ION582 for Angelman Syndrome

Recruiting at 18 trial locations

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

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial investigates a treatment called ION582 for Angelman syndrome, a rare genetic disorder affecting the UBE3A gene. The goal is to evaluate the effectiveness and safety of ION582 for individuals with Angelman syndrome. Participants will receive either the treatment or a placebo (a harmless, inactive substance) via injection every 12 weeks. The trial seeks children and adults who are medically stable, have a confirmed UBE3A gene issue, and are on stable medications for Angelman syndrome. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the chance to contribute to potentially bringing a new treatment to the market.

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.

Is there any evidence suggesting that ION582 is likely to be safe for humans?

Research has shown that ION582 was safe and well-tolerated in earlier studies. Participants received various doses, and the treatment was manageable at all levels. No serious negative side effects were reported, indicating that patients did not experience major health issues. This suggests that ION582 is generally safe for individuals with Angelman syndrome, a condition caused by a specific gene problem. However, participants should always discuss any concerns with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Angelman syndrome?

Unlike the standard treatments for Angelman Syndrome, which typically involve managing symptoms with medications like anticonvulsants or behavioral therapies, ION582 is designed to target the condition more directly. Researchers are excited about ION582 because it uses an innovative approach by being administered through an intrathecal injection, delivering the treatment directly into the spinal fluid. This method allows the drug to reach the central nervous system more effectively, which could lead to improved outcomes for individuals with Angelman Syndrome.

What evidence suggests that ION582 might be an effective treatment for Angelman syndrome?

Research has shown that ION582 may help treat Angelman syndrome. In this trial, participants will receive different doses of ION582, with some receiving 40 mg and others 80 mg, while a placebo group will receive a matching placebo. A previous study found that 97% of participants who took medium or high doses experienced improvements in their symptoms, measured using a special scale for Angelman syndrome. The treatment was also well tolerated, as it did not cause serious side effects. This suggests ION582 could be a promising option for people with Angelman syndrome. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

Citations

1. ir.ionis.com ir.ionis.com/news-releases/news-release-details/ionis-announces-positive-detailed-results-halos-study-ion582

Ionis announces positive detailed results from the HALOS ... Overall, 97% of people in the medium and high dose groups saw an improvement in overall AS symptoms as measured by the Symptoms of Angelman ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06914609

REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome 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 ...

3. ir.ionis.com ir.ionis.com/news-releases/news-release-details/ionis-announces-positive-topline-results-phase-12a-trial-ion582

Ionis announces positive topline results from Phase 1/2a ... ION582 was safe and well tolerated in the study and showed encouraging and consistent benefits in individuals living with Angelman syndrome.

4. oligotherapeutics.org oligotherapeutics.org/angelman-syndrome-therapies-show-positive-results-in-early-phase-clinical-trials/

Angelman Syndrome Therapies Show Positive Results in ... Notably, after three doses and six months, 97% of people in the medium and high dose groups saw an improvement in overall AS symptoms as ...

5. neurologylive.com neurologylive.com/view/details-surrounding-phase-3-study-ion582-angelman-syndrome-announced

Details Surrounding Phase 3 Study of ION582 in Angelman ... After 6 months of treatment, 97% of the 51-patient cohort demonstrated clinically meaningful improvement on the Symptoms of Angelman Syndrome- ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05127226

Study Details | NCT05127226 | HALOS: A Safety, ... The purpose of this study is to evaluate the safety and tolerability of ascending doses of ION582 administered intrathecally in participants with Angelman ...

7. ir.ionis.com ir.ionis.com/news-releases/news-release-details/ionis-receives-us-fda-breakthrough-therapy-designation-ion582

Ionis receives U.S. FDA Breakthrough Therapy designation ... ION582 is an investigational RNA-targeted antisense medicine designed to inhibit the expression of the UBE3A antisense transcript (UBE3A-ATS) ...

8. nicklauschildrens.org nicklauschildrens.org/medical-services/research-institute-(clinical-trials)/clinical-trials/neu24071-(ion582-cs2)

REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome 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 ...