PTC923 for Phenylketonuria

Recruiting at 78 trial locations

Overseen By Aneal Khan

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: PTC Therapeutics

Must not be taking: Folate inhibitors, BH4 supplements

Disqualifiers: Pregnancy, Renal impairment, Neuropsychiatric illness, 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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This clinical trial tests a new treatment called PTC923 (also known as Sepiapterin) for individuals with phenylketonuria (PKU), a condition where the body cannot effectively break down the amino acid phenylalanine. The trial aims to determine if PTC923 is safe for long-term use and how it impacts diet and protein intake. Individuals diagnosed with PKU and high phenylalanine levels in their blood may be suitable candidates for this trial. Participants must be able to take oral medication and maintain their current diet throughout the study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment for PKU.

Will I have to stop taking my current medications?

The trial requires that you do not take any medications that inhibit folate synthesis or certain supplements like tetrahydrobiopterin (BH4) or pegvaliase-pqpz. If you're on these, you may need to stop them to participate.

Is there any evidence suggesting that PTC923 is likely to be safe for humans?

Research has shown that PTC923 is generally safe for people with phenylketonuria (PKU). In earlier studies, PTC923 demonstrated a good safety record, with participants experiencing few side effects, mostly mild. Additionally, PTC923 effectively reduced high levels of phenylalanine, which is important for managing PKU.

The treatment is now in an advanced research stage, indicating strong confidence in its safety. While current studies examine long-term safety, the evidence so far reassures those considering joining the trial. ^{1 2 3 4 5}

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

PTC923 is unique because it offers a new approach for treating phenylketonuria (PKU) by acting as a synthetic form of tetrahydrobiopterin (BH4), a cofactor that helps break down phenylalanine. Unlike traditional treatments that often rely on strict dietary restrictions to manage phenylalanine levels, PTC923 aims to lower these levels by enhancing the activity of the enzyme that breaks down phenylalanine. Researchers are excited about PTC923 because it could simplify management for patients with PKU, potentially reducing the need for stringent diet control and improving quality of life.

What evidence suggests that PTC923 might be an effective treatment for phenylketonuria?

Research has shown that PTC923, also known as sepiapterin, can significantly lower blood phenylalanine (Phe) levels in individuals with phenylketonuria (PKU). Studies have found it more effective than sapropterin in reducing Phe levels. Patients in clinical trials have tolerated oral sepiapterin well. The treatment has led to significant reductions in Phe levels, which is crucial for managing PKU. These findings suggest that PTC923 could serve as an effective treatment for PKU. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for individuals with Phenylketonuria (PKU) who have had high blood phenylalanine levels. They must stick to their current diet unless told otherwise, not be on certain other PKU treatments, and use effective contraception if applicable. People with significant lab abnormalities, renal disease, gastrointestinal issues that affect drug absorption, or serious uncontrolled neuropsychiatric illness cannot join.

Inclusion Criteria

I agree to use birth control and not donate sperm during and up to 90 days after the study.

Women of childbearing potential must have a negative pregnancy test at screening and agree to abstinence or the use of at least one highly effective form of contraception for the duration of the study, and for up to 90 days after the last dose of the study drug

Willing to continue current diet unchanged while participating in the study (unless specifically instructed to change diet during the study by the investigator)

Exclusion Criteria

I have a stomach or bowel condition that could affect how I absorb medication.

I cannot take medicine by mouth.

I have kidney problems with a GFR under 60 mL/min.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive PTC923 orally once daily for a minimum of 12 months

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to approximately 2.5 years

Long-term safety evaluation

Evaluation of long-term safety and changes in dietary Phe/protein consumption

up to approximately 2.5 years

What Are the Treatments Tested in This Trial?

Interventions

• PTC923

Trial Overview The study tests the long-term safety of a drug called PTC923 in people with PKU. It also looks at how the treatment might allow participants to change their dietary intake of phenylalanine/protein from what they usually consume.

How Is the Trial Designed?

Group I: PTC923 Experimental Treatment 1 Intervention

Participants will receive PTC923 7.5 mg/kg (participants 0 to \<6 months of age), 15 mg/kg (participants 6 to \<12 months of age), 30 mg/kg (participants 12 months to \<2 years of age), or 60 mg/kg (participants ≥2 years of age) orally once daily for a minimum of 12 months or until participant experiences lack of efficacy, adverse events (AEs) that lead to discontinuation, withdraws from treatment, or PTC923 is authorized and commercially available in the specific country.

PTC923 is already approved in United States, European Union for the following indications:

Approved in United States as PTC923 for:

• Phenylketonuria (PKU)
• Hyperphenylalaninemia

Approved in European Union as PTC923 for:

• Phenylketonuria (PKU)
• Hyperphenylalaninemia

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

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]

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]

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]

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]

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]

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]

In a study of 127 PKU patients in Croatia, only 36% were found to be BH4-responsive, which is significantly lower than expected, highlighting the need for careful genotype assessment in predicting treatment response.

The p.E390G mutation was consistently associated with BH4-responsiveness, while other single allele mutations were not reliable indicators for selecting candidates for BH4 therapy, emphasizing the importance of a full genotype for effective treatment planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency. Karacić, I., Meili, D., Sarnavka, V., et al.[2023]

In a study of 557 newborns and children with varying degrees of phenylketonuria (PKU), 48% of patients showed a significant reduction in blood phenylalanine levels after treatment with 6R-tetrahydrobiopterin (BH4), indicating that BH4 responsiveness is more common than previously thought.

The study established that patients with mild hyperphenylalaninemia and mild PKU had higher responsiveness rates (79%-83% and 49%-60%, respectively), suggesting that selection criteria for BH4 treatment should consider a 20%-40% reduction in phenylalanine levels after 24 hours.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria. Fiege, B., Blau, N.[2023]

Sapropterin dihydrochloride, a pharmacological treatment for phenylketonuria (PKU), has been shown to significantly reduce blood phenylalanine levels and increase dietary tolerance in some patients, particularly those with milder forms of the condition.

This treatment offers a promising alternative to the lifelong dietary restrictions typically required for PKU management, although more research is needed to understand its long-term effects and safety, especially in neuropsychological outcomes and during pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sapropterin dihydrochloride: a new drug and a new concept in the management of phenylketonuria. Trefz, FK., Belanger-Quintana, A.[2023]

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]

A survey of 166 healthcare professionals revealed that long-term responsiveness to tetrahydrobiopterin (BH4) in phenylketonuria (PKU) patients is commonly defined by factors such as natural protein tolerance (95.6%) and improvement in metabolic control (73.5%).

There is significant variability in the definitions of BH4 responsiveness, with different cut-off values for phenylalanine reduction and protein tolerance reported, indicating a need for a standardized, evidence-based definition to enhance treatment quality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defining tetrahydrobiopterin responsiveness in phenylketonuria: Survey results from 38 countries. Evers, RAF., van Wegberg, AMJ., Ahring, K., et al.[2023]

Citations

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

PTC923 (sepiapterin) lowers elevated blood phenylalanine ... PTC923 treatment significantly reduced blood phenylalanine (Phe) in PKU subjects. PTC923 is significantly more effective than sapropterin in reducing blood Phe.

2. 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.

3. 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 ...

4. clinicaltrials.ptcbio.com clinicaltrials.ptcbio.com/trials/PTC923-MD-004-PKU

A Long-Term Safety Study of PTC923 in Participants With ... 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 ...

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2025/219666Orig1s000IntegratedR.pdf

219666Orig1s000 INTEGRATED REVIEW - accessdata.fda.gov Sepiapterin was administered with food in clinical efficacy and safety trials in PKU patients. It is recommended to administer sepiapterin ...

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. 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 ...

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

center for drug evaluation and research - accessdata.fda.gov The major efficacy and safety endpoint data were verifiable. 2. Roberto T. Zori, M.D.. Protocol PTC923-MD-003-PKU, Site 501. 1600 South West ...

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

eu risk management plan sepiapterin This study is designed to gather important long-term safety and. Phe tolerance data for sepiapterin in subjects with PKU. As of 02 September ...