A Study of PTC923 in Participants With Phenylketonuria

Study Overview
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Brief Summary
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The main purpose of this trial is to evaluate the efficacy of PTC923 in reducing blood phenylalanine (Phe) levels in participants with phenylketonuria as measured by mean change in blood Phe levels from baseline to Weeks 5 and 6 (that is, the average of each respective treatment dose 2-week period of double-blind treatment).

Detailed Description
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The study includes 2 parts: Part 1 and 2. Part 1 of the study tests for responsiveness to PTC923, with 14 days of open-label treatment with PTC923. At the end of treatment in Part 1, the mean change in blood Phe levels over the 14-day treatment period for all participants will be assessed against their pretreatment (baseline) blood Phe level. Participants ≥2 years of age who experience a <15% reduction in blood Phe levels will be classified as non-responsive and participation in the study will be terminated. Participants (≥2 years of age) who experience a ≥15% reduction in blood Phe levels will continue into Part 2. Participants <2 years of age who experience ≥15% reduction in blood Phe levels will be offered the option to enroll directly into an open-label extension Study PTC923-MD-004-PKU. Participants <2 years of age who experience a <15% reduction in blood Phe levels will be classified as nonresponsive, and participation in the study will be terminated. Following the minimum 14-day PTC923 washout period, all eligible participants will be randomized in Part 2 to receive either PTC923 or placebo. After 6 weeks of treatment with either PTC923 or placebo, participants will be offered the option to enter an open-label extension Study PTC923-MD-004-PKU (NCT05166161).

Official Title
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A Phase 3 Study of PTC923 in Subjects With Phenylketonuria

Conditions
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Phenylketonuria

Intervention / Treatment
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* Drug: PTC923
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Uncontrolled blood Phe level ≥360 μmol/L on current therapy anytime during screening and uncontrolled blood Phe level ≥360 μmol/L on current therapy when taking the average of the 3 most recent Phe levels from the participant's medical history (inclusive of the screening value). Clinical diagnosis of phenylketonuria with hyperphenylalaninemia (HPA) documented by past medical history of at least 2 blood Phe measurements ≥600 μmol/L. 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 study drug. Males who are sexually active with women of childbearing potential who have not had a vasectomy must agree to use a barrier method of birth control during the study and for up to 90 days after the last dose of study drug. Males must also refrain from sperm donations during this time period. Willing to continue current diet unchanged while participating in the study. Exclusion Criteria: Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, chronic gastritis, and peptic ulcer disease, etc.) that could affect the absorption of study drug. History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy. History of allergies or adverse reactions to synthetic tetrahydrobiopterin (BH4) or sepiapterin. Current participation in any other investigational drug study or use of any investigational agent within 30 days prior to screening. Any clinically significant laboratory abnormality as determined by the investigator. A female who is pregnant or breastfeeding, or considering pregnancy. Serious neuropsychiatric illness (for example, major depression) not currently under medical control, that in the opinion of the investigator or sponsor, would interfere with the participant's ability to participate in the study or increase the risk of participation for that participant. Past medical history and/or evidence of renal impairment and/or condition including moderate/severe renal insufficiency (glomerular filtration rate [GFR] <60 milliliters [mL]/minute [min]) and/or under care of a nephrologist. Any abnormal physical examination and/or laboratory findings indicative of signs or symptoms of renal disease, including calculated GFR <60 mL/min/1.73 square meter (m^2). Requirement for concomitant treatment with any drug known to inhibit folate synthesis (for example, methotrexate). Confirmed diagnosis of a primary BH4 deficiency as evidenced by biallelic pathogenic mutations in 6-pyruvoyltetrahydropterin synthase, recessive guanosine-5'-triphosphate (GTP) cyclohydrolase I, sepiapterin reductase, quinoid dihydropteridine reductase, or pterin-4-alpha-carbinolamine dehydratase genes. Major surgery within the prior 90 days of screening. Concomitant treatment with BH4 supplementation (for example, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ). Unwillingness to washout from BH4 supplementation (for example, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ)
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: PTC923<br>Participants will receive PTC923 7.5 milligrams (mg)/kilogram (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 14 days. | Drug: PTC923<br>* PTC923 powder for oral use will be suspended in water or apple juice prior to administration.<br>|
| Experimental: Part 2: PTC923<br>Participants will receive PTC923 20 mg/kg daily for Weeks 1 and 2, then PTC923 40 mg/kg daily for Weeks 3 and 4, then PTC923 60 mg/kg daily for Weeks 5 and 6. | Drug: PTC923<br>* PTC923 powder for oral use will be suspended in water or apple juice prior to administration.<br>|
| Placebo Comparator: Part 2: Placebo<br>Participants will receive equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the PTC923 treatment arm. | Drug: Placebo<br>* Placebo matching to PTC923<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Phe Levels at Part 2 Weeks 5 and 6 | Baseline blood Phe level will be the mean of Day -1 and Day 1 (predose) blood Phe levels. | Baseline, Weeks 5 and 6 (average of the 2-week period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Baseline Phe Levels ≥600 micromoles (μmol)/liter (L) who Achieved Phe Levels <600 μmol/L at the End of the Double-Blind Treatment Period |  | Baseline to Week 6 | 
| Change From Baseline in Mean Blood Phe Levels at Each PTC923 Dose Level (Average of the Each 2-Week Period in Part 2) | Baseline blood Phe level will be the mean of Day -1 and Day 1 (predose) blood Phe levels. | Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 |