Ionis reports positive Phase 1/2a results for ION582 in Angelman syndrome

Ionis Pharmaceuticals recently released encouraging topline data from its HALOS Phase 1/2a open-label study of ION582, a new treatment for Angelman syndrome. The study revealed that ION582 not only demonstrated safety and tolerability across all dose levels but also showed significant improvements in various functional domains in patients with Angelman syndrome. Most notably, the drug showed benefits in areas such as cognition, communication, and motor function.

Angelman syndrome, a genetic disorder caused by a loss of function in the maternal UBE3A gene, presents significant challenges such as developmental delays, cognitive impairment, and severe communication difficulties. The condition affects between 1 in 12,000 to 20,000 people globally and requires lifelong caregiving. The traditional lack of effective treatments heightens the importance of the promising results from the HALOS study.

ION582 operates by unsilencing the paternal UBE3A allele, thereby increasing the production of the UBE3A protein in the brain. This mechanism has shown potential in alleviating the profound developmental delays and motor dysfunction characteristic of the syndrome. The HALOS study included multiple phases: an initial three-month multiple-ascending dose (MAD) study involving 51 patients aged 2-50, followed by a long-term extension (LTE) phase evaluating the two higher doses for an additional 12 months, and a final phase extending the evaluation for another three years.

Safety was the primary objective of the trial, with ION582 proving to be well tolerated. The adverse events reported were consistent with the medical histories of participants and typical for Angelman syndrome. The drug showed a consistent positive impact across various assessment tools including the Bayley-4, the SAS-CGI-C scale, the Vineland-3, and the Observer-Reported Communication Ability (ORCA) measures. The improvements were also reflected in EEG activity, notably a reduction in slow wave delta activity.

At the six-month mark, approximately 65% of patients exhibited cognitive improvements on the Bayley-4 scale. In terms of communication, around 70% of patients showed progress in both receptive and expressive abilities. Additionally, about 65% of the participants demonstrated advancements in fine and gross motor skills. These results surpass the improvements typically observed in natural history studies.

Ionis Pharmaceuticals intends to advance ION582 into a pivotal trial phase. The company plans to present detailed data at an upcoming Angelman Syndrome Foundation meeting. The positive outcomes from the HALOS study have bolstered Ionis' commitment to developing transformative neurological treatments.

Dr. Lynne Bird, a clinical pediatrics professor at UC San Diego and an investigator in the HALOS study, expressed optimism about the potential impact of ION582. She emphasized the transformative possibilities these functional improvements could bring to the lives of patients and their caregivers. Brett Monia, CEO of Ionis, echoed this sentiment, highlighting the importance of the positive study results and the company's dedication to advancing ION582 through the regulatory process.

In addition to ION582, Ionis' neurology portfolio includes multiple therapies in various stages of development, targeting a range of neurological disorders. The company's focus on RNA-targeted medicines has already led to the development of several commercially available treatments for diseases like spinal muscular atrophy, amyloid polyneuropathy, and SOD1-ALS.

The promising results from the HALOS study mark a significant step forward in the search for effective treatments for Angelman syndrome, offering new hope to patients and caregivers affected by this challenging condition.