Bibliographic
The goal of this study was to evaluate the beta amyloid lowering effects of a combined intervention of a BACE1 inhibitor and beta amyloid specific antibody,speciifically to comapre the efficacy of the combination to that of the individual therapeutic agents. To this end investigators performed a chronic study in APPLondon transgenic mice that received treatment with anti-Aβ antibody gantenerumab and BACE inhibitor RO5508887, either as mono- or combination treatment. Mono-treatments with either compound caused a dose-dependent reduction of total brain Aβ and amyloid burden.Mono therapy using the BACE inhibitor significantly reduced the amounts of total brain Aβ40 and Aβ42 compared with the vehicle group, with a clear dose-dependency. Gantenerumab alone significantly reduced the amount of brain Aβ42 species by 39%, whereas no significant decrease was observed for Aβ40. Combination treatment with both compounds significantly enhanced the anti-amyloid effect as measured by total brain Aβ40 and Aβ42. The decrease of Aβ42 in the combination treatment was 66% compared with 28% with BACE inhibitor alone, a clear doubling of efficacy. The effect is additive, because the reduction with antibody alone was 39%. The effect of the combination on Aβ40 as much less pronounced.The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number, which suggests effective inhibition of de novo plaque formation. Moreover, significantly enhanced clearance of pre-existing amyloid plaques was observed with the combination therapy compared to the mono-therapies. In addition BACE inhibition by RO5508887 led to a significant time- and dose-dependent decrease in CSF Aβ, which was not observed for gantenerumab treatment. These results demonstrate that combining these two anti-amyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance.