Phenylketonuria (PKU)

The primary objective of this clinical trial is to evaluate the safety and tolerability of single and multiple administrations of PL54 in patients aged 18-55 years. The key questions it aims to answer include: How safe and tolerable is PL54 in PKU patients following single and multiple administrations? Researchers will compare the safety and tolerability profiles between single and multiple dosing regimens to assess PL54. Participants will be required to: Phase Ia (Single Administration): Receive a single subcutaneous injection of PL54 based on body weight. Undergo a 28-day observation period post-injection. Visit the clinic for assessments on: D1 (administration day), D2, D7, D8, D10, D15, D22, and D29. Phase Ib (Multiple Administrations): Receive subcutaneous injections of PL54 every 7 days (4 doses total) based on body weight. Undergo a 35-day observation period after the last injection. Visit the clinic for assessments on: D1 (first administration), D3, D8, D15, D21, D22, D29, D36, D43, and D57 Data to be recorded include: Incidence, severity, seriousness, relationship to PL54 treatment, duration, and outcome of adverse events (AEs). Change from baseline in blood phenylalanine (Phe) concentration.

Phenylalanine (Phe) free protein substitutes are typically presented in ready to drink liquid or powder format and are made up with water to a set volume. Despite recent advancements related to the taste, scent and texture of commercially available protein substitutes, a proportion of PKU patients choose to consume tablet-based protein substitutes. Protein substitutes in tablet format may help overcome taste, scent and texture concerns associated with powdered and liquid preparations. Indeed, previous research has shown that protein substitute tablets are an effective strategy to manage PKU in children, teenagers and adults. Nonetheless, the daily burden and discipline required often impedes compliance, especially alongside the restrictive low-protein diet. Achieving compliance with multivitamin supplements when given alongside protein substitutes therefore becomes especially challenging. This is particularly true for adolescent, adult and maternal populations. PKU Microtablets have recently been developed. PKU Microtablets are a new phenylalanine-free tablet protein substitute combined with vitamins, minerals and trace elements. As patient acceptability is fundamental to the successful use of any protein substitute, investigation is needed to assess the compliance, tolerance and acceptability of PKU Microtablets as part of a low phenylalanine dietary regimen in PKU patients. This series of case-studies aims to evaluate the gastrointestinal tolerance, acceptability, compliance, and safety of this protein substitute in both adults and children from 4 years. These case studies will last 29 days in total, including a 1-day baseline period followed by a 28-day intervention period. The case studies will be conducted across multiple specialist metabolic centres in the UK.

The GENOPHEN study aims to explore the links between the genome, metabolomic profile, and clinical phenotype in adults with early-treated PKU.

The goal of this Phase 3, open-label study is to evaluate the long-term safety of JNT-517 in pediatric and adult participants with Phenylketonuria (PKU) after completion of either Study JNT517-101 (NCT05781399) or JNT517-201 (NCT06637514) as well as participants who have not participated in a prior JNT-517 study. In this trial, all participants will receive JNT-517 using age- and weight-banded dosing as outlined in the protocol, regardless of any dose received in a previous study.

This is a 10-year multi-center, global, observational study to further characterize the safety profile of pegvaliase, including hypersensitivity reactions, long-term safety and tolerability, and the effectiveness of the additional risk minimization measures (aRMMs) (European Union (EU) only) in subjects receiving pegvaliase for the treatment of PKU. Subjects for whom a clinical decision has been made that they will receive pegvaliase to treat their PKU within 30 days following the date of enrollment (incident-users) or have previously started treatment with pegvaliase at the date of enrollment (prevalent-users) are eligible for participation in this study.

This is a 10-year multi-center, prospective, longitudinal, single arm study evaluating immunologic, inflammatory and laboratory parameters associated with long-term Palynziq treatment in subjects with phenylketonuria (PKU) in the United States (US). Subjects in the US for whom a clinical decision has been made that they will receive pegvaliase to treat their PKU within 30 days following the date of enrollment in Study 165-501 (incident-users) or who have previously started treatment with pegvaliase at the date of enrollment in Study 165-501 (prevalent-users) are eligible for participation in Study 165-503.

Current recommendations are to maintain Phe levels \< 360 µmol/L throughout life (US consensus) or \< 600 µmol/L from the age of 12 (European consensus). Nevertheless, these recommendations do not take into account the individuality of each PKU patient who, in reality, reacts differently to Phe levels, with some patients with high levels (\> 1200 µmol/L) escaping the neurological consequences of high Phe levels without this being well understood (OJRD 2018; 13: 149. Can untreated PKU patients escape from intellectual disability? A systematic review). It is therefore unclear what blood levels of phenylalanine are required during adolescence and adulthood to maintain an optimal cognitive, emotional and neurophysiological state in individual PKU patients, depending on their personal responsiveness to Phe.

This study is a single-arm, open-label, dose-escalation, exploratory study to evaluate the safety, tolerability, and efficacy of a single administration of GS1168 Injection in Chinese adult phenylketonuria (PKU) with PAH mutation.

Background: Historically, the primary goal in managing phenylketonuria (PKU) has been to prevent severe and irreversible intellectual disability, as well as to address nutritional deficiencies that could lead to growth impairments or intellectual decline. Since the introduction of neonatal PKU screening in the mid-1960s, early treatment during childhood with a low phenylalanine diet or pharmacological interventions have been effective and prevent severe long-term sequelae. However, concerns persist that insufficient treatment during adulthood may cause subtle and, over time, possibly increasing cognitive and brain alterations. Recently, the first generation of early-treated patients has reached mid-adulthood. Hence, there is an urgent need to understand how PKU and metabolic control impact cognitive and brain aging and vice versa. The investigators preliminary cross-sectional findings suggest that brain aging trajectories may diverge significantly between patients with PKU and healthy controls in mid-adulthood. Until now, no comprehensive research has longitudinally tracked brain aging in patients with PKU through MRI markers and their correlation with cognition, metabolic control, and cardiometabolic risk factors. The "brain age" approach enables the identification of individual health characteristics and risk patterns for age-related changes. The evaluation of brain age in addition to the chronological age allows for the development and monitoring of personalized neuroprotective treatments and interventions. Advancing the investigators understanding of disease progression during aging in patients with PKU and identifying strategies for preventing potential harm later in life is of utmost importance for patients' well-being and clinical practice and, through this, follows the WHO's brain health plan. Study aims: This longitudinal study will, for the first time, investigate the trajectory of brain aging relative to chronological aging across early and middle adulthood in individuals with PKU compared to healthy controls. Data collected in the investigators previous SNSF study (Nr 192706; 184453) will serve as baseline data and allow the examination of brain health by means of brain age modeling. The association between brain age trajectories and cognitive performance, metabolic control, and cardiometabolic risk factors will be studied to disentangle risk patterns of accelerated brain aging in patients with a rare disease. Relevance of the study: This study will show whether and how the brain aging trajectory is accelerated in patients with PKU and will determine the functional relevance of brain aging with respect to cognitive performance and metabolic control (i.e., phenylalanine levels). This is one of the first studies to closely examine long-term brain and cognitive changes in PKU during early and mid-adulthood. Its findings could provide valuable insights into the long-term effects of PKU on brain structure and aging processes. Furthermore, the results may support the development of future treatment strategies and improve the quality of life for adults with PKU.