PURPOSE:To report interim results from the ongoing, open-label, phase 3 APHENITY Extension Study (NCT05166161), evaluating long-term treatment with sepiapterin in patients with phenylketonuria. METHODS:Participants received an age-based dose of oral sepiapterin daily; those with mean blood phenylalanine (Phe) levels <360 μmol/L (<5.95 mg/dL) after 2 weeks underwent a 26-week dietary Phe tolerance assessment, wherein dietary Phe intake was adjusted and blood Phe levels monitored. Other participants continued treatment with optional diet liberalization. Primary endpoints included change from baseline to week 26 in dietary Phe intake and treatment-emergent adverse events (TEAEs). RESULTS:As of September 2, 2024, 169 participants received sepiapterin (median [minimum, maximum] age: 14.0 [0.2, 55.0] years, median exposure: 72.9 weeks); 102 participants underwent dietary Phe tolerance assessments. Mean (SD) dietary Phe intake increased from 27.6 (18.0) mg/kg/day at baseline to 62.5 (41.5) mg/kg/day at week 26 (least-squares mean change [SE]: 36.4 [2.8] mg/kg/day from baseline) (P < .0001 from post hoc analysis). The incidence of treatment-related TEAEs was 29.0%; 3 participants (1.8%) discontinued treatment owing to treatment-related TEAEs. There were no treatment-related serious TEAEs or deaths. CONCLUSION:Interim results support the long-term safety of sepiapterin and demonstrate the potential for diet liberalization in adults and children with phenylketonuria. CLINICALTRIALS: GOV IDENTIFIER:NCT05166161 (https://www. CLINICALTRIALS:gov/study/NCT05166161; date of registration, December 8, 2021).

Objective To provide key considerations and best practices for restarting pegvaliase based on real-world experiences of healthcare professionals managing individuals with phenylketonuria (PKU). Methods An in-person advisory board with 11 experienced PKU practitioners identified strategies for restarting pegvaliase after a treatment pause. The advisors presented real-world restart cases detailing treatment history, reasons for discontinuation, restart approach, and outcomes, followed by discussions about best practices for clinical decision-making. Results Among 11 restart cases, reasons for treatment discontinuation included adverse events (AEs) (3 cases), limited blood phenylalanine (Phe) response (4 cases), clinical trial participation (1 case), and pregnancy (3 cases). Time off treatment ranged from 3 to 64 months. Eight cases restarted pegvaliase with an expedited titration schedule, while 2 cases resumed with a slowed approach and 1 case used the standard titration. At the time of the advisory board, 9 cases had achieved blood Phe ≤360 μmol/L, 1 case still had elevated blood Phe levels but had not yet completed titration and 1 case discontinued after 18 months on therapy.Key considerations for restarting pegvaliase after AE-related discontinuations include proactively addressing anxiety, optimizing premedications, ensuring access to on-demand medications and using a flexible, individualized titration approach. For individuals discontinuing primarily due to a limited blood Phe response, resuming at the previously tolerated dose and titrating adaptively as tolerated may be considered. For individuals desiring an expedited titration, more frequent blood Phe monitoring may be warranted to guide dietary adjustments and dosing. Life changes, individual preferences and social determinants of health should inform timing and resources for restart. For pregnancy-related discontinuations restart decisions should be made collaboratively with the individual and care team (geneticist, metabolic dietitian, obstetrician, and other relevant caregivers). Conclusion Pegvaliase can help achieve blood Phe control, which may mitigate neurocognitive effects and can result in greater dietary flexibility and improved quality of life. Restarting pegvaliase is feasible for most individuals, with many having a better experience during the restart process compared with the first treatment initiation. AEs were reported (eg, injection site reactions, rash, and arthralgia) but were milder compared to the previous treatment course in most cases and some individuals responded at lower doses or after shorter treatment duration. Restarting pegvaliase should be considered as part of a shared decision-making process for individuals seeking to further optimize outcomes.

Introduction The approval of pegvaliase (PALYNZIQ®) represented a paradigm shift in the management of phenylketonuria (PKU) by enabling sustained reductions in blood phenylalanine levels and permitting an unrestricted diet. However, as it is a bacterially derived injectable therapy, individuals receiving pegvaliase may experience skin-related adverse events (AEs). Anticipating these AEs and other pegvaliase-related skin concerns and having best-practice strategies to manage them may be crucial to achieving optimal patient outcomes. Methods An expert panel comprising eight clinicians from the USA and Europe convened to develop best practice recommendations for managing pegvaliase-associated skin concerns. Employing a modified Delphi process, the panel generated 39 initial statements based on their clinical insights and results of a targeted literature review. These statements were refined over two phases of anonymous voting using a 10-point scale, with consensus predefined as ≥75% of panellists rating a statement ≥7. Results The Delphi process resulted in 18 consensus statements. These were organized into three themes: patient-centric recommendations/considerations; considerations for premedications and concomitant medications; and recommendations for monitoring. Key recommendations included comprehensive patient education to overcome needle phobia and promote self-injection; training on injection technique and rotation to reduce scar tissue formation; and the proactive use of premedications and as-needed concomitant medications to mitigate skin reactions. Recommendations also emphasize the importance of regular in-person follow-up to assess injection sites and monitor for scar tissue. Mean agreement scores ranged from 8.5 to 10, reflecting robust consensus among panel members. Conclusions These internationally relevant, evidence-based recommendations provide a structured framework for managing pegvaliase-related skin concerns. Adoption of this guidance may enhance treatment adherence, mitigate adverse events, and ultimately improve patient outcomes.

Background: Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy historically characterized by seizures that are resistant to antiseizure medications. Treatment with pyridoxine and lysine reduction therapies are associated with seizure control and improved developmental outcomes. In rare circumstances, patients have died prior to diagnosis and treatment with pyridoxine, and many patients are diagnosed after six months of age when lysine reduction therapies have limited efficacy. Recently two new metabolites were identified (2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid, 2-OPP and 6-oxo-pipecolate, 6-oxo-pip), and we evaluated these metabolites as potential newborn screening biomarkers. Methods: We recruited participants with a confirmed diagnosis of PDE-ALDH7A1 and retrieved their residual dried blood spots from state-sponsored newborn screening programs. We evaluated the dried blood spots for 2OPP using commercially available newborn screening kits and equipment, and developed a second-tier test for 6oxo-pip using LC-MS/MS. Results: We received eight residual dried blood spots collected before the onset of seizures and the diagnosis of PDE-ALDH7A1. In our newborn screening experiments, 2-OPP was elevated in 7 of 8 samples from affected participants with a mean of 3.08 mu mol/L (95 % CI 2.17-3.99) compared to a mean of 0.09 mu mol/L (95 % CI 0.09-0.10) in controls (p < 0.001). Second tier testing demonstrated elevated 6-oxo-pip in all samples from affected participants with a mean of 5.66 mu mol/L (95 % CI 1.51-9.81) and was undetectable in controls (p < 0.001). Conclusion: Patients with PDE-ALDH7A1 can be identified using neonatal dried blood spots prior to the onset of symptoms. The use of commercially available newborn screening approaches demonstrates the feasibility of newborn screening for this treatable condition.

PURPOSE:Because the standard-of-care treatment for classical homocystinuria (HCU) often cannot achieve adequate metabolic control, the phase 1/2 COMPOSE trial (NCT03406611) evaluated pegtibatinase enzyme replacement therapy. METHODS:Participants with HCU aged 12 to 65 years with elevated total plasma homocysteine (tHcy) receiving standard-of-care treatment were randomized 3:1 into 6 increasing dose cohorts (each n ≈ 4) of subcutaneous pegtibatinase (≤2.5 mg/kg twice weekly [BIW]) or placebo. Primary end points included adverse event incidence and immunogenicity. Secondary end points included tHcy change from baseline to posttreatment (geometric mean of weeks 6-12). RESULTS:Overall, 24 participants were enrolled. Pegtibatinase was generally well tolerated at all doses with no anaphylaxis or severe immune reactions; 15 participants (62.5%) experienced ≥1 treatment-related treatment-emergent adverse event (most commonly injection-site reactions; 1 serious [acute urticaria]). At the 2 highest doses, substantial tHcy reductions were observed after treatment (relative reduction: 57% for 1.5 mg/kg BIW; 67% for 2.5 mg/kg BIW), and all participants maintained tHcy < 100 μM. One participant receiving 2.5 mg/kg BIW achieved tHcy < 15 μM (normal) and methionine < 14 μM (below normal), enabling increased dietary intact protein intake. Changes in other metabolites aligned with tHcy. CONCLUSION:Pegtibatinase was generally well tolerated and substantially reduced tHcy levels, demonstrating potential as a treatment for HCU.

The NIH Rare Disease Clinical Research Network is designed to further research into rare diseases. The primary goals of PHEFREE (Phenylalanine Families and Researchers Exploring Evidence) are to assess biomarkers, neurocognitive functioning (including validating the NIH Toolbox), bone health and growth outcomes in patients with hyperphenylalaninemia due to phenylalanine (Phe) hydroxylase deficiency, biopterin synthesis/recycling disorders, and DNAJC12 deficiency. Additional projects will compare two methods of assessing total body Phe clearance using 13C-breath test testing.

Over fifty years have passed since the last large scale longitudinal study of individuals with PAH deficiency in the U.S. Since then, there have been significant changes in terms of treatment recommendations as well as treatment options. The Phenylalanine Families and Researchers Exploring Evidence (PHEFREE) Consortium was recently established to collect a more up-to-date and extensive longitudinal natural history in individuals with phenylketonuria across the lifespan. In the present paper, we describe the structure and methods of the PHEFREE longitudinal study protocol and report cross-sectional data from an initial sample of 73 individuals (5 months to 54 years of age) with PAH deficiency who have enrolled. Looking forward, the study holds the promise for advancing the field on several fronts including the validation of novel neurocognitive tools for assessment in individuals with PKU as well as evaluation of the long-term effects of changes in metabolic control (e.g., effects of Phe-lowering therapies) on outcome.

To evaluate the pharmacodynamic effects and clinical outcomes of orally administered once-daily govorestat (AT-007), a central nervous system penetrant aldose reductase inhibitor, the double-blind placebo-controlled ACTION-Galactosemia Kids study (NCT04902781) randomly assigned 47 participants (2-17 years old) with Classic Galactosemia to 18 months of govorestat or placebo (2:1) treatment. Mean change in galactitol was compared between the treatment groups at each post-baseline timepoint using a t-test, with a mixed model for repeated measures (MMRM) analysis as a sensitivity analysis. Changes from baseline in clinical outcomes were compared between treatment groups also using a t-test with two different MMRM models as sensitivity models, one including baseline clinical outcome score. The pharmacodynamic effect of govorestat was assessed by correlating galactitol level at 3 months with change from baseline in clinical measures at 18 months using a Pearson correlation. Govorestat treatment resulted in a rapid and sustained reduction in plasma galactitol. Govorestat treatment stabilized or improved clinical measures of behavior, daily living skills, adaptive skills, cognition, tremor, and fine motor skills, which declined over time in the placebo group. Govorestat treatment did not demonstrate a benefit compared with placebo on speech outcomes or gross motor skills, which improved in both treatment groups over 18 months. Govorestat was safe and well tolerated, with adverse events well balanced between the active and placebo groups. Aldose reductase inhibition with govorestat represents a potential opportunity to lower galactitol and improve clinical outcomes in children with Classic Galactosemia.

Introduction: Before the COVID-19 public health emergency, few genetics providers used telehealth. As a response to this, many genetics providers began conducting telehealth care, referred to as telegenetics, usually with guidance from their institutions but without specific guidance related to the uniqueness of genetic services.Objectives: The Telegenetics Workgroup of the National Coordinating Center for Regional Genetics Networks convened a panel of experts in the fields of telemedicine, genetics, and genomics to review the existing literature on telegenetics and synthesize best operating practices for medical geneticists, genetic counselors, and metabolic dietitians providing telegenetics services.Methods: The group searched PubMed using the terms "telegenetics," "telemedicine + genetics," and "telehealth + genetics." The group also reviewed the Northeast Telehealth Resource Center's telegenetics webliography. Websites were searched, including the American Telemedicine Association's website, Center for Connected Health Policy, and National Telehealth Resource Center for position statements, standards documents, and guidelines. The group met frequently by videoconference and discussed the literature, and using expert consensus, the group determined best practices in providing telegenetics services.Results: These telegenetics best practices cover important aspects of telegenetics services, including, but not limited to, ongoing delivery of telegenetics services, use of special technology, legal and regulatory requirements, and considerations regarding special settings and circumstances in which telegenetics may be conducted.Conclusions: Recognizing the growing use of telegenetics and a future in which telegenetics continues to be part of the regular practice of genetics, this guide informs genetics providers of best practices for delivering telegenetics services to patients.

Phenylketonuria (PKU) is a genetic disorder caused by deficiency of the enzyme phenylalanine hydroxylase (PAH), which results in phenylalanine (Phe) accumulation in the blood and brain, and requires lifelong treatment to keep blood Phe in a safe range. Pegvaliase is an enzyme-substitution therapy approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 mu mol/L) despite prior management. Aggregated results from the PRISM clinical trials demonstrated substantial and sustained reductions in blood Phe with a manageable safety profile, but also noted individual variation in time to and dose needed for a first response. This analysis reports longer -term aggregate findings and characterizes individual participant responses to pegvaliase using final data from the randomized trials PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862), and the openlabel extension study 165-304 (NCT03694353). In 261 adult participants with a mean of 36.6 months of pegvaliase treatment, 71.3%, 65.1%, and 59.4% achieved clinically significant blood Phe levels of <= 600, <= 360, and <= 120 mu mol/L, respectively. Some participants achieved blood Phe reductions with <20 mg/day pegvaliase, although most required higher doses. Based on Kaplan -Meier analysis, median (minimum, maximum) time to first achievement of a blood Phe threshold of <= 600, <= 360, or <= 120 mol/L was 4.4 (0.0, 54.0), 8.0 (0.0, 57.0), and 11.6 (0.0, 66.0) months, respectively. Once achieved, blood Phe levels remained below clinical threshold in most participants. Sustained Phe response (SPR), a new method described within for measuring durability of blood Phe response, was achieved by 85.5%, 84.7%, and 78.1% of blood Phe responders at blood Phe thresholds of <= 600, <= 360, or <= 120 mu mol/L, respectively. Longer -term safety data were consistent with previous reports, with the most common adverse events (AEs) being arthralgia, injection site reactions, headache, and injection site erythema. The incidence of most AEs, including hypersensitivity AEs, was higher during the early treatment phase (<= 6 months) than later during treatment. In conclusion, using data from three key pegvaliase clinical trials, participants treated with pegvaliase were able to reach clinically significant blood Phe reductions to clinical thresholds of <= 600, <= 360, or <= 120 mu mol/L during early treatment, with safety profiles improving from early to sustained treatment. This study also supports the use of participant -level data and new ways of looking at durable blood Phe responses to better characterize patients' individual PKU treatment journeys.