Phase 3 Study to Evaluate the Efficacy and Safety of ION582 in Children and Adults with Angelman Syndrome

Trial ID: 2024-519711-33-01
Protocol: ION582-CS2
Sponsor: Ionis Pharmaceuticals Inc.

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Diseases & Conditions

Angelman's syndrome

Objectives

The primary objective of this phase 3 study is to evaluate the efficacy and safety of ION582 in pediatric and adult patients diagnosed with Angelman syndrome resulting from a deletion or mutation of the UBE3A gene. ION582 is a 2'-O-(2-methoxyethyl) modified antisense oligonucleotide administered via intrathecal injection. This investigation also includes assessments regarding pharmacokinetics.

Participants

This study involves 128 participants diagnosed with Angelman syndrome. The study population consists of male and female individuals ranging from 2 to 50 years of age. Inclusion requires molecular confirmation of a UBE3A deletion or mutation. Participants must be medically stable and capable of undergoing sedation or general anesthesia without intubation. Eligible subjects are required to have maintained stable doses of concomitant medications, such as anti-epileptic medication, behavioral management medications, sleep medications, gabapentin, or cannabidiol, for at least 8 weeks prior to the baseline visit. Additionally, individuals may be utilizing special diets, supplements, or nutritional support.

Plans and Procedures

This Phase 3 clinical trial is designed to evaluate the efficacy and safety of ION582, an antisense oligonucleotide administered via intrathecal use, in children and adults diagnosed with Angelman syndrome. The study involves participants with molecular confirmation of a UBE3A deletion or mutation. The research methodology includes a screening visit to assess eligibility, followed by a baseline visit to establish initial measurements. Participants will undergo assessments over a period of 52 weeks to monitor changes in primary and secondary endpoints, such as expressive communication, cognition, and sleep problems. The protocol involves regular follow-up visits to evaluate clinical outcomes and safety parameters, including treatment-emergent adverse events and serious adverse events. The total estimated duration of the study period is expected to conclude by December 2029.

Treatment

The experimental treatment consists of ION582, which is a 2'-O-(2-methoxyethyl) modified antisense oligonucleotide designed to target UBE3A antisense transcript RNA. This substance is administered as an injection via the intrathecal route at a dosage of 80 mg.

Efficacy

The primary efficacy endpoint is the change in the Expressive Communication subdomain raw score of the Bayley Scales for Infant and Toddler Development-4 (Bayley-4) without caregiver input in Cohort 1, assessed from baseline to Week 52.

Secondary efficacy parameters evaluated from baseline to Week 52 include:

Change in the Bayley-4 Cognition subdomain raw score without caregiver input.
Change in the Bayley-4 Fine Motor subdomain raw score without caregiver input.
Change in the Symptoms of Angelman Syndrome - Clinician Global Impression of Change (SAS-CGI-C) for Overall AS and Sleep Problems.
Change in the Vineland Adaptive Behavior Scale-3 (Vineland-3) Receptive Communication subdomain raw score and Daily Living Skills, Personal subdomain raw score.
Change in the Observer-Reported Communication Ability (ORCA) Overall Emerging T score.

Additional assessments include monitoring changes in Vital Signs and Clinical Laboratory Results.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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.
Medically stable and can undergo sedation and/or general anesthesia without intubation.
Male or female between 2 and ≤50 years of age, depending on specific cohort, at the time of the in-clinic Screening visit.
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.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.
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.

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Exclusion Criteria

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.
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.
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.
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.
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.
Has molecular confirmation of AS due to paternal uniparental disomy, imprinting defect, or mosaic findings.