ABSTRACT
Abstract
OC60: 9-MONTHS AND 12-MONTHS SAFETY AND EXPLORATORY EFFICACY DATA OF ANAVEX 2-73 IN A PHASE 2A STUDY IN MILD-TO-MODERATE ALZHEIMER’S DISEASE PATIENTS. Stephen Macfarlane1, Marco Cecchi2, Paul Maruff3, Kristina M Kapiak4, Christopher U Missling4 ((1) Caulfield Hospital, Melbourne, Australia; (2) Neuronetrix, Louisville, KY, USA; (3) Cogstate Ltd., Melbourne, Australia; (4)
Anavex Life Sciences Corp., New York, NY, USA)
Background: ANAVEX 2-73, a selective sigma-1 and muscarinic receptor agonist was tested in a Phase 2a study in patients with mild-to-moderate AD. Adverse Events (AEs) were recorded for assessment of safety and maximum tolerated dose (MTD), the Primary Endpoint of the study. Cognitive (MMSE, Cogstate, QEEG/ERP) and the functional (ADCS-ADL) marker were measured so as to establish a functional relationship between dosing regimen and exploratory efficacy outcomes, the Secondary Endpoint.
Methods: Thirty-two AD patients 55-85 years old with MMSE between 16 and 28 were recruited. After establishing the MTD and dose response in PART A of the trial, in PART B, all patients received ANAVEX 2-73 between 10mg and 50mg daily orally and re-assessed at 12, 26, 36, 48 weeks. For safety and MTD determination, mathematical modeling was fitted to the recorded AEs to establish the dose-risk relationship. For efficacy, statistical hypothesis tests were performed on cognitive and functional markers.
These functional markers were compared to the corresponding baselines.
Results: Safety: ANAVEX 2-73 demonstrated a favorable safety profile when administered to a clinical population of elderly AD patients with varying degrees of physical fragility. The most common side effects across all AE categories tended to be of mild severity grade 1, and were resolved with dose reductions that were anticipated within the adaptive design of the study protocol. Positive unexpected therapeutic response events, such as improved mood, improved social engagement and increased independent activities were recorded.
Exploratory Efficacy: 9-months and 12-months data of all available patients demonstrate that ANAVEX 2-73 preserves average MMSE and ADCS-ADL (PART B) scores across the entire patient group. ANAVEX 2-73 continues to show benefits over baseline for both Cogstate and QEEG/ERP.Conclusions: The safety of ANAVEX 2-73 was assessed and MTD was determined. Despite not optimal dosing in the longitudinal PART B of the study, both cognitive and functional performance is sustained over at least 9 months, suggesting that the effect of the compound does not seem to worsen AD symptoms with repeated dosing. In a disease state where progression is invariable over time, a stable MMSE and ADCS-ADL score is considered a positive outcome.
Population pharmacokinetic analysis is currently ongoing. The data collected so far support further clinical development of ANAVEX 2-73 and preparation for a larger confirmatory study is underway.
