ION582 Improves Cognition, Motor Function, and Communication in Phase 1/2 Trial of Angelman Syndrome


ION582, delivered intrathecally into the cerebral spinal fluid with a lumbar puncture, resulted in significant improvements in cognition, fine and gross motor skills, and expressive communication.

Lynne Bird, MD, professor of clinical pediatrics at UC San Diego

Lynne Bird, MD

Newly announced topline data from the phase 1/2 HALOS trial (NCT05127226) showed that treatment with investigational ION582 (Ionis Pharmaceuticals) was safe and well tolerated in patients with Angelman syndrome, with robust improvements in outcomes of cognition, motor function, and communication. The company is expecting to report additional data from the study at the upcoming Angelman Syndrome Foundation meeting in July.1

The study consists of 3 parts. Part 1, a multiple-ascending dose (MAD) study, includes a 13-week MAD treatment period and a minimum 12-week but up to 32-week post-MAD follow-up period. All 51 participants transitioned into the part 2 long-term extension portion of the study, where they receive intrathecal bolus doses of ION582 for an additional 12 months. Part 3 of the study extends the treatment period for participants who completed part 2 for up to an additional 3 years.

Topline results were available for all patients at 4 months and 6 months, and were consistent with preliminary findings reported at the 2023 Foundation for Angelman Syndrome Therapeutics (FAST) meeting. All told, the therapy was considered well tolerated at all doses, with adverse events (AEs) that were consistent with patient medical histories, Angelman syndrome diagnosis, or related to intrathecal administration.

"There are currently no approved treatments for Angelman syndrome, which causes developmental delays, cognitive impairment and severe communications challenges, with most individuals unable to speak or live independently,” study investigator Lynne Bird, MD, professor of clinical pediatrics at UC San Diego, said in a statement.1 "We are encouraged by the positive and consistent improvements seen in the HALOS study across multiple measures, as these functional improvements could have a transformative impact in the lives of people living with Angelman syndrome and their caregivers. We are also encouraged by the favorable safety and tolerability profile observed in the study, which is particularly important when treating children. We very much look forward to further evaluation of ION582 in a pivotal program."

ION582, delivered intrathecally into the cerebral spinal fluid with a lumbar puncture, is designed to unsilenced the paternal UBE3A allele, the root cause of Angelman syndrome. Through its mechanism of action, the therapy increases the production of the UBE3A protein in the brain, producing positive effects.

In addition to demonstrating a safe profile, ION582 showed consistent effects on a number objective and subjective measures, including Bayley-4, Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale, and the Vineland-3 and Observer-Reported Communication (ORCA) measures. These assessments, which factor functioning, clinician impressions, and parent-reported views, were correlated with positive changes in EEG activity including a reduction in slow wave delta activity.

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After 6 months of treatment with ION582, 65% of patients achieved improvement on cognition and 65% of patients demonstrated improvements on fine and gross motor skills, assessed through Bayley-4. In addition, 70% of patients on active treatment gained benefits in Bayley-4 measures of receptive and/or expressive communication. While no direct comparisons could be made, these improvements exceeded improvements seen in natural history studies over the same time period.

"We are encouraged by the data from the HALOS study and pleased to add this promising medicine to our growing independent pipeline of neurology medicines," Brett Monia, PhD, chief executive officer at Ionis, said in a statement.1 "We look forward to sharing detailed data at the upcoming Angelman Syndrome Foundation meeting and to advancing ION582 into a pivotal study. Individuals with Angelman syndrome face significant neuro-developmental challenges and have no approved therapies today. We are committed to working closely with the community, investigators and regulators to advance this promising investigational medicine."

The study featured those with Angelman syndrome, aged between 2-50 years old, who had diagnosis confirmed with either UBE3A deletion or UBE3A mutation. It excluded those with documented molecular Angelman Syndrome confirmation of paternal uniparental disomy or imprinting defect. Additionally, those with any clinically significant cardiovascular, endocrine, hepatic, renal, pulmonary, gastrointestinal, neurologic, malignant, metabolic, psychiatric, or other condition that, in the judgment of the investigator, would pose a safety risk, were ineligible for the trial.

1. Ionis announces positive topline results from phase 1/2a trial of ION582 for Angelman syndrome. Ionis Pharmaceuticals. News release. May 16, 2024. Accessed May 20, 2024.
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