Palynziq (pegvaliase-pqpz) / BioMarin - LARVOL DELTA

GSC002874, a highly potent inhibitor of SLC6A19, for treatment of phenylketonuria (ENDO 2025) - "For the classic PKU cohort accounting for over 60 percent of cases, the only approved drug is pegvaliase; however, it is associated with inconvenient dosing and side effects...In an PAH pR408W PKU mouse model with its mouse SLC6A19 replaced by human orthologue, GSC002874 significant decreased phenylalanine level in plasma at lower dosage that of JNT-517...GSC002874 also displayed good safety window in 14-day toxicology study in rats. GSC002874 is under active IND-enabling studies and expected to enter clinic in early 2026."

Genetic Disorders • Metabolic Disorders • Phenylketonuria • Rare Diseases • SLC6A19

GSC002874, a highly potent inhibitor of SLC6A19, for treatment of phenylketonuria (ENDO 2025) - "For the classic PKU cohort accounting for over 60 percent of cases, the only approved drug is pegvaliase; however, it is associated with inconvenient dosing and side effects...In an PAH pR408W PKU mouse model with its mouse SLC6A19 replaced by human orthologue, GSC002874 significant decreased phenylalanine level in plasma at lower dosage that of JNT-517...GSC002874 also displayed good safety window in 14-day toxicology study in rats. GSC002874 is under active IND-enabling studies and expected to enter clinic in early 2026."

Genetic Disorders • Metabolic Disorders • Phenylketonuria • Rare Diseases • SLC6A19

Long-term management strategies for pegvaliase use in phenylketonuria: Lessons learned from the phase 3 PRISM open-label extension study. (PubMed, Genet Med) - P3 | "These analyses establish how tolerization presents clinically and suggest a staged therapeutic approach: (1) tolerance induction; (2) diet liberalization; (3) gradual dose adjustment."

Journal • P3 data • CNS Disorders • Developmental Disorders • Mental Retardation • Metabolic Disorders • Phenylketonuria • Psychiatry • Rare Diseases

Considerations for Health Economic Modeling in Phenylketonuria (PKU): Insights From a Modified Delphi Panel (ISPOR 2025) - "In Round 2, consensus was reached on 6/10 questions, including on age ranges when Phe levels are typically maintained, safety of Phe 30-120 µmol/L with sufficient protein intake, mechanisms underlying the association between PKU and chronic comorbidities, possibility of dietary-Phe tolerance challenges at Phe 240-299 µmol/L, and possibility of resuming pegvaliase after discontinuation... Findings from this study could inform future CEAs in PKU by establishing expert consensus on outcomes to include, as well as clinically-accurate modeling of such outcomes. These insights address the limitations in previous CEAs of PKU treatments."

HEOR • Developmental Disorders • Mental Retardation • Metabolic Disorders • Phenylketonuria • Rare Diseases

Blood Phenylalanine (Phe) Levels in Individuals With Phenylketonuria (PKU): A United States Electronic Health Records (US EHR) and Medical Notes Study (ISPOR 2025) - "Sapropterin was discontinued in 44% (79/181) and pegvaliase discontinued in 38% (16/42) of individuals... This study demonstrated that individuals with PKU continued to have Phe levels above target therapeutic range despite receipt of current diet and pharmacological therapies; elevated blood Phe was reported more frequently as age increased. Moreover, high rates of discontinuing pharmacologic treatment were observed. These findings highlight that novel PKU therapies are crucial to control Phe levels and address unmet needs."

Clinical • Metabolic Disorders • Phenylketonuria • Rare Diseases

Evaluating adverse events of pegvaliase-pqpz in phenylketonuria treatment: A comprehensive safety assessment. (PubMed, SAGE Open Med) - "Weibull distribution analysis revealed that the incidence of adverse events decreased over time. Our study provides a deeper insight into the safety profile of pegvaliase-pqpz, thereby aiding healthcare professionals in clinical surveillance and risk identification."

Adverse events • Journal • Metabolic Disorders • Musculoskeletal Pain • Phenylketonuria • Rare Diseases

Sepiapterin for the treatment of phenylketonuria. (PubMed, Expert Opin Pharmacother) - "We discuss the role of tetrahydrobiopterin (BH4), an essential PAH cofactor in Phe metabolism, describe the pharmacodynamics, pharmacokinetics, and metabolism of sepiapterin, as well as reporting on the efficacy and safety of sepiapterin in children and adults with PKU...The reductions in blood Phe observed with sepiapterin in the phase III APHENITY trial has the potential to allow more PKU patients to attain Phe treatment targets or alternatively easing of the onerous dietary Phe restrictions. Results of longer-term studies of in patients with PKU, including neurocognitive and functional outcomes, nutritional status, and quality of life are awaited."

Journal • Review • Metabolic Disorders • Phenylketonuria • Rare Diseases

BioMarin Announces Positive Pivotal Data for PALYNZIQ (pegvaliase-pqpz) in Adolescents with Phenylketonuria (PRNewswire) - P3 | N=55 | PEGASUS (NCT06037148) | Sponsor: BioMarin Pharmaceutical | "BioMarin Pharmaceutical ...today announced that the Phase 3 PEGASUS trial evaluating PALYNZIQ (pegvaliase-pqpz) met its primary efficacy endpoint, demonstrating a statistically significant lowering in blood Phe levels in adolescents aged 12-17 with phenylketonuria (PKU) compared to diet alone. Safety results were consistent with the known profile of the medicine. PALYNZIQ is the first and only enzyme therapy approved to treat adults with PKU....Detailed results from the PEGASUS study will be presented at an upcoming medical meeting and submitted to global health authorities starting later this year to request a label expansion for PALYNZIQ to include adolescents."

Filing • P3 data • Phenylketonuria

Our lives with PKU: German patient voices - "Nothing about us without us". (PubMed, Mol Genet Metab Rep) - "To further support adults in reaching target blood Phe concentrations and personal goals, pegvaliase can be offered to those eligible. Finally, exchanging experiences with others from the PKU community through social media and live/virtual meetings may help individuals with PKU and caregivers to improve their knowledge and skills to manage PKU. These consensus statements provide unique insights on how challenges faced by individuals with PKU may be addressed and may provide guidance to HCPs as well as the PKU community and caregivers on ways to improve patient care and support."

Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases

Pegvaliase therapy for phenylketonuria: Real-world safety, efficacy, and medication access outcomes in a pharmacist-led pegvaliase program. (PubMed, Genet Med) - "Pegvaliase effectively reduced phenylalanine levels in PKU patients, though carried significant risks of anaphylaxis and other adverse events. A pharmacist-led program and interdisciplinary collaboration was crucial for prompt access and effective management."

Journal • Real-world evidence • Metabolic Disorders • Musculoskeletal Pain • Phenylketonuria • Rare Diseases

Genotype-Phenotype Correlation in a Large Cohort of Eastern Sicilian Patients Affected by Phenylketonuria: Newborn Screening Program, Clinical Features, and Follow-Up. (PubMed, Nutrients) - "Regular assessment of Phe/Tyr ratios is crucial for monitoring adherence and health. Phenotype determination, dietary management, and emerging therapies (Pegvaliase and gene therapy) are key to improving outcomes for PKU patients."

Journal • Retrospective data • Gene Therapies • Metabolic Disorders • Phenylketonuria • Rare Diseases

PALLADIUM: Rapid Drug Desensitization Study in Adults Experiencing Hypersensitivity Reactions to Palynziq (clinicaltrials.gov) - P4 | N=10 | Recruiting | Sponsor: BioMarin Pharmaceutical

New P4 trial • Immunology • Metabolic Disorders • Phenylketonuria • Rare Diseases

Lessons learned from 5 years of pegvaliase in US clinics: A case series. (PubMed, Mol Genet Metab Rep) - "These cases demonstrate that, through comprehensive assessment and addressing barriers, pegvaliase treatment can be successful in adults with PKU, regardless of prior treatment success, age, socioeconomic, cognitive, or executive function challenges, as well as in those with comorbidities or considering pregnancy. Ongoing documentation of clinical experience is crucial for advancing the management of individuals receiving this treatment."

Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases

Phenylalanine hydroxylase deficiency diagnosis and management: A 2023 evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). (PubMed, Genet Med) - "We strongly recommend lifelong maintenance of Phe ≤360 μmol/L (using plasma or whole blood) for optimal intellectual outcomes and for reduced teratogenicity, utilizing all available and necessary dietary, pharmaceutical, and patient-educational modalities."

Clinical guideline • Journal • Metabolic Disorders • Phenylketonuria

Challenges in Health-Economic Modeling of Phenylketonuria (PKU): A Targeted Review of HTA Evaluations (ISPOR-EU 2024) - "Varied cost-effectiveness analysis (CEA) approaches for health technology assessment (HTA) have been used for two regulatory-approved treatments, sapropterin dihydrochloride and pegvaliase... Across the 10 PKU HTA CEAs reviewed, the clinical condition was not appropriately captured; future models will need to address clinical accuracy. The challenges identified are common fundamental challenges in health-economic modeling of rare diseases."

HEOR • Review • CNS Disorders • Cognitive Disorders • Developmental Disorders • Metabolic Disorders • Pediatrics • Phenylketonuria • Rare Diseases

Nutritional Counseling Promotes Adherence to the Mediterranean Diet and Healthy Eating in Italian Patients Affected by Phenylketonuria and Treated with Pegvaliase. (PubMed, Nutrients) - "While more work is necessary to help patients treated with Pegvaliase to progress toward healthy eating, our study suggests that nutritional counseling routinely performed during inpatient visits, typically twice a year, effectively promotes healthier eating habits than those observed in the general population."

Adherence • Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases

Pegvaliase treatment normalizes blood neurotransmitter metabolites in adults with phenylketonuria. (PubMed, Mol Genet Metab) - P3 | "In participants with longitudinal NTM measurements available at baseline, 12 months, and 24 months (Pegvaliase Subgroup; n = 91), blood NTM levels improved from baseline with pegvaliase treatment at 12 months and 24 months, and median levels were normalized with blood Phe level reductions below 360 μmol/L after 24 months of treatment with pegvaliase, including in participants with blood Phe <30 μmol/L. In conclusion, blood NTM levels correlated with blood Phe levels, and pegvaliase improved blood NTM levels in a large cohort of individuals with PKU."

Journal • CNS Disorders • Gene Therapies • Metabolic Disorders • Phenylketonuria • Psychiatry • Rare Diseases

Effect of enzyme substitution therapy on brain magnetic resonance imaging and cognition in adults with phenylketonuria: A case series of three patients. (PubMed, Eur J Neurol) - "Pegvaliase, a derivative of the phenylalanine ammonia-lyase enzyme, metabolizes phenylalanine to trans-cinnamic acid and ammonia, and is approved by the US Food and Drug Administration and European Medicines Agency for subcutaneous administration in adults with phenylketonuria and blood phenylalanine concentrations > 600 μmol/L...Our results show that all three patients had significantly reduced white matter hyperintensities on brain MRI and improved executive function on neuropsychological assessment, especially on the Paced Auditory Serial Addition Test, which is known to be very sensitive to white matter functioning. To the best of our knowledge, this is the first report of concomitant improvements in cognitive performance and white matter damage after a pharmacological intervention to normalize phenylalanine levels in adults with phenylketonuria consuming an unrestricted diet."

Journal • MRI • Cognitive Disorders • Metabolic Disorders • Phenylketonuria • Rare Diseases

Evaluating the Influence of Social Determinants of Health on Blood Phenylalanine Levels in Phenylketonuria Patients. (PubMed, Am J Med Genet A) - "Age interacted separately with sex assigned at birth, pegvaliase use, total Phe samples submitted, and the presence of genetic testing to significantly influence the average Phe level. This study highlights the multifactorial influences on PKU management and underscores the importance of social resources, such as clinic social workers and state-provided formula, in modulating the effects of SDOH on PKU control. Further research in different healthcare settings is needed to understand the social determinants affecting PKU patients comprehensively, which will strengthen advocacy efforts for this population."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Mental Retardation • Metabolic Disorders • Phenylketonuria • Rare Diseases

Perspectives and Insights Into Phenylketonuria: Patient Narratives About the Early Years Following Newborn Screening. (PubMed, Am J Med Genet C Semin Med Genet) - "We present narratives by people living with PKU during these years, including individuals actively following in PKU clinic and those who have been out of PKU clinic for many years. These stories describe different individual experiences, including diet discontinuation in childhood, changing treatment guidelines, and new treatments that have become available."

Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases

PHASE 1/2 OPEN-LABEL STUDY DESIGN TO EVALUATE SAFETY, TOLERABILITY, AND EFFICACY OF SAR444836, AN AAV-MEDIATED GENE TRANSFER IN PKU PATIENTS (SSIEM 2024) - P1/2 | "Background: Patients with phenylketonuria (PKU) require lifelong treatment with dietary Phenylalanine (Phe) restriction, tetrahydrobiopterin (BH4), and/or PEGylated phenylalanine ammonia lyase (Pegvaliase). Discussion/Conclusion Targeting the unmet need in the treatment of PKU, this innovative trial will investigate whether AAV gene therapy can provide a substantial treatment advantage over existing therapy. NCT number: NCT05972629 Palavras-chave : Phenylketonuria, Safety, Efficacy, Study design, AAV-mediated gene transfer"

Clinical • P1/2 data • Gene Therapies • Metabolic Disorders • Phenylketonuria • Rare Diseases

CHANGES IN PHENYLALANINE FLUCTUATIONS WITH SUSTAINED PEGVALIASE THERAPY (SSIEM 2024) - "Phe variability decreased with sustained Pegvaliase therapy. Future studies may explore how Phe fluctuations beyond one year of pegvaliase treatment affect neurocognitive outcomes."

Metabolic Disorders • Phenylketonuria • Rare Diseases

UPDATE FROM THE PHENYLALANINE FAMILIES AND RESEARCHERS EXPLORING EVIDENCE (PHEFREE) CONSORTIUM: A RARE DISEASE CONSORTIUM DEDICATED TO THE STUDY OF HYPERPHENYLALANINEMIA (SSIEM 2024) - "16% of participants were on pegvaliase and 39% taking sapropterin... Preliminary cross-sectional assessment of participants with PAH deficiency reveal persistent deficits in attention and fluid cognition despite early therapy. Further longitudinal assessment will be necessary to define the persistence and clinical meaningfulness of these deficits. Recruitment of further individuals with biopterin synthesis/recycling or DNAJC12 deficiency and to expand the racial and ethnic diversity of the study cohort will be sought."

CNS Disorders • Depression • Genetic Disorders • Metabolic Disorders • Mood Disorders • Phenylketonuria • Psychiatry • Rare Diseases • DNAJC12

C3/C4 AS MARKERS OF TREATMENT TREND DURING PEGVALIASE ADMINISTRATION IN PKU PATIENTS. (SSIEM 2024) - "C3/C4 serum monitoring (easy feasible in clinical practice) was successfully used as predictor of patient's response to pegvaliase. Decreases in C3/C4 levels were used as indirect signs of complement activation, therefore of a still sustained immune response to the drug. To have available markers to monitor drug response, independently of the phenylalanine levels, provided us of a consistent element on which to base the choices of increasing/reducing the pharmacological dosage, while allowed patients to be aware of their progress with the drug even if still on same Phe levels."

Clinical • Metabolic Disorders • Phenylketonuria • Rare Diseases

Pegvaliase-induced immediate hypersensitivity reaction after the discontinuation of antihistamine therapy in a patient with phenylketonuria - Case report. (PubMed, Mol Genet Metab Rep) - "HAEs could be successfully mitigated by scheduling daily antihistamines administration closer to the pegvaliase injection. This approach can enable PKU patients to maintain their access to an effective and quality-of-life-improving therapy."

Journal • Immunology • Metabolic Disorders • Phenylketonuria • Rare Diseases