A Study to Evaluate Mivelsiran in Adult Participants With Early-Stage Down Syndrome-Associated Alzheimer's Disease (DS-AD)

A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study, to Evaluate Efficacy, Safety, Tolerability, and Pharmacodynamics of Intrathecally Administered Mivelsiran in Adult Participants With Early-Stage Down Syndrome-Associated Alzheimer's Disease (DS-AD)

The purpose of the study is to evaluate the effect of mivelsiran in adult participants with early-stage DS-AD and to characterize the safety, tolerability, and pharmacodynamics (PD) of mivelsiran. The study will be conducted over 2 periods: a 24-month double-blind period and an optional 12-month open-label treatment extension (OLE) period. The estimated duration of study participation, inclusive of screening, treatment, and additional safety follow-up, is up to 39 months.

Study Overview

• Status: Not yet recruiting
• Conditions: Down Syndrome-Associated Alzheimer's Disease (DS-AD)
• Intervention / Treatment: Drug: Placebo; Drug: Mivelsiran

• Study Type: Interventional
• Enrollment (Estimated): 58
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Alnylam Clinical Trial Information Line; Phone Number: 1-877-ALNYLAM; Email: clinicaltrials@alnylam.com
• Study Contact Backup: Name: Alnylam Clinical Trial Information Line; Phone Number: 1-877-256-9526; Email: clinicaltrials@alnylam.com

Study Locations

• United States
  • Florida
    • Maitland, Florida, United States, 32751
      • Clinical Study Site
    • Naples, Florida, United States, 34105
      • Clinical Study Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Clinical diagnosis of Down-Syndrome (DS) associated with trisomy 21
• Positive amyloid PET scan
• Cognitively stable in the opinion of the investigator
• Seizures must be well controlled with no occurrence of seizures in the 6 months prior to screening

Exclusion Criteria:

• Has severe intellectual disability (ID)
• Has a history of DS regression disorder
• Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2×upper limit of normal (ULN) at Screening
• Has estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m^2 at Screening
• Has recently received an investigational agent
• Has had treatment with amyloid-targeting antibody
• Comorbidities such as obstructive sleep apnea and hypothyroidism that are not well controlled

Note: other protocol defined inclusion / exclusion criteria apply

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mivelsiran (Treatment Group A); Participants will be administered multiple low doses of mivelsiran.	Drug: Mivelsiran; Mivelsiran will be administered intrathecally; Other Names: ALN-APP
Experimental: Mivelsiran (Treatment Group B); Participants will be administered multiple high doses of mivelsiran.	Drug: Mivelsiran; Mivelsiran will be administered intrathecally; Other Names: ALN-APP
Placebo Comparator: Placebo (Treatment Group C); Participants will be administered multiple doses of placebo.	Drug: Placebo; Placebo will be administered intrathecally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Double-Blind Period: Change from baseline in brain amyloid burden measured in centiloids (CLs)	Up to 24 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Double-Blind Period: Change from baseline in APP protein concentration in cerebrospinal fluid (CSF)	Up to 24 months
Double-Blind Period: Change from baseline in the concentration of amyloid beta proteins in CSF	Up to 24 months
Double-Blind Period: Change from baseline in the concentration of tau proteins in plasma	Up to 24 months
Double-Blind Period: Change from baseline on a cognitive scale	Up to 24 months
Double-blind Period and Open-label Extension (OLE) Period: Frequency of adverse events (AEs)	Up to 36 months

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Medical Director, Alnylam Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): May 18, 2030
• Study Completion (Estimated): July 23, 2031

Study Registration Dates

• First Submitted: June 4, 2026
• First Submitted That Met QC Criteria: June 4, 2026
• First Posted (Actual): June 9, 2026

Study Record Updates

• Last Update Posted (Actual): June 9, 2026
• Last Update Submitted That Met QC Criteria: June 4, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Alzheimer's; DS-AD; Down Syndrome; ALZ
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, Inborn; Neurobehavioral Manifestations; Congenital Abnormalities; Abnormalities, Multiple; Intellectual Disability; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Down Syndrome
• Other Study ID Numbers: ALN-APP-003; 2025-523390-42-00 (Ctis)

Plan for Individual participant data (IPD)

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

IPD Plan Description

Access to Anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the US and/or the EU.

Access to data may be declined where there is likelihood a patient could be identified or other feasibility issue, where there is a potential conflict of interest, a planned business activities or an actual or potential competitive risk. Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Timeframes for data access may vary and can take up to 6 months or more.

Requests for access to data can be submitted via the website www.vivli.org. Questions can also be directed to datasharing@alnylam.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No