P4‐356: Safety and Efficacy 31 Week Data of Anavex 2‐73 in a Phase 2A Study in Mild‐Moderate Alzheimer’S Disease Patients
Stephen Macfarlane, Marco Cecchi, Dennis K. Moore, Paul T. Maruff, Tasos Zografidis, Christopher U. Missling · Alzheimer s & Dementia · 2016
ANAVEX2-73, a 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 determination of maximum tolerated dose (MTD), the Primary Endpoint of the study. Cognitive (MMSE, Cogstate, QEEG/ERP) and the functional (ADCS-ADL) markers were measured so as to establish a functional relationship between dosing regimen and efficacy outcomes, the Secondary Endpoint. Thirty-two AD patients 55-85 years old with MMSE between 16 and 28 were recruited. In PART A, participants were administered ANAVEX2-73 in a randomized, open-label, 2-period, cross-over, adaptive study lasting 5 weeks. In PART B all patients received ANAVEX2-73 daily orally and re-assessed at 5, 17 and 31 weeks. At 31 weeks 28 patients are continuing the study, with 36% receiving 20 mg and 32% receiving 30 mg dose. 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 paired with the corresponding baselines and Δ-scores were analyzed. Primary Endpoints: A total of 170 AEs most frequent AEs (48) were dizziness and headache, thereof 37 with severity grade one and 11 severity grade two. 96% of all adverse events were of mild or moderate severity and all events resolved/recovered. MTD was estimated at 48 mg ANAVEX2-73. Secondary Endpoints: ANOVA reveals that the treatment effect remains the only factor that significantly influences the MMSE-Δ- (p=0.0285) and ERP-Δ-scores (p=0.0168). Those results were confirmed with post-hoc and Bayesian hierarchical analysis. For longitudinal 31 weeks data, repeated-measures ANOVA shows that MMSE-Δ, Cogstate-Δ and ADCS-ADL-Δ-scores were maintained at a constant level. Literature search does not seem to indicate existence of cases of not worsening both cognitive and functional scores over this period. The safety of ANAVEX2-73 was assessed and MTD was determined. Results from the clinical trial show that ANAVEX2-73 dose-dependently affects cognitive performance. Both cognitive and functional performance is maintained constant up to 31 weeks. Study will be completed with the pharmacokinetic part, currently ongoing. The data collected so far support further clinical development of ANAVEX2-73.