A Study to Evaluate the Safety and Tolerability of ALN-APP in Patients With EOAD

A Randomized, Double-blind, Placebo-controlled Single Ascending Dose and Open-label Multi-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ALN-APP in Adult Patients With Early-onset Alzheimer's Disease (EOAD)

The purpose of this study is to evaluate the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of a single dose and multiple doses of ALN-APP administered by intrathecal (IT) injection in adult patients with early-onset Alzheimer's Disease (EOAD). Maximum treatment duration for Part A: single dose. Maximum treatment duration for Part B: 12 months.

Study Overview

• Status: Recruiting
• Conditions: Early-Onset Alzheimer Disease
• Intervention / Treatment: Drug: ALN-APP; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 1

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

• Canada
  • Montreal, Canada, H3A 2B4
    • Recruiting
    • Clinical Trial Site
  • Toronto, Canada, M3B 2S7
    • Recruiting
    • Clinical Trial Site
• Netherlands
  • Amsterdam, Netherlands, 1081 BT
    • Recruiting
    • Clinical Trial Site
  • Groningen, Netherlands, 9713 GG
    • Completed
    • Clinical Trial Site
• United Kingdom
  • Huntley Street, United Kingdom, WC1E 6AG
    • Recruiting
    • Clinical Trial Site
  • Sheffield, United Kingdom, S10 2JF
    • Recruiting
    • Clinical Trial Site
• United States
  • California
    • La Jolla, California, United States, 92037
      • Completed
      • Clinical Trial Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has mild cognitive impairment or mild dementia due to EOAD
• Has Clinical Dementia Rating (CDR) global score 0.5 or 1.0 and Mini Mental State Examination (MMSE) >20

Exclusion Criteria:

• Has Non-Alzheimer's disease dementia
• Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2×upper limit of normal (ULN)
• Has estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m^2 at Screening
• Has recently received an investigational agent
• Has recent treatment with amyloid-targeting antibody

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: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: ALN-APP; Participants will be administered a single dose of ALN-APP.	Drug: ALN-APP; ALN-APP will be administered intrathecally (IT); Other Names: mivelsiran
Placebo Comparator: Part A: Placebo; Participants will be administered a single dose of placebo.	Drug: Placebo; Placebo will be administered IT
Experimental: Part B: Participants will be administered multiple doses of ALN-APP.	Drug: ALN-APP; ALN-APP will be administered intrathecally (IT); Other Names: mivelsiran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part A: Frequency of Adverse Events	Up to 12 months
Part B: Frequency of Adverse Events	Up to 42 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Part A and Part B: Change from Baseline in Levels of Cerebrospinal Fluid (CSF) Soluble Amyloid Precursor Protein Alpha (sAPPα) and Soluble Amyloid Precursor Protein Beta (sAPPβ)	Part A up to 12 months; Part B up to 24 months
Part A and Part B: Area Under the Plasma Concentration-time Curve (AUC) of ALN-APP and of Potential Metabolites	Part A up to 12 months; Part B up to 24 months
Part A and Part B: Maximum Observed Plasma Concentration (Cmax) of ALN-APP and of Potential Metabolites	Part A up to 12 months; Part B up to 24 months
Part A: Fraction of ALN-APP and Potential Metabolites Excreted in the Urine (fe)	Up to 1 day
Part A and Part B: Concentration of ALN-APP and Potential Metabolites at Time 't' (Ct) in Plasma and CSF	Part A up to 12 months; Part B up to 24 months

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2022
• Primary Completion (Estimated): April 20, 2029
• Study Completion (Estimated): April 20, 2029

Study Registration Dates

• First Submitted: January 30, 2022
• First Submitted That Met QC Criteria: January 30, 2022
• First Posted (Actual): February 9, 2022

Study Record Updates

• Last Update Posted (Actual): May 7, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: EOAD
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs
• Other Study ID Numbers: ALN-APP-001; 2023-508363-79-00 (Other Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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