New data published on KW-7158, a novel treatment of overactive bladder

New data published on KW-7158, a novel treatment of overactive bladder   DailyUpdates 29th March: Overactive bladder, a condition associated with a variety of other pathologies affects over 17 million Americans and costs the US over $12 billion per year.  Current treatments focus on the muscarinic receptor antagonists such as tolterodine and oxybutanin with further examples from this class expected on the market.  Therapeutics from novel pharmacological classes are expected to offer further improvements and in an upcoming edition of the Journal of Pharmacology & Experimental Therapeutics University of Pittsburgh researchers report on one novel therapeutic, KW-7158.   Overactive bladder, a condition associated with a variety of other pathologies affects over 17 million Americans and costs the US over $12 billion per year.  In 1998 Pharmacia & Upjohn's (now Pfizer) received FDA approval for the use of Detrol (tolterodine tartrate) for the treatment of this patient group.

The muscarinic receptor antagonist tolterodine was the first new medication approved for treatment of overactive bladder in more than 20 years.  Pfizer’s aggressive marketing activity stimulated sales of Detrol (tolterodine) and also successfully raised wider awareness of urinary incontinence. The market for agents to treat urinary incontinence (which includes overactive bladder) totalled nearly $722 million in 2000. With treatments for urinary incontinence suffering from poor side-effect profiles, and sometimes poor efficacy, there is still considerable unmet need in the market. Improved diagnosis, better patient compliance, and the emergence of a broader choice of drug therapies is expected to boost the market for urinary incontinence therapies, allowing it to reach nearly $2 billion by 2010.

Two further muscarinic receptor antagonists are expected to be launched for the treatment of overactive bladder in 2004, Vesicare, which will be co-marketed by GlaxoSmithKline and Yamanouchi; and Novartis'  Enablex. Vesicare is expected to prove more popular than Enablex, backed up by favorable results from a head-to-head study with Detrol. It is expected that sales of Vesicare will surge to $971m by 2011 while Enablex will reach $743m  (for a full analysis of the urinary incontinence field click here).

Therapeutics from new pharmacologic classes are expected and include KW-7158, originally developed by Kyowa Hakko. In 2000, Lu et al, reported the effects of KW-7158 in a model of bladder hyper-reflexia.  The interval between large amplitude spontaneous bladder contractions induced by distending the bladder was increased by KW-7158.  After xylene-irritation, which decreased distension volume threshold and intercontraction interval and induced small amplitude bladder contractions, KW-7158 increased volume threshold and intercontraction interval and decreased the number of small amplitude bladder contractions. Vesico-vascular reflexes were suppressed in this model of bladder hyper-reflexia by KW-7158. KW-7158 was therefore proposed to act uniquely on the peripheral sensory nerves to control bladder activities. KW-7158 is expected to have reduced side effects compared with anticholinergic drugs which are well known to produce side effects such as dry mouth, urinary retention, blurred vision and more.

In a further more recent study, the University of Pittsburgh group lead by Dr William de Groat, report that KW-7158 increased transient, A-type K(+) currents and shortened the action potential duration in DRG neurons. In their upcoming Journal of Pharmacology & Experimental Therapeutics article,  the authors suggest therefore that the therapeutic effects of KW-7158 in overactive bladder may be due to the activation of A-type K(+) channels which regulate afferent neuron excitability and firing properties.

(source DailyUpdates 29th March; for a full abstract of the original papers see   J Pharmacol Exp Ther. 2004 Mar 9 [Epub ahead of print] and Brain Res. 2002 Aug 9;946(1):72-8.; for further information on urinary incontinence see Urinary Incontinence: Market Update - Growing Market Brings Opportunities for New Drugs - for information on ion channel modulators go to Ion Channel Assays in the Drug Discovery Process)

In this edition of DailyUpdates, LeadDiscovery also highlights data describing the vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125...the development of antagonists of the human CCR5 receptor...a potent small molecule mimetics of plasminogen kringle 5 which inhibits angiogenesis...and much more.