Angelman Syndrome
Conditions
Keywords
Paternal Uniparental Disomy, ION582, imprinting defects
Brief summary
The primary purpose of the study is to evaluate efficacy of obudanersen in participants with AS due to uniparental disomy or imprinting defects (UPD/ID) as measured through expressive communication.
Detailed description
This is a Phase 3, open-label, single treatment arm, multi-center study in participants with Angelman syndrome due to paternal uniparental disomy or imprinting defects. The study will consist of 4 periods: a screening period of up to 28 days, an approximate 60-week Treatment Evaluation Period, followed by 101 weeks of Long-Term Extension (LTE) period, and an 8-month Post-Treatment Follow-up Period. There will be two age-based Cohorts enrolled in this study: Cohort 1 (pediatric participants (aged 2 to \<18 years old)) and Cohort 2 (adult participants (aged 18 to ≤50 years old). More individuals will be enrolled in Cohort 1 than in Cohort 2.
Interventions
DRUGobudanersen
ION582 will be administered by IT injection.
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Clinical diagnosis of AS with molecular result indicating either paternal UPD of 15q11.2-q13 or ID of the maternal 15q11.2-q13 region, provided by the Investigator and confirmed by either a qualified central vendor or a qualified local geneticist at the site. 2. The participant's caregiver(s)/legally-authorized representative (LAR) must have given written informed consent and any authorizations required by local law and be able and willing to comply with all study requirements. 3. Medically stable and can undergo sedation and/or general anesthesia without intubation. 4. Male or female between 2 and ≤ 50 years of age, depending on the specific cohort, at the time of the in-clinic Screening visit. 5. If applicable, is 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. If recent changes (\< 8 weeks stable) in medications, the participant may be allowed per Investigator judgment if the change is not expected to have an impact on the signs and symptoms of AS. 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, YouTube, TikTok, WhatsApp) from the time of enrollment until they are notified that the study is completed. Key
Exclusion criteria
1. Participant has a clinical diagnosis of AS with molecular confirmation of a UBE3A deletion or UBE3A mutation. 2. 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 Investigator, could confound the results of this study. 3. Known brain or spinal disease that would interfere with the lumbar puncture (LP) procedure, cerebrospinal fluid (CSF) circulation, or presence of other factors that would affect the safety of the LP procedure, including tumors or abnormalities by MRI or computed tomography (CT), subarachnoid hemorrhage, suggestion of raised intracranial pressure (ICP) on magnetic resonance imaging (MRI) or ophthalmic examination, Chiari malformation, obstructive hydrocephalus, syringomyelia, tethered spinal cord syndrome, or connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome. 4. 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 \[siRNA\] and ASOs) or gene therapy or gene editing. This exclusion criterion does not apply to approved nucleic acid-based vaccines, including messenger Ribonucleic Acid (mRNA) vaccines, which are allowed. Other inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Performance on the Expressive Communication Domain Raw Score Without Caregiver Input of the Bayley Scales for Infant and Toddler Development-4 (Bayley-4) in Cohort 1 | Baseline and Week 52 |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline in Bayley-4: Cognition Scale Raw Score Without Caregiver Input | Baseline and Week 52 |
| Change From Baseline in Aberrant Behavior Checklist - Second Edition - Community Version (ABC-2-C): Hyperactivity | Baseline and Week 52 |
| Change From Baseline in (ABC-2-C): Irritability | Baseline and Week 52 |
| Change From Baseline in Vineland Adaptive Behavior Scale-3 (Vineland-3): Receptive Communication Domain Raw Score | Baseline and Week 52 |
| Change From Baseline in Vineland-3: Daily Living Skills, Personal Domain Raw Score | Baseline and Week 52 |
| Change From Baseline in (Bayley-4): Fine Motor Domain Raw Score Without Caregiver Input | Baseline and Week 52 |
| Change From Baseline in Observer-Reported Communication Ability (ORCA): Overall Emerging and Mastery T Score | Baseline and Week 52 |
Contacts
CONTACTIonis Pharmaceuticals, Inc.
Outcome results
None listed