Background/Objectives: Oral donepezil, an acetylcholinesterase (AChE) inhibitor for Alzheimer’s disease, faces adherence challenges. Long-acting injectable (LAI) formulations like GB-5001 aim to enhance adherence by reducing dosing frequency. This Phase 1, open-label, active-controlled, dose-escalation study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GB-5001 in healthy male adults. Methods: Participants were assigned to cohorts receiving GB-5001A or GB-5001D (LAI formulations) via intramuscular (IM) or subcutaneous (SC) injection, or oral Aricept®. Safety, PK, and PD (AChE inhibition) were assessed. The influence of CYP2D6 phenotype was explored, and modeling/simulation was performed. Results: Fifty healthy male participants completed the study. After IM administration, GB-5001A (70 mg, 140 mg, 280 mg) showed dose-dependent increases in exposure (AUCinf and Cmax), resulting in significantly extended exposure compared to oral Aricept® 10 mg. No serious adverse events were reported; the most common AEs were mild injection site reactions, which occurred in all treatment groups except the GB-5001A IM 70 mg group and the Aricept group. GB-5001A also demonstrated sustained AChE inhibition. Conclusions: GB-5001A, an LAI donepezil, showed favorable safety, dose-proportional PK, and sustained plasma exposure. It achieved a 3–4-fold longer half-life than oral donepezil. These findings, supported by modeling, highlight GB-5001A’s potential as a once-monthly IM alternative for Alzheimer’s disease treatment.
