood phenylalanine control (blood phenylalanine concentrations less than or equal to 600 micromol/L), taking into account patient tolerability to Palynziq and dietary protein intake (see Table 1). Maintain the Palynziq dosage at 20 mg once daily for at least 24 weeks. Consider increasing the Palynziq dosage to 40 mg once daily in patients who have been on 20 mg once daily continuously for at least 24 weeks without achieving blood phenylalanine control. Consider increasing the Palynziq dosage to a maximum of 60 mg once daily in patients who have been on 40 mg once daily continuously for at least 16 weeks without achieving blood phenylalanine control. Discontinuation Discontinue Palynziq in patients who have not achieved an adequate response after 16 weeks of continuous treatment with the maximum dosage of 60 mg once daily [see Clinical Studies ( 14 )]. Table 1: Recommended Dosing Regimen Treatment Palynziq Dosage Duration Additional time may be required prior to each dosage escalation based on patient tolerability. Induction 2.5 mg once weekly 4 weeks Titration 2.5 mg twice weekly 1 week 10 mg once weekly 1 week 10 mg twice weekly 1 week 10 mg four times per week 1 week 10 mg once daily 1 week Maintenance Individualize treatment to the lowest effective and tolerated dosage. Consider increasing to 40 mg once daily in patients who have not achieved a response with 20 mg once daily continuous treatment for at least 24 weeks. Consider increasing to a maximum of 60 mg once daily in patients who have not achieved a response with 40 mg once daily continuous treatment for at least 16 weeks [see Clinical Studies (14)]. 20 mg once daily 24 weeks 40 mg once daily 16 weeks Maximum Discontinue Palynziq in patients who have not achieved an adequate response after 16 weeks of continuous treatment at the maximum dosage of 60 mg once daily. 60 mg once daily 16 weeks Dose Reduction for Low Phenylalanine Concentrations During titration and maintenance of Palynziq treatment, patients may experience blood phenylalanine concentrations below 30 micromol/L. For blood phenylalanine concentrations below 30 micromol/L, the dosage of Palynziq may be re

6 ADVERSE REACTIONS The following serious adverse reactions are discussed below and in other sections of labeling: Anaphylaxis [see Warnings and Precautions ( 5.1 )] Other Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )] Most common adverse reactions (at least 20% in either treatment phase) are: injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, nausea, abdominal pain, vomiting, cough, oropharyngeal pain, pruritus, diarrhea, nasal congestion, fatigue, dizziness, and anxiety. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect a total treatment exposure of 789 patient-years in 285 patients who received Palynziq in an induction/titration/maintenance regimen in clinical trials [see Clinical Studies ( 14 )] . Of the 285 patients, 229 patients were exposed to Palynziq for 24 weeks, 209 patients were exposed for 1 year, 181 patients were exposed for 2 years, and 160 patients were exposed for 3 years or longer. The patient population was evenly distributed between male and female patients, the mean age was 29 years (range: 16 to 56 years), and 98% of patients were White. The most common adverse reactions (at least 20% of patients in either treatment phase) were injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, nausea, abdominal pain, vomiting, cough, oropharyngeal pain, pruritus, diarrhea, nasal congestion, fatigue, dizziness, and anxiety. Of the 285 patients exposed to Palynziq in an induction/titration/maintenance regimen in clinical trials, 44 (15%) patients discontinued treatment due to adverse reactions. The most common adverse reactions leading to treatment discontinuation were hypersensitivity reactions (6% of patients) including anaphylaxis (3% of patients), angioedema (1% of patients), arthralgia (4% of patients), generalized skin reactions lasting at least 14 days (2% of patients), and injection site reactions (1% of patients). The most common adverse reactions leading to dosage reduction were arthralgia (15% of patients), hypersensitivity reactions (9% of patients), injection site reactions (4% of patients), alopecia (3% of patients), and generalized skin reactions lasting at least 14 days (2% of patients). The most common adverse reactions leading to temporary drug interruption were hypersensitivity reactions (14% of patients), arthralgia (13% of patients), anaphylaxis (4% of patients), and injection site reactions (4% of patients). Table 2 lists adverse reactions reported in at least 15% of patients treated with Palynziq in an induction/titration/maintenance dosage regimen in clinical trials, and illustrates the adverse reaction rates over time by treatment phase. Table 3 lists laboratory abnormalities reported in at least 10% of patients treated with Palynziq in an induction/titration/maintenance dosage regimen in clinical trials. For these analyses, the induction/titration phase was defined as the time prior to reaching a stable dose (completing an 8‑week phase at the same dose level). Once a stable dosage was reached, patients were considered to be in the maintenance phase thereafter. Safety data for patients who reached the maintenance phase are included within either the induction/titration or maintenance phases depending on the onset date of the adverse reaction. Safety data for patients who did not reach the maintenance phase are included within the induction/titration phase. The maintenance phase includes data for patients who were previously on Palynziq and transitioned to placebo during the randomized withdrawal period of Study 302 [see Clinical Studies ( 14 )]. Rates of adverse reactions (adjusted for duration of exposure) generally decreased over time and for some stayed relatively stable. In the maintenance phase, the rate of adverse reactions (adjusted for duration of exposure) in patients who reached the maintenance phase was comparable across dosages evaluated. The types and rate of adverse reactions reported during the maintenance phase in patients who received 20 mg once daily, 40 mg once daily, and 60 mg once daily were similar. During long-term treatment (greater than 36 months), the exposure-adjusted rates of adverse reactions decreased. Rates of laboratory abnormalities (adjusted for duration of exposure) stayed relatively stable over time, except for complement C4 below lower limit of normal (LLN) and hs-CRP above 0.287 mg/dL over a 6 month period (both decreased over time) and hypopheny

7 DRUG INTERACTIONS Effect of Palynziq on Other PEGylated Products : Monitor for hypersensitivity reactions, including anaphylaxis, with concomitant treatment. ( 7.1 ) 7.1 Effect of Palynziq on Other PEGylated Products In a single dose study of Palynziq in adult patients with PKU, two patients receiving concomitant injections of medroxyprogesterone acetate suspension (a formulation containing PEG 3350) experienced a hypersensitivity reaction. One of the two patients experienced a hypersensitivity reaction on day 15 after a single Palynziq dosage of 0.67 mg within 15 minutes following medroxyprogesterone acetate injectable suspension, and subsequently experienced anaphylaxis on day 89 within 30 minutes after the next dose of medroxyprogesterone acetate injectable suspension. The other patient experienced a hypersensitivity reaction on day 40 after a single Palynziq dosage of 0.08 mg within 10 minutes following medroxyprogesterone acetate injectable suspension. Both patients had high anti‑PEG IgG antibody titers at or around the time of the hypersensitivity reactions. In Palynziq clinical trials, the majority of patients developed anti‑PEG IgM and IgG antibodies after treatment with Palynziq [see Adverse Reactions ( 6.2 )] . The clinical effects of concomitant treatment with different PEGylated products is unknown. Monitor patients treated with Palynziq and concomitantly with other PEGylated products for hypersensitivity reactions including anaphylaxis.