Pegvaliase-Pqpz

Obtain baseline blood Phe concentration before initiating treatment. ( 2.1 ) Consider premedication for hypersensitivity reactions. ( 2.1 , 5.1 , 5.3 ) The recommended initial dosage for PALYNZIQ is 2.5 mg subcutaneously once weekly for 4 weeks. ( 2.2 ) See the Full Prescribing Information for titration, maintenance, discontinuation, and dose reduction. ( 2.2 ) See Full Prescribing Information for dosage and administration modifications due to anaphylaxis. ( 2.3 ) Obtain blood Phe concentrations every 4 weeks until a maintenance dosage is established. ( 2.4 ) Periodically monitor blood Phe concentrations during maintenance therapy and monitor dietary protein and phenylalanine intake throughout treatment. ( 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. ( 2.5 )

2.1 Important Recommendation Prior to PALYNZIQ Treatment Treatment with PALYNZIQ should be managed by a healthcare provider experienced in the management of PKU. Obtain baseline blood phenylalanine concentration before initiating treatment. Consider premedication with an H 1 -receptor antagonist, H 2 -receptor antagonist, and/or antipyretic based upon individual patient tolerability [see Warnings and Precautions (5.1 , 5.3) ] .

2.2 Recommended Dosage and Administration 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 (2.5) ]. 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 and phenylalanine 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 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 reduced and/or dietary protein and phenylalanine intake may be modified to maintain blood phenylalanine concentrations within a clinically acceptable range and above 30 micromol/L [see Warning and Precaution (5.5) ] . Missed Dose If a dose is missed, instruct patients to take their next dose as scheduled and to not take two doses of PALYNZIQ to make up for the missed dose.

2.3 Dosage and Administration Modifications Due to Anaphylaxis If the decision is made to readminister PALYNZIQ after an anaphylaxis episode, administer the first dose following the anaphylaxis episode under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe the patient for at least 60 minutes following the dose. Subsequent dose titration should be based on patient tolerability and therapeutic response [see Warnings and Precautions (5.1) ] .

2.4 Blood Phenylalanine Monitoring and Diet After initiating treatment with PALYNZIQ, obtain blood phenylalanine concentrations every 4 weeks until a maintenance dosage is established. After a maintenance dosage is established, periodic blood phenylalanine monitoring is recommended to assess blood phenylalanine control. Frequent blood Phe monitoring is recommended in the pediatric population. Monitor patients' dietary protein and phenylalanine intake throughout treatment with PALYNZIQ and counsel them on how to adjust their dietary protein and phenylalanine intake, as needed, based on blood phenylalanine concentrations.

2.5 Administration Instructions Each prefilled syringe of PALYNZIQ is intended for use as a single subcutaneous injection. Inspect PALYNZIQ visually for particulate matter and discoloration prior to administration. PALYNZIQ is a clear to slightly opalescent, colorless to pale yellow solution. Discard if discolored, cloudy, or if particulate matter is present. Prior to first dose of PALYNZIQ, prescribe epinephrine, and instruct the patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer epinephrine, and to seek immediate medical care upon its use. Perform initial administration(s) and/or readministration after an anaphylaxis episode under the supervision of a healthcare provider equipped to manage anaphylaxis, and closely observe patients for at least 60 minutes following injection [see Warnings and Precautions (5.1) ] . Prior to self-injection, confirm patient competency with self-administration using aseptic technique. Discard after use. Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during PALYNZIQ treatment. If an adult observer is needed, the observer should be present during and for at least 60 minutes after each PALYNZIQ administration, should be able to administer epinephrine, and call for emergency medical support upon its use [see Warnings and Precautions (5.1) ] . The recommended injection sites for PALYNZIQ are: the front middle of thighs and the abdomen at least 2 inches (five centimeters) away from the navel. If a caregiver is giving the injection, the top of the buttocks and the back of the upper arms are also appropriate injection sites. Do not inject PALYNZIQ into moles, scars, birthmarks, bruises, rashes, or areas where the skin is hard, tender, red, damaged, burned, inflamed, or tattooed. Check the injection site for redness, swelling, or tenderness. Rotate sites for subcutaneous injections of PALYNZIQ. If more than one injection is needed for a single dose of PALYNZIQ, the injection sites should be at least 2 inches away from each other. The second injection site can be on the same part of the body or a different part of the body.

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions, Other than Anaphylaxis : Management should be based on the severity of the reaction, recurrence, and clinical judgement. ( 5.3 ) Injection Site Infections : Serious injection site infections, including abscess, cellulitis, necrosis, and ulcer have been reported. Instruct patients to contact their healthcare provider if signs or symptoms of an infection develop, persist, or worsen. ( 5.4 ) Hypophenylalaninemia : Some PKU patients treated with PALYNZIQ have experienced hypophenylalaninemia; monitor blood Phe levels periodically during treatment. ( 5.5 )

5.1 Anaphylaxis In PALYNZIQ Studies 1, 2, and 3 with an induction/titration/maintenance dosage regimen, 10% (29/285) of PALYNZIQ-treated patients experienced a total of 42 anaphylaxis episodes [see Adverse Reactions (6.1) and Clinical Pharmacology (12.6) ]. The exposure-adjusted rate of anaphylaxis was highest during the induction and titration phases (0.25 episodes/person-years; 5% of PALYNZIQ-treated patients with at least one episode) and decreased in the maintenance phase (0.05 episodes/person-years; 7% of PALYNZIQ-treated patients with at least one episode). Signs and symptoms of anaphylaxis reported in PALYNZIQ-treated patients included syncope, hypotension, hypoxia, dyspnea, wheezing, chest discomfort/chest tightness, tachycardia, angioedema (swelling of face, lips, eyes, tongue), throat tightness, skin flushing, rash, urticaria, pruritus, and gastrointestinal symptoms (vomiting, nausea, diarrhea). Anaphylaxis occurred within 1 hour after injection in 81% of PALYNZIQ-treated patients (34/42 episodes); however, delayed episodes also occurred up to 48 hours after PALYNZIQ administration. Anaphylaxis occurred within the first year of dosing in 69% of PALYNZIQ-treated patients (29/42 episodes), but cases also occurred after one year of dosing and up to 1,604 days (4.4 years) into treatment. Management of anaphylaxis in PALYNZIQ-treated patients included: administration of epinephrine (48%; 20/42 episodes), corticosteroids (55%; 23/42 episodes), antihistamines (57%; 24/42 episodes), and/or oxygen (5%; 2/42 episodes). In these trials, 72% (21/29) of patients who experienced anaphylaxis were rechallenged with PALYNZIQ and 29% (6/21) of patients who were rechallenged had recurrence of anaphylaxis. All anaphylaxis episodes resolved without sequelae. In Study 4, conducted in patients who were 12 to less than 18 years of age [see Clinical Trials (14) ], premedication was administered to all patients. A single episode of anaphylaxis, was reported in 11% (4/36) of PALYNZIQ-treated patients with symptoms similar to those reported in the adult clinical trials. All 4 patients were managed with administration of epinephrine. Treatment with PALYNZIQ was discontinued in two patients and the other two patients were rechallenged with PALYNZIQ without recurrence of anaphylaxis. Steps to Take to Prevent, Mitigate, Monitor for, and Manage Anaphylaxis Prior to PALYNZIQ administration, consider premedication with an H 1 -receptor antagonist, H 2 -receptor antagonist, and/or antipyretic based upon individual patient tolerability. Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during PALYNZIQ treatment. If an adult observer is needed, the observer should be present during and for at least 60 minutes after PALYNZIQ administration, should be able to administer epinephrine, and call for emergency medical support upon its use. Anaphylaxis requires immediate treatment with epinephrine. Prescribe epinephrine to all PALYNZIQ-treated patients while considering the risks associated with epinephrine use (refer to the epinephrine prescribing information for complete information). Instruct patients to carry epinephrine with them at all times during PALYNZIQ treatment. Prior to the first PALYNZIQ dose, instruct the patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer epinephrine, and to seek immediate medical care upon its use. Consider the risks and benefits of readministering PALYNZIQ following an episode of anaphylaxis. If the decision is made to readminister PALYNZIQ, administer the first dose under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe the patient for at least 60 minutes following the dose. Subsequent PALYNZIQ dose titration should be based on patient tolerability and therapeutic response. PALYNZIQ is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ].

5.2 PALYNZIQ REMS PALYNZIQ is available only through a restricted program under a REMS called the PALYNZIQ REMS because of the risk of anaphylaxis [see Warnings and Precautions (5.1) ]. Notable requirements of the PALYNZIQ REMS include the following: Prescribers must be certified with the program by enrolling in the program and completing training. Prescribers must prescribe epinephrine with PALYNZIQ. Pharmacies must be certified with the program and must dispense only to patients who are authorized to receive PALYNZIQ. Patients must enroll in the program and be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with PALYNZIQ. Patients must have epinephrine available at all times while taking PALYNZIQ. Further information, including a list of qualified pharmacies, is available at www.PALYNZIQREMS.com or by telephone 1-855-758-REMS (1-855-758-7367).

5.3 Other Hypersensitivity Reactions In Studies 1, 2, and 3 of PALYNZIQ with induction/titration/maintenance dosage regimen, hypersensitivity reactions, other than anaphylaxis [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) , and Immunogenicity (12.6) ], have been reported in 72% (204/285) PALYNZIQ-treated patients. The exposure adjusted rate of other hypersensitivity reactions was highest during the induction and titration phases (4.3 episodes/person-year; 50% of PALYNZIQ-treated patients with at least one adverse reaction) and decreased in the maintenance phase (1.3 episodes/person-year; 61% of PALYNZIQ-treated patients with at least one adverse reaction). Hypersensitivity reactions generally occurred more frequently in PALYNZIQ-treated patients with higher anti-pegvaliase-pqpz antibody titers [see Clinical Pharmacology (12.6) ]. In Study 4, hypersensitivity reactions other than anaphylaxis were reported in 33% (12/36) of PALYNZIQ-treated patients who were 12 to less than 18 years of age. The exposure adjusted rate of other hypersensitivity reactions during the induction and titration phases was 1 episodes/person-year; 3/36 (8%) of PALYNZIQ-treated patients had at least one adverse reaction. The exposure adjusted rate of other hypersensitivity reactions during the maintenance phase was 1.4 episodes/person-year; 11/34 (32%) of PALYNZIQ-treated patients had at least one adverse reaction. Prior to PALYNZIQ administration, consider premedication with an H 1 -receptor antagonist, H 2 -receptor antagonist, and/or antipyretic based upon individual patient tolerability [see Dosage and Administration (2.1) ] . Management of hypersensitivity reactions should be based on the severity of the reaction, recurrence of the reaction, and the clinical judgement of the healthcare provider, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids.

5.4 Injection Site Infections Serious injection site infections including abscess, cellulitis, necrosis, and ulcer have been reported with PALYNZIQ in clinical trials and in the postmarketing setting. Some cases required hospitalization, surgical debridement, intravenous antibiotics, and discontinuation of PALYNZIQ. Provide proper training to patients and/or caregivers on the use of aseptic injection technique. Advise patients to rotate injection sites with each dose and to check the site for redness, swelling, or tenderness. Instruct patients to contact their healthcare provider if signs or symptoms of an infection develop, persist, or worsen. Advise patients to not administer PALYNZIQ into the affected area until the infection has resolved [see Dosage and Administration (2.5) and Adverse Reactions (6.1 , 6.2) ].

5.5 Hypophenylalaninemia In clinical trials of PALYNZIQ, some PKU patients have experienced hypophenylalaninemia (low blood Phe), including some patients with prolonged low blood Phe levels, during treatment with PALYNZIQ [see Adverse Reactions (6.1) ] . Prolonged levels of blood Phe that are too low have been associated with catabolism and endogenous protein breakdown, which has been associated with adverse developmental outcomes. Monitor blood Phe levels periodically during treatment. During titration and maintenance of PALYNZIQ treatment, patients may experience blood phenylalanine concentrations below 30 micromol/L [ Adverse Reactions (6.1) ] . For blood phenylalanine concentrations below 30 micromol/L, 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 above 30 micromol/L. Frequent blood Phe monitoring is recommended in the pediatric population.

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) ] Injection Site Infections [see Warnings and Precautions (5.4) ] Hypophenylalaninemia [see Warnings and Precautions (5.5) ] 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 ) Most common adverse reactions in patients who are 12 to less than 18 years of age (at least 20% and greater than in control) are: injection site reactions, arthralgia, headache, pyrexia, hypersensitivity reactions, dizziness, nausea, vomiting, fatigue, and pain in extremity. ( 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. Clinical Trials With Induction/Titration/Maintenance Dosage Regimen in Patients With PKU (Study 1, Study 2, and Study 3) 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 a pooled safety analysis of a phase 2 study (Study 1), and 2 phase 3 studies (Studies 2 and 3, respectively) [see Clinical Studies (14) ] . Twelve patients aged 16-17 years at enrollment received PALYNZIQ as part of the overall induction/titration/maintenance population and are included in this analysis. 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 from the pooled safety analysis, 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 this pooled safety analysis. 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 3 [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 high sensitivity-C Reactive Protein (hs-CRP) above 0.287 mg/dL over a 6-month period (both decreased over time) and hypophenylalaninemia (blood phenylalanine concentration below 30 micromol/L) on a single measurement (increased over time). There were no dose-related trends in type or rate of laboratory abnormalities (adjusted for duration of exposure) reported during the maintenance phase in patients receiving 20 mg once daily, 40 mg once daily, or 60 mg once daily. Table 2: Adverse Reactions ≥ 15% incidence in either treatment phase Reported in at Least 15% of PKU Patients Treated with PALYNZIQ in an Induction/Titration/Maintenance Regimen in Studies 1, 2, and 3 – Incidence and Exposure-Adjusted Rates Treatment Phase Treatment Duration Induction/Titration Phase (N = 285) 141 person-years Mean: 188 days Median: 116 days Range: 1 to 2266 days Maintenance Phase (N = 225) 652 person-years Mean: 1087 days Median: 1158 days Range: 5 to 2017 days Adverse Reaction N (%) N (%) = Number of patients with at least 1 Adverse Reaction (%); Rate = Exposure-Adjusted Rate of Adverse Reactions (Adverse Reactions/Person-Years) Episodes (Rate) N (%) Episodes (Rate) Injection site reactions Includes injection site: reaction, erythema, pruritus, pain, bruising, rash, swelling, urticaria, induration, hemorrhage, edema, mass, inflammation, nodule, discoloration, warmth, hematoma, irritation, vesicles, hypersensitivity, papule, discomfort, scar, paresthesia, hypertrophy, extravasation, dryness, scab 252 (88%) 2965 (21) 166 (74%) 2169 (3.3) Arthralgia Includes arthralgia, pain in extremity, back pain, musculoskeletal pain, neck pain 211 (74%) 1049 (7.4) 154 (68%) 893 (1.4) Hypersensitivity reactions Includes rash, urticaria, anaphylaxis, rash generalized, hypersensitivity, rash erythematous, rash maculo-papular, rash pruritic, serum sickness, swelling face, dermatitis contact, swollen tongue, lip swelling, rash macular, pharyngeal edema, injection site hypersensitivity, eczema, drug eruption, dermatitis allergic, dermatitis, tongue edema, palatal edema, edema mouth, multiple allergies, lip edema, eye edema, exfoliative rash, drug hypersensitivity, dermatitis atopic, dermatitis acneiform, pruritus allergic, mouth swelling, implant site rash, gingival swelling, face edema, eyelid edema, eye swelling, dermatitis psoriasiform, dermatitis infected, conjunctivitis allergic, bronchospasm, angioedema, allergic sinusitis, allergic cough, eczema nummular, rhinitis allergic 153 (54%) 634 (4.5) 145 (64%) 845 (1.3) Headache Includes headache, migraine, sinus headache 102 (36%) 214 (1.5) 126 (56%) 1049 (1.6) Generalized skin reaction lasting at least 14 days Includes pruritus, rash, urticaria, dry skin, rash erythematous, erythema, cellulitis, rash macular, pruritus generalized, petechiae, dermatitis allergic, skin infection, skin induration, rash maculo-papular, rash generalized, pharyngeal edema, macule, granulomatous dermatitis, exfoliative rash, drug eruption, dermatitis atopic, dermatitis, xanthogranuloma, skin plaque, skin mass, skin lesion, skin hypopigmentation, skin hyperpigmentation, skin exfoliation, septal panniculitis, scar, rash pruritic, rash papular, psoriatic arthropathy, pruritus allergic, papule, necrobiosis lipoidica diabeticorum, furuncle, eczema, ecchymosis, dermatitis psoriasiform, dermatitis infected, blister, eczema nummular, granuloma, infected dermal cyst, lipohypertrophy, psoriasis, skin irritation 61 (21%) 97 (0.7) 93 (41%) 186 (0.3) Nausea 52 (18%) 68 (0.5) 69 (31%) 141 (0.2) Abdominal pain Includes abdominal pain, abdominal pain upper, abdominal discomfort 39 (14%) 54 (0.4) 67 (30%) 162 (0.3) Vomiting 36 (13%) 53 (0.4) 68 (30%) 139 (0.2) Cough 27 (9%) 33 (0.2) 67 (30%) 100 (0.2) Oropharyngeal pain 38 (13%) 45 (0.3) 65 (29%) 108 (0.2) Pruritus 58 (20%) 102 (0.7) 61 (27%) 424 (0.7) Diarrhea 26 (9%) 32 (0.2) 61 (27%) 116 (0.2) Nasal congestion 12 (4%) 16 (0.1) 61 (27%) 87 (0.1) Fatigue 37 (13%) 81 (0.6) 55 (24%) 110 (0.2) Dizziness 47 (16%) 65 (0.5) 48 (21%) 100 (0.2) Anxiety 14 (5%) 23 (0.2) 48 (21%) 100 (0.2) Alopecia 13 (5%) 14 (0.1) 43 (19%) 62 (0.1) Table 3: Laboratory Abnormalities Reported in at Least 10% of PKU Patients Treated with PALYNZIQ in an Induction/Titration/Maintenance Regimen in Studies 1, 2, and 3 – Incidence and Exposure-Adjusted Rates Treatment Phase Induction/Titration Phase (N = 285) Maintenance Phase (N = 225) Treatment Duration 141 person-years Mean: 188 days Median: 116 days Range: 1 to 2266 days 652 person-years Mean: 1087 days Median: 1158 days Range: 5 to 2017 days Laboratory Measurement N (%) N (%) = Number of patients with at least 1 laboratory abnormality (%); Rate = Exposure-Adjusted Rate of Laboratory Abnormalities (Laboratory Abnormalities/Person-Years) Episodes (Rate) N (%) Episodes (Rate) LLN – lower limit of normal ULN – upper limit of normal Hs – high sensitivity Complement factor C3 below LLN 195 (68%) 453 (3.2) 188 (84%) 2259 (3.5) C-reactive protein (CRP) above ULN 182 (64%) 359 (2.5) 160 (71%) 1414 (2.2) Hypophenylalaninemia Blood phenylalanine concentration below 30 micromol/L on a single measurement 53 (19%) 216 (1.5) 147 (65 %) 1553 (2.4) Complement factor C4 below LLN 177 (62%) 318 (2.3) 111 (49%) 714 (1.1) Hypophenylalaninemia on 2 or more consecutive measurements 45 (16%) 62 (0.4) 111 (49%) 204 (0.3) Blood creatine phosphokinase (CPK) above ULN 50 (18%) 88 (0.6) 108 (48%) 377 (0.6) Hs-CRP above 0.287 mg/dL over a 6 month period 34 (12%) 34 (0.4) 36 (16%) 46 (0.1) Description of Selected Adverse Reactions Arthralgia In clinical trials, 245 out of 285 (86%) patients experienced episodes consistent with arthralgia (includes back pain, musculoskeletal pain, pain in extremity, and neck pain). Arthralgia episodes were more frequent during the induction/titration phase (7.4 episodes/patient-year) and decreased over time (1.4 episodes/patient-year in the maintenance phase). Forty-four out of 285 (15%) patients had one episode of arthralgia, 32 (11%) patients had 2 episodes of arthralgia, 18 (6%) had 3 episodes of arthralgia, and 146 (51%) had 4 or more episodes of arthralgia. Arthralgia occurred as early as after the first dose of PALYNZIQ and occurred at any time during treatment. The mean duration of arthralgia was 16 days (median: 3 days, range: 1 to 936 days), and 19% of arthralgia episodes had a duration of at least 14 days. Severe arthralgia (severe pain limiting self-care activities of daily living) was reported by 11 (4%) patients. In addition to arthralgia, other joint-related signs and symptoms reported were: joint swelling (24 patients; 8%), joint stiffness (22 patients; 8%), and musculoskeletal stiffness (20 patients; 7%). Arthralgia episodes were managed with medications (e.g., nonsteroidal anti-inflammatory drugs, glucocorticoids, and acetaminophen), PALYNZIQ dosage reduction (4% of episodes), PALYNZIQ interruption (4% of episodes), or PALYNZIQ withdrawal (0.6% of episodes). 97% of arthralgia episodes were reported as resolved at the time of last observation (up to 77 months of follow-up). Injection Site Reactions Injection site reactions were reported as early as after the first dose of PALYNZIQ and occurred at any time during treatment. Injection site reactions were more frequent during the induction/titration phase (21 episodes/patient-years) and decreased over time (3 episodes/patient-years in the maintenance phase). The mean duration of injection site reaction was 10 days (median: 2 days, range: 1 to 1612 days), and 8% of injection site reactions had a duration of at least 14 days. 99% of injection site reactions were reported as resolved at the time of last observation (up to 77 months of follow-up). Three injection site reactions consistent with granulomatous skin lesions were reported (each reaction occurring in one patient): granulomatous dermatitis (occurred after 464 days of PALYNZIQ treatment and lasted 16 days), xanthogranuloma (occurred after 378 days of PALYNZIQ treatment and lasted 638 days) was treated with a topical antihistamine, corticosteroid, and PALYNZIQ treatment was discontinued, and necrobiosis lipoidica diabeticorum (occurred after 281 days of PALYNZIQ treatment and lasted 281 days). Necrobiosis lipoidica diabeticorum was treated with steroid injections and complicated by Pseudomonas infection. All three injection site reactions resolved. One patient reported soft tissue infection (occurred after 196 days of PALYNZIQ treatment and lasted 8 days) associated with mesenteric panniculitis treated with antibiotics which resulted in treatment discontinuation. Generalized Skin Reactions (not limited to the injection site) Lasting at Least 14 Days In clinical trials, 134 out of 285 (47%) patients treated with PALYNZIQ experienced generalized skin reactions (not limited to the injection site) lasting at least 14 days. Mean duration of these reactions was 63 days (median: 37 days; range: 14 to 638 days). Generalized skin reactions were more frequent during the induction/titration phase (0.7 episodes/patient-years) and decreased over time (0.3 episodes/patient-years in the maintenance phase). The mean time from first dose of PALYNZIQ to onset of skin reactions was 373 days (median: 213 days; range: 2 to 1970 days). 5% of these reactions persisted at least 180 days, and 86% of these reactions were reported as resolved at the time of last observation (up to 77 months of follow-up). Angioedema In clinical trials, 22 out of 285 (8%) patients experienced 45 episodes of angioedema (symptoms included: pharyngeal edema, swollen tongue, lip swelling, mouth swelling, eyelid edema and face edema) occurring independent of anaphylaxis. Angioedema (included under Hypersensitivity in Table 2) was more frequent during the induction/titration phase (0.14 episodes/patient-year) and decreased over time (0.04 episodes/patient-year in the maintenance phase). Three patients discontinued treatment. All episodes resolved. Angioedema can present as a symptom of anaphylaxis [see Warnings and Precautions (5.1) ]. Serum Sickness In clinical trials, serum sickness was reported in 7 out of 285 (2%) patients. Serum sickness episodes were more frequent during the induction/titration phase (0.04 episodes/patient-year) and decreased over time (less than 0.01 episodes/patient-year during the maintenance phase). All serum sickness reactions resolved without sequelae (duration of serum sickness ranged from 1 to 8 days). Out of the 7 patients who experienced serum sickness, 5 patients continued treatment without a recurrence and managed serum sickness with drug interruption, dosage reduction and/or concomitant medication. Two patients discontinued treatment. Clinical Trial in Patients who are 12 to Less Than 18 Years of Age With PKU (Study 4) The safety of PALYNZIQ in patients who are 12 to less than 18 years of age was evaluated in Study 4, which was an open label, randomized study in 55 patients with PKU. Patients were randomized in a 2:1 ratio to receive PALYNZIQ in an induction/titration/maintenance regimen or to continue dietary management only for 72 weeks [see Clinical Studies (14) ] . In Study 4, the total exposure to PALYNZIQ was 45.4 person-years in 36 patients [see Clinical Trials (14) ] with a mean (SD) daily dose of 21 (10) mg, mean (SD) total duration of 461 (151) days, and a median duration of 518 days. Of the 36 patients, anaphylaxis was reported in 4 (11%) and 2 (6%) discontinued from the study due to anaphylaxis [see Warnings and Precautions (5.1) ] . A total of 19 (53%) patients reported dose interruption and the most common adverse reactions leading to dose interruption were arthralgia (n=8) and headache (n=4). Dose reductions were reported in 9 (25%) patients and was most commonly due to arthralgia (n=4) and hypophenylalaninemia (n=3). The most common adverse reactions in patients who are 12 to less than 18 years of age (at least 20% and greater than in control) were injection site reactions, arthralgia, headache, pyrexia, hypersensitivity reactions, dizziness, nausea, vomiting, fatigue, and pain in extremity. Table 4 lists the adverse reactions that were reported in at least 15% of patients treated with PALYNZIQ and greater than that of the diet-only arm in Study 4. Table 4: Adverse Reactions Reported in at Least 15% of PKU Patients Treated with PALYNZIQ and Greater Than the Diet-Only Arm in Study 4 Adverse Reaction PALYNZIQ N = 36 (%) DIET-ONLY N = 19 (%) Injection site reactions Injection site reactions include injection site: reaction, erythema, pruritus, pain, bruising, rash, swelling, urticaria, induration, hemorrhage, edema, mass, inflammation, nodule, discoloration, warmth, hematoma, irritation, vesicles, hypersensitivity, papule, discomfort, scar, paresthesia, hypertrophy, extravasation, dryness, scab. 31 (86) 0 (0) Arthralgia 27 (75) 1 (5) Headache 24 (67) 8 (42) Pyrexia 15 (42) 1 (5) Hypersensitivity reactions Hypersensitivity includes rash, urticaria, anaphylactic reaction, rash generalized, hypersensitivity, rash erythematous, rash maculo-papular, rash pruritic, serum sickness, swelling face, dermatitis contact, swollen tongue, lip swelling, rash macular, pharyngeal edema, injection site hypersensitivity, eczema, drug eruption, dermatitis allergic, dermatitis, tongue edema, palatal edema, edema mouth, multiple allergies, lip edema, eye edema, exfoliative rash, drug hypersensitivity, dermatitis atopic, dermatitis acneiform, pruritus allergic, mouth swelling, implant site rash, gingival swelling, face edema, eyelid edema, eye swelling, dermatitis psoriasiform, dermatitis infected, conjunctivitis allergic, bronchospasm, angioedema, allergic sinusitis, allergic cough, eczema nummular, rhinitis allergic. 15 (42) 2 (11) Dizziness 11 (31) 2 (11) Nausea 11 (31) 3 (16) Vomiting 10 (28) 2 (11) Fatigue 8 (22) 2 (11) Pain in extremity 8 (22) 2 (11) Myalgia 7 (19) 1 (5) Erythema 6 (17) 0 Back pain 6 (17) 3 (16) Laboratory Abnormalities Eosinophilia : In Study 4, 44% of patients in the PALYNZIQ-treated group experienced eosinophilia above the ULN compared to 11% of patients in the diet-only group. Hypophenylalaninemia : In Study 4, 28% of patients in the PALYNZIQ-treated group experienced hypophenylalaninemia, defined as blood Phe level < 30 µmol/L on 1 or more measurements, compared to 5% of patients in the diet-only group. Creatine Phosphokinase (CPK) Elevation : In Study 4, 14% of patients in the PALYNZIQ-treated group experienced CPK level greater than 3 times the ULN compared to 0% of patients in the diet-only group.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of PALYNZIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Administration site conditions : injection site infection, cellulitis, necrosis, and abscess.

8.1 Pregnancy Risk Summary Available data from pharmacovigilance and published literature with pegvaliase-pqpz use in pregnant women have not identified a clear association with major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data ) . There are risks to the fetus associated with poorly controlled phenylalanine concentrations in women with PKU during pregnancy including increased risk for miscarriage, major birth defects (including microcephaly and major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ; therefore, phenylalanine concentrations should be closely monitored in women with PKU during pregnancy (see Clinical Considerations and Data ). Advise pregnant women of the potential risks to the fetus. A reproduction study in pregnant rabbits without PKU treated with pegvaliase-pqpz demonstrated a high incidence of fetal malformations throughout the skeletal system, and in kidneys, lungs, and eyes. Embryo-fetal toxicity (increased resorptions and reduced fetal weight) was also observed. These effects occurred at 5 times the maximum recommended daily dose and were associated with strong signs of maternal toxicity, including marked reductions in weight gain and food consumption, and death. A reproduction study in pregnant rats without PKU treated with pegvaliase-pqpz demonstrated an increase in skeletal variations with no malformations observed. The effects in rats occurred at 2.8 times the maximum recommended daily dose. In a pre-/post-natal development study in rats, pegvaliase-pqpz produced reduced survival of offspring during lactation, decreases in pup weight and litter size, and delayed sexual maturation of offspring when administered daily at 13 times the maximum recommended daily dose. Observed embryofetal and postnatal findings could be attributable to maternal toxicity. All pregnancies have a background risk of major birth defects, pregnancy loss, or other adverse pregnancy outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood phenylalanine concentrations greater than 600 micromol/L during pregnancy is 12-73% and 24%, respectively. There is a pregnancy surveillance program for PALYNZIQ. If PALYNZIQ is administered during pregnancy, or if a patient becomes pregnant while receiving PALYNZIQ or within one month following the last dose of PALYNZIQ, healthcare providers should report PALYNZIQ exposure by calling 1-866-906-6100. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Uncontrolled blood phenylalanine concentrations above 600 micromol/L before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects, including increased risk for miscarriage, major birth defects (including microcephaly and major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ (see Data ). To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood phenylalanine concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception [see Dosage and Administration (2.4) ]. Dose Adjustments During Pregnancy and the Postpartum Period Phenylalanine concentrations below 30 micromol/L in pregnant women with PKU treated with PALYNZIQ may be associated with adverse fetal outcomes. Monitor blood phenylalanine concentrations during pregnancy. Adjust the dosage of PALYNZIQ or modify dietary protein and phenylalanine intake to avoid blood phenylalanine concentrations below 30 micromol/L [see Dosage and Administration (2.4) ]. Data Human Data Uncontrolled Maternal PKU: Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in pregnant women with PKU demonstrated that uncontrolled phenylalanine concentrations above 600 micromol/L are associated with an increased risk for miscarriage, major birth defects (including microcephaly and major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ. Animal Data All developmental toxicity studies were conducted in animals (rats and rabbits) without PKU, in which treatment with pegvaliase-pqpz produced a dose-dependent reduction in maternal blood phenylalanine concentrations. At doses that produced maternal toxicity and/or effects on embryo-fetal development, the maternal plasma phenylalanine concentrations were markedly reduced compared to the control group. The contribution of maternal phenylalanine depletion to the incidence of embryo-fetal developmental effects was not evaluated. Subcutaneous administration of 5 mg/kg/day pegvaliase-pqpz (5 times the maximum recommended daily dose based on bodyweight [mg/kg]) in pregnant rabbits during the period of organogenesis produced embryo-lethality (increased resorptions), marked reduction in fetal weight, and fetal malformations. The malformations included multiple external abnormalities of the head, body and limbs, multiple soft tissue malformations (reduced size or absence of kidneys, diaphragmatic hernia, corneal opacity, discoloration or reduced size of eyes, and reduced size of lungs) and multiple skeletal malformations of the craniofacial bones, vertebrae, sternebrae, ribs, pelvis, limbs, and digits. An increase in variations and delayed ossification was also observed in all skeletal regions. The adverse developmental effects were associated with maternal toxicity, as indicated by marked impairment of weight gain and food consumption. Deaths associated with weight loss and abortion occurred in 8% of the pregnant rabbits treated with 5 mg/kg/day pegvaliase-pqpz. Subcutaneous administration of 2 mg/kg/day pegvaliase-pqpz (2 times the maximum recommended daily dose based on bodyweight [mg/kg]) in pregnant rabbits had no adverse effects on embryo-fetal development. Systemic exposure to pegvaliase-pqpz was detected in fetuses from rabbits treated with 2 or 5 mg/kg/day. Pegvaliase-pqpz increased fetal alterations when administered daily in pregnant rats at doses of 8 mg/kg subcutaneously and higher (2.8 times the human steady-state area under the curve [AUC] at the maximum recommended daily dose) during a 28-day premating period, mating, and through the period of organogenesis. The fetal alterations were limited to skeletal variations such as cervical ribs, bifid centra of lumbar and thoracic vertebrae, and incomplete ossification of squamosal bones, frontal bones, lumbar vertebra arch, and ribs. Daily administration of 20 mg/kg subcutaneously (13 times the human steady-state AUC at the recommended maximum daily dose) to pregnant rats produced reductions in litter sizes and fetal weights, which was associated with maternal toxicity (decreased body weight, ovarian weight, and food consumption). The decrease in litter sizes at 20 mg/kg subcutaneously was secondary to reductions in corpora lutea and implantations. Systemic exposure to pegvaliase-pqpz was detected in fetuses from rats treated with 20 mg/kg of pegvaliase-pqpz (13 times the human steady-state AUC at the recommended maximum daily dose). Subcutaneous administration of 2 mg/kg/day pegvaliase-pqpz (less than the human steady state AUC at the maximum recommended daily dose) in pregnant rats had no adverse effects on embryo-fetal development. Pegvaliase-pqpz decreased pup weight, litter size, and survival of offspring during lactation, and delayed sexual maturation of offspring when administered daily in rats at 20 mg/kg subcutaneously (13 times the human steady-state AUC at the recommended maximum daily dose), with dosing starting before mating and continuing through lactation. The effects in offspring were associated with maternal toxicity. No effects in offspring were observed at 8 mg/kg/day subcutaneously (2.8 times the human steady-state AUC at the recommended maximum daily dose). A follow-up study of the same design evaluated additional parameters of physical and neurobehavioral development in offsprings; No effects of pegvaliase-pqpz were noted at the maternal NOAEL dose of 8 mg/kg/day.

8.2 Lactation Risk Summary There are no data on the presence of pegvaliase-pqpz in human milk, the effects on the breastfed infant, or the effects on milk production. A pre-/post-natal study in rats showed that pegvaliase-pqpz is present in rat milk and that administration of pegvaliase-pqpz during lactation decreased pup weight and survival [see Use in Specific Populations (8.1) ] . However, systemic absorption of pegvaliase-pqpz was not detected in the rat pups . PALYNZIQ may cause low phenylalanine concentrations in human milk . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PALYNZIQ and any potential adverse effects on the breastfed infant from PALYNZIQ or from the underlying condition (see Clinical Considerations ) . Clinical Considerations Monitor blood phenylalanine concentrations in breastfeeding women treated with PALYNZIQ.

8.4 Pediatric Use The safety and effectiveness of PALYNZIQ to reduce blood phenylalanine concentrations have been established in pediatric patients 12 years and older with PKU who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management. Use of PALYNZIQ for this indication is supported by evidence from Study 4, an open label randomized 2-arm study in patients who are 12 to less than 18 years of age [see Clinical Pharmacology (12) and Clinical studies (14) ] . In Study 4, 16 out of 36 (44%) pegvaliase-treated patients experienced eosinophilia. Incidence of eosinophil levels higher than upper limit of normal was more frequent during the induction/titration phase and decreased during the maintenance phase [see Adverse Reactions (6.1) ] . The safety and effectiveness of PALYNZIQ in pediatric patients younger than 12 years of age have not been established.

8.5 Geriatric Use Clinical studies of PALYNZIQ did not include patients aged 65 years and older.

Risk Summary Available data from pharmacovigilance and published literature with pegvaliase-pqpz use in pregnant women have not identified a clear association with major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data ) . There are risks to the fetus associated with poorly controlled phenylalanine concentrations in women with PKU during pregnancy including increased risk for miscarriage, major birth defects (including microcephaly and major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ; therefore, phenylalanine concentrations should be closely monitored in women with PKU during pregnancy (see Clinical Considerations and Data ). Advise pregnant women of the potential risks to the fetus. A reproduction study in pregnant rabbits without PKU treated with pegvaliase-pqpz demonstrated a high incidence of fetal malformations throughout the skeletal system, and in kidneys, lungs, and eyes. Embryo-fetal toxicity (increased resorptions and reduced fetal weight) was also observed. These effects occurred at 5 times the maximum recommended daily dose and were associated with strong signs of maternal toxicity, including marked reductions in weight gain and food consumption, and death. A reproduction study in pregnant rats without PKU treated with pegvaliase-pqpz demonstrated an increase in skeletal variations with no malformations observed. The effects in rats occurred at 2.8 times the maximum recommended daily dose. In a pre-/post-natal development study in rats, pegvaliase-pqpz produced reduced survival of offspring during lactation, decreases in pup weight and litter size, and delayed sexual maturation of offspring when administered daily at 13 times the maximum recommended daily dose. Observed embryofetal and postnatal findings could be attributable to maternal toxicity. All pregnancies have a background risk of major birth defects, pregnancy loss, or other adverse pregnancy outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood phenylalanine concentrations greater than 600 micromol/L during pregnancy is 12-73% and 24%, respectively. There is a pregnancy surveillance program for PALYNZIQ. If PALYNZIQ is administered during pregnancy, or if a patient becomes pregnant while receiving PALYNZIQ or within one month following the last dose of PALYNZIQ, healthcare providers should report PALYNZIQ exposure by calling 1-866-906-6100. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Uncontrolled blood phenylalanine concentrations above 600 micromol/L before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects, including increased risk for miscarriage, major birth defects (including microcephaly and major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ (see Data ). To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood phenylalanine concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception [see Dosage and Administration (2.4) ]. Dose Adjustments During Pregnancy and the Postpartum Period Phenylalanine concentrations below 30 micromol/L in pregnant women with PKU treated with PALYNZIQ may be associated with adverse fetal outcomes. Monitor blood phenylalanine concentrations during pregnancy. Adjust the dosage of PALYNZIQ or modify dietary protein and phenylalanine intake to avoid blood phenylalanine concentrations below 30 micromol/L [see Dosage and Administration (2.4) ]. Data Human Data Uncontrolled Maternal PKU: Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in pregnant women with PKU demonstrated that uncontrolled phenylalanine concentrations above 600 micromol/L are associated with an increased risk for miscarriage, major birth defects (including microcephaly and major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ. Animal Data All developmental toxicity studies were conducted in animals (rats and rabbits) without PKU, in which treatment with pegvaliase-pqpz produced a dose-dependent reduction in maternal blood phenylalanine concentrations. At doses that produced maternal toxicity and/or effects on embryo-fetal development, the maternal plasma phenylalanine concentrations were markedly reduced compared to the control group. The contribution of maternal phenylalanine depletion to the incidence of embryo-fetal developmental effects was not evaluated. Subcutaneous administration of 5 mg/kg/day pegvaliase-pqpz (5 times the maximum recommended daily dose based on bodyweight [mg/kg]) in pregnant rabbits during the period of organogenesis produced embryo-lethality (increased resorptions), marked reduction in fetal weight, and fetal malformations. The malformations included multiple external abnormalities of the head, body and limbs, multiple soft tissue malformations (reduced size or absence of kidneys, diaphragmatic hernia, corneal opacity, discoloration or reduced size of eyes, and reduced size of lungs) and multiple skeletal malformations of the craniofacial bones, vertebrae, sternebrae, ribs, pelvis, limbs, and digits. An increase in variations and delayed ossification was also observed in all skeletal regions. The adverse developmental effects were associated with maternal toxicity, as indicated by marked impairment of weight gain and food consumption. Deaths associated with weight loss and abortion occurred in 8% of the pregnant rabbits treated with 5 mg/kg/day pegvaliase-pqpz. Subcutaneous administration of 2 mg/kg/day pegvaliase-pqpz (2 times the maximum recommended daily dose based on bodyweight [mg/kg]) in pregnant rabbits had no adverse effects on embryo-fetal development. Systemic exposure to pegvaliase-pqpz was detected in fetuses from rabbits treated with 2 or 5 mg/kg/day. Pegvaliase-pqpz increased fetal alterations when administered daily in pregnant rats at doses of 8 mg/kg subcutaneously and higher (2.8 times the human steady-state area under the curve [AUC] at the maximum recommended daily dose) during a 28-day premating period, mating, and through the period of organogenesis. The fetal alterations were limited to skeletal variations such as cervical ribs, bifid centra of lumbar and thoracic vertebrae, and incomplete ossification of squamosal bones, frontal bones, lumbar vertebra arch, and ribs. Daily administration of 20 mg/kg subcutaneously (13 times the human steady-state AUC at the recommended maximum daily dose) to pregnant rats produced reductions in litter sizes and fetal weights, which was associated with maternal toxicity (decreased body weight, ovarian weight, and food consumption). The decrease in litter sizes at 20 mg/kg subcutaneously was secondary to reductions in corpora lutea and implantations. Systemic exposure to pegvaliase-pqpz was detected in fetuses from rats treated with 20 mg/kg of pegvaliase-pqpz (13 times the human steady-state AUC at the recommended maximum daily dose). Subcutaneous administration of 2 mg/kg/day pegvaliase-pqpz (less than the human steady state AUC at the maximum recommended daily dose) in pregnant rats had no adverse effects on embryo-fetal development. Pegvaliase-pqpz decreased pup weight, litter size, and survival of offspring during lactation, and delayed sexual maturation of offspring when administered daily in rats at 20 mg/kg subcutaneously (13 times the human steady-state AUC at the recommended maximum daily dose), with dosing starting before mating and continuing through lactation. The effects in offspring were associated with maternal toxicity. No effects in offspring were observed at 8 mg/kg/day subcutaneously (2.8 times the human steady-state AUC at the recommended maximum daily dose). A follow-up study of the same design evaluated additional parameters of physical and neurobehavioral development in offsprings; No effects of pegvaliase-pqpz were noted at the maternal NOAEL dose of 8 mg/kg/day.

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.

12.2 Pharmacodynamics PALYNZIQ treatment of adult patients with PKU resulted in the reduction of blood phenylalanine concentrations from pre-treatment baseline [see Clinical Studies (14) ] . The reduction of blood phenylalanine concentrations diminished with decreased pegvaliase-pqpz plasma concentrations . PALYNZIQ treatment of patients with PKU resulted in increased ammonia and trans -cinnamic acid concentrations from pre-treatment baseline. The time course of ammonia and trans -cinnamic acid concentrations and the exposure-response relationships for the safety of ammonia and trans -cinnamic acid have not been well-characterized in patients with PKU.

12.3 Pharmacokinetics The pharmacokinetics of pegvaliase-pqpz exhibit high inter-patient and intra-patient variability due to the heterogeneity of the immune response in adult patients with PKU. Higher antibody titers correlated with higher apparent clearance of pegvaliase-pqpz. In the first eight weeks of induction/titration treatment, plasma pegvaliase-pqpz concentrations were low to not measurable. At steady state during maintenance treatment with PALYNZIQ 20 mg, 40 mg, and 60 mg subcutaneously once daily, the mean ± SD (range) plasma trough pegvaliase-pqpz concentrations were: 11.2 ± 9 (0.21 to 29.6) mg/L, 10.4 ± 12.7 (0.18 to 43.1) mg/L and 4.8 ± 10.7 (0 to 39.7) mg/L, respectively. The following pharmacokinetic parameters were observed in adult patients with PKU treated with PALYNZIQ at maintenance dosages of 20 mg once daily and 40 mg once daily. Absorption The median T max was approximately 8 hours. The mean ± SD (range) peak concentration (C max ) at steady state was: 14 ± 16.3 (0.26 to 68.5) mg/L and 16.7 ± 19.5 (0.24 to 63.8) mg/L, respectively. Distribution The mean ± SD (range) apparent volume of distribution was 26.4 ± 64.8 (1.8 to 241) L and 22.2 ± 19.7 (3.1 to 49.5) L, respectively. Elimination The mean ± SD (range) apparent clearance at steady state was 0.39 ± 0.87 (0.018 to 3.66) L/h and 1.25 ± 2.46 (0.034 to 8.88) L/h, respectively. The mean ± SD (range) half-life was 47 ± 42 (14 to 132) hours and 60 ± 45 (14 to 127) hours, 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. Special Populations In patients who are 12 to less than 18 years of age in Study 4, the mean ± SD (range) plasma peak concentration (C max ) at steady state during maintenance treatment with PALYNZIQ 20 mg, 40 mg, and 60 mg subcutaneously once daily was: 2.33 mg/L (n=1), 2.48 ± 3.81 (0.038 to 12.5) mg/L, and 1.75 ± 2.2 (0.074 to 6.01) mg/L, respectively.

12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of pegvaliase-pqpz or of other pegvaliase products. Anti-Drug Antibodies In Studies 1, 2, and 3 (clinical trials of PALYNZIQ with induction/titration/maintenance dosage regimen), 100% of PALYNZIQ-treated patients developed anti-pegvaliase-pqpz antibodies, including 91% (N = 235/258) of patients who developed anti-pegvaliase-pqpz antibodies by Week 4 of treatment. Mean anti-pegvaliase-pqpz antibody titers peaked 2 weeks after PALYNZIQ initiation and remained elevated throughout treatment (greater than 3 years after treatment initiation). Anti-Phenylalanine Ammonia Lyase Antibodies Anti-phenylalanine ammonia lyase (PAL) IgM antibodies were detected in 98% (265/270) of PALYNZIQ-treated patients by 2 months after treatment initiation, with incidence declining over time to 67% of patients (114/171) at 36 months. Anti-PAL IgG antibodies were detected in 99.6% (226/227) of PALYNZIQ-treated patients by 4 months after treatment initiation. Mean anti-PAL IgM and IgG titers peaked at approximately 3 and 6 months, respectively, after treatment initiation and remained elevated throughout treatment (greater than 3 years after treatment initiation). Anti-PEG Antibodies Drug-induced anti-PEG IgM antibodies were detected in 98% (277/284) of PALYNZIQ-treated patients. Drug-induced anti-PEG IgG antibodies were detected in 98% (278/284) of PALYNZIQ-treated patients. Mean anti-PEG IgM and IgG titers peaked at 1 to 3 months after treatment initiation [see Drug Interactions (7.1) ] . In Study 4, 100% of PALYNZIQ-treated patients who were 12 to less than 18 years of age developed anti-pegvaliase-pqpz antibodies, anti-PAL IgG and IgM, anti-PEG IgG and IgM. The overall time course of anti-drug antibody development in these patients was similar to that in adult patients; however, the anti-pegvaliase-pqpz antibody titers were generally higher in patients who were 12 to less than 18 years of age compared to those in adult patients with PKU. Neutralizing Antibodies Neutralizing antibodies (NAb) capable of inhibiting PAL enzyme activity were detected on at least one measurement in 89% (253/284) of PALYNZIQ-treated patients over time in Studies 1, 2 and 3. Mean NAb titers peaked and reached a plateau at 16 to 20 weeks of treatment and then remained present throughout treatment (greater than 3 years after treatment initiation). In Study 4, 100% of PALYNZIQ-treated patients who were 12 to less than 18 years of age developed NAb with a similar time course to that in adult patients. IgE Antibodies In Studies 1, 2, and 3, twenty-seven of 29 PALYNZIQ-treated patients who had anaphylaxis were tested for anti-pegvaliase-pqpz IgE antibodies which recognize the PEGylated protein product. Of the 27 patients tested for anti-pegvaliase-pqpz IgE antibodies, 26 patients tested negative. The one patient who tested positive for anti-pegvaliase-pqpz- IgE antibodies on the screening test did not have sufficient sample to confirm IgE positivity. This patient tested negative for anti-pegvaliase-pqpz- IgE at routine visits prior to and after the anaphylaxis episode (not at times of anaphylaxis) [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . In Study 4, of the four PALYNZIQ-treated patients who were 12 to less than 18 years of age that experienced anaphylaxis, three were tested and all were negative for pegvaliase-specific IgE antibodies [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . Sixty-seven of 285 PALYNZIQ-treated patients in Studies 1, 2 and 3 were tested for both anti-PAL IgE antibodies, which recognize the recombinant PAL protein, and for anti-pegvaliase-pqpz IgE antibodies during routine study visits (not at times of anaphylaxis episodes) or during additional visits for hypersensitivity reactions. Of those 67 patients, 5 (8%) tested positive at least once for anti-PAL IgE antibodies but negative for anti-pegvaliase-pqpz-IgE antibodies. Circulating Immune Complexes In Studies 1, 2, and 3, the highest frequency of hypersensitivity reactions (consistent with a Type III immune complex-mediated hypersensitivity mechanism) occurred within the first 6 months of PALYNZIQ treatment when the mean circulating immune complex (CIC) concentrations were at their highest and mean complement C3 and C4 concentrations were at their lowest [see Warnings and Precautions (5.3) and Adverse Reactions (6.1) ] . Mean CIC concentrations decreased and complement levels increased over time as the exposure-adjusted rate of hypersensitivity reactions decreased. At 12 weeks of treatment, IgG CIC and IgM CIC concentrations were above the upper limit of normal in 63% (164/259) and 42% (109/259) of PALYNZIQ-treated patients, respectively, and returned towards baseline 3 years after treatment initiation. At 6 months after treatment initiation, 61% (110/180) of PALYNZIQ-treated patients had complement C3 concentrations less than lower limit of normal (LLN). At 3 months after treatment initiation, 38% (94/248) of PALYNZIQ-treated patients had complement C4 concentrations less than LLN. At 36 months after treatment initiation, the incidence of low complement C3 and C4 concentrations decreased over time, but approximately 35% (34/96) and 12% (11/96) of PALYNZIQ-treated patients had low C3 and C4 concentrations, respectively. Anti-Drug Antibody Effects on Pharmacokinetics and Efficacy Higher antibody responses for all antibody analytes, including NAb, were associated with lower mean trough pegvaliase-pqpz concentrations and with higher blood phenylalanine concentrations. Anti-Drug Antibody Effects on Safety Hypersensitivity reactions generally occurred more frequently in PALYNZIQ-treated patients with higher antibody titers. PALYNZIQ-treated patients with higher mean change in IgG CIC concentrations from pre-treatment baseline tended to have higher discontinuation rates than those with lower mean change in IgG CIC concentrations. The effect of ADAs on safety of PALYNZIQ in pediatric patients 12 years of age and older with PKU has not been fully characterized.