Ionis Reports Positive Results from HALOS Study on ION582 for Angelman Syndrome

Ionis Pharmaceuticals, Inc. has announced positive outcomes from the recently concluded multiple ascending dose (MAD) phase of its Phase 1/2 open-label study of ION582 for Angelman syndrome (AS). The study reveals that ION582 brings consistent and notable improvements in communication, cognition, and motor functions across a broad patient demographic. A significant 97% of patients in medium and high-dose groups experienced overall symptom improvement based on the Symptoms of Angelman Syndrome–Clinician Global Impression-Change (SAS-CGI-C) scale. ION582 demonstrated favorable safety and tolerability at all dose levels within the study.

Detailed results are set to be presented in a company webcast and at the 2024 Angelman Syndrome Foundation (ASF) Family Conference. Brett Monia, Ph.D., Ionis' CEO, expressed enthusiasm about the results and the company's plans to initiate Phase 3 development of ION582 by the first half of 2025. He emphasized Ionis' commitment to pioneering revolutionary treatments for neurological conditions, with ION582 positioned as a future cornerstone in their portfolio.

Angelman syndrome is a rare neurodevelopmental disorder caused by the loss of function in the maternal UBE3A gene, affecting about 1 in 21,000 people globally. It manifests early in life with severe developmental delays, seizures, and motor and cognitive impairments. ION582, an investigational antisense medicine, aims to increase production of the UBE3A protein in the brain by unsilencing the normal paternal UBE3A gene.

Lynne Bird, M.D., a professor of clinical pediatrics at UC San Diego and investigator in the HALOS study, highlighted the significance of these promising results, noting that consistent improvements were observed beyond what is typically seen in the natural progression of the disease.

The HALOS study enrolled 51 participants aged between two and fifty years. Results from the final timepoint at six months of the completed MAD phase showed ION582's robust safety and tolerability at all dose levels. Improvements in communication, cognition, and motor functions were observed using the Bayley-4 assessment, surpassing those recorded in natural history studies. Clinical improvements were also noted across other assessment tools like Vineland-3 and Observer-Reported Communication Ability (ORCA), with 97% of participants showing meaningful overall improvement on the SAS-CGI-C scale.

Ionis plans to meet with regulators to finalize the Phase 3 study design later this year, aiming to start the pivotal study in the first half of 2025. For those interested in more details, Ionis will host a webcast, with a replay available for a limited time.

The HALOS study is a global, open-label, MAD Phase 1-2a trial that includes 51 patients with AS across 11 sites in six countries. Part 1 of the trial, which lasted three months, assessed three doses of ION582, with evaluations at six months. Eligible patients transitioned into the long-term extension (LTE) phase, which is assessing the two higher doses over an additional 12 months. Part 3 will further evaluate eligible patients for up to four additional years. The primary goal is to assess the safety and tolerability of multiple ION582 doses administered intrathecally, with key exploratory measures including changes in communication, cognition, motor function, sleep, seizures, and daily living skills.

ION582, granted Orphan Drug and Rare Pediatric designations by the FDA, is designed to inhibit the UBE3A antisense transcript and increase UBE3A protein production, offering a potential treatment for AS. Angelman syndrome, a rare genetic neurological disorder, presents in infancy and is characterized by severe intellectual disability, balance and motor impairments, and debilitating seizures, requiring lifelong caregiver support.

Ionis Pharmaceuticals is a leader in developing innovative treatments for neurological diseases, with a rich portfolio including marketed medicines like SPINRAZA®, WAINUATM, and QALSODY®. The company remains committed to advancing RNA-targeted therapies and new approaches in gene editing, with a strong pipeline addressing high patient needs in neurology and cardiology.