REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome

Phase 3

Recruiting

• Conditions: Angelman Syndrome
• Interventions: Drug: ION582; Drug: Placebo

• Registration Number: NCT06914609
• Lead Sponsor: Ionis Pharmaceuticals, Inc.

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of ION582 in children and adults with Angelman syndrome caused by a deletion or mutation of the UBE3A gene.

Detailed Description

This is a Phase 3, randomized, double-blind, placebo-controlled study in people with Angelman syndrome. The study will consist of 4 periods: a screening period of up to 28 days, an approximate 60-week double blind, placebo-controlled treatment period, followed by an approximate 25-month Long-Term Extension (LTE) treatment period, and an approximate 8-month Post-LTE follow-up period. The study will be comprised of 2 cohorts. Cohort 1 will include pediatric participants, aged 2 to less than (\<)18 years old and serve as the population for evaluation of primary and secondary outcome measures; Cohort 2 will include adult participants, aged 18 to ≤50 years old. Participants will be randomized 1:1:1 to 40 mg ION582, 80 mg ION582 or placebo during the double-blind placebo-controlled treatment period. Participants from both cohorts completing the placebo-controlled treatment period will be eligible to transition into the LTE Treatment Period wherein all trial participants will receive ION582. Participant, Caregiver, Investigator and Sponsor will remain blinded to the ION582 dose administered to participants during the LTE.

Study Timeline

• Study First Submitted: 2025-03-22
• Study First Submitted QC: 2025-03-31
• Study First Posted: 2025-04-06
• Status Verified: 2025-05
• Study Start: 2025-05
• Last Update Submitted: 2025-05-01
• Last Update Posted: 2025-05-06
• Primary Completion: 2027-08
• Study Completion: 2030-04

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 210

Inclusion Criteria

1. The participants caregiver(s)/ legally authorized representative must have given written informed consent and any authorizations required by local law and be able to comply with all study requirements.
2. Medically stable and can undergo sedation and/or general anesthesia without intubation.
3. Male or female between 2 and lesser than or equal to (≤)50 years of age, depending on specific cohort, at the time of the in-clinic Screening visit.
4. Participant has a documented diagnosis of Angelman syndrome (AS) due to either Ubiquitin-protein ligase E3A (UBE3A) deletion or UBE3A mutation.
5. Currently receiving stable doses of concomitant medications typically prescribed for AS, such as anti-epileptic medication, behavioral management medications, sleep medications, gabapentin, cannabidiol, and special diets, supplements, or nutritional support for at least 8 weeks prior to the Baseline visit.
6. Legally authorized representative/caregiver(s) agree(s) not to post any of the participant's personal medical data or information related to the study on any website or social media site (e.g., Facebook, Instagram, Twitter, YouTube, TikTok, etc.) from the time of enrollment until they are notified that the study is completed.

Key

Exclusion Criteria

1. Must not have any clinically significant abnormalities in medical history (e.g., major surgery within 3 months of screening), or on physical examination for which treatment with an antisense oligonucleotide (ASO) would be contraindicated or which, in the opinion of the Principal Investigator (PI), could confound the results of this study.
2. Known brain or spinal disease that would interfere with the lumbar puncture (LP) procedure, cerebrospinal fluid (CSF) circulation, or presence of other factors would affect the safety of the LP procedure.
3. Must not have any other conditions, which, in the opinion of the Investigator, would make the participant unsuitable for inclusion or could interfere with the participant participating in or completing the study.
4. Must not have any laboratory abnormalities or any other clinically significant abnormalities that would, as assessed by the Investigator, at screening or Baseline, render a participant unsuitable for inclusion.
5. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid (RNA) [siRNA], ASOs) or gene therapy. This exclusion criterion does not apply to coronavirus disease 2019 (COVID-19) vaccinations, which are allowed.
6. Has documented molecular AS confirmation of paternal uniparental disomy or imprinting center defect.

Other inclusion/exclusion criteria may apply.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1 ION582 40 milligrams (mg)	ION582	Participants (aged 2 to \<18 years old) will be administered ION582 40 mg via intrathecal (IT) injection every 12 weeks (Q12W) during the double blind and LTE treatment periods.
Cohort 1 ION582 80 mg	ION582	Participants (aged 2 to \<18 years old) will be administered ION582 80 mg via IT injection Q12W during the double blind and LTE treatment periods.
Cohort 1 Placebo	Placebo	Participants (aged 2 to \<18 years old) will be administered ION582 matching placebo via IT injection Q12W during the double-blind treatment period and then administered ION582 40 mg or 80 mg Q12W during the LTE treatment period.
Cohort 2 ION582 40 mg	ION582	Participants (aged 18 to ≤50 years old) will be administered ION582 40 mg via IT injection Q12W during the double blind and LTE treatment periods.
Cohort 2 ION582 80 mg	ION582	Participants (aged 18 to ≤50 years old) will be administered ION582 80 mg via IT injection Q12W during the double blind and LTE treatment periods.
Cohort 2 Placebo	Placebo	Participants (aged 18 to ≤50 years old) will be administered ION582 matching placebo via IT injection Q12W during the double-blind treatment period and then randomized to ION582 40 mg or 80 mg Q12W during the LTE treatment period.

Primary Outcome Measures

Name	Time	Method
Change in Performance on the Expressive Communication Subdomain Raw Score of the Bayley Scales for Infant and Toddler Development-4 (Bayley-4) in Cohort 1	Baseline and Week 52	The Bayley-4 is a performance-based assessment of developmental functioning across communication, cognition, and motor skills. The expressive communication subdomain of communication measures preverbal and verbal communication. The total raw score reflects the sum of all the item scores within the expressive communication subdomain, with higher scores reflecting greater expressive communication ability.

Secondary Outcome Measures

Name	Time	Method
Change in Bayley Scales for Infant and Toddler Development-4 (Bayley-4): Cognition Subdomain Raw Score	Baseline and Week 52	The Bayley-4 is a performance-based assessment of developmental functioning across communication, cognition, and motor skills. The cognitive subdomain measures learning, memory and concept formation. The total raw score reflects the sum of all the item scores within the expressive communication subdomain, with higher scores reflecting greater cognitive ability.
Change in Symptoms of Angelman Syndrome -Clinician Global Impression of Change (SAS-CGI-C): Overall AS	Baseline and Week 52	The SAS-CGI-C for Overall AS is a disease-specific clinician-reported outcome assessment measure for Angelman syndrome. The clinicians rate their overall impression of the change of the participant's Angelman syndrome symptoms utilizing a 7-point scale, ranging from "very much improved" (1) to "very much worse" (7).
Change in Symptoms of Angelman Syndrome - Clinician Global Impression of Change (SAS-CGI-C): Sleep Problems	Baseline and Week 52	The SAS-CGI-C for Sleep Problems is a disease-specific clinician-reported outcome assessment measure for Angelman syndrome. The clinicians rate their overall impression of the change in the participant's sleep problems utilizing a 7-point scale, ranging from "very much improved" (1) to "very much worse" (7).
Change in Vineland Adaptive Behavior Scale-3 (Vineland-3): Receptive Communication Subdomain Raw Score	Baseline and Week 52	The Vineland-3 assesses adaptive behaviors across 4 domains via a semi-structured interview between a trained clinician and the caregiver of the participant with AS. The receptive communication subdomain of communication measures the participant's ability to attend, understand, and respond appropriately to information from others. The total raw score reflects the sum of all the item scores within the receptive communication subdomain, with higher scores reflecting greater receptive communication ability.
Change in Observer-Reported Communication Ability (ORCA): Overall T score	Baseline and Week 52	The ORCA measure assesses, from the caregiver's perspective, the communication ability of individuals with neurodevelopmental disorders, like Angelman syndrome. This questionnaire assesses expressive, receptive, and pragmatic communication. The ORCA measure produces a single score that is an estimate of an individual's overall level of communication ability, with higher T-scores reflecting greater communication ability.
Change in Vineland Adaptive Behavior Scale-3 (Vineland-3): Daily Living Skills, Personal Subdomain Raw Score	Baseline and Week 52	The Vineland-3 assesses adaptive behaviors across 4 domains via a semi-structured interview between a trained clinician and the caregiver of the participant with AS. The Personal subdomain of the Daily Living Skills domain measures the participant's self-sufficiency in such areas as eating, dressing, washing, hygiene, and health care. The total raw score reflects the sum of all the item scores within the Personal subdomain, with higher scores reflecting greater ability.
Change in Bayley Scales for Infant and Toddler Development-4 (Bayley-4): Fine Motor Subdomain Raw Score	Baseline to Week 52	The Bayley-4 is a performance-based assessment of developmental functioning across communication, cognition, and motor skills. The Fine Motor subdomain of communication measures motor abilities such as reaching, object manipulation, and grasping. The total raw score reflects the sum of all the item scores within the fine motor subdomain, with higher scores reflecting greater fine motor ability.
Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Up to Week 52
Change in Vital Signs and Clinical Laboratory Results	Baseline and Week 52

Trial Locations

Locations (1)

University of North Carolina at Chapel Hill School of Medicine; 🇺🇸 Carrboro, North Carolina, United States