Ionis Pharmaceuticals is advancing its investigational medicine, ION582, into a pivotal Phase 3 clinical trial for Angelman syndrome (AS) following a successful end-of-Phase 2 discussion with the U.S. Food and Drug Administration (FDA). The Phase 3 study, named REVEAL, is planned to begin in the first half of 2025.
Trial Design and Endpoints
The global, randomized, placebo-controlled Phase 3 trial will enroll approximately 200 children and adults with AS who have a maternal UBE3A gene deletion or mutation. Participants will be randomized 2:1 to receive either ION582 or a placebo. The drug will be administered quarterly without a loading regimen. The primary endpoint will be the change from baseline in expressive communication, as measured by the Bayley Scales for Infant and Toddler Development-4 (Bayley-4). Secondary endpoints include overall disease severity, cognition, communication, sleep, motor functioning, and daily living skills.
Rationale for ION582
ION582 is an antisense oligonucleotide (ASO) designed to inhibit the expression of the UBE3A antisense transcript (UBE3A-ATS), thereby increasing the production of UBE3A protein. Angelman syndrome is characterized by a loss of function of the maternally inherited UBE3A gene, leading to profound intellectual disability, impaired verbal abilities, and severe motor impairment. There are currently no approved disease-modifying therapies for AS, with existing treatments focusing on symptom management.
Supporting Phase 2 Data
The decision to move forward with Phase 3 was supported by data from the Phase 2 open-label HALOS study. Results from the multiple ascending dose (MAD) portion of the study showed strong evidence of clinically meaningful improvement across all functional domains, including communication, cognition, and motor function. Specifically, 97% of participants in the medium and high dose groups showed improvement in overall AS symptoms as measured by the Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale. ION582 also demonstrated favorable safety and tolerability at all dose levels in the study.
Company Statements
"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," said Brett Monia, Ph.D., chief executive officer of Ionis. "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."
