A Phase 3 Study of JNT-517 in Participants with Phenylketonuria

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Otsuka Pharmaceutical Development & Commercialization Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10], Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

16 Jan 2026 → ongoing

Decision date (initial)

2025-11-04

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Otsuka Pharmaceutical Development and Commercialization Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the efficacy of JNT-517 150 mg twice daily (BID) compared with placebo during 6 weeks of double-blind treatment (Period 1)

Secondary objectives 8

1. To assess the effects of JNT-517 doses of 75 mg BID and 150 mg BID compared with placebo on plasma Phe during Period 1
2. To assess effects of JNT-517 doses of 75 mg BID and 150 mg BID compared with placebo treatment on the attention deficit hyperactivity disorder rating scale 5 (ADHD-RS-5) inattentive subscore during Period 1
3. Effects of JNT-517 on dietary Phe intake during Period 2
4. Safety and tolerability of JNT-517 doses of 75 mg BID and 150 mg BID in Periods 1 and 2
5. To assess the effects of JNT-517 doses of 75 mg BID and 150 mg BID in plasma Phe levels in Period 1
6. To assess the effects of JNT-517 doses of 75 mg BID and 150 mg BID in plasma Phe levels in Period 2
7. To assess effects of JNT-517 treatment on Clinical Outcome Assessments during Periods 1 and 2
8. Effects of JNT-517 on dietary Phe/protein intake during Period 2

Conditions and MedDRA coding

Phenylketonuria

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003531-PIP01-23

Plan to share IPD

Yes

IPD plan description

Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing. Data will be available after marketing approval in global markets or beginning 1-3 years following article publication. There is no end date to the availability of the data. Otsuka will share data supported by the protocol, statistical analysis plan (SAP) and clinical study report (CSR) on the Vivli data sharing platform which can be found here:https://vivli.org/ourmember/Otsuka/

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Males and females ≥18 years of age on Day 1
2. Clinical diagnosis of PKU
3. Average of at least 3 plasma Phe levels (after ≥4-hour fast) during Screening period of ≥360 µmol/L
4. Not on pegvaliase within 4 weeks prior to Screening
5. If on sapropterin or large neutral amino acids, such as PheBloc®, NeoPhe®, and PreKunil® at Screening, must be on a stable dose 4 weeks prior to Screening and for the entire study duration.
6. Willing and able to maintain a stable diet in Phe and total protein (intact protein and medical food protein) and able to adjust diet through the duration of the study according to the Dietary Management Guidelines
7. Body weight >40 kg
8. If biologically female of childbearing potential: a. Must have a negative serum pregnancy test at Screening and a negative urine pregnancy test by Day 1 b. Must practice sexual abstinence, or if involved in any sexual intercourse that could lead to pregnancy, must agree to use 2 different contraceptive methods, where at least 1 must be highly effective, from Screening until at least 30 days after the last study drug administration c. If taking estrogen- or progesterone-based oral contraceptives, must agree to use 2 other methods of contraception, where at least 1 must be highly effective, or must agree to sexual abstinence during the study d. Must refrain from donating ova during the course of the study and for 30 days after the last dose of the study drug.
9. If a biologically female not of childbearing potential or postmenopausal, defined as follows: a. Has had surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) b. Has had amenorrhea for minimum of 1 year with confirmation by levels of follicle stimulating hormone testing c. Has not achieved menarche (has not had first menstrual period). If a female achieves menarche during the study, she will need to follow the contraception requirement for females of childbearing potential
10. If biologically male, must practice sexual abstinence, or if involved in any sexual intercourse that could lead to pregnancy, must agree to use 2 different contraceptive methods, where at least 1 must be highly effective, from Day 1 until at least 30 days after the last study drug administration and must refrain from donating sperm during the course of the study and for 30 days after the last dose of the study drug NOTE: No restrictions are required for biological males who have undergone a documented vasectomy at least 4 months prior to Screening. If the vasectomy procedure is not documented or was performed less than 4 months prior to Screening, males must follow the same contraception as for non-vasectomized participants.
11. Participants with psychiatric illness must be well-controlled for the last 6 months prior to the Screening visit and if on medication, on stable medications for the last 3 months.
12. Capable of giving signed informed consent and confirm able to comply with study procedures

Exclusion criteria 16

1. Any acute or uncontrolled chronic medical condition that would prevent the participant from complying with the procedures or place the participant at risk if they participate in the study
2. Positive for hepatitis B or C or human immunodeficiency virus
3. Any history of malignancy of any organ system (other than non-melanoma skin cancer or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
4. Any history of significant liver disease
5. Any history of cataracts or more than minimal cataracts observed during the Screening ophthalmologic examination. Minimal cataracts are defined as changes similar to lens opacities classification system III (LOCS III), lens grade C1, N1 or P1
6. Any surgical or medical conditions that may affect study drug absorption, distribution, metabolism, or excretion
7. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 by 2021 Chronic Kidney Disease Epidemiology Collaboration formula
8. Participation in another investigational drug trial within 30 days or, if known, 5 half-lives of the investigational drug (whichever is longer). For gene therapy or editing trials, participants must have received the intervention >6 months prior to Screening visit and with stable plasma Phe in the past 2 months prior to Screening visit
9. Alcohol consumption within 5 days of randomization and/or unwilling to limit to 1 alcoholic drink per day until after the 6-month study visit
10. History of drug/alcohol abuse in the last year
11. Use of any medications that are inhibitors or inducers of cytochrome P450 (CYP3A4) or inhibitors of the transporter P-glycoprotein (P-gp) within 4 weeks prior to randomization and unwilling and/or unable to avoid these medications throughout the treatment duration
12. Use of any medications that are substrates of breast cancer resistance protein (BCRP), multidrug and toxin extrusion (MATE)1, or MATE2-K within 4 weeks prior to randomization and unwilling and/or unable to avoid these medications throughout the treatment duration NOTE: Participants will be permitted to continue with estrogen- or progesterone-based oral contraceptives, but must agree to use 2 other methods of contraception, where at least 1 must be highly effective, or must agree to sexual abstinence during the study.
13. Current, recent, or suspected active viral or bacterial infection within 2 weeks prior to and during the Screening Period
14. Unable to tolerate oral medication or have a condition that would interfere with the absorption of JNT-517
15. Allergy to JNT-517 or any component of the investigational product
16. Any of the following laboratory values at the Screening visit: -Alanine aminotransferase or aspartate aminotransferase values >1.5× the upper limit of normal (ULN) -Total bilirubin ˃ULN unless history of Gilbert Syndrome and then total bilirubin >4 mg/dL is exclusionary -Hemoglobin <11.0 g/dL (<110.0 g/L) -White blood cell count >ULN -Platelets <150 × 109/L (<150,000/mm3)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Absolute change in plasma phenylalanine (Phe) levels from baseline to mean of Weeks 2, 4, and 6 in the JNT-517 150 mg BID dose group at end of Period 1

Secondary endpoints 8

1. Percent change in plasma Phe levels from baseline to mean of Weeks 2, 4, and 6 in the JNT-517 150 mg BID group at end of Period 1. Participants achieving plasma Phe <600 µmol/L at end of Period 1 among those with baseline ≥600 µmol/L in the 150 mg BID and 75 mg BID groups, respectively. Participants achieving plasma Phe levels <360 µmol/L at end of Period 1 in the 150 mg BID and 75 mg BID groups, respectively... (contd)
2. Change from baseline in the ADHD-RS-5 inattentive subscore in participants with baseline inattentive subscore >9 in the JNT-517 150 mg BID and 75 mg BID dose groups, respectively at end of Period 1.
3. Change from baseline in dietary Phe intake as determined by 3-day diet diary reports and while achieving plasma Phe <360 µmol/L in those participating in the diet normalization.
4. Incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs in Periods 1 and 2.
5. Participants with reduction from baseline ≥30% and ≥50% in plasma Phe levels at Week 6 in Period 1. Participants achieving plasma Phe levels <120 µmol/L at end of Period 1 in the 150 mg BID and 75 mg BID groups, respectively. Absolute and percent change in plasma Phe from baseline to Weeks 2, 4, and 6 of Period 1 in the 150 mg BID and 75 mg BID groups, respectively.
6. Participants achieving plasma Phe <600 µmol/L among the participants with a baseline Phe ≥600 µmol/L in each of the JNT 517 75 mg BID and 150 mg BID dose groups at end of Period 2. Participants who achieve plasma Phe levels <360 µmol/L in each of the JNT-517 75 mg BID and 150 mg BID dose groups at end of Period 2. Participants who achieve plasma Phe levels <120 µmol/L in each of the JNT-517 75 mg BID and 150 mg BID dose groups at end of Period 2... (contd)
7. Change from baseline in the Cambridge Neuropsychological Test Automated Battery (CANTAB) stop signal reaction time in each of the JNT-517 75 mg BID and 150 mg BID dose groups, respectively, at the end of Period 1. Change from baseline in CANTAB stop signal reaction time in both JNT-517 dose groups during Period 2. Change from baseline in ADHD-RS-5 inattentive subscore in participants with baseline inattentive subscore >9 in both JNT 517 dose groups during Period 2.
8. Change from baseline in dietary protein intake while maintaining plasma Phe <360 µmol/L in those participating in the diet normalization. Participants achieving the recommended dietary allowance (RDA) for natural intact protein intakes while maintaining plasma Phe <360 µmol/L in those participating in the diet normalization. Participants achieving 2 × RDA for natural intact protein intakes, consistent with an unrestricted diet, while maintaining plasma Phe <360 µmol/L... (contd)

Investigational products

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

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Otsuka Pharmaceutical Development & Commercialization Inc.

Sponsor organisation

Otsuka Pharmaceutical Development & Commercialization Inc.

Address

2440 Research Boulevard

City

Rockville

Postcode

20850-3238

Country

United States

Scientific contact point

Organisation

Otsuka Pharmaceutical Development & Commercialization Inc.

Contact name

Fernanda Leal-Pardinas

Public contact point

Organisation

Otsuka Pharmaceutical Development & Commercialization Inc.

Contact name

Leslyn Hermonstine

Third parties 15

Locations

7 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

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

Documents 59 files

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

Application history

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