Phase 2 Randomized, Double‑Blind, Placebo‑Controlled Trial of Intrathecal Mivelsiran (ALN‑961583) in Adults with Early‑Stage Down Syndrome‑Associated Alzheimer’s Disease

Primary objective: To evaluate the effect of mivelsiran on a neuroimaging biomarker of brain amyloid accumulation, reflecting disease‑modifying potential in early‑stage Down syndrome‑associated Alzheimer’s disease. Secondary objectives:

• Assessment of the drug’s pharmacodynamic effects.
• Evaluation of changes in disease‑related fluid biomarkers.
• Examination of impact on early cognitive changes.

The trial enrolled 41 participants diagnosed with early‑stage Down syndrome‑associated Alzheimer’s disease. Eligible individuals were male or female, aged 40 to 55 years at consent, and had a clinical diagnosis of trisomy 21. All participants were cognitively stable, as assessed by a consensus case conference and a National Task Group‑Early Detection Screen for Dementia score of ≤2 in memory and language domains, and demonstrated an amyloid PET burden of at least 18 centiloids. Inclusion required the presence of a supportive psychosocial environment and a study partner capable of providing reliable informant data. When applicable, participants with a history of seizures were required to have been seizure‑free for six months prior to screening, with antiepileptic medication permitted. Subjects needed to be able to travel to the study center and comply with all study procedures, with informed consent obtained according to local regulations.

The study is a randomized, double-blind, placebo-controlled Phase 2 trial evaluating intrathecally administered Mivelsiran in adults with early Down syndrome-associated Alzheimer’s disease. After an initial screening visit to confirm eligibility criteria—including amyloid PET imaging, CSF sampling, and clinical assessments—participants are assigned in a 1:1 ratio to receive either Mivelsiran or an isotonic aqueous buffer placebo via intrathecal injection. The investigational period spans 24 months of active treatment, with study visits scheduled at baseline (day 0), and at months 3, 6, 12, 18, and 24 for safety monitoring, biomarker collection (CSF and plasma), and neurocognitive testing. The final visit at month 24 serves as the end‑of‑study assessment, encompassing repeat amyloid PET imaging and all secondary endpoint measurements. Participant involvement therefore extends approximately 24 months plus the initial screening period. Early termination may occur if a participant experiences a serious adverse event, exhibits uncontrolled seizures, fails to adhere to protocol‑required procedures, withdraws consent, or loses decision‑making capacity, in which case a legally authorized representative must provide consent for continued assessments.

The investigational product Mivelsiran is supplied as a sterile solution for injection intended for intrathecal administration. The formulation contains the active substance ALN‑961583. The protocol specifies a fixed dose of 0 mg per administration; the exact volume and dosing frequency are defined in the study schedule and are identical for all participants receiving the active arm.

A second test‑group component, water for injection, is also provided as a sterile solution for injection for intrathecal use. The preparation contains no active pharmaceutical ingredient and is administered at a dose of 0.00 mg. It serves as the diluent for the active product in the investigational arm.

The control arm receives a matching placebo consisting of an isotonic aqueous buffer suitable for IT injection. The placebo is presented as a sterile solution for injection, administered via the same intrathecal route and at the same volume and schedule as the active product to maintain blinding.

All study medications are administered by qualified personnel according to the predefined dosing schedule. Administration details, including date, time, and volume injected, are recorded in the case‑report forms. Participant compliance with the dosing regimen is monitored through site‑based documentation and verification of injection logs.

Efficacy will be assessed by quantifying the change from baseline to Month 24 in the neuroimaging biomarker of brain amyloid accumulation using amyloid PET measured in Centiloid units (CLs). Baseline PET scans will be performed prior to the first intrathecal administration, and follow‑up scans will be obtained at the 24‑month visit. Images will be analyzed centrally with a validated quantitative method to determine the CL value for each participant.

Secondary efficacy assessments include the change from baseline to Month 24 in cerebrospinal fluid concentrations of sAPPβ, sAPPα, and Aβ42, as well as the plasma concentration of p‑tau217. CSF and plasma samples will be collected at the same baseline and 24‑month visits, processed according to standardized protocols, and analyzed in a central laboratory using validated immunoassays. Additionally, cognitive performance will be evaluated by the change from baseline to Month 24 on the modified Cognitive Rating Test (mCRT), administered by trained assessors at both time points.