Ionis Pharmaceuticals is set to begin a pivotal Phase III trial, named REVEAL, for ION582, an investigational treatment for Angelman Syndrome (AS). This development follows discussions with the U.S. Food and Drug Administration (FDA) and is based on promising Phase II data. The trial aims to evaluate the efficacy and safety of ION582 in a broad population of individuals living with AS, a debilitating neurological condition lacking approved medicines.
Trial Design and Patient Population
The Phase III REVEAL study is a randomized, global, placebo-controlled trial designed to enroll approximately 200 adults and children diagnosed with AS. Participants will specifically include those with a maternal ubiquitin-protein ligase E3A (UBE3A) gene mutation or deletion, which is a common genetic cause of the syndrome. Patients will be randomized in a 2:1 ratio to receive either ION582 or a placebo.
Dosing and Endpoints
ION582 will be administered at two different dose levels every quarter, 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 standardized clinical assessment tool. Secondary endpoints include assessments of sleep, overall disease severity, communication, motor functioning, and everyday living skills, along with other exploratory measures. After one year of treatment, participants will transition to an open-label, long-term extension phase.
Clinical Significance and Previous Data
According to Ionis Pharmaceuticals CEO Brett Monia, the trial is planned to begin in the first half of 2025. Data from the Phase II HALOS study supported the advancement to Phase III. 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 in the Phase II study.
Regulatory Designations
ION582 has been granted orphan drug designation (ODD) and rare pediatric disease designation by the FDA, which can provide incentives such as market exclusivity and potential for priority review, underscoring the unmet need for effective treatments for Angelman Syndrome.
