JNT-517 for Phenylketonuria

Not currently recruiting at 14 trial locations

Overseen By John Throup, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Jnana Therapeutics

Disqualifiers: Hepatitis, HIV, Liver disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new treatment called JNT-517 for individuals with phenylketonuria (PKU), a condition where the body cannot break down the amino acid phenylalanine. Initially, the trial will assess the treatment's safety and behavior in the body by testing it on healthy participants. Subsequently, it will evaluate how JNT-517 affects individuals with PKU by comparing it to a placebo (a non-active substance). Those with PKU who have experienced high phenylalanine levels over the past year might be suitable for the later stages of this trial. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to be among the first to benefit from this new treatment.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, you should discuss your current medications with the study team to ensure they don't interfere with the trial.

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that JNT-517 is likely to be safe for humans?

Research has shown that JNT-517 appears safe based on earlier studies. Previous patients have generally tolerated it well. For example, one study found that JNT-517 was safe and helped lower blood phenylalanine levels, which is important for treating phenylketonuria (PKU). Another study with healthy volunteers also found that JNT-517 was well-tolerated.

This treatment remains in the early testing phase, focusing on how people handle it and how it moves through the body. While no major safety issues have been reported so far, these studies are crucial to confirm its safety in both healthy individuals and those with PKU. Participants should always understand potential risks and consult their healthcare provider before joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for PKU?

Unlike the standard treatments for phenylketonuria (PKU), which often involve strict dietary restrictions and supplements like sapropterin or pegvaliase, JNT-517 offers a potentially groundbreaking approach. Researchers are excited about JNT-517 because it targets the underlying metabolic issue in PKU by possibly modulating phenylalanine levels more directly and effectively. This could mean fewer dietary limitations and a better quality of life for people with PKU. Additionally, JNT-517 is being tested in various forms, such as tablets and suspensions, which might provide more flexible and convenient dosing options compared to existing treatments.

What evidence suggests that JNT-517 might be an effective treatment for phenylketonuria?

Research has shown that JNT-517 may help with phenylketonuria (PKU), a condition where the body cannot break down phenylalanine. Early results suggest that JNT-517 might lower phenylalanine levels, which is crucial because excess phenylalanine can cause serious health problems. In this trial, participants will receive JNT-517 in various forms and dosages across different treatment arms to evaluate its effectiveness and safety. Although detailed information from human studies remains limited, the drug targets specific processes that control amino acid levels. Initial studies in healthy individuals have focused on how the body processes JNT-517, an important step in demonstrating its potential benefits for those with PKU. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for healthy adults aged 18-55, and those with phenylketonuria (PKU) aged 18-65. Healthy participants must not smoke and have a BMI of 18-40 kg/m2. Women should agree to use two forms of contraception. PKU patients need a confirmed diagnosis and at least two plasma Phe levels >600 μM in the past year.

Inclusion Criteria

Your body mass index (BMI) is between 18 and 40.

I agree to use two effective birth control methods if I can have children.

My BMI is between 18-40 and I weigh more than 110 lbs.

Exclusion Criteria

I don't have conditions that affect how drugs work in my body.

I have not had any cancer except for non-melanoma skin cancer in the last 5 years.

I have not received a COVID-19 vaccine in the last 14 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Single Ascending Dose (SAD) in healthy participants, randomized, double-blind, placebo-controlled

1 week

Multiple visits for dosing and monitoring

Treatment Part B

Multiple Ascending Dose (MAD) in healthy participants, randomized, double-blind, placebo-controlled

14 days

Daily visits for dosing and monitoring

Treatment Part C

Evaluation of bioavailability and food effect in healthy participants, randomized, open-label

1 week

Sequential dosing with multiple visits

Treatment Part D

Phase 1b in participants with PKU, randomized, double-blind, placebo-controlled

4 weeks

Weekly visits for dosing and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

1-4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• JNT-517

Trial Overview The study tests JNT-517's safety, tolerability, dosage effects, and impact on urinary Phe in healthy individuals and those with PKU across four parts: single & multiple dose studies, bioavailability comparison between tablet/suspension forms with food effect analysis in healthy volunteers, and a placebo-controlled test in PKU patients.

How Is the Trial Designed?

Group I: JNT-517 Tablet Fed Then Suspension Then Tablet Fasted (Part C) Experimental Treatment 2 Interventions

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.

Group II: JNT-517 Tablet Fasted Then Tablet Fed Then Suspension (Part C) Experimental Treatment 2 Interventions

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.

Group III: JNT-517 Suspension Then Tablet Fasted Then Tablet Fed (Part C) Experimental Treatment 2 Interventions

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.

Group IV: JNT-517 SAD (Part A and Part F) Experimental Treatment 2 Interventions

Single dose of JNT-517 or placebo in fasted state.

Group V: JNT-517 PKU (Part D and E) Experimental Treatment 2 Interventions

JNT-517 or placebo daily for 4 weeks. Dose is based on data from Parts A, B, and C.

Group VI: JNT-517 MAD (Part B) Experimental Treatment 2 Interventions

JNT-517 or placebo once or twice daily for 14 days, with first daily dose given after an overnight fast.

Who Is Running the Clinical Trial?

Jnana Therapeutics

Lead Sponsor

Trials

3

Recruited

170+

Otsuka Pharmaceutical Development & Commercialization, Inc.

Lead Sponsor

Trials

271

Recruited

170,000+

John Kraus

Otsuka Pharmaceutical Development & Commercialization, Inc.

Chief Medical Officer since 2023

MD, PhD

Tarek Rabah

Otsuka Pharmaceutical Development & Commercialization, Inc.

Chief Executive Officer since 2022

BS in Biology and BA in Business from the American University of Beirut, MBA from McGill University

Published Research Related to This Trial

The FDA-approved radiotracer 18F-flortaucipir is increasingly used in PET imaging to visualize tau pathology in patients with cognitive impairment, particularly Alzheimer's disease.

An international consensus has been established to standardize the procedural use of 18F-flortaucipir PET imaging, which will enhance its application in clinical practice for diagnosing and managing Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

International consensus on the use of tau PET imaging agent 18F-flortaucipir in Alzheimer's disease. Tian, M., Civelek, AC., Carrio, I., et al.[2022]

The study evaluated five tau PET radiotracers in postmortem brain tissue from patients diagnosed with chronic traumatic encephalopathy (CTE), finding that 3H-flortaucipir showed significant binding to tau protein in all CTE cases, indicating its potential as a diagnostic tool.

3H-MK-6240 and 3H-PI-2620 demonstrated limited binding in most cases but may be effective in severe or mixed-pathology cases, suggesting that these radiotracers could be useful for further research in diagnosing CTE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Tau Radiotracers in Chronic Traumatic Encephalopathy. Varlow, C., Vasdev, N.[2023]

The use of [18F]PM-PBB3 tau PET imaging successfully identified tau deposition in a patient with frontotemporal dementia (FTD) caused by a MAPT mutation, indicating its potential as a diagnostic tool for this condition.

In a comparison of tau PET tracers, [18F]PM-PBB3 showed positive retention in all patients with both 3-repeat and 4-repeat tau, while AV-1451 was less consistent, highlighting [18F]PM-PBB3's broader utility in detecting tau strains associated with FTD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tau PET Imaging with [18F]PM-PBB3 in Frontotemporal Dementia with MAPT Mutation. Su, Y., Fu, J., Yu, J., et al.[2021]

The radiotracer [18F]9, designed for imaging kappa opioid receptors (KOR), was produced with a specific activity of 41-89 GBq/μmol but showed no significant specific binding in the brain, making it unsuitable for KOR PET imaging.

The study revealed that the parent compound JDTic is much more stable than [18F]9, suggesting that insights from this research could guide the development of new JDTic derivatives for better in vivo applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-[18F]-FluoropropylJDTic for κ-opioid receptor PET imaging: Radiosynthesis, pre-clinical evaluation, and metabolic investigation in comparison with parent JDTic. Schmitt, S., Delamare, J., Tirel, O., et al.[2018]

The study identified compound 3c as a potent and irreversible inhibitor of both ENT1 and ENT2, which are important for nucleotide transport and chemotherapy, without affecting cell viability or protein expression.

Structural modifications of FPMINT analogues revealed that specific changes can enhance inhibitory effects on ENTs, suggesting potential for developing new pharmacological agents targeting these transporters.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structure-Activity Relationship Studies of 4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-6-imino-N-(naphthalen-2-yl)-1,3,5-triazin-2-amine (FPMINT) Analogues as Inhibitors of Human Equilibrative Nucleoside Transporters. Li, R., Mak, WW., Li, J., et al.[2022]

Certain genetic variations (SNPs) in the NAT1 gene, particularly the 560G > A (R187Q) variant, significantly reduce the enzyme's ability to process carcinogens like 4-aminobiphenyl (ABP), which may increase cancer risk depending on exposure levels.

Other SNPs tested did not significantly affect the enzyme's activity, indicating that not all genetic variations in NAT1 have the same impact on its function and potential cancer susceptibility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

560G>A (rs4986782) (R187Q) Single Nucleotide Polymorphism in Arylamine N-Acetyltransferase 1 Increases Affinity for the Aromatic Amine Carcinogens 4-Aminobiphenyl and N-Hydroxy-4-Aminobiphenyl: Implications for Cancer Risk Assessment. Doll, MA., Hein, DW.[2022]

The study successfully expressed and characterized the human AANAT enzyme, which is crucial for melatonin regulation, and developed a rapid assay to measure its activity using high performance liquid chromatography.

Several peptides were identified as potential inhibitors of AANAT, with one specific pentapeptide showing low micromolar inhibitory potency, indicating a promising avenue for developing AANAT-targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Substrate specificity and inhibition studies of human serotonin N-acetyltransferase. Ferry, G., Loynel, A., Kucharczyk, N., et al.[2021]

A new LC-MS-MS method was successfully developed to measure the antidiabetic drug JTT-501 and its metabolite JTP-20604 in human plasma, demonstrating a wide calibration range of 5-10000 ng/ml.

The method was validated for accuracy and precision, and it was utilized in a clinical tolerability study to assess plasma concentrations, ensuring reliable results for future research on this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simultaneous determination of JTT-501 and its main metabolite in human plasma by liquid chromatography-ionspray mass spectrometry. Breda, M., Basileo, G., James, CA.[2019]

A specific enzyme in rat brains, called N-myristoyl transferase (NMT), is responsible for transferring myristic acid to the N-terminus of certain peptides, and its activity is significantly higher in the brain compared to other tissues.

NMT shows distinct kinetic properties with different peptide substrates, indicating its potential role in brain function, particularly in areas like the hippocampus, which has the highest enzyme activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterisation of a myristoyl CoA:glycylpeptide N-myristoyl transferase activity in rat brain: subcellular and regional distribution. McIlhinney, RA., McGlone, K.[2019]

A new assay for measuring human liver NNMT activity revealed that the average enzyme activity in liver samples from 163 patients was 51.5 U per mg protein, with significant individual variation, including a subgroup with high activity (26%).

NNMT activity was specifically inhibited by its own products, suggesting a feedback mechanism, and the findings may help explore how differences in NNMT activity could affect the metabolism and efficacy of pyridine-based drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human liver nicotinamide N-methyltransferase: ion-pairing radiochemical assay, biochemical properties and individual variation. Rini, J., Szumlanski, C., Guerciolini, R., et al.[2019]

A new nonradioactive ELISA-based method has been developed to measure the activity of N-myristoyltransferase (NMT), which is crucial for the function of many human pathogens and is linked to tumor growth.

This assay allows for the exploration of NMT activity, substrate specificity, and potential inhibitors, making it a valuable tool for studying NMT in both recombinant forms and tissue samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new, robust, and nonradioactive approach for exploring N-myristoylation. Rampoldi, F., Sandhoff, R., Owen, RW., et al.[2021]

Retigabine is primarily metabolized in humans and dogs through N-glucuronidation, which suggests a consistent metabolic pathway in these species, unlike in rats where multiple metabolites are produced.

In humans, the enzyme UGT1A4 plays a significant role in the N-glucuronidation of retigabine, contributing to its enterohepatic circulation, which is not observed in rats.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Hiller, A., Nguyen, N., Strassburg, CP., et al.[2013]

The study identified specific amino acids in UGT1A9 that contribute to its unique substrate specificity compared to similar enzymes, highlighting the importance of Arg42 and Asn152 in determining how UGT1A9 processes different drugs and compounds.

Mutant forms of UGT1A9 were created to analyze how changes in amino acids affected the enzyme's activity, revealing that certain mutations increased the enzyme's efficiency for specific glucuronidation reactions, which could have implications for drug metabolism and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Key amino acid residues responsible for the differences in substrate specificity of human UDP-glucuronosyltransferase (UGT)1A9 and UGT1A8. Fujiwara, R., Nakajima, M., Yamanaka, H., et al.[2021]

Tanzisertib, a selective JNK inhibitor, showed significant variability in metabolism across different species, with less than 10% metabolized in humans and dogs, but over 75% in rats and mice, indicating potential differences in drug processing that could affect efficacy and safety in humans.

Human aldo-keto reductases (AKR1C enzymes) play a crucial role in the metabolism of tanzisertib, particularly AKR1C4, which has a high affinity for converting the keto form of tanzisertib back to its active form, highlighting the importance of specific enzymes in the drug's metabolic pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro metabolism of a novel JNK inhibitor tanzisertib: interspecies differences in oxido-reduction and characterization of enzymes involved in metabolism. Atsriku, C., Hoffmann, M., Moghaddam, M., et al.[2017]

Retigabine, a novel antiepileptic drug in phase II clinical development, is primarily metabolized through N-glucuronidation, mainly by the enzyme UGT1A9, which produces two key metabolites essential for its clearance.

The study found no significant drug-drug interactions with commonly used medications at clinically relevant concentrations, indicating that retigabine can be safely co-administered with other drugs that undergo glucuronidation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-Glucuronidation of the antiepileptic drug retigabine: results from studies with human volunteers, heterologously expressed human UGTs, human liver, kidney, and liver microsomal membranes of Crigler-Najjar type II. Borlak, J., Gasparic, A., Locher, M., et al.[2013]

Citations

1. go.drugbank.com go.drugbank.com/drugs/DB19305

JNT-517: Uses, Interactions, Mechanism of Action Structure for JNT-517 (DB19305) · (R)-3-(1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)piperidine-1-carboxamide · 1- ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06971731

A Study to Evaluate the Safety and Efficacy of JNT-517 in ... The goal of this Phase 3, randomized study is to assess the safety, efficacy, tolerability, and pharmacokinetics (PK) of oral JNT-517 in adults (18 years of ...

3. trials.otsuka-us.com trials.otsuka-us.com/trials/JNT517-301

A Study to Evaluate the Safety and Efficacy of JNT-517 in ... The goal of this Phase 3, randomized study is to assess the safety, efficacy, tolerability, and pharmacokinetics (PK) of oral JNT-517 in adults (18 years of ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05781399

First-in-Human, Multiple Part Clinical Study of JNT-517 ... First-in-Human, Multiple Part Clinical Study of JNT-517 in Healthy Participants and in Participants With Phenylketonuria. ClinicalTrials.gov ID NCT05781399.

5. trials.otsuka-us.com trials.otsuka-us.com/trials/JNT517-201

A Phase 2 Study of JNT-517 in Adolescent Participants With ... The goal of this Phase 2, randomized study is to assess the safety, tolerability, and pharmacokinetics (PK) of oral JNT-517 in adolescents (12 to less than 18 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06971731

A Study to Evaluate the Safety and Efficacy of JNT-517 in ... The goal of this Phase 3, randomized study is to assess the safety, efficacy, tolerability, and pharmacokinetics (PK) of oral JNT-517 in adults (18 years of ...

7. synapse.patsnap.com synapse.patsnap.com/drug/4605f644c0804c7384970416dbbcd881

Repinatrabit - Drug Targets, Indications, Patents 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 ...

8. jnanatx.com jnanatx.com/jnana-therapeutics-announces-positive-clinical-proof-of-concept-achieved-with-jnt-517-a-potential-first-in-class-oral-treatment-for-pku/

Treatment with JNT-517 demonstrated a ... Treatment with JNT-517 demonstrated a statistically significant mean blood phenylalanine reduction of 51% versus baseline. JNT-517 was safe ...