Urge Urinary Incontinence (Overactive Bladder)
Urge urinary incontinence (UUI) and the associated syndrome of “overactive bladder” (OAB) is characterised by an unpredictable, frequent and sudden need to urinate. Non-malignant enlargement of the prostate (“benign prostatic hyperplasia”) can give rise to OAB-like symptoms in men.
Treatment may involve lifestyle changes, such as smoking cessation, food and fluid regulation, bladder training or pharmacological options. Antimuscarinic drugs are widely used for the treatment of UUI in women, and have combined annual global sales in excess of $1 billion. Although often effective, treatment compliance is compromised due to a high incidence of side effects including “dry mouth” and constipation experienced by more than 30% of patients.
OAB is more commonly diagnosed in older adults, and the control of its symptoms is often a significant factor in the institutionalisation of the elderly.
Quality of life is compromised significantly because patients may not be able to work, are less likely to leave their homes and may therefore become isolated, and are likely to suffer anxiety and other psychological problems.
The estimated female moderate to severe UUI treatment population in North America and Western Europe is over 6 million women. A further 10 million women suffer from moderate to severe mixed incontinence (SUI+UUI). More than 38 million men between the ages of 40 and 80 will experience moderate to severe OAB-like symptoms.
Antimuscarinic agents are the accepted pharmacological approach to OAB. The established antimuscarinic drugs for OAB, such as tolterodine and oxybutynin currently have joint global annual sales exceeding US$1 billion.
Low tolerance to these drugs has been frequently reported because they are often associated with xerostomia (dry mouth), and high discontinuation rates have been documented.
Recent introduction of revised formulations of antimuscarinic agents has sought to improve dosing regimens and reduce side-effects, thus improving compliance with therapy, but with limited success. There is still significant unmet need for the pharmacological treatment of OAB.
Plethora is developing PSD506, a selective antimuscarinic agent that should have an improved side effect profile.
PSD506 has completed successful preclinical and early clinical development by Hoffman-La Roche. Data from these studies indicate that PSD506 has a good pharmacokinetic profile and is more selective for muscarinic receptors in the bladder than those in other tissues (such as salivary glands). It is anticipated that the incidence of side effects should be reduced in patients treated with PSD506 and patient compliance improved. There was only one case of dry mouth experienced in the Phase I clinical studies that involved more than 170 healthy volunteers.
Preliminary analysis of the results of a dose escalation study from patients with unstable bladder contractions demonstrated that PSD506, is effective at doses equal to or greater than 20mg. Importantly there were no reports of dry mouth.