Ionis Pharmaceuticals Advances ION582 for Angelman Syndrome to Phase 3 Trial
核心洞察
Ionis Pharmaceuticals (搜索) is initiating a Phase 3 trial (REVEAL) for ION582, a potential treatment for Angelman Syndrome (搜索), following positive Phase 2 results and FDA agreement.
The global, placebo-controlled study will involve 200 children and adults with Angelman Syndrome (搜索), assessing ION582's efficacy over 12 months using expressive communication as the primary endpoint.
ION582, an antisense oligonucleotide, aims to increase UBE3A (搜索) protein production, addressing the underlying cause of Angelman Syndrome (搜索), for which there are currently no FDA-approved treatments.
Ionis Pharmaceuticals (搜索) has announced the design of its Phase 3 REVEAL trial to evaluate ION582 as a potential treatment for Angelman syndrome (搜索) (AS). The study, a placebo-controlled trial involving 200 children and adults with AS, is scheduled to begin in the first half of 2025.
The global study will randomize patients with AS, confirmed by a maternal UBE3A (搜索) gene deletion or mutation, in a 2:1 ratio to receive either ION582 or a placebo over a 12-month period. This will be followed by an optional open-label long-term extension. The primary endpoint will be the change in expressive communication, measured using the Bayley Scales for Infant and Toddler Development-4 (Bayley-4) tool, over the 12-month treatment duration.
Targeting the Root Cause of Angelman Syndrome
Currently, there are no FDA-approved treatments that target the underlying pathology of AS. ION582, which has been granted orphan drug and rare pediatric disease designations by the FDA, is an investigational antisense oligonucleotide designed to inhibit the expression of the UBE3A (搜索) antisense transcript, thereby increasing the production of the UBE3A protein. This mechanism aims to address the fundamental genetic deficiency in individuals with Angelman Syndrome (搜索).
"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, PhD, chief executive officer at Ionis, in a statement. "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."
Promising Results from Phase 1/2 HALOS Trial
Ionis previously reported positive data from the multiple-ascending dose (MAD) portion of the Phase 1/2 HALOS trial (NCT05127226), which supported the continued development of ION582. After six months of treatment, 97% of the 51-patient cohort demonstrated clinically meaningful improvement on the Symptoms of Angelman Syndrome (搜索)-Clinician Global Impression of Change scale (SAS-CGI-C), indicating a positive impact on AS symptoms. The therapy was also reported to be safe and tolerable across all dose levels.
The HALOS study was structured in three parts: a 13-week MAD treatment period followed by a minimum 12-week (up to 32-week) post-MAD follow-up (Part 1), a 12-month long-term extension where participants received intrathecal bolus doses of ION582 (Part 2), and an extension of the treatment period for up to an additional three years for participants completing Part 2 (Part 3).
Broad Improvements Observed in HALOS Trial
Similar to the design of the new Phase 3 trial, the HALOS study included participants with AS whose diagnoses were confirmed via UBE3A (搜索) deletion or mutation. The HALOS study demonstrated benefits across multiple assessed domains, including the Bayley Scales of Infant and Toddler Development, 4th Edition (Bayley-4), Vineland Adaptive Behavior Scales, 3rd Edition (Vineland-3), Observer-Reported Communication Ability (ORCA), and the SAS-CGI-C. Specifically, on the SAS-CGI-C, 85% of participants showed improvements in cognition, 69% in expressive communication, 74% in gross motor skills, 64% in fine motor skills, 62% in daily living skills, 61% in sleep, and 56% in behavior.
These improvements surpassed those typically seen in natural history studies, where individuals with Angelman syndrome (搜索) generally exhibit significant developmental delays from birth through adulthood, with stable functioning and minimal improvement after approximately four years of age. Additional data indicated that 60% of treated patients showed improvements in receptive and expressive communication on the ORCA. On the Bayley-4, improvements were observed in cognition (67%), receptive communication (67%), expressive communication (69%), gross motor skills (46%), and fine motor skills (72%).