Ionis Announces Phase III Trial Design for Angelman Syndrome Therapy ION582

• Ionis Pharmaceuticals has finalized the design for a Phase III clinical trial, named REVEAL, to evaluate ION582 as a potential treatment for Angelman syndrome.
• The global, randomized, placebo-controlled trial will enroll approximately 200 adults and children with Angelman syndrome who have a maternal UBE3A gene mutation or deletion.
• The primary endpoint of the REVEAL study will assess improvements in expressive communication using the Bayley Scales for Infant and Toddler Development-4 (Bayley-4) after one year of treatment.
• ION582 previously demonstrated clinically meaningful improvements across various functional domains in a Phase II study, with a favorable safety and tolerability profile.

Ionis Pharmaceuticals has announced the design for its pivotal Phase III REVEAL study of ION582, an investigational therapy for Angelman syndrome (AS), following discussions with the FDA. The trial is set to begin in the first half of 2025.

The REVEAL study is a randomized, global, placebo-controlled trial designed to enroll approximately 200 adults and children with AS, specifically those with a maternal ubiquitin-protein ligase E3A (UBE3A) gene mutation or deletion. Participants will be randomized in a 2:1 ratio to receive either ION582 or a placebo. The active therapy will be assessed at two different dose levels administered quarterly, without the need for a loading regimen.

The primary endpoint of the study is to measure improvements in expressive communication using the Bayley Scales for Infant and Toddler Development-4 (Bayley-4), a clinical assessment tool. Secondary endpoints include assessments of sleep, overall disease severity, communication, motor functioning, and everyday living skills, along with other exploratory endpoints. After one year of treatment, participants will transition to an open-label, long-term extension phase.

Prior Clinical Data

The design of the Phase III trial is supported by data from the Phase II HALOS study. In the multiple ascending dose (MAD) portion of the HALOS study, ION582 demonstrated clinically meaningful improvements across various functional domains. Notably, 97% of participants in the medium and high dose groups exhibited improvements in overall AS symptoms as per the Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale. The safety and tolerability of ION582 were also favorable across all doses tested.

Management Commentary

"We will enrol a broad group of individuals living with AS in the global pivotal Phase III trial, planned to begin in the first half of 2025," said Brett Monia, CEO of Ionis Pharmaceuticals. "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."

Regulatory Designations

In 2022, ION582 received orphan drug designation (ODD) and rare pediatric disease designation from the FDA.