REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome

Ionis Pharmaceuticals

Status and phase: Enrolling; Phase 3

Conditions: Angelman Syndrome

Treatments: Drug: ION582; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT06914609

ION582-CS2

U1111-1319-2765 (Other Identifier)

2024-519711-33-00 (EU Trial (CTIS) Number)

Details and patient eligibility

About

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.

Full 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 1:1:1 to 40 mg ION582, 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.

Enrollment: 210 estimated patients

Sex: All

Ages: 2 to 50 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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 documented diagnosis of Angelman syndrome (AS) due to 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, 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) or gene therapy. This exclusion criterion does not apply to coronavirus disease 2019 (COVID-19) vaccinations, which are allowed.
6. Has documented molecular AS confirmation of paternal uniparental disomy or imprinting center defect.

Other inclusion/exclusion criteria may apply.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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210 participants in 6 patient groups, including a placebo group

Cohort 1 ION582 40 milligrams (mg)

Experimental group

Description:

Participants (aged 2 to \<18 years old) will be administered ION582 40 mg via intrathecal (IT) injection every 12 weeks (Q12W) during the double blind and LTE treatment periods.

Treatment:

Drug: ION582

Cohort 1 ION582 80 mg

Experimental group

Description:

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.

Treatment:

Drug: ION582

Cohort 1 Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

Cohort 2 ION582 40 mg

Experimental group

Description:

Participants (aged 18 to ≤50 years old) will be administered ION582 40 mg via IT injection Q12W during the double blind and LTE treatment periods.

Treatment:

Drug: ION582

Cohort 2 ION582 80 mg

Experimental group

Description:

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.

Treatment:

Drug: ION582

Cohort 2 Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo