Evaluation of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intrathecal ION582 in Angelman Syndrome Patients

The primary objective of this study is to evaluate the **safety** and **tolerability** of ascending dose levels of multiple intrathecal bolus administrations of ION582 in patients with **Angelman syndrome**. This evaluation is based on the incidence and severity of treatment-emergent adverse events and serious adverse events, as well as changes in vital signs and clinical laboratory results. The clinical relevance of this objective lies in ensuring that the treatment is safe and well-tolerated, which is crucial for the potential therapeutic use of ION582 in managing Angelman syndrome.

Secondary objectives include characterizing the **pharmacokinetics** in cerebrospinal fluid, plasma, and urine of ascending dose levels of multiple intrathecal bolus administrations of ION582 in patients with Angelman syndrome. Understanding the pharmacokinetics is essential for determining the appropriate dosing regimen and optimizing therapeutic efficacy while minimizing potential side effects.

The clinical trial involves a total of **50 participants** diagnosed with **Angelman syndrome**, characterized by a documented and certified diagnosis of ubiquitin-protein ligase E3A deletion or UBE3A mutation. The study population includes both male and female subjects, ranging in age from 2 to 50 years. Participants are required to have been on stable standard of care treatments, such as anti-epileptic medication, behavioral management medications, sleep medications, gabapentin, cannabidiol, and special diets or nutritional support, for at least three months prior to the first dose. The trial population was selected based on specific inclusion criteria, ensuring that participants have a stable health status and are able to follow good study practices. The study does not allow the sharing of personal or study information on social media platforms until the study is completed. The trial includes a vulnerable population, and all participants have provided informed consent through their parent(s) or legal guardian(s).

The clinical trial is designed to evaluate the **safety** and **tolerability** of ascending dose levels of multiple intrathecal bolus administrations of ION582 in patients with **Angelman syndrome**. This study is a Phase 1-2a, open-label, multi-center trial, classified as a Category 2 study under the Clinical Trial Regulation. The trial will assess the incidence and severity of treatment-emergent adverse events and serious adverse events, as well as changes in vital signs and clinical laboratory results. The primary endpoint focuses on evaluating the safety and tolerability of single and multiple doses of ION582, while secondary endpoints include pharmacokinetic parameters such as maximum observed plasma concentration, time to reach maximal plasma concentration, plasma elimination half-life, and concentration in cerebrospinal fluid.

The trial is expected to run from December 30, 2021, to January 31, 2029. Participants will be involved in the study for the duration of their treatment and follow-up periods, which will be determined based on the dosing schedule and individual response to the treatment. The study will include an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor safety and efficacy parameters. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.

Inclusion criteria require participants to have a documented diagnosis of Angelman syndrome, be between the ages of 2-50 years, and currently receive stable standard of care treatments. Participants must also adhere to study protocols, including refraining from sharing personal or study information on social media until the study is completed. Conditions that may lead to early termination from the study include non-compliance with study protocols, withdrawal of consent, or the occurrence of significant adverse events that warrant discontinuation of treatment.

The clinical trial involves the administration of the experimental medication **ION582**, which is an **antisense oligonucleotide (ASO)**. The active substance in ION582 is a **2'-O-(2-methoxyethyl) modified antisense oligonucleotide targeting UBE3A antisense transcript RNA**. This medication is provided in the form of an **injection** and is administered via **intrathecal use**. The trial is designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ION582 in patients diagnosed with Angelman Syndrome. The dosing regimen involves multiple intrathecal bolus administrations, with ascending dose levels to assess the incidence and severity of treatment-emergent adverse events and serious adverse events, as well as changes in vital signs and clinical laboratory results.

There are no non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, specified in this study. The trial focuses solely on the administration of ION582. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The trial does not include a pediatric formulation of the medication, and the product is designated as an orphan drug, indicating its use for a rare condition. The study is conducted under the sponsorship of Ionis Pharmaceuticals, Inc.

Efficacy in the clinical trial of ION582 for patients with Angelman Syndrome will be assessed through several primary and secondary endpoints. The primary endpoint focuses on evaluating the safety and tolerability of single and multiple doses of ION582. This will be determined by the incidence, severity, and dose-relationship of adverse effects, as well as changes in laboratory parameters. Secondary endpoints include pharmacokinetic measures such as the Maximum Observed Plasma Concentration of ION582, Time to Reach Maximal Plasma Concentration, Plasma Elimination Half-Life, and the concentration of ION582 in cerebrospinal fluid. These parameters will be measured and analyzed to provide a comprehensive understanding of the drug's efficacy and pharmacokinetic profile.