RNA-Targeted Drug for Angelman Syndrome Receives Breakthrough Therapy Designation

The Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to ION582 (Ionis Pharmaceuticals, Carlsbad, CA) for the treatment of Angelman syndrome (AS), a rare genetic neurologic condition marked by severe developmental impairments, motor dysfunction, and seizures. ION582 is an investigational antisense drug that targets RNA to inhibit UBE3A antisense transcript (UBE3A-ATS) expression and increase UBE3A protein production. The Breakthrough Therapy designation, intended to expedite development of therapies with preliminary evidence of meaningful clinical benefit in serious conditions, was based on positive results from the phase 1/2 HALOS clinical trial (NCT05127226).

HALOS was an open-label, multiple ascending dose study that included 51 participants aged 2 to 50 years with AS. Participants received ION582 across low, medium, and high dose groups. Part 1 of the study consisted of a 3-month period with a primary end point of safety and tolerability assessed up to week 45. Eligible participants from part 1 transitioned to part 2, a long-term extension (LTE) evaluating outcomes up to week 81. A third portion of the study will evaluate treatment up to 4 years. 

Key results from the HALOS study included:

• 97% of medium- and high-dose–treated participants demonstrated improvement on the Symptoms of Angelman Syndrome–Clinician Global Impression–Change (SAS-CGI-C) scale.
• Clinician-administered Bayley-4 assessments showed improvements in cognition, communication, and motor function that exceeded changes observed in the Angelman Syndrome Natural History Study.
• Parent-reported measures (Vineland-3 and Observer-Reported Communication Ability [ORCA]) showed consistent benefits in key functional areas.
• ION582 was well tolerated across dose groups, with no new safety signals reported.

The phase 3 REVEAL clinical trial (NCT06914609) is now underway to further evaluate efficacy and safety in a larger population with AS who have a maternal UBE3A gene deletion or mutation. 

Source: Ionis Pharmaceuticals Ionis announces positive detailed results from the HALOS Study of ION582 in people with Angelman syndrome. IR.Ionis.com. Published 22 July, 2024. Accessed 12 September, 2025.