REPINATRABIT for Phenylketonuria

Inclusion criteria

• {"criterion_text":"- Males and females ≥18 years of age on Day 1\n- Clinical diagnosis of PKU\n- Average of at least 3 plasma Phe levels (after ≥4-hour fast) during Screening period of ≥360 µmol/L\n- Not on pegvaliase within 4 weeks prior to Screening\n- 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.\n- 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\n- Body weight >40 kg\n- If biologically female of childbearing potential: a.\tMust have a negative serum pregnancy test at Screening and a negative urine pregnancy test by Day 1 b.\tMust 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 must be highly effective, from Screening until at least 30 days after the last study drug administration c.\tIf taking estrogen- or progesterone-based oral contraceptives, 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 d.\tMust refrain from donating ova during the course of the study and for 30 days after the last dose of the study drug.\n- If a biologically female not of childbearing potential or postmenopausal, defined as follows: a.\tHas had surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) b.\tHas had amenorrhea for minimum of 1 year with confirmation by levels of follicle stimulating hormone testing c.\tHas 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\n- If biologically 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 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 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.\n- 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.\n- Capable of giving signed informed consent and confirm able to comply with study procedures"}

Exclusion criteria

• {"criterion_text":"- 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\n- Positive for hepatitis B or C or human immunodeficiency virus\n- 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\n- Any history of significant liver disease\n- 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\n- Any surgical or medical conditions that may affect study drug absorption, distribution, metabolism, or excretion\n- Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 by 2021 Chronic Kidney Disease Epidemiology Collaboration formula\n- 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\n- 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\n- History of drug/alcohol abuse in the last year\n- 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\n- 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.\n- Current, recent, or suspected active viral or bacterial infection within 2 weeks prior to and during the Screening Period\n- Unable to tolerate oral medication or have a condition that would interfere with the absorption of JNT-517\n- Allergy to JNT-517 or any component of the investigational product\n- 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 mg/dL is exclusionary -Hemoglobin <11.0 g/dL (<110.0 g/L) -White blood cell count >ULN -Platelets <150 × 109/L (<150,000/mm3)"}

Primary endpoints

• {"endpoint_text":"- Absolute change in plasma phenylalanine (Phe) levels from baseline to mean of Weeks 2, 4, and 6 in the JNT-517 150 mg BID dose group at end of Period 1","definition_or_measurement_approach":"Absolute change in plasma phenylalanine (Phe) from baseline to the mean of Weeks 2, 4 and 6 (measured plasma Phe levels) in the JNT-517 150 mg BID group at end of Period 1"}

Secondary endpoints

• {"endpoint_text":"- Percent change in plasma Phe levels from baseline to mean of Weeks 2, 4, and 6 in the JNT-517 150 mg BID group at end of Period 1. Participants achieving plasma Phe <600 µmol/L at end of Period 1 among those with baseline ≥600 µmol/L in the 150 mg BID and 75 mg BID groups, respectively. Participants achieving plasma Phe levels <360 µmol/L at end of Period 1 in the 150 mg BID and 75 mg BID groups, respectively... (contd)","definition_or_measurement_approach":"Percent change in plasma Phe from baseline to mean of Weeks 2, 4 and 6; responder analyses for achieving prespecified plasma Phe thresholds (<600 µmol/L, <360 µmol/L) at end of Period 1"}
• {"endpoint_text":"- Change from baseline in the ADHD-RS-5 inattentive subscore in participants with baseline inattentive subscore >9 in the JNT-517 150 mg BID and 75 mg BID dose groups, respectively at end of Period 1.","definition_or_measurement_approach":"Change from baseline in ADHD-RS-5 inattentive subscore (clinical rating scale) measured at end of Period 1 in participants with baseline inattentive subscore >9"}
• {"endpoint_text":"- Change from baseline in dietary Phe intake as determined by 3-day diet diary reports and while achieving plasma Phe <360 µmol/L in those participating in the diet normalization.","definition_or_measurement_approach":"Change in dietary phenylalanine intake assessed via 3-day diet diary reports; evaluated in context of participants achieving plasma Phe <360 µmol/L during diet normalization"}
• {"endpoint_text":"- Incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs in Periods 1 and 2.","definition_or_measurement_approach":"Safety endpoint: incidence counts and rates of TEAEs and serious TEAEs recorded during Periods 1 and 2"}
• {"endpoint_text":"- Participants with reduction from baseline ≥30% and ≥50% in plasma Phe levels at Week 6 in Period 1. Participants achieving plasma Phe levels <120 µmol/L at end of Period 1 in the 150 mg BID and 75 mg BID groups, respectively. Absolute and percent change in plasma Phe from baseline to Weeks 2, 4, and 6 of Period 1 in the 150 mg BID and 75 mg BID groups, respectively.","definition_or_measurement_approach":"Responder analyses for proportion achieving ≥30% and ≥50% reductions in plasma Phe at Week 6; proportions achieving absolute thresholds (e.g., <120 µmol/L); absolute and percent change in plasma Phe at Weeks 2, 4, 6"}
• {"endpoint_text":"- Participants achieving plasma Phe <600 µmol/L among the participants with a baseline Phe ≥600 µmol/L in each of the JNT 517 75 mg BID and 150 mg BID dose groups at end of Period 2. Participants who achieve plasma Phe levels <360 µmol/L in each of the JNT-517 75 mg BID and 150 mg BID dose groups at end of Period 2. Participants who achieve plasma Phe levels <120 µmol/L in each of the JNT-517 75 mg BID and 150 mg BID dose groups at end of Period 2... (contd)","definition_or_measurement_approach":"Responder analyses at end of Period 2 for prespecified plasma Phe thresholds (<600, <360, <120 µmol/L) among dose groups"}
• {"endpoint_text":"- Change from baseline in the Cambridge Neuropsychological Test Automated Battery (CANTAB) stop signal reaction time in each of the JNT-517 75 mg BID and 150 mg BID dose groups, respectively, at the end of Period 1. Change from baseline in CANTAB stop signal reaction time in both JNT-517 dose groups during Period 2. Change from baseline in ADHD-RS-5 inattentive subscore in participants with baseline inattentive subscore >9 in both JNT 517 dose groups during Period 2.","definition_or_measurement_approach":"Change from baseline in CANTAB stop signal reaction time (automated neuropsychological test) and ADHD-RS-5 inattentive subscore measured at specified times in Periods 1 and 2"}
• {"endpoint_text":"- Change from baseline in dietary protein intake while maintaining plasma Phe <360 µmol/L in those participating in the diet normalization. Participants achieving the recommended dietary allowance (RDA) for natural intact protein intakes while maintaining plasma Phe <360 µmol/L in those participating in the diet normalization. Participants achieving 2 × RDA for natural intact protein intakes, consistent with an unrestricted diet, while maintaining plasma Phe <360 µmol/L... (contd)","definition_or_measurement_approach":"Change in dietary protein intake (assessed via diet diaries) while maintaining plasma Phe <360 µmol/L; proportions achieving RDA or 2×RDA natural intact protein intake during diet normalization"}

Czechia

Earliest CTIS Part Ii Submission Date

10-10-2025

Latest Decision Or Authorization Date

04-11-2025

Processing Time Days

25

Number Of Sites

1

Number Of Participants

5

France

Earliest CTIS Part Ii Submission Date

17-10-2025

Latest Decision Or Authorization Date

04-11-2025

Processing Time Days

18

Number Of Sites

1

Number Of Participants

4

Germany

Earliest CTIS Part Ii Submission Date

17-10-2025

Latest Decision Or Authorization Date

03-11-2025

Processing Time Days

17

Number Of Sites

3

Number Of Participants

10

Italy

Earliest CTIS Part Ii Submission Date

10-10-2025

Latest Decision Or Authorization Date

14-11-2025

Processing Time Days

35

Number Of Sites

1

Number Of Participants

3

Spain

Earliest CTIS Part Ii Submission Date

27-10-2025

Latest Decision Or Authorization Date

07-11-2025

Processing Time Days

11

Number Of Sites

2

Number Of Participants

6

Poland

Earliest CTIS Part Ii Submission Date

14-10-2025

Latest Decision Or Authorization Date

13-11-2025

Processing Time Days

30

Number Of Sites

1

Number Of Participants

5

Netherlands

Earliest CTIS Part Ii Submission Date

15-10-2025

Latest Decision Or Authorization Date

17-03-2026

Processing Time Days

153

Number Of Sites

2

Number Of Participants

5

Primary sponsor

Full Name

Otsuka Pharmaceutical Development & Commercialization Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Syneos Health Inc.

Responsibilities

Site budgets and Clinical Trial Agreements

Name

CTI Clinical Trial and Consulting Services Europe GmbH

Name

Almac Clinical Services LLC

Responsibilities

Clinical Supplies, Distribution, Primary and secondary packaging.

Third parties

• {"country":"United States","full_name":"Lexitas Pharma Services Inc.","duties_or_roles":"Ophthalmic central reader","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"Site budgets and Clinical Trial Agreements","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Mde Healthcare Services Inc.","duties_or_roles":"Home Health","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"CTI Clinical Trial and Consulting Services Europe GmbH","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Veeva Systems Inc.","duties_or_roles":"Electronic Trial master file (TMF)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Atreo Inc.","duties_or_roles":"IXRS/IRT","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Almac Clinical Services LLC","duties_or_roles":"Clinical Supplies, Distribution, Primary and secondary packaging.","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Patient reimbursement, travel planning","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Mayo Clinic Hospital Rochester","duties_or_roles":"Central Lab - Aminoacids dosing (plasma/urine) and PKU genotyping","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Certara USA Inc.","duties_or_roles":"Modeling and simulation on the clinical data","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"ECG central reader","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Definitive Media Corp.","duties_or_roles":"Patient Diary/ Outcomes (eCOA)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Spain","full_name":"CTI Laboratory Services Spain S.L.","duties_or_roles":"Central Lab - Safety and PK","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Cambridge Cognition Limited","duties_or_roles":"eCOA (CANTAB stop signal test)","organisation_type":"Pharmaceutical company"}