Sephience (synthetic sepiapterin) / PTC Therap - LARVOL DELTA

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

COMPARATIVE EFFICACY OF SEPIAPTERIN VS. SAPROPTERIN IN PHENYLKETONURIA: A SYSTEMATIC LITERATURE REVIEW AND MULTI-LEVEL NETWORK META-REGRESSION (SSIEM 2024) - "This study shows statistically significant Phe reduction with SEP over that of SAP among patients with PKU, with a similar safety profile. These findings align with results from the head-to-head trial PKU-002. Strengths included the use of multiple models, including ML NMR, to validate findings from the NMA; results were consistent across models, which supported the robustness of these findings."

Clinical • Review • Metabolic Disorders • Phenylketonuria • Rare Diseases

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

EPIPHENY: A Study of Sepiapterin in Participants With Phenylketonuria (PKU) (clinicaltrials.gov) - P3 | N=56 | Recruiting | Sponsor: PTC Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open • Metabolic Disorders • Phenylketonuria • Rare Diseases

Efficacy and safety of oral sepiapterin in participants with phenylketonuria on sapropterin dihydrochloride at time of Phase 3 aphenity study entry (SIMD 2024) - "Sepiapterin is an intermediate in tetrahydrobiopterin (BH4) biosynthesis and is being developed as a novel oral treatment for PKU. Treatment with sepiapterin resulted in a clinically meaningful and significant reduction in blood Phe in children and adults with PKU receiving sapropterin dihydrochloride at study entry."

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

Preliminary results from the ongoing aphenity extension study: Sepiapterin reduces blood PHE with improved dietary PHE tolerance in participants with phenylketonuria (SIMD 2024) - "Preliminary data from the ongoing APHENITY extension study demonstrate continued clinical benefit and a consistent safety profile with sepiapterin. The gradual increase in dietary Phe consumption by participants while maintaining their blood Phe within target levels suggests sepiapterin may allow a more liberalized diet in a broad range of patients with PKU. Sepiapterin was well tolerated and no safety concerns related to long-term use were observed."

Metabolic Disorders • Phenylketonuria • Psychiatry • Rare Diseases

EPIPHENY: A Study of Sepiapterin in Participants With Phenylketonuria (PKU) (clinicaltrials.gov) - P3 | N=56 | Not yet recruiting | Sponsor: PTC Therapeutics

New P3 trial • Metabolic Disorders • Phenylketonuria • Rare Diseases

Relative Oral Bioavailability and Food Effects of Two Sepiapterin Formulations in Healthy Participants. (PubMed, Clin Pharmacol Drug Dev) - "Both sepiapterin formulations were well tolerated, with no serious or severe adverse events reported. All treatment-emergent adverse events were mild or moderate in severity."

Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases

LC-MS/MS methods for direct measurement of sepiapterin and tetrahydrobiopterin in human plasma and clinical applications. (PubMed, Bioanalysis) - "Quantification of analytes was challenging due to their susceptibility to redox reactions. The validated methods were utilized successfully to support clinical development of sepiapterin."

Journal

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

A Study of PTC923 in Participants With Phenylketonuria (clinicaltrials.gov) - P3 | N=156 | Completed | Sponsor: PTC Therapeutics | Recruiting ➔ Completed

Trial completion • Metabolic Disorders • Phenylketonuria • Rare Diseases

PTC Therapeutics announces that the APHENITY clinical trial reached the primary endpoint with sepiapterin in patients with Phenylketonuria (PKU) (PRNewswire) - "PTC Therapeutics...today announced that the primary endpoint was achieved in the APHENITY registry-driven Phase 3 clinical trial of sepiapterin in adult and pediatric patients with phenylketonuria (PKU). 'The positive results from the APHENITY trial bring us one step closer to providing a treatment that can offer significant benefit to patients with PKU.'...The placebo-controlled part of the study included 98 patients in the primary analysis population. The mean percent reduction in Phe in sepiapterin-treated patients was 63%. In the subset of patients with classic PKU, the mean percent decrease in Phe was 69%. Minimal reductions in Phe levels were observed in the placebo-treated patients, resulting in a high and statistically significant (p<0.0001) sepiapterin treatment benefit. Sepiapterin was generally well tolerated, with no serious adverse events."

P3 data • Parkinson's Disease • Phenylketonuria

Validation and application of volumetric absorptive microsampling (VAMS) dried blood method for phenylalanine measurement in patients with phenylketonuria. (PubMed, Clin Biochem) - "Concordant results were obtained using VAMS and plasma methods, which demonstrated that VAMS is a reliable method for clinical applications to monitor blood Phe for PKU patients."

Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases