Ionis Reports Positive Results from Phase 1/2a Trial in Angelman Syndrome

Rare Daily Staff

Ionis Pharmaceuticals said topline data from its HALOS phase 1/2a open-label study of ION582 in the rare neurodevelopmental condition Angelman syndrome showed encouraging and consistent benefits in individuals.

The most robust improvements observed in key areas of functioning including cognition, communication, and motor function. The study also found ION582 was safe and well tolerated.

Biogen has elected not to exercise its option to license ION582. Ionis said that it will independently advance ION582. The company plans to review the ION582 phase 1/2a results with regulatory authorities to align on the design of the pivotal program.

Angelman syndrome is caused by a loss of function in the maternal UBE3A gene. ION582 is designed to unsilence the paternal UBE3A allele in order to increase production of the UBE3A protein in the brain. It presents as profound and severe developmental delays in motor, language, and cognitive functioning, seizures, and ataxia. It manifests in early childhood, resulting in complete dependence on a caregiver.

ION582 is an investigational antisense medicine designed to inhibit the expression of the UBE3A transcript and increase production of UBE3A protein, for the potential treatment of Angelman syndrome. It is administered intrathecally into the cerebral spinal fluid with a lumbar puncture. The U.S. Food and Drug Administration granted ION582 Orphan Drug designation.

ION582 showed consistent effects across multiple objective and subjective measures used to assess functioning in individuals living with Angelman syndrome. These include the Bayley-4, an objective physician assessment of clinical functioning, Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale, which evaluates clinicians’ impressions, and the Vineland-3 and Observer-Reported Communication Ability (ORCA) measures, which are parent-reported assessment tools. These positive results correlated with positive changes in EEG activity including a reduction in slow wave delta activity.

At six months, approximately 65 percent of patients achieved an improvement in cognition on the Bayley-4. While no direct comparisons should be made, these improvements exceeded improvements seen in natural history studies over the same time period.

At six months, approximately 70 percent of patients showed improvement on Bayley-4 measures of receptive and/or expressive communication. While no direct comparisons should be made, these changes exceeded improvements seen in natural history studies over the same time period.

Ionis expects to report detailed results from the HALOS study at the Angelman Syndrome Foundation meeting in July.

“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,” said Lynne Bird, professor of clinical pediatrics at UC San Diego and HALOS study investigator. “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.”

Photo: Lynne Bird, professor of clinical pediatrics at UC San Diego and HALOS study investigator