Sephience (synthetic sepiapterin) / PTC Therapeutics - 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

A Long-Term Safety Study of PTC923 in Participants With Phenylketonuria (clinicaltrials.gov) - P3 | N=247 | Completed | Sponsor: PTC Therapeutics | Active, not recruiting ➔ Completed

Trial completion • Metabolic Disorders • Phenylketonuria • Rare Diseases

The Ministry of Food and Drug Safety (MFDS) said Thursday that it has approved Sephience (sepiapterin) for the treatment of hyperphenylalaninemia in patients with phenylketonuria (PKU). (Korea Biomedical Review)

Korea approval • Phenylketonuria

Efficacy and safety of sepiapterin in individuals with phenylketonuria and baseline phenylalanine levels ≥900 µmol/L (SSIEM 2026) - "In participants with PKU and high baseline Phe levels, sepiapterin resulted in clinically meaningful reductions in blood Phe levels within 14 days, with response rates comparable to the overall population, and was generally well tolerated. Therefore, sepiapterin may be a suitable treatment option for patients with PKU with high Phe levels."

Clinical • Metabolic Disorders • Phenylketonuria • Rare Diseases

Mixing studies with sepiapterin to provide Phenylketonuria (PKU) patients with additional administration options (SSIEM 2026) - "Sepiapterin can be mixed with some beverages, soft foods and PKU Formula, providing patients more flexibility when taking this medication."

Clinical • Metabolic Disorders • Phenylketonuria • Rare Diseases

Dietary liberalization in patients with phenylketonuria and controlled blood phenylalanine levels: APHENITY Extension Study findings (SSIEM 2026) - P3 | "Sepiapterin treatment resulted in a substantial increase in dietary Phe intake in participants with controlled blood Phe at study entry who underwent dietary Phe tolerance assessment, while generally maintaining blood Phe levels within the recommended range (<360 µmol/L) up to Month 24."

Clinical • Metabolic Disorders • Phenylketonuria • Rare Diseases

EPIPHENY study design: Phase 3b study of long-term neurocognitive outcomes in sepiapterin-treated children with phenylketonuria (SSIEM 2026) - P3 | "EPIPHENY will evaluate the long-term efficacy of sepiapterin on preserving neurocognitive function in children with PKU when treatment is initiated in early childhood. Recruitment is ongoing globally."

Clinical • P3 data • Alzheimer's Disease • Cognitive Disorders • Metabolic Disorders • Phenylketonuria • Rare Diseases

Trends in BMI, Protein and Energy Intake During Sepiapterin Treatment in Brazilian Patients with PKU (SSIEM 2026) - P3 | "Sepiapterin treatment was associated with marked reductions in blood Phe levels and substantial increases in natural protein intake. No significant changes were observed in energy intake or anthropometric parameters. However, these findings reinforce the importance of ongoing dietary counseling and guidance toward healthy food choices during diet liberalization."

Clinical • Genetic Disorders • Metabolic Disorders • Obesity • 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

Redefining the number of true null PAH variants in phenylketonuria and sepiapterin response (SSIEM 2026) - "Based on in vitro and clinical evidence, PAH variants historically classified as null alleles have demonstrated response to sepiapterin. Hardy–Weinberg calculations indicate that <1% of individuals with PKU have null–null genotypes, supporting the broad sepiapterin responsiveness observed clinically. These results suggest that any individual with PKU should be considered for sepiapterin responsiveness testing."

Metabolic Disorders • Phenylketonuria • Rare Diseases

Impact Of A Phe-Restricted Diet On Gut Health In Children With PKU (clinicaltrials.gov) - P=N/A | N=148 | Recruiting | Sponsor: Birmingham Women's and Children's NHS Foundation Trust

New trial • Metabolic Disorders • Phenylketonuria • Rare Diseases

Sepiapterin: A Distinct, Dual Mechanism of Action that Leads to Potential Treatment Benefits Across the Spectrum of Phenylketonuria Disease Severities. (PubMed, Adv Ther) - "In PKU, the PAH enzyme has reduced affinity for its substrate [phenylalanine (Phe)] or cofactor [tetrahydrobiopterin (BH4)], shows decreased substrate activation or becomes destabilized owing to protein misfolding...Until recently, only two pharmacological therapies were approved for PKU: sapropterin and pegvaliase; however, the need for additional treatment options remained...On the basis of its dual mechanism of action and favorable safety and tolerability profile, sepiapterin has the potential to treat a broad range of individuals with PKU across the spectrum of disease severities and ages. Thus, all individuals should be considered for an initial treatment trial with sepiapterin to establish responsiveness, regardless of genetic variant or phenotypic severity."

Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases

SAFETY OF SEPIAPTERIN AND PEGVALIASE FOR THE TREATMENT OF PHENYLKETONURIA (PKU): A SIMULATED TREATMENT COMPARISON (STC) (ISPOR 2026) - "OBJECTIVES: PKU causes elevated blood phenylalanine (Phe) leading to neurological damage and cognitive disability. In this analysis, sepiapterin exhibited a significantly more favorable safety profile than pegvaliase. Immune reactions are prominent in pegvaliase-treated patients. As such, it has been graded a black box warning and is available only under a restricted program (Risk Evaluation and Mitigation Strategy)."

Clinical • CNS Disorders • Cognitive Disorders • Developmental Disorders • Infectious Disease • Metabolic Disorders • Musculoskeletal Pain • Phenylketonuria • Rare Diseases • Respiratory Diseases

Ethnic Bridging of Sepiapterin in Chinese and Korean Populations Based on Predictions From Genetic Polymorphism of Breast Cancer Resistance Protein. (PubMed, Clin Transl Sci) - "Based on this correlation, it was predicted that compared to White, the mean BH4 Cmax and AUC0-24h were 1.16-fold and 1.23-fold higher, respectively, in Chinese subjects, and 1.12-fold and 1.17-fold higher, respectively, in Korean subjects. These findings, including the clinically insignificant differences in PK exposures, the comprehensive evidence of sepiapterin's efficacy and safety, the recognition of PKU as a rare disease and designation of sepiapterin as an orphan drug for treatment of PKU in EU, the USA, Japan, South Korea, and several other countries, and the urgent unmet medical need, collectively support that conducting an ethnic bridging study in Chinese and Korean populations is not warranted."

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

Sepiapterin Responsiveness Over 14 Days in Children and Adults with Phenylketonuria: Pooled Results from Three Phase 3 Clinical Trials (ACMG 2026) - P3 | "Most participants enrolled in the Phase 3 APHENITY and AMPLIPHY studies and the APHENITY Extension Study achieved a sustained response to sepiapterin within 14 days, supporting the use of a response test conducted over at least 14 days to identify patients likely to benefit from sepiapterin treatment."

Clinical • P3 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Metabolic Disorders • Phenylketonuria • Rare Diseases

A Long-Term Safety Study of PTC923 in Participants With Phenylketonuria (clinicaltrials.gov) - P3 | N=200 | Active, not recruiting | Sponsor: PTC Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Metabolic Disorders • Phenylketonuria • Rare Diseases

Efficacy and safety of sepiapterin versus sapropterin in patients with phenylketonuria: Results from the Phase 3, randomized, crossover, open-label, active-controlled AMPLIPHY trial. (PubMed, Metabolism) - "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)."

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

Effect of long-term sepiapterin treatment on dietary phenylalanine tolerance in patients with phenylketonuria: interim results from the Phase 3 APHENITY Extension Study. (PubMed, Genet Med) - P3 | "Interim results support the long-term safety of sepiapterin and demonstrate the potential for diet liberalization in adults and children with phenylketonuria."

Journal • P3 data • P3 data: top line • Metabolic Disorders • Phenylketonuria • Rare Diseases

PTC Therapeutics reports $92.5M in Q4 Sephience revenue (Investing.com) - "PTC reported 946 patients on commercial Sephience therapy worldwide as of December 31, with 1,134 patient start forms received in the United States. The drug generated approximately $112.1 million in total net revenue since its launch in 2025...In December 2025, PTC sold the remainder of its Evrysdi royalty to Royalty Pharma for $240 million upfront and up to $60 million in sales-based milestones. The company maintains the right to receive a $150 million milestone based on single-year Evrysdi sales of $2.5 billion by Roche."

Commercial • Muscular Atrophy • Parkinson's Disease

No QTcF Prolongation with Sepiapterin: Results From a Thorough QT Study in Healthy Subjects at Therapeutic and Supratherapeutic Doses. (PubMed, J Clin Pharmacol) - "Thirty-two participants were randomized into one of 12 sequences and received single doses of sepiapterin (60 or 120 mg/kg), moxifloxacin 400 mg, or placebo in separate periods. An effect on ΔΔQTcF exceeding 10 ms was excluded within the observed concentration range of baseline-corrected BH4 up to 1088 ng/mL and sepiapterin up to 5.77 ng/mL. The consistency of results from this study and the previous concentration-QTc analysis based on pooled data from multiple clinical studies demonstrated the reliability of using concentration-QTc for assessing cardiovascular risks in early clinical development."

Clinical • Journal • Cardiovascular • Metabolic Disorders • Phenylketonuria • Rare Diseases

Endogenous tetrahydrobiopterin in humans: circadian rhythm, sex, race, age, and disease status. (PubMed, Front Pharmacol) - "Exogenous BH4, or its natural precursor sepiapterin, is utilized to treat patients with phenylketonuria (PKU), a disease caused by PAH deficiency...BH4 concentrations were relatively stable between 7:00 and 10:59, providing a window for measurements with minimal variation. The significant difference in BH4 concentrations between patients with PBD, patients with PKU, and healthy adults could be utilized as a diagnostic tool."

Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases

PTC Therapeutics Announces Approval of Sephience (sepiapterin) for the Treatment of Children and Adults Living with Phenylketonuria (PKU) in Japan (PRNewswire) - "PTC will now engage in pricing discussions which are expected to conclude in Q1 2026, with launch occurring shortly thereafter."

Japan approval • Phenylketonuria

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