Eli Lilly's Duloxetine set to become the first widely used therapeutic treatment of stress urinary incontinence

DailyUpdates 7th April: A recent survey of community-dwelling women in France, Germany, Spain and the UK found that 35% women suffer urinary incontinence, the most prevalent form of which was stress urinary incontinence. The findings also revealed that two-thirds of women affected with urinary incontinence never consulted a health care professional for treatment.  The perceived and real lack of pharmaceutical options for the treatment of stress urinary incontinence is a major factor contributing to women ignoring this troublesome condition however Eli Lilly's duloxetine is set to address this unmet need.

A recent survey of community-dwelling women in France, Germany, Spain and the UK found that 35% women suffer urinary incontinence. Thirty-seven percent of these incontinent women reported having stress incontinence, the most prevalent form of urinary incontinence. The findings also revealed that two-thirds of women affected with urinary incontinence never consulted a health care professional for treatment.

Primary causes of stress incontinence are nerve damage, muscle damage or weakness, and damage to the support of the bladder and urethra. Risk factors include childbirth, obesity, chronic coughing and constipation.

Despite the frequency of stress incontinence there has until recently been no widely accepted pharmaceutical treatment of this condition and instead presently available treatment options include behavioral therapy, pelvic floor muscle training and surgery.  Eli Lilly's Duloxetine is set to address this unmet need (click here for an analysis of emerging treatments for urinary incontinence).

Duloxetine is a balanced potent dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine which is believed to affect stress incontinence by blocking the reuptake of serotonin and norepinephrine in the spinal cord.  The increase in the neurotransmitters in turn stimulates increased activity of the nerve that stimulates the urethral sphincter. This stimulation is thought to increase contraction of the urethral sphincter at the opening of the bladder, thereby helping prevent accidental urine leakage with physical activity.

Duloxetine has recently been evaluated in three phase III studies.  In the March edition of the journal BJOG, van Kerrebroeck from the Duloxetine Urinary Incontinence Study Group compared duloxetine to placebo in the treatment of European and Canadian women with stress urinary incontinence.  This randomised double-blind, placebo-controlled clinical trial assessed the efficacy and safety of duloxetine in women with stress urinary incontinence. Conducted across 46 centers in seven European countries and Canada, the efficacy and safety of duloxetine were evaluated in 494 women aged 24-83 years identified as having predominant symptoms of stress urinary incontinence.  After a two-week placebo lead-in, women received placebo or duloxetine 40 mg BD for 12 weeks.   The percentage decrease in incontinence episode frequency and the change in the Incontinence Quality of Life (I-QOL) questionnaire total score were prespecified as co-primary outcome variables in the protocol.   Incontinence episode frequency decreased significantly with duloxetine compared with placebo (median decrease of 50% vs 29%) and this efficacy was apparently independent of the severity of incontinence. In women that did not withdraw from the study due to adverse events, I-QOL scores was significantly greater for duloxetine than for placebo at each of the three postrandomisation visits after 4, 8, and 12 weeks of treatment. Discontinuation rates for adverse events were higher for duloxetine (22% vs 5%) with nausea being the most common reason for discontinuation (5.3%). Nausea tended to be mild to moderate, not progressive, and transient.

This study supports the findings of both a North American and a global Phase III clinical trial of duloxetine.  The North American trial was conducted in 683 women.  The global study was conducted in 38 study centers, randomized 458 women from seven countries: Argentina, Australia, Brazil, Finland, Poland, South Africa and Spain. This studies published in January and February showed that patients treated with 80 mg of duloxetine experienced a median reduction of 50-54% in the frequency of incontinence episodes, a primary measure of efficacy, compared to a median reduction of 27-40% in the placebo group.

The findings of these studies support duloxetine as a potential treatment for women with stress urinary incontinence.  As a result of data from a total of 10 studies enrolling a total of more than 2,000 women, Eli Lilly and Boehringer Ingelheim announced on March 25th that the European Committee for Proprietary Medicinal Products (CPMP) issued a positive opinion for duloxetine for the treatment of moderate to severe stress urinary incontinence in women. The CPMP recommended to the European Commission that authorisation to market the drug be granted. If approved, this pharmaceutical treatment for stress urinary incontinence will be marketed throughout the European Union by Lilly under the brand name Yentreve(R) and by Boehringer Ingelheim under the brand names Yentreve(R) and Ariclaim(R). Marketing authorization by the European Commission can be expected later this year. The US FDA has also recently issued an approvable letter for duloxetine for stress urinary incontinence.

Duloxetine could be marketed as early as the second half of 2004 in the European Union, and in the first half of 2005 in the United States. Analysts predict that sales of Duloxetine should reach $1 billion by 2008.

Source DailyUpdates 7th April; for a full abstract of the original papers see   BJOG. 2004 Mar;111(3):249-257; J Urol. 2003 Oct;170(4 Pt 1):1259-63; BJU Int. 2004 Feb;93(3):311-8

Recommended further reading:

• Urinary Incontinence: Market Update - Growing Market Brings Opportunities for New Drugs

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