repinatrabit (JNT-517) / Otsuka - LARVOL DELTA

A Study to Evaluate the Safety and Efficacy of JNT-517 in Participants With Phenylketonuria (PKU) (clinicaltrials.gov) - P3 | N=120 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Trial primary completion date: Nov 2026 ➔ Nov 2027

Trial primary completion date • Metabolic Disorders • Phenylketonuria • Rare Diseases

Design of a Randomized, Double-Blind, Placebo-Controlled, Phase 3, Efficacy and Safety Trial of Repinatrabit in Adults with Phenylketonuria (ACMG 2026) - P3 | "Participants with a history of pegvaliase treatment must have at least a 4-week washout before screening... This Phase 3, randomized, placebo-controlled, 52-week trial will provide pivotal efficacy and safety data on the use of repinatrabit in adults with PKU. Enrollment criteria will enable the recruitment of a population with a broad range of disease severity and treatment history. Sponsored by Otsuka Pharmaceutical Development and Commercialization, Inc."

Clinical • P3 data • Metabolic Disorders • Phenylketonuria • Rare Diseases • SLC6A19

Clinical Efficacy and Safety Data in Adolescents Treated with Repinatrabit for Phenylketonuria (ACMG 2026) - P2, P3 | "Previous PKU pharmacotherapy is discontinued before screening, with washout of >30 days for pegvaliase and >7 days for sapropterin or other cofactor therapies... Treatment response in these preliminary data is of a similar magnitude to that seen in a Phase 2 study of adult patients with PKU on the low dose of repinatrabit (75 mg BID). The time-frame for duration of exposure presented here is longer than that of the 8-week primary efficacy analyses conducted in trials of approved PKU therapies, supporting continued efficacy of repinatrabit relative to those treatments. Study of this novel therapeutic strategy for pediatric PKU is ongoing."

Clinical • CNS Disorders • Depression • Metabolic Disorders • Mood Disorders • Phenylketonuria • Rare Diseases • Sleep Disorder

A Study to Evaluate the Safety and Efficacy of JNT-517 in Participants With Phenylketonuria (PKU) (clinicaltrials.gov) - P3 | N=120 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Metabolic Disorders • Phenylketonuria • Rare Diseases

First in human clinical study of a novel drug JNT-517 to assess its safety and tolerability in healthy volunteers (ANZCTR) - P1 | N=91 | Completed | Sponsor: CTI Clinical Trial and Consulting Services Australia Pty Ltd. | Recruiting ➔ Completed

Trial completion • Metabolic Disorders • Phenylketonuria • Rare Diseases

Safety, Tolerability and Proof-Of-Mechanism in Healthy Volunteers for JNT-517, a First-In-Class SLC6A19 Inhibitor for the Treatment of Phenylketonuria (SSIEM 2023) - "JNT-517 is a safe and well-tolerated novel SLC6A19 inhibitor, which effectively increases the excretion of neutral amino acids including Phe in urine and warrants investigation as a potential therapeutic candidate for PKU."

Clinical • Metabolic Disorders • Phenylketonuria • Rare Diseases • SLC6A19

Engineering and immobilization of imine reductase enable chemoenzymatic synthesis of SLC6A19 inhibitor JNT-517. (PubMed, Bioresour Technol) - "This biocatalytic system was successfully integrated into the chemoenzymatic synthesis of SLC6A19 inhibitor JNT-517, where the enzymatically produced (R)-N-cyclopropylpiperidin-3-amine was efficiently converted to JNT-517 in three chemical steps, demonstrating promising potential for industrial-scale applications. Protein engineering and enzyme immobilization technology endow IRED with superior catalytic performance, stability, and reusability, thereby enabling sustainable bioprocessing for industrial applications."

Journal • SLC6A19

First-in-Human, Multiple Part Clinical Study of JNT-517 in Healthy Participants and in Participants With Phenylketonuria (clinicaltrials.gov) - P1/2 | N=135 | Active, not recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Trial completion date: Jul 2025 ➔ Dec 2025 | Trial primary completion date: Jun 2025 ➔ Sep 2025

Trial completion date • Trial primary completion date • Metabolic Disorders • Phenylketonuria • Rare Diseases

A Phase 2 Study of JNT-517 in Adolescent Participants With Phenylketonuria (clinicaltrials.gov) - P2 | N=10 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Metabolic Disorders • Phenylketonuria • Rare Diseases

GSC002874, a highly potent inhibitor of SLC6A19, for treatment of phenylketonuria (ENDO 2025) - "For the classic PKU cohort accounting for over 60 percent of cases, the only approved drug is pegvaliase; however, it is associated with inconvenient dosing and side effects...In an PAH pR408W PKU mouse model with its mouse SLC6A19 replaced by human orthologue, GSC002874 significant decreased phenylalanine level in plasma at lower dosage that of JNT-517...GSC002874 also displayed good safety window in 14-day toxicology study in rats. GSC002874 is under active IND-enabling studies and expected to enter clinic in early 2026."

Genetic Disorders • Metabolic Disorders • Phenylketonuria • Rare Diseases • SLC6A19

GSC002874, a highly potent inhibitor of SLC6A19, for treatment of phenylketonuria (ENDO 2025) - "For the classic PKU cohort accounting for over 60 percent of cases, the only approved drug is pegvaliase; however, it is associated with inconvenient dosing and side effects...In an PAH pR408W PKU mouse model with its mouse SLC6A19 replaced by human orthologue, GSC002874 significant decreased phenylalanine level in plasma at lower dosage that of JNT-517...GSC002874 also displayed good safety window in 14-day toxicology study in rats. GSC002874 is under active IND-enabling studies and expected to enter clinic in early 2026."

Genetic Disorders • Metabolic Disorders • Phenylketonuria • Rare Diseases • SLC6A19

First-in-Human, Multiple Part Clinical Study of JNT-517 in Healthy Participants and in Participants With Phenylketonuria (clinicaltrials.gov) - P1/2 | N=135 | Active, not recruiting | Sponsor: Jnana Therapeutics | Recruiting ➔ Active, not recruiting | Phase classification: P1 ➔ P1/2 | Trial completion date: Mar 2025 ➔ Jul 2025 | Trial primary completion date: Dec 2024 ➔ Jun 2025

Enrollment closed • Phase classification • Trial completion date • Trial primary completion date • Metabolic Disorders • Phenylketonuria • Rare Diseases

First in human clinical study of a novel drug JNT-517 to assess its safety and tolerability in healthy volunteers (ANZCTR) - P1 | N=91 | Recruiting | Sponsor: CTI Clinical Trial and Consulting Services Australia Pty Ltd. | Completed ➔ Recruiting

Enrollment open • Metabolic Disorders • Phenylketonuria • Rare Diseases

A Study to Evaluate the Long-Term Safety and Efficacy of JNT-517 in Participants With Phenylketonuria (clinicaltrials.gov) - P3 | N=45 | Not yet recruiting | Sponsor: Jnana Therapeutics | Initiation date: Nov 2024 ➔ Jun 2025

Trial initiation date • Metabolic Disorders • Phenylketonuria • Rare Diseases

A Study to Evaluate the Safety and Efficacy of JNT-517 in Participants With Phenylketonuria (PKU) (clinicaltrials.gov) - P3 | N=120 | Not yet recruiting | Sponsor: Jnana Therapeutics

New P3 trial • Metabolic Disorders • Phenylketonuria • Rare Diseases

A Phase 2 Study of JNT-517 in Adolescent Participants With Phenylketonuria (clinicaltrials.gov) - P2 | N=10 | Not yet recruiting | Sponsor: Jnana Therapeutics | Trial completion date: Sep 2025 ➔ Feb 2026 | Initiation date: Nov 2024 ➔ Jul 2025 | Trial primary completion date: Jul 2025 ➔ Dec 2025

Trial completion date • Trial initiation date • Trial primary completion date • Metabolic Disorders • Phenylketonuria • Rare Diseases

SLC6A19 inhibition facilitates urinary neutral amino acid excretion and lowers plasma phenylalanine. (PubMed, JCI Insight) - P1 | "Secondary objectives included pharmacokinetic and pharmacodynamic studies.RESULTSInhibition of SLC6A19 increased the urinary excretion of Phe in a mouse model of PKU, thereby reducing plasma Phe levels. JNT-517, an investigational oral SLC6A19 inhibitor, was found to be safe and well tolerated and increased the urinary excretion of Phe in a phase 1 healthy volunteer study.CONCLUSIONSThese data indicate that pharmacological inhibition of SLC6A19 presents a promising approach to lower toxic elevated levels of amino acids found in PKU and related amino acid metabolism disorders by facilitating their renal elimination.TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12622001222730.FUNDINGThe studies in this paper were funded by Jnana Therapeutics."

Journal • Metabolic Disorders • Phenylketonuria • Rare Diseases • SLC6A19

A Phase 2 Study of JNT-517 in Adolescent Participants with Phenylketonuria (clinicaltrials.gov) - P2 | N=10 | Not yet recruiting | Sponsor: Jnana Therapeutics

New P2 trial • Metabolic Disorders • Phenylketonuria • Rare Diseases

A Study to Evaluate the Long-Term Safety and Efficacy of JNT-517 in Participants with Phenylketonuria (clinicaltrials.gov) - P3 | N=45 | Not yet recruiting | Sponsor: Jnana Therapeutics

New P3 trial • Metabolic Disorders • Phenylketonuria • Rare Diseases

JNT-517, A FIRST-IN-CLASS SLC6A19 INHIBITOR, REDUCES PLASMA PHENYLALANINE LEVELS IN SUBJECTS WITH PHENYLKETONURIA IN A PHASE 1/2 STUDY (SSIEM 2024) - "Treatment with JNT-517 in individuals with PKU demonstrated rapid clinically meaningful reductions in plasma Phe and was safe and well-tolerated."

Clinical • P1/2 data • Metabolic Disorders • Phenylketonuria • Rare Diseases • SLC6A19

Where are we now: Update on JNT-517 clinical trials in PKU (SSIEM 2024) - "Sponsored by JNANA THERAPEUTICS"

Clinical

JNT-517, A FIRST-IN-CLASS SLC6A19 INHIBITOR, REDUCES PLASMA PHENYLALANINE LEVELS IN SUBJECTS WITH PHENYLKETONURIA IN A PHASE 1/2 STUDY (SSIEM 2024) - "Treatment with JNT-517 in individuals with PKU demonstrated rapid clinically meaningful reductions in plasma Phe and was safe and well-tolerated."

Clinical • P1/2 data • Metabolic Disorders • Phenylketonuria • Rare Diseases • SLC6A19

Harnessing SLC6A19 as a potential treatment approach for PKU and related amino acid disorders (SSIEM 2024) - "Next, clinical trial data will be shared on treatment with JNT-517, the selective small molecule inhibitor, in PKU adults. The last part addresses the unmet medical needs of PKU and other amino acid disorders and potential for SLC6A19 inhibition as a treatment approach."

SLC6A19

A Phase 1, Three-Part Open-Label Drug-Drug Interaction Study in Healthy participants to Determine the Effects of Itraconazole on the Pharmacokinetics of JNT-517 (Victim) and the Effects of JNT-517 (Perpetrator) on the Pharmacokinetics of Midazolam and Pravastatin (ANZCTR) - P1 | N=36 | Completed | Sponsor: CTI Clinical Trial and Consulting Services Australia Pty Ltd | Recruiting ➔ Completed

Trial completion • Metabolic Disorders • Phenylketonuria • Rare Diseases

A Phase 1, Three-Part Open-Label Drug-Drug Interaction Study in Healthy participants to Determine the Effects of Itraconazole on the Pharmacokinetics of JNT-517 (Victim) and the Effects of JNT-517 (Perpetrator) on the Pharmacokinetics of Midazolam and Pravastatin (ANZCTR) - P1 | N=36 | Recruiting | Sponsor: CTI Clinical Trial and Consulting Services Australia Pty Ltd | Not yet recruiting ➔ Recruiting

Enrollment open • Metabolic Disorders • Phenylketonuria • Rare Diseases