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We believe BACE inhibition offers advantages over g-secretase inhibitors by being able to reduce
Ab production without serious off-target activities, and advantages over antibody therapies by ease of oral administration for long-term chronic treatment, being
able to penetrate the brain to reach the drug target, cost of goods for a potential life-long therapy, and ease of dose adjustment. Because of these advantages and what we expect to be a very safe
profile, we feel that BACE inhibition is the preferred way to lower brain Ab levels for the prevention and treatment of Alzheimer's.
Alzheimer's is the most common type of dementia and is increasing in prevalence as the United States population ages. According to the
Centers for Disease Control, Alzheimer's was the 6th leading cause of death in the United States in 2013. In addition, as of 2013, an estimated 5.1 million Americans had
Alzheimer's, nearly all of whom are aged 65 or older, and approximately 200,000 individuals under age 65 have early-onset Alzheimer's. The demographics highlight that the economic impact of
Alzheimer's is large and continuing to grow. According to the Alzheimer's Foundation of America, in 2010, the cost of care for people over age 70 in the United States in 2010 was between
$157 billion and $210 billion. Aricept, a leading treatment for managing the symptoms of Alzheimer's achieved United States sales of approximately $2.1 billion in its final full
year of sales before a generic entrant.
are two classes of medication currently approved to treat the symptoms of patients with Alzheimer's, cholinesterase inhibitors and NMDA inhibitors. Both classes of drugs are used
to treat symptoms of Alzheimer's such as confusion and memory loss but they do not impact disease progression. Compared to these palliative agents, we believe VTP-37948 has the potential to promote
neuronal survival which will modify progression of disease and maintain cognitive function.
Using our Contour platform, we discovered certain BACE inhibitors that were orally active for lowering brain
Ab levels in animal models. In collaboration with BI, these potent, selective BACE inhibitors were further optimized, and VTP-37948 was selected to advance into
clinical development. Inhibition of BACE enzymatic activity was determined in cell-free biochemical assays using purified recombinant human BACE. As shown in Figure 4 below, results from this
preclinical study demonstrated that VTP-37948 is a potent low nM inhibitor of BACE activity.
Inhibition of BACE by VTP-37948
Figure 4: Inhibition of purified human BACE by VTP-37948.
shares a degree of structural homology with several other proteins that cleave proteins, including renin, pepsin and cathepsins D and E. To determine the selectivity of VTP-37948,
we tested its