The goal of this Phase 3, open-label study is to evaluate the long-term safety of JNT-517 in pediatric and adult participants with Phenylketonuria (PKU) after completion of either Study JNT517-101 (NCT05781399) or JNT517-201 (NCT06637514) as well as participants who have not participated in a prior JNT-517 study. In this trial, all participants will receive JNT-517 using age- and weight-banded dosing as outlined in the protocol, regardless of any dose received in a previous study.

Key Inclusion Criteria:

1. Diagnosis of phenylketonuria (ie, PAH deficiency) by either molecular testing or biochemical criteria consistent with the applicable regional guidelines.

2. Participants 4 years of age and older, inclusive, at time of Screening.

3. Not on pegvaliase within 4 weeks of Screening.

4. Not on sepiapterin within 2 weeks of Screening.

5. If on sapropterin or large neutral amino acids at Screening, must be on a stable dose for 4 weeks prior to Screening.

6. Willing and able to maintain a diet consistent in Phe content from the Screening period through the duration of the study, unless otherwise directed by a dietician as allowed in the protocol.

7. Body weight ≥ 12.5 kg.

8. If female of childbearing potential:

   1. Must have a negative serum pregnancy test at Screening and a negative urine pregnancy test by Day 1.
   2. 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 method must be highly effective, from Screening until at least 30 days after the last study drug administration.
   3. Must refrain from donating ova during the course of the study and for 30 days after the last dose of the study drug.

9. Is a female not of childbearing potential or postmenopausal, defined as follows:

   1. Has had surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy).
   2. Has had amenorrhea for minimum of 1 year with confirmation by levels of follicle stimulating hormone testing.
   3. 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 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 method 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 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. Capable of giving signed informed consent, or parent/legal guardian to provide informed consent and pediatric participant to give assent, and be able to comply with study procedures.

12. Participants with psychiatric illness must be well-controlled for the last 3 months prior to screening visit and, if on medication, on stable medications for the last 3 months.

Key Exclusion Criteria:

1. Participation in this study is not considered safe and/or feasible in the opinion of the Investigator.

2. Participants have not completed a previous JNT-517 study and are eligible for another active JNT-517 trial at the site, unless approval is obtained from the medical monitor.

3. Any acute or 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.

4. Positive for hepatitis B or C or human immunodeficiency virus.

5. Any history of significant liver disease.

6. Any history of cataracts or more than minimal cataracts observed during the Screening ophthalmologic examination.

7. Any surgical or medical conditions that may affect study drug absorption, distribution, metabolism, or excretion.

8. Estimated glomerular filtration rate < 60 milliliters per minute per 1.73 square meters (mL/min/1.73 m^2) by 2021 Chronic Kidney Disease Epidemiology Collaboration formula (participants aged 17 years or greater) or by Schwartz formula (participants aged 4 to 16 years of age).

9. History of drug or alcohol abuse in the last year.

10. Use of any medication that are inhibitors or inducers of cytochrome P450 (CYP)3A4 or inhibitors of the transporter P glycoprotein (P-gp) within 4 weeks prior to the first dose of study drug and unwilling and/or unable to avoid these medications throughout the treatment duration.

11. Use of any medications that are a substrate of breast cancer resistance protein (BCRP), multidrug and toxin extrusion (MATE)1, MATE2-K, organic anion transporter 3 (OAT3), or CYP3A4 within 4 weeks prior to the first dose of study drug and unwilling and/or unable to avoid these medications throughout the treatment duration (Appendix A). CYP3A4 substrates may be allowed if reduction in exposure is not expected to impact safety of the participant after consultation with the Medical Monitor.

    NOTE: Participants of childbearing potential 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.

12. Current, recent, or suspected infection within 2 weeks of Screening of Severe Acute Respiratory Syndrome Coronavirus 2/Coronavirus Disease 2019 (SARS-CoV-2/COVID-19).

13. Unable to tolerate oral medication or inability to swallow tablets.

14. Allergy to JNT-517 or any component of the investigational product.

15. Any of the following laboratory values at the Screening visit:

    1. Alanine aminotransferase or aspartate aminotransferase values ˃ 1.5 x the upper limit of normal (ULN).
    2. Total bilirubin ˃ULN unless history of Gilbert Syndrome and then total bilirubin >4 milligrams per deciliter [mg/dL] is exclusionary.
    3. Hemoglobin ˂10.0 g/dL (˂100.0 grams per liter [g/L])
    4. White blood cell count ˃1 x ULN
    5. Platelet count ˂150 × 109/L (˂150,000/cubic millimeters[mm^3])

16. Participation in another investigational drug trial within 30 days (other than for JNT-517) or, if known 5 half-lives of investigational drug (whichever is longer).

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 on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/