sapropterin / Generic mfg. - LARVOL DELTA

Lower blood phenylalanine concentrations may be of clinical benefit in adults with phenylketonuria. (PubMed, Mol Genet Metab Rep) - P3 | "To describe the experience of adults with PKU regarding mood and self-reported functioning during a period with higher and/or lower blood Phe levels than they were used to during an interventional trial with Sepiapterin...Adults with PKU may experience worsened self-reported functioning at higher blood Phe levels and improved functioning when Phe is lower than their usual blood Phe levels. Therapies that reduce blood Phe levels without the need of a strict diet offer the possibility to objectively study the impact of lower blood Phe levels in adults with PKU and may eventually facilitate individualized target blood Phe levels."

Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases

A phase 1/2 dose-escalation study of sepiapterin in patients with 6-pyruvoyl-tetrahydropterin synthase deficiency with hyperphenylalaninemia. (PubMed, Mol Ther) - "Oral sepiapterin (PTC923), a precursor of tetrahydrobiopterin (BH4), was evaluated in patients with 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency in a phase 1/2, multicenter, open-label, randomized, intra-individual dose-escalation study. Blood BH4 concentrations increased with increasing single doses of sepiapterin, reaching a peak at approximately 3-4 hours, which was 2-3 hours after the sepiapterin peak. These results show that in patients with PTPS deficiency, sepiapterin is rapidly converted to BH4 and normalizes blood phenylalanine concentrations, with no dose-limiting toxicity or dose-related adverse events."

Journal • P1/2 data

Bone mineral density in participants with phenylalanine hydroxylase (PAH) deficiency: a report from the PHEFREE rare disorders consortium. (PubMed, Mol Genet Metab) - "20 adults (37%) reported receiving enzyme replacement therapy with pegvaliase...Whether novel therapeutics, that both correct hyperphenylalaninemia and allow increased dietary intact protein intake, will impact bone mineralization is yet unknown. Longitudinal monitoring of BMD throughout the lifespan is warranted."

Journal • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Phenylketonuria • Rare Diseases • Rheumatology

Resistance training and metabolic control in phenylketonuria: A paradoxical observation in a sapropterin responder. (PubMed, Med Clin (Barc)) - No abstract available

Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases

Targeting Mutant Phenylalanine Hydroxylase With Pyrimidine-Triazole Conjugates: A Primary Framework for Candidate Chaperone-Based Strategies in Phenylketonuria. (PubMed, FASEB J) - "Dietary management, sapropterin dihydrochloride, and pegvaliase are the current therapies; however, their limited efficacy and adverse effects highlight the pressing need for pharmacological treatments that restore PAH activity...Biological validation in R252Q mutant cells demonstrated significant upregulation of PAH and key tetrahydrobiopterin (BH4) pathway genes, including quinonoid dihydropteridine reductase (QDPR), sepiapterin reductase (SPR), and 6-pyruvoyl-tetrahydropterin synthase (PTS), following Pyr-TZ-2O treatment. Consistent with these findings, sandwich ELISA revealed a dose-dependent increase in PAH protein abundance post-Pyr-TZ-2O treatment. Conclusively, Pyr-TZ-2O can be considered a potential pharmacological chaperone capable of stabilizing mutant PAH and enhancing cofactor regeneration, offering a rational therapeutic approach for PKU."

Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases

The Chaperonopathies: Early Intervention in DNAJC12-Related Hyperphenylalaninemia (SSIEM 2026) - "Background: Hyperphenylalaninemia (HPA) is a common biochemical feature of aminoacidopathies, typically caused by phenylalanine hydroxylase (PAH) deficiency or tetrahydrobiopterin (BH4) deficiency... HPA exhibits genetic heterogeneity, and early molecular diagnosis—including screening for chaperone-related genes such as DNAJC12—is essential for timely and targeted treatment. Early intervention can prevent neurological complications and improve developmental outcomes in affected children."

Autism Spectrum Disorder • CNS Disorders • Dystonia • Genetic Disorders • Infectious Disease • Metabolic Disorders • Movement Disorders • Novel Coronavirus Disease • Phenylketonuria • DNAJC12

Insufficient metabolic control and unmet therapeutic need in patients with phenylketonuria (PKU) in Spain (CLARIPHY-SP) (SSIEM 2026) - "Although the proportion of uncontrolled individuals in this cohort appears lower than international rates reported in the PKU literature, likely owing to multiple factors, metabolic control in PKU remains inadequate in Spain, especially among adults and patients managed with diet alone. Despite improved outcomes with pharmacological therapy (predominantly in patients who had relatively low Phe levels at diagnosis), a substantial proportion of individuals remain outside guideline targets, highlighting the need for additional therapeutic strategies to achieve sustained Phe control."

Clinical • Metabolic Disorders • Phenylketonuria • Rare Diseases

Geogenetic Stratification Correlates with Anthropometric Outcomes in a Mediterranean Cohort with PAH Deficiency (SSIEM 2026) - "Eighteen percent of the cohort is currently on pharmacological therapy (Sapropterin or Pegvaliase)... Our study reveals that the nutritional burden of PKU is not uniform. The Inland cluster faces a double challenge: a severe genetic phenotype and an increased risk of metabolic and anthropometric complications (e.g., higher BMI). Conversely, the Mediterranean Coastal cluster demonstrates a natural resilience thanks to milder mutations."

Metabolic Disorders • Phenylketonuria

Real world metabolic control in phenylketonuria in France: results from the national multicentre CLARIPHY FR study (SSIEM 2026) - "CLARIPHY-FR provides a real-world estimate of guideline-based quality of metabolic (Phe) control of patients with PKU in France using individual median Phe over a year. Despite routine monitoring, approximately half of individuals did not meet European targets, with a marked decline from childhood to adulthood. The proportion of uncontrolled individuals in this cohort appears lower than other rates reported in the PKU literature, likely owing to multiple factors such as selection bias potentially under-representing individuals with lower care adherence."

Clinical • Real-world • Real-world evidence • Metabolic Disorders • Phenylketonuria • Rare Diseases

Oxidative and mitochondrial status in long-term PKU patients: age and treatment-dependent profiles (SSIEM 2026) - "Early diagnosis and treatment reduces oxidative stress in PKU patients diagnosed and treated since birth, despite higher GDF15 expression evidences subclinical mitochondrial dys-function. Kuvan®-treated patients preserve mitochondrial function by reducing GDF15 levels. HPA subjects, considered a milder PKU, resembled controls."

Clinical • Metabolic Disorders • Phenylketonuria • Rare Diseases • FGF21 • GDF15

Clinical audit to look at compliance with HSE Sapropterin prescribing guidelines in neonates at NCIMD. (SSIEM 2026) - "We found majority of our cohort (55 % )were non responsive to Sapropterin, which is similar to previously reported international cohorts. Overall compliance with national testing protocol was good. Compliance with obtaining liquid Phe levels and DBS timings during Sapropterin loading test is an area for improvement."

Clinical • Compliance • CNS Disorders • Epilepsy • Genetic Disorders • Metabolic Disorders • Phenylketonuria • Rare Diseases • Vascular Neurology

Protein and Micronutrient Intake After Two Years of Sapropterin Treatment in PKU (SSIEM 2026) - "After two years of sapropterin treatment, dietary liberalisation increased natural protein intake but did not reliably ensure micronutrient adequacy. Four children had intakes below DRVs for calcium, iron, zinc, and vita-min D, while vitamin B12 intake remained adequate. Gradual, dietitian-led adjustments to protein substitutes, alongside targeted dietary guidance, are essential to maintain micronutrient sufficiency as diets become more flexible in sapropterin-treated children with PKU."

Metabolic Disorders • Phenylketonuria • Rare Diseases

A deep analysis of the 14 day sepiapterin responsiveness test in PKU (SSIEM 2026) - "Sepiapterin consistently lowered Phe levels and tended to increase Tyr concentrations. Most responders maintained satisfactory Phe control during follow up, suggesting that the 14 day responsiveness test is a useful tool to guide long term treatment decisions. Previous non response to sapropterin, splice site variants, low GPV and classical PKU phenotype did not reliably predict a poor response to sepiapterin."

Gastrointestinal Symptoms Are Common in PKU But Under Recognised in Routine Care (SSIEM 2026) - "Sapropterin was used by 25% (n=97), sepiapterin by 4% (n=14), and one respondent used pegvaliase... GI symptoms were common across all ages in PKU, with many individuals experiencing persistent or moderate–severe symptoms that substantially affect daily life. A significant proportion required long-term medication or clinical investigation, and protein substitutes may contribute to symptom burden. Routine assessment of GI health should be embedded within PKU care pathways, and dietary management optimised to reduce symptoms and improve quality of life."

Constipation • Gastroenterology • Gastrointestinal Disorder • Metabolic Disorders • Phenylketonuria • Rare Diseases

Clinical outcomes of the first patients with phenylketonuria treated with sepiapterin in Italy (SSIEM 2026) - P3 | "In this Italian case series, most patients with PKU, including individuals previously treated with sapropterin, responded to sepiapterin. Patients demonstrated clinically meaningful reductions in blood Phe levels and a reduced reliance on low Phe supplemental protein during ongoing treatment, supporting the effectiveness of sepiapterin in routine clinical practice."

Clinical • Clinical data • Metabolic Disorders • Phenylketonuria • Rare Diseases

Two-Year Sapropterin Outcomes in Phenylketonuria: Longitudinal Study of Metabolic, Dietary, Psychosocial Effects (SSIEM 2026) - "Sapropterin enabled more flexible, sustainable dietary management in responsive children with PKU, supporting metabolic control, growth, and improved family well-being and reduced burden of care; however, the extent of dietary liberalization varied between individuals according to their PKU severity. Equitable access to therapies and long-term dietetic support remain essential to optimize outcomes."

Longitudinal study • Observational data • CNS Disorders • Depression • Metabolic Disorders • Phenylketonuria • Rare Diseases

Clinical outcomes in an adult with classic phenylketonuria treated with sepiapterin: first Italian real-life experience (SSIEM 2026) - " A female with classic PKU diagnosed via newborn screening (heterozygous c.194T>C and c.473G>A; 50% tetrahydrobiopterin [BH4]-responsive) was followed longitudinally...In 2022, pegvaliase treatment was initiated and then withdrawn after 2 months of dose-titration owing to an IgE mediated adverse event... In this first Italian real-world experience, sepiapterin enabled rapid metabolic control and increased protein intake in an adult patient with difficult-to-treat PKU and prior treatment failure. These findings support sepiapterin as a promising and well-tolerated treatment with the potential to improve PKU management and quality of life."

Clinical • Clinical data • Metabolic Disorders • Phenylketonuria • Rare Diseases

Humanistic burden and unmet needs of patients with phenylketonuria (PKU): a US physician-reported survey perspective (SSIEM 2026) - "Patients received appropriate care: 91% prescribed low-Phe diet, 71% managed pharmacologically (29 on sapropterin, 8 pegvaliase, 9 sepiapterin)...Discussion. The burden of PKU and unmet treatment needs remain high in general and among patients with classical PKU."

Clinical • Metabolic Disorders • Mood Disorders • Phenylketonuria • Rare Diseases

Maternal PKU in the Post-MPKUCS Era: Reproductive Outcomes from the PHEFREE Rare-Disease Consortium for Phenylketonuria (SSIEM 2026) - "No women were on pegvaliase during pregnancy... Four decades after the Maternal Phenylketonuria Collaborative Study (MPKUCS) adverse pregnancy outcomes continue but at a substantially lower frequency. In this cohort 6% of offspring had CHD vs 14% in MPKUCS. Microcephaly in offspring to mothers with classic PKU prior to the MPKUCS occurred in 73%, and 23% with the MPKUCS intervention."

Cervical Cancer • Developmental Disorders • Endometriosis • Erectile Dysfunction • Gynecology • Infertility • Metabolic Disorders • Phenylketonuria • Polyendocrine Metabolic Ovarian Syndrome • Rare Diseases • Sexual Disorders • Uterine Leiomyoma • Women's Health

An Exercise and Dietary Induced Fat-Free Mass Increase in Two Patients with Phenylketonuria (PKU) (SSIEM 2026) - "These cases show the differences in exercise undertook, dietary advice provided and resulting increases in fat-free mass for both athletes. It illustrates how a fat-free mass increase is possible in PKU, with adequate training, nutrition and support."

Clinical • Cardiovascular • Metabolic Disorders • Phenylketonuria • Rare Diseases

Functional Gastrointestinal Disorders in School-Aged Children with Hyperphenylalaninemia: An Italian Multicentre Survey (SSIEM 2026) - "A total of 55 participants were enrolled (21 males, 34 females), with a mean age of 9.9±4.3 years. The cohort included 28 patients with PKU (51%), of whom 14 had classical form, and 27 with HPA (49%). Regarding treatment, 47.3% were on dietary therapy using amino acid mixtures or glycomacropeptide, and 14.5% received Sapropterin."

Clinical • CNS Disorders • Constipation • Dyspepsia • Gastroenterology • Gastrointestinal Disorder • Metabolic Disorders • Migraine • Phenylketonuria • Rare Diseases

Eating disorders and disordered eating in PKU: a systematic review (SSIEM 2026) - "Inclusion criteria comprised: patients early diagnosed, treated with a Phe-restricted diet at least until adolescence, +/- sapropterin/pegvaliase; not pregnant/lactating...They may misclassify treatment-related behaviours as pathological or, fail to detect PKU-specific patterns of concern. Purpose-designed screening instruments would support clinicians in initiating open, routine conversations about eating behaviour, food attitudes and the psychosocial burden of dietary management, enabling timely identification of individuals requiring assessment or referral to specialist ED services."

Review • Anorexia • Bulimia • CNS Disorders • Metabolic Disorders • Phenylketonuria • Rare Diseases

Heterogeneity in Sapropterin Administration Among Paediatric/Adult Patients with Phenylketonuria: Findings from a National Survey (SSIEM 2026) - "129 individuals completed the survey, of whom 123 were current sapropterin users. Most respondents were caregivers of children or adolescents (69% aged 0–18 years). Over half (55%) had been taking sapropterin for two to three years."

Clinical • Heterogeneity • Metabolic Disorders • Pediatrics • Phenylketonuria • Rare Diseases

Sepiapterin responsiveness and improved protein tolerance in a child with phenylketonuria previously unresponsive to sapropterin (SSIEM 2026) - "Responsiveness to tetrahydrobiopterin (BH4) therapy varies, and some individuals who do not respond to sapropterin treatment may respond to alternative approaches...Discussion/Conclusion This case demonstrates substantial biochemical response to sepiapterin and clinically relevant improvement in natural protein tolerance in a young child with PKU who previously showed no response to sapropterin. Intercurrent illness in daycare was associated with Phe increases, limiting further diet liberalisation despite protocol amendments."

Clinical • Metabolic Disorders • Phenylketonuria • Rare Diseases

Improved efficacy with sepiapterin in participants with phenylketonuria receiving sapropterin at study screening in AMPLIPHY (SSIEM 2026) - "Among AMPLIPHY participants receiving sapropterin at screening, sepiapterin was superior to the highest approved dose of sapropterin in lowering blood Phe, with comparable safety profiles. This finding further supports data from previous trials, wherein participants previously on sapropterin had improved blood Phe reduction with sepiapterin."

Clinical • Metabolic Disorders • Phenylketonuria • Rare Diseases