Sponsor decision to terminate study early. Decision not based on safety concerns.

The primary purpose of this study is to evaluate the safety and tolerability of ION269 in adults with Down syndrome with evidence of brain amyloid positivity.

This is a phase 1b multi-center, open-label, single ascending dose (SAD) study in adult participants with Down syndrome with evidence of brain amyloid positivity. Participants will be examined in 3 separate cohorts and will receive a single dose of study drug during the 36-week treatment period, followed by a 4-week follow-up period.

Inclusion criteria:

1. Has a reliable study partner, that is, a parent, sibling, or caregiver ≥ 21 years of age, who has known the participant for > 6 months (i.e., a reliable and competent individual with a close relationship with the participant) and is capable of providing accurate information about the participant's history, can attend all scheduled study visits and provide feedback regarding the participant's symptoms and performance as described in the protocol, and can comply with all study requirements and activities.
2. Has a diagnosis of Down syndrome and has an intelligence quotient (IQ) ≥ 45.
3. Has evidence of amyloid pathology on amyloid-positron emission tomography (PET) scan.
4. Is assessed as being cognitively stable.
5. Is in good health as evidenced by medical history, physical, and neurological examination, and with no diagnosis of dementia or mild cognitive impairment.

Exclusion criteria:

1. Has unstable psychiatric illness, including psychosis, or untreated major depression within 90 days before Screening, as determined by the Investigator.
2. Has any unstable medical condition likely to hamper the evaluation of safety and/or efficacy of the Study Drug (e.g., moderate or severe untreated obstructive sleep apnea, medical history of clinically significant B12 or folate deficiency that is currently uncontrolled, clinically significant abnormalities of thyroid function, stroke, or other cerebrovascular conditions), as per Investigator's judgment.
3. Is unable to complete MRI and amyloid/tau-PET procedures or has any contraindications to having a brain MRI (e.g., MRI-incompatible pacemaker, aneurysm clips, artificial heart valves, or other metal foreign body; claustrophobia that cannot be medically managed without requiring general anesthesia).

Note: Other protocol defined inclusion/exclusion criteria may apply.

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/.