Safety, tolerability, pharmacokinetics and pharmacodynamics of ascending single and multiple doses of lecozotan in healthy young and elderly subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Alzheimer's disease (AD) is a progressive brain disorder that gradually destroys a victim's memory and cognitive processes. • Currently there are no approved treatments for AD capable of modifying the disease process. • Symptomatic agents available target the neurotransmitter systems known to decline during the progression of the disease (including cholinesterase inhibitors); however, overall effects on clinical deterioration are known to be modest. • It has been hypothesized that 5‐HT 1A antagonists such as lecozotan might function as an effective treatment of the cognitive deficits associated with AD, as they have been shown to improve cognitive performance in multiple animal models of learning and memory. WHAT THIS STUDY ADDS • This study provides information on the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of a potential new treatment for memory disturbances associated with AD. • Acting through a new mechanism of action, lecozotan antagonizes the 5HT 1A receptor potentiating both cholinergic and glutamatergic neurotransmission. • The three initial safety, PK and PD studies described in this study establish that lecozotan immediate release (IR) was safe and well tolerated in both healthy young and elderly subjects at total daily doses up to 10 mg (5 mg every 12 h). • There were no counter‐indicative PD findings during the study. • With the development of a sustained‐release formulation for once‐daily dosing, lecozotan is currently under investigation in advanced Phase II clinical trials. AIMS To determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral immediate release (IR) lecozotan in healthy young and elderly subjects. METHODS Three randomized, double‐blind, placebo‐controlled, sequential, ascending dose Phase I studies of lecozotan were conducted. In a single‐dose study, ascending doses of 2, 5 and 10 mg were administered to cohorts of eight young subjects. In the two ascending 14‐day multiple‐dose studies, 41 young subjects received 0.1, 0.25, 0.5, 1 and 5 mg q12h of lecozotan or placebo and 24 elderly received 0.5 mg and 5 mg q12h of lecozotan or placebo. Assessments included safety evaluations, a complete PK profile and PD. RESULTS Lecozotan was safe and well tolerated at steady state up to 5 mg q12. The maximum tolerated dose after multiple doses was >10 mg (5 mg q12). In the single‐dose study, the maximum tolerated dose was 10 mg. Dose‐limiting mild‐to‐moderate adverse events included paraesthesia, dizziness and visual disturbances peaking at t max and disappearing concomitantly with plasma concentrations. No clinically relevant changes in vital signs, ECG intervals or routine laboratory tests occurred. Lecozotan did not significantly change cognitive function, EEG or hormone levels. PK was characterized by rapid absorption, dose proportionality, extensive distribution and rapid elimination. The mean CL/ F was approximately 35% lower in the elderly. CONCLUSIONS Lecozotan IR was safe and well tolerated after administration of multiple oral doses up to 5 mg q12h in young and elderly subjects. These results support the development of lecozotan in patients with Alzheimer's disease.