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As depicted in Figure 3 below, Ab peptides are produced by excision from a larger protein,
APP. The path to the production of Ab begins with the cleavage of APP by BACE. A second cut occurs by the membrane bound
g-secretase complex, which releases the Ab peptide, or a small fragment of the protein.
Figure 3: Production of Ab peptides is mediated by cleavage of APP by BACE and
targeting Alzheimer's have included anti-Ab antibodies that bind to different forms of Ab to promote
the clearance of Ab and plaques from the brain, and small molecule inhibitors of the g-secretase complex or of BACE to
decrease the production of Ab. Recently, two anti-Ab antibodies, bapineuzumab and solanezumab, were tested in several large
Phase 3 clinical trials by Pfizer Inc. and Eli Lilly & Co. The therapeutic hypothesis was that the antibodies would promote Ab
clearance and affect disease progression. Both sets of trials failed to meet their primary end points. However, a post-hoc analysis of solanezumab showed an improvement versus placebo in a subgroup of
patients with early Alzheimer's. In addition, animal studies have suggested that when Alzheimer's has progressed beyond a certain point, the disease becomes self-sustaining and resistant to therapy.
These data and data from other studies suggest that initiating Ab lowering therapy earlier in the disease process, which we intend to do in our development
program, will be important to generating a positive therapeutic effect.
inhibition of g-secretase activity for Alzheimer's with small molecules has been pursued, and Ab lowering
has been demonstrated. However, the lack of specificity for inhibiting only Ab production has been a problem. In addition to its role in
Ab production, the g-secretase complex generates a vital signaling protein named Notch, which is key to the survival of many
cell types. Inactivation in mice by gene knockout methods of a component of the g-secretase complex, presenilin, leads to developmental defects that cause a
lethality around the time of birth due to Notch suppression. In
addition, in human trials with g-secretase inhibitors, there have been serious adverse events including colitis, which is inflammation of the colon, and skin
cancer. Thus, inhibiting g-secretase has multiple unintended and serious consequences. In contrast to g-secretase, the
absence of BACE in gene knock-out mice has been shown to have insignificant impact on mouse physiology.