The speed in the race for the incontinence market picks up

Much data has been published on the prevalence of urinary incontinence (UI) and its cost to society. Different sources quote different figures, but even taking the World Health Organization's (WHO) conservative estimates that world-wide direct and indirect costs of urinary incontinence exceed $16 billion annually and assuming that it affects about 50 million people in the major pharmaceutical markets (U.S., Top 5 Europe and Japan) it becomes clear that it is a widespread condition with severe economic and psychosocial impact.

According to HBS Consulting analysis of published data on prevalence rates and figures, it can be stated that around 7.5 percent of the total population in any European country suffer from some form of UI. UI displays a high prevalence among adult women, mostly in the form of stress, urge or mixed incontinence. Unlike the common assumption that incontinence is a disease of the elderly, it can occur at any age. Around 15 percent of the female population aged 15 or older is suffering from UI, and the age group 15 to 45 represents over a quarter of incontinent women. There is a simple explanation – one of the most common causes of Stress Urinary Incontinence is pregnancy and vaginal delivery. There are plenty other risk factors, most of which are not directly age related, but the chances to contract a lower urinary tract infection, interstitial cystitis or atrophic vaginitis, to experience apoplexy or to be prescribed medication causing increased bladder irritability – all possible causes of Urge Incontinence - increase with advancing age.

Major contributors to the economical impact are care for incontinent persons in nursing homes and the use of incontinence aids; only a fraction is currently accounted for by the treatment of this disease. The psychosocial impact of UI encompasses embarrassment, severe restrictions in activities and sexual difficulties and does not correlate strongly with the degree of leakage, type of incontinence or age of the sufferer. Thus, virtually every sufferer may be regarded as a potential patient.

Still, only a minority of incontinent women consult a doctor because of the disorder. The main reasons for not seeking help, delaying or refraining from consulting are embarrassment, fear of surgery or that they consider the symptoms to be too insignificant. In particular, older women tend to view UI as an inevitable manifestation of old age. Instead of seeking treatment, the majority resort to wearing incontinence aids (e.g. pads and pants) in order to manage their condition. However, the nihilistic belief that nothing can be done is about to be overcome as the race for the lucrative market of new and existing UI therapy options picks up.

The chart below provides an overview of the most important milestones in the development of therapeutic tools for the management of female incontinence in general practice.

Milestones in UI Treatment

In 1948 Arnold Kegel described pelvic floor exercises as a treatment option in stress incontinence. This has resulted in the development of a number of devices such as perineometers and vaginal cones, which have become established as freely available adjunctive therapy aids. Bladder drill was found to be more effective in urge incontinence.

In the 1950’s, Propantheline, a pure anticholinergic inhibiting parasympathetic, cholinergically mediated bladder contractions, was developed. It was widely used in urinary incontinence, but had a low response rate and a high incidence of side-effects.

Biofeedback and electrostimulation devices were developed in the 60’s. While biofeedback simply raises muscle awareness during exercises, electrical stimulation of the pelvic floor is an effective alternative to PFE in the therapy of both stress and urge incontinence.

Trospium, a bladder-selective muscarinic receptor antagonist with anticholinergic properties, was developed in the late 60s by Dr. Pfleger and Madaus in Germany for the treatment of detrusor instability or hyperreflexia with the symptoms of pollakiuria, imperative urinary urge and urge incontinence. While it was well accepted in Germany, the limited geographic reach and marketing power of the suppliers hindered international marketing until 1999, since when it has been marketed in over 18 countries globally.

Flavoxate, a direct-acting smooth muscle depressant with antispasmodic activity marketed as Genurin®/Urispas® since the early 1970’s in over 60 countries worldwide, is specifically indicated for the symptomatic treatment of pollakiuria, imperative urinary urge and urge incontinence.

The first major commercial and clinical breakthrough in pharmacological treatment of UI was achieved with the introduction of Oxybutynin, a direct smooth muscle relaxant combining anticholinergic and antispasmodic properties. It was first launched as Ditropan by Marion Merrell Dow in 1975 in the US and over the following years in many countries globally. Ditropan is indicated for the relief of symptoms of bladder instability associated with voiding in patients with uninhibited neurogenic or reflex neurogenic bladder, such as urinary frequency, urgency and incontinence and nocturnal enuresis and quickly became the most widely prescribed drug for urinary incontinence.

Subsequent to the introduction of Trospium and Flavoxate and prior to the launch of Oxybutynin, the majority of prevalence studies on urinary incontinence have been conducted in the 1970's in Europe. Around this time the pharma industry began to realise the potential of the UI treatment market. But it should still take the best part of the rest of the century until the launch of the first real ‘blockbuster’ drug for UI.

Propiverine, an anticholinergic with combined calcium antagonist and antimuscarinic action, has been used in Germany for years as an urospasmolytic agent and was licensed in the UK in 1998 for the treatment of urinary (stress and urge) incontinence, as well as urgency and frequency in unstable bladder conditions. Similar to Trospium it did not manage to achieve significant global market penetration.

Although historically characterized by low patient presentation, the UI market has recently seen an influx of new patients thanks to increasing public and clinician awareness of the condition. Anticholinergics will continue their dominance of the UI market bolstered by the emergence of newer-generation agents with improved side-effect profiles and less-frequent dosing schedules. Novel agents will help expand the UI market by addressing UI subtypes that are currently not treated pharmacologically. Considerable unmet need exists for more effective, targeted, well-tolerated therapies to treat this indication.

In June 2000, Sanofi-Synthelabo, European marketer of Ditropan, an immediate-release oral formulation of oxybutynin, has received licenses from the UK Medicines Control Agency granting authorisation to market three dosage strengths of Ditropan® XL (oxybutynin chloride) - the first once-daily treatment for urinary urge incontinence in Europe - in the United Kingdom, which will serve as the reference member state for mutual recognition procedures in the European Union. Ditropan XL was introduced by Alza Corporation in the United States in February 1999 and had quickly captured 24 percent of the market for overactive bladder treatments. However, the acquisition of Alza Corporation, by Johnson & Johnson and subsequent changes in licensing agreements with Sanofi are expected to cause delays in the launch of Ditropan XL in Germany and Italy, which will decrease its market chances against the sustained release version of Detrusitol, a drug marketed by Pharmacia.

Since its launch in 1998, Pharmacia has transformed Detrol from a small niche product into a major growth-driving treatment. This has been achieved through its global reach and through physician and patient education programs. Pharmacia has effectively pioneered the development of the Overactive Bladder market. Pharmacia further advanced the leadership position of Detrol in 2001 with the launch of a sustained release formulation. Patients and physicians swiftly accepted this new treatment, resulting in a 50 percent increase in US sales of the Detrol family in 2001. The once-daily formulation has also been launched under various brand names in several European countries, including the United Kingdom (Detrusitol XL) and Germany (Detrusitol® retard), where it was equally well accepted. Detrusitol retard will soon be launched in Italy.

The advent of emerging treatments for Urinary Incontinence and Overactive Bladder symptoms is expected to significantly increase the size of the market. It is not expected that new drug developments will only substitute current products. Most notably in the short term in this context will be Darifenacin by Pfizer and Duloxetine by Eli Lilly.

Although there are drugs available to treat symptoms of UI, studies of GPs' management of the condition indicate that available therapeutic tools are not used to their full potential. Medical device technology has developed sufficiently over the last decade to suggest that the use of drugs to treat UI may become a secondary option in therapy. The expected opportunities in this market have attracted a number of new market entrants.

InterStim® Therapy, developed by Medtronic, Inc., has been commercially used in Europe since 1994

Neotonus, Inc. (USA) began manufacturing and marketing devices using its Extracorporeal Magnetic Innervation (ExMI) technology in September 1998 for the treatment and management of urinary incontinence.

Stoller Afferent Nerve Stimulation (SANS) technology was conceived by Marshall Stoller, M.D., a professor of urology from the University of California/San Francisco and further developed and investigated in collaboration with UroSurge Corporation. In February 2000.

While pharmaceutical manufacturers seem to display little fear that device technology will impinge on their revenues within this segment of the pharmaceutical market, they would be well advised to keep a watchful eye on the developments within the devices sector.