Phenylketonuria
Conditions
Keywords
PKU
Brief summary
The goal of Parts A and B of this Phase 1/2, first-in-human, randomized study is to assess the safety, tolerability, and pharmacokinetics (PK) of single (SAD) and multiple (MAD) ascending doses of oral JNT-517 in healthy participants. In Part C, the goal is to evaluate the differences in bioavailability between a tablet and suspension formulation of JNT-517 and the food effect in healthy volunteers. All participants in Part C will receive JNT-517. The goal of Part D is to assess the safety, tolerability, PK, and effect on urinary Phe and other amino acids of JNT-517 in participants with phenylketonuria (PKU). Participants in Part D will receive either JNT-517 or placebo and will be blinded to their treatment assignment. The study consists of 6 parts: * Part A: SAD in healthy participants -randomized, double-blind, placebo-controlled * Part B: MAD in healthy participants (14 days)-randomized, double-blind, placebo-controlled * Part C: Relative bioavailability of 2 formulations and food effect in healthy participants-randomized, open-label * Part D: Phase 2 in participants with PKU (4 weeks)-randomized, double-blind, placebo-controlled * Part E: Phase 2 in participants with PKU (4 weeks) open label * Part F: SAD Phase 1 in healthy participants, randomized, double-blind, placebo-controlled In each part, participants will complete a Screening Period, a Treatment Period, and a Follow-up Period for safety.
Interventions
DRUGJNT-517 Suspension
JNT-517 in on-site compounded suspension
On-site compounded placebo suspension
DRUGJNT-517 Tablet
JNT-517 tablets, 25 mg and 75 mg
DRUGPlacebo Tablet
Matching film-coated placebo tablet
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Parts A, B, D, and F are blinded. Parts C and E are open-label.
Intervention model description
The study will be conducted in 6 parts: Parts A, B, C,D, E, and F. This study will be seamless, meaning various study parts could begin while other parts are still ongoing, but dose escalation will occur only after satisfactory review of safety and tolerability data from a minimum of 6 participants completing through Day 3, and available PK data.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: Parts A, B, C, and F: 1. Males and females 18 to 55 years of age. 2. Medically healthy with no clinically significant medical history. 3. Body mass index (BMI) of 18-40 kg/m2 and total body weight \>50 kg (110 lbs). 4. Non-smoker for at least 2 weeks prior to dosing and willing to abstain during the study. Part D and E: 5. Males and females 18 to 65 years of age, inclusive. 6. Diagnosis of PKU with a confirmed genotype. 7. At least 2 plasma Phe levels \>600 μM over the past 12 months. 8. BMI of 18-40 kg/m2. All Parts: 9. Females of childbearing potential must agree to use 2 highly effective contraceptive methods. 10. Capable of giving signed informed consent and able to comply with study procedures. Key
Exclusion criteria
All Parts: 1. 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. 2. Positive for hepatitis B or C or human immunodeficiency virus. 3. Any history of malignancy in the last 5 years, excluding non-melanoma skin cancer. 4. Any history of liver disease. 5. Any surgical or medical conditions that may affect study drug absorption, distribution, metabolism, or excretion. 6. Participation in another investigational drug trial within 30 days or, if known, 5 half-lives of the investigational drug (whichever is longer). 7. History of drug/alcohol abuse in the last year. 8. Current, recent, or suspected infection within 4 weeks of Screening of SARS-CoV-2/COVID-19. 9. Received a vaccine for SARS-CoV-2/COVID-19 within 14 days of Screening. 10. Unable to tolerate oral medication. 11. Allergy to JNT-517 or any component of the investigational product. 12. Received \>50 mL of blood or plasma within 30 days of Screening or \>500 mL of blood or plasma within 60 days of Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with treatment-emergent adverse events | Parts A/C/F: Screening to Day 8; Part B: Screening to Day 21; Part D/E: Screening to Day 35 | Reported based on results of 12-lead ECGs, vital signs, clinical laboratory tests, and other medical assessments. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum observed plasma concentration (Cmax) of JNT-517 | Parts A/C/F: pre-dose to 72 hrs post-dose on Day 1; Part B: pre-dose to 24 hrs post-dose on Days 1, 14 and pre-dose on Days 3, 13; Part D/E: pre-dose to 4 hrs post-dose on Days 1, 14, 28 | — |
| Time to maximum plasma concentration (Tmax) of JNT-517 | Parts A/C/F: pre-dose to 72 hrs post-dose on Day 1; Part B: pre-dose to 24 hrs post-dose on Days 1, 14 and pre-dose on Days 3, 13; Part D/E: pre-dose to 4 hrs post-dose on Days 1, 14, 28 | — |
| Plasma terminal half-life (t1/2) of JNT-517 | Parts A/C/F: pre-dose to 72 hrs post-dose on Day 1; Part B: pre-dose to 24 hrs post-dose on Days 1, 14 and pre-dose on Days 3, 13; Part D/E: pre-dose to 4 hrs post-dose on Days 1, 14, 28 | — |
| Plasma area under the concentration-time curve (AUC) of JNT-517 | Parts A/C/F: pre-dose to 72 hrs post-dose on Day 1; Part B: pre-dose to 24 hrs post-dose on Days 1, 14 and pre-dose on Days 3, 13; Part D/E: pre-dose to 4 hrs post-dose on Days 1, 14, 28 | — |
| Comparison of Cmax of JNT-517 in fed and fasted states | Pre-dose to 72 hrs post-dose on Day 1 | Part C only |
| Comparison of AUC of JNT-517 in fed and fasted states | Pre-dose to 72 hrs post-dose on Day 1 | Part C only |
| Changes in urinary amino acid levels | Screening and Days 1, 7, 14, 21, 28 | Part D/E only. Urine samples will be collected at the indicated timepoints and analyzed for amino acid levels, including Phe. |
| Comparison of Tmax of JNT-517 in fed and fasted states | Pre-dose to 72 hrs post-dose on Day 1 | Part C only |
Countries
Australia, United States
Outcome results
None listed