Fernanda Leal-Pardinas, MD, MSc, Global Clinical Development Lead, Rare & Metabolic Disorders at Otsuka Pharmaceutical, discusses the open-label extension data from their study testing repinatrabit for patients with phenylketonuria (PKU).
PKU is a genetic metabolic disorder that increases the body’s levels of phenylalanine to toxic levels. Phenylalanine is a natural part of the foods we eat.. People with PKU lack the enzyme phenylalanine hydroxylase to break down this phenylalanine, causing a build up in the blood, urine, and body. Without treatment, children with classic PKU develop permanent intellectual disability. Light skin and hair, seizures, developmental delays, behavioral problems, and psychiatric disorders are also common. In most cases, PKU is caused by changes in the PAH gene.
At the 2026 American College of Medical Genetics and Genomics (ACMG) meeting, open-label extension data of repinatrabit and the study design for the phase 3 PheORD clinical trial were presented. Repinatrabit is an investigational, selective, small-molecule inhibitor of the Phe transporter SLC6A19 developed to reduce blood Phe levels.
In a long-term, open-label extension, the first cohort of adolescents receiving repinatrabit 75 mg twice daily, evaluated in the Phase 2 adolescent study (NCT06637514), achieved sustained Phe reductions at day 56. At this assessment, adolescents achieved an average –67% reduction from baseline. The scale and consistency of Phe reduction observed in adolescents were comparable to those reported in adult phase 2 studies.
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 phase 2 findings in adults. No new treatment-related adverse events were identified, and no serious adverse events were reported.
This study is ongoing, with patients in the open-label extension advancing to the higher dose (150 mg) of repinatrabit in the second cohort. The pivotal global, randomized, double-blind, placebo-controlled phase 3 PheORD trial in adults with PKU is also advancing, designed to evaluate the efficacy and safety of two oral dose regimens of repinatrabit (75 mg or 150 mg twice daily) compared with placebo.
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. This trial is actively recruiting. Visit Phase 3 PheORD clinical trial (NCT06971731) for more information.
To learn more about PKU and other rare metabolic conditions, visit https://checkrare.com/diseases/metabolic-disorders/