SELECTION OF DOSING REGIMEN FOR ELND005 (SCYLLO-INOSITOL) STUDY IN PATIENTS WITH AGITATION AND AGGRESSION OF ALZHEIMER'S DISEASE (AD)

Abstract

In a 78-week study in Mild to Moderate AD patients (Study AD201, Salloway et al., Neurology, 2011), oral ELND005 (scyllo-inositol, a myo-inositol stereoisomer) led to beneficial trends on agitation/aggression (Abushakra et al. CTAD 2012), significant decrease in CSF Abeta42, and dose-dependent scyllo-inositol increase and myo-inositol decrease on brain imaging (Liang et al., CTAD, 2012). ELND005 is being evaluated as potential treatment for Agitation and Aggression in AD patients in a 12-week randomized, placebo-controlled, 2-arm, Phase 2 study (Study AG201, NCT01735630). Plasma ELND005 exposures that can provide similar biomarker (pharmcodynamic) effects to those following chronic 250mg BID in Study AD201 are considered target exposures. We herein describe the rationale for the dosing regimen selection based on previously developed population pharmacokinetic (PopPK) Modeling and Simulations (M&S, Liang et al., AAIC, 2011) in order t o achieve target exposures in 12 weeks with the loading dose strategy. PopPK M&S, implemented within NONMEM VI or 7.1.0 with Intel ® Visual Fortran, were performed to characterize the effects of dosing regimens, inter-individual variability, and uncertainty on expected plasma PK profiles. The simulations were based on 30 subjects per dosing regimen, and 50 replicates of each dosing regimen group to capture the expected inter-trial variability of exposures. Various dosing regimens of ELND005 that can achieve earlier target brain exposure were considered and simulated. A dosing regimen of: a loading dose of 1000mg BID for 4 weeks and maintenance dose of 250mg BID for 8 weeks is projected to provide comparable plasma/brain ELND005 exposures to those following a fixed 250mg BID for 24 weeks. Dosing regimen selection for ongoing Agitation/Aggression study was based on safety and PK/biomarker (PK/PD) correlations from Study AD201. In the completed 78-wk AD Study, a dose of 1000mg BID showed acceptable safety profiles over 24 weeks in Mild/Moderate AD. A loading dose of 1000mg BID for 4weeks followed by 250mg BID for 8 weeks is hence selected in Study AG201, and expected to have acceptable safety profiles while achieving target exposures earlier with fixed dosing regimen with 250mg BID.