Sponsor decision to terminate study early due to sufficient data collected, the study objectives met and defined unmet need and disease trajectory in males with MECP2 duplication syndrome.

The purpose of the study is to prospectively assess longitudinal changes in biomarkers (MECP2, potential biomarkers of target engagement and disease activity) in cerebrospinal fluid (CSF) and blood; characterize longitudinal changes in performance on clinical scales (clinician-reported measures of neurodevelopment and functioning) and caregiver-reported outcome assessments (communication, gastrointestinal, social-emotional-adaptive behavioral measures); evaluate longitudinal changes in caregiver-reported health-related quality-of-life measures; and assess the frequency, type, and severity of seizures over time.

This is a multi-center, non-randomized, non-interventional prospective and retrospective study in up to 40 participants with MECP2 duplication syndrome (MDS) who can undergo general anesthesia or conscious sedation to collect fluid biomarkers (CSF and blood), undergo electrophysiological assessments (electroencephalogram [EEG], evoked potentials [EP], pupillometry), clinical assessments and caregiver reported outcomes measures, to be used in support of the development of therapies for MDS. The study duration for each participant will be approximately 110 weeks.

Key Inclusion Criteria

• Participant has a diagnosis of MDS with genetic confirmation of MECP2 duplication (or triplication)
• Participant has a parent or caregiver (CG) ≥ 18 years old capable of providing informed consent (signed and dated), and able to attend all scheduled study visits and provide feedback regarding the participant's symptoms and performance as described in the protocol and be able to comply with all study requirements and activities
• Male ≥ 1 month and ≤ 65 years of age
• No contraindications for lumbar puncture (LP)'s, blood draws, sedation (if necessary) or other study activities
• Medically stable to complete the study and will tolerate sedation or general anesthesia and other study activities

Key Exclusion Criteria

• Clinically significant abnormalities in medical history (e.g., clinically significant renal, hepatic, or cardiac abnormalities; major surgery within 3 months of screening) or upon physical examination that could potentially impact the NH of MDS
• Unwillingness or inability to comply with study procedures, including follow up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
• Treatment with an investigational drug, gene therapy, stem cell therapy, biological agent, or device within 30 days of screening, or 5 half-lives of investigational agent, whichever is longer (participants cannot be concurrently enrolled in NH00006 and ION440-CS1).

Male participants who have a diagnosis of MDS, with genetic confirmation of MECP2 duplication (or triplication) will be enrolled.

Participants who have a diagnosis of MDS with genetic confirmation of MECP2 duplication or triplication will be enrolled into this study.

Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.