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to inhibit the activity of these enzymes in biochemical assays. VTP-37948 was greater than 1000-fold more potent for BACE as compared to renin and cathepsin D, and showed no activity against
pepsin and cathepsin E.
has been shown to be highly effective at lowering brain and cerebral spinal fluid, or CSF, Ab in rats. To test the ability of VTP-37948 to
lower CSF Ab in rats, the product candidate was administered orally and CSF levels of drug and Ab were measured using
various doses and at multiple time points. As shown in Figure 5 below, VTP-37948 lowered CSF Ab levels in a drug exposure-dependent manner.
Figure 5: Rats brain tissue assayed for levels of Ab and concentrations of VTP-37948. The various symbols in the figure represent
results for individual specimens.
studies in rats and dogs of VTP-37948 show that the compound was well absorbed in both species with high oral bioavailability, good brain penetration, and a relatively long
plasma half-life, which we believe is consistent with once-a-day dosing in humans.
BI is currently conducting two Phase 1 clinical trials for VTP-37948 in 68 total individuals. The first Phase 1 clinical
trial for VTP-37948 was initiated in January 2014. It is a single dose, randomized, double-blind, placebo controlled Phase 1 clinical trial. The clinical trial started at a low dose and
increased the dose in each new dose group. The clinical trial will assess the safety and tolerability of VTP-37948 as well as the pharmacokinetics. The Phase 1 clinical trial results are
expected in the second half of 2014. The second Phase 1 clinical trial is a single dose trial at various dose levels of drug in healthy volunteers. This trial will assess safety, tolerability,
and pharmacokinetics, and in addition, will assess changes in the levels of CSF Ab at various times after dosing of VTP-37948. The data on CSF
Ab lowering will enable us to determine how well VTP-37948 inhibits BACE in the brain and lowers brain Ab levels, which will
give us early insights into the potential for clinical efficacy. Results from both of these clinical trials are expected in the second half of 2014.
VTP-43742 Targeting RAR-Related Orphan Receptor gamma-t (RORgt) for Autoimmune Disorders
We discovered and are developing VTP-43742, an orally active small molecule inhibitor of RORgt
activity which is wholly owned by us, for the treatment of a variety of autoimmune disorders. Autoimmune disorders comprise a large number of diseases in which the body mounts an inappropriate
immunological response against normal human tissues. These disorders include common autoimmune disorders such as psoriasis, MS, RA and steroid-resistant asthma, as well as rarer conditions such as
Behcet's disease and autoimmune uveitis. Increased activity of a class of lymphocytes called Th17 cells and excess production
of inflammatory proteins, including Interleukin 17, or IL-17, by these cells are believed to be critical parts of the pathophysiology of many human autoimmune disorders.
RORgt is a nuclear hormone receptor that is essential for the formation and function of Th17 cells. We believe inhibition of
RORgt activity in