Ionis Begins Pivotal Phase 3 REVEAL Study of ION582 in Angelman Syndrome, Dosing First Patient in Global Trial
Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) has announced the dosing of the first patient in the Phase 3 REVEAL clinical trial, marking a significant milestone in the development of ION582, an investigational therapy for Angelman syndrome (AS). The study represents a major step toward addressing the unmet medical needs of individuals affected by this rare and severe neurodevelopmental disorder, which currently has no approved disease-modifying treatments.
Angelman syndrome is a complex genetic disorder that causes profound developmental delays, intellectual disability, speech impairment, problems with movement and balance, and seizures. It is typically caused by the loss of function of the maternal copy of the UBE3A gene. Due to the specificity of gene expression in neurons, where only the maternal copy is active, its deletion or mutation leads to the characteristic symptoms of AS. Currently, treatment options are limited to supportive care aimed at managing symptoms rather than targeting the underlying cause.
The REVEAL study (ClinicalTrials.gov Identifier: NCT06914609) is a global, randomized, double-blind, placebo-controlled Phase 3 trial that aims to evaluate the efficacy and safety of ION582 in both pediatric and adult populations with Angelman syndrome. This trial will build on previous positive data from the earlier Phase 1/2 HALOS study and is designed to rigorously assess the potential of ION582 as a disease-modifying therapy.
We are proud to have dosed the first participant in the pivotal REVEAL study, which marks an important advancement for the Angelman syndrome community,” said Dr. Holly Kordasiewicz, Senior Vice President of Neurology at Ionis. “This trial represents the culmination of years of scientific innovation and dedication, and we believe ION582 has the potential to make a meaningful difference in the lives of those affected by this debilitating condition.”
The REVEAL study will enroll approximately 200 participants globally, including both children and adults diagnosed with AS who have either a maternal UBE3A gene deletion or a mutation that disrupts gene function. Participants will be randomized in a 2:1 ratio to receive either ION582 or a placebo over the course of a 52-week treatment period. Those assigned to the active treatment arm will receive quarterly doses of ION582 at either 40 mg or 80 mg.
Following the initial 12-month treatment phase, eligible participants will be able to enter a long-term extension (LTE) phase of the study. During this portion, all participants—including those initially assigned to placebo—will have the opportunity to receive ION582 for an extended period of up to two years. This open-label extension aims to provide further insights into the long-term safety and efficacy of the drug while allowing continued access to therapy for trial participants.
The study’s primary endpoint focuses on expressive communication, one of the most impaired and distressing symptoms of Angelman syndrome. This outcome will be measured using the Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4). This standardized, clinician-administered tool provides a comprehensive and objective assessment of communication development, making it well-suited to evaluate meaningful change in patients with AS. The selection of expressive communication as the primary endpoint reflects its high priority among caregivers, who often cite the inability to communicate as the most challenging aspect of the disorder.
In addition to the primary endpoint, REVEAL includes a series of secondary and exploratory endpoints that will offer a more holistic understanding of the treatment’s impact. These include assessments of overall disease severity, cognitive ability, receptive and expressive language, motor skills, sleep quality, and activities of daily living. By capturing a broad range of clinical outcomes, the study aims to elucidate the full therapeutic potential of ION582 across multiple functional domains.
ION582 is an antisense oligonucleotide designed to target the underlying molecular mechanism of Angelman syndrome by restoring the expression of the UBE3A gene in neurons. In individuals with AS, the paternal copy of the gene is typically silenced due to genomic imprinting. ION582 works by inhibiting a natural antisense transcript that suppresses the expression of the paternal UBE3A allele, thereby allowing it to be reactivated. This mechanism has the potential to partially restore UBE3A protein production in neurons, addressing the root cause of the disorder.
Encouraging results from the previously completed Phase 1/2 HALOS study support the continued development of ION582. The open-label trial involved multiple ascending dose (MAD) cohorts and demonstrated consistent clinical improvements across various functional areas, including communication, cognition, and motor performance. Moreover, ION582 was generally well-tolerated at all tested dose levels, with no significant safety concerns identified.
These early results gave us a strong foundation to proceed with confidence into the pivotal Phase 3 REVEAL trial,” noted Dr. Kordasiewicz. “Our mission is to deliver meaningful therapies to people living with rare neurological diseases, and the progress of ION582 is a testament to the strength of our neurology pipeline and our ongoing commitment to the rare disease community.”
Ionis Pharmaceuticals has a well-established track record in the development of antisense therapies for neurological disorders. The company was instrumental in the development of SPINRAZA® (nusinersen), the first FDA-approved treatment for spinal muscular atrophy (SMA), and QALSODY™ (tofersen), an investigational treatment for superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS). Both programs highlighted the potential of antisense technology to modify the course of genetic neurological diseases, paving the way for novel approaches such as ION582.
The REVEAL trial represents a critical step forward not only for ION582 but also for the broader field of precision neurology. With eight wholly owned neurology programs currently in clinical development, Ionis continues to expand its pipeline targeting a diverse array of rare and more prevalent neurological disorders. The company’s strategic focus on genetic precision medicine positions it as a leader in the pursuit of innovative therapies aimed at transforming lives.
As enrollment continues in the REVEAL study, the Angelman community is watching closely, with hope that ION582 could become the first approved treatment to address the genetic root of this devastating condition. The successful development of such a therapy would represent a paradigm shift in the management of Angelman syndrome and offer families renewed hope for improved outcomes and quality of life.
In summary, the initiation of the REVEAL Phase 3 trial and the dosing of the first patient underscore Ionis Pharmaceuticals’ dedication to advancing innovative treatments for underserved patient populations. With ION582, the company aims to deliver a much-needed therapeutic option for individuals living with Angelman syndrome and reaffirm its role at the forefront of neurology drug development.
