CompletedPhase 1ACTRN12622001222730

First in human clinical study of a novel drug JNT-517 to assess its safety and tolerability in healthy volunteers

A phase 1/2, first-in-human, single ascending and multiple dose study of JNT-517 in healthy participants.

Sponsor

CTI Clinical Trial and Consulting Services Australia Pty Ltd.

Enrollment

91 participants

Start Date

Oct 31, 2022

Study Type

Interventional

Conditions

Phenylketonuria

Summary

This will be a Phase 1 first-in-human (FIH) study in 3 parts to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of JNT-517 at various incremental doses administered as single and multiple doses in healthy volunteers. The study will begin with a single ascending dose portion (Part A) followed by the multiple ascending dose portion (Part B), and subsequently followed by high single ascending dose portion (Part F) in healthy volunteers in Australia to evaluate the safety, tolerability, PK, and PD of JNT-517 at various incremental doses.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 55 Yearss

Inclusion Criteria13

Males and females 18 to 55 years of age, inclusive.
Medically healthy with no clinically significant medical history, physical examination, laboratory results, vital signs, or ECGs at Screening and Day 1.
Body mass index (BMI) of 18-40 kg/m2 and total body weight >50 kg.
Non-smoker for at least 2 weeks prior to dosing and willing to abstain during the study.
Females of childbearing potential involved in any sexual intercourse that could lead to pregnancy: the participant must agree to use two highly effective contraceptive methods from Screening until at least 1 week after the last study drug administration.
a. Female participants of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test by Day 1.
Females not of childbearing potential or postmenopausal defined as follows:
a. Have had surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy)
b. Have had amenorrhea for minimum of 1 year with confirmation by levels of follicle stimulating hormone testing
For male participants involved in any sexual intercourse that could lead to pregnancy, participant must agree to use highly effective contraceptive methods from Day 1 until at least 12 weeks after the last study drug administration.
Note: No restrictions are required for males who have undergone a documented vasectomy at least 4 months prior to Screening. If 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.
Participants with psychiatric illness must be well-controlled for last 6 months prior to the Screening visit and if on medication, on stable medications for the last 3 months.
Capable of giving signed informed consent and ability to comply with study procedures.

Exclusion Criteria23

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.
Creatinine clearance <90 mL/min by Cockcroft-Gault formula.
Participation in another investigational drug trial within 30 days or, if known, 5 half-lives of the investigational drug (whichever is longer).
Alcohol consumption within 5 days of randomization and/or unwilling to abstain during the study.
Use of any medications that are inhibitors or inducers of cytochrome P450 (CYP)3A4 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.
Use of any medication that is a substrate of CYP3A4, or a substrate of the transporters P-gp, breast cancer resistance protein (BCRP), organic anion transporter 3 (OAT3), 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.
History of drug/alcohol abuse in the last year.
Inability to tolerate oral medication.
Allergy to JNT-517 or any component of the investigational product.
Given >50 mL of blood or plasma within 30 days of Screening or >500 mL of blood or plasma within 60 days of Screening.
Any of the following laboratory values at the Screening visit:
Alanine aminotransferase or aspartate aminotransferase values >upper limit of normal (ULN)
Total bilirubin >ULN
Haemoglobin <11.0 g/dL (<110.0 g/L)
White blood cell count <4.5 × 10 9/L (<4500/mm3)
Platelet count <150 × 10 9/L (<150,000/mm3)
Smoker (defined as an individual who has used nicotine-containing products, including cigarettes and e-cigarettes) within the last 2 weeks prior to dosing.
Positive for cotinine or drug screen.

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Interventions

Part A is a single ascending dose part of the study in healthy volunteers. It will consist of up to 5 sequential cohorts of 8 participants each. In each cohort, participants will be randomised to receive a single dose of JNT-517 or placebo in a 3:1 ratio (6 participants will receive JNT-517 and 2 - placebo) in a fasted state and in a double-blinded fashion. JNT-517 and placebo will be administered as a suspension orally. The starting dose will be 25 mg of JNT-517. The maximum dose dose will not exceed 240 mg. The maximum dose escalation between cohorts will be no more than 3-fold. A dose level may be repeated or decreased, or a new dose cohort added as required, based on emerging results. Dose escalation to a consecutive higher exposure dose regiment, or to a consecutive study part at the same or lower dose, 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. Part B is a multiple ascending doses part of the study in healthy volunteers. Enrolment in Part B is expected to commence between 5 and 6 weeks after commencement of Part A. It is expected that up to 3 cohorts of 8 participants each will be enrolled. Doses of JNT-517 in Part B will be selected based on blinded review of safety data of single doses in Part A. In each cohort participants will be randomised in double-blinded fashion to receive JNT-517 or placebo in a 3:1 ratio. Participants will receive JNT-517 or matching placebo BID (twice daily) as oral suspension for 14 consecutive days. Morning dose will be administered after an overnight fast (at least 8 hours) and evening dose will be administered between 8 hours and 8 hours and 15 minutes after the morning dose. An additional fourth cohort can be added, during which 8 participants will receive JNT-517 or placebo in a 3:1 ratio once daily for 14 consecutive days. Part F is single ascending dose part of the study, where healthy volunteers will receive JNT-517 or placebo at high doses. Part F of the study commences following completion of Parts A and B of the study. Eligible participants will receive single doses if JNT-517 at high doses in up to 3 sequential cohorts of 9 participants each. In each cohort participants will be randomised to receive a single dose of JNT-517 or placebo in a 2:1 ratio (6 participants will receive JNT-517 and 3 - placebo) in a fasted state and in a double-blind fashion. JNT-517 and placebo will be administered as tablets orally after an at least 8 hours overnight fast. The starting dose will be 300 mg of JNT-517. The maximum dose escalation between cohorts will be no more than 1.5-fold. Dose escalation decisions will be based on satisfactory review of blinded safety, tolerability, and available PK data by the Investigator and the Medical Monitor from at least 6 participants who have completed Day 3 of the previous dose. Inclusion and exclusion criteria for Parts A, B and F are identical. In both parts healthy volunteers will stay in the clinical research unit for the entire duration of dosing and will take study drug under direct supervision of the clinical research unit staff.