BEACON - Phase III Clinical Study of Rugonersen in Angelman Syndrome.

This study is a Phase III, randomized, double-blind, sham-controlled, multi center study designed to evaluate the efficacy and safety of intrathecally (IT) administered rugonersen compared with sham in up to 165 participants with AS (Part 1), followed by an open-label extension (OLE) of approximately 116 weeks (2 years) for long-term evaluation of the efficacy and safety of IT administered rugonersen in participants with AS (Part 2).

Inclusion criteria

• Male or female and ≥ 1 year to ≤ 50 years of age at signing of the informed consent form.
• Independent of the age of the participant, the participant has a parent, caregiver or legal representative (herein after referred to as caregiver) who is reliable and competent in the Investigator's judgement. The caregiver is:

• Able to consent for the participant according to ICH and local regulations,
• At least 18 years of age,
• Willing and able to accompany the participant to clinic visits and be available to the investigational site by telephone, email, or other electronic form as needed,
• Is, and will likely remain, sufficiently knowledgeable of participant's condition throughout the study to be able to respond to queries, and is willing and able to complete caregiver assessments and inform the site personnel about the participant's condition as requested.
• Clinical diagnosis of Angelman syndrome.
• Pre-existing medical records confirm the clinical diagnosis of AS and the molecular diagnosis with genotypic classification of either:

• Mutation in the UBE3A gene, and the pathogenic or likely pathogenic variant identified,
• Deletion on the maternally inherited chromosome 15q11-q13 that encompasses the UBE3A gene.
• Able to comply with all study requirements.
• Able to tolerate blood draws.
• Able to undergo LP and IT injection, under sedation or anesthesia without intubation as deemed appropriate.
• Has stable medical status for at least 4 weeks prior to screening and at the time of enrolment.
• Bodyweight > 7.5 kg
• Legally authorized representative/caregiver(s) agree(s) not to share any of the participant's personal medical data or information related to the study by any means, including, e.g., a website or a post on a 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.
• Stable permitted medications (including cannabidiol [CBD]) for epilepsy for 12 weeks prior to screening and at the time of enrolment, with the exception of age/weight-based or blood level (toxicity) dose adjustments.
• Stable concurrent psychotropic medications for 4 weeks prior to screening and at time of enrolment.
• Complies with the requirements regarding contraception and is confirmed by caregiver consent.

Exclusion criteria

• Molecular diagnosis of AS with genotypic classification of:

• Uniparental paternal disomy (UPD) of 15q11-q13,
• Imprinting center defect (ICD) within 15q11-q13,
• A partial molecular diagnosis of AS, that cannot exclude UPD or ICD despite appropriate genetic testing.
• Clinically significant vital signs or laboratory abnormalities during screening, including:

o Abnormal coagulation profile demonstrated by platelet count at or below lower limit of normal (140 × 109/L), or by abnormal international normalized ratio (INR) and/or prothrombin time (PT), or activated partial thromboplastin time (aPTT).

• Presence of clinically relevant electrocardiogram (ECG) abnormalities prior to dosing such as QT interval corrected for heart rate using Fredericia's formula (QTcF) > 460 ms, personal or family history of congenital long QT syndrome indicating safety risk in the Investigator's opinion. First-degree atrioventricular block or isolated right bundle branch block is allowed.
• Clinically relevant disease or condition, including hematological, hepatic, cardiac or renal disease or abnormality, that would, in the judgement of the Investigator, pose an unacceptable risk to the participant or interfere with the conduct of the study
• Any concomitant condition that might interfere with the clinical evaluation of AS and that is not related to AS.
• Known history of human immunodeficiency virus (HIV), hepatitis B, C, or E virus.
• Any condition that increases the risk of meningitis.
• History of bleeding diathesis or coagulopathy.
• Medical history of brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment, including:

• Tumors or abnormalities detected by magnetic resonance imaging (MRI) or computed tomography (CT),
• Subarachnoid hemorrhage,
• Clinical suggestion of raised intracranial pressure confirmed by MRI or ophthalmic examination,
• Spinal stenosis or curvature (considered sufficient to prohibit LP),
• Chiari malformation,
• Hydrocephalus,
• Syringomyelia,
• Tethered spinal cord syndrome and connective tissue disorders such as Ehlers-Danos syndrome and Marfan syndrome,
• Radiculopathy or radiculitis.
• Ventriculoperitoneal (VP) shunt for the drainage of CSF or an implanted CNS catheter.
• Medical history of brain or spinal injury, of traumatic, hemorrhagic, or any other origin, that may result in symptoms interfering with AS.
• History of clinically significant post LP headache of moderate or severe intensity and/or blood patch that would, in the judgement of the Investigator, pose an unacceptable risk to the participant or interfere with the conduct of the study.
• Malignancy within 5 years of screening.
• Hospitalization for any major medical or surgical procedure involving general anesthesia planned during the study, or within 4 weeks prior to screening, that - in the opinion of the Investigator - may pose a risk to the participant.
• Prohibited use of antiplatelet or anticoagulant therapy for 2 weeks prior to screening and at the time of enrolment.
• Have any other conditions which would make the participant unsuitable for inclusion or could interfere with the participant participating in or completing the study, including any contraindication to administration of IT therapy.
• Extremely or very preterm birth complications which, in the opinion of the Investigator, may interfere with study outcomes.
• Birth complications, confirmed or suspected asphyxia before, during, or after birth.
• Ascertained or presumptive hypersensitivity to the investigational medicinal product (IMP) or its excipients.
• Participated in a clinical trial and received an IMP within 90 days or 5 half-lives (whichever is longer) or tested an investigational medical device within 90 days prior to dosing or if the device is still active.
• Concurrent or planned concurrent participation in any clinical study (including observational, non-drug and non-interventional studies) without a signed data sharing agreement in place between the other clinical study and the Sponsor.
• Previous participation in cellular therapy, gene therapy, gene editing, or any other gene expression modulating clinical trial, such as an ASO treatment.