Download Title: Dose Selection of Potential Cognitive Enhancing Agent

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