REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ionis Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

17 Apr 2026 → ongoing

Decision date (initial)

2026-03-16

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ionis Pharmaceuticals Inc.

External identifiers

EU CT number

2024-519711-33-01

WHO UTN

U1111-1319-2765

ClinicalTrials.gov

NCT06914609

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic

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.

Conditions and MedDRA coding

Angelman syndrome

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Federal Institute For Drugs And Medical Devices, Food And Drug Administration

Plan to share 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/.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. The participants caregiver(s)/ legally-authorized representative (LAR) must have given written informed consent and any authorizations required by local law and be able to comply with all study requirements.
2. 2. Medically stable and can undergo sedation and/or general anesthesia without intubation.
3. 3. Male or female between 2 and ≤50 years of age, depending on specific cohort, at the time of the in-clinic Screening visit.
4. 4. Participant has a clinical diagnosis of Angelman syndrome (AS) with molecular confirmation of either a Ubiquitin-protein ligase E3A (UBE3A) deletion or UBE3A mutation.
5. 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. 6. LAR/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.

Exclusion criteria 6

1. 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. 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. 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. 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. 5. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid (RNA) [siRNA], ASOs) or gene editing. This exclusion criterion does not apply to approved nucleic acid-based vaccines, including mRNA vaccines, which are allowed.
6. 6. Has molecular confirmation of AS due to paternal uniparental disomy, imprinting defect, or mosaic findings.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 [Time Frame: Baseline and Week 52]

Secondary endpoints 9

1. 1. Change in Bayley Scales for Infant and Toddler Development-4 (Bayley-4): Cognition Subdomain Raw Score without caregiver input [Time Frame: Baseline and Week 52]
2. 2. Change in Symptoms of Angelman Syndrome -Clinician Global Impression of Change (SAS-CGI-C): Overall AS [Time Frame: Baseline and Week 52]
3. 3. Change in Vineland Adaptive Behavior Scale-3 (Vineland-3): Receptive Communication Subdomain Raw Score [Time Frame: Baseline and Week 52]
4. 4. Change in Vineland Adaptive Behavior Scale-3 (Vineland-3): Daily Living Skills, Personal Subdomain Raw Score [Time Frame: Baseline and Week 52]
5. 5. Change in Symptoms of Angelman Syndrome - Clinician Global Impression of Change (SAS-CGI-C): Sleep Problems [Time Frame: Baseline and Week 52]
6. 6. Change in Bayley Scales for Infant and Toddler Development-4 (Bayley-4): Fine Motor Subdomain Raw Score without caregiver input [Time Frame: Baseline to Week 52]
7. 7. Change in Observer-Reported Communication Ability (ORCA): Overall Emerging T score [Time Frame: Baseline and Week 52]
8. 8. Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Time Frame: Up to Week 52]
9. 9. Change in Vital Signs and Clinical Laboratory Results [Time Frame: Baseline and Week 52]

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ionis Pharmaceuticals Inc.

Sponsor organisation

Ionis Pharmaceuticals Inc.

Address

2855 Gazelle Court

City

Carlsbad

Postcode

92010-6670

Country

United States

Scientific contact point

Organisation

Ionis Pharmaceuticals Inc.

Contact name

Global Regulatory Affairs

Public contact point

Organisation

Ionis Pharmaceuticals Inc.

Contact name

Global Regulatory Affairs

Third parties 12

Locations

4 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 33 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications