Drug Development

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Mivelsiran is an investigational RNA interference (RNAi) therapeutic targeting the central nervous system (CNS).
• Previous studies showed single mivelsiran doses effectively lowered amyloid-beta precursor protein (APP).
• This study reports interim safety and pharmacodynamic data from a Phase 1 trial in early-onset Alzheimer's disease (EOAD) patients.

Purpose of the Study:

• To evaluate the safety and tolerability of single ascending doses (SAD) and multiple ascending doses (MAD) of mivelsiran in EOAD patients.
• To assess the pharmacodynamic effects of mivelsiran on cerebrospinal fluid (CSF) soluble APP beta (sAPPβ) levels.
• To provide initial clinical data on a CNS-targeting RNAi therapeutic for Alzheimer's disease.

Main Methods:

• Patients with EOAD were randomized to receive single intrathecal doses of mivelsiran (25-100mg) or placebo.
• A subset of patients received open-label, multiple ascending doses of mivelsiran (50mg every 6 months) after washout.
• Safety was assessed by adverse event (AE) frequency, and pharmacodynamics by changes in CSF sAPPβ levels.

Main Results:

• In SAD cohorts, most AEs were mild/moderate; peak CSF sAPPβ reduction of -84.5% at Month 1 was sustained through Month 10 (-61.1%).
• In the MAD cohort, no serious or severe AEs were reported.
• After the first mivelsiran dose in MAD, CSF sAPPβ decreased by -63.7%; a second dose led to further reduction (-83.8%).

Conclusions:

• Single and multiple doses of mivelsiran were generally well tolerated in EOAD patients.
• Mivelsiran demonstrated robust, durable, and dose-dependent reductions in CSF sAPPβ.
• Results support further investigation of mivelsiran for Alzheimer's disease and cerebral amyloid angiopathy.