REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome

Phase 3 Study of the Efficacy and Safety of ION582 in Children and Adults With Angelman Syndrome

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.

Study Overview

• Status: Recruiting
• Conditions: Angelman Syndrome
• Intervention / Treatment: Drug: ION582; Drug: Placebo

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 to 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.

The study initiated in 2024 with three dosing groups (40 mg ION582, 80 mg ION582, and placebo). Following additional review of data from the ongoing Phase 1/2 trial of ION582 (HALOS), REVEAL was amended in December 2025 to its current form as a two-arm study: 80 mg ION582 and placebo. Following the amendment, participants who were randomized to receive 40 mg ION582 will be transitioned to receive 80 mg ION582.

• Study Type: Interventional
• Enrollment (Estimated): 158
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ionis Pharmaceuticals, Inc.; Phone Number: (844) 285-7172; Email: IonisION582-CS2@clinicaltrialmedia.com

Study Locations

• Australia
  • Nedlands, Australia, 6009
    • Recruiting
    • Perth Children's Hospital
  • Randwick, Australia, 2031
    • Recruiting
    • Sydney Children's Hospital
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Recruiting
      • Queensland Children's Hospital
• Canada
  • Edmonton, Canada, T6G 2B7
    • Recruiting
    • University of Alberta Hospital
  • Vancouver, Canada, V6H 3V4
    • Recruiting
    • British Columbia Children's Hospital
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Recruiting
      • London Health Science Centre - Children's Hospital
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Recruiting
      • McGill University Health Centre
• Germany
  • München, Germany, 81377
    • Recruiting
    • Klinikum der Ludwig-Maximilians-Universitaet Muenchen
• Israel
  • Ramat Gan, Israel, 5265601
    • Recruiting
    • Sheba Medical Center
• Italy
  • Conegliano, Italy, 31015
    • Not yet recruiting
    • Associazione La Nostra Famiglia - IRCCS Eugenio Medea
  • Milan, Italy, 20133
    • Recruiting
    • Fondazione IRCCS Istituto Neurologico Carlo Besta
  • Pisa, Italy, 56126
    • Recruiting
    • Azienda Ospedaliero Universitaria Pisana
  • Roma, Italy, 00165
    • Recruiting
    • Ospedale Pediatrico Bambino Gesu
• Japan
  • Osaka
    • Izumi, Osaka, Japan, 594-1101
      • Recruiting
      • Osaka Women's and Children's Hospital
  • Tokyo
    • Kodaira, Tokyo, Japan, 187-8551
      • Recruiting
      • National Center of Neurology and Psychiatry
• Poland
  • Gdansk, Poland, 80-952
    • Recruiting
    • Uniwersyteckie Centrum Kliniczne
• Singapore
  • Singapore, Singapore, 229899
    • Recruiting
    • KK Women's and Children's Hospital
• South Korea
  • Seoul, South Korea, 03080
    • Recruiting
    • Seoul National University Hospital
  • Seoul, South Korea, 06351
    • Recruiting
    • Samsung Medical Center
• Spain
  • Barcelona, Spain, 08950
    • Recruiting
    • Hospital Sant Joan de Déu
  • Sabadell, Spain, 08208
    • Recruiting
    • Corporacio Sanitaria Parc Tauli - Hospital de Sabadell
• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Recruiting
    • Great Ormond Street Hospital for Children - NHS Foundation Trust
  • Oxford, United Kingdom, OX3 9DU
    • Recruiting
    • John Radcliffe Hospital
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Recruiting
      • Cedars-Sinai Medical Center
    • San Diego, California, United States, 92123
      • Recruiting
      • Rady Children's Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • Colorado Children's Hospital Research Institute
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20011
      • Recruiting
      • Children's National Hospital
  • Florida
    • Miami, Florida, United States, 33155
      • Recruiting
      • Nicklaus Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Recruiting
      • Children's Healthcare of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • Rush University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Recruiting
      • Children's Mercy
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Ichan School of Medicine at Mount Sinai
  • North Carolina
    • Carrboro, North Carolina, United States, 27510
      • Recruiting
      • University of North Carolina at Chapel Hill School of Medicine
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Recruiting
      • Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt Clinical Research Center
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Texas Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Key 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 clinical diagnosis of Angelman syndrome (AS) with molecular confirmation of 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, X (formerly 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) gene therapy or gene editing. This exclusion criterion does not apply to approved nucleic acid-based vaccines, including mRNA vaccines, which are allowed.
6. Has molecular confirmation of AS due to paternal uniparental disomy, imprinting center defect, or mosaic findings.

Other inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 ION582 80 mg; 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.	Drug: ION582; ION582 will be administered by IT injection.
Placebo Comparator: Cohort 1 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.	Drug: Placebo; ION582 matching placebo will be administered by IT injection.
Experimental: Cohort 2 ION582 80 mg; 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.	Drug: ION582; ION582 will be administered by IT injection.
Placebo Comparator: Cohort 2 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.	Drug: Placebo; ION582 matching placebo will be administered by IT injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Performance on the Expressive Communication Subdomain Raw Score of the Bayley Scales for Infant and Toddler Development-4 (Bayley-4) Without Caregiver Input in Cohort 1	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.	Baseline and Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Symptoms of Angelman Syndrome -Clinician Global Impression of Change (SAS-CGI-C): Overall AS	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).	Baseline and Week 52
Change in Vineland Adaptive Behavior Scale-3 (Vineland-3): Receptive Communication Subdomain Raw Score	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.	Baseline and Week 52
Change in Vineland Adaptive Behavior Scale-3 (Vineland-3): Daily Living Skills, Personal Subdomain Raw Score	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.	Baseline and Week 52
Change in Symptoms of Angelman Syndrome - Clinician Global Impression of Change (SAS-CGI-C): Sleep Problems	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).	Baseline and Week 52
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
Change in Bayley Scales for Infant and Toddler Development-4 (Bayley-4): Cognition Subdomain Raw Score Without Caregiver Input	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.	Baseline and Week 52
Change in Bayley Scales for Infant and Toddler Development-4 (Bayley-4): Fine Motor Subdomain Raw Score Without Caregiver Input	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.	Baseline to Week 52
Change in Observer-Reported Communication Ability (ORCA): Overall Emerging T Score	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.	Baseline and Week 52

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2025
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): April 1, 2030

Study Registration Dates

• First Submitted: March 22, 2025
• First Submitted That Met QC Criteria: March 31, 2025
• First Posted (Actual): April 6, 2025

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 14, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Angelman Syndrome; ION582
• Additional Relevant MeSH Terms: Imprinting Disorders; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Congenital Abnormalities; Movement Disorders; Abnormalities, Multiple; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Angelman Syndrome; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs
• Other Study ID Numbers: ION582-CS2; 2024-519711-33-00 (Ctis); U1111-1319-2765 (Other Identifier: WHO Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No