Ionis Pharmaceuticals (IONS) Study Result summary

Study background and rationale

• HALOS is a global, open-label, multiple-ascending dose Phase I/II study evaluating ION582 in Angelman syndrome, a severe neurodevelopmental disorder with no approved treatments and significant unmet need, enrolling patients aged 2–50 across 11 sites in six countries.

• ION582 is an antisense oligonucleotide designed to reactivate the paternal UBE3A gene, restoring protein production in neurons.

• The program aligns with a broader neurology pipeline focused on disease-modifying therapies for severe disorders, leveraging Ionis' CNS platform and RNA-targeted therapeutics expertise.

• ION582 has received Orphan Drug and Rare Pediatric designations from the FDA.

• Preclinical models showed restoration of UBE3A protein and functional improvements, supporting clinical development.

Study design and methodology

• The study included participants with confirmed UBE3A deletions or mutations, reflecting the broader Angelman population.

• HALOS consisted of a multiple ascending dose phase and a long-term extension, with primary endpoints of safety and tolerability.

• Participants received low, medium, or high doses of ION582, with medium and high doses selected for ongoing evaluation.

• Efficacy was assessed using Bayley-4, Vineland-3, ORCA, and SAS-CGI-C, covering communication, cognition, motor function, and daily living skills.

• Natural history data were used as comparators due to the lack of validated minimal clinically important differences for some measures.

Key efficacy and safety results

• ION582 demonstrated a favorable safety and tolerability profile across all dose groups, with no drug-related discontinuations or serious adverse events.

• 97% of participants in medium and high dose groups showed clinically meaningful improvement in overall symptoms on the SAS-CGI-C at 6 months.

• Improvements in communication, cognition, and motor function exceeded natural history expectations on Bayley-4, Vineland-3, and ORCA.

• Consistent benefit was observed across genotypes (deletion and mutation) and age groups, with similar magnitude of improvement.

• Benefit rates included 67–85% for cognition and communication, 46–74% for motor function, and 61–82% for daily living and socialization domains.