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Phenylketonuria – Trials in Disease

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Ongoing Clinical Trials for Phenylketonuria

There are currently 6 clinical trials investigating new treatments for Phenylketonuria, a genetic disorder affecting the body’s ability to process phenylalanine. These studies are being conducted across multiple European countries and involve investigational therapies including sepiapterin, pegvaliase, mRNA-based treatments, and engineered bacteria. The trials are designed to evaluate both the safety and effectiveness of these novel approaches in managing blood phenylalanine levels and improving quality of life for patients. (Also known as: PKU)

Clinical trial locations

Study on the Long-Term Safety of PTC923 (Sepiapterin) for Patients with Phenylketonuria

This trial evaluates the long-term safety of PTC923 (Sepiapterin), a medication taken as an oral powder, for managing Phenylketonuria. The study runs for up to 24 months and monitors how the treatment affects participants’ dietary phenylalanine and protein intake.

Inclusion criteria: Participants of any age and gender can join if they have a clinical diagnosis of PKU with a history of at least two blood phenylalanine levels of 600 micromoles per liter or higher. Women of childbearing potential must have a negative pregnancy test and agree to use effective birth control during the study and for 90 days afterward. Men who are sexually active with women of childbearing potential must use barrier contraception unless they have had a vasectomy. Participants must maintain their current diet unless instructed otherwise by study doctors.

Exclusion criteria: Patients cannot participate if they have serious health conditions that could interfere with the study, are currently in another clinical trial, have had or plan recent surgery, are pregnant or breastfeeding, have a history of drug or alcohol abuse, cannot follow study procedures, have allergies to the study medication, have a history of severe allergic reactions, have mental health conditions affecting participation, or have a history of non-compliance with medical treatments.

Study focus: The primary goal is to assess the long-term safety of PTC923 by monitoring for side effects through regular health assessments including laboratory tests and physical exams. Researchers will also observe changes in dietary phenylalanine and protein consumption, and evaluate quality of life through age-appropriate questionnaires in participants whose primary language is supported by the study.

Investigational drug: PTC923 (Sepiapterin) works by providing a precursor to tetrahydrobiopterin, a cofactor necessary for the proper function of the enzyme that breaks down phenylalanine. This may improve the body’s ability to process phenylalanine and help manage PKU.

Study of Long-Term Neurocognitive Outcomes in Children with Phenylketonuria Treated with Sepiapterin

This study evaluates how well sepiapterin preserves brain function in children with PKU when treatment begins early in childhood. The research follows children under 10 years of age over several years to measure changes in their thinking abilities and intelligence.

Inclusion criteria: Children must be under 10 years old when signing consent. They must have a PKU diagnosis with at least two blood phenylalanine measurements of 600 μmol/L or higher in their medical history. Children 1 month or older need at least one documented blood phenylalanine measurement below 480 μmol/L within 1 month before screening, and two screening values between 120 and 480 μmol/L. Newborns under 1 month must have a newborn screening phenylalanine of 600 μmol/L or higher. Children between 30 months and 10 years must have a baseline intelligence score of 80 or higher. Women who can become pregnant must use effective birth control, and sexually active males must use barrier contraception during the study and for 90 days after.

Exclusion criteria: Children cannot participate if they have a known allergy to sepiapterin or its ingredients, have other medical conditions that might interfere with participation, are in another clinical trial, have severe liver or kidney problems, have a history of not following medical treatments or dietary restrictions, have cognitive impairments preventing understanding of study procedures, have parents unable to provide consent, have previously received sepiapterin treatment, or have been diagnosed with neurological disorders other than PKU.

Study focus: The trial tracks cognitive development through age-appropriate intelligence tests (WPPSI-IV for ages 30 months to 6 years, WISC-V for ages 6 and older) conducted at the start and periodically over 2 and 4 years. Researchers monitor blood phenylalanine levels and assess quality of life using PKU-specific and general health questionnaires. The study aims to determine if sepiapterin provides lasting protection for brain development in children with PKU.

Investigational drug: Sepiapterin is designed to help the body convert phenylalanine into tyrosine, potentially reducing the harmful buildup of phenylalanine in the blood and brain. It belongs to the class of synthetic pterins and acts as a cofactor for the enzyme phenylalanine hydroxylase.

Study Comparing Sepiapterin and Sapropterin for Treating Phenylketonuria in Patients Aged 2 Years and Older

This crossover study compares two treatments for PKU: Sepiapterin, a new medication being tested, and Sapropterin, an existing approved medication. The study aims to determine how effective each treatment is in reducing blood phenylalanine levels.

Inclusion criteria: Participants must be at least 2 years old with a clinical diagnosis of PKU and a history of at least two blood phenylalanine measurements of 600 μmol/L or higher. Blood phenylalanine levels must be at least 360 μmol/L during screening and when averaging the three most recent levels from medical history. Women of childbearing potential must have a negative pregnancy test and use effective birth control during the study and for 90 days after. Men who are sexually active with women of childbearing potential must use barrier contraception for 90 days after the last dose unless they have had a vasectomy at least 16 weeks prior. Participants must maintain their current diet unchanged during the study.

Exclusion criteria: Individuals without a PKU diagnosis cannot participate. Participants must be within the specified age range, and those outside it are excluded. The study seeks specific characteristics in participants, so those not meeting these criteria are excluded.

Study focus: The trial randomly assigns participants to receive either Sepiapterin or Sapropterin for a certain period, then switches them to the other treatment. Researchers monitor blood phenylalanine levels throughout the study to assess how well each treatment works. Some participants may receive a placebo during the study. Regular assessments include physical examinations, vital sign checks, ECGs, and laboratory tests.

Investigational drugs: Sepiapterin enhances the production of tetrahydrobiopterin, a cofactor that helps break down phenylalanine. Sapropterin is a synthetic form of tetrahydrobiopterin that increases the activity of the enzyme phenylalanine hydroxylase, helping convert phenylalanine into substances the body can use.

Study of pegvaliase injections compared to diet control in adolescents aged 12-17 with phenylketonuria (PKU)

This study tests Palynziq (pegvaliase), a medication given as an injection under the skin, in adolescents aged 12-17 years who have not achieved good control of their PKU with diet alone. The trial evaluates if this treatment is safe and effective for young patients.

Inclusion criteria: Participants must be between 12-17 years old (US) or 12-15 years old (non-US). They must have a PKU diagnosis and be unable to maintain recommended blood phenylalanine levels despite previous treatments. At least two blood phenylalanine measurements above 600 µmol/L during screening (taken 7-10 days apart) are required, with average levels above 600 µmol/L over the past 12 months. Participants must be willing to maintain and adjust protein intake under supervision. Those taking medications for ADHD, depression, or other psychiatric conditions must be on stable doses for at least 8 weeks before joining. An adult (18 years or older) must be available to observe the participant during treatment and for one hour afterward. Participants must be in good general health and able to follow all study procedures. Female participants who can become pregnant must have negative pregnancy tests.

Exclusion criteria: Participants cannot join if they are below 12 or above 18 years old, have previously participated in pegvaliase trials, are pregnant or breastfeeding, have a history of severe allergic reactions to medications, have significant liver or kidney problems, are using other experimental treatments, cannot follow dietary restrictions, have mental health conditions interfering with participation, have uncontrolled medical conditions like high blood pressure or diabetes, are taking medications that could interact with the study drug, have a history of substance abuse within the past year, cannot provide informed consent or follow study procedures, have blood disorders, have had major surgery within 3 months, or have active infections or serious illness.

Study focus: The treatment involves receiving subcutaneous injections of Palynziq at different doses (2.5 mg, 10 mg, or 20 mg) using pre-filled syringes. Some participants receive the medication while others continue with dietary management only. The study lasts approximately 215 days, with regular medical check-ups and blood tests to monitor the condition. Healthcare providers track how well the medication helps control blood protein levels and assess the ability to include more protein in the diet. An adult must be present to observe the participant for at least one hour after each injection.

Investigational drug: Pegvaliase is an enzyme replacement therapy that helps the body break down phenylalanine, potentially reducing its levels in the blood. It represents an alternative or supplement to the traditional dietary management of PKU, which involves following a strict diet that limits foods containing phenylalanine such as meat, fish, eggs, dairy products, nuts, and some grains.

Study on the Effectiveness and Safety of SYNB1934 for Adults with Phenylketonuria (PKU)

This trial tests SYNB1934v1, a specially modified strain of bacteria designed to help reduce phenylalanine levels in the blood. The treatment is given as a powder mixed with water and taken by mouth.

Inclusion criteria: Participants must be at least 18 years old. Those aged 12 to 17 may join after the first 20 adults have completed the initial part with special approval. Participants must have a PKU diagnosis and difficulty maintaining recommended blood phenylalanine levels despite current treatments, shown by uncontrolled levels greater than 360 μmol/L during screening and in recent medical history. Women who can have children must have a negative pregnancy test and use highly effective birth control during the study and for 2 weeks after the last dose. Sexually active women of childbearing potential must agree to effective contraception. Participants must have a stable diet, including any special medical formula, for at least 1 month before screening. If using medications like sapropterin or sepiapterin, they must be on a stable dose for at least 3 months before the study. Participants must continue their current diet and medications without changes during the study.

Exclusion criteria: Patients without PKU cannot participate. Those outside the specified age range are excluded. Participants unwilling to follow study procedures, those with other interfering medical conditions, pregnant or breastfeeding women, those in another clinical trial, those with a history of allergic reactions to the study medication, and those who have used certain medications recently that might affect results are excluded.

Study focus: The study is divided into three parts. First, participants receive increasing doses of SYNB1934v1 to find the most effective dose while monitoring blood phenylalanine levels. Second, participants are randomly assigned to continue with the treatment or switch to a placebo for four weeks to compare effectiveness. Finally, all participants receive the treatment in an open-label period to assess long-term safety and tolerability. Some participants may also receive medications like Ondansetron to prevent nausea and Esomeprazole to reduce stomach acid.

Investigational drug: SYNB1934 uses engineered bacteria to consume phenylalanine in the gut, thereby lowering its levels in the bloodstream. It is classified as a therapeutic agent for metabolic disorders.

Study to Evaluate mRNA-3210 for Safety and Tolerability in Patients with Phenylketonuria

This trial evaluates mRNA-3210, a new treatment designed to provide the body with instructions to produce a specific enzyme that helps break down phenylalanine. The treatment is given through an injection into the vein.

Inclusion criteria: Participants must be between 18 and 70 years old and have a confirmed PKU diagnosis due to PAH deficiency through genetic testing. They must have at least three blood phenylalanine levels of 600 μmol/L or higher: two during screening and one from 6 to 24 months before screening. Approval from a study dietitian confirming maintenance of usual protein intake and from the investigator confirming diet alone can control the disease during the study is required. If taking medication for mental health conditions, participants must be on a stable dose before joining and willing to keep it stable unless medically necessary. Sexually active women of childbearing potential and sexually active men must use highly effective birth control during the study and for three months after the last dose.

Exclusion criteria: Participants without PKU, those outside the specified age range, those not meeting specific study characteristics, and vulnerable populations such as children or those unable to give consent cannot participate.

Study focus: The study evaluates the safety and tolerability of mRNA-3210 through a dose escalation approach, meaning doses increase over time. Participants undergo an initial assessment including a review of medical history and genetic testing to confirm PKU diagnosis. Blood samples are taken at least 72 hours apart during screening to measure phenylalanine levels. A study dietitian evaluates dietary protein intake to ensure consistency throughout the study. If applicable, any neuropsychiatric medication must remain stable unless a change is clinically necessary. Regular monitoring includes blood tests to measure changes in phenylalanine levels and to assess pharmacokinetic parameters. The presence and levels of anti-PEG antibodies are also evaluated.

Investigational drug: mRNA-3210 delivers messenger RNA to cells, instructing them to produce specific proteins that may be deficient or dysfunctional in PKU. It falls under the pharmacological classification of gene therapy products and is currently in Phase 1/2 clinical trials.

Summary

The six ongoing clinical trials for Phenylketonuria reflect diverse therapeutic approaches to managing this metabolic disorder. A notable concentration of research activity is focused on sepiapterin, with three trials evaluating this treatment across multiple European countries. These studies examine sepiapterin’s long-term safety, its effects on preserving neurocognitive function in children, and its effectiveness compared to the existing treatment sapropterin.

Geographically, the trials show significant activity in Central and Western Europe, with France, Poland, Germany, Italy, and Spain hosting multiple studies. This distribution suggests strong research infrastructure and patient populations in these regions. Denmark is unique in hosting both a sepiapterin trial and a study evaluating SYNB1934, a novel bacteria-based therapy.

The investigational treatments represent different therapeutic mechanisms. Sepiapterin and sapropterin work by enhancing the body’s natural ability to break down phenylalanine through cofactor supplementation. Pegvaliase, being tested in Germany for adolescents, uses enzyme replacement therapy. SYNB1934 employs engineered bacteria to consume phenylalanine in the gut, while mRNA-3210 uses gene therapy principles to instruct cells to produce necessary enzymes.

Age-specific studies are also notable, with dedicated trials for children under 10 years and adolescents aged 12-17 years, reflecting the importance of early intervention in PKU management and the need for age-appropriate treatment options. The long-term nature of several studies, with some extending up to 4 years, demonstrates commitment to understanding the lasting effects and safety profiles of these novel therapies.

Ongoing Clinical Trials on Phenylketonuria

  • A Study of Repinatrabit Compared to Placebo for Treatment of Patients with Phenylketonuria

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    Investigated diseases:
    Czechia France Germany Italy The Netherlands Poland +1

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