Ionis Pharmaceuticals announced the pivotal Phase 3 study design for ION582, an investigational medicine for Angelman syndrome (AS), following alignment with the U.S. Food and Drug Administration (FDA). The Phase 3 REVEAL trial is set to begin in the first half of 2025.
Phase 3 Trial Design
The global, randomized, placebo-controlled Phase 3 study 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 either active therapy or placebo. ION582 will be administered quarterly at two dose levels without a loading regimen. The primary analysis will occur after approximately one year of treatment, after which all patients will transition to an open-label long-term extension (LTE) phase.
Primary and Secondary Endpoints
The primary endpoint for the Phase 3 trial is the improvement in expressive communication, as assessed by the Bayley Scales for Infant and Toddler Development-4 (Bayley-4). This is an objective, clinician-administered assessment of clinical functioning. Secondary endpoints include overall disease severity, cognition, communication, sleep, motor functioning, and daily living skills, along with other exploratory endpoints.
Supporting Phase 2 Data
The End of Phase 2 meeting was supported by data from the Phase 2 open-label HALOS study. The multiple ascending dose (MAD) portion of the study showed strong evidence of clinically meaningful improvement on all functional domains, including communication, cognition, and motor function. Overall, 97% of people in the medium and high dose groups assessed in the study saw an 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.
ION582 and Angelman Syndrome
ION582 is an investigational antisense medicine designed to inhibit the expression of the UBE3A antisense transcript (UBE3A-ATS) and increase the production of UBE3A protein. Angelman syndrome is a rare, genetic neurological disease caused by the loss of function of the maternally inherited UBE3A gene. It typically presents in infancy and is characterized by profound intellectual disability, balance issues, motor impairment, and debilitating seizures. Most patients are unable to speak and require complete care from a caregiver. While some symptoms can be managed with existing medicines, there are currently no approved disease-modifying therapies for AS.
Ionis' Neurology Franchise
Ionis has been at the forefront of discovering and developing leading neurological disease medicines, including SPINRAZA® (nusinersen) for spinal muscular atrophy, WAINUA™ (eplontersen) for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), and QALSODY® (tofersen) for SOD1-ALS. The clinical-stage portfolio includes 11 therapies, of which five are wholly owned by Ionis. Ionis' investigational portfolio includes medicines for which there are few or no disease-modifying treatments, such as rare diseases including Prion disease and Alexander disease and more common conditions such as Alzheimer's and Parkinson's disease.
Brett Monia, Ph.D., chief executive officer of Ionis, stated, "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."
