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A matter of urgency

Better tolerated treatments are needed in overactive bladder and urinary incontinence
Police sirensOveractive bladder and urinary incontinence (UI), although rarely life-threatening, can damage self esteem and hamper an individual's ability to travel or work. It can also cost a great deal of time and money in laundry. Estimates put the number of people with these conditions  at up to 100 million people worldwide, and this number is set to rise as the population ages. As yet, no fully satisfactory treatments exist. With the market opening up all the time as people gain awareness of the diseases, the development of an effective drug with few side effects would be a major achievement for a pharma company.

The two conditions are similar but not identical. Overactive bladder is characterised by contractions in the detrusor muscle that lead to very frequent urination or the feeling of fullness and urge to pass water. It is accompanied by incontinence in about one in three patients.

Urinary incontinence, or the involuntary voiding of urine, is not always the result of overactive bladder. There are several types that can be caused by a range of dysfunctions of the lower urinary tract or damage to the mechanisms of urination.

The conditions can be consequences of pregnancy, weak pelvic floor muscles, drugs like alcohol or opioids, urinary tract infections, strokes or diseases such as Alzheimer's or Parkinson's. Although a patient of any age can be affected, they are strongly associated with ageing; Urigen Pharmaceuticals, a Vancouver-based company specialising in urological ailments, estimates that one in four women and one in ten men aged over 65 are affected. Stress urinary incontinence, where pressure on the bladder leads to leakage - such as when coughing or laughing - affects only women.

Treatment
About 80 per cent of people with these conditions are thought never to seek treatment, perhaps because of embarrassment or the belief that the symptoms are a natural consequence of ageing. There are non-pharmacological therapeutic routes - which include bladder retraining - and a range of drugs which are currently dominated by the anticholinergic class.

Many of those who do receive pharmaceutical treatment stop taking the drugs because of the high level of side effects. Given its prevalence and the number of patients who remain undiagnosed it is not surprising that the area is attracting much attention and investment from pharmaceutical companies.

Anticholinergics
Orally-dosed anticholinergic drugs are the most common pharmaceutical treatment for overactive bladder. They reduce bladder contractility by blocking muscarinic receptors at the detrusor muscle. However, none of these drugs is exclusively selective for the detrusor so they may cause side effects - such as constipation and dry mouth - which can force doses to be kept low. This can limit the drugs' effectiveness. Questions also remain about the strong placebo effect seen in clinical trials.

Of greater concern is a recent report linking the use of this class of drug to cognitive decline. Dr Jack W Tsao presented a study in April 2008 at the American Academy of Neurology annual meeting in Chicago, Illinois which showed a 1.5-fold faster rate of decline in elderly patients on anticholinergics than those who were not. The deterioration was seen in patients both with and without dementia.

Detrusitol
Oxybutynin is the most often prescribed of the anticholinergics, as it is widely available as a generic and is relatively cheap. However, the big hitter is Pfizer's Detrusitol (tolterodine), approved in the EU in October 1997. It captures up to half of all new overactive bladder patient prescriptions, and $1.2 billion in worldwide sales in 2007 made it the company's seventh best-selling drug, far below the cholesterol drug Lipitor but on a par with blockbusters like Viagra and Zyrtec. It has the weight of the world's largest pharmaceutical company behind it, a strong clinical profile for an anticholinergic and it appears better tolerated than the alternatives. About 40 per cent of patients on sanofi-aventis's long-acting oxybutynin formulation, Ditropan XL, report dry mouth compared to just under a quarter on Pfizer's drug, even though Ditropan may be marginally more effective.

Vesicare
Detrusitol is well established both in Europe and the US. It will go off patent in 2012, but until that time it faces competition from the newer anticholinergics such as Astellas Pharma's Vesicare (solifenacin), an M3 muscarinic receptor antagonist that has been shown to be much better at cutting back urge incontinence episodes. In a phase III trial, episodes of urge incontinence dropped by 62 per cent on once-daily 10 mg Vesicare compared to 47 per cent on a 2 mg twice-daily dose of Detrusitol and 29 per cent on placebo. 

Toviaz
However, Pfizer will not give up its dominance of the market easily. It bought the anticholinergic, Toviaz (fesoterodine) for over $100 million in April 2006 from German company Schwarz Pharma. One of the newest entrants in the EU market, Toviaz is a muscarinic antagonist that was superior in phase III trials to Ditropan with a lower frequency of constipation or blurred vision. It reduced the number of times patients needed to urinate in 24 hours from 12, on placebo, to 10.

SVT-40776
A promising early-stage drug is SVT-40776, a selective M3 antimuscarinic under development by the Barcelona-based pharmaceutical group, Salvat. The drug has produced impressive results in pharmacokinetic studies, appearing highly selective and with a low propensity for dry mouth and no cardiac side effects. It is in phase II trials, and Salvat believes it will be the first of a new generation of compounds developed for urinary incontinence caused by overactive bladder.

Alternative routes of delivery
Many of the side effects of anticholinergics could be lessened by avoiding the oral delivery route, with the subsequent gastric and hepatic metabolism, that leads to dry mouth and constipation.

Gel formulations
Several companies' pipelines contain gel formulations of oxybutynin for topical application. One such is Antares Pharma's Anturol, shown in phase II studies to lead to only minimal dry mouth. Watson Pharmaceuticals also has a gel formulation in its pipeline, which looks set to be first to market in 2009. In January this year, Watson reported phase III results showing that the drug had a 6.9 per cent dry mouth rate, compared to the 40 per cent rate seen with oral formulations.

Other options
Other routes for oxybutynin delivery include vaginal rings or transmucosal sprays.
Dynogen, a Massachusetts-based company, is attempting to lessen the side effects through the development of a combination, which enables lower dosing. DDP-200, a fixed-dose oral combination of oxybutynin and gabapentin for overactive bladder, is in phase I trials. Its two components have shown synergy in animal tests.

New modes of action
Yentreve
Yet another path for developers is a drug with a different mode of action. In Europe, one of the most established is Boehringer Ingelheim's Yentreve (duloxetine), a dual serotonin and norepinephrine reuptake inhibitor that is also approved for depression and works at the spinal cord level rather than the bladder level. However, while this drug was approved in Europe for incontinence, it failed to make it past the FDA in the US, for undisclosed reasons. It can also cause  the same dry mouth side effect as the anticholinergics.

The NK-1 antagonists
One of the most encouraging new directions for the future of overactive bladder and incontinence treatment lies in blocking the action of tachykinins, specifically through the NK-1 receptor. Tachykinins, first identified in 1931, have multiple roles in the central nervous system. The tachykinin substance P is an antagonist of NK-1 and is involved in the urination reflex, which suggests that NK-1 may be useful for urge incontinence. Anticholinergic drugs act on efferent nerves to counteract overactive bladder after it occurs, but  NK-1 antagonists work on the afferent nerves that modulate bladder contraction. This means they have no risk of urinary retention and a much better side effect profile. The NK-1 antagonists include sanofi-aventis's SSR-240600 and Mitsubishi Tanabe Pharma's TA-5538, both in phase II studies.

Botox
The use of Botox (botulinum toxin) to induce paralysis of the bladder muscles is also proving remarkably effective for overactive bladder. A phase III study carried out by Guy's Hospital and Kings College London showed that bladder capacity was increased by 72 per cent four weeks after injection of botulinum into the detrusor, compared to 15 per cent on placebo. At 12 weeks, these rates were 45 per cent and 15 per cent respectively. If too much is used, however, it may lead to voiding difficulties and NICE has stated that the risks of Botox treatment are too high for general use. It therefore looks unlikely to become a mainstay of treatment.

Future prospects
Whether the future lies in the discovery of an extraordinarily selective antimuscarinic, an entirely new mechanism or an effective topical gel, the overactive bladder and incontinence therapy areas represent an untapped market that will expand dramatically worldwide. Patient education would help those with these disorders overcome debilitating social stigma and seek treatment.

The Author
Lisa Murch
is a drug information editor at Thomson Reuters

To comment on this feature please email pme@pmlive.com

3rd July 2008

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