Details Surrounding Phase 3 Study of ION582 in Angelman Syndrome Announced

Brett Monia, PhD

Following a positive end of phase 2 discussion with the FDA, Ionis Pharmaceuticals has announced the study design of a new phase 3 trial to assess the efficacy and safety of the company’s investigational agent ION582 as a potential treatment for Angelman syndrome (AS). The placebo-controlled study, expected to include 200 children and adults with AS, is anticipated to begin in the first half of 2025.¹

The global study will randomly assigned patients with AS that have a maternal UBE3A gene deletion or mutation 2:1 to either active ION582 or placebo for a 12-month period, followed by an optional open-label long-term extension. Investigators will use change in expressive communication, assessed through the Bayley Scales for Infant and Toddler Development-4 (Bayley-4) tool, as the primary end point over the 12-month period.

Currently, there are no FDA-approved treatments for AS that work to target the underlying pathology of the disease. ION582, which has shown promise in a previously completed phase 1/2 trial, dubbed HALOS (NCT05127226), is an investigational antisense oligonucleotide designed to inhibit the expression of the UBE3Aantisense transcript and increase production of the UBE3A protein. To date, it has received orphan drug and rare pediatric designation from the FDA.

"Following positive results for ION582 in the Phase 2 HALOS trial, we are pleased to have alignment with the FDA on the design of our Phase 3 REVEAL trial, which will address clinical endpoints that reflect the most pressing and meaningful outcomes for people living with AS and their caregivers," Brett Monia, PhD, chief executive officer at Ionis, said in a statement.¹ "We will enroll a broad group of individuals living with AS in the global pivotal Phase 3 trial, planned to begin in the first half of 2025. We look forward to working with the community to advance a potential new treatment targeting the underlying cause of disease in this debilitating neurological condition that has no approved medicines."

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During the summer, Ionis announced positive data from the multiple-ascending dose (MAD) portion of HALOS, with results further supporting the development of ION582 in AS. After 6 months of treatment, 97% of the 51-patient cohort demonstrated clinically meaningful improvement on the Symptoms of Angelman Syndrome-Clinician Global Impression of Change scale (SAS-CGI-C), an outcome of AS symptoms. In addition, the therapy was considered safe and tolerable at all dose levels.²

The study consisted of 3 parts. Part 1, a 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.

Similar to the newly announced phase 3 trial, HALOS included those with AS who had diagnosis confirmed with either UBE3A deletion or UBE3A mutation. In the HALOS study, most participants showed benefits across nearly all assessed domains, including the Bayley Scales of Infant and Toddler Development, 4th Edition (Bayley-4), Vineland Adaptive Behavior Scales, 3rd Edition (Vineland-3), Observer-Reported Communication Ability (ORCA), and the SAS-CGI-C. On the SAS-CGI-C, 85% demonstrated improvements in cognition, 69% in expressive communication, 74% in gross motor skills, 64% in fine motor skills, 62% in daily living skills, 61% in sleep, and 56% in behavior.

These results, along with outcomes from other scales, surpassed improvements seen in natural history studies, where individuals with Angelman syndrome typically exhibit significant developmental delays from birth through adulthood, with stable functioning and little to no improvement after about 4 years of age. Additional data showed that 60% of treated patients had improvements in receptive and expressive communication on the ORCA. On the Bayley-4, 67%, 67%, 69%, 46%, and 72% of patients showed gains in cognition, receptive communication, expressive communication, gross motor skills, and fine motor skills, respectively.

REFERENCES
1. Ionis Announces Pivotal Phase 3 Trial Design for ION582 in Angelman Syndrome. News release. Ionis Pharmaceuticals. November 6, 2024. Accessed November 7, 2024. https://www.prnewswire.com/news-releases/ionis-announces-pivotal-phase-3-trial-design-for-ion582-in-angelman-syndrome-302297166.html
2. Ionis announces positive detailed results from the HALOS study of ION582 in people with Angelman syndrome. News release. July 22, 2024. Accessed November 7, 2024. https://www.prnewswire.com/news-releases/ionis-announces-positive-detailed-results-from-the-halos-study-of-ion582-in-people-with-angelman-syndrome-302202157.html