Abstract Body: Background: Cerebral amyloid angiopathy (CAA) is a progressive and debilitating disease characterized by amyloid beta (Aβ) deposition in cerebral blood vessels. Hemorrhagic manifestations of CAA include cerebral microbleeds (CMBs) and recurrent intracerebral hemorrhage (ICH). Although often comorbid with Alzheimer’s disease (AD), CAA also independently contributes to cognitive impairment. There are no disease-modifying therapies for patients with CAA. Mivelsiran is an investigational RNA interference (RNAi) therapeutic that reduces expression of Aβ precursor protein (APP), which is the source of Aβ production. An ongoing Phase 1 study of mivelsiran in early-onset AD has shown encouraging safety data and robust, durable reductions of soluble APP fragments and Aβ peptides in cerebrospinal fluid. These findings supported the initiation of cAPPricorn-1 (NCT06393712), a global Phase 2 study evaluating the efficacy, safety, and pharmacodynamics of mivelsiran in patients with sporadic CAA (sCAA) or Dutch-type CAA (D-CAA), a rare, aggressive, genetic form of the disease.
Design: Approximately 200 patients with sCAA (≥50 years old, probable CAA [adapted Boston criteria v2.0]) or D-CAA (≥30 years old, E693Q APP variant) will be enrolled. Patients with an ICH within 90 days before randomization, moderate/severe AD, severe cognitive impairment, or use of antithrombotics (except aspirin) are excluded. Patients are randomized to receive intrathecally administered mivelsiran or placebo for a 24-month double-blind period followed by an optional 18-month open-label extension. The primary endpoint is the annualized rate of new lobar CMBs on MRI. Other key outcome measures are: frequency of adverse events, pharmacodynamics, a novel global rank endpoint that integrates clinical and imaging data cardinal hemorrhagic and nonhemorrhagic CAA imaging biomarkers, and measures of function and cognition. The study enrolled its first patient in mid-2024 and will continue to enroll in 2025.
Discussion: Mivelsiran is an investigational first-in-class RNAi therapeutic designed to target the underlying pathophysiology of CAA by lowering APP, thereby reducing Aβ accumulation. To date, cAPPricorn-1 is the only active global interventional study for the treatment of patients with CAA.