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

The primary objective of this study is to assess the **safety** and **tolerability** profile of RO7248824, also known as Rugonersen, in participants with **Angelman Syndrome**. Evaluating the safety and tolerability is crucial as it determines the potential risks and adverse effects associated with the treatment, ensuring that it is safe for further clinical use.

Secondary objectives include investigating the plasma **pharmacokinetics** (PK) of RO7248824. Understanding the pharmacokinetics is essential for determining the drug's absorption, distribution, metabolism, and excretion, which are critical for optimizing dosing regimens and enhancing therapeutic efficacy.

The clinical trial involves a total of **25 participants** diagnosed with **Angelman Syndrome (AS)**. The study population includes both male and female subjects, with an age range starting from 2 years old. Participants were selected based on a confirmed clinical diagnosis of AS, supported by a molecular diagnosis with specific genotypic classifications. The trial population is characterized by a stable medical status for at least four weeks prior to screening and at the time of enrollment. Participants are required to have adequate supportive psychosocial circumstances and the ability to tolerate blood draws. The trial includes a vulnerable population, necessitating the presence of a reliable caregiver who is at least 18 years old, competent, and able to accompany the participant to clinic visits. The caregiver must also be available for communication with the investigational site as needed. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **safety** and tolerability of **Rugonersen**, a **solution for injection**, in participants diagnosed with **Angelman Syndrome**. This is a Phase 3, open-label, multicenter study. The trial will assess the pharmacokinetics and pharmacodynamics of the investigational product. The study is expected to run from October 2020 to July 2025. Participants will be administered the drug via **intratracheal use**. The trial will include several key phases, starting with a screening visit to confirm eligibility based on specific inclusion criteria, such as a confirmed clinical diagnosis of Angelman Syndrome and stable medical status. Participants must have a reliable caregiver who can accompany them to clinic visits.

Following the screening, eligible participants will undergo a series of study visits. These visits are structured to monitor the frequency and severity of adverse events, abnormal laboratory findings, and changes in vital signs. The primary endpoints include the frequency of adverse events and treatment discontinuations due to adverse events. Secondary endpoints focus on pharmacokinetic parameters such as time to maximum concentration and maximum plasma concentration observed. The study will also measure the area under the concentration-time curve (AUC) from time zero to the last quantifiable sample.

The expected duration of participant involvement will vary, but it is anticipated to last until the end of the study in July 2025, unless early termination is warranted. Conditions that may lead to early termination include the occurrence of serious adverse events or significant deviations from the study protocol. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to ensure participant safety and gather comprehensive data on the investigational product's effects.

The clinical trial involves the administration of **Rugonersen**, an investigational medicinal product, to evaluate its safety and tolerability in participants with Angelman Syndrome. **Rugonersen** is formulated as a **solution for injection** and is administered via the **intratracheal route**. The active substance in Rugonersen is derived from **nucleic acid**. The pharmaceutical form is specifically designed for this route of administration, ensuring optimal delivery to the target site. The product is identified by the sponsor product code RO 724-8824/F02-01 and is manufactured by F. Hoffmann-La Roche Ltd. The trial does not utilize a pediatric formulation, and Rugonersen has been designated as an orphan drug under the designation number EU/3/20/2379.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of Rugonersen to assess its pharmacokinetic and pharmacodynamic properties. The trial protocol does not specify a maximum daily dose, total dose, or treatment period, indicating that dosing may be adjusted based on individual participant response and tolerability. Participant compliance with the dosing regimen will be monitored throughout the study to ensure adherence to the protocol and to accurately assess the safety profile of Rugonersen.

Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints focus on safety and tolerability, including the frequency and severity of adverse events, serious adverse events, and treatment discontinuations due to adverse events. Additionally, the frequency of abnormal laboratory findings in blood and cerebrospinal fluid, as well as abnormal vital signs and ECG values, will be monitored. Mean changes from baseline in vital signs such as temperature, systolic and diastolic blood pressure, heart rate, and respiratory rate over time will also be evaluated.

Secondary endpoints will assess pharmacokinetic parameters, including the time to maximum concentration (**Tmax**), maximum plasma concentration observed (**Cmax**), and the area under the curve from time 0 to the last sampling point or last quantifiable sample (**AUClast**), as well as from time 0 to infinity (**AUCinf**). These measurements will be collected and analyzed at various timepoints throughout the study to provide a comprehensive evaluation of the drug's efficacy in participants with Angelman Syndrome.