Overactive bladder is a common condition thought to. women, and is a serious condition that can lead to. significant lifestyle changes.

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1 Overactive bladder is a common condition thought to FADE UP TO WIDE SHOT OF FEMALE MODEL WITH TRANSPARENT SKIN. URINARY BLADDER VISIBLE IN PELVIC REGION affect over 16 percent of adults. It affects men and SLOW ZOOM IN TO CU ON BLADDER women, and is a serious condition that can lead to significant lifestyle changes. Unfortunately, approximately two thirds of people affected never discuss their symptoms with a physician and are never DISSOLVE TO CROSS SECTION OF BLADDER W treated even though a combination of behavioral techniques and drug therapy can provide highly effective treatment. Overactive bladder is caused by involuntary CUT AWAY PERITONEUM TO SHOW DETRUSOR MUSCLE AND FILL THE BLADDER WITH A SUBSTANTIAL AMOUNT OF URINE contractions of the detrusor muscle surrounding the urinary bladder. The detrusor muscle normally relaxes and contracts as the bladder fills and voids. The first sensation of an urge to urinate occurs when about 200 ml of urine is stored in the bladder. The average bladder stores from 350 to 500 ml of urine. In patients suffering from overactive bladder, the detrusor muscle contracts spontaneously, often with no obvious reason, causing urge incontinence. With urge incontinence, SHOW DETRUSOR CONTRACTING AND URINE FLOWS OUT SHOW BLADDER SLOWLY REFILLING AND INDICATE 200 ML AT APPROXIMATELY THE LOWER THIRD OF THE BLADDER. USE ANIMATED EFFECT TO REPRESENT SENSATION AS BLADDER APPROACHES FULL INDICATE ML DISSOLVE TO BLADDER WITH MINIMAL URINE. SHOW CONTRACTION OF DETRUSOR AND DROPS OF URINE FLOWING OUT OF URETHRA the contractions can cause leakage of urine and a strong desire to void even though pressure in the bladder is within normal range. 1

2 Overactive bladder can also manifest as stress SHOTS OF FEMALE MODELS LAUGHING, SNEEZING, DOING AEROBICS incontinence, where an increase in abdominal pressure from sneezing, laughing, or exercise causes an involuntary muscle contraction and leakage of urine from the bladder. Mixed incontinence is typically a 60% - 40% combination of stress incontinence and urge incontinence. The bladder is a musculomembranous sac composed of an inner urothelium, the lamina propria and a CLOSE UP OF CROSS SECTION OF BLADDER POP ON LABELS AS CALLED submucous coat surrounded by three layers of muscle comprising the detrusor. The fibers of the detrusor muscle at the sides of the bladder are arranged obliquely and intersect each other. FADE IN CUTAWAY SECTION TO FULL SHOT OF BLADDER THEN FADE DOWN OUTER LAYER TO SHOW CRISS-CROSSED MUSCLE PATTERN OF DETRUSOR The bladder is innervated by the sympathetic and parasympathetic fibers of the autonomic nervous SHOT OF BLADDER AND SPINAL CORD WITH NERVES TRAVELING TO THE BLADDER. POP ON LABELS AS CALLED system. The autonomic fibers innervating the bladder are carried through the pelvic splanchnic nerves and the hypograstric plexus along the body and base of the bladder. The somatic pudendal nerve supplies the external sphincter of the bladder. 2

3 Efferent fibers of the parasympathetic system provide the primary excitatory input to the bladder. Afferent neurons are located in the lamina propria and the smooth muscle of the detrusor. These sensory fibers are activated by smooth muscle cell contraction and bladder wall stretch. Impulses from the afferent neurons are HIGHLIGHT PARASYMPATHETIC FIBERS DISSOLVE TO CUTAWAY OF BLADDER HIGHLIGHT LAMINA PROPRIA HIGHLIGHT DETRUSOR SHOW DETRUSOR CONTRACT AND IMPULSES TRAVEL ALONG THE SPLANCHNIC NERVE TO THE SPINAL CORD conveyed by the pelvic splanchnic nerves to centers in the central nervous system. M2 and M3 muscarinic receptors are expressed in the smooth muscle of the bladder. While M2 CU OF SMOOTH MUSCLE TISSUE WITH M2 AND M3 RECEPTORS SCATTERED THROUGHOUT receptors outnumber M3 receptors by a three to one ratio, the M3 receptors are the primary mediators of detrusor contraction. The role of DISSOLVE TO CU M3 RECEPTOR CU M2 RECEPTOR M2 receptors is not currently known. 3

4 Acetylcholine released from postganglionic parasympathetic fibers binds to M3 receptors and causes the release of intracellular calcium which initiates contraction of the detrusor. With overactive CU PARASYMPATHETIC NERVE FIBER. SIGNAL TRAVELS DOWN FIBER AND ACETYLCHOLINE IS RELEASED. IT TRAVELS TO AND BINDS WITH RECEPTORS. SHOW CALCIUM PARTICLES RELEASED AND MULTIPLY IN MUSCLE MUSCLE CONTRACTS bladder, acetylcholine is released sporadically causing asynchronous contractions of the detrusor in different regions of the bladder wall. These contractions stretch and excite sensory axons leading to a buildup of stray DISSOLVE TO SHOT OF BLADDER WITH NERVE FIBERS. ANIMATE RANDOM FLASHES AROUND THE SURFACE TO INDICATE STIMULATION AND CONTRACT BLADDER WITH EACH FLASH. EACH CONTRACTION CAUSES URINE TO LEAK FROM THE URETHRA excitatory signals that can activate the micturition reflex. M2 and M3 receptors may also be present in the urothelium, but how they are activated and what role they play in the urothelium is not currently known. There are a number of other receptor subtypes, both pre and post junctional in the system as well, but the roles of these receptors is not completely understood. Treatment of overactive bladder by antimuscarinic drug therapy reduces contractions of the detrusor by blocking M3 receptors in the muscle. Acetytlcholine DISSOLVE TO CU OF MUSCLE LAYER. SHOW ANTIMUSCARINIC ANTAGONISTS BLOCKING M3 RECEPTORS, ACETYLCHOLINE BOUNCING AWAY FROM RECEPTORS AND FADING AWAY is unable to bind with the M3 receptors and is broken down by enzymes in the system. 4

5 Currently used antimuscarinic drugs are not receptor selective and blocking all five muscarinic receptors can lead to unwanted side effects. M1 receptors are DISSOLVE TO TRANSPARENT MODEL WITH BRAIN AND NERVOUS SYSTEM VISIBLE highly expressed in the brain and nervous system and blocking these receptors has been linked to neurobehavioral toxicity and cognitive dysfunction. M2 receptors are highly expressed in muscles of the ZOOM IN TO MS SHOWING TORSO DISSOLVE FROM NERVOUS SYSTEM TO HEART heart and blocking M2 receptors has been linked to tachycardia. Darifenacin is highly M3 receptor selective compared DISSOLVE TO FULL BODY SHOT AND ROTATE to other antimuscarinic drugs, delivering comparable efficacy with fewer potential side effects Since currently used antimuscarinics are not receptor CUT TO CU M1, M2 AND M3 RECEPTORS WITH ANTIMUSCARINIC MOLECULES ATTACHED or bladder selective, there is a need for pharmacotherapy targeted to M3 receptors in the bladder. 5

6 Darifenacin is a potent and selective antagonist of the M3 receptor, the subtype that primarily mediates DISSOLVE TO ECU MAGNIFIED VIEW OF M3 RECEPTOR WITH [PRODUCT] IN RECEPTOR. BLADDER IN BACKGROUND. bladder contraction. This selectivity is important because muscarinic receptors are found throughout the body. M1 receptors are highly expressed in the brain and nervous system and blocking the receptors has DISSOLVE TO SHOT OF MODEL WITH CNS AND HEART VISIBLE been linked to neurobehavioral toxicity and cognitive dysfunction. M2 receptors are highly expressed in the heart and blocking M2 receptors has been linked with tachycardia. In addition to the bladder, M3 receptors are expressed DISSOLVE TO SHOW GI TRACT AND SALIVARY GLANDS in the gastrointestinal tract and the salivary glands. Preclinical data demonstrate that darifenacin has functional selectivity for the bladder over the salivary gland and suggest that it has a lower incidence of side effects than non-selective muscarinics. 6

7 Anti-muscarinic drugs can penetrate the tight junction endothelial cells of the blood-brain barrier and block ZOOM IN TO BRAIN. FADE UP INSET SHOWING MAGNIFIED M1 RECEPTOR WITH ANTIMUSCARINIC ATTACHED M1 receptors in the brain. Blocking M1 receptors in the brain and nervous system can have serious implications and represents a risk with currently used muscarinics. Blocking M1 receptors has been linked SUPER LIST OF SYMPTOMS AS CALLED with learning difficulties, memory impairment, hallucinations and other cognitive dysfunction. Neurobehavioral effects of less selective overactive bladder therapy can occur in any age group, regardless of existing cognitive function. These side effects are often difficult to recognize by physicians or patients MS SHOT OF FEMALE PATIENT IN EXAMINATION ROOM WITH PHYSICIAN and present potentially serious safety consequences. Patients with significant M1 receptor blockage can function physically at a level equivalent to someone SHOT OF FEMALE MODEL LOSING BALANCE AND HAVING TO STEADY HERSELF. with a blood alcohol level of 1.0, compromising activities such as driving and other physical activity. 7

8 Darifenacin has a low affinity for M1 receptors and a high affinity for M3 receptors, especially in the CU M1 AND M3 RECEPTORS. [PRODUCT] ATTACHED TO M3 RECEPTOR AND BOUNCES OFF M1 RECEPTOR bladder. This represents a significant advantage in treating overactive bladder over a muscarinic drug with a high affinity for M1 receptors. M2 receptors in the heart muscle mediate the inotropic and chronotropic changes induced by parasympathetic nerve stimulation. Acetylcholine binds with M2 receptors in the heart muscle and slows the heart rate. DISSOLVE TO CU OF HEART, SCREEN LEFT, BEATING FADE UP M2 RECEPTOR SCREEN RIGHT. SHOW ACETYLCHOLINE BINDING TO RECEPTOR. HEARTBEAT SLOWS. Treatment of overactive bladder using muscarinic drugs with M2 receptor affinity can cause tachycardia and represent a risk for patients with heart conditions. Drugs with an M2 receptor sparing profile will have very little impact on heart rate. Darifenacin has a low affinity for M2 receptors and a high affinity for M3 receptors, especially in the DISSOLVE TO CU M2 AND M3 RECEPTORS. [PRODUCT] BINDS WITH M3 RECEPTORS BUT BOUNCES OFF M2 RECEPTOR bladder, which represents a significant advantage in treating overactive bladder over a muscarinic drug with a high affinity for M2 receptors. 8

9 Current muscarinic therapy lacks a receptor selective, bladder selective muscarinic agent that lessens CU M1, M2, M3 RECEPTORS. [PRODUCT] EASILY BINDS WITH M3 RECEPTORS BUT BOUNCES OFF M1 AND M2 RECEPTORS neurobehavioral and cardiac side effects. Darifenacin is the only M3 receptor selective antagonist and represents a significant advance in muscarinic therapy. Darifenacin spares M1 receptors in the brain, lessening the likelihood of central nervous system dysfunction, and spares M2 receptors in the heart, so it has little effect on heart rate. Preclinical data indicate that darifenacin also has a higher affinity DISSOLVE TO BODY SHOT OF MODEL HIGHLIGHT BRAIN HIGHLIGHT HEART HIGHLIGHT BLADDER for M3 receptors in the bladder than in the salivary glands. Darifenacin is the only M3 receptor selective antagonist that treats overactive bladder regardless of severity, eliminating or improving overactive bladder symptoms and reducing incontinence. A high affinity BACKGROUND MONTAGE OF IMAGES FROM PROGRAM. SUPER TITLES AS CALLED: EFFECTIVE IN ALL PHASES IMPROVES OR ELIMINATES SYMPTOMS IMPROVED SAFETY PROFILE for M3 receptors and sparing of M1 and M2 receptors gives darifenacin a safety profile that distinguishes it from other antimuscarinics and represents an important improvement in treating overactive bladder. FADE TO BLACK 9