Ascentx Medical

U125 Injectable Bulking Agent for Stress Urinary Incontinence

Stress Urinary Incontinence (SUI) is a major ubiquitous health problem and the most common form of urinary incontinence (75%). SUI is often associated with childbearing and weakening of the pelvic floor muscles that support the bladder and can be defined as a brief involuntary loss of urine due to increase of abdominal pressure in the absence of detrusor activity. The primary symptom of SUI is urine 'leakage' during physical activities such as coughing, laughing, sneezing, lifting, or exercise. An estimated 85% of all patients with SUI are women with a prevalence of SUI in the U.S. ranging from 26% to 31% for all women (1 in 3 women). The highest incidence in women occurs between 40 to 60 years of age, representing 30 million and 13 million American women, respectively. More specifically, the prevalence of severe SUI, defined as large amounts of urine leakage weekly, affects approximately 29% of women aged 25 to 44 years, 33% of women 45 to 60 years, and 86% of women over age 60 years.

Historically, patients have been divided into 2 groups: Those with urethral hypermobility and those with intrinsic sphincteric deficiency (ISD). ISD, a term defined in 1992, is used to describe damage to the urethral sphincteric mechanism, regardless of etiology. The urethra might be damaged owing to fixation (as in cases of spina bifida), prior surgery, or denervation or muscle damage during childbirth. ISD and hypermobility can exist concomitantly, as well as isolated. Approximately 10% to 15% (3-4 million) of women with SUI suffer from 'ISD'. These figures are expected to continue to change, as the understanding of the process and diagnostic acumen improve and baby boomers continue to age.

Urinary incontinence not only causes skin irritation and break-down, but more importantly social isolation, disability, depression and dependency. Because of the significant burden of care incontinence puts on family members, it is the second most common reason elderly people are admitted to nursing homes. Urinary Incontinence represents a staggering $30 billion economic burden on U.S. society annually.

Studies show that women in general believe Urinary Incontinence is their #1 most embarrassing health issue. As a result, patients and their physicians are often reluctant to discuss the subject of SUI during office visits, and for this reason the condition remains largely underreported, undiagnosed, and consequently untreated. Melville et al. (2005) reported that only 47% of women with SUI actually consulted a physician about their symptoms.

The most common treatment option remain absorbent products such as pads and adult diapers (e.g. Depends^®), a >$5 billion /year industry in the U.S. alone-- now exceeding the infant diaper market. The adult diaper/pad market is projected to grow at a rate of 25% per year, indicating the severity of this medical condition. With a continuing and accelerating geriatric population growth rate, it is anticipated that the Urinary Incontinence market will grow respectively.

Current treatment options for SUI beyond the use of absorbent products include behavioral or muscle therapy, medication, non-surgical medical devices including Urinary Bulking Agents (UBAs) and more invasive procedures such as slings and vaginal tapes, as well as surgical procedures such as the Burch retropubic suspension.⁽³⁾ An estimated 260,000 'sling procedures' are performed annually in the U.S. with a reported 20-30% long-term failure rate. We believe this presents an opportunity for improved UBAs as an alternative treatment option. 'Urethral bulking' with UBAs is a low-risk, 30-minute outpatient procedure providing the main advantage of proven safety, even in very ill and fragile elderly patients.

The first-line treatment for SUI commonly is pelvic floor muscle exercise (Kegel). Medication and electro-stimulation are usually reserved for an overactive bladder (urge incontinence). Because SUI is largely a structural, sphincter-related problem, 'tissue bulking' has proven to provide significant relief for those patients. Bulking procedures are designed to treat SUI due to ISD by artificially inflating the submucosal tissues of the bladder neck and creating a 'mucosal plug'. 'Bulking up' the bladder neck with a 'bulking agent' effectively closes the lumen of the urethra, which improves urethral coaptation and restores the 'mucosal seal mechanism' of continence. 'Bulking procedures' are minimally invasive outpatient procedures and are extremely useful for treating women with SUI, who wish to avoid more invasive surgical procedures.⁽³⁾

Severity Grades of Urinary Incontinence

A commonly used method to evaluate the level of continence was first described by Stamey in 1979. The Stamey Scale has since been used in various clinical studies related to SUI to determine the efficacy of new treatment options. Effectiveness evaluation is usually based on improvement on the Stamey Urinary Incontinence Scale (Stamey Grade), where the primary effectiveness as compared to a control is measured by at least a one-grade improvement at 12 months after initial treatment over the baseline measurement.

The grades within the Stamey Urinary Incontinence Scale are defined as:

Grade 0:	Continent (dry)
Grade 1:	Urine leakage is associated with vigorous activities such as lifting weights, coughing or sneezing, but never in bed at night.
Grade 2:	Urine leakage is associated with activities of minimal stress, such as walking or standing up.
Grade 3:	Urine leakage occurs at all times regardless of activity or position.

 

SUI due to 'Intrinsic Sphincter Deficiency' (ISD): Indication for Urinary Sphincter Bulking Agents

ISD is defined as a weakening of the urethra and is characterized by the inability to stop the involuntary flow of urine in situations of increased intra-abdominal pressure, such as laughing, coughing, sneezing, or physical exercise. It is often diagnosed by urodynamics with a Valsalva leak point pressure (VLPP) of less than 90 mmHg. UBAs are injectable materials used as minimally invasive procedures to treat ISD by increasing the urethral closure pressure, aiming to increase resistance to urinary flow. UBAs are composed of either biologic (collagen, autologous fat) or synthetic materials (silicone particles, carbon beads, calcium derivatives, PMMA microspheres). Since the human body absorbs any strictly biologic agents over time, re-injections are usually required to maintain long-term benefits. Synthetic agents less likely require re-injection, therefore improving long-term efficacy. With the introduction of mid-urethral sling procedures, the number of UBA procedures declined from 1998 to 2005, and has since stabilized and risen slightly. Using publicly available 2008 Medicare procedure data as a basis for estimation, approximately 42,000 total UBA procedures are performed annually in the U.S. It is estimated that the total number of UBA procedures is 2-3 times as high, considering all non-Medicare procedures.

Urinary Bulking Agents (UBAs)⁽³⁾

Urinary 'bulking procedures' are minimally invasive outpatient injection treatments and are extremely useful for treating women with stress urinary incontinence who wish to avoid surgical procedures for various reasons. Methods used to bulk up the female urethra include transurethral and periurethral injection techniques. The delivery techniques for the male urethra include transurethral and antegrade injection.

Injection therapy using bulking agents composed of synthetic materials, bovine collagen (discontinued), or an autologous substance such as fat, augments the urethral wall and increases urethral resistance to urinary flow. Injection of bulking agents to treat a dysfunctional urethra is a minimally invasive outpatient procedure to correct ISD that results in SUI.

The use of injectable agents for the treatment of SUI has first been described in 1938 by Murless and later popularized by Quackles and Sachse in the 1950s and 1960s. Their application has been limited by placement, durability, antigenicity and tissue biocompatibility issues. The lack of a single reproducible agent has since led to the development and application of improved agents that provide reasonable efficacy with minimal associated morbidity. Successful UBA injection leads to more effecient pressure transmission to the proximal urethra during stress maneuvers as a result of improved functional urethral length. Furthermore several studies have demonstrated an increase in Valsalva leak point pressure following successful injection therapy, whereas other investigators have suggested that obstruction may play a role. Studies have shown that patient satisfaction following injection therapy compares favorably with traditional surgical anti-incontinence procedures.

Continuous development of techniques and materials provides the basis for new and improved bulking agents, which continue to evolve along with advances in biomaterial science. Clinical trials continue to provide further evidence-based experience with this form of minimally invasive treatment of SUI.

The "ideal" Urinary Bulking Agent (UBA) should possess all of the following properties:

• Non-immunogenic
• Permanent
• Non-migratory
• Non-erosive
• Non-inflammatory
• Easily stored and handled
• Easily injected
• Painless
• No long-term side effects
• High safety profile
• Persistent pliability

We believe U125 meets all requirements for an 'ideal' Urinary Bulking Agent. Our pre-clinical studies⁽²⁾ have established the appropriate PMMA microsphere size to avoid migration and dislocation from the injection site when injected submucosally into the bladder neck: