Title: Dose Selection of Potential Cognitive Enhancing Agent (ELND005, Scyllo-Inositol) in Adults with Down Syndrome without Dementia Authors: Liang, E,1 Kesslak, JP,1 Kurth, M1, Bairu, M,1 and Abushakra, S1 (1) Elan Pharmaceuticals, LLC, Cambridge, MA USA Methodological Question: Dose selection for a Phase 2a study in Down Syndrome (DS) adults without dementia based on population pharmacokinetic (PK), correlations between PK and biomarker/pharmacodynamic effects (PK/PD correlation), and modeling and simulations Introduction: In the brain of Down Syndrome (DS) subjects, both Amyloid oligomer toxicity and abnormal myo-inositol levels are thought to contribute to cognitive dysfunction. In patients with Alzheimer’s disease (AD), ELND005 at a dose of 250 mg BID showed acceptable long-term safety and was associated with beneficial cognitive trends in Mild AD patients, and with significant reduction of cerebrospinal fluid (CSF) amyloid and brain myo-inositol levels (Salloway et al., 2011; Tariot et al., 2012). ELND005 (an endogenous myo-inositol stereoisomer) is therefore being evaluated as a potential cognitive enhancing agent in young adults with DS without dementia. This placebo-controlled study evaluates safety, pharmacokinetics, and cognitive/behavioral outcomes with 2 active doses over 4 weeks (Study DS201; NCT01791725). A population pharmacokinetic (PopPK) model of ELND005 was developed based on Phase 2 data in AD patients and prior Phase 1 data in heathy subjects that describes plasma, CSF, and brain exposures (Liang et al., AAIC 2011). Based on this PopPK model, Modeling and Simulations (M&S) in DS subjects were performed to estimate likely ELND005 exposures in DS subjects. Methods: PopPK analyses and model development of ELND005 were implemented within NONMEM VI or 7.1.0 with Intel® Visual Fortran. PopPK M&S were performed to characterize the effects of dosing regimens, inter-individual variability, and uncertainty on expected plasma PK profiles. Simulations of ELND005 exposure in plasma were conducted considering AD-like beta amyloid disposition in DS subjects. The simulations were based on 30 subjects per dose group, and 50 replicates of each dose group to capture the expected inter-trial variability of exposures. Results: Plasma concentrations of ELND005 were adequately characterized by a 2-compartmental population PK model with zero-order input and first order absorption and elimination from the central (plasma) compartment. Apparent ELND005 plasma clearance was mainly affected by estimated creatinine clearance and disease state. Plasma concentrations of ELND005 were expected to reach steady state after two weeks of dosing. In the ongoing DS study, placebo and 2 doses of 250mg QD and 250mg BID are being evaluated. At the 2 doses used in this study, plasma exposures to ELND005 at steady state in DS subjects were projected to be much lower at 250mg QD and slightly lower at 250mg BID than those of AD patients at 250mg BID. Conclusions: Dose consideration of the ongoing 3-arm DS201 study was mainly based on projected plasma exposures to ELND005, using the final ELND005 population PK model simulations. The two selected doses for the DS201 study may provide potentially efficacious and sub-efficacious exposures. In addition to providing safety data, actual observed PK data in this population would support the validity of the Modeling and Simulation assumptions, and further optimize the PopPK model to improve dose selection for future trials in DS subjects. Disclosures: Drs. Liang, Kesslak, Kurth, Bairu, and Abushakra are full time Elan employees, and stock holders in Elan Pharmaceuticals