A Phase 3 Open-Label Study of PTC923 (Sepiapterin) in Phenylketonuria

Overview

Sponsor-declared trial summary

Key facts

Sponsor

PTC Therapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Metabolism [G03]

Trial duration

28 Sep 2022 → ongoing

Decision date (initial)

2024-10-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

PTC Therapeutics Inc.

External identifiers

EU CT number

2023-509229-31-00

EudraCT number

2021-000497-28

ClinicalTrials.gov

NCT05166161

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Safety

To evaluate the long-term safety of PTC923 in subjects with PKU.
To evaluate changes from baseline in dietary Phe/protein consumption.

Secondary objectives 4

1. To evaluate PTC923 effect on quality of life (QOL) using the Phenylketonuria-quality of life (PKU-QOL) questionnaire in the subset of subjects who are able to complete the PKU-QOL (ie, subjects whose primary language is English [British or American], Turkish, Dutch, German, Spanish, Italian, Portuguese, or French) (ages 6 to 8 years Parent PKU-QOL; ages 9 to 11 years Child PKU-QOL; ages 12 to 17 years Adolescent PKU-QOL; ages ≥18 years Adult PKU-QOL)
2. To evaluate PTC923 effect on QOL using the European Quality of Life - 5 Dimensions (EQ-5D) (EQ-5D for Youth [EQ-5D-Y] Proxy Version 1 [3 to 7 years]; EQ-5D-Y [8 to 15 years]; EQ-5D – 5 Levels (EQ-5D-5L) ([≥16 years])
3. To evaluate the pharmacokinetics (PK) of sepiapterin and tetrahydrobiopterin (BH4) following PTC923 dosing
4. To assess the taste, palatability, and acceptability of PTC923 (non-feeder subjects <18 years)

Conditions and MedDRA coding

Metabolic Disorders - Phenylketonuria

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-003027-PIP02-23

Plan to share IPD

No

IPD plan description

Data from all sites participating in the study will be pooled and analyzed by the sponsor or the sponsor’s designee. The first publication of the study results shall be made in conjunction with the results from other study sites as a multicenter publication. If a multicenter publication is not forthcoming within 24 months of completion of the study at all sites, the investigator may publish or present the results generated at his or her site. Individual participant data (IPD) sharing plan The data-sharing plans for the current study are unknown and will be made available at a later date. IPD sharing plan summary Data sharing statement to be made available at a later date

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Informed consent and assent (if necessary, at the investigator’s discretion [ie, for children]) with parental/legal guardian consent
2. Male or female subjects of any age
3. Clinical diagnosis of PKU with HPA documented by past medical history of at least 2 blood Phe measurements ≥600 μmol/L
4. Women of childbearing potential, as defined in the Clinical Trial Facilitation Group guidance (CTFG 2020), must have a negative pregnancy test at study entry 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): • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: − Oral − Intravaginal − Transdermal • Progestogen-only hormonal contraception associated with inhibition of ovulation: − Oral − Injectable − Implantable • Intrauterine device • Intrauterine hormone-releasing system • Bilateral tubal occlusion • 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).
5. 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.
6. Willing and able to comply with the protocol and study procedures.
7. Willing to continue current diet unchanged while participating in the study (unless specifically instructed to change diet during the study by the investigator).
8. 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.

Exclusion criteria 17

1. The individual, in the opinion of the investigator, is unwilling or unable to adhere to the requirements of the study
2. Inability to tolerate oral medication
3. A female who is pregnant or breastfeeding, or considering pregnancy
4. Serious neuropsychiatric illness (eg, major depression) not currently under medical control, that in the opinion of the investigator or PTC, would interfere with the subject’s ability to participate in the study or increase the risk of participation for that subject
5. Past medical history and/or evidence of renal impairment and/or condition including moderate/severe renal insufficiency (glomerular filtration rate [GFR] <60 mL/min as estimated most recently during qualifying participation in a feeder study) and/or under care of a nephrologist
6. Any other condition that in the opinion of the investigator or PTC, would interfere with the subject’s ability to participate in the study or increase the risk of participation for that subject
7. Requirement for concomitant treatment with any drug known to inhibit folate synthesis (eg, methotrexate)
8. Concomitant treatment with BH4 supplementation (eg, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ)
9. Additional criteria for subjects who did not participate in a feeder 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
10. Additional criteria for subjects who did not participate in a feeder study: History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy
11. Additional criteria for subjects who did not participate in a feeder study: History of allergies or adverse reactions to synthetic BH4 or sepiapterin
12. Additional criteria for subjects who did not participate in a feeder study: Current participation in any other investigational drug study or use of any investigational agent within 30 days prior to Screening
13. Additional criteria for subjects who did not participate in a feeder study: 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
14. Additional criteria for subjects who did not participate in a feeder study: Any abnormal physical examination and/or laboratory findings indicative of signs or symptoms of renal disease, including calculated GFR <60 mL/min/1.73 m2. In subjects ≥18 years of age, the Modification of Diet in Renal Disease Equation should be used to determine GFR. In subjects <18 years of age, the Bedside Schwartz Equation should be used to determine GFR.
15. Additional criteria for subjects who did not participate in a feeder study: Confirmed diagnosis of a primary BH4 deficiency as evidenced by biallelic pathogenic mutations in 6-pyruvoyltetrahydropterin synthase, recessive GTP cyclohydrolase I, sepiapterin reductase, quinoid dihydropteridine reductase, or pterin-4-alpha-carbinolamine dehydratase genes
16. Additional criteria for subjects who did not participate in a feeder study: Major surgery within the prior 90 days of screening
17. Additional criteria for subjects who did not participate in a feeder study: Unwillingness to washout from BH4 supplementation (eg, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety of long-term treatment with PTC923 will be measured by number of treatment-emergent adverse events (TEAEs), including assessment of severity of TEAEs, clinical laboratory tests, vital signs, and physical examinations.
2. The primary efficacy endpoint is the change from baseline in dietary Phe/protein consumption measured during Dietary Phe Tolerance Assessment period.

Secondary endpoints 4

1. Changes from baseline in QOL using PKU-QOL questionnaire in the subset of subjects who are able to complete the PKU-QOL (ie, subjects whose primary language is English [British or American], Turkish, Dutch, German, Spanish, Italian, Portuguese, or French) (ages 6 to 8 years Parent PKU-QOL; ages 9 to 11 years Child PKU-QOL; ages 12 to 17 years Adolescent PKU-QOL; ages ≥18 years Adult PKU-QOL)
2. Changes from baseline in QOL using the EQ-5D (EQ-5D-Y Proxy Version 1 [3 to 7 years]; EQ-5D-Y [8 to 15 years]; EQ-5D-5L ([≥16 years])
3. PK assessment of sepiapterin and BH4 concentrations in plasma following dosing of sepiapterin
4. Acceptability scores (<12 years); taste and palatability scores (<18 years)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

PTC Therapeutics Inc.

Sponsor organisation

PTC Therapeutics Inc.

Address

500 Warren Corporate Center Drive

City

Warren

Postcode

07059

Country

United States

Scientific contact point

Organisation

PTC Therapeutics Inc.

Contact name

Kim Ingalls

Public contact point

Organisation

PTC Therapeutics Inc.

Contact name

Kim Ingalls

Third parties 7

Locations

10 EU/EEA countries · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 120 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

13 submissions — initial application plus substantial / non-substantial modifications