Inclusion Criteria:
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 kilograms (kg)
8. If biologically 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 highly effective contraceptive methods from Screening until at least 30 days after the last study drug administration
3. If taking estrogen- or progesterone-based oral contraceptives, must agree to use 2 other highly effective methods of contraception or must agree to sexual abstinence during the study
4. 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:
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 biologically male, must practice sexual abstinence, or if involved in any sexual intercourse that could lead to pregnancy, must agree to use highly effective contraceptive methods 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 or parent/legal guardian to provide informed consent and the participant to give assent and confirm able to comply with study procedures
Exclusion Criteria:
Participants will be excluded from the study if any of the following criteria are met:
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 milligrams per deciliter (mg/dL) is exclusionary-Hemoglobin <11.0 grams per deciliter (g/dL) \[<110.0 grams per liter (g/L)\]-White blood cell count >ULN-Platelets <150 × 10\^9/Liter (L) (<150,000/cubic millimeters \[mm\^3\]).