A Phase 3, Randomized, Crossover, Open-Label, Active-Controlled Study of Sepiapterin versus Sapropterin in Participants With Phenylketonuria ≥2 years of Age

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

10 May 2024 → 13 Mar 2025

Decision date (initial)

2024-04-16

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

PTC Therapeutics, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

To compare the efficacy of sepiapterin to sapropterin in reducing blood Phe levels in participants with PKU

Secondary objectives 2

1. To evaluate the efficacy of sepiapterin in reducing blood Phe levels
2. To assess the safety and tolerability of sepiapterin

Conditions and MedDRA coding

Phenylketonuria

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Informed consent, and if necessary, assent (with parent/legally designated representative consent)
2. Male or female participants ≥2 years of age
3. Blood Phe level ≥360 μmol/L on current therapy anytime during Screening and 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): 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 ie, fertile, following menarche and until becoming 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 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 17

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 any of the ingredients or excipients of 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, 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Mean change in blood Phe levels from baseline to Weeks 3 and 4 of each treatment period (the average of the last 2 weeks of each treatment period) in Part 2

Secondary endpoints 3

1. Proportion of participants with baseline blood Phe levels ≥600 µmol/L who achieve Phe levels <600 µmol/L after each treatment period in Part 2
2. Proportion of participants reaching blood Phe <360 µmol/L after each treatment period in Part 2
3. AEs, physical examinations, vital sign assessments, 12-lead ECGs, and routine clinical laboratory assessments

Investigational products

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

Test 2

Comparator 1

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 8

Locations

9 EU/EEA countries · 13 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 47 files

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

Application history

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