Developing Topics.

BACKGROUND

Genetic-driven deregulation of the amyloid pathway and overproduction of downstream amyloid-β are known to cause early-onset Alzheimer's disease (EOAD)

METHOD

ALN-APP-001 (NCT05231785) Part A is an ongoing randomized, double-blind, placebo-controlled, Phase 1 single-ascending dose study in patients with EOAD. Patients are required to have disease onset at age <65 years, Clinical Dementia Rating® global score of 0.5 or 1.0, and Mini Mental State Examination score >20. Patients are being evaluated over 6 months, with further follow-up of up to 6 months as needed. The primary endpoint is the safety and tolerability of ALN-APP. Secondary objectives include the evaluation of pharmacokinetics and pharmacodynamic effects of ALN-APP.

RESULT

12 patients were enrolled and randomized 2:1 to receive ALN-APP or placebo in 25mg and 75mg dose cohorts. Baseline characteristics are shown in Table 1. Mean (SD) duration on study was 6.7 (1.7) months for cohort 1 (25mg) and 2.0 (1.0) months for cohort 2 (75mg). Dose-dependent reductions of soluble APPα and APPβ (sAPPα and sAPPβ) levels in cerebrospinal fluid (CSF) at day 15 were observed following a single dose of ALN-APP, with mean reductions from baseline of 55% (sAPPα) and 69% (sAPPβ), and maximum reductions of 71% (sAPPα) and 83% (sAPPβ) in the 75mg cohort (n = 4) (Table 2). All adverse events (AEs) by data cut-off on 01/17/2023 were mild or moderate (Table 3), with no AEs deemed related to study drug by the investigators. Additional cohort data will be presented at the meeting.

CONCLUSION

This first clinical study of a CNS-administered RNAi therapeutic demonstrates target engagement of APP, with reductions in CSF sAPPα and sAPPβ. To date, ALN-APP remains generally well tolerated with all reported AEs mild or moderate. These interim results support further evaluation of ALN-APP in patients with EOAD. Reference: 1. Hampel H et al. Molecular Psychiatry (2021). 26:5481-5503.

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