Angelman Syndrome
Conditions
Keywords
ION582, Angelman Syndrome
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 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.
Interventions
DRUGION582
ION582 will be administered by IT injection.
DRUGPlacebo
ION582 matching placebo will be administered by IT injection.
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Bayley Scales for Infant and Toddler Development-4 (Bayley-4): Cognition Subdomain Raw Score Without Caregiver Input | 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 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 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 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 Bayley Scales for Infant and Toddler Development-4 (Bayley-4): Fine Motor Subdomain Raw Score Without Caregiver Input | 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. |
| Change in Observer-Reported Communication Ability (ORCA): Overall Emerging 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. |
| 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 | — |
Countries
Australia, Canada, Germany, Israel, Italy, Japan, Poland, Singapore, South Korea, Spain, United Kingdom, United States
Contacts
CONTACTIonis Pharmaceuticals, Inc.
Outcome results
None listed