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VITAE PHARMACEUTICALS, INC filed this Form S-1 on 08/12/2014
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    VTP-37948 Targeting b-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE) for Alzheimer's Disease


        VTP-37948, our orally active BACE inhibitor, is being developed in collaboration with BI for Alzheimer's. Alzheimer's is a devastating disease that causes problems with memory, thinking and behavior. According to the Alzheimer's Foundation of America, or the AFA, an estimated 5.1 million Americans had Alzheimer's as of 2013 and due to the increasing number of people age 65 or older that the number of Americans with Alzheimer's or dementia will double by 2015. In addition, according to the AFA, the average annual cost of care for Alzheimer's patients over the age of 70 in the United States was estimated to be between $157 billion and $210 billion in 2010. Alzheimer's eventually impairs an individual's ability to carry out such basic bodily functions as walking and swallowing and can ultimately be fatal. One of the primary indicators of Alzheimer's is the presence in the brain of large complexes or plaques of a toxic peptide, called amyloid beta or Ab. One of the proteins involved in the generation of Ab is b-Site Amyloid Precursor Protein Cleaving Enzyme 1, also known as beta secretase or BACE. BACE cleaves a larger protein, called amyloid precursor protein, or APP, into two pieces at a particular site, and then another protein complex makes a second cleavage resulting in the generation of the Ab peptide. We believe there is strong genetic evidence for Ab and BACE being important factors in the pathogenesis of Alzheimer's.

        Using our Contour platform, we discovered potent BACE inhibitors that were orally active for lowering brain Ab levels in animal models. In collaboration with BI, these potent, selective BACE inhibitors were optimized. The resulting optimized BACE inhibitor, VTP-37948, penetrates the brain and has been shown to lower Ab levels by up to 95% in preclinical studies. In these studies, VTP-37948 shows no significant off-target activity, has high bioavailability and is projected to be a once-a-day drug in humans. BI has initiated clinical development of VTP-37948. A human single dose Phase 1 clinical trial for safety, tolerability and pharmacokinetics was initiated in January 2014. A second human single dose Phase 1 clinical trial is expected to be initiated in the second half of 2014, in which cerebral spinal fluid, or CSF, will be assayed for Ab lowering.

    Amyloidb and Alzheimer's Disease

        Alzheimer's is the most common form of dementia. Alzheimer's is characterized by the accumulation of extracellular protein deposits in the brain that are called amyloid plaques. The plaques are composed of Ab peptides, which are derived from the larger protein APP. The accumulation of Ab containing plaques, or small soluble complexes derived from the plaques, in the brain is thought to damage neurons, or nerve cells, which, in turn, triggers additional inflammatory responses that further aggravate the disease. Studies show that Ab accumulation is critical to the pathogenesis of Alzheimer's. Human genetics studies have established that mutations that accelerate the rate of production of Ab peptides universally cause early onset Alzheimer's. Conversely, a mutation in the APP protein at the BACE cleavage site that suppresses production of Ab peptides by 40% and decreases the rate of cleavage by BACE is associated with a decreased incidence of Alzheimer's of approximately 7.5x and an improvement in cognitive function in non-Alzheimer's elderly individuals. Therefore, we believe that the inhibition of Ab production in the brain should benefit patients with Alzheimer's.