Hero: A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics (PK) and Pharmacodynamics (PD) of ION269 in Participants With Down Syndrome (DS) at Risk for Alzheimer's Disease (AD)

A Phase 1b Study to Assess the Safety, Tolerability, and Pharmacokinetics of ION269 in Adults With Down Syndrome (Hero Study)

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.

Study Overview

• Status: Terminated
• Conditions: Alzheimer Disease; Down Syndrome
• Intervention / Treatment: Drug: ION269

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 1

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08041
    • Ionis Investigative Site
• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Ionis Investigative Site
  • Kansas
    • Kansas City, Kansas, United States, 66205
      • Ionis Investigative Site
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Ionis Investigative Site
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Ionis Investigative Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • Ionis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Participants will receive a single dose of ION269.	Drug: ION269; Administered as intrathecal (IT) injection.
Experimental: Cohort 2; Participants will receive a single dose of ION269.	Drug: ION269; Administered as intrathecal (IT) injection.
Experimental: Cohort 3; Participants will receive a single dose of ION269.	Drug: ION269; Administered as intrathecal (IT) injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Up to approximately Week 40
Number of Participants With Change from Baseline in Laboratory Assessments	Up to approximately Week 40
Number of Participants With Change from Baseline in Cerebrospinal fluid (CSF) Safety Laboratory Assessments	Up to approximately Week 40
Number of Participants With Change From Baseline in Vital Signs	Up to approximately Week 40
Number of Participants With Change From Baseline in Weight	Up to approximately Week 40
Number of Participants With Change From Baseline in Electrocardiogram (ECG)	Up to approximately Week 40
Number of Participants With Change From Baseline in Suicide Risk Measured by Columbia Suicide Severity Rating Scale [C-SSRS] Child Version	Up to approximately Week 40
Number of Participants With Change From Baseline in Physical and Neurological Examination Findings	Up to approximately Week 40

Secondary Outcome Measures

Outcome Measure	Time Frame
CSF Concentrations of ION269	Pre-dose and post-dose at multiple timepoints up to Week 40
Area Under the Plasma Concentration-time Curve (AUC) of ION269 From Time 0 to Time of Last Measurable Concentration	Pre-dose and post-dose at multiple timepoints up to Week 40
Maximum Observed Plasma Concentration (Cmax) of ION269	Pre-dose and post-dose at multiple timepoints up to Week 40
Time to reach Cmax (Tmax) of ION269	Pre-dose and post-dose at multiple timepoints up to Week 40
Change From Baseline in Concentration of CSF Soluble Amyloid Precursor Protein Alpha (sAPPα)	Baseline (Day 1) and Week 36
Change From Baseline in Concentration of CSF Soluble Amyloid Precursor Protein Beta (sAPPβ)	Baseline (Day 1) and Week 36

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2024
• Primary Completion (Actual): December 3, 2025
• Study Completion (Actual): December 3, 2025

Study Registration Dates

• First Submitted: October 31, 2024
• First Submitted That Met QC Criteria: November 1, 2024
• First Posted (Actual): November 4, 2024

Study Record Updates

• Last Update Posted (Actual): February 20, 2026
• Last Update Submitted That Met QC Criteria: February 18, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Genetic Diseases, Inborn; Neurobehavioral Manifestations; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Congenital Abnormalities; Abnormalities, Multiple; Intellectual Disability; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Alzheimer Disease; Down Syndrome
• Other Study ID Numbers: ION269-CS1; 2023-509257-31-00 (Ctis); U1111-1306-9498 (Other Identifier: WHO Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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/.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No