CAMBRIDGE, Mass. — Early trial results of rugonersen, a potential treatment for Angelman syndrome, have been published in Nature Medicine, showing improvements in brain function and developmental skills in affected children. The data comes from the Phase 1 TANGELO study, which enrolled 61 children aged 1 to 12 years.
The trial found that rugonersen led to a dose-dependent reduction in abnormal brain activity as measured by EEG delta power, a biomarker linked to functional outcomes in Angelman syndrome. Developmental assessments also indicated gains in multiple behavioral domains compared to what is typically seen in the natural course of the disease.
“These promising results further support our decision to license exclusive rights to rugonersen. We are proud to support the continued development of this potential new treatment option,” said Josh Distler, CEO of Oak Hill Bio, which recently acquired exclusive rights to the drug.
Angelman syndrome is caused by the absence of UBE3A protein in neurons, typically due to a genetic defect on the maternal chromosome. Rugonersen (OHB-724) is an antisense oligonucleotide designed to suppress the UBE3A-ATS transcript, which normally silences the paternal UBE3A gene. By targeting this mechanism, the drug aims to restore UBE3A expression from the otherwise inactive paternal allele.
TANGELO was an open-label, multiple ascending dose study conducted across multiple sites. The children in the study had either mutation or deletion genotypes associated with Angelman syndrome. In addition to the EEG improvements, clinical efficacy was evaluated using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), and the Vineland Adaptive Behavior Scales, Third Edition (Vineland). Most of the behavioral domains assessed showed developmental gains that approached or exceeded the thresholds for minimal clinically important differences.
“These are promising results that mark a major milestone in the development of disease-modifying therapies for Angelman syndrome,” said Dr. Mark Shen, Assistant Professor of Neuroscience and Psychiatry at the University of North Carolina School of Medicine and one of the study’s principal investigators. “In this paper, we have shown that an investigational treatment targeting the root cause of a genetic neurodevelopmental disorder can improve both brain activity and behavioral symptoms as compared to natural history in a consistent and measurable way.”
Dr. Wen-Hann Tan, Attending Physician in the Division of Genetics and Genomics at Boston Children’s Hospital and Associate Professor of Pediatrics at Harvard Medical School, commented on the findings, though he was not involved in the study. “Although these results are exploratory, rugonersen shows promise based upon the evidence published today of improvements in both a neurophysiologic biomarker and functional endpoints in individuals with Angelman syndrome,” he said. “These results provide support for further investigation of rugonersen and UBE3A-targeting strategies in randomized controlled trials and highlight the potential value of EEG as a biomarker.”
Rugonersen was generally well tolerated. Across more than 450 intrathecal administrations, the most common side effects were temporary fever and vomiting. Serious adverse events occurred in 34 percent of participants, though only 13 percent were deemed related to the treatment. These included seizure, epilepsy, and post-lumbar puncture syndrome. No patients were withdrawn due to side effects.
“This publication in Nature Medicine reflects the strength of the science and the importance of advancing treatments that can meaningfully improve the lives of people living with Angelman syndrome and their families,” Distler said.
Oak Hill Bio plans to initiate a Phase 3 trial of rugonersen in early 2026. Angelman syndrome affects an estimated 500,000 people globally and is marked by developmental delays, impaired speech, motor challenges, and epilepsy.
