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levels indicating inhibition of 11b HSD2 were observed. The second Phase 1 clinical trial was a once-a-day dose, two week trial in 70 overweight
type 2 diabetic patients, starting at a low dose, with the dose being increased in each subsequent study group. VTP-34072 was well tolerated at all doses. There were no clinically relevant
changes in vital signs, laboratory values, or electrocardiograms. No dose dependent adverse events and no serious adverse events were reported. There were no clinically significant changes in plasma
cortisol levels or in levels of ACTH, the hormone that regulates cortisol production by the adrenal gland, and there were no changes in plasma or urinary hormone levels indicating inhibition of
11b HSD2. The activity of 11b HSD1 was assessed in adipose tissue biopsies taken before the first day of
dosing and at 24 hours after the day 14 dose. The enzyme activity in the adipose tissue biopsies showed that the 11b HSD1 activity was inhibited by greater
than 90% at 24 hours in multiple dose groups.
VTP-34072's ability to inhibit 11b HSD1 was tested in an in
vitro enzyme assay and it was shown to have low, single digit nanomolar, or nM, activity. In addition, it was shown to be greater than 1000-fold more potent for
11b HSD1 as compared to 11b HSD2. As shown in Figure 2 below, VTP-34072 demonstrated potent, single digit nanomolar
inhibition of 11b HSD1 activity in human adipose tissue.
Inhibition of Human 11b HSD1 by VTP-34072
Figure 2: Inhibition of 11b HSD1 activity by VTP-34072 in human adipose tissue.
pharmacokinetic profile was assessed in rats and cynomolgus monkeys by administering VTP-34072 via oral and intravenous routes in both species. The pharmacokinetics results
showed that the compound was well absorbed with high oral bioavailability and with a plasma half-life, which we believe is consistent with once-a-day dosing in humans.
VTP-34072 is being tested by BI in a Phase 2 clinical trial in 126 overweight type 2 diabetic patients, which commenced
in July 2014. The patients will have their anti-diabetic medications discontinued, or if they are on metformin, their metformin will be continued. This is a placebo-controlled, randomized,
double-blinded clinical trial, where neither the patient nor the physicians treating the patient know if the patient is getting the drug or a placebo, in which patients will be dosed once-a-day for
four weeks at one of three dose levels. The endpoints in this clinical trial include safety, tolerability and glucose lowering. Data from this clinical trial are expected in the first half of 2015.