Phenylketonuria (PKU) Nutritional, Metabolic, Endocrine
Conditions
Interventions
The study consists of two parts:
In Part 1 all enrolled participants will receive 60 mg/kg per day of the study drug sepiapterin for 2 weeks followed by a minimum 14-day sepiapterin washout period.
Sponsors
PTC Therapeutics (United States)
Eligibility
Sex/Gender
All
Age
2 Years to 99 Years
Inclusion criteria
Inclusion criteria: Participants with any PAH mutation are permitted to screen and enroll into the study. However, participants with biochemically diagnosed classical PKU will be capped at 30% of the total study population. Biochemically diagnosed classical PKU includes those with =2 historical blood Phe concentrations =1200 µmol/L in their medical history. Furthermore, participants with initial newborn screen performed >3 days after birth demonstrating values =1200 µmol/L may have these values excluded from the =2 historical blood Phe concentration requirement. Genotyping will not be required for study eligibility; however, all participants will undergo genotyping unless documented in their medical history, and these data will be collected for analysis. Participants are eligible to be included in the study only if all the following criteria apply: 1. Informed consent, and if necessary, assent (with parent/legally designated representative consent) 2. Male or female participants =2 years of age 3. Uncontrolled blood Phe level =360 µmol/L on current therapy at any time 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) 4. Clinical diagnosis of PKU with hyperphenylalaninemia documented by past medical history of at least 2 blood Phe measurements =600 µmol/L 5. Women of childbearing potential, as defined in (CTFG 2020), must have a negative pregnancy test at Screening and agree to abstinence or the use of at least one highly effective form of contraception (with a failure rate of <1% per year when used consistently and correctly): 5.1. Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: 5.1.1. Oral 5.1.2. Intravaginal 5.1.3. Transdermal 5.2. Progestogen-only hormonal contraception associated with inhibition of ovulation: 5.2.1. Oral 5.2.2. Injectable 5.2.3. Implantable 5.3. Intrauterine device 5.4. Intrauterine hormone-releasing system 5.5. Bilateral tubal occlusion 5.6. Vasectomized partner with confirmed azoospermia Highly effective contraception or abstinence must be continued for the duration of the study and for up to 90 days after the last dose of the study drug. All females will be considered of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age group without other known or suspected cause) or have been permanently sterilized surgically (eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy). 6. 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 the study drug. Males must also refrain from sperm donations during this time period. Males who are abstinent will not be required to use a contraceptive method unless they become sexually active. Males who have undergone a vasectomy are not required to use a contraceptive method if at least 16 weeks post-procedure. 7. Willing and able to comply with the protocol and study procedures 8. Willing to continue current diet unchanged while participating in the study
Exclusion criteria
Exclusion criteria: 1. The individual, in the opinion of the investigator, is unwilling or unable to adhere to the requirements of the study. Incapacitated adults are not eligible for participation in this study. 2. Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, chronic gastritis, peptic ulcer disease, etc.) that could affect the absorption of study drug 3. History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy 4. Inability to tolerate oral medication 5. History of allergies or adverse reactions to synthetic BH4 or sepiapterin 6. Current participation in any other investigational drug study or use of any investigational agent within 30 days prior to Screening 7. Any clinically significant laboratory abnormality as determined by the investigator. In general, each laboratory value from Screening and baseline chemistry and hematology panels should fall within the limits of the normal laboratory reference range, unless deemed not clinically significant by the investigator 8. A female who is pregnant or breastfeeding, or considering pregnancy 9. Serious neuropsychiatric illness (eg, 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 10. Past medical history and/or evidence of renal impairment and/or condition including moderate/severe renal insufficiency (glomerular filtration rate [GFR] <60 mL/min) and/or under care of a nephrologist 11. Any abnormal physical examination and/or laboratory findings indicative of signs or symptoms of renal disease, including calculated GFR <60 mL/min/1.73m2 In participants =18 years of age, the Modification of Diet in Renal Disease Equation should be used to determine GFR. In participants <18 years, the Bedside Schwartz Equation should be used to determine GFR. 12. Requirement for concomitant treatment with levodopa or with any drug known to inhibit folate synthesis (eg, methotrexate) 13. Confirmed diagnosis of a primary BH4 deficiency as evidenced by biallelic pathogenic mutations in 6-pyruvoyltetrahydropterin synthase, recessive guanosine triphosphate (GTP) cyclohydrolase I, sepiapterin reductase, quinoid dihydropteridine reductase, or pterin 4-alpha-carbinolamine dehydratase genes 14. Major surgery within the prior 90 days of Screening 15. Unwillingness to washout from BH4 supplementation (eg, sapropterin dihydrochloride, KUVAN) 16. Use of pegvaliase-pqpz (PALYNZIQ) concurrently or within the 60 days prior to Screening 17. Greater than 20% variance in dietary Phe consumption as measured by mandatory weekly 3-day diet record collection for 4 consecutive weeks (Dietary Control Observation Period during Screening)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Mean change in blood phenylalanine levels is measured using an HPLC/MS/MS method from baseline to Weeks 3 and 4 (i.e., the average of the 2-week treatment period of each treatment). Dried blood spots (DBS) will be collected on Days -1, 1, 7, 10, 14, 19, 24, & 28 in Part 2, Treatment Periods 1 and 2. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. The proportion of participants with baseline blood phenylalanine (Phe) levels =600 µmol/L who achieve Phe levels <600 µmol/L after each treatment period is measured by an HPLC/MS/MS method. Dried blood spots (DBS) will be collected on Days -1, 1, 7, 10, 14, 19, 24, & 28 in Part 2, Treatment Periods 1 and 2. 2. The proportion of participants reaching blood Phe <360 µmol/L after each treatment period is measured by an HPLC/MS/MS method. DBS will be collected on Days -1, 1, 7, 10, 14, 19, 24, & 28 in Part 2, Treatment Periods 1 and 2. 3. Adverse events measured using records that are collected throughout the study. 4. Physical examinations are assessed at Screening, Part 1 Day 1; Part 2 Treatment Periods 1 and 2 – Days 1 and 28, Early Termination Visit (if applicable), and End of Study Visit 5. Vital signs are assessed at Screening, Part 1 Day 1; Part 2 Treatment Periods 1 and 2 – Days 1 and 28, Early Termination Visit (if applicable), and End of Study Visit 6. 12-lead ECGs are assessed at Part 1 Day 1; Part 2 Treatment Periods 1 and 2 – Day 28, Early Termination Visit (if applicable), and End of Study Visit 7. Clinical laboratory assessments are assessed at Screening, Part 1 Day 1; Part 2 Treatment Periods 1 and 2 – Days 1 and 28, Early Termination Visit (if applicable), and End of Study Visit | — |
Countries
Australia, Canada, Czech Republic, Denmark, England, France, Germany, Italy, Netherlands, Poland, Slovenia, Spain
Contacts
Public ContactMed Info
Outcome results
None listed