A Study of PTC923 in Participants With Phenylketonuria
- Registration Number
- NCT05099640
- Lead Sponsor
- PTC Therapeutics
- Brief Summary
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
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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 157
- 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.
- 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 1: PTC923 PTC923 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. Part 2: PTC923 PTC923 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. Part 2: Placebo Placebo Participants will receive equivalent quantities of placebo to match the 20 to 40 to 60 mg/kg dose escalation of the PTC923 treatment arm.
- Primary Outcome Measures
Name Time Method Part 2 Double-blind Phase: Mean Change From Baseline in Blood Phenylketonuria (Phe) Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1 Baseline, Weeks 5 and 6 (average of the 2-week period) Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window. Least square (LS) mean and standard error (SE) were calculated using mixed model repeated measures (MMRM) method.
Part 2 Double-blind Phase: Percent Change From Baseline in Blood Phe Level to Weeks 5 and 6 (Averaged Over a 2-week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1 Baseline, Weeks 5 and 6 (average of the 2-week period) Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window. LS mean and SE were calculated using MMRM method.
- Secondary Outcome Measures
Name Time Method Part 2 Double-blind Phase: Percentage of Participants With Baseline Phe Levels ≥600 μmol/L Who Achieved Phe Levels <600 μmol/L in Participants With Phe Reduction From Baseline ≥30% During Part 1 Weeks 5 and 6 (average of the 2-week period) Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window.
Part 2 Double-blind Phase: Percentage of Participants With Baseline Phe Levels ≥360 μmol/L Who Achieved Phe Levels <360 μmol/L in Participants With Phe Reduction From Baseline ≥30% During Part 1 Weeks 5 and 6 (average of the 2-week period) Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean level at Weeks 5 and 6 was calculated as the average of blood Phe levels collected during the Week 5-6 analysis visit window.
Part 2 Double-blind Phase: Percent Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1 Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period) Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean levels at Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 were calculated as the average of blood Phe levels collected during the Week 1-2, Week 3-4, and Week 5-6 analysis visit windows, respectively.
Part 1 Open-label Run-in Phase: Plasma Concentration of Tetrahydrobiopterin (BH4) and Sepiapterin Predose, 0.5, 1, 2, 4, 6, 8, and 24 hours postdose at Day 1; 2 and 6 hours postdose at Day 14 Part 2 Double-blind Phase: Mean Change From Baseline in Blood Phe Level at Each 2-Week Period (Averaged Over Each 2-Week Period) in Participants With Phe Reduction From Baseline ≥30% During Part 1 Baseline, Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 (average of each 2-week period) Baseline was defined as the average of Day -1 and Day 1 predose blood Phe levels in Part 2, and mean levels at Weeks 1 and 2, Weeks 3 and 4, and Weeks 5 and 6 were calculated as the average of blood Phe levels collected during the Week 1-2, Week 3-4, and Week 5-6 analysis visit windows, respectively.
Part 2 Double-blind Phase: Plasma Concentration of BH4 and Sepiapterin Predose and 4 hours postdose at Days 1, 14, 28, and 42 Part 1 Open-label Run-in Phase: Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) of Sepiapterin and BH4 Following the First Dose of Sepiapterin at 60 mg/kg 0 to 24 hours postdose at Day 1 Number of Participants With Treatment-emergent Adverse Events (TEAEs) Baseline up to Day 42 An adverse event (AE) was as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. TEAEs were considered:
* Part 1 TEAEs, which included all AEs occurring after first dose in Part 1 but before first dose in Part 2;
* Part 2 TEAEs, which included all AEs after first randomized dose in Part 2. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Trial Locations
- Locations (43)
Bretonneau Hospital - CHRU de Tours
🇫🇷Tours, Centre-Val De Loire, France
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
Icahn School of Medicine at Mount Sinai (ISMMS)
🇺🇸New York, New York, United States
Hospital de clinicas de Porto Alegre
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
UPMC Children's Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
University of Texas Health Science Center of Texas
🇺🇸Houston, Texas, United States
Stanford University Center for Academic Medicine
🇺🇸Stanford, California, United States
Children's Medical Center Dallas
🇺🇸Dallas, Texas, United States
Centro Hospitalar Universitário Do Porto, Epe
🇵🇹Porto, Douro Litoral, Portugal
Great Ormond Street Hospital
🇬🇧London, United Kingdom
Ege University Faculty of Medicine Children Hospital
🇹🇷Bornova, Izmir, Turkey
Indiana University School of Medicine
🇺🇸Indianapolis, Indiana, United States
University of Utah, Division of Medical Genetics (pediatric and adult clinic)
🇺🇸Salt Lake City, Utah, United States
Birmingham Children's Hospital NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
Universitätsklinikum Münster
🇩🇪Münster, Germany
Westmead Hospital
🇦🇺Westmead, New South Wales, Australia
The Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
PARC Clinical Research
🇦🇺Adelaide, South Australia, Australia
Royal Melbourne Hospital
🇦🇺Melbourne, Victoria, Australia
Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo
🇧🇷Ribeirão Preto, São Paulo, Brazil
Metabolics and Genetics in Calgary (MAGIC) Clinic, Ltd.
🇨🇦Calgary, Alberta, Canada
The Hospital for Sick Children University of Toronto, Adult Clinic: The Fred A Litwin Family Centre in Genetic Medicine University Health Network & Mt. Sinai Hospital
🇨🇦Toronto, Ontario, Canada
Copenhagen University Hospital, Rigshospitalet
🇩🇰Copenhagen, Denmark
Pediatric Surgery Center
🇬🇪Tbilisi, Georgia
University Children's Hospital Hamburg Eppendorf (Kinder-UKE) Klinik für Kinder- und Jugendmedizin (Kinder-UKE)
🇩🇪Hamburg, Germany
CHRU de Tours- Hôpital Pédiatrique de Clocheville
🇫🇷Tours, Centre-Val De Loire, France
Policlinico Umberto I
🇮🇹Rome, Lazio, Italy
İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi
🇹🇷Fatih, Istanbul, Turkey
Universitätsklinikum Heidelberg / Zentrum für Kinder- und Jugendmedizin / Sektion für Neuropädiatrie & Stoffwechselmedizin
🇩🇪Heidelberg, Germany
Grupo Médico Camino SC
🇲🇽Benito Juarez, Mexico City, Mexico
Division of Inherited Metabolic Diseases, Azienda Ospedaliera-Università Padova
🇮🇹Padua, Veneto, Italy
PanAmerican Clinical Research
🇲🇽Guadalajara, Jalisco, Mexico
Hospital Universitario Ramón y Cajal
🇪🇸Madrid, Spain
CENTRO HOSPITALAR UNIVERSITÁRIO LISBOA NORTE Hospital de Santa Maria
🇵🇹Lisboa, Estremadura, Portugal
UMCG Beatrix Children's Hospital
🇳🇱Groningen, Netherlands
CENTRO HOSPITALAR UNIVERSITÁRIO LISBOA NORTE Hospital de Santa Maria,
🇵🇹Lisboa, Estremadura, Portugal
Hospital Sant Joan de Déu
🇪🇸Barcelona, Esplugues De Llobregat, Spain
Gazi Üniversitesi Tıp Fakültesi
🇹🇷Yenimahalle, Ankara, Turkey
Hacettepe University Medical Faculty
🇹🇷Altındağ, Ankara, Turkey
Cukurova Üniversity Balcali Hospital Health Application and Research Center
🇹🇷Adana, Turkey
University of Colorado and the Children's Hospital CO
🇺🇸Aurora, Colorado, United States
UF College of Medicine, Department of Pediatrics Division of Genetics and Metabolism
🇺🇸Gainesville, Florida, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States