What is the mechanism of action of this treatment?

Phenylketonuria (PKU) treatments often focus on reducing phenylalanine levels in the blood to prevent neurotoxicity and cognitive impairment. One common treatment is the use of synthetic tetrahydrobiopterin (BH4), which enhances the activity of the enzyme phenylalanine hydroxylase (PAH). By increasing PAH activity, BH4 helps convert phenylalanine to tyrosine more effectively, lowering phenylalanine levels and reducing the risk of neurotoxic effects. This treatment is particularly beneficial for patients with some residual PAH activity, as it allows for a less restrictive diet and improves overall quality of life.

What side effects are associated with this type of intervention?

Common treatments for Phenylketonuria (PKU) include synthetic tetrahydrobiopterin (BH4) analogs like sapropterin, which enhance phenylalanine hydroxylase activity. Known side effects of these treatments can include headaches, gastrointestinal issues such as nausea and diarrhea, and respiratory symptoms like nasal congestion. Additionally, some patients may experience allergic reactions or changes in mood. It is important for patients to discuss these potential side effects with their healthcare provider to manage and mitigate any adverse effects effectively.

What prior FDA approvals exist?

The FDA has approved several treatments for Phenylketonuria (PKU) that focus on enhancing phenylalanine hydroxylase activity. One notable example is sapropterin dihydrochloride (Kuvan), a synthetic form of tetrahydrobiopterin (BH4), which acts as a cofactor for the enzyme phenylalanine hydroxylase, helping to reduce blood phenylalanine levels in patients with PKU. This treatment is similar to PTC923, which is also a synthetic BH4 aimed at improving the enzyme's activity to manage phenylalanine levels.

What other types of research exist?

Promising novel alternatives to PTC923 for Phenylketonuria patients include gene therapy approaches, such as HMI-102, which aims to deliver a functional PAH gene to liver cells, and enzyme substitution therapies like Pegvaliase, which breaks down phenylalanine in the bloodstream. Both therapies are in advanced stages of clinical development and offer potential new treatment options for PKU patients.

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PTC923 for Phenylketonuria

Phase 3

Recruiting

Research Sponsored by PTC Therapeutics

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Clinical diagnosis of PKU with hyperphenylalaninemia (HPA) documented by past medical history of at least 2 blood Phe measurements ≥600 μmol/L

Must not have

Inability to tolerate oral medication

Requirement for concomitant treatment with any drug known to inhibit folate synthesis (for example, methotrexate)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up baseline up to end of study (up to approximately 2.5 years)

Awards & highlights

No Placebo-Only Group

Pivotal Trial

Summary

This trial is testing the safety of a medication called PTC923 in people with phenylketonuria (PKU). PKU patients need to manage their blood phenylalanine levels carefully. PTC923 aims to help control these levels, making it easier for patients to manage their condition. PTC923 is a newer treatment for PKU, following earlier treatments like sapropterin and pegvaliase.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

While specific side effects are not listed here, this trial will monitor any adverse reactions to PTC923 over an extended period as it relates to its safety profile in treating individuals with PKU.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have PKU with two blood tests showing Phe levels over 600 μmol/L.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I cannot take medicine by mouth.

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I am currently taking medication that affects folate synthesis, like methotrexate.

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

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My kidney function is reduced, with a GFR under 60 mL/min/1.73m^2.

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I am currently pregnant, breastfeeding, or considering getting pregnant.

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I am currently taking BH4 supplements or PALYNZIQ.

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I have had surgery on my stomach.

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I have a confirmed diagnosis of BH4 deficiency due to specific genetic mutations.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ baseline up to end of study (up to approximately 2.5 years)

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~baseline up to end of study (up to approximately 2.5 years)

This trial's timeline: 3 weeks for screening, Varies for treatment, and baseline up to end of study (up to approximately 2.5 years) for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Change From Baseline in Dietary Phe/Protein Consumption at Week 26, Measured During Phe Tolerance Assessment Period

Number of Treatment-Emergent Adverse Events (TEAEs)

Secondary study objectives

Change From Baseline in QOL Using the European Quality of Life - 5 Dimensions (EQ-5D) at Months 8, 14, 20, 26, 32, and 38

Change From Baseline in Quality of Life (QOL) Using Phenylketonuria-Quality of Life (PKU-QOL) Questionnaire at Months 8, 14, 20, 26, 32, and 38

Side effects data

From 2023 Phase 3 trial • 157 Patients • NCT05099640

Diarrhoea

Upper respiratory tract infection

100%

80%

60%

40%

20%

Study treatment Arm

Part 2: Placebo

Part 1: Sepiapterin

Part 2: Sepiapterin

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

1Treatment groups

Experimental Treatment

Group I: PTC923Experimental Treatment1 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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

PTC923

2019

Completed Phase 3

~170

0 / 9Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Phenylketonuria (PKU) treatments often focus on reducing phenylalanine levels in the blood to prevent neurotoxicity and cognitive impairment. One common treatment is the use of synthetic tetrahydrobiopterin (BH4), which enhances the activity of the enzyme phenylalanine hydroxylase (PAH). By increasing PAH activity, BH4 helps convert phenylalanine to tyrosine more effectively, lowering phenylalanine levels and reducing the risk of neurotoxic effects. This treatment is particularly beneficial for patients with some residual PAH activity, as it allows for a less restrictive diet and improves overall quality of life.

Recombinant human tyrosine hydroxylase types 1-4 show regulatory kinetic properties for the natural (6R)-tetrahydrobiopterin cofactor.PKU mutation (D143G) associated with an apparent high residual enzyme activity: expression of a kinetic variant form of phenylalanine hydroxylase in three different systems.