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Phenylketonuria is an inherited condition characterised by neurotoxic accumulation of phenylalanine (Phe). APHENITY assessed the efficacy and safety of orally administered synthetic sepiapterin in children and adults with phenylketonuria. APHENITY was a phase 3, randomised, double-blind, placebo-controlled study performed at 34 clinics, hospitals, and university sites in 13 countries. Individuals of all ages with a clinical diagnosis of phenylketonuria were eligible for inclusion if they had a blood Phe concentration of 360 μmol/L or higher at study entry, whereas individuals with hyperphenylalaninaemia due to pathogenic variants in GCH1, PTS, QDPR, SPR, and PCBD1, consistent with a diagnosis of primary BH4 deficiency, were excluded. Part 1 was a 14-day open-label assessment of blood Phe concentration response to sepiapterin. In part 2, sepiapterin-responsive participants were randomly assigned (1:1) by a web-response system based on a block randomisation schedule (permuted block size of 2 and 4) to 6 weeks of sepiapterin (forced-dose escalation: 20, 40, and 60 mg/kg per day per consecutive 2-week period) or placebo. The investigational drug and placebo were identical in their appearance and delivery. Dried blood samples were collected for analysis of Phe concentration on days –1, 1 (before dose was administered), 5, 10, 14, 19, 24, 28, 33, 38, and 42 in part 2, either in-clinic or at home. The primary endpoint for part 2, mean change from baseline in blood Phe after 6 weeks, was assessed in the primary analysis set of participants with at least a 30% reduction in blood Phe concentration in part 1, who took at least one dose in part 2. Safety was evaluated in all participants receiving at least one dose of treatment. The completed study is registered at EudraCT (2021-000474-29) and ClinicalTrials.gov (NCT05099640). APHENITY was conducted between Sept 30, 2021, and April 3, 2023. 187 people were assessed for eligibility, of whom 157 were enrolled. In part 1, 156 participants were assessed or evaluated, of whom 114 (73%) were sepiapterin-responsive (ie, ≥15% reduction in blood Phe from baseline). In part 2, 98 participants (49 in the placebo group and 49 in the sepiapterin group) were in the primary analysis set. There was a significant reduction of blood Phe concentration after 6 weeks of sepiapterin (–63%, SD 20) compared with placebo (1%, 29; least squares mean change –395·9 μmol/L, SE 33·8; p<0·0001). Treatment-emergent adverse events were reported in 33 (59%) of 56 participants who received sepiapterin and 18 (33%) of 54 participants who received placebo. Most treatment-emergent adverse events were mild gastrointestinal events (11 [20%] of 56 participants who received sepiapterin and ten [19%] of 54 participants who received placebo) that resolved quickly. There were no deaths and no serious or severe adverse events. Sepiapterin is a promising oral therapy for individuals with phenylketonuria, was well tolerated, and resulted in significant and clinically meaningful reductions in blood Phe concentration in participants with varying disease severity. PTC Therapeutics.

Background: Phenylketonuria (PKU) is an inherited metabolic disorder that requires early diagnosis and strict phenylalanine (Phe)-restricted diet to prevent neurocognitive impairment. Various infant feeding models have been used to achieve optimal metabolic control during early life. The aim of this study was to compare two different feeding models for infants with classical PKU in terms of metabolic control, growth parameters, micronutrient status, the process of introducing complementary foods, and with a particular focus on sleep quality. Methods: In this prospective observational study, 26 infants with classical PKU were followed for 12 months. Patients were assigned to one of two feeding groups: Group-1 received breast milk and Phe-free formula in alternating feeds, while Group-2 received Phe-free formula followed by breastfeeding until satiety. Blood Phe, micronutrient levels and anthropometric measurements were recorded. Sleep quality was evaluated using the Brief Infant Sleep Questionnaire-Revised (BISQ-R). A structured set of parental questions was used to evaluate their experiences during the complementary feeding period. Results: No statistically significant differences were observed between the groups in terms of blood Phe levels, anthropometric measurements, serum levels of iron, ferritin, vitamin-B12, vitamin-D, and zinc. Complementary feeding tolerance were similar across the groups. The BISQ-R analysis revealed no significant differences between the groups. Conclusions: Both feeding models were equally effective in maintaining metabolic control, supporting normal growth, complementary feeding processes, and preserving sleep quality during infancy. These findings suggest that either approach can be adopted based on the preference of the caregiver and the practicality of the clinical setting.

Phenylketonuria is an inherited metabolic disorder that leads to neurobehavioral dysfunction. The main treatment is a low-phenylalanine diet and/or the cofactor tetrahydrobiopterin. Regular outpatient follow-up care and measurement of the phenylalanine levels in the blood are required. We aimed to analyze the economic burden of phenylketonuria on families and the state. The patients with phenylketonuria were divided into three groups according to their treatment: a low-phenylalanine diet group (n = 50), a tetrahydrobiopterin group (n = 44), and a group taking tetrahydrobiopterin together with the diet (n = 25). A comparative cost analysis was carried out. The annual economic burden to the state was calculated to average EUR 18,801 ± 15,345 and was lowest in the diet group, then in the tetrahydrobiopterin group, and highest in the tetrahydrobiopterin + diet group (p < 0.001). Out-of-pocket costs amounted to EUR 1531 ± 1173 per year, and indirect losses averaged EUR 2125 ± 1930 per year for all families. The economic loss was significantly lower in the families taking tetrahydrobiopterin than in the other groups (p = 0.001). The combined use of medical nutrition and BH4 treatments has been shown to increase the economic burden on the state. Reimbursing low-protein products and increasing the number of patients eligible for financial allowances may reduce the economic burden on families.

Early and strict dietary management of phenylketonuria is the only option to prevent mental retardation. We aimed to test the efficacy of sapropterin, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration. We enrolled 89 patients with phenylketonuria in a Phase III, multicentre, randomised, double-blind, placebo-controlled trial. We randomly assigned 42 patients to receive oral doses of sapropterin (10 mg/kg) and 47 patients to receive placebo, once daily for 6 weeks. The primary endpoint was mean change from baseline in concentration of phenylalanine in blood after 6 weeks. Analysis was on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT00104247. 88 of 89 enrolled patients received at least one dose of study drug, and 87 attended the week 6 visit. Mean age was 20 (SD 9·7) years. At baseline, mean concentration of phenylalanine in blood was 843 (300) μmol/L in patients assigned to receive sapropterin, and 888 (323) μmol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) μmol/L, compared with a 3 (240) μmol/L increase in the placebo group (p<0·0001). After 6 weeks, 18/41 (44%) patients (95% CI 28–60) in the sapropterin group and 4/47 (9%) controls (95% CI 2–20) had a reduction in blood phenylalanine concentration of 30% or greater from baseline. Blood phenylalanine concentrations fell by about 200 μmol/L after 1 week in the sapropterin group and this reduction persisted for the remaining 5 weeks of the study (p<0·0001). 11/47 (23%) patients in the sapropterin group and 8/41 (20%) in the placebo group experienced adverse events that might have been drug-related (p=0·80). Upper respiratory tract infections were the most common disorder. In some patients with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine could be used as an adjunct to a restrictive low-phenylalanine diet, and might even replace the diet in some instances.

The main debate in the treatment of Phenylketonuria (PKU) is whether adult patients need the strict phenylalanine (Phe)-restricted diet. Physicians and patients lack evidence-based guidelines to help them make well-informed choices. We have carried out the first randomised double-blind placebo-controlled trial into the effects of short-term elevation of Phe levels on neuropsychological functions and mood of adults with PKU. Nine continuously treated adults with PKU underwent two 4-week supplementation periods: one with Phe, mimicking normal dietary intake, and one with placebo in randomly allocated order via a randomisation coding list in a double-blind cross-over design. A set of neuropsychological tests (Amsterdam Neuropsychological Tasks) was administered at the end of each study period. In addition, patients and for each patient a friend or relative, completed weekly Profile of Mood States (POMS) questionnaires, evaluating the patients' mood. Phe levels were measured twice weekly. Mean plasma Phe levels were significantly higher during Phe supplementation compared with placebo (p = 0.008). Neuropsychological tests demonstrated an impairment in sustained attention during Phe supplementation (p = 0.029). Both patients and their friend or relative reported lower scores on the POMS questionnaires during Phe supplementation (p = 0.017 and p = 0.040, respectively). High plasma Phe levels have a direct negative effect on both sustained attention and on mood in adult patients with PKU. A Phe-restricted “diet for life” might be an advisable option for many.

Background Sapropterin dihydrochloride, a synthetic formulation of BH 4 , the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH 4 -responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years. Results In total, 109 male or female children <4 years with confirmed BH 4 -responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7–42.3) mg/kg/day higher than in the diet-only group ( p  < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters. Conclusions The addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH 4 -responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients <4 years with BH 4 -responsive phenylketonuria. Trial registration ClinicalTrials.gov, NCT01376908 . Registered June 17, 2011.

In phenylketonuria, casein glycomacropeptide (CGMP) requires modification with the addition of some essential and semi essential amino acids to ensure suitability as a protein substitute. The optimal amount and ratio of additional amino acids is undefined. Aim A longitudinal, parallel, controlled study over 12 months evaluating a CGMP (CGMP-AA2) formulation compared with phenylalanine-free L-amino acid supplements (L-AA) on blood Phe, Tyr, Phe:Tyr ratio, biochemical nutritional status and growth in children with PKU. The CGMP-AA2 contained 36 mg Phe per 20 g protein equivalent. Methods Children with PKU, with a median age of 9.2 y (5-16y) were divided into 2 groups: 29 were given CGMP-AA2, 19 remained on Phe-free L-AA. The CGMP-AA2 formula gradually replaced L-AA, providing blood Phe concentrations were maintained within target range. Median blood Phe, Tyr, Phe:Tyr ratio and anthropometry, were compared within and between the two groups at baseline, 26 and 52 weeks. Nutritional biochemistry was studied at baseline and 26 weeks only. Results At the end of 52 weeks only 48% of subjects were able to completely use CGMP-AA2 as their single source of protein substitute. At 52 weeks CGMP-AA2 provided a median of 75% (30–100) of the total protein substitute with the remainder being given as L-AA. Within the CGMP-AA2 group, blood Phe increased significantly between baseline and 52 weeks: [baseline to 26 weeks; baseline Phe 270 μmol/L (170–430); 26 weeks, Phe 300 μmol/L (125–485) p  = 0.06; baseline to 52 weeks: baseline, Phe 270 μmol/L (170–430), 52 weeks Phe 300 μmol/L (200–490), p  < 0.001)]. However, there were no differences between the CGMP-AA2 and L-AA group for Phe, Tyr, Phe:Tyr ratio or anthropometry at any of the three measured time points. Within the CGMP-AA2 group only weight ( p  = 0.0001) and BMI z scores (p = 0.0001) increased significantly between baseline to 52 weeks. Whole blood and plasma selenium were significantly higher (whole blood selenium [ p  = 0.0002]; plasma selenium [ p  = 0.0007]) at 26 weeks in the CGMP-AA2 group compared L-AA. No differences were observed within the L-AA group for any of the nutritional markers. Conclusions CGMP-AA increases blood Phe concentrations and so it can only be used partly to contribute to protein substitute in some children with PKU. CGMP-AA should be carefully introduced in children with PKU and close monitoring of blood Phe control is essential.

Background The population of adult patients with early-treated phenylketonuria (PKU) following newborn screening is growing substantially. The ideal target range of blood phenylalanine (Phe) levels in adults outside pregnancy is a matter of debate. Therefore, prospective intervention studies are needed to evaluate the effects of an elevated Phe concentration on cognition and structural, functional, and neurometabolic parameters of the brain. Methods The PICO (Phenylalanine and Its Impact on Cognition) Study evaluates the effect of a 4-week Phe load on cognition and cerebral parameters in adults with early-treated PKU in a double-blind, randomized, placebo-controlled, crossover, noninferiority trial. Participants Thirty adult patients with early-treated PKU and 30 healthy controls comparable to patients with regard to age, sex, and educational level will be recruited from the University Hospitals Bern and Zurich, Switzerland. Patients are eligible for the study if they are 18 years of age or older and had PKU diagnosed after a positive newborn screening and were treated with a Phe-restricted diet starting within the first 30 days of life. Intervention: The cross-over intervention consists of 4-week oral Phe or placebo administration in patients with PKU. The study design mimics a Phe-restricted and a Phe-unrestricted diet using a double-blinded, placebo-controlled approach. Objectives The primary objective of the PICO Study is to prospectively assess whether a temporarily elevated Phe level influences cognitive performance (working memory assessed with a n-back task) in adults with early-treated PKU. As a secondary objective, the PICO Study will elucidate the cerebral (fMRI, neural activation during a n-back task; rsfMRI, functional connectivity at rest; DTI, white matter integrity; and ASL, cerebral blood flow) and neurometabolic mechanisms (cerebral Phe level) that accompany changes in Phe concentration. Cognition, and structural and functional parameters of the brain of adult patients with early-treated PKU will be cross-sectionally compared to healthy controls. All assessments will take place at the University Hospital Bern, Switzerland. Randomization Central randomization will be used to assign participants to the different treatment arms with age, sex, and center serving as the stratification factors. Randomization lists will be generated by an independent statistician. Blinding: All trial personnel other than the statistician generating the randomization list and the personnel at the facility preparing the interventional product are blinded to the assigned treatment. Discussion Using a combination of neuropsychological and neuroimaging data, the PICO Study will considerably contribute to improve the currently insufficient level of evidence on how adult patients with early-treated PKU should be managed. Trial registration The study is registered at clinicaltrials.gov ( NCT03788343 ) on the 27th of December 2018, at kofam.ch ( SNCTP000003117 ) on the 17th of December 2018, and on the International Clinical Trials Registry Platform of the WHO.

Background/Objectives: The treatment of phenylketonuria (PKU) requires consistent restriction of protein intake from natural sources. Therefore, protein from all foods has to be accounted for, even the small amounts in fruits and vegetables. We studied whether free consumption of fruits and vegetables containing less than 75 mg phenylalanine (phe) per 100 g affects metabolic control in children with PKU. Subjects/Methods: Fourteen children (2–10 years) were included in a cross-over study, with a two-week period of conventional treatment (accounting for protein from fruits and vegetables) and a two-week period with free fruit and vegetable consumption. The instruction to follow liberal fruit and vegetable consumption in the first or second study period was randomized. Detailed daily dietary records were obtained throughout the study. Phe and nutrient content was calculated. Dried-blood phe concentration was monitored daily. Results: Although total phe intake increased by an average of 58 mg per day ( P =0.037) during the 2 weeks of free fruit and vegetable consumption, dried-blood phe concentrations were unchanged. Total intake of fruits and vegetables did not increase, but patients instead used the higher phe tolerance to consume more of other foods, which were calculated and accounted for. Conclusion: Free consumption of fruits and vegetables does not impair metabolic control in PKU patients over a 2-week period.

Background/Objectives: In phenylketonuria (PKU), high blood phenylalanine (Phe) levels during pregnancy negatively influence foetal organogenesis and growth, leading to maternal PKU syndrome. Pregnancies must be carefully planned in order to maintain blood Phe levels ≤ 360 µmol/L pre-conception and throughout pregnancy. Our aim was to study metabolic control in PKU pregnancies across Europe. Methods: Eleven centres managing PKU participated. Data on blood Phe levels (µmol/L), natural protein intake (g/day), protein substitute intake (g/day) and maternal weight (kg) during pregnancy were collected retrospectively from dietetic records between 2012 and 2018. Results: In total, 84 female patients with PKU, accounting for 102 pregnancies (mean age: 30.4 ± 4.8 years), participated. Of these, 7 had hyperphenylalaninemia (HPA), 26 had mild PKU, 55 had classical PKU and 14 were unclassified. Sapropterin was prescribed in two pregnancies. Only 27% (28/102) of pregnancies successfully achieved consistent blood Phe levels ≤ 360 µmol/L for at least 2 weeks pre-conception. During pregnancy, 88% of blood Phe levels were ≤360 µmol/L, with a mean Phe of 229 ± 65 µmol/L. The mean number of blood Phe samples was 60 (1.5 per week) per pregnancy. In pre-pregnancy, over a mean of 2.9 years, only 35% of blood Phe levels were ≤360 µmol/L and 61% were <600 µmol/L. Post-pregnancy, over a mean of 2.8 years, 43% of Phe levels were <600 µmol/L with mean Phe 462 ± 226 µmol/L and 724 ± 230 µmol/L, respectively. 25% (25/102) had no levels performed post-pregnancy (mean of 2.8 ± 1.6 years) compared to 7% (7/102) pre-pregnancy (mean of 2.9 ± 1.5 years). Mean prescribed Phe intake pre-/during/post-pregnancy was 810 ± 721 vs. 787 ± 552 vs. 1110 ± 722 mg/day. Natural protein intake was 17 ± 15 vs. 17 ± 11 vs. 23 ± 15 g/day. Protein equivalent from protein substitute intake was 57 ± 21 vs. 66 ± 16 vs. 50 ± 23 g/day and total protein remained stable, 73 ± 14 vs. 83 ± 14 vs. 71 ± 19 g/day (1.1 ± 0.3 vs. 1.1 ± 0.4 vs. 1.0 ± 0.4 g/kg/day). Conclusions: Although a high level of metabolic control was maintained during pregnancy, fewer than 30% of pregnancies achieved constant Phe levels ≤ 360 µmol/L prior to conception, with minimal monitoring post-pregnancy. The long-term impact on the offspring remains unknown and requires further investigation.