Variable effects of the gamma-secretase inhibitor ELND006 on Aβ across different compartments (brain, ISF, CSF, and plasma) following sustained exposure via subcutaneous osmotic pumps in wild-type mice

ELND006 is a potent gamma-secretase inhibitor which demonstrates in vitro substrate selectivity towards inhibiting APP cleavage compared to Notch and has been evaluated in Phase 1 human clinical trials. Preclinical PK/PD models are essential in assisting in clinical development, including dose selection. To more effectively model the extended human half-life observed in Phase 1, we established a wildtype mouse model in which ELND006 was continuously infused via a subcutaneous Alzet minipump and Aß levels in the CSF, interstitial fluid (ISF), brain and plasma were evaluated. Alzet osmotic pumps containing ELND006 or vehicle were implanted subcutaneously in FVB mice, followed by a subcutaneous loading dose. Animals were terminated, and tissues collected after 6 -72 hours of infusion. Microdialysis studies were performed by implanting FVB mice with hippocampal microdialysis probes to assess ISF Aß. Aß levels in brain, ISF, CSF and plasma were analyzed by ELISA. Compound levels in plasma and brain were determined by an LC-MS/MS assay. After sustained administration of 2, 10 and 50 mg/kg/day, brain Aß was significantly reduced (26%, 59% and 72%, respectively). Plasma Aß was elevated 37% at 2 mg/kg/dose, and was reduced 17% (nonsignificantly, n.s.) and 62% at 10 and 50 mg/kg/day, respectively. CSF Aß was elevated 34% (n.s.) at 2 mg/kg/day and significantly reduced 43% and 85% at 10 and 50 mg/kg/day, respectively. Plasma ELND006 concentrations of 35, 197, and 281 ng/mL were associated with 25% lowering of Aß in the brain, CSF and plasma respectively. Preliminary microdialysis experiments suggested that ISF Aß was reduced at doses as low as 0.5 mg/kg/day. Sustained infusion of ELND006 via Alzet subcutaneous minipumps in FVB mice demonstrated that therapeutically relevant lowering of Aß in the brain (25%) occurs at doses below those needed to effect similar responses in CSF and plasma. In addition, Aß reduction in the brain occurs at an exposure where CSF and plasma Aß is either unaffected or elevated. Understanding these relationships is important in interpreting Aß biomarkers in plasma and CSF in the clinic.