Otsuka Initiates Global Phase 3 Clinical Trial Evaluating Repinatrabit for the Treatment of Phenylketonuria (PKU)

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.PRINCETON, N.J. and TOKYO, JAPAN – December 19, 2025 – Otsuka Pharmaceutical Development & Commercialization, Inc. and Otsuka Pharmaceutical, Co. Ltd. (Otsuka) announces today 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.5About RepinatrabitRepinatrabit (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 PhenylketonuriaPhenylketonuria (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.3About OtsukaOtsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: Otsuka–people creating new products for better health worldwide. Otsuka researches, develops, manufactures, and markets innovative products, with a focus on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health. In pharmaceuticals, Otsuka is a leader in the challenging areas of mental, kidney, and cardiovascular health and has additional research programs in oncology and on several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate how Otsuka is a “big venture” company at heart, applying a youthful spirit of creativity in everything it does.Otsuka established a presence in the U.S. in 1973 and today its U.S. affiliates include Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Otsuka America Pharmaceutical, Inc. (OAPI). These two companies’ 2,250 employees in the U.S. develop and commercialize medicines in the areas of mental health and nephrology, using cutting-edge technology to address unmet healthcare needs.OPDC and OAPI are indirect subsidiaries of Otsuka Pharmaceutical Co., Ltd., which is a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of companies employed 35,340 people worldwide and had consolidated sales of approximately USD 14.7 billion in 2024.All Otsuka stories start by taking the road less traveled. Learn more about Otsuka in the U.S. at www.otsuka-us.com and connect with us on LinkedIn and Twitter at @OtsukaUS. Otsuka Pharmaceutical Co., Ltd.’s global website is accessible at https://www.otsuka.co.jp/en/. Contacts for MediaOtsuka in the U.S.Jill RomanCorporate CommunicationsOtsuka America Pharmaceutical, [email protected] in JapanJeffrey Gilbert Leader, Pharmaceutical PR Otsuka Pharmaceutical Co., [email protected]+81 3 6361 7379References: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.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: PMC5683291Hillert 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.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.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. DECEMBER 2025 27US25EUC0008 Contacts for media Otsuka in Japan Jeffrey Gilbert (Outside the US)Leader, Pharmaceutical PR Otsuka Pharmaceutical, Co., Ltd. [email protected] Phone: +81 3 6361 7379 Otsuka in the US Jill RomanDirector, External Communications,Otsuka America Pharmaceutical, Inc. [email protected] Phone: +1 (609) 524-6788 Otsuka Announces FDA Acceptance and Priority Review of New Drug Application for Centanafadine for the Treatment of ADHD in Children, Adolescents, and Adults Next article We defy limitation, so that others can too. Follow us LinkedIn Facebook X Instagram Threads YouTube Footer Links California Supply Chains Act Returned Goods Authorized Distributor of Record Terms and Conditions OAPI and OPDC Privacy Policy Anthem Transparency in Coverage OAPI and OPDC Locations 508 Carnegie Center Dr,Princeton, NJ 08540, United States Phone 609-524-6788 2440 Research Blvd,Rockville, MD 20850, United States Phone 301-424-9055 3956 Point Eden WayHayward, CA 94545, United States Phone 800-562-3974 © 2025 Otsuka America Pharmaceutical, Inc All rights reserved. June 2024 01US24EXC0009 Otsuka's affiliated companies around the world work with a shared commitment to contribute to better health worldwide. Otsuka Global Site Japan Asia, The Middle East& Oceania Australia China Egypt Indonesia Pakistan Philippines South Korea Taiwan Thailand Vietnam North &South America Brazil Canada US Europe EU Denmark Finland France Germany Italy Norway Spain Sweden Switzerland UK Search

The release as fetched from its publisher. otsuka-us.com ↗