To evaluate the pharmacokinetics (PK), PD, and safety of IVL3003, a novel once-monthly long-acting injectable acetylcholinesterase inhibitor, compared with oral donepezil.

Acetylcholinesterase inhibitors remain the standard of care for symptomatic treatment of Alzheimer’s disease (AD). However, oral formulations such as donepezil require daily administration and dose titration due to gastrointestinal side effects, resulting in variable compliance and fluctuating pharmacodynamic (PD) responses. Long-acting injectable formulations may address these limitations by providing sustained drug exposure and consistent PD effects.

In this phase 1 study, approximately 50 healthy adult males (18–55 years) were enrolled across four cohorts to receive either 5mg donepezil tablet daily for 28 days or a single intramuscular (IM) injection of IVL3003. Tolerability was monitored throughout the study. Plasma concentrations of donepezil, 6-O-desmethyl donepezil, and acetylcholinesterase activity were measured using validated analytical methods. PK and PD parameters, along with safety outcomes, were evaluated for up to 85 days.

IVL3003 was generally safe and well tolerated. Following IM administration, IVL3003 demonstrated dose-proportional increases in exposure (AUC and Cmax). Compared with oral donepezil, IVL3003 achieved more consistent plasma concentrations without an initial burst release or marked peak-to-trough variability, which are characteristic of daily oral dosing. Pharmacodynamic assessments showed sustained acetylcholinesterase inhibition for 28 days, in consistent with its mechanism of action. The overall safety profile including nervous system disorders and general disorders was comparable to oral donepezil, with no unexpected adverse events. Only mild injection site reactions were observed.

IVL3003 demonstrated favorable safety, PK, and PD characteristics. Unlike daily oral donepezil, IVL3003 maintained consistent plasma levels within the therapeutic range for up to four weeks, supporting its potential as a once-monthly treatment option for AD. These findings suggest that IVL3003 may improve patient adherence and reduce variability in clinical outcomes, representing a promising therapeutic alternative for patients with AD.