BioMarin: Positive Phase 3 PALYNZIQ® Data in Adolescents with PKU Presented at ICIEM 2024

New data from Phase 3 PEGASUS study demonstrates a 49.7% decrease in mean blood Phe levels in adolescents aged 12-17 treated with PALYNZIQ

BioMarin’s planned submission to global health authorities on track for second half of 2025

SAN RAFAEL, Calif., Sept. 6, 2025 /PRNewswire/ — BioMarin Pharmaceutical Inc. (Nasdaq: BMRN) announced today at the 15th International Congress of Inborn Errors of Metabolism (ICIEM) in Kyoto, Japan, new data highlighting the significant efficacy and safety of PALYNZIQ^® (pegvaliase-pqpz) in treating adolescents with phenylketonuria (PKU). The findings, presented between Sept. 2-6, 2025, offer a promising outlook for expanding the treatment options for this patient population.

The Phase 3 PEGASUS study rigorously evaluated PALYNZIQ’s effectiveness and safety profile in adolescents aged 12-17. The results showcased a statistically significant reduction in blood phenylalanine (Phe) levels compared to those managed solely through dietary restrictions. The study included 55 adolescents, randomly assigned to either PALYNZIQ (n=36) or diet alone (n=19). The baseline characteristics revealed an average age of 14.3 years and a mean blood Phe level of 1026.4 µmol/L, with nearly half (49.1%) exhibiting Phe levels exceeding 1000 µmol/L.

After the 72-week primary treatment phase, a notable proportion of participants in the PALYNZIQ arm (n=14; 45.2%) achieved substantial blood Phe reductions of 50% or greater from their initial levels. Importantly, many of these patients reached guideline-recommended and even normal Phe target levels. This suggests a potential for improved long-term health outcomes and a reduced risk of neurological complications associated with elevated Phe levels.

Table 1. Primary and Secondary Efficacy Results After 72 Weeks

The safety profile observed in the adolescent participants mirrored the established safety profile in adult patients. AEs were generally manageable and the incidence of serious AEs (anaphylaxis) leading to trial discontinuation stood at 5.6%. The ongoing extension phase of the PEGASUS trial aims to provide further insights into the long-term efficacy and safety of PALYNZIQ in adolescents.

“The PEGASUS study results highlight PALYNZIQ’s potential to significantly alleviate the burden of PKU for adolescents, a particularly crucial period as they transition into adulthood,” stated Greg Friberg, M.D., Executive Vice President and Chief Research & Development Officer at BioMarin. “We are committed to advancing the scientific understanding and treatment of PKU, and we are eager to present these findings to global regulators, with the ultimate goal of making PALYNZIQ’s demonstrable efficacy accessible to an even wider population of individuals living with PKU.” The company expects to submit this data to global health authorities in the second half of 2025.

PALYNZIQ represents a paradigm shift in PKU treatment as the first and only enzyme substitution therapy approved for adults with the condition. The drug’s mechanism involves substituting the deficient phenylalanine hydroxylase (PAH) enzyme with a PEGylated version of phenylalanine ammonia lyase, facilitating the breakdown of Phe.

Key presentations related to BioMarin and PALYNZIQ at ICIEM (all times Japan Standard Time):

Neuropsychiatric Comorbidities in Adults with PKU in Sweden
Oral #3
Wednesday, Sept. 3, 2025, 11 a.m. – 12:30 p.m.

Safety and Efficacy of Pegvaliase in Adolescents with Phenylketonuria: Primary Results from PEGASUS, a Phase 3, Open-Label Randomized Controlled Study 
Oral #21
Friday, Sept. 5, 2025, 10:15 – 11:45 a.m.

Lifetime Monitoring of Phe Levels in PKU from Birth to Adulthood in the Swedish Registry for Inherited Metabolic Diseases
Poster #P-593 
Wednesday, Sept. 3, 2025, 6 – 7 p.m.

Work Ability in Adults with PKU in Sweden in 2020
Poster #P-594
Wednesday, Sept. 3, 2025, 6 – 7 p.m.

Neuropsychiatric Comorbidities in Adolescents with PKU in the United States
Poster #P-595
Wednesday, Sept. 3, 2025, 6 – 7 p.m.

PALLADIUM: A Phase 4 Study to Evaluate a Rapid Drug Desensitization Protocol for Adults with Phenylketonuria Experiencing Hypersensitivity Reactions to Pegvaliase
Poster #P-586
Thursday, Sept. 4, 2025, 5:30 – 6:30 p.m.

Real-World Safety and Tolerability of Pegvaliase: A Non-Interventional Surveillance Study in Japan
Poster #P-584 
Thursday, Sept. 4, 2025, 5:30 – 6:30 p.m.

About PEGASUS

PEGASUS is a Phase 3 multi-center open-label randomized controlled study evaluating the efficacy and safety of PALYNZIQ compared to diet alone in 55 adolescents aged 12-17 with phenylketonuria. The primary endpoints are change in blood Phe concentration and characterization of the safety profile in adolescents. Secondary endpoints include change in total dietary protein intake and pharmacokinetics.

The study is being conducted in two parts: the primary treatment phase ranging from weeks 1-73 (Part 1), and the extension phase (Part 2), which lasts for up to an additional 80 weeks of monitoring for the PALYNZIQ arm and allows for crossover for those in the diet-only arm.

About PALYNZIQ

PALYNZIQ substitutes the deficient phenylalanine hydroxylase (PAH) enzyme in PKU with a PEGylated version of the enzyme phenylalanine ammonia lyase to break down Phe. PALYNZIQ is administered using a dosing regimen designed to facilitate tolerability; PALYNZIQ’s safety profile consists primarily of immune-mediated responses, which can include anaphylaxis, for which robust risk management measures effective in clinical trials are in place.

PALYNZIQ is approved to reduce blood Phe concentrations for adults in the U.S., for people 16 and older in the EU, Canada and Brazil, and for people 15 and older in Japan with PKU who have uncontrolled blood Phe concentrations greater than 600 micromol/L on existing management.

About Phenylketonuria

PKU, or phenylalanine hydroxylase (PAH) deficiency, is a genetic condition affecting approximately 70,000 people in the regions of the world where BioMarin operates. This enzyme is required for the metabolism of Phe, an essential amino acid found in most protein-containing foods. If functional enzyme is not present in sufficient quantities, Phe accumulates to abnormally high levels in the blood and becomes toxic to the brain, resulting in a variety of complications including severe intellectual disability, seizures, tremors, behavioral problems and psychiatric symptoms.

As a result of newborn screening efforts implemented in the 1960s and early 1970s, virtually all individuals with PKU born after this period in countries with newborn screening programs are diagnosed at birth and treatment is implemented soon after.

PKU can be managed with a severe Phe-restricted diet, which is supplemented by low-protein modified foods and Phe-free medical foods; however, it is difficult for most individuals to adhere to the lifelong strict diet to the extent needed to achieve adequate control of blood Phe levels. Dietary control of Phe in childhood can prevent major developmental neurological toxicities, but poor control of Phe in adolescence and adulthood is associated with a range of neurocognitive disabilities with significant functional impact.

PALYNZIQ U.S. Indication and Important Safety Information

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

BOXED WARNING: RISK OF ANAPHYLAXIS

• Anaphylaxis has been reported after administration of PALYNZIQ and may occur at any time during treatment
• 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
• 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 auto-injectable epinephrine, and call for emergency medical support upon its use
• Prescribe auto-injectable epinephrine. 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 PALYNZIQ treatment
• PALYNZIQ is available only through a restricted program called PALYNZIQ REMS (Risk Evaluation and Mitigation Strategy). 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 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 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 PALYNZIQ treatment. Prior to the first dose, instruct the patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer auto-injectable epinephrine, and to seek immediate medical care upon its use. 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 PALYNZIQ dose titration should be based on patient tolerability and therapeutic response
• Consider premedication with an H₁-receptor antagonist, H₂-receptor antagonist, and/or antipyretic prior to PALYNZIQ administration based upon individual patient tolerability

Other Hypersensitivity Reactions

• Hypersensitivity reactions other than anaphylaxis have been reported in 204 of 285 (72%) patients treated with PALYNZIQ in clinical trials
• 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, 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 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)
• Angioedema and serum sickness: 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. In clinical trials, serum sickness was reported in 7 out of 285 (2%) patients

Blood Phenylalanine Monitoring and Diet

• Obtain blood Phe levels every 4 weeks until a maintenance dosage is established. Periodically monitor blood Phe levels during maintenance therapy
• Counsel patients to monitor dietary protein and Phe 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, two patients receiving concomitant injections of medroxyprogesterone acetate suspension (a formulation containing PEG 3350) experienced a hypersensitivity reaction. One of the two patients 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 including anaphylaxis

USE IN SPECIFIC POPULATIONS

Pregnancy and Lactation

• PALYNZIQ may cause fetal harm when administered to a pregnant woman
• Advise women who are exposed to PALYNZIQ during pregnancy or who become pregnant within one month following the last dose of PALYNZIQ that there is a pregnancy surveillance program that monitors pregnancy outcomes. Healthcare providers should report PALYNZIQ exposure and encourage these patients to report their pregnancy to BioMarin (1-866-906-6100)
• Monitor blood Phe levels in breastfeeding women treated with PALYNZIQ

Pediatric Use

• The safety and effectiveness 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 1-866-906-6100, or to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see accompanying full Prescribing Information, including Boxed Warning.

About BioMarin

BioMarin is a global biotechnology company dedicated to translating the promise of genetic discovery into medicines that make a profound impact on the life of each patient. The San Rafael, California-based company, founded in 1997, has a proven track record of innovation with eight commercial therapies and a strong clinical and preclinical pipeline. Using a distinctive approach to drug discovery and development, BioMarin seeks to unleash the full potential of genetic science by pursuing category-defining medicines that offer new possibilities for people living with genetically defined conditions around the world. To learn more, please visit www.biomarin.com.

Forward-Looking Statements

This press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc. (BioMarin), including without limitation, statements about: data from the Phase 3 PEGASUS study presented at the 15th International Congress of Inborn Errors of Metabolism, including the oral and poster presentations; the safety profile and potential benefits of PALYNZIQ for adolescents, including ability to lower blood Phe levels in adolescents aged 12-17 with phenylketonuria (PKU) compared to diet alone; the development of BioMarin’s PALYNZIQ program generally, including plans to submit PEGASUS study to global health authorities during the second half of 2025 to expand the approved indication for PALYNZIQ to include the treatment of adolescents; and the continued clinical development of PALYNZIQ, including BioMarin’s plans to continue to evaluate long-term results of PALYNZIQ treatment for adolescents through the ongoing extension phase of the PEGASUS trial. These forward-looking statements are predictions and involve risks and uncertainties such that actual results may differ materially from these statements. These risks and uncertainties include, among others: results and timing of current and planned preclinical studies and clinical trials of PALYNZIQ; any potential adverse events observed in the continuing monitoring of the patients in the clinical trials; the content and timing of decisions by the U.S. Food and Drug Administration, the European Medicines Agency, the European Commission and other regulatory authorities; and those factors detailed in BioMarin’s filings with the Securities and Exchange Commission, including, without limitation, the factors contained under the caption “Risk Factors” in BioMarin’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2025, as such factors may be updated by any subsequent reports. Investors are urged not to place undue reliance on forward-looking statements, which speak only as of the date hereof. BioMarin is under no obligation, and expressly disclaims any obligation to update or alter any forward-looking statement, whether as a result of new information, future events or otherwise.

BioMarin^®, BioMarin RareConnections^® and PALYNZIQ^® are registered trademarks of BioMarin Pharmaceutical Inc.