DOV Pharmaceutical, Inc. has announced phase Ib results for DOV 21,947, its lead triple reuptake inhibitor ("TRIP") for the treatment of depression and obesity. Preliminary analysis of the study results indicates DOV 21,947 was safe and well-tolerated at the doses examined and produced a significant decline in plasma triglyceride levels. The company intends to initiate a phase II study of DOV 21,947 for the treatment of depression in the fourth quarter of this year.
"Prior studies with DOV 21,947 at up to 100 mg per day demonstrated the safety and tolerability of this compound over dosing periods of up to ten days. The goal of this phase Ib study was to confirm DOV 21,947's safety and tolerability over an eight-week period at escalating doses of up to 150 mg per day. These data give us added confidence in the drug's safety and tolerability in preparation for our upcoming phase II trial in patients with major depressive disorder. The significant reductions in plasma triglyceride levels observed during the conduct of this study are consistent with preclinical evidence that DOV 21,947 is able to produce a significant and sustained reduction in both triglyceride levels and body weight in animal models of obesity. These findings underscore the therapeutic versatility of triple reuptake inhibitors such as DOV 21,947," said Dr Phil Skolnick, president and chief scientific officer of DOV.
This double-blind, placebo-controlled phase Ib study enrolled 46 male and female subjects. Following a one-week placebo run-in, subjects received either escalating daily doses of 50 mg, 100 mg and 150 mg of DOV 21,947 (31 subjects) or placebo (15 subjects), for a total of eight weeks. The study demonstrated that DOV 21,947 was safe and well-tolerated in this dose range with no reported serious adverse events. The proportion of patients with treatment emergent adverse events was similar in the two treatment groups, with 36 per cent and 47 per cent in the DOV 21,947 and the placebo treated group, respectively.
Reported adverse events with greater than 3 per cent incidence in both the DOV 21,947 and placebo treated arms included headache, nausea, diarrhoea and dizziness. No other reported adverse event with a greater than 5 per cent incidence was observed in the DOV 21,947 treated subjects. The incidence of subjects that dropped out of the study due to adverse events was 6.5 per cent and 13.3 per cent in the DOV 21,947 and placebo treated group, respectively.
In addition, preliminary analysis of the clinical chemistry laboratory data indicates that DOV 21,947 treated subjects had lowered plasma triglyceride levels compared to placebo treated subjects. This reduction in mean triglyceride levels was noted following two weeks of treatment (~23% reduction), was maintained at the end of the DOV 21,947 treatment period (~ 29% reduction) and was reversed after the one-week washout period at the end of the study. Although the exact mechanism is unclear, high triglyceride levels may contribute to hardening of the arteries (atherosclerosis) or thickening of the artery walls, which increases the risk of stroke, heart attack and heart disease. High triglyceride levels often accompany other conditions known to increase the risk of heart disease and stroke as well, including obesity and metabolic syndrome.
Eight Phase I studies have now been completed with DOV 21,947. The double-blind, Phase II study scheduled for initiation later this year will compare up to 100 mg per day of DOV 21,947 versus placebo in approximately 200 patients with major depressive disorder over a six-week treatment period. The company expects the results from this phase II study will be available in the fourth quarter of 2008.
DOV 21,947 is a TRIP that inhibits the reuptake of the neurotransmitters serotonin, norepinephrine and dopamine. A two-week trial with a 100 mg daily dose of DOV 216,303, the parent compound of DOV 21,947, produced a statistically significant reduction in Hamilton Depression Rating Scales in a Phase II clinical trial in patients with major depressive disorder. In animal models highly predictive of antidepressant action, DOV 21,947 was more potent than Tofranil, a serotonin and norepinephrine reuptake inhibitor and the selective serotonin reuptake inhibitors Prozac and Celexa. Because of its ability to inhibit the reuptake of the three neurotransmitters most closely linked to depression, DOV 21,947 may be more effective and have a more rapid onset than other antidepressants which inhibit the reuptake of one or two of these neurotransmitters. This novel combination of properties in a single molecule could provide a breakthrough in the treatment of depression. In addition, at doses similar to those active in models predictive of antidepressant action, DOV 21,947 produced a significant weight loss in two animal models of diet-induced obesity. Such models of diet-induced obesity are often used to predict the effectiveness of drugs to produce weight loss in obese individuals.