Breaking barriers in stress urinary incontinence care: TAS-303 as a game-changer in pharmacological innovation

Introduction

Stress urinary incontinence (SUI) remains both prevalent and challenging, disproportionately affecting women while profoundly diminishing their quality of life. Defined as involuntary urine leakage during activities such as physical exertion, coughing, or sneezing, SUI is associated with a range of risk factors, including menopause, prior pelvic surgical procedures, obesity, chronic constipation, and multiple vaginal deliveries (1). These factors highlight the multifaceted nature of SUI, which arises from two overlapping pathophysiological mechanisms: urethral hypermobility and intrinsic sphincter deficiency. Urethral hypermobility results from inadequate support of the bladder neck and urethra, while intrinsic sphincter deficiency reflects impaired sphincter function. These intertwined mechanisms underscore the pathophysiological complexity of SUI, demanding therapeutic strategies tailored to its multifactorial etiology (1). In addition to phenotypic risk factors, emerging research highlights genetic and biochemical contributions to SUI. Increased collagen and elastin breakdown within the extracellular matrix compromises tissue support, contributing to urethral dysfunction. These insights underscore the importance of exploring both structural and molecular mechanisms in developing comprehensive treatment approaches.

Despite its high prevalence and significant impact, advancements in therapeutic innovations for SUI have been limited. Conservative approaches, such as pelvic floor muscle training (PFMT), often accompanied by electrostimulation and/or biofeedback, alongside surgical interventions like midurethral slings, remain well-established treatment options. However, these modalities have notable limitations. Conservative therapies frequently suffer from low patient adherence, while surgical interventions are associated with potential complications, particularly those related to mesh implants. Pharmacological options for SUI are similarly restricted; duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is approved for SUI management in Europe, but lacks approval for this indication in the United States (2). Additionally, tricyclic antidepressants are sometimes used due to their alpha-adrenergic effects, which enhance bladder neck constriction and suppress detrusor muscle activity (1,2).

Among the recent advancements in experimental therapeutics, TAS-303 has emerged as a particularly promising pharmacological agent. This selective norepinephrine reuptake inhibitor (NRI) acts peripherally, avoiding the serotonergic effects often associated with central nervous system (CNS)-related adverse events. Beyond SUI, TAS-303 holds potential utility in other lower urinary tract disorders, such as detrusor underactivity and mixed urinary incontinence. Preclinical and clinical studies suggest that TAS-303 enhances urethral sphincter contractility without significant CNS side effects, marking it as a potential breakthrough in SUI treatment (3-5).

TAS-303: a therapeutic breakthrough

Preclinical investigations by Mizutani et al. demonstrated that TAS-303 enhances urethral closing pressure and leak point pressure in a dose-dependent manner in rat models (3). Oral administration of TAS-303 significantly elevated plasma norepinephrine levels without markedly affecting epinephrine, dopamine, or serotonin concentrations (3). Notably, even at a maximal dose of 100 mg/kg, TAS-303 did not significantly reduce the immobility time in the forced swimming test in rats, suggesting minimal CNS-related side effects at doses effective for improving urethral function (3).

Based on these promising preclinical findings, Yono et al. conducted a phase I clinical trial in 2020 (4). This double-blind, crossover study enrolled 16 women who received a single oral dose of TAS-303 (Group A: 18 mg followed by placebo; Group B: placebo followed by 18 mg). Although a modest increase in maximum urethral closure pressure was observed, the difference between treatment and placebo groups did not reach statistical significance (P=0.80). Furthermore, no significant differences in drug-induced contractile effects were detected between the proximal, middle, and distal urethra. Despite these limitations, the study confirmed TAS-303’s safety and encouraged larger-scale trials (4).

These findings affected the design of a pivotal phase II trial, the results of which were recently published by Takahashi et al. in the Journal of Urology. Representing the most rigorous evaluation of TAS-303 to date, the trial enrolled 231 Japanese women with SUI and assessed the efficacy of a daily 18 mg dose over 12 weeks (6). Baseline characteristics were well-balanced between groups, with over 90% of participants presenting with pure SUI, and an average age of 54 years. The study yielded a statistically significant 57.7% reduction in SUI episode frequency in the TAS-303 group compared to a 46.9% reduction in the placebo group [absolute difference: 10.8%; 95% confidence interval (CI): 0.7–20.9%; P=0.036]. Subgroup analyses revealed that participants with at least two incontinence episodes per 24 hours, older age (≥60 years), and pure SUI derived greater benefit from TAS-303 compared to those with fewer episodes, younger age, or mixed incontinence. When assessed against baseline, a higher increase in the Incontinence-Quality of Life (I-QOL) score was noted in the TAS-303 group opposed to the placebo group; however, the between-group difference was not statistically significant (+10.2 vs. +8; P=0.338). Importantly, TAS-303 was well-tolerated, with an adverse event profile comparable to placebo. Serious adverse events and therapy discontinuations were not observed, and mild drug-related side effects occurred in 3.4% and 3.5% of participants in the TAS-303 and placebo groups, respectively (6).

These findings underscore TAS-303’s potential to address the unmet clinical needs of women with SUI while avoiding the CNS-related side effects that frequently limit duloxetine’s tolerability and patient adherence.

Comparative analysis: TAS-303 vs. duloxetine

Direct head-to-head comparative evidence regarding the efficacy and safety of pharmacological treatments for female patients with SUI remains unavailable. Elevated norepinephrine levels can enhance the contractility of the external urethral sphincter through interactions with central mechanisms, specifically within Onuf’s nucleus in the anterior horn of the sacral spinal cord segments S2–S3 (1,2).

To date, duloxetine has been the most extensively studied pharmacotherapy for SUI. This SNRI is approved for the treatment of SUI in women within the European Union and has demonstrated efficacy in improving urethral sphincter contractility (7). A systematic review conducted in 2007 by Mariappan et al. analyzed nine placebo-controlled randomized controlled trials (RCTs) involving 3,063 participants, aggregating data on duloxetine’s effects on SUI (7). Treatment durations ranged from 3 to 36 weeks. Subjective cure rates favored duloxetine, with 10.8% of participants reporting resolution of symptoms compared to 7.7% in the placebo group [risk ratio (RR) =1.42; 95% CI: 1.02–1.98; P=0.04].

Objective cure rates, though limited in availability, followed a similar trend. Individual studies reported a significant reduction in incontinence episode frequency of approximately 50% during duloxetine treatment. Additionally, patients treated with duloxetine 80 mg/daily demonstrated significantly increased I-QOL scores (weighted mean difference: +4.5; 95% CI: 2.83–6.18; P<0.00001) and higher rates of symptom improvement. However, adverse events associated with duloxetine were common, with 71% of participants reporting side effects compared to 59% in the placebo group. Most adverse events were non-severe but included CNS-related effects such as nausea, dizziness, and fatigue, which hampered patient adherence (7). This resulted in adherence becoming a significant challenge, as 17% of male participants discontinued duloxetine therapy due to adverse effects, compared to only 4% in the placebo groups (7).

In contrast, TAS-303 selectively targets peripheral norepinephrine uptake, avoiding the CNS-related adverse effects that frequently accompany duloxetine treatment. Unlike duloxetine, TAS-303 specifically avoids serotonergic pathways, thereby minimizing CNS-related side effects such as nausea, dizziness, and fatigue. This pharmacological distinction underpins its superior tolerability profile, making it a promising candidate for patients who are unable to adhere to duloxetine therapy. Preclinical studies have indicated that TAS-303 achieves superior urethral closing pressures in vaginal delivery models compared to duloxetine, suggesting enhanced efficacy (3-5). Furthermore, TAS-303 offers comparable clinical efficacy with a markedly better tolerability profile, as outlined in Table 1.

Unlike TAS-303, duloxetine has also been studied in male patients with mild to moderate SUI following radical prostatectomy. A systematic review by Kotecha et al. identified eight suitable studies, which demonstrated that short-term duloxetine therapy achieved complete continence in 58% of patients (range, 25–89%), reduction of pad usage by 61% (range, 12–100%), and decrease of pad weight in the 1-hour pad test by an average of 68% (range, 53–90%) (8). However, adverse events led to discontinuation of medication in 21%, and the overall discontinuation (due to adverse events and lack of efficacy) rate was 38% (8).

Strengths and limitations of the TAS-303 study

The study by Takahashi et al. is methodologically robust, with stratified randomization and comprehensive patient-reported outcomes enhancing its credibility (6). Nevertheless, several limitations warrant consideration.

First, the trial exclusively included Japanese women, which constrains the generalizability of its findings to more diverse populations with varying ethnic, cultural, and geographic backgrounds. Cultural and physiological differences may influence both baseline characteristics and therapeutic responses, necessitating further studies across broader demographics. Second, the study primarily targeted patients with mild-to-moderate SUI symptoms, thereby limiting insights into the drug’s potential efficacy in moderate-to-severe cases. This limitation highlights the need for future trials involving patients with more advanced disease presentations to determine whether TAS-303’s therapeutic benefits extend across the full spectrum of SUI severity. Third, the omission of pelvic examinations (with, for example, urethral pressure profiles) precluded the ability to evaluate TAS-303’s efficacy in patients with differing underlying pathophysiologies, such as urethral hypermobility versus intrinsic sphincter deficiency. Distinguishing between these subtypes is critical for optimizing patient selection and tailoring treatment strategies. Fourth, the substantial placebo effect observed in this study, a common challenge in SUI research, complicates the interpretation of drug efficacy. Future trials should adopt strategies to mitigate placebo responses, such as extended pre-randomization observation periods or enrichment designs to identify placebo responders. Fifth, while TAS-303 revealed improvements in incontinence episode frequency and tolerability, longer treatment durations and follow-up are necessary to determine whether these benefits translate into sustained quality-of-life enhancements. The 12-week study period may have been insufficient to capture the full scope of TAS-303’s impact on patient-reported outcomes.

Additionally, the study did not address the relationship between SUI and genitourinary syndrome of menopause (GSM), which is particularly relevant for postmenopausal women. GSM, characterized by atrophic vaginitis and associated symptoms such as vaginal and urethral atrophy, exacerbates SUI in many patients. The integration of local estrogen therapy for women with GSM could potentially improve treatment outcomes by addressing GSM-related factors. Current clinical guidelines already recommend local estrogen therapy for GSM management, and its combination with TAS-303 could yield synergistic benefits (9,10).

Further experimental approaches

While TAS-303 represents a significant advancement in the pharmacological treatment of SUI, ongoing research into alternative therapeutic strategies highlights the complexity of this condition and the need for diverse treatment options.

One promising avenue is the development of myostatin inhibitors, such as bimagrumab, which have demonstrated efficacy in enhancing muscle growth and increasing leak point pressures in preclinical models. By promoting hypertrophy of the urethral sphincter, these agents could theoretically improve the functional contractility of the sphincter. However, significant adverse effects, including substantial weight gain, limit their clinical applicability (11).

Another approach involves 5-HT2C receptor agonists, such as TAK-233 (OP-233), which target serotonergic pathways to enhance urethral sphincter closure. Although preclinical studies have shown promising results, clinical development of these agents remains limited (12). For instance, lorcaserin (Belviq^®, Eisai, Tokyo, Japan), another 5-HT2C receptor agonist, was withdrawn from the market despite its potential efficacy, due to concerns regarding its safety profile (11). Such setbacks underscore the challenges in translating preclinical findings into viable clinical therapies.

Emerging research into molecular therapies highlights the potential of growth-promoting molecules such as CXCL12 (stromal cell-derived factor-1) to enhance tissue regeneration and repair. CXCL12 has demonstrated promising effects in promoting extracellular matrix remodeling and supporting urethral sphincter function in preclinical models. Integrating such molecular therapies with pharmacological agents like TAS-303 could pave the way for synergistic treatment approaches, particularly for patients with severe intrinsic sphincter deficiency or complex pathophysiologies (13).

These experimental approaches reinforce the importance of pursuing novel mechanisms of action to address the limitations of existing therapies. While TAS-303 holds promise as a first-line pharmacological option, complementary or alternative treatments will likely play a critical role in expanding the therapeutic landscape for SUI.

Implications for clinical practice and future research

The introduction of TAS-303 into the therapeutic arsenal for SUI offers a significant opportunity to enhance patient care by addressing longstanding gaps in treatment. Although conservative and surgical options are available, a substantial unmet need remains for pharmacological solutions that bridge the gap between these approaches. TAS-303 emerges as a novel and promising alternative, particularly for patients who are unable or unwilling to undergo surgery or to tolerate duloxetine. However, to maximize its potential and fully integrate TAS-303 into clinical practice, several areas of research and implementation warrant prioritization:

• Expanding patient populations: the current study focused exclusively on Japanese women with mild SUI. Future trials must include diverse populations across ethnic, geographic, and socioeconomic groups to evaluate the generalizability of TAS-303’s efficacy and safety. Moreover, trials involving male patients with SUI, such as those with post-prostatectomy incontinence, could broaden its therapeutic scope.
• Investigating multimodal approaches: combining TAS-303 with other treatments, such as PFMT, biofeedback, or local estrogen therapy, may enhance therapeutic outcomes. For instance, TAS-303’s ability to improve urethral sphincter contractility could complement the structural benefits of PFMT or the localized effects of estrogen therapy, particularly in postmenopausal women suffering from GSM.
• Assessing long-term outcomes and safety: while the current study demonstrated short-term efficacy and tolerability, longer follow-up periods are essential to determine the durability of TAS-303’s benefits. Understanding the long-term safety profile, including the potential for rare or cumulative adverse effects, is essential, particularly for patients requiring long-term therapy.
• Conducting economic analyses: cost-effectiveness studies should evaluate the affordability and accessibility of TAS-303 in comparison to existing treatments, such as conservative therapies and surgical interventions. These analyses will provide critical insights for policymakers, healthcare providers, and patients.
• Exploring broader applications beyond SUI: given its pharmacological mechanism, TAS-303 may hold potential for other urological conditions, such as mixed urinary incontinence or lower urinary tract symptoms (LUTS). Future research should investigate its utility in these contexts to expand its clinical applications.
• Mitigating the placebo effect: the substantial placebo response observed in this trial highlights a broader challenge in SUI research. Future studies should adopt refined methodologies, such as extended pre-randomization observation periods or enrichment designs, to minimize placebo-related confounders and improve the accuracy of efficacy assessments.
• Advancing evidence through network meta-analyses and real-world studies: network meta-analyses provide an innovative framework to evaluate the relative efficacy and safety of multiple therapeutic options by integrating both direct and indirect evidence from RCTs. Such analyses are particularly beneficial in therapeutic areas like SUI, where direct head-to-head comparisons of pharmacological agents are limited. Applying network meta-analyses to treatments such as TAS-303, duloxetine, and other emerging interventions could elucidate their comparative clinical effectiveness, tolerability, and patient-reported outcomes. These insights would be invaluable for optimizing treatment hierarchies and refining clinical guidelines.

In addition to network meta-analyses, real-world evidence studies are essential for assessing the long-term performance of TAS-303 beyond controlled trial settings. By capturing data from diverse patient populations and everyday clinical practices, real-world studies can complement findings from randomized trials, offering a holistic view of the medication’s effectiveness, safety, and adherence patterns. These studies would further inform the development of personalized treatment strategies and enhance the external validity of research findings.

Conclusions

The study by Takahashi et al. represents a pivotal milestone in SUI research and management, showcasing the efficacy, safety, and tolerability of TAS-303 as a novel therapeutic option. This novel pharmacological agent has the potential to redefine the standard of care, offering a viable alternative for patients who cannot tolerate existing therapies or are reluctant to undergo surgical interventions.

As the field advances, TAS-303 could fill a critical gap in the therapeutic landscape, empowering patients to regain control over their lives. However, the promise of TAS-303 must be tempered with the recognition that further research is essential. Rigorous, large-scale, and diverse clinical trials will be pivotal in validating its long-term efficacy, safety, and cost-effectiveness.

While TAS-303 represents a promising innovation in SUI management, its clinical impact remains preliminary. The observed placebo effect underscores the need for further research to delineate its therapeutic value. By integrating TAS-303 into clinical practice, underpinned by robust evidence from future studies, we stand poised to redefine the management paradigm for SUI. This innovation not only heralds a new chapter in pharmacological treatment but also provides hope for countless individuals worldwide, reaffirming the importance of innovation in addressing complex and pervasive health challenges.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2024-691/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2024-691/coif). The authors have no conflicts of interest to declare.

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