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Ionis to Advance ION582 in Phase 3 Studies of Angelman Syndrome Following Positive Open-Label Data
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Treated patients demonstrated improvements on the Bayley-4 in cognition, communication, and motor function that exceeded those seen in natural history studies of Angelman syndrome.
Brett Monia, PhD
Newly announced data from a multiple-ascending dose (MAD) portion of the open-label, phase 1/2 HALOS study (NCT05127226) showed a resounding number of individuals with Angelman syndrome who had improvements in overall symptoms following treatment with investigational ION582. Ionis Pharmaceuticals, the drug manufacturers of ION582, announced it will initiate phase 3 studies testing the agent in the first half of 2025.1
At the final timepoint of the completed MAD portion of the study at 6 months, 97% of the 51-patient cohort showed clinically meaningful improvement on the Symptoms of Angelman Syndrome-Clinician Global Impression of Change (SAS-CGI-C) scale, an outcome of Angelman syndrome symptoms. ION582, an antisense oligonucleotide designed to inhibit the expression of the UBE3A antisense transcript, was considered safe and tolerable at all dose levels.
"Ionis looks forward to collaborating with investigators, regulators and members of the Angelman syndrome community to initiate Phase 3 development for ION582 in the first half of 2025," Brett Monia, PhD, chief executive officer at Ionis, said in a statement. "Ionis has pioneered the discovery and development of groundbreaking medicines for serious neurological conditions including spinal muscular atrophy and amyotrophic lateral sclerosis. These encouraging results from the HALOS study position ION582 to be the cornerstone of Ionis' next wave of transformational, wholly owned medicines for neurological conditions, which currently includes five clinical-stage programs."
In HALOS, the majority of participants demonstrated benefit in nearly all domains assessed, which included Bayley Scales of Infant and Toddler Development-4th edition, Vineland Adaptive Behavior Scale-3rd edition (Vineland-3), Observer-Reported Communication Ability (ORCA), and SAS-CGI-C. On SAS-CGI-C, 85% had improvements in cognition, 69% in expressive communication, 74% in gross motor, 64% in fine motor, 62% in daily living skills, 61% in sleep, and 56% in behavior.
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These results, along with the other scales, exceeded improvements seen in natural history studies, where available, in which people with Angelman syndrome show significant developmental delay from birth through adulthood with function remaining stable with essentially no improvement after about 4 years of age. Additional data from these results showed that 60% of treated patients had enhancements in receptive and expressive communication on ORCA. On Bayley-4, 67%, 67%, 69%, 46%, and 72% of patients had improvements in cognition, receptive communication, expressive communication, gross motor, and fine motor skills, respectively.
HALOS, an ongoing multicenter study, includes 3 parts. Part 1 comprised the 3-month multiple-ascending dose study which evaluated 3 doses of ION582, with final assessments at 6 months. All eligible patients transitioned into the part 2 long-term extension portion of the study, which assesses 2 higher doses of the therapy for an additional 12 months. Part 3 of the study will evaluate eligible patients for up to an additional 4 years.
Lynne Bird, MD
"Angelman syndrome is a serious neurodevelopmental disorder with life-long impairments and dependence on caregivers, for which we currently have only supportive care,” study investigator Lynne Bird, MD, a professor of clinical pediatrics at UC San Diego, said in a statement. "We are very encouraged by these promising data with ION582, showing consistent improvements over what we observe in the natural course of the disease."
