Angelman syndrome treatment ION582 eases symptoms: Trial data

Ionis Pharmaceuticals’ investigational Angelman syndrome treatment ION582 demonstrated a favorable safety profile and lessened overall symptoms in patients participating in the HALOS clinical trial.

That’s according to six-month follow-up data from part one of Phase 1/2 study (NCT05127226), which tested three doses of ION582 — low, medium and high — injected directly into the spinal canal for three months.

Overall and clinically meaningful improvements were observed in 97% of patients given medium and high doses of ION582, as assessed by the Symptoms of Angelman Syndrome-Clinician Global Impression of Change (SAS-CGI-C) scale, which measures clinicians’ impressions of Angelman symptoms, according to a company press release.  Improvements in communication, cognition and motor skills were also reported, and the investigational therapy was deemed safe and well tolerated across all tested doses.

Ionis said it expects to launch a pivotal Phase 3 study to continue to test ION582 in Angelman patients in the first half of 2025. The company will discuss trial design with regulators later this year.

Results position Angelman syndrome treatment as ‘cornerstone’

“Ionis looks forward to collaborating with investigators, regulators and members of the Angelman syndrome community to initiate Phase 3 development for ION582 in the first half of 2025,” said Brett Monia, PhD, Ionis CEO. The “encouraging results” from the trial “position ION582 to be the cornerstone of Ionis’ next wave of transformational, wholly owned medicines for neurological conditions, which currently includes five clinical-stage programs,” Monia said.

Angelman syndrome is caused by mutations in the maternal copy of the UBE3A gene, which prevents a working version of the UBE3A protein from being made. While two copies of each gene are inherited — one from each biological parent — in certain areas of the brain, only the UBE3A copy inherited from the mother is active.

ION582 was designed to turn on the paternal copy of the UBE3A gene by blocking a molecule, Ubiquitin Protein Ligase E3A-Antisense Transcript, that silences it.

The open-label HALOS clinical trial enrolled 51 patients, ages 2 to 50. With the completion of the first part, eligible patients will now transition to the second part of the study, which will evaluate the effects of the medium and high doses of ION582 for an additional 12 months. In the third part, patients will be followed for more four years.

The trial’s main goal is to assess the safety and tolerability of multiple ascending doses of ION582.

Exploratory efficacy parameters include changes in patients’ communication, cognition, motor function, sleep, seizures, and daily living skills. These effects were measured using the SAS-CGI-C and the Bayley-4, also a clinician-administered assessment of clinical functioning.

Improvements seen across patient population

Parent-reported evaluations were done using the Vineland Adaptive Behavior Scales-3 (Vineland-3) and the Observer-Reported Communication Ability (ORCA), which assesses the quality of nonverbal communication by parents or caregivers.

Patients exhibited improvements in communication, cognition, and motor function when compared with the natural development delay seen in natural history studies of Angelman syndrome. Fine motor skills (handwriting and grasping, for example) improved in 72% of the patients, cognition in 67%, and expressive communication in 69% when assessed using the Bayley-4.

According to ORCA, 60% of patients showed improvements in nonverbal communication. Receptive communication skills in the Vineland-3 improved in 89% of participants and expressive communication in 84%. Socialization skills were improved in 63% to 87% of the patients, and daily living skills in 74% to 82%. Fine motor skills improved in 63%, and gross motor skills (such as walking and climbing stairs) in 53%.

When measured using the SAS-CGI-C scale, cognition improved in 85% of patients. Sleep improved in 61%, and behavior in 56%. These improvements were seen in a “broad patient population,” Ionis said.

“Angelman syndrome is a serious neurodevelopmental disorder with life-long impairments and dependence on caregivers, for which we currently have only supportive care,” said Lynne Bird, MD, professor of clinical pediatrics at the University of California San Diego and an investigator on the HALOS study. “We are very encouraged by these promising data with ION582, showing consistent improvements over what we observe in the natural course of the disease.”

Detailed results of the HALOS clinical trial were shared at the 2024 Angelman Syndrome Foundation Family Conference, which took place July 23-26 in Sandusky, Ohio.

ION582 was granted orphan drug and rare pediatric disease status by the U.S. Food and Drug Administration (FDA), two designations aimed at supporting and help speed its development.