ATTUNE: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intrathecally-Administered ION440 in Participants With Methyl CpG Binding Protein 2 (MECP2) Duplication Syndrome (MDS)

The primary purpose of this study is to evaluate the safety and tolerability of ION440.

This is a phase 1-2 randomized, double-blind, sham-controlled, multiple-ascending dose (MAD) study to evaluate ION440 in pediatric and adult participants with MECP2 Duplication Syndrome (MDS) and will be conducted in two parts. During Part 1 (MAD) (36 weeks), participants will be randomized in a 3:1 ratio to receive ION440 or sham. Individuals who complete Part 1 may enter Part 2, an open label long-term extension study (LTE), where they will receive ION440 for up to approximately 156 weeks. Multiple dose cohorts (Dose A, Dose B, and Dose C) will be evaluated in the study.

All dosing cohorts will be further subdivided by age. Sub cohort A will include participants 8 years of age and older and sub cohort B will include participants 2 through 7 years of age. Dosing cohorts will be enrolled sequentially with sub cohort A initiating prior to sub cohort B.

Eligibility Criteria:
Inclusion criteria for Part 1:

1. Males age ≥ 2 years to ≤ 65 years old, depending on specific cohort and group, at the time of informed consent.

   1. Group A: ≥ 8 to ≤ 65 years old
   2. Group B: 2 to 7 years old, inclusive
2. Participant has at least one parent or caregiver ≥ 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 able to comply with all study requirements and activities,
3. Participant has a documented diagnosis of MDS, with genetic confirmation of MECP2 duplication
4. Is currently receiving stable doses of concomitant medications for at least 3 months prior to baseline. If recent changes (\< 3 months stable) in medications, the participant may be allowed per Investigator judgment in consult with Sponsor Medical Monitor.
5. Able to complete all study procedures, measurements and visits and caregiver/participant has adequately supportive psychosocial circumstances, in the opinion of the Investigator.

Exclusion criteria for Part 1:

1. Documented diagnosis of complex MECP2 duplications including terminal duplication and/or translocation or MECP2 triplication OR clinical features associated with complex variant structure including (a) onset of seizures prior to age 5 (for those age 5 and above at signing of ICF), (b) oxygen dependence, (c) microcephaly, IF MECP2 genetic structure information is unavailable.
2. Clinically significant vital sign or ECG abnormality at Screening \[including heart rate (HR) \< 45 beats per minute; systolic blood pressure \< 90 millimeters of mercury (mmHg); confirmed blood pressure readings \> 170/105 mmHg\]
3. Known brain or spinal disease that would interfere with the LP procedure, or CSF circulation or presence of other factors would affect the safety of the LP procedure.
4. Has any concomitant disease or condition or circumstance, or any finding at Screening that, in the opinion of the Investigator, makes the participant unsuitable for enrollment or that could interfere with the conduct of the study or that would pose an unacceptable risk to the participant in this study.
5. Treatment with an investigational drug, biological agent, or device within 30 days of Screening, or 5 half-lives of investigational agent, whichever is longer.
6. Previous treatment with an oligonucleotide (including siRNA) within 4 months of Screening if single dose received, or within 12 months of Screening if multiple doses received (this exclusion does not apply to vaccines - both mRNA and viral vector vaccines are allowed including COVID-19). For centrally administered ASOs, a minimum of 12 months washout is required irrespective of the number of doses received.
7. Currently enrolled in a clinical trial of an investigational agent or device or has used any investigational agent or device within 5 half-lives of investigational agent, whichever is longer.
8. Has a history of gene therapy or cell transplantation or any other experimental brain surgery.
9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Baseline (Day 1).
10. Has experienced Status Epilepticus in the past 6 months.

Inclusion criteria for Part 2:

1. Completed ION440-CS1, Part 1/MAD. Completers are defined as participants who received at least one dose of Study Drug and attended all study visits through Follow Up.
2. All inclusion criteria in Part 1/MAD apply (participants will not be required to undergo new Screening bloodwork).

Exclusion criteria for Part 2:

1. Has developed any concomitant disease (e.g., gastrointestinal, renal, hepatic, endocrine, respiratory, or cardiovascular system disease) or condition or circumstance, or any finding during Part 1/MAD that, in the opinion of the Investigator, makes the participant unsuitable for continued treatment (e.g. could interfere with the conduct of the study or that would pose an unacceptable risk to the participant in this study).