Ionis Unveils Phase 3 Trial Design for ION582 in Angelman Syndrome

Ionis Pharmaceuticals, Inc. has announced a significant milestone in the development of ION582, an investigational treatment for Angelman syndrome (AS). Following a successful Phase 2 trial, the company has received alignment with the U.S. Food and Drug Administration (FDA) on the design for their Phase 3 study. This marks a pivotal step towards potentially offering a new therapeutic option for individuals affected by this debilitating neurological condition.

Angelman syndrome is a rare genetic disorder that manifests in early childhood. It is characterized by severe intellectual disabilities, impaired speech, and significant motor challenges. Currently, there are no approved treatments that address the underlying causes of AS, making the development of ION582 highly anticipated within the medical community.

Dr. Brett Monia, CEO of Ionis Pharmaceuticals, expressed optimism about the progress, stating that the Phase 3 REVEAL trial has been meticulously designed to address the most critical and impactful outcomes for individuals with AS and their caregivers. The trial is set to commence in the first half of 2025 and aims to enroll around 200 participants globally. These participants will be either children or adults with a maternal UBE3A gene deletion or mutation.

The Phase 3 study will be a randomized, placebo-controlled trial, with participants divided into two groups: one receiving the active therapy and the other a placebo, in a 2:1 ratio. Importantly, ION582 will be evaluated at two different dose levels and administered quarterly without a loading regimen. The primary goal of the study is to assess improvement in expressive communication, measured by the Bayley Scales for Infant and Toddler Development-4 (Bayley-4). This scale is a direct, clinician-administered assessment of a patient's communication abilities, which are notably a major challenge for those living with AS.

In addition to the primary endpoint, the study will also consider several secondary endpoints. These include overall disease severity, cognitive and motor function, communication, sleep quality, and daily living skills. The comprehensive approach aims to provide a thorough understanding of the potential benefits of ION582 across multiple aspects of AS.

The positive results from the Phase 2 HALOS trial provide a strong foundation for the upcoming Phase 3 study. In the Phase 2 trial, ION582 demonstrated substantial improvements across various functional domains, including communication and motor skills. Notably, 97% of participants in the medium and high dose groups showed an improvement in overall AS symptoms according to the Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale, which evaluates clinician impressions. Moreover, the treatment exhibited favorable safety and tolerability across all dose levels.

Ionis Pharmaceuticals plans to share further updates on the ION582 program at the FAST Global Science Summit in November. This will include a detailed review of the data from the multiple ascending dose portion of the HALOS trial, providing the community with deeper insights into the progress and potential of the investigational treatment.

In summary, the announcement of the Phase 3 study design for ION582 represents a significant advancement in the pursuit of a treatment for Angelman syndrome. With the support of the FDA and positive data from earlier trials, Ionis Pharmaceuticals is poised to make a meaningful impact on the lives of those affected by this challenging condition. The forthcoming trial and continued community engagement underscore the company’s commitment to addressing unmet medical needs in the field of neurology.