COMBINATION THERAPY WITH A PLAQUE-SPECIFIC ABETA ANTIBODY AND A BACE INHIBITOR RESULTS IN DRAMATIC PLAQUE REDUCTION IN A DOSE-DEPENDENT MANNER IN AGED PDAPP TRANSGENIC MICE

The use of combination therapies is an emerging and exciting potential path forward for treatment of Alzheimer’s disease (AD). Our understanding of the AD cascade continues to evolve and show the proximal deposition of Aβ precedes cognitive impairment by 10 to 15 years and that deposition of Aβ has reached a plaque ceiling by the time mild to moderate symptoms manifest. Thus, an increasing belief in the field is that aggressive anti-amyloid interventions, such as combination therapy, may be necessary for treatment of symptomatic Alzheimer’s patients. In order to provide clinically translatable data that moves beyond simple proof-of-concept, we conducted a large dose response combination therapy study. Aged PDAPP mice (18-20 months, N = 285) were randomized into an eleven-arm study that consisted of a BACE inhibitor (LY2811376) monotherapy dose response, plaque-specific Aβ antibody mE8-IgG2a (anti-Aβp3-x) dose response plus high-dose BACE inhibitor, high-dose, plaque-specific Aβ antibody mE8-IgG2a (anti-Aβp3-x) plus BACE inhibitor dose response, and control/time zero cohorts. Animals were sacrificed after 4 months on study and samples were analyzed by various biochemical and immunohistological techniques. We observed a significant dose-response relationship on deposited Aβ1-42 (ELISA) for BACE inhibitor monotherapy compared to the control treated animals (-7%, -23%, and -60%). Additionally, histological analyses demonstrated BACE inhibitor treatment significantly lowered the diffuse deposits of Aβ. For combination drug treatment arms, we observed a significant broad dose response on deposited Aβ1-42 (ELISA) 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 on deposited Aβ1-42 (from -60% through -84%). The histological analyses for deposited Aβ paralleled observed biochemical changes for combination therapy groups. Several of the of drug combination treatments resulted in significant synergistic lowering of deposited Aβ. The combination therapy showed a robust, highly significant and synergistic dose response relationship to plaque lowering in the transgenic mouse model. These results support rationale for using combination therapies in clinical trials.