Birmingham Children's Hospital is a specialist children's hospital located in Birmingham, England. The hospital provides a range of specialist services and operates the Child and Adolescent Mental Health Services (CAMHS) for the city. The service operates as part of Birmingham Women's and Children's NHS Foundation Trust, whose CEO is Sarah-Jane Marsh.
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 assess the 2022 American College of Rheumatology (ACR)/EULAR classification criteria for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) in children with chronic small-to-medium vessel vasculitis. METHODS:A cohort of 574 patients, identified by physician's diagnosis (MD-diagnosis) in A Registry of Childhood Vasculitis, was classified by computation of registry data as having granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or eosinophilic GPA after applying (1) ACR/EULAR AAV criteria and (2) pediatric-adapted European Medicines Agency (Ped-EMA) classification algorithm (incorporating Ankara GPA criteria). Venn diagrams compared the resulting GPA and MPA cohorts with MD-diagnosis. Sensitivity and specificity of criteria for GPA were evaluated against MD-diagnosis. Fisher exact test evaluated differences in the frequencies of individual clinical features in GPA versus MPA. RESULTS:Comparing ACR/EULAR criteria against the Ped-EMA algorithm for classifying AAV, more patients were classified as GPA or MPA (n = 396 vs 360, respectively), fewer had GPA (n = 261 vs 288, respectively), more had MPA (n = 135 vs 72, respectively), and fewer GPA cases coclassified as MPA (12% vs 28%, respectively); there were more differences between GPA and MPA in Pediatric Vasculitis Activity Score-defined clinical features (n = 14 vs 10, respectively). When classifying GPA by ACR/EULAR or Ankara criteria, sensitivity (74.5% vs 72.1%, respectively) was comparable, and specificity for ACR/EULAR criteria (93.9% vs 79.9%, respectively) was improved. CONCLUSION:The 2022 ACR/EULAR classification criteria for AAV perform at least as well as previous pediatric criteria and provide categorical MPA criteria where none existed previously; the criteria for GPA and MPA now specifically differentiate each other, with more differences between them in the frequencies of clinical features. Our findings support the preferential use of ACR/EULAR over Ankara criteria for GPA in pediatrics.
Background/Objectives: In Phenylketonuria (PKU), engaging in regular physical activity and exercise (PA/E) is important for physical and psychological health, but additional considerations may be required to facilitate uptake and performance as well as to optimise metabolic control. The aim of this study, therefore, was to investigate the stakeholder perspectives on the barriers, facilitators, and solutions to completing PA/E, sport, and nutrition in PKU. Methods: In total, 7 in-person and 6 online semi-structured focus groups (FGs) were conducted with individuals with PKU (n = 31), caregivers (n = 13), clinicians (n = 17), and medical industry professionals (n = 14) in PKU (n = 75 total participants). Three main questions about the barriers, facilitators, and solutions to performing PA/E with PKU were explored. Identified themes were mapped onto the capability, opportunity, motivation, and behaviour (COM-B) model of behaviour change with anonymous quotes from relevant stakeholders used to illustrate the findings. Results: Five common themes were identified. Most notably, individuals with PKU and their caregivers stated fatigue, poor recovery, low energy, and fear around the impact of exercise on blood phenylalanine (Phe) control were barriers to PA/E. Individuals with PKU were aware of the potential benefits of exercise, stating PA/E impacted positively on their mental well-being, daily functioning, and happiness and improved their self-confidence and long-term health. Identified solutions to PA/E participation included greater knowledge in regard to the impact of PA/E on Phe levels, improvements in advice on amount and supplementation with protein substitutes, tailored PKU nutritional advice, more awareness of PA/E within and outside the PKU community, specific PKU guidelines for PA/E, more scientific research, and PA/E events. Misalignment was evident, such that individuals with PKU reported additional barriers to PA/E, whereas other key stakeholder groups perceived the same barriers as the general public. Conclusions: There seems to be a misalignment between individuals with PKU, caregivers, clinicians, and industry professionals regarding PA/E, sport, and nutrition. Individuals with PKU and caregivers reported additional barriers to undertaking PA/E, sport, and nutrition compared to the general public. This suggests that further education and collaboration is needed through stakeholders to better understand how such barriers could be overcome in respect of PA/E, sport, and nutrition in individuals with PKU.
AIM:AMPLIPHY is the first Phase 3 study comparing sepiapterin versus sapropterin in children and adults with phenylketonuria (PKU). METHODS:AMPLIPHY was an international, Phase 3, two-part, open-label study in participants with PKU aged ≥2 years. Participants responsive to sepiapterin (60 mg/kg/day) in Part 1 (≥20% reduction in blood phenylalanine [Phe]) entered Part 2, a crossover treatment period, and were randomized 1:1 to alternative treatment sequences of sepiapterin (60 mg/kg/day, licensed dosage) and sapropterin (20 mg/kg/day, maximum licensed dosage) for 4 weeks each, with a 14-day washout between treatments. The primary endpoint was mean change in blood Phe from baseline to Weeks 3-4 of each treatment period (Part 2). RESULTS:Of 82 participants enrolled, 67 (81.7%) and 62 (75.6%) had reductions in blood Phe ≥20% and ≥30%, respectively, in Part 1. Sixty-two participants were randomized in Part 2 (mean [SD] age, 15.8 [10.8] years). In the primary analysis set (≥30% reduction in blood Phe in Part 1, n = 58), mean (SD) baseline blood Phe before sepiapterin and sapropterin treatment was 725.8 (302.1) and 790.4 (370.0) μmol/L, respectively. Least-squares mean (SE) reduction in blood Phe from baseline was -437.0 (28.0) and -256.6 (28.2) μmol/L, respectively, representing a least-squares mean difference of -180.4 μmol/L (95% CI: -229.5, -131.4; p < 0.0001) and a relative 70% greater reduction with sepiapterin versus sapropterin. Both treatments were well tolerated, with safety profiles consistent with previous reports. CONCLUSIONS:Sepiapterin was superior to the highest approved dose of sapropterin in lowering blood Phe. No new safety signals were observed. The trial was registered in the UK Clinical Study Registry, ISRCTN, on January 29, 2024 (ID number, ISRCTN79102999; https://www.isrctn.com/ISRCTN79102999).
