PRECLINICAL DEVELOPMENT
We have three compounds currently in preclinical development for the
treatment of central nervous system disorders. The first, DOV 22,047, is
believed to act at a specific GABA(A) receptor subtype and is under development
for the treatment of panic disorder. The second compound, DOV 21,947 and is a
triple uptake inhibitor under development to treat depression. The third
compound, DOV 102,677, is a selective dopamine uptake inhibitor that may be used
in the treatment of attention deficit disorder and Parkinson's disease.
CARDIOVASCULAR DISORDERS
DOV DILTIAZEM. DOV diltiazem, our proprietary formulation of diltiazem, is
our product candidate for the treatment of angina and hypertension. Diltiazem
belongs to a well-known class of drugs called calcium channel blockers. DOV
diltiazem combines an immediate release component with
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an extended release component in order to provide improved blood levels
throughout the day compared to currently marketed diltiazem products.
Chronic stable angina, or angina pectoris, refers to recurring severe
constricting pain in the chest due to inadequate blood supply to the heart
caused by heart disease. Angina attacks are more likely to occur during the
morning and afternoon hours. Likewise, hypertension is greater in the morning
hours. According to 1999 practice guidelines published by the American College
of Cardiology/American Heart Association/American College of Physicians-American
Society of Internal Medicine, chronic stable angina was estimated to have
affected over 16.5 million people in the United States. According to Decision
Resources, high blood pressure or hypertension was estimated to affect over
50 million people in the United States in 1999.
Calcium channel blockers remain the standard-of-care for treatment of
chronic stable angina and hypertension and continue to be highly endorsed by the
medical community. Although comparative studies have demonstrated equivalent
anti-angina effects for many marketed calcium channel blockers, a lower
incidence of side effects with diltiazem was often reported in these studies.
According to IMS figures for 2000, total sales of diltiazem in the United States
were $981 million.
In an effort to provide both therapeutic blood levels of diltiazem for
longer periods of time and improved patient compliance, several slow or extended
release preparations of diltiazem have been developed for the treatment of
hypertension and chronic stable angina. However, these commercially available,
once-daily, extended release formulations produce only a partial reduction of
chronic stable angina. According to published studies, currently marketed
diltiazem products such as Tiazac, Cardizem CD and Dilacor XR only reduce the
number of angina attacks by approximately 50% - 60% when given at FDA-approved
therapeutic doses. We believe incomplete reduction in angina demonstrated by
current treatments may be the result of inadequate blood levels of the drug in
the morning hours, when approximately half of angina attacks occur. Experts in
chronic stable angina have confirmed their dissatisfaction with the ability of
current extended release products to adequately treat many of their patients on
a once-a-day basis.
We believe that DOV diltiazem will reduce morning angina attacks to a
significantly greater extent than commercially available products because of its
combination of immediate and extended release components. Data from three Phase
I trials indicate that our formulation produced clinically relevant blood levels
within 30 minutes of administration and resulted in higher blood levels in the
morning than Tiazac. We plan to begin a Phase III clinical trial by the end of
2002 comparing our formulation to placebo and a currently marketed diltiazem
formulation.
UROLOGICAL DISORDERS
We are evaluating bicifadine and DOV 102,177, a structurally related
molecule, in preclinical studies for stress incontinence. Urine leakage that
occurs during exercise, coughing, laughing or lifting is referred to as stress
incontinence. This condition results from a weakness or anatomical defect in the
lower urinary tract, often as a result of childbirth, weight gain or surgery.
The Simon Foundation for Continence reports that approximately 200 million
people worldwide are affected by urinary incontinence and that approximately
65 million women worldwide are affected by stress incontinence. While not life
threatening, stress incontinence has a significant impact on quality of life,
particularly in the aging female population. At present, there are no approved
drug therapies specifically for stress incontinence.
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The function of the lower urinary tract is controlled by muscles that are,
in turn, controlled by nerves throughout the body. Several neurotransmitters,
including serotonin, norepinephrine and glutamate, are thought to play key roles
in regulating the storage and release of urine via their actions on the brain.
We believe the neurochemical profile of bicifadine, with its unique ability to
increase synaptic levels of norepinephrine and serotonin, as well as to block
glutamate transmission through a specific subtype of glutamate receptor, makes
it a potential candidate for use in the treatment of stress incontinence.
Bicifadine is active in a preclinical model used to assess the potential
effectiveness of drugs for the treatment of stress incontinence. |
