First-in-Human, Multiple Part Clinical Study of JNT-517 in Healthy Participants and in Participants With Phenylketonuria

Study Overview
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Brief Summary
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The goal of Parts A and B of this Phase 1, 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 4 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 1b in participants with PKU (4 weeks)-randomized, double-blind, placebo-controlled In each part, participants will complete a Screening Period, a Treatment Period, and a Follow-up Period for safety.

Official Title
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A Phase 1, First-In-Human, Multiple Part, Single Ascending and Multiple Dose Study of JNT-517 in Healthy Participants and in Participants With Phenylketonuria

Conditions
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Phenylketonuria

Intervention / Treatment
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* Drug: JNT-517 Suspension
* Drug: Placebo Suspension
* Drug: JNT-517 Tablet
* Drug: Placebo Tablet


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Parts A, B, and C: Males and females 18 to 55 years of age. Medically healthy with no clinically significant medical history. Body mass index (BMI) of 18-40 kg/m2 and total body weight >50 kg (110 lbs). Non-smoker for at least 2 weeks prior to dosing and willing to abstain during the study. Part D: Males and females 18 to 65 years of age, inclusive. Diagnosis of PKU with a confirmed genotype. At least 2 plasma Phe levels >600 μM over the past 12 months. BMI of 18-40 kg/m2. All Parts: Females of childbearing potential must agree to use 2 highly effective contraceptive methods. Capable of giving signed informed consent and able to comply with study procedures. Key Exclusion Criteria: All Parts: 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. Positive for hepatitis B or C or human immunodeficiency virus. Any history of malignancy in the last 5 years, excluding non-melanoma skin cancer. Any history of liver disease. Any surgical or medical conditions that may affect study drug absorption, distribution, metabolism, or excretion. Participation in another investigational drug trial within 30 days or, if known, 5 half-lives of the investigational drug (whichever is longer). History of drug/alcohol abuse in the last year. Current, recent, or suspected infection within 4 weeks of Screening of SARS-CoV-2/COVID-19. Received a vaccine for SARS-CoV-2/COVID-19 within 14 days of Screening. Unable to tolerate oral medication. Allergy to JNT-517 or any component of the investigational product. Received >50 mL of blood or plasma within 30 days of Screening or >500 mL of blood or plasma within 60 days of Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study will be conducted in 4 parts: Parts A, B, C, and D. 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JNT-517 SAD (Part A)<br>Single dose of JNT-517 or placebo in fasted state. | Drug: JNT-517 Suspension<br>* JNT-517 in on-site compounded suspension<br>Drug: Placebo Suspension<br>* On-site compounded placebo suspension<br>|
| Experimental: JNT-517 MAD (Part B)<br>JNT-517 or placebo once or twice daily for 14 days, with first daily dose given after an overnight fast. | Drug: JNT-517 Suspension<br>* JNT-517 in on-site compounded suspension<br>Drug: Placebo Suspension<br>* On-site compounded placebo suspension<br>|
| Experimental: JNT-517 Suspension Then Tablet Fasted Then Tablet Fed (Part C)<br>Single dose of JNT-517 suspension, JNT-517 tablet in a fasted state, and JNT-517 tablet in a fed state in a sequential, open-label manner. Each treatment is separated by a minimum of 5 half-lives. | Drug: JNT-517 Suspension<br>* JNT-517 in on-site compounded suspension<br>Drug: JNT-517 Tablet<br>* JNT-517 tablets, 25 mg and 75 mg<br>|
| Experimental: JNT-517 Tablet Fasted Then Tablet Fed Then Suspension (Part C)<br>Single dose of JNT-517 tablet in a fasted state, JNT-517 tablet in a fed state, and JNT-517 suspension in a sequential, open-label manner. Each treatment is separated by a minimum of 5 half-lives. | Drug: JNT-517 Suspension<br>* JNT-517 in on-site compounded suspension<br>Drug: JNT-517 Tablet<br>* JNT-517 tablets, 25 mg and 75 mg<br>|
| Experimental: JNT-517 Tablet Fed Then Suspension Then Tablet Fasted (Part C)<br>Single dose of JNT-517 tablet in a fed state, JNT-517 suspension, and JNT-517 tablet in a fasted state in a sequential, open-label manner. Each treatment is separated by a minimum of 5 half-lives. | Drug: JNT-517 Suspension<br>* JNT-517 in on-site compounded suspension<br>Drug: JNT-517 Tablet<br>* JNT-517 tablets, 25 mg and 75 mg<br>|
| Experimental: JNT-517 PKU (Part D)<br>JNT-517 or placebo daily for 4 weeks. Dose is based on data from Parts A, B, and C. | Drug: JNT-517 Tablet<br>* JNT-517 tablets, 25 mg and 75 mg<br>Drug: Placebo Tablet<br>* Matching film-coated placebo tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-emergent adverse events | Reported based on results of 12-lead ECGs, vital signs, clinical laboratory tests, and other medical assessments. | Parts A and C: Screening to Day 8; Part B: Screening to Day 21; Part D: Screening to Day 35 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma area under the concentration-time curve (AUC) of JNT-517 |  | Parts A and C: 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: pre-dose to 4 hrs post-dose on Days 1, 14, 28 | 
| Maximum observed plasma concentration (Cmax) of JNT-517 |  | Parts A and C: 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: pre-dose to 4 hrs post-dose on Days 1, 14, 28 | 
| Time to maximum plasma concentration (Tmax) of JNT-517 |  | Parts A and C: 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: pre-dose to 4 hrs post-dose on Days 1, 14, 28 | 
| Plasma terminal half-life (t1/2) of JNT-517 |  | Parts A and C: 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: pre-dose to 4 hrs post-dose on Days 1, 14, 28 | 
| Comparison of Tmax of JNT-517 in fed and fasted states | Part C only | Pre-dose to 72 hrs post-dose on Day 1 | 
| Comparison of Cmax of JNT-517 in fed and fasted states | Part C only | Pre-dose to 72 hrs post-dose on Day 1 | 
| Comparison of AUC of JNT-517 in fed and fasted states | Part C only | Pre-dose to 72 hrs post-dose on Day 1 | 
| Changes in urinary amino acid levels | Part D only. Urine samples will be collected at the indicated timepoints and analyzed for amino acid levels, including Phe. | Screening and Days 1, 7, 14, 21, 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PKU