Sepiapterin for Phenylketonuria

(EPIPHENY Trial)

Overseen By Melissa Lah

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: PTC Therapeutics

Must not be taking: BH4 supplementation

Disqualifiers: Neuropsychiatric illness, Renal disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 6 years

56 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how well sepiapterin (also known as PTC-923 or CNSA-001) protects brain function in children with phenylketonuria (PKU) when started early. PKU is a condition where the body can't break down a certain amino acid, leading to health issues. Participants will take sepiapterin once daily for up to six years. Children diagnosed with PKU and specific blood test results related to this condition might be suitable candidates. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have taken BH4 supplements like sapropterin or KUVAN within 3 months before the trial. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that sepiapterin is likely to be safe for humans?

Research has shown that sepiapterin is generally safe and well-tolerated for people with phenylketonuria (PKU). In earlier studies, participants experienced lower levels of phenylalanine (Phe) in their blood, an important treatment goal for PKU. Importantly, these studies did not find any serious side effects from the treatment.

The FDA has also approved sepiapterin for treating PKU, indicating that its safety has been thoroughly reviewed and deemed acceptable for use. This approval confirms it has passed a detailed review process to ensure patient safety.

In summary, current evidence suggests that sepiapterin is generally safe for treating PKU, with no major safety concerns reported in studies so far. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for PKU?

Unlike the standard treatments for phenylketonuria (PKU), which often involve dietary restrictions and supplements like sapropterin, sepiapterin acts as a precursor to tetrahydrobiopterin (BH4), a crucial cofactor for breaking down phenylalanine. This new approach could potentially enhance the natural production of BH4 in the body, offering a more direct and efficient way to manage PKU. Researchers are excited about sepiapterin because it could simplify treatment by reducing the need for strict diets and providing a more consistent response in patients.

What evidence suggests that sepiapterin might be an effective treatment for PKU?

Research has shown that sepiapterin, the treatment under study in this trial, can help people with phenylketonuria (PKU) by lowering high levels of phenylalanine (Phe) in the blood. In previous studies, most participants could eat more foods containing Phe without issues. Sepiapterin reduced blood Phe levels by 20-30%, a significant improvement. This suggests that sepiapterin might help manage PKU and improve quality of life by allowing a more varied diet. Additionally, participants have tolerated it well, experiencing few side effects. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for children with Phenylketonuria (PKU) who have high blood Phe levels but can maintain them within a specific range with diet. They must not have had major surgery recently, be on other trials, or have certain genetic conditions or kidney disease. Girls who can have babies must not be pregnant and agree to use birth control.

Inclusion Criteria

I have PKU with a blood Phe level over 600 μmol/L.

My blood Phe level was below 480 μmol/L within the last month.

Willing to continue prescribed diet during Screening and Part 1

Exclusion Criteria

Any clinically significant laboratory abnormality as determined by the investigator

I have not had major surgery in the last 3 months.

Current participation in another investigational drug study or use of any investigational agent within 30 days prior to Screening

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Sepiapterin-responsiveness test

Participants undergo an open-label sepiapterin-responsiveness test

Duration not specified

Treatment

Participants receive age- and weight-adjusted doses of sepiapterin orally once daily

Up to 6 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Sepiapterin

Trial Overview The trial is testing the long-term effects of a drug called Sepiapterin on brain function in kids with PKU when started early in life. It's checking if this drug helps maintain their thinking and problem-solving abilities over time.

How Is the Trial Designed?

Group I: Sepiapterin Experimental Treatment 1 Intervention

Participants will receive age- and weight-adjusted doses of sepiapterin orally once daily for up to 6 years.

Sepiapterin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Sepiapterin for:

• Phenylketonuria (PKU) - Orphan designation only, not approved for use

Approved in United States as Sepiapterin for:

• No FDA approval yet; NDA submitted for Phenylketonuria (PKU)

Approved in Canada as Sepiapterin for:

• Phenylketonuria (PKU) - Priority review status, not yet approved

Who Is Running the Clinical Trial?

PTC Therapeutics

Lead Sponsor

Trials

75

Recruited

6,300+

Dr. Matthew B. Klein

PTC Therapeutics

Chief Executive Officer since 2023

BA from the University of Pennsylvania, MD from Yale University School of Medicine, MS in Epidemiology from the University of Washington School of Public Health

Dr. Stuart W. Peltz

PTC Therapeutics

Chief Medical Officer since 2023

MD from Harvard Medical School

Published Research Related to This Trial

Sapropterin hydrochloride is a newly approved oral treatment for phenylketonuria (PKU), a metabolic disorder caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH), which leads to high levels of phenylalanine in the blood.

This medication works by acting as a synthetic version of tetrahydrobiopterin, a natural cofactor for PAH, and can effectively lower blood phenylalanine levels in some patients, providing an alternative to the challenging dietary restrictions typically required for managing PKU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New era in treatment for phenylketonuria: Pharmacologic therapy with sapropterin dihydrochloride. Harding, CO.[2022]

Sapropterin dihydrochloride (Kuvan) is an orally active treatment for phenylketonuria (PKU) that can significantly reduce blood phenylalanine (Phe) levels and increase dietary Phe tolerance, potentially allowing patients to relax or discontinue their strict Phe-restricted diet.

The proposed treatment protocol includes a 48-hour loading test followed by a trial period of 1-4 weeks to determine patient responsiveness and optimize dosage, marking a significant advancement in PKU management beyond traditional dietary restrictions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the use of sapropterin (BH(4)) in the management of phenylketonuria. Blau, N., Bélanger-Quintana, A., Demirkol, M., et al.[2023]

Sapropterin dihydrochloride (SD) has been shown to be effective and safe for metabolic control and phenylalanine tolerance in pregnant women with phenylketonuria (PKU) who are responsive to BH4, based on data from eight pregnancies.

All seven pregnancies treated with SD in known BH4-responsive women resulted in normal offspring, while one case of SD use without prior BH4 responsiveness led to severe complications, highlighting the importance of identifying responsive patients before treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of sapropterin dihydrochloride in maternal phenylketonuria. A European experience of eight cases. Feillet, F., Muntau, AC., Debray, FG., et al.[2023]

Tetrahydrobiopterin (BH(4)), available as sapropterin, offers a new treatment option for phenylketonuria (PKU) that may improve metabolic control and increase dietary tolerance for phenylalanine in some patients.

New management recommendations for sapropterin therapy were developed by a group of metabolic dietitians and experienced physicians, focusing on patient selection, monitoring response, and optimizing long-term outcomes through target phenylalanine levels and adherence to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recommendations for the use of sapropterin in phenylketonuria. Cunningham, A., Bausell, H., Brown, M., et al.[2023]

CNSA-001, a novel formulation of sepiapterin, was shown to effectively increase plasma levels of both sepiapterin and BH4 in a Phase I clinical trial involving 83 healthy volunteers, indicating its potential as a treatment for conditions related to BH4 deficiency.

The study demonstrated that CNSA-001 was well tolerated with no serious adverse events, and it produced significantly higher plasma BH4 concentrations compared to the synthetic form of BH4, suggesting it may be a more effective pharmacological agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers. Smith, N., Longo, N., Levert, K., et al.[2023]

In a Phase 2 study involving 24 adults with phenylketonuria (PKU), PTC923 at 60 mg/kg significantly reduced blood phenylalanine (Phe) levels more effectively than sapropterin, with a mean reduction of -206.4 μmol/L compared to -91.5 μmol/L for sapropterin.

PTC923 not only showed a faster onset of action but also demonstrated efficacy in classical PKU subjects, indicating its potential as a superior treatment option for managing elevated Phe levels in PKU patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PTC923 (sepiapterin) lowers elevated blood phenylalanine in subjects with phenylketonuria: a phase 2 randomized, multi-center, three-period crossover, open-label, active controlled, all-comers study. Bratkovic, D., Margvelashvili, L., Tchan, MC., et al.[2023]

Tetrahydrobiopterin (BH(4)), available as sapropterin dihydrochloride (KUVAN), can significantly reduce blood phenylalanine levels in some individuals with phenylketonuria (PKU), potentially allowing for increased dietary tolerance or even the replacement of a phenylalanine-restricted diet.

To determine responsiveness to sapropterin, a recommended challenge involves an initial dose of 20 mg/kg, with blood phenylalanine measurements taken at specific intervals, aiming for at least a 30% reduction in levels to consider the treatment effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH(4)) in phenylketonuria and its use in treatment. Levy, H., Burton, B., Cederbaum, S., et al.[2023]

In a study involving 1189 subjects with Phenylketonuria (PKU), continuous treatment with sapropterin dihydrochloride led to a significant 34% reduction in blood phenylalanine levels over 5 years, improving dietary tolerance for phenylalanine.

The safety profile of sapropterin was found to be tolerable, with only 6% of subjects reporting non-serious drug-related adverse events, and serious adverse events occurring in less than 1% of subjects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety and efficacy of sapropterin: the PKUDOS registry experience. Longo, N., Arnold, GL., Pridjian, G., et al.[2023]

Sapropterin dihydrochloride effectively reduces plasma phenylalanine (Phe) levels in patients with BH4-responsive phenylketonuria (PKU), showing a dose-dependent decrease from an average of 844.0 micromol/L to 645.2 micromol/L over 10 weeks in a study involving 80 patients.

The treatment is well tolerated, with 85% of patients experiencing mild to moderate adverse events, and no serious adverse events were linked to sapropterin, indicating a favorable safety profile for doses ranging from 5 to 20 mg/kg/day over 22 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria. Lee, P., Treacy, EP., Crombez, E., et al.[2023]

A patient with atypical phenylketonuria showed a deficiency in 7, 8-dihydrobiopterin synthetase, as indicated by the presence of neopterin but not biopterin or dihydrobiopterin in urine.

Oral administration of L-sepiapterin significantly reduced serum phenylalanine levels from 17.1 to 1.1 mg/dl within 6 hours, demonstrating its efficacy as a treatment option for managing phenylalanine levels in this patient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atypical phenylketonuria caused by 7, 8-dihydrobiopterin synthetase deficiency. Niederwieser, A., Curtius, HC., Bettoni, O., et al.[2023]

In a study involving 46 children aged 4 to 12 with phenylketonuria (PKU), sapropterin dihydrochloride significantly increased the amount of phenylalanine (Phe) they could tolerate while keeping their blood Phe levels under control.

The treatment was well-tolerated with no severe or serious adverse events reported, indicating that sapropterin has a good safety profile for children with PKU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. Trefz, FK., Burton, BK., Longo, N., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05099640

A Study of PTC923 in Participants With Phenylketonuria The main purpose of this trial is to evaluate the efficacy of PTC923 in reducing blood phenylalanine (Phe) levels in participants with phenylketonuria.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0026049521004169

PTC923 (sepiapterin) lowers elevated blood phenylalanine ... Sapropterin is clinically effective in a minority of subjects with PKU with effectiveness defined as blood Phe reduction ≥20–30%, and permits some relaxation of ...

3. ir.ptcbio.com ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-presents-new-sepiapterin-data-ongoing-studies?mobile=1

PTC Therapeutics Presents New Sepiapterin Data from ... Results show 97% of phenylalanine (Phe) tolerance study participants were able to increase their dietary Phe intake with a mean increase of ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39368841/

Effects of oral sepiapterin on blood Phe concentration in a ... Sepiapterin is a promising oral therapy for individuals with phenylketonuria, was well tolerated, and resulted in significant and clinically meaningful ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06302348

NCT06302348 | A Study of Sepiapterin in Participants With ... The main purpose of this trial is to evaluate the long-term efficacy of sepiapterin on preserving neurocognitive functioning in children with PKU when treatment ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05166161

NCT05166161 | A Long-Term Safety Study of PTC923 in ... The main purpose of this study is to evaluate the long-term safety of PTC923 in participants with phenylketonuria, and to evaluate the changes from baseline in ...

7. ema.europa.eu ema.europa.eu/en/documents/rmp/sephience-epar-risk-management-plan_en.pdf

EU Risk Management Plan Sepiapterin - EMA This study is designed to gather important long-term safety and. Phe tolerance data for sepiapterin in subjects with PKU. As of 02 September ...

8. ir.ptcbio.com ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-fda-approval-sephiencetm-sepiapterin?mobile=1&mobile=1

PTC Therapeutics Announces FDA Approval of Sephience ... PTC Therapeutics Announces FDA Approval of Sephience™ (sepiapterin) for the Treatment of Children and Adults Living with Phenylketonuria (PKU).

9. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2025/219666Orig1s000OtherR.pdf

center for drug evaluation and research - accessdata.fda.gov The human data regarding the safety of sepiapterin during pregnancy are limited to a single subject who had a positive pregnancy test after ...