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

NCT07636811 — Phase 2, Recruiting, 58 participants, Alnylam Pharmaceuticals

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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)

Registry	NCT07636811
Status	Recruiting
Phase	Phase 2
Study type	Interventional; randomized, parallel, masking: quadruple, treatment
Enrollment	58 (Estimated)
Sponsor	Alnylam Pharmaceuticals (Industry)
Conditions	Down Syndrome-Associated Alzheimer's Disease (DS-AD)
Interventions	Mivelsiran, Placebo (Drug)
Dates	start 2026-08-17, primary completion 2030-05-18 (estimated), completion 2031-07-30 (estimated), first posted 2026-06-09, last updated 2026-10-13
Locations	10 sites in United States, Spain

-Summary

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.

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+Arms and interventions

Arm	Type	Interventions	Description
Mivelsiran (Treatment Group A)	Experimental	Drug: Mivelsiran	Participants will be administered multiple low doses of mivelsiran.
Mivelsiran (Treatment Group B)	Experimental	Drug: Mivelsiran	Participants will be administered multiple high doses of mivelsiran.
Placebo (Treatment Group C)	Placebo comparator	Drug: Placebo	Participants will be administered multiple doses of placebo.

Mivelsiran (Drug), also known as ALN-APP: Mivelsiran will be administered intrathecally
Placebo (Drug): Placebo will be administered intrathecally

+Outcome measures

Primary outcomes

Double-Blind Period: Change from baseline in brain amyloid burden measured in centiloids (CLs) [Up to 24 months]

Secondary outcomes

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]

+Eligibility

Sex: All, ages: 40 Years to 55 Years

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

+Locations (10)

Facility	City	Country	Status
Clinical Trial Site	Maitland, Florida	United States	Recruiting
Clinical Trial Site	Naples, Florida	United States	Recruiting
Clinical Trial Site	Indianapolis, Indiana	United States	Recruiting
Clinical Trial Site	St Louis, Missouri	United States	Recruiting
Clinical Trial Site	Barcelona	Spain	Recruiting
Clinical Trial Site	Dos Hermanas	Spain	Recruiting
Clinical Trial Site	Madrid	Spain	Recruiting
Clinical Trial Site	Pamplona	Spain	Recruiting
Clinical Trial Site	Seville	Spain	Recruiting
Clinical Trial Site	Valencia	Spain	Recruiting

+Investigators

Medical Director, Study director, Alnylam Pharmaceuticals

+Funding

NIH grants: 2025