Oak Hill Bio has secured exclusive global rights to rugonersen, a novel antisense oligonucleotide therapy for Angelman syndrome, following encouraging Phase 1 trial results published in Nature Medicine. The biotechnology company plans to initiate a pivotal Phase 3 study in early 2026 for this potential first-in-class treatment targeting a rare genetic neurodevelopmental disorder affecting an estimated 500,000 individuals worldwide.
Phase 1 TANGELO Trial Demonstrates Clinical Promise
The TANGELO study, a Phase 1 multicenter, open-label, multiple ascending dose escalation trial, enrolled 61 patients aged 1-12 years with Angelman syndrome. Results published in Nature Medicine showed that rugonersen treatment led to dose-dependent partial normalization of pathological brain activity measured by electroencephalogram (EEG) delta power, a validated biomarker of abnormal brain function in Angelman syndrome.
"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," said Dr. Mark Shen, Assistant Professor of Neuroscience and Psychiatry at the University of North Carolina School of Medicine and principal investigator of the study.
The trial demonstrated improvements across multiple exploratory clinical endpoints measuring core symptoms of Angelman syndrome. Four out of five behavioral domains tested by the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) and all five Vineland Adaptive Behavior Scales domains showed developmental gains above expectations from natural history, with most gains approaching or surpassing thresholds for minimal clinically important group differences.
Mechanism of Action Targets Disease Root Cause
Angelman syndrome is caused by lack of the UBE3A protein in neurons due to a genetic defect on the maternal allele. While UBE3A is expressed only from the maternal allele in neurons, the paternal allele remains silenced by a long non-coding antisense transcript (UBE3A-ATS). Rugonersen is designed to restore UBE3A expression by suppressing the UBE3A-ATS transcript, thereby leveraging the intact paternal allele to address the underlying molecular cause of the disorder.
Safety Profile Supports Continued Development
Rugonersen demonstrated a favorable safety profile across more than 450 intrathecal administrations among 61 participants, with some receiving treatment for up to four years. The most common adverse events were transient pyrexia and vomiting, typically occurring shortly after dosing. Serious adverse events occurred in 34% of participants, with treatment-related serious adverse events in 13% of participants (2% of administrations). No participants were withdrawn from the study due to adverse events.
"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," said Dr. Wen-Hann Tan, Attending Physician at Boston Children's Hospital and Associate Professor of Pediatrics at Harvard Medical School, who was not involved in the study.
Strategic Partnership Advances Development
Oak Hill Bio's exclusive license agreement with Roche positions the company to advance rugonersen through pivotal Phase 3 development. The licensing deal reflects confidence in the therapy's potential to become the first approved disease-modifying treatment for Angelman syndrome.
"We are excited to take on this program. We are incredibly impressed by the rigorous research Roche has conducted, and the promising clinical data generated to date," said Josh Distler, Chief Executive Officer of Oak Hill Bio. "We have also been moved by the dedication of the patients, families, and investigators in the Angelman community and look forward to working closely with them to fully evaluate rugonersen's potential."
The Angelman syndrome community has expressed strong support for the continued development. "We are incredibly excited and deeply grateful to see Oak Hill stepping in to continue the rugonersen program for Angelman syndrome," said Amanda Moore, CEO of the Angelman Syndrome Foundation, and Ryan Fischer, COO of the Foundation for Angelman Syndrome Therapeutics.
Angelman syndrome typically presents during early childhood and is characterized by cognitive and developmental issues, including speech and communication difficulties, motor impairment, balance issues, and debilitating seizures. The condition currently has no approved disease-modifying treatments, representing a significant unmet medical need for affected individuals and their families.
