VIVE: Potential game-changer for stress urinary incontinence in women

By Beth Senko, CFA

NASDAQ:VIVE

Among start-up investors, "Femtech" is capturing attention. Femtech refers to technology, services, and products geared towards women's health. According to the Economist, femtech received nearly $1.2 billion in funding in 2021, nearly 50% higher than the previous record in 2019.

Market interest has been driven by increased awareness of women's health inequities that haven't been well addressed by medical technology and services. Much of investor focus has been on apps and consumer products; however, innovation is also happening on the medical device front.

One example is urinary incontinence, which affects as many as one in four women at some point in their adult lives. While one can see increased advertisement of consumer products so women can manage their incontinence, medical professionals insist that prevalent urinary incontinence should not be accepted as inevitable or normal.

Founded in 2005 by an OB/GYN, Viveve VIVE went public in 2014. In 2016, Viveve received FDA clearance for its proprietary cryogen-cooled monopolar RF ablation system (CMRF) for electrocoagulation and hemostasis in general surgical procedures. The device was primarily used off-label by aesthetic surgeons as a non-invasive treatment for vaginal laxity and rejuvenation to improve sexual function.

By 2018, the Company achieved moderate commercial success selling $18.5 million from 703 units worldwide; however, management recognized that its upside was limited without FDA clearance for specific indications, so it embarked on clinical trials to show efficacy as a non-invasive treatment to improve sexual function and for stress urinary incontinence (SUI).

Pivot to stress urinary incontinence indication

Unfortunately, Viveve faced setbacks. In 2020, its pivotal trial for sexual function did not meet its primary endpoint with statistical significance between the treatment and sham-treatment groups. In retrospect, Viveve believed that the study, which relied on qualitative responses from patients, was prone to placebo bias, and in the absence of clear clinical markers, proving gains in sexual function would be difficult. As a result, Viveve abandoned a sexual function indication to focus on stress urinary incontinence (SUI). An unexpected benefit of Viveve's vaginal laxity treatment was that patients often reported a reduction in urinary incontinence symptoms. The company then pivoted to focus on what it saw as a significant treatment gap in the large, under-addressed, stress urinary incontinence market.

Urinary incontinence – prevalent, but not inevitable

Incontinence symptoms can have a substantial impact on quality of life. Those with urinary incontinence report higher rates of psychological distress and social disruption. Patients often limit their activities and social interactions outside the home, and may suffer sexual dysfunction.

Prevalence estimates of urinary incontinence vary widely, in large part because information is usually gathered as part of a general health questionnaire and not in population-representative samples using validated, symptom-based questionnaires. The stigma of urinary incontinence creates a high risk for respondent bias in many studies.

Over 50% of women have reported at least one episode of incontinence at some point in their adult life. The range of reported prevalence for urinary incontinence (UI) of any subtype in adult women is broad (5–72%), with studies converging on a prevalence of approximately 30% (Aoki et al, 2017).

Urinary incontinence can be transient (< six months duration) or chronic and it is classified from mild to severe based on frequency and volume. Indeed, studies specifically measuring severe urinary incontinence, defined as urine leakage several times per week, have a more consistent reported prevalence of 6–10% in Europe and the United States. However, not all women who develop urinary incontinence will have symptoms indefinitely. In a longitudinal cohort study of 4,127 middle-aged women, the annual incidence rate of urinary incontinence was 3.3% and the annual remission rate was 6.2% (Legendre, 2015).

Urinary incontinence is divided into two main types – stress incontinence and urge incontinence; patients who exhibit symptoms of both stress and urge incontinence are considered to have "mixed" incontinence. Approximately one-third of all cases are stress urinary incontinence (SUI), are urge incontinence (UUI) and the balance mixed incontinence (MUI).

Stress urinary incontinence is characterized by involuntary urine leakage caused by physical exertion (e.g., coughing, sneezing, exercise). In stress incontinence, the urethra has lost its anatomical support as a result of childbirth, physical stress/trauma, obesity, constipation or aging. Loss of anatomical support affects the urethral closure mechanism, leading to leakage.

Urge incontinence occurs when urine leaks in association with a sudden compelling desire to void and is caused by bladder spasms. Urge incontinence generally has no known cause (idiopathic), although it is more common with age and is associated with neurologic conditions such as Parkinson disease, multiple sclerosis, or nerve injury (Lukacz et al, 2017).

One challenge to measuring prevalence is the "taboo" surrounding incontinence. At the same time, not all urinary incontinence reaches a clinical threshold where patients are more likely to seek treatment. A common misperception is that incontinence comes with aging, or is a natural consequence of childbirth. As a result, women often delay or defer seeking diagnosis; among those who receive diagnosis, fewer than half receive effective therapy.

Stress urinary incontinence – better understanding of causes, treatments largely unchanged

Despite continued progress into the causes of urinary incontinence, treatment options are largely unchanged since the 1990s. Patients generally start with conservative interventions such as pelvic floor exercises. More aggressive therapies range from injectable fillers to surgery.

The first systematic approach to understanding the causes of urinary incontinence occurred in 1923, when Victor Bonney presented his paper "On Diurnal Incontinence of Urine in Women." Prior to Bonney, most studies of urinary incontinence were based on theories of how particular therapies addressed the problem. Bonney's paper introduced key epidemiologic findings (e.g., it is more common in women who have given birth, it is more common with age) that were confirmed in later studies. Bonney's key contribution, however, is that female urinary incontinence arose from laxity in the vaginal support of the urethra. By the 1940s, additional anatomic causes were identified including an increase in expulsive forces (bladder spasm), abdominal stress (heavy lifting) and/or a decrease in urethral resistance (sphincter disfunction). By the 1960s, researchers identified the role of nerve dysfunction (either from neuromuscular trauma, or other degeneration). Despite all these advances, urinary incontinence is considered to result from one or more disruptions to the continence mechanism.

Conservative therapies for stress urinary incontinence

Approximately two million women in the US seek conservative treatment for urinary incontinence each year. Conservative management of SUI in women includes: weight loss, smoking cessation, constipation management, pelvic floor muscle exercises (PFMT), extracorporeal magnetic innervation, electrical stimulation, and devices such as incontinence pessaries.

In addition to lifestyle changes, front line therapy focuses on strengthening the pelvic floor, either with or without biofeedback. In pelvic floor work (PFMT), patients contract pelvic muscles repeatedly several times a day and several days a week. To maintain improvement, the exercises must be continued indefinitely.

The success depends on the patient's motivation and the quality of her instruction and long-term compliance. Reported improvement/cure rates vary from 27% to 90%, averaging 40-50%; however, a systematic review found no evidence that PFMT results in a difference in urinary incontinence at more than six to twelve months post-partum and that data quality was low (Cochrane, 2020).

Pessaries are worn internally (similar to a tampon) to provide intravaginal support in both pelvic organ prolapse and SUI. Pessaries are sometimes used in conjunction with PFMT. Incontinence pessaries are made of silicone or rubber and prevent leakage by supporting both the urethra and bladder wall. Pessaries are more than 70% effective, and have a 76% continuation rate beyond the first year (Al-Shaikh, et. al, 2018). However, pessaries have a few downsides. First, they need to be properly fitted, which can be somewhat trial and error, and often require several doctor visits for both fitting and patient education. In addition, anatomical differences prevent some women from being properly fitted or comfortable wearing a pessary. Discontinued use generally arises from continued incontinence, discomfort, bleeding or repeated unintended device expulsion. Some patients experience complications including vaginal erosion, pain, and constipation after long-term (six-to-ten years) pessary use.

When conservative therapies don't work – injectable fillers and surgeries

Since the early 1990s, attention has focused on developing less-invasive therapies for SUI that replicate the high success rates of surgical interventions, but with reduced morbidity and little-to-no hospital stay.

One less-invasive approach is injecting filler to bulk the tissues surrounding the urethra so that it seals tightly. While injectable fillers have gone in and out of favor since they were first introduced in the 1930s, fillers can be highly effective and are associated with low rates of complication. However, fillers are generally not successful over the long-term (Herschorn, 2015).

Fillers are injected usually under local anesthesia in a doctor's office visit. Bulking materials may be place through the skin, through the urethra or through the vagina. By using local anesthetic, the patient can stand at times during the procedure to see if leakage is adequately addressed. If leakage persists, additional injections can be given.

There are few long-term studies evaluating the efficacy of bulking agents. Studies report 60-80% initial cure rates, but generally decline to 40% after two years (Balmforth, 2003), and as far as 13% at five years (Buckley, 1993). As a result, while injectable fillers are less invasive than surgical therapies, the lack of durability and retreatment cost have limited their use.

Each year, approximately 180,000 women undergo surgery for SUI in the USA; the rate increased 27% in women aged 18-64 from 2000-2009 (Funk, 2012). In the 1980s, there was a move to less-invasive surgery for SUI, as endoscopic techniques took hold across multiple surgical practices. Endoscopic techniques were attractive because they allowed for a shorter hospital stay and had low complication rates. Needle suspensions were quite common as they were easy to perform and gave good short-term results (Cochrane, 2017). However, longer-term studies found that needle suspensions were not as durable as more invasive surgeries, and therefore, have limited use.

There are over 20 different surgical procedures to correct stress urinary incontinence (Rovner, 2004). The choice of procedure depends on both the surgeon's experience and patient needs. Surgical correction for SUI aims to 1) stabilize the urethra and bladder neck in a well-supported position that reduces the impact of changes in intraabdominal pressure, or 2) strengthen the urethral sphincter so it doesn't leak in response to changes in pressure. Sling surgery is the most commonly used procedure; the surgeon uses tissue (from the patient or a donor) or a synthetic mesh to create a sling that repositions and supports the urethra. Another procedure, colposuspension, uses sutures to lift the tissues supporting the bladder, and tethers it to the ligaments along the pubic bone.

Both procedures have high success rates, but there is still significant debate over relative long-term efficacy and safety. A recent meta-analysis focused on randomized clinical trials, reported higher cure rates for sling surgeries (82%) vs. colposuspension (74%) on any continence measures (Fusco, 2017). However, sling surgeries are associated with higher risk of consequences such as vaginal and bladder perforations (Novara, 2010). In general, a significant drawback to surgical treatment of SUI is that revision surgeries can be complex. Therefore, surgery is not recommended as first line therapy. In addition, surgery may be more appropriate for women who have finished having children, although studies of recurrent SUI following sling surgery and childbirth are limited.

A new non-invasive alternative – the Viveve System

Viveve's non-invasive treatment for SUI regenerates collagen in vaginal tissue. The collagen regenerates and reinforces vaginal tissues to better support the bladder neck and urethra. Since 2016, the Viveve System has been used safely in over 25,000 patients, and 500 in clinical studies. Viveve's current pivotal PURSUIT trial will measure reduction in SUI symptoms based on a single 45 minute in-office treatment. The treatment does not require anesthesia or numbing creams, and patients have little to no downtime/recovery.

In the procedure, a practitioner (doctor or trained nurse) attaches the single-use treatment tip to the handpiece. An electrode (return pad) is placed on the patient's upper leg to complete the circuit. Similar to an ultrasound, a lubricating/conductive gel is applied to the treatment area.

Viveve's treatment administers radiofrequency (RF) energy coupled with cryogen cooling. The RF penetrates the deeper tissue layers, stimulating collagen regeneration; the cooling protects the surface tissue. After treatment, collagen regenerates over one to-three months, building fullness around the bladder neck and urethra to reduce/eliminate leakage. Patients generally report an improvement in symptoms after one-to-two months, and many continue to improve for up to six months. Previous clinical studies indicate that the treatment is effective for at least twelve months.

Viveve's path to regulatory clearance and commercialization.

In January 2021, Viveve began its pivotal clinical trial to support FDA clearance of its treatment for stress urinary incontinence. The PURSUIT trial is a multicenter, randomized, double-blinded, sham-controlled trial of ~390 subjects at 30 clinical sites. The subjects are pre-menopausal women with moderate stress urinary incontinence (SUI). The primary endpoint is a >50% reduction in leakage based on a 1-hour pad weight test (PWT) at 12 months after treatment. Measurements are also taken three-and six-months post treatment.

Full enrollment was completed at the end of 2021, and the Company expects a full readout at the end of 2022. Once results are finalized, Viveve will deliver its application to the FDA.

Viveve has begun to build out other aspects needed to commercialize its system. The Company has identified a manufacturer, and the FDA has completed its GMP audit. Viveve has sought out support from key medical societies, and it has received CPT III codes for the procedure. Once it receives clearance, Viveve plans to build a direct sales force and pursue future insurance coverage. With an existing installed base approaching 1,000 units, Viveve believes it will have a relatively low hurdle to new sales as physicians will be able to promote and perform treatments once the device is cleared and "on-label."

At September 30, Viveve had $22.7 million in cash on its balance sheet, and less than $5 million in debt. With a relatively low cash burn rate of $3 – 4 million per quarter, the Company is funded until early 2023.

We believe that Viveve is well positioned to add a valuable less-invasive treatment to the expansive stress urinary incontinence market, where treatment modalities are largely unchanged in 30 years, and where there is a significant gap between conservative (behavioral, physical therapy) and invasive treatment. The Company has a proven technology with a long safety record, a well-designed clinical trial with objective endpoints, and the resources to see its treatment through commercialization. Likewise, with a positive PURSUIT trial readout and FDA label, the estimated 25-30 million women with SUI in the U.S. alone represents a multi-billion dollar commercial opportunity for Viveve.

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