Investigation of Dose-Responses and Longitudinal Effects of Combination Therapy with a Plaque-Specific Amyloid Beta Antibody and Bace Inhibitor in Aged Transgenic Mice

The utilization of combination therapies in the clinic is an exciting new avenue for the Alzheimer's disease field. Although there are non-clinical data in transgenic mice that support the rationale for combination therapy, the design of these studies were largely limited to the demonstration of proof of concept and they did not include detailed experimental designs that are important for clinical translation. In order to extend the understanding of the timing and dose-relationships of the combination therapies, we performed two large combination studies. Aged PDAPP transgenic mice (17-19 months) were used in two large combination studies. Combination Dose-Response: 285 aged mice were randomized into a multi-arm study that consisted of a BACE inhibitor (LY2811376) monotherapy dose response, plaque specific Aβ antibody (anti-Aβp3-x) + BACE inhibitor dose response and control/time zero cohorts. Longitudinal pharmacodynamic study: 359 aged mice were randomized into four large cohorts: compound controls, plaque-specific Aβ antibody, BACE inhibitor, and Aβ antibody + BACE inhibitor and analyzed longitudinally at the following time points: 0, 4, 8, 12, and 16-weeks. We observed a significant dose-response relationship on deposited Aβ1-42 (ELISA) for the BACE inhibitor monotherapy (-7%, -23%, and -60%). For the combination drug treatment arms, we observed a significant broad dose response in the presence of high dose antibody and varying dose levels of BACE inhibitor (from -33% through -84%). The combination drug treatments of a high dose BACE inhibitor in the presence of varying dose levels of Aβ antibody revealed a significant, yet steeper dose response (from -60% through -84%). Several of the of drug combination treatments resulted in significant synergistic lowering of deposited Aβ. The longitudinal study demonstrated significant time dependent effects on plaque removal that was detected as early as 4-weeks and the combination therapy showed a continual significant reduction over time that resulted in a dramatic reduction of deposited Aβ as compared to the time zero cohort. The combination therapy studies demonstrated significant dose-response and longitudinal relationships for the plaque specific antibody and BACE inhibitor that further support/enable the rationale for utilizing combinational anti-amyloid therapies in the clinic.