ION582 for Angelman Syndrome

Overseen By Ionis Pharmaceuticals, Inc.

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Ionis Pharmaceuticals, Inc.

Must be taking: Anti-epileptics, behavioral meds

Disqualifiers: Brain disease, spinal disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 14

Duration: 60 weeks

210 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires participants to be on stable doses of their current medications for at least 8 weeks before starting the study, so you will not need to stop taking them.

How does the drug ION582 differ from other treatments for Angelman Syndrome?

ION582 is unique because it targets the underlying genetic cause of Angelman Syndrome by addressing the deficiency of the UBE3A gene, which is not the focus of most existing treatments that primarily manage symptoms like seizures. ^{1 2 3 4 5}

What is the purpose of this trial?

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.

Eligibility Criteria

This trial is for children and adults with Angelman syndrome, which must be due to a UBE3A gene deletion or mutation. Participants need stable doses of their current medications for at least 8 weeks before starting the study. They should be medically stable for sedation without intubation and aged between 2 to ≤50 years.

Inclusion Criteria

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

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

I can be sedated or have anesthesia without needing a breathing tube.

Exclusion Criteria

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

I haven't had major surgery in the last 3 months and have no health issues that would interfere with the study treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive ION582 or placebo via intrathecal injection every 12 weeks during the double-blind treatment period

60 weeks

5 visits (in-person)

Long-Term Extension (LTE)

Participants receive ION582 via intrathecal injection every 12 weeks, with all participants receiving active treatment

25 months

9 visits (in-person)

Post-LTE Follow-up

Participants are monitored for safety and effectiveness after the LTE treatment period

8 months

Treatment Details

Interventions

• ION582

Trial Overview The REVEAL study is testing ION582's effectiveness and safety in treating Angelman syndrome compared to a placebo. The participants will receive either the investigational drug or an inactive substance, randomly assigned.

Participant Groups

Group I: Cohort 2 ION582 80 mg Experimental Treatment 1 Intervention

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.

Group II: Cohort 2 ION582 40 mg Experimental Treatment 1 Intervention

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.

Group III: Cohort 1 ION582 80 mg Experimental Treatment 1 Intervention

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.

Group IV: Cohort 1 ION582 40 milligrams (mg) Experimental Treatment 1 Intervention

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.

Group V: Cohort 1 Placebo Placebo Group 1 Intervention

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.

Group VI: Cohort 2 Placebo Placebo Group 1 Intervention

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.

Who Is Running the Clinical Trial?

Ionis Pharmaceuticals, Inc.

Lead Sponsor

Trials

151

Recruited

27,800+

Dr. Brett P. Monia

Ionis Pharmaceuticals, Inc.

Chief Executive Officer since 2020

PhD in Pharmacology from the University of Pennsylvania, BSc in Molecular Biology and Analytical Chemistry from Stockton State College

Dr. Eric Bastings

Ionis Pharmaceuticals, Inc.

Chief Medical Officer

MD

Findings from Research

In a study involving 7 patients with Angelman syndrome (AS) and 4 healthy controls, GABA(A) receptor expression was found to be significantly higher in the cerebral cortex and cerebellum of patients with certain genotypes, indicating a potential alteration in receptor function.

The findings suggest that there is a developmental dysregulation of GABA(A) receptor subunits in AS, which could have implications for understanding the neurological aspects of the syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[(11)C]flumazenil positron emission tomography analyses of brain gamma-aminobutyric acid type A receptors in Angelman syndrome. Asahina, N., Shiga, T., Egawa, K., et al.[2016]

References

1. England pubmed.ncbi.nlm.nih.gov

Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype-phenotype correlations. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

[(11)C]flumazenil positron emission tomography analyses of brain gamma-aminobutyric acid type A receptors in Angelman syndrome. [2016]

3. United States pubmed.ncbi.nlm.nih.gov

Novel mutations of ubiquitin protein ligase 3A gene in Italian patients with Angelman syndrome. [2016]

4. Iran pubmed.ncbi.nlm.nih.gov

Angelman Syndrome: A Case Report. [2023]

5. Korea (South) pubmed.ncbi.nlm.nih.gov

Epilepsy in Korean patients with Angelman syndrome. [2021]