• Repinatrabit (JNT-517) is an investigational, oral, small-molecule compound; it received orphan drug designation and rare pediatric disease designation for the treatment of PKU from the U.S. FDA.
• There is an unmet need for additional treatment options for PKU, a genetic disorder impacting approximately 1 in 24,000 individuals globally.

Otsuka Pharmaceutical, Co. Ltd. (Otsuka) and Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) announce the initiation of the global Phase 3 clinical trial evaluating repinatrabit (JNT-517), an investigational, oral, small-molecule compound for the treatment of phenylketonuria (PKU). The goal of the PheORD Phase 3, randomized study is to assess the efficacy, safety and tolerability of oral repinatrabit, administered twice a day, in participants with PKU.¹ Repinatrabit received orphan drug designation and rare pediatric disease designation for the treatment of PKU from the U.S. Food and Drug Administration (FDA).

PKU is a genetic disorder that leads to an accumulation of amino acid phenylalanine (Phe) in the blood, which, if left untreated, can adversely affect brain development and lead to intellectual disability and other serious health problems. The condition is estimated to impact approximately 1 in 24,000 individuals globally, including approximately 1 in 10,000 individuals in the U.S. annually. ² Current treatment involves dietary therapy that restricts intact protein intake to limit Phe consumption and supplements other essential amino acids through a specialized medical formula.³ However, strict dietary restrictions leave many patients without adequate treatment, highlighting the need for new therapeutic approaches for PKU.³

"Despite adherence to the standard low-protein diet therapy, many people living with PKU continue to face challenges maintaining phenylalanine control, and they experience clinical symptoms such as executive function impairment, mood regulation difficulties, and other mental health issues," said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka. "Patients also face social and emotional challenges, including feelings of isolation and stigma related to dietary restrictions. We are committed to addressing the significant unmet needs of the global PKU community and delivering groundbreaking advancements."

Interim analysis data from the Phase 1b/2 study demonstrated a robust reduction in blood Phe levels within one week of dosing, regardless of disease severity or non-responsiveness to existing treatments. The 150mg BID dose of repinatrabit led to a statistically significant (p=<0.0002 vs. placebo) mean blood Phe reduction from baseline of 60% on average across days 14, 21, and 28⁵ and a 58% reduction from baseline to day 28.⁴ No serious adverse events were observed in any dosing group, no clinically significant changes in laboratory parameters, and no clinically significant changes in plasma amino acids other than Phe observed, confirming safety and tolerability.⁵

About Repinatrabit

Repinatrabit (JNT-517) is an investigational, selective, small-molecule inhibitor of the Phe transporter SLC6A19 that has the potential to be a first-in-class oral therapy used to treat any person with PKU, regardless of age or genotype.¹ Repinatrabit acts at a novel, cryptic allosteric site to block kidney reabsorption of Phe and offers a promising new approach to reduce blood Phe levels.¹ Repinatrabit was developed by Jnana Therapeutics, which became a wholly owned subsidiary of Otsuka Pharmaceutical in September 2024. It was created using Jnana's proprietary and innovative drug discovery approach, the RAPID platform.

This Phase 3 clinical trial is registered on ClinicalTrials.gov under the identifier NCT06971731. More information about the trial can be found at https://www.clinicaltrials.gov/study/NCT06971731.

About Phenylketonuria

Phenylketonuria (PKU) is a rare, genetic disorder that follows an autosomal recessive inheritance pattern. It is a congenital amino acid metabolism disorder caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH), which converts phenylalanine--an essential amino acid--into tyrosine, or by abnormalities in its cofactor, tetrahydrobiopterin (BH4). If left untreated, toxic levels of phenylalanine accumulate in the blood, and can adversely affect brain development and cause progressive and severe neurological impairment.³

References:

1. Otsuka Pharmaceutical Development & Commercialization, Inc. "A Study to Evaluate the Safety and Efficacy of JNT-517 in Participants With Phenylketonuria (PKU)." Clinicaltrials.Gov, clinicaltrials.gov/study/NCT06971731.
2. Rocha JC, MacDonald A. Dietary intervention in the management of phenylketonuria: current perspectives. Pediatric Health Med Ther. 2016 Dec 1;7:155-163. doi: 10.2147/PHMT.S49329. PMID: 29388626; PMCID: PMC5683291
3. Hillert A, Anikster Y, Belanger-Quintana A, Burlina A, Burton BK, Carducci C, Chiesa AE, Christodoulou J, Đorđević M, Desviat LR, Eliyahu A, Evers RAF, Fajkusova L, Feillet F, Bonfim-Freitas PE, Giżewska M, Gundorova P, Karall D, Kneller K, Kutsev SI, Leuzzi V, Levy HL, Lichter-Konecki U, Muntau AC, Namour F, Oltarzewski M, Paras A, Perez B, Polak E, Polyakov AV, Porta F, Rohrbach M, Scholl-Bürgi S, Spécola N, Stojiljković M, Shen N, Santana-da Silva LC, Skouma A, van Spronsen F, Stoppioni V, Thöny B, Trefz FK, Vockley J, Yu Y, Zschocke J, Hoffmann GF, Garbade SF, Blau N. The Genetic Landscape and Epidemiology of Phenylketonuria. Am J Hum Genet. 2020 Aug 6;107(2):234-250. doi: 10.1016/j.ajhg.2020.06.006. Epub 2020 Jul 14. PMID: 32668217; PMCID: PMC7413859.
4. Jnana Therapeutics. Efficacy and safety outcomes of JNT-517, a first-in-class SLC6A19 inhibitor for phenylketonuria (PKU): Phase 1/2 study results presented at the Society for the Study of Inborn Errors of Metabolism (SSIEM) 2024 Annual Symposium, Porto, Portugal. Data demonstrated statistically significant mean blood phenylalanine reduction and favorable safety profile with JNT-517 treatment.
5. Cary Harding, Nicola Longo, Andreu Viader, Toby Vaughn, Fernanda Leal-Pardinas, Elaina Jurecki, Markey McNutt, Ania Muntau, Rani Singh, Joel Barrish, George Vratsanos, Haoling Weng, John Throup, O01: Efficacy and safety outcomes of JNT-517, a first-in-class SLC6A19 inhibitor, in adults with phenylketonuria: A randomized study, Genetics in Medicine Open, Volume 3, Supplement 2, 2025, 101964, ISSN 2949-7744, https://doi.org/10.1016/j.gimo.2025.101964.