Oak Hill Bio Announces Publication of Rugonersen Phase 1 Study Results in Nature Medicine

Data from the TANGELO trial provides evidence of improvement in brain activity and developmental ability in children with Angelman syndrome compared to natural history

Oak Hill Bio, a biotechnology company focused on developing life-changing therapies for people with rare diseases, today announced the publication in Nature Medicine of the results of the rugonersen Phase 1 TANGELO study in 1 to 12 year old children with Angelman syndrome.¹ Oak Hill Bio recently obtained exclusive rights to rugonersen and plans to initiate a Phase 3 study in patients with Angelman syndrome in early 2026. The results published today (The UBE3A-ATS antisense oligonucleotide rugonersen in children with Angelman syndrome: a phase 1 trial, Hipp et al., Nature Medicine, DOI 10.1038/s41591-025-03784-7) showed adverse event rates for rugonersen consistent with other antisense oligonucleotides, the route of administration, and the patient population. The results also showed that treatment with rugonersen led to dose-dependent partial normalization of pathological brain activity on a pharmacodynamic biomarker of brain function, electroencephalogram (EEG) delta power, and improvements on multiple exploratory endpoints measuring the core symptoms of Angelman syndrome as compared to natural history. The safety and tolerability profile, as well as the encouraging pharmacodynamic and exploratory clinical effects observed in TANGELO, provide strong support for further testing of rugonersen for the treatment of Angelman syndrome.

Angelman syndrome is caused by lack of the protein UBE3A in neurons due to a genetic defect on the maternal allele. UBE3A is expressed only from the maternal allele in neurons, while the paternal allele is silenced (imprinted) by a long non-coding antisense transcript (UBE3A-ATS) that interferes with the transcription of UBE3A from the paternal allele. Rugonersen (OHB-724) is designed to restore expression of UBE3A by suppressing the UBE3A-ATS transcript, thereby leveraging the intact paternal allele. TANGELO was a Phase 1, multicenter, open-label, multiple ascending, intra-patient dose escalation study that enrolled 61 patients aged 1-12 years with Angelman syndrome (mutation and deletion genotypes). In TANGELO, rugonersen led to a dose-dependent reduction in EEG delta power—a biomarker of abnormal brain activity in Angelman syndrome that has been shown to correlate with functional outcomes. The dynamics of the EEG biomarker provide robust pharmacodynamic data to inform the dose regimen of the planned Phase 3 trial.

Exploratory clinical efficacy on developmental skills was assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), and the Vineland Adaptive Behavior Scales, Third Edition (Vineland). Four out of five behavioral domains tested by the Bayley-III and all five of the Vineland domains analyzed showed developmental gains above expectations from natural history. Of these results, most gains in developmental ability approached or surpassed thresholds for minimal clinically important group 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 principal investigators and authors of the paper. “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.”

“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, Division of Genetics and Genomics at Boston Children’s Hospital and Associate Professor of Pediatrics at Harvard Medical School, an expert on Angelman syndrome, who was not involved in the study. “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.”

Angelman syndrome affects an estimated 500,000 individuals worldwide. It 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.

Rugonersen was generally well tolerated across more than 450 intrathecal administrations among 61 participants, some of whom received treatment for up to four years. The most common adverse events (AEs) were transient pyrexia and vomiting, typically occurring shortly after dosing. Serious adverse events (SAEs) were experienced by 34% of participants and those deemed related to treatment occurred in 13% of participants (or 2% of administrations). Treatment-related SAEs included seizure, epilepsy, vomiting, pyrexia and post-lumbar puncture syndrome. No participants were withdrawn from the study due to AEs.

“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 and are deeply appreciative of the patients, families, and investigators whose commitment made this work possible,” said Josh Distler, Chief Executive Officer of Oak Hill Bio. “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.”

About Oak Hill Bio

Oak Hill Bio is a clinical-stage biotechnology company dedicated to developing life-changing therapies for people with rare diseases. Its pipeline includes late-stage programs in Angelman syndrome and complications of extreme prematurity, as well as a preclinical asset for diabetic macular edema. For more information, visit www.oakhillbio.com.

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“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.