• Adolescents in a long-term, open-label extension study receiving a twice-daily low dose of repinatrabit achieved clinically meaningful reductions in blood Phe levels at month one of the open-label extension study, with all participants demonstrating clinical response
• A new pivotal global Phase 3 trial is underway, advancing repinatrabit development in a broad adult PKU population
• Repinatrabit is an investigational, selective, small-molecule inhibitor of the phenylalanine transporter solute carrier family 6 member 19 (SLC6A19)

Otsuka Pharmaceutical Development & Commercialization, Inc. and Otsuka Pharmaceutical Co., Ltd. (Otsuka) today announced new open-label extension study data for repinatrabit (JNT-517), demonstrating early and clinically meaningful reductions in blood phenylalanine (Phe) levels (-67% mean change from baseline) in adolescents with phenylketonuria (PKU). These new data, along with the study design for the pivotal global Phase 3 PheORD trial (NCT06971731) in adults, were presented at the 2026 American College of Medical Genetics and Genomics (ACMG) meeting.

“These data mark an important milestone in our efforts to advance the understanding and treatment of PKU,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka. “Maintaining control of blood Phe levels poses a critical challenge for adolescent patients, with higher levels leading to clinical symptoms such as executive function impairment and other intellectual disabilities. Repinatrabit represents a novel investigational approach with the potential to reduce Phe levels and broaden treatment options for the PKU community.”

In a long-term, open-label extension, the first cohort of adolescents receiving repinatrabit 75 mg twice daily – the lower of the two doses evaluated in the Phase 2 adolescent study (NCT06637514) – achieved sustained Phe reductions at the first timepoint that could be evaluated in the open‑label setting (Day 56 / OLE Month 1). At this assessment, adolescents achieved an average –67% reduction from baseline. The parent Phase 2 trial that patients are rolling over from remains blinded. Early time points in the long-term open-label extension are embargoed to protect the integrity (i.e., blinding) of the parent study. Additional blinded early‑treatment data from the randomized period will be presented in the future. The scale and consistency of Phe reduction observed in adolescents were comparable to those reported in adult Phase 2 studies, reinforcing the strong potential of repinatrabit across diverse age groups¹.

All participants in the cohort demonstrated a clinical response, including adolescents with prior sapropterin experience (both responders and non-responders), as well as one sapropterin-naïve participant. Repinatrabit was well tolerated, with a safety profile consistent with prior adult Phase 2 findings. No new treatment-related adverse events were identified, and no serious adverse events were reported. The study of this novel therapeutic strategy for pediatric PKU is ongoing, with patients in the open-label extension advancing to the higher dose (150 mg) of repinatrabit in the second cohort.

Otsuka is also advancing the pivotal Phase 3 PheORD trial in adults with PKU². The global, randomized, double-blind, placebo-controlled study is designed to evaluate the efficacy and safety of two oral dose regimens of repinatrabit (75 mg or 150 mg twice daily) compared with placebo². In the first treatment period, approximately 120 patients will be randomized in a 1:1:1 ratio to one of the two repinatrabit dose groups or placebo for six weeks, with the primary endpoint assessing short-term mean reduction in blood Phe levels at Weeks 2, 4 and 6². During the secondary study period, participants originally assigned to repinatrabit will continue on their respective dose for an additional 46 weeks, while those originally assigned to placebo will transition to repinatrabit 150 mg twice daily, with continued safety and efficacy follow-up through 52 weeks².

The trial intentionally enrolls a broad adult PKU population across disease severity and prior treatment experience, reflecting real-world clinical practice². Completion of the primary endpoint of the adult population in the Phase 3 study is anticipated in late 2026, with full study completion expected in 2028.

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 genotype³. Repinatrabit acts at a novel, cryptic allosteric site to block kidney reabsorption of Phe and offers a novel investigational approach to reduce blood Phe levels³. Repinatrabit was developed by Jnana Therapeutics, which became a wholly owned subsidiary of Otsuka in September 2024. It was created using Jnana’s proprietary and innovative drug discovery approach, the RAPID platform.

Repinatrabit has received orphan drug designation and rare pediatric disease designation from the U.S. Food and Drug Administration (FDA) for the treatment of PKU. Otsuka is actively recruiting in the global Phase 3 PheORD clinical trial (NCT06971731) to assess the efficacy, safety and tolerability of oral Repinatrabit in participants with PKU².

About Phenylketonuria
Phenylketonuria (PKU) is a disorder caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene, rendering the enzyme unable to metabolize Phe and leading to its toxic accumulation in the body, including the brain⁴. PKU affects approximately 1 in 24,000 individuals globally, including approximately 1 in 10,000 individuals in the United States⁴. If left untreated, PKU can adversely affect brain development and lead to intellectual disability and other serious health problems⁴. High levels of Phe have been associated with neurological and psychiatric presentations such as executive function impairment, headaches, sleep disorders, anxiety, and depression^5,6. Maintaining control of blood Phe levels remains one of the most significant challenges for people living with PKU, particularly during adolescence, a critical period of neurodevelopment when elevated Phe levels can contribute to cognitive and psychiatric complications⁷.

About Otsuka
Otsuka Pharmaceutical Co., Ltd. is a total healthcare company that focuses on each individual's potential to enhance their well-being. Our medical-related business provides treatments and diagnostics for both physical and mental health. Our nutraceutical business supports daily health maintenance and improvement. Otsuka's unique products and services are based on scientific evidence, under the guidance of our corporate philosophy: Otsuka-people creating new products for better health worldwide.  

Otsuka America Pharmaceutical, Inc. and Otsuka Pharmaceutical Development & Commercialization, Inc. are the US-based indirect subsidiaries of the global healthcare company Otsuka Pharmaceutical Co. Ltd. Otsuka’s US companies share a deep commitment to the development and commercialization of innovative products in the spaces of neuroscience, nephrology, and immunology. At our core is perseverance—a fierce determination to overcome any obstacle, regardless of setbacks, on behalf of patients, caregivers, and their loved ones. We will not be bound by doing what’s been done before. Learn more at www.otsuka-us.com.

References

1. Fernanda Leal-Pardinas, Nicola Longo, Cary O. Harding, Ania C. Muntau, Rani H. Singh, Andreu Viader, George Vratsanos, Haoling H. Weng, Elaina Jurecki, Wei Li, Guissou Dabiri, John P. Throup, Markey McNutt. Phase 2 Efficacy of Repinatrabit in Reducing Plasma Phenylalanine (Phe) Concentration in Adults with Phenylketonuria (PKU): Subgroup Analyses by Baseline Characteristics. 2026 NPKUA Scientific Conference.
2. O. Harding C., et al. Design of a Randomized, Double-Blind, Placebo-Controlled, Phase 3, Efficacy and Safety Trial of Repinatrabit in Adults with Phenylketonuria. Acmg.planion.com. Accessed March 5, 2026. https://acmg.planion.com/Web.User/AbstractDet?ACCOUNT=ACMG&ABSID=876450&CONF=AM26&ssoOverride=OFF&CKEY=6543N084O.
3. 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.
4. Hillert A, Anikster Y, Belanger-Quintana A, Burlina A, Burton BK, Carducci C, Chiesa AE, Christodoulou J, Đorđević M, et al. 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.
5. Ashe K;Kelso W;Farrand S;Panetta J;Fazio T;De Jong G;Walterfang M; Psychiatric and cognitive aspects of phenylketonuria: The limitations of diet and promise of new treatments. Frontiers in psychiatry. Accessed March 5, 2026. https://pubmed.ncbi.nlm.nih.gov/31551819/.
6. Gassi R., et al. Prevalence of sleep disorders in early-treated phenylketonuric children and adolescents. Correlation with dopamine and serotonin status. ScienceDirect. Accessed March 5, 2026. https://www.sciencedirect.com/science/article/pii/S109037981930176X.
7. G; R. Phenylketonuria as an adherence disease. Patient preference and adherence. 2025. Accessed March 5, 2026. https://pubmed.ncbi.nlm.nih.gov/40248132/.

View source version on businesswire.com: https://www.businesswire.com/news/home/20260312101608/en/