Sephience (synthetic sepiapterin) / PTC Therap - LARVOL DELTA

From dietary restriction to disease-targeted therapy: Sephience TM (sepiapterin) in phenylketonuria. (PubMed, Ann Med Surg (Lond)) - "Sepiapterin, a precursor of tetrahydrobiopterin (BH₄), enhances enzyme activity and stability, offering therapeutic benefit even in patients unresponsive to BH₄ alone. While careful monitoring for adverse effects such as gastrointestinal symptoms and hypophenylalaninemia is required, this approval represents a transformative step in precision medicine. Sephience has the potential to redefine the standard of care and improve long-term quality of life for individuals living with PKU."

Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases

PTC Therapeutics Announces Health Canada Approval of Sephience (sepiapterin) for the Treatment of Children and Adults Living with Phenylketonuria (PKU) (Canada Newswire) - "The Health Canada approval is based on the evidence of significant efficacy and safety from the Phase 3 APHENITY trial as well as durability of treatment effect in the APHENITY long-term extension study."

Canada approval • Phenylketonuria

Modeling Intelligence Quotient (IQ) Changes Relative to Blood Phe Levels in Individuals With Phenylketonuria (PKU) Treated With Sepiapterin and Sapropterin Dihydrochloride (ISPOR-EU 2025) - "This model demonstrated that, compared to sapropterin, sepiapterin provided a greater reduction in blood Phe levels and consequently a lower probability of low IQ. These findings support the clinical relevance of effectively controlling blood Phe levels in PKU and highlight the value of sepiapterin in addressing the adverse cognitive outcomes that patients experience."

Clinical • Metabolic Disorders • Phenylketonuria • Rare Diseases

Cost-Utility Analysis (CUA) of Sepiapterin for Treatment of Phenylketonuria (PKU) (ISPOR-EU 2025) - "The pharmacological therapies sapropterin dihydrochloride and pegvaliase have received approvals for PKU... This CUA model reflects a clinically-accurate approach for evaluating the benefits of sepiapterin compared to sapropterin or PRD for the treatment of PKU. The approach takes into account the heterogeneity in unmet need among individuals with PKU when evaluating relative treatment benefits."

HEOR • Developmental Disorders • Mental Retardation • Metabolic Disorders • Phenylketonuria • Rare Diseases

Phase 3 APHENITY long-term study: Sepiapterin for treatment of phenylketonuria (SSIEM 2023) - P3 | "There is no cure; current treatments include dietary Phe restriction with amino acid supplementation, sapropterin (synthetic tetrahydrobiopterin [BH4], a key PAH cofactor), and phenylalanine ammonia lyase. Secondary endpoints are change from baseline in QOL (PKUQOL questionnaire, EuroQOL 5 Dimension), pharmacokinetics, and sepiapterin palatability/acceptability in children. It is anticipated that sepiapterin will be well tolerated and an increase in dietary Phe/protein consumption will be observed with daily administration of sepiapterin."

P3 data • Metabolic Disorders • Phenylketonuria • Psychiatry • Rare Diseases

Phase 3 APHENITY study: Oral sepiapterin for treatment of phenylketonuria (SSIEM 2023) - P3 | "There is no cure; current treatments include dietary Phe restriction with amino acid supplementation, sapropterin (synthetic tetrahydrobiopterin [BH4], a key PAH cofactor), and phenylalanine ammonia lyase. Secondary endpoints are % of subjects with baseline Phe levels ≥600 μmol/L who reach levels 600 μmol/L at the end of study, PK, and safety. This study was designed to support registration of sepiapterin for PKU and it is anticipated that a greater reduction in blood Phe will be observed after treatment with sepiapterin vs. placebo."

P3 data • Metabolic Disorders • Phenylketonuria • Psychiatry • Rare Diseases

Key Clinical and Regulatory Updates (PTC Therapeutics Press Release) - "Additional Sephience marketing authorization reviews ongoing including in Japan where decision is expected in Q4 2025; FDA meeting for votoplam Huntington's disease program planned for Q4; FDA meeting planned for vatiquinone Friedreich's ataxia program in Q4; Translarna NDA remains under FDA review."

FDA event • Japan filing • Duchenne Muscular Dystrophy • Friedreich ataxia • Huntington's Disease • Phenylketonuria

L-sepiapterin treatment reduces renal cortical gene expression associated with oxidative stress and fibrosis in NZM2410 murine lupus nephritis (ACR Convergence 2025) - "PTC923 therapy in the NZM2410 model of lupus nephritis reduces injured cells and genes associated with inflammation and fibrosis and increases EC expression of genes in pathways associated with ion channels and nitric oxide production. These data suggest that targeting eNOS uncoupling in ECs acts via reducing redox-regulated pathways and increasing nitric oxide production."

Oxidative stress • Preclinical • Fibrosis • Glomerulonephritis • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease • Systemic Lupus Erythematosus • COL1A1 • COL3A1 • NOS3 • PDGFC • PDGFRA • PDGFRB

SEPHIENCE (sepiapterin). (PubMed, Clin Ther) - No abstract available

Journal

Sepiapterin: First Approval. (PubMed, Drugs) - "This was followed by approval in the USA on 28 July 2025, for the treatment of HPA in adult and paediatric patients ≥ 1 month of age with sepiapterin-responsive PKU. This article summarizes the milestones in the development of sepiapterin leading to its first approval for HPA in adult and paediatric patients with PKU."

Journal • Metabolic Disorders • Pediatrics • Phenylketonuria • Rare Diseases

PTC Therapeutics Announces FDA Approval of Sephience (sepiapterin) for the Treatment of Children and Adults Living with Phenylketonuria (PKU) (PRNewswire) - "PTC Therapeutics...announced today that the U.S. Food and Drug Administration (FDA) has approved SEPHIENCE (sepiapterin) for the treatment of children and adults living with phenylketonuria (PKU). The approval includes broad labeling for the treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients 1 month of age and older with sepiapterin-responsive PKU....The FDA approval is based on the evidence of significant efficacy and safety from the Phase 3 APHENITY trial as well as durability of treatment effect in the APHENITY long-term extension study."

FDA approval • Phenylketonuria

Orsini Selected as Specialty Pharmacy Partner for PTC Therapeutics' SEPHIENCE (sepiapterin) (Cision) - "Orsini...has been chosen by PTC Therapeutics as a specialty pharmacy partner for SEPHIENCE (sepiapterin), an FDA-approved oral therapy indicated for the treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients 1 month of age and older with sepiapterin-responsive phenylketonuria (PKU)."

Commercial • Phenylketonuria

Sephience (sepiapterin) Granted Marketing Authorization by the European Commission for the Treatment of Children and Adults Living with Phenylketonuria (PKU) (PRNewswire) - "PTC Therapeutics, Inc...announced that Sephience (sepiapterin) was granted marketing authorization by the European Commission for the treatment of children and adults living with phenylketonuria (PKU). The authorization includes a broad label inclusive of all ages and disease severities...The European approval is based on the highly statistically significant results from the Phase 3 APHENITY trial as well as evidence of durable treatment effect and the ability of study participants to liberalize their diet in the APHENITY long-term extension study."

EMA approval • Phenylketonuria

PTC Therapeutics Receives Positive CHMP Opinion for Sephience (sepiapterin) for the Treatment of Children and Adults Living with Phenylketonuria (PKU) (PRNewswire) - "PTC Therapeutics, Inc...announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion on the marketing authorization application for Sephience (sepiapterin) for the treatment of children and adults living with phenylketonuria (PKU). The opinion includes a broad label inclusive of all ages and disease severities....PTC expects the European Commission to ratify the marketing authorization for Sephience in approximately two months. The decision will be applicable to all 27 European Union member states, as well as Iceland, Norway and Liechtenstein....The New Drug Application (NDA) for sepiapterin is under review by the U.S. Food and Drug Administration (FDA) with a Prescription Drug User Fee Act (PDUFA) target action date of July 29, 2025."

CHMP • EMA approval • PDUFA • Phenylketonuria

PTC Therapeutics Presents New Sepiapterin Data from Ongoing Studies (PRNewswire) - P3 | N=157 | APHENITY (NCT05099640) | Sponsor: PTC Therapeutics | "Over 97% of subjects participating in the Phe tolerance protocol of the APHENITY open-label extension study demonstrate the ability to liberalize their diet while on sepiapterin treatment, with a mean increase in protein intake of 126%; 66% of subjects participating in the Phe tolerance sub study reached or exceeded the age-adjusted recommended daily allowance of protein intake for an individual without PKU, while maintaining control of blood Phe levels; Genetic variant analysis of subjects participating in the APHENITY study demonstrates that over 70% had a Genotype-Phenotype Value (GPV) consistent with classical PKU."

P3 data • Phenylketonuria

PTC Therapeutics Provides Corporate Update and Reports Fourth Quarter and Full Year 2024 Financial Results (PRNewswire) - "PTC submitted four regulatory approval applications to FDA in 2024....Sepiapterin for children and adults with PKU, with a target regulatory action date of July 29, 2025....PTC submitted several additional marketing authorization applications outside the U.S. for sepiapterin in 2024, with CHMP opinion on sepiapterin MAA expected in Q2 2025 and a regulatory decision in Japan expected in Q4 2025....12-month results from the PIVOT-HD Phase 2 study of PTC518 expected in Q2 2025."

CHMP • Japan approval • P2 data • PDUFA • Huntington's Disease • Phenylketonuria

PTC Therapeutics Announces Sepiapterin NDA Submission to FDA (PRNewswire) - "PTC Therapeutics, Inc...announced today the submission of the sepiapterin NDA to the U.S. FDA. The NDA submission is for the treatment of pediatric and adult patients with phenylketonuria (PKU), including the full spectrum of ages and disease subtypes....The sepiapterin NDA is based on the highly statistically significant and clinically meaningful results from the phase 3 APHENITY trial....The European marketing authorization application is currently under review and the marketing authorization applications for Japan and Brazil are expected to be submitted later in 2024."

EMA filing • FDA filing • Metabolic Disorders • Phenylketonuria

No QT interval prolongation effect of sepiapterin: a concentration-QTc analysis of pooled data from phase 1 and phase 3 studies in healthy volunteers and patients with phenylketonuria. (PubMed, J Pharmacokinet Pharmacodyn) - "Various covariates, such as clinical study ID, age, sex, food effect, race, body weight, and disease status, on QTcF interval were investigated and were found insignificant, except for food effect and age. This study concludes that there is no QTcF prolongation risk in patients with PKU following sepiapterin dosing up to 60 mg/kg/day, and BH4 and sepiapterin concentrations minimally affect ΔQTcF after adjustment for time, sex, and meal."

Clinical • Journal • P1 data • P3 data • Metabolic Disorders • Pediatrics • Phenylketonuria • Rare Diseases

A Phase 1 Study to Assess the Pharmacokinetics, Food Effect, Safety, and Tolerability of Sepiapterin in Healthy Japanese and Non-Japanese Participants. (PubMed, Pharmaceuticals (Basel)) - "BH4 exposures (Cmax and AUC0-last) in Japanese participants were 10-30% higher than in non-Japanese participants, which is deemed not clinically relevant; no dose adjustment is warranted. The slightly higher BH4 exposures in Japanese participants are likely due to the higher frequency of ABCG2 c.421C>A mutation in the Japanese population."

Journal • P1 data • PK/PD data • Metabolic Disorders • Phenylketonuria • Rare Diseases • ABCG2

A Long-Term Safety Study of PTC923 in Participants With Phenylketonuria (clinicaltrials.gov) - P3 | N=200 | Recruiting | Sponsor: PTC Therapeutics | Trial completion date: Feb 2025 ➔ Apr 2026 | Trial primary completion date: Feb 2025 ➔ Apr 2026

Trial completion date • Trial primary completion date • Metabolic Disorders • Phenylketonuria • Rare Diseases

Effects of oral sepiapterin on blood Phe concentration in a broad range of patients with phenylketonuria (APHENITY): results of an international, phase 3, randomised, double-blind, placebo-controlled trial. (PubMed, Lancet) - P3 | "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."

Clinical • Journal • P3 data • Gastrointestinal Disorder • Metabolic Disorders • Phenylketonuria • Rare Diseases

PTC Therapeutics Announces FDA Acceptance for Filing of NDA for Sepiapterin for the Treatment of Pediatric and Adult Phenylketonuria Patients (PRNewswire) - "PTC Therapeutics, Inc...announced today the FDA has accepted for filing the New Drug Application (NDA) of sepiapterin for the treatment of pediatric and adult patients living with phenylketonuria (PKU). A Prescription Drug User Fee Act (PDUFA) target action date is expected to be provided in the Day 74 Letter....The sepiapterin NDA is based on the highly statistically significant and clinically meaningful results from the phase 3 APHENITY trial."

FDA filing • Metabolic Disorders • Phenylketonuria

Clinical Assessment of Breast Cancer Resistance Protein (BCRP)-Mediated Drug-Drug Interactions of Sepiapterin with Curcumin and Rosuvastatin in Healthy Volunteers. (PubMed, Drugs R D) - "Oral coadministration of the BCRP inhibitor curcumin slightly increased the plasma exposure of sepiapterin and its metabolite BH4 in healthy volunteers. This modest increase was deemed not clinically meaningful. Sepiapterin did not alter the pharmacokinetics of the BCRP substrate rosuvastatin."

Journal • Breast Cancer • Metabolic Disorders • Oncology • Phenylketonuria • Rare Diseases • Solid Tumor

INVESTIGATING THE PHARMACOLOGICAL CHAPERONE EFFECT OF SEPIAPTERIN IN PHENYLKETONURIA (SSIEM 2024) - "Our results support sepiapterin's independent effect as a pharmacological chaperone for PKU; it functions not only as a co-factor precursor but also binds and stabilizes PAH variants independently, underscoring its potential to improve treatment outcomes, particularly for those previously unresponsive to BH4."

Metabolic Disorders • Phenylketonuria • Rare Diseases

POPULATION PHARMACOKINETICS MODELING AND ANALYSIS OF SEPIAPTERIN AND ITS METABOLITE TETRAHYDROBIOPTERIN FOR DOSE RECOMMENDATION IN PEDIATRIC PATIENTS WITH PHENYLKETONURIA (SSIEM 2024) - "The PopPK model adequately described BH4 PK in healthy volunteers and participants with PKU. Dose level, food, body weight, race, and age were the covariates retained in the final model. The results support the body-weight-based dose strategy and administration of sepiapterin with food that has been utilized in all late-phase clinical trials to date."

Clinical • PK/PD data • Metabolic Disorders • Pediatrics • Phenylketonuria • Rare Diseases