PALYNZIQ® Clinical Study Design

The largest clinical trial program ever conducted in adult patients with PKU1

More than 350 patients over 10 years participated in the extensive clinical trial program that established the efficacy, safety, and dosing regimen of PALYNZIQ® (pegvaliase-pqpz) Injection.

Phase 3 program: PRISM-1 and PRISM-2 studies2

Randomized withdrawal period (RWP)

  • The pivotal efficacy study (n=86) was conducted through an RWP, an 8-week, double-blind, placebo-controlled trial in which patients were randomized 2:1 to either continue their randomized dosage of PALYNZIQ (20 mg or 40 mg once daily) or receive matching placebo2
  • Entry into the RWP was determined by whether patients achieved a ≥20% reduction in blood Phe levels from pretreatment baseline, following a period of up to 13 weeks of additional treatment with PALYNZIQ1
    • Of the 164 patients who entered PRISM-2, 86 (52%) met this target and continued to the RWP1
  • The RWP study design was selected in order to address the risk of unblinding due to hypersensitivity adverse events that occurred early in treatment and to minimize long-term exposure to placebo1

Primary endpoint: Change in blood Phe levels from randomized withdrawal baseline to week 8 between patients randomized to PALYNZIQ and patients randomized to placebo2

Secondary endpoints: Change in inattention and mood symptoms, as measured by the ADHD RS-IV IA and POMS instruments from randomized withdrawal baseline to week 8 between patients randomized to PALYNZIQ and patients randomized to placebo1

Patient baseline characteristics

  • The majority of patients were not on a Phe-restricted diet prior to and during the study2a

Patient demographics and characteristics at treatment-naive baseline (ITT population; N=261)1,2

Age at enrollment, years
Mean (SD)
29.2 (8.8)
Min, Max
16.0, 55.0
Blood Phe, µmol/L
Mean (SD)
1232.7 (386.3)
 
BMI, kg/m2 (n=260)
Mean (SD)
28.4 (6.7)
Sex
Male
130 (49.8%)
Female
131 (50.2%)
Race
White
254 (97.3%)
Dietary Phe intake, mg/day
Mean (SD)
1700.2 (1194.4)
Total protein intake, g/day (n=250)
Mean (SD)
64.89 (32.2)
Median
62.6
Protein intake from natural food, g/day (n=250)b
Mean (SD)
38.5 (27.7)
Median
29.9
Protein intake from medical food, g/day (n=250)
Mean (SD)
26.3 (28.5)
Median
16.8
Receiving protein from medical food
149 (57.1%)
On a Phe-restricted dieta
41 (15.7%)
 

ITT, intent-to-treat.
aA Phe-restricted diet is defined as >75% of protein intake from medical food.3
bThe US recommendation for total protein intake from natural food is 0.8 g/kg for adults, which equals 56 g/day for a person who weighs 70 kg.4

References: 1. Thomas J, Levy H, Amato S, et al, for the PRISM investigators. Pegvaliase for the treatment of phenylketonuria: results of a long-term phase 3 clinical trial program (PRISM). Mol Genet Metab. 2018;124(1):27-38. 2. PALYNZIQ [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2018. 3. Harding CO, Amato RS, Stuy M, et al, for the PRISM-2 Investigators. Pegvaliase for the treatment of phenylketonuria: a pivotal, double-blind randomized discontinuation phase 3 clinical trial. Mol Genet Metab. 2018;124(1):20-26. 4. Singh, RH, Cunningham AC, Mofidi S, et al. Updated, web-based nutrition management guideline for PKU: an evidence and consensus based approach. Mol Genet Metab. 2016;118(2):72-83.

Important Safety Information
WARNING: RISK OF ANAPHYLAXIS
 

BOXED WARNING: RISK OF ANAPHYLAXIS

  • Anaphylaxis has been reported after administration of PALYNZIQ and may occur at any time during treatment with PALYNZIQ
  • Administer the initial dose of PALYNZIQ under the supervision of a healthcare provider equipped to manage anaphylaxis, and closely observe patients for at least 60 minutes following injection. Prior to self-injection, confirm patient competency with self-administration, and patient’s and observer’s (if applicable) ability to recognize signs and symptoms of anaphylaxis and to administer auto-injectable epinephrine, if needed
  • Prescribe auto-injectable epinephrine to all patients treated with PALYNZIQ. Prior to the first dose, instruct the patient and observer (if applicable) on its appropriate use. Instruct the patient to seek immediate medical care upon its use. Instruct patients to carry auto-injectable epinephrine with them at all times during treatment with PALYNZIQ
  • PALYNZIQ is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the PALYNZIQ REMS. Further information, including a list of qualified pharmacies, is available at www.PALYNZIQREMS.com or by telephone at 1-855-758-REMS (1-855-758-7367)
 

WARNINGS AND PRECAUTIONS

Anaphylaxis

  • Signs and symptoms of anaphylaxis reported include 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 generally occurred within 1 hour after injection; however, delayed episodes occurred up to 48 hours after PALYNZIQ administration
  • Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during treatment with PALYNZIQ. If an adult observer is needed, the observer should be present during and for at least 60 minutes after administration of PALYNZIQ, and should be able to administer auto-injectable epinephrine and call for emergency medical support upon its use
  • Anaphylaxis requires immediate treatment with auto-injectable epinephrine. Prescribe auto-injectable epinephrine to all patients receiving PALYNZIQ and instruct patients to carry auto-injectable epinephrine with them at all times during treatment with PALYNZIQ. Prior to the first dose, instruct the patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, on how to properly administer auto-injectable epinephrine, and to seek immediate medical care upon its use. Consider the risks associated with auto-injectable epinephrine use when prescribing PALYNZIQ. Refer to the auto-injectable epinephrine Prescribing Information for complete information
  • 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 dose titration of PALYNZIQ should be based on patient tolerability and therapeutic response
  • Consider premedication with an H1-receptor antagonist, H2-receptor antagonist, and/or antipyretic prior to administration of PALYNZIQ based upon individual patient tolerability

Other Hypersensitivity Reactions

  • Hypersensitivity reactions other than anaphylaxis have been reported in 196 of 285 (69%) patients treated with PALYNZIQ
  • Consider premedication with an H1-receptor antagonist, H2-receptor antagonist, and/or antipyretic prior to PALYNZIQ administration based upon individual patient tolerability
  • Management of hypersensitivity reactions should be based on the severity of the reaction, recurrence of the reaction, and the clinical judgment of the healthcare provider, and may include dosage adjustment, temporary drug interruption, drug discontinuation, or treatment with antihistamines, antipyretics, and/or corticosteroids

ADVERSE REACTIONS

  • The most common adverse reactions (at least 20% of patients in either treatment phase) were injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reaction lasting at least 14 days, pruritus, nausea, abdominal pain, oropharyngeal pain, vomiting, cough, diarrhea, and fatigue
  • Of the 285 patients exposed to PALYNZIQ in an induction/titration/maintenance regimen in clinical trials, 31 (11%) 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) and 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 (14% 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 arthralgia (13% of patients), hypersensitivity reactions (13% of patients), anaphylaxis (4% of patients), and injection site reactions (4% of patients)

Blood Phenylalanine Monitoring and Diet

  • Obtain blood phenylalanine concentrations every 4 weeks until a maintenance dosage is established
  • After a maintenance dosage is established, periodically monitor blood phenylalanine concentrations
  • Counsel patients to monitor dietary protein and phenylalanine intake, and adjust as directed by their healthcare provider

DRUG INTERACTIONS

Effect of PALYNZIQ on Other PEGylated Products

  • In a single-dose study of PALYNZIQ in adult patients with PKU, 2 patients receiving concomitant injections of medroxyprogesterone acetate suspension (a formulation containing PEG 3350) experienced hypersensitivity reactions, and 1 of the 2 patients also experienced anaphylaxis
  • 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

USE IN SPECIFIC POPULATIONS

Pregnancy and Lactation

  • PALYNZIQ may cause fetal harm when administered to a pregnant woman
  • If PALYNZIQ is administered during pregnancy, or if a patient becomes pregnant while receiving PALYNZIQ or within 1 month following the last dose of PALYNZIQ, healthcare providers should report PALYNZIQ exposure by calling 1-866-906-6100
  • Monitor blood phenylalanine concentrations in breastfeeding women treated with PALYNZIQ

Pediatric Use

  • The safety and efficacy of PALYNZIQ in pediatric patients have not been established

Geriatric Use

  • Clinical studies of PALYNZIQ did not include patients aged 65 years and older

You are encouraged to report suspected adverse reactions to BioMarin at 1-877-695-8826 and the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information, including Boxed Warning, at PALYNZIQ.com/hcp.

US/PAL/0442 0619

US/PAL/0490 0819

US/PAL/0491 0819

US/PAL/0705 0320

US/PAL/0642 0220

USPAL0671 0320

USPAL0770 0820

US-PAL-00005 0121

INDICATION

PALYNZIQ® (pegvaliase-pqpz) Injection is a phenylalanine-metabolizing enzyme indicated to reduce blood phenylalanine concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations greater than 600 µmol/L on existing management.

Important Safety Information
WARNING: RISK OF ANAPHYLAXIS
 

BOXED WARNING: RISK OF ANAPHYLAXIS

  • Anaphylaxis has been reported after administration of PALYNZIQ and may occur at any time during treatment with PALYNZIQ
  • Administer the initial dose of PALYNZIQ under the supervision of a healthcare provider equipped to manage anaphylaxis, and closely observe patients for at least 60 minutes following injection. Prior to self-injection, confirm patient competency with self-administration, and patient’s and observer’s (if applicable) ability to recognize signs and symptoms of anaphylaxis and to administer auto-injectable epinephrine, if needed
  • Prescribe auto-injectable epinephrine to all patients treated with PALYNZIQ. Prior to the first dose, instruct the patient and observer (if applicable) on its appropriate use. Instruct the patient to seek immediate medical care upon its use. Instruct patients to carry auto-injectable epinephrine with them at all times during treatment with PALYNZIQ
  • PALYNZIQ is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the PALYNZIQ REMS. Further information, including a list of qualified pharmacies, is available at www.PALYNZIQREMS.com or by telephone at 1-855-758-REMS (1-855-758-7367)

WARNINGS AND PRECAUTIONS

Anaphylaxis

  • Signs and symptoms of anaphylaxis reported include 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 generally occurred within 1 hour after injection; however, delayed episodes occurred up to 48 hours after PALYNZIQ administration
  • Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during treatment with PALYNZIQ. If an adult observer is needed, the observer should be present during and for at least 60 minutes after administration of PALYNZIQ, and should be able to administer auto-injectable epinephrine and call for emergency medical support upon its use
  • Anaphylaxis requires immediate treatment with auto-injectable epinephrine. Prescribe auto-injectable epinephrine to all patients receiving PALYNZIQ and instruct patients to carry auto-injectable epinephrine with them at all times during treatment with PALYNZIQ. Prior to the first dose, instruct the patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, on how to properly administer auto-injectable epinephrine, and to seek immediate medical care upon its use. Consider the risks associated with auto-injectable epinephrine use when prescribing PALYNZIQ. Refer to the auto-injectable epinephrine Prescribing Information for complete information
  • 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 dose titration of PALYNZIQ should be based on patient tolerability and therapeutic response
  • Consider premedication with an H1-receptor antagonist, H2-receptor antagonist, and/or antipyretic prior to administration of PALYNZIQ based upon individual patient tolerability

Other Hypersensitivity Reactions

  • Hypersensitivity reactions other than anaphylaxis have been reported in 196 of 285 (69%) patients treated with PALYNZIQ
  • Consider premedication with an H1-receptor antagonist, H2-receptor antagonist, and/or antipyretic prior to PALYNZIQ administration based upon individual patient tolerability
  • Management of hypersensitivity reactions should be based on the severity of the reaction, recurrence of the reaction, and the clinical judgment of the healthcare provider, and may include dosage adjustment, temporary drug interruption, drug discontinuation, or treatment with antihistamines, antipyretics, and/or corticosteroids

ADVERSE REACTIONS

  • The most common adverse reactions (at least 20% of patients in either treatment phase) were injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reaction lasting at least 14 days, pruritus, nausea, abdominal pain, oropharyngeal pain, vomiting, cough, diarrhea, and fatigue
  • Of the 285 patients exposed to PALYNZIQ in an induction/titration/maintenance regimen in clinical trials, 31 (11%) 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) and 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 (14% 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 arthralgia (13% of patients), hypersensitivity reactions (13% of patients), anaphylaxis (4% of patients), and injection site reactions (4% of patients)

Blood Phenylalanine Monitoring and Diet

  • Obtain blood phenylalanine concentrations every 4 weeks until a maintenance dosage is established
  • After a maintenance dosage is established, periodically monitor blood phenylalanine concentrations
  • Counsel patients to monitor dietary protein and phenylalanine intake, and adjust as directed by their healthcare provider

DRUG INTERACTIONS

Effect of PALYNZIQ on Other PEGylated Products

  • In a single-dose study of PALYNZIQ in adult patients with PKU, 2 patients receiving concomitant injections of medroxyprogesterone acetate suspension (a formulation containing PEG 3350) experienced hypersensitivity reactions, and 1 of the 2 patients also experienced anaphylaxis
  • 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

USE IN SPECIFIC POPULATIONS

Pregnancy and Lactation

  • PALYNZIQ may cause fetal harm when administered to a pregnant woman
  • If PALYNZIQ is administered during pregnancy, or if a patient becomes pregnant while receiving PALYNZIQ or within 1 month following the last dose of PALYNZIQ, healthcare providers should report PALYNZIQ exposure by calling 1-866-906-6100
  • Monitor blood phenylalanine concentrations in breastfeeding women treated with PALYNZIQ

Pediatric Use

  • The safety and efficacy of PALYNZIQ in pediatric patients have not been established

Geriatric Use

  • Clinical studies of PALYNZIQ did not include patients aged 65 years and older

You are encouraged to report suspected adverse reactions to BioMarin at 1-877-695-8826 and the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information, including Boxed Warning, at PALYNZIQ.com/hcp.

US/PAL/0442 0619

US/PAL/0490 0819

US/PAL/0491 0819

US/PAL/0642 0220

US/PAL/0705 0320

USPAL0671 0320

USPAL0770 0820

US-PAL-00005 0121

INDICATION

PALYNZIQ® (pegvaliase-pqpz) Injection is a phenylalanine-metabolizing enzyme indicated to reduce blood phenylalanine concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations greater than 600 µmol/L on existing management.