The efficacy and tolerability of mirabegron, a β3 adrenoceptor agonist, in patients with symptoms of overactive bladder

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1 614237TAU / Therapeutic Advances in UrologyG Thiagamoorthy, S Kotes research-article2015 Therapeutic Advances in Urology Review The efficacy and tolerability of mirabegron, a β3 adrenoceptor agonist, in patients with symptoms of overactive bladder Ganesh Thiagamoorthy, Stephanie Kotes, Martino Zacchè and Linda Cardozo Ther Adv Urol 2016, Vol. 8(1) DOI: / The Author(s), Reprints and permissions: journalspermissions.nav Abstract: Mirabegron, is the only β-3 adrenoreceptor (AR) agonist available for the treatment of overactive bladder (OAB). To assess the efficacy and tolerability of this novel drug therapy, two phase II and six phase III Astellas-sponsored trials have been conducted with over 10,500 adults with OAB recruited. Of these, seven were randomized, double blind, 12-week placebo controlled studies and the other was for 12 months and not placebo controlled. The evidence described would suggest that mirabegron is as efficacious as most antimuscarinics, including tolterodine extended release (ER) 4 mg, compared with placebo with regard to objective measures such as reduction in number of voids per 24 hours, mean volume per void, mean number of episodes of general urinary incontinence, urgency urinary incontinence and urgency per 24 hours; and subjective measures such as severity of urgency, patient perception of bladder condition and validated continence quality of life questionnaires. Regarding tolerability, these data would suggest that patients taking mirabegron suffer a similar rate of adverse effects as those taking placebo alone, whereas the rate in those taking antimuscarinics is greater. Thus mirabegron presents a safe and effective alternative treatment to antimuscarinics for patients with OAB symptoms. Patients who may particularly benefit from mirabegron include those who are unsuitable for antimuscarinics or who have previously struggled with antimuscarinic side effects. Keywords: drug therapy, mirabegron, overactive bladder (OAB), urgency, urinary incontinence Background Overactive bladder (OAB) syndrome is defined by the International Continence Society (ICS) and International Urogynecological Association (IUGA) as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection or other obvious pathology [Haylen et al. 2010]. OAB has been shown to affect up to 36% of adult women in Europe and the US [Abrams, 2003; Coyne et al. 2009; Milsom et al. 2001; Abrams et al. 2003]. OAB has a significant impact on quality of life and treatment is aimed at improving symptoms. There are many factors which contribute to the OAB symptom complex and these are addressed via behavioural modification, including bladder retraining and reduced fluid and caffeine intake, alongside drug therapy [Abrams et al. 2013]. Comprehension of the micturition reflex has led to the developments in OAB drug therapy. Involuntary detrusor contractions arise secondary to stimulation of muscarinic receptors (MRs) in the bladder detrusor muscle by acetylcholine (Ach) released from parasympathetic nerves [Fowler et al. 2008; Andersson, 2004]. The medical management of OAB had therefore until recently focused on antimuscarinic agents. These bind competitively to MRs to dampen the amplitude of bladder contractions, improving bladder capacity and reducing involuntary detrusor contractions, reducing urgency and frequency of micturition. Antimuscarinics may also decrease afferent bladder activity by blocking urothelial MRs, thereby further improving OAB symptoms [Yamaguchi, 2010]. Patient-reported qualitative and quantitative measures have shown a Correspondence to: Ganesh Thiagamoorthy, MBBS, MRCOG Urogynaecology Department, King s College Hospital, Denmark Hill, London SE5 9RS, UK gans.t@nhs.net Martino Zacchè, MBBS, MSc Linda Cardozo, MBChB, FRCOG King s College Hospital, London, UK Stephanie Kotes, MRCS(Ed), FEBU Mater Dei Hospital, Msida, Malta 38

2 G Thiagamoorthy, S Kotes et al. statistically significant improvement in OAB symptoms with antimuscarinics compared with placebo. The drawbacks of antimuscarinic treatment include limited tolerability due to the side effects [Nabi et al. 2006]. The most commonly reported side effects include dry mouth, constipation, blurred vision and cognitive impairment, especially in the elderly [Wagg et al. 2014; Wagg, 2012]. The predominant MRs in the bladder are the M2 and M3 sub-type, and so to reduce systemic side effects, newer antimuscarinics have more selectively attempted to block M2 and M3 MRs. Despite more selective newer drugs and extended release preparations, this group of treatments has limited long-term benefit as persistence rates are only % at 12 months [Wagg et al. 2012; Jayarajan and Radomski, 2014; Sexton et al. 2011; Veenboer and Bosch, 2014]. Further concerns regarding antimuscarinics have been brought to light as recent cohort studies have correlated an increased likelihood of Alzheimer s disease or dementia in those who are undergoing cumulative anticholinergic exposure [Gray et al. 2015]. In view of the problems with antimuscarinic therapy, recent research has concentrated on novel classes of treatment and considered alternative pathways within the micturition reflex. As involuntary detrusor contractions occur during the filling/storage phase of micturition and are suppressed by activation of β-adrenergic receptors, the role of β-adrenoceptors has been studied [Wagg et al. 2012; Abrams et al. 2013; Madhuvrata et al. 2012]. Cellular, in vitro and subsequent in vivo studies have shown the predominant adrenoceptor in bladder tissue to β-3 adrenergic receptors (β-3 AR) [Igawa et al. 1998, 2001]. Stimulation of β-3 AR results in detrusor relaxation, thus increasing bladder capacity and reducing OAB symptoms [Igawa et al. 2012]. Three β-3 AR agonists, mirabegron, ritobegron and solabegron, have been studied in detail regarding to their efficacy in treating OAB. The latter two are in differing phases of research whilst mirabegron (YM178) is available for the treatment of OAB in many countries after being approved by the US Food and Drug Administration (FDA) in June 2012 and by the National Institute for Health and Care Excellence (NICE) in the UK in June It is also licensed in Japan, Europe and Canada. Mirabegron was originally developed as a treatment for diabetes prior to Astellas Pharma Inc. transferring the drug s therapeutic focus to OAB [Tyagi and Tyagi, 2010]. Experiments in Chinese hamster ovary cells showed that mirabegron significantly increased cyclic AMP accumulation in cells expressing human β-3 AR more than in those expressing β-1 AR and β-2 AR. Cystometric experiments in rats treated with mirabegron reported a reduction in resting intravesical pressure and contraction frequency without any effect on the amplitude of micturition contraction [Takasu et al. 2007]. These findings, along with subsequent in vitro human bladder testing, suggested the suitability of mirabegron as a therapeutic drug for the treatment of symptoms of OAB [Takasu et al. 2007]. Based on these findings, two phase II and six phase III Astellas-sponsored trials recruited over 10,500 patients with OAB [Chapple et al. 2013a, 2013b, 2013c; Herschorn et al. 2013; Khullar et al. 2013; Nitti et al. 2013; Kuo et al. 2014; Yamaguchi et al. 2014]. Seven of these were randomized, double blind, placebo-controlled studies; one was not placebo controlled. All trials recruited both male and female patients over 18 years of age who had experienced symptoms of OAB for a minimum of 3 months prior to starting the study. Inclusion criteria for randomization were 8 voids per 24 hours with 3 urgency episodes as recorded on a bladder diary for 3 consecutive days. Urgency scores were assessed using Patient Perception of Intensity of Urgency Scale (PPIUS) and both OAB dry and wet patients were included [Notte et al. 2012]. A summary of the primary outcome results from the eight randomized controlled trials (RCTs) is given in Table 1. BLOSSOM The BLOSSOM trial, a multicentre, randomized, double-blind, double-dummy, parallel group, placebo and active-controlled, phase IIa, proof-ofconcept study compared efficacy of treatment with mirabegron 100 and 150 mg twice daily with placebo over a 4 week period in 2012 [Chapple et al. 2013a]. Tolterodine extended release (ER) 4 mg once daily (OD) was utilized as an active comparator. A total of 314 patients were enrolled, but only 262 fulfilled the complete inclusion criteria and were then randomized. The primary endpoint was change in mean number of voids per 24 hours from baseline to end of treatment. Secondary endpoints included changes in mean volume per void; mean 39

3 Therapeutic Advances in Urology 8(1) Table 1. Summary of the primary outcome results from the eight mirabegron RCTs. Study title N Voids per 24 hours Mean incontinence episodes per 24 hours Placebo Mirabegron Tolterodine ER 4 mg 25 mg 50 mg 100 mg 150 or 200 mg Placebo Mirabegron Tolterodine ER 4 mg 25 mg 50 mg 100 mg 150 or 200 mg BLOSSOM DRAGON SCORPIO ARIES CAPRICORN TAURUS JAPAN ASIA ER, extended release. number of episodes of urinary incontinence, urgency urinary incontinence and urgency per 24 hours. Severity of urgency, nocturia and Patient Perception of Bladder Condition (PPBC) were also assessed. Both doses of mirabegron treatment showed statistically significant improvement in mean voids per 24 hours when compared with placebo (p 0.01). This was not the case for tolterodine ER. There were also statistically significant improvements in most of the secondary endpoints for mirabegron; however, there were no statistically significant differences between tolterodine ER 4 mg and placebo for any of these. Patients taking either tolterodine ER 4 mg or mirabegron 150 mg noted significant improvement in PPBC compared with placebo but not in those taking mirabegron 100 mg. Overall, mirabegron was found to be well tolerated in the study group. The most commonly noted treatment emergent adverse event (TEAE) was a mean increase in heart rate of just 5 beats per minute in the 150 mg mirabegron group. The 100 mg mirabegron dose and tolterodine ER 4 mg had no effect on heart rates. DRAGON Based on the BLOSSOM study, Astellas conducted a 12-week phase IIB trial in 2013, code named DRAGON [Chapple et al. 2013b]. A total of 927 women were studied to compare the efficacy of mirabegron at doses of 25, 50, 100 and 200 mg OD against placebo. Tolterodine ER 4 mg OD was again used as an active comparator. The primary endpoint was change in the mean number of voids per 24 hours from baseline to end of treatment. This was not statistically significant in the mirabegron 25 mg group but was in the 50, 100, and 200 mg OD groups with dose-dependent results (Table 1). The secondary outcomes followed a similar dose dependent pattern of improvement compared with placebo: mean volume per void (50, 100 and 200 mg, p 0.001), incontinence episodes (25 and 50 mg, p 0.05), urgency incontinence episodes (all doses p 0.05), urgency episodes (25, 100 and 200 mg, p 0.05), level of urgency (100 and 200 mg, p 0.05) and nocturia episodes (50 mg, p 0.05). A statistically significant difference (p < 0.01) between tolterodine and placebo was noted for mean volume voided per micturition, but not for the number of voids per 24 hours or other secondary endpoints. Quality of life changes were subjectively measured using the International Consultation on Incontinence Modular Questionnaire (ICIQ) OAB and ICIQ Overactive Bladder Symptoms 40

4 G Thiagamoorthy, S Kotes et al. Quality of Life (OABqol). Only mirabegron 100 and 200 mg improved ICIQ-OAB scores significantly more than placebo and only the 200 mg dose improved ICIQ-OABqol significantly. There were no significant improvements in either quality of life measure compared with placebo in the tolterodine group. It is stated that a statistically significant treatment effect favoring mirabegron 200 mg compared with tolterodine ER 4 mg was seen on the ICIQ-OAB, but a comparison of tolterodine with the other mirabegron doses was omitted [Chapple et al. 2013b]. Whereas the efficacy of mirabegron is comparable with established treatment with tolterodine, the reported TEAEs in all mirabegron groups regardless of dose were less compared with tolterodine. There was a maximum increase of 1.9 mmhg in the blood pressure of patients treated with mirabegron at any dose level and these increases were not statistically significant compared with placebo. There were no significant changes in heart rate with placebo, 25 and 50 mg of mirabegron. There were statistically significant increases in heart rate of beats per minute (bpm) for mirabegron 100 mg (p 0.05) and bpm for mirabegron 200 mg (p 0.001). This increase in heart rate, however, was not associated with an increase in cardiovascular adverse events (AEs) such as atrial fibrillation or palpitations. Similar to the initial proof of concept study, the results of the DRAGON study suggested that, whilst the efficacy of mirabegron was comparable with established treatment with tolterodine, the reported TEAEs in all mirabegron groups regardless of dose were less. There were no other significant clinical untoward effects. SCORPIO The first phase III trial, SCORPIO, compared mirabegron 50 and 100 mg or tolterodine ER 4 mg with placebo in a European, Australian and South African population (n = 1978) over 12 weeks [Khullar et al. 2013]. Coprimary endpoints were the reduction in number of voids and number of incontinence episodes per 24 hours by week 12. Secondary endpoints were changes by weeks 4, 8 and 12 in mean level of urgency, mean number of urge incontinence episodes per 24 hours, mean number of overall incontinence episodes per 24 hours, mean number of voids per 24 hours and mean volume per void. Patientreported outcomes were assessed using the OABquestionnaire (OAB-q), PPBC and a Treatment Satisfaction Visual Analogue Scale. Results confirmed statistically significant improvements in all primary and secondary endpoints in both mirabegron doses compared with placebo (p 0.05). Compared with placebo, tolterodine was not significantly different in terms of the primary outcome measures, but did show significant improvement in all the secondary outcome measures. All the active treatment groups compared with placebo demonstrated a statistically significant improvement in the subjective quality of life assessments. In both doses, mirabegron was as well tolerated as placebo with regard to TEAEs. The incidences of dry mouth in the mirabegron groups were similar to placebo (2.8% at mirabegron 50 mg, 2.8% at mirabegron 100 mg and 2.6% for placebo). The incidence of dry mouth was much higher in the tolterodine ER 4 mg group (10.1%). Hypertension was reported in the mirabegron 50 and 100 mg groups (5.9% and 5.4%, respectively), but the incidence was lower than placebo (7.7%) or tolterodine ER 4 mg treated patients (8.1%). ARIES These results were confirmed by a second phase III study, ARIES, conducted in Canada and the US [Nitti et al. 2013]. The methodology was similar to SCORPIO and was carried out over a 12 week period. Mirabegron 50 mg and 100 mg were compared with placebo without an active comparator. There were 1329 participants. As for SCORPIO, coprimary efficacy endpoints were changes in mean number of incontinence episodes per 24 hours and voids per 24 hours when comparing baseline and final visit. The secondary endpoints, including quality of life measures, were also the same as previously. All endpoints showed statistically significant improvement (p 0.05). Safety assessments included TEAEs. The incidence of the commonest TEAEs (hypertension, urinary tract infection, headache, nasopharyngitis) was comparable with that of placebo, and dry mouth was even less common with mirabegron 50 mg than with placebo (0.5% versus 1.5%). Overall, TEAEs were comparable with incidences of 2.0%, 2.5% and 3.2% for placebo, mirabegron 50 mg and 100 mg, respectively. CAPRICORN CAPRICORN was a phase III study which recruited 1306 patients with OAB from the US and countries within Europe to test the efficacy, 41

5 Therapeutic Advances in Urology 8(1) safety and tolerability of 25 and 50 mg OD mirabegron against placebo [Herschorn et al. 2013]. Similar to SCORPIO, the coprimary outcome measures were change from baseline to end of treatment at 12 weeks with regard to the mean number of incontinence episodes per 24 hours and mean number of voids per 24 hours. Secondary endpoints were the same as the previous studies. Both mirabegron groups demonstrated statistically significant improvements in the coprimary endpoints compared with placebo in a dose-dependent manner. Mirabegron 50 mg compared with placebo demonstrated statistically significant improvements in all patient-reported outcome measures without increase in the incidence of TEAE. Interestingly, the proportion of patients discontinuing treatment was lower with mirabegron 25 mg (10.6%) and 50 mg (12.3%) than placebo (15.2%). The commonest TEAEs reported by patients included hypertension (5.3%, 6.9% and 7.0%) and headache (2.1%, 0.9% and 0.9%) in the placebo, mirabegron 25 and 50 mg, groups, respectively. Herschorn and colleagues stated that no urinary retention was reported in the mirabegron treated groups, although 1 patient in the mirabegron 50 mg group had a post void residual volume of 300 ml at the final visit [Herschorn et al. 2013]. The definition of urinary retention is in the study protocol is not described, but in other urogynaecological papers, it has commonly been defined as between 100 and 200 ml [Skriapas et al. 2006]. JAPAN A phase III double-blind, parallel-group, multicentre 12 week study randomized 1139 Japanese adults to mirabegron 50 mg, tolterodine 4 mg ER or placebo [Yamaguchi et al. 2014]. The primary endpoint was change in the mean number of voids per 24 hours from baseline to final visit. Mirabegron 50 mg was associated with a significantly greater change from baseline compared with placebo. As seen in Table 1, there was a reduction of 1.67 voids with mirabegron compared with a reduction of 0.86 voids in those taking placebo. The reduction in those taking tolterodine was 1.40 voids, but no statistical analysis was published comparing tolterodine and placebo. The secondary outcome measures included urgency episodes per 24 hours, which were again significantly better in those taking mirabegron compared with placebo, but again no statistical analysis comparing tolterodine and placebo was published. The percentage of subjects with zero incontinence episodes at the final assessment in the placebo, mirabegron and tolterodine groups were 39.4%, 50.8% and 48.8%, respectively. No statistical analysis comparing mirabegron with placebo was published for this outcome measure. The incidence of TEAEs in the mirabegron group (24.5%) was similar to that of the placebo group (24.0%) whilst higher in the tolterodine group (34.9%). ASIA Another phase III study was carried out in OAB patients in Asia (67 sites in China, India, Korea and Taiwan) to further evaluate the efficacy and safety of mirabegron 50 mg or tolterodine ER 4 mg OD compared with placebo [Kuo et al. 2014]. In total, 1126 patients were randomized and participated in the multicentre, doubleblind, parallel-group 12 week study. A significant improvement relative to treatment with placebo was noted in the primary endpoint, change in mean number of voids in 24 hours with mirabegron 50 mg. This was not the case with tolterodine ER 4 mg. The mirabegron 50 mg group demonstrated a statistically significant improvement from baseline in mean volume per void relative to placebo. The difference between the tolterodine ER 4 mg and placebo was not significant. The other secondary outcome measures were the same as previous studies, but there were no significant differences between mirabegron and placebo. Changes in quality of life were assessed using the King s Health Questionnaire (KHQ). The change from baseline in most of the KHQ domain scores showed improvement comparing both mirabegron 50 mg and tolterodine ER 4 mg with placebo, but these differences were not statistically significant. The TEAEs with mirabegron were not significantly different to those with placebo. With placebo, mirabegron 50 mg and tolterodine ER 4 mg, the commonest TEAEs were dry mouth (4.9%, 4.9%, 8.1%), constipation (2.2%, 2.2%, 2.4%) nasopharyngitis (2.2%, 2.5%, 2.4%) and dizziness (1.4%, 1.4%, 2.2%). TEAEs of potential cardiac arrhythmia were 4.4%, 2.5% and 1.1%, respectively. TAURUS To date, one longer term study (TAURUS) has provided results for up to 1 year of mirabegron 42

6 G Thiagamoorthy, S Kotes et al. use [Chapple et al. 2013c]. The study was intended to test the safety, tolerability and efficacy of 50 and 100 mg OD treatment of mirabegron in patients with symptoms of OAB and compare these with tolterodine without formal statistical analysis. A total of 2452 eligible patients from 306 centres over four continents were randomly allocated to receive mirabegron 50 mg, 100 mg or tolterodine ER 4 mg OD for 12 months. For the first time, the primary outcome measures were the number of patients with TEAEs and the severity of these TEAEs. The secondary outcomes measured were change in mean number of voids and incontinence or urgency episodes per 24 hours and volume per micturition over 24 hours from baseline to 1, 3, 6, 9 and 12 months. The usual quality of life assessments were also conducted at each time point. TEAEs with mirabegron 50 mg, 100 mg and tolterodine ER 4 mg were reported in 59.7%, 61.3% and 62.6% of patients, respectively; most were mild or moderate. Dry mouth, a common anticholinergic side effect, affected fewer patients taking mirabegron 50 and 100 mg (2.8% and 2.3%, respectively) than tolterodine (8.6%). Serious TEAEs were reported in 5.2%, 6.2% and 5.4% of patients, respectively. These included haemolytic anaemia, thrombocytopaenia, arrhythmias, atrial fibrillation, myocardial infarction, heart failure, vertigo, closed angle closure glaucoma and blepharospasm, upper gastrointestinal (GI) bleed and gastritis. Mirabegron was found to raise mean blood pressure over the study period by 0.2 and 0.4 mmhg (dose dependent) compared with an increase by 0.5 mmhg with tolterodine. These minimal increases are clinically insignificant. Improvement in OAB symptoms were reported in all groups from as early as 4 weeks after initiating treatment and was maintained throughout the 12 month period. The study did not compare efficacy and safety with a placebo arm, however, which may be considered a limitation. Mirabegron and antimuscarinic combination therapy A phase II, multicentre, randomized, doubleblind 12 week study assessing the effect of combination of mirabegron with solifenacin was conducted involving 1306 patients [Abrams et al. 2015]. Patients were randomized to one of 12 groups, five of which were solifenacin 2.5, 5 or 10 mg, or mirabegron 25 or 50 mg, six were combinations of the previously mentioned solifenacin and mirabegron doses, and a final group was a placebo. The primary objective was to evaluate the efficacy of combination therapy compared with solifenacin 5 mg monotherapy. The secondary objectives were to assess the safety and tolerability of the combination treatments with placebo and the relevant monotherapies. The primary objective was change from baseline to end of treatment in mean volume voided per micturition. The secondary objectives included mean number of voids per 24 hours and mean number of incontinence episodes per 24 hours, as well as mean number of urgency episodes per 24 hours according to PPIUS. Compared with the improvement from baseline with solifenacin 5 mg, there were statistically significant improvements with all combinations except solifenacin 2.5 mg plus mirabegron 25 mg. The antimuscarinic associated TEAEs (dry mouth, constipation, blurred vision and dyspepsia) showed a dose-dependent relationship with solifenacin monotherapy, suggesting no increased AE of mirabegron in the combination therapy. The incidence of dry mouth in the combination groups with solifenacin 10 mg was less than the equivalent solifenacin 10 mg monotherapy groups, but this was not tested for statistical significance. Systematic review and meta-analysis A systematic review and meta-analysis of extractable data from six RCTs (BLOSSOM, DRAGON, SCORPIO, ARIES, CAPRICORN and TAURUS) was conducted [Wu et al. 2014]. This showed that mirabegron was more effective than placebo in treating OAB despite different drug dosages in the efficacy endpoints: mean number of incontinence episodes per 24 hours and mean number of micturitions per 24 hours. Compared with placebo, mirabegron had a similar risk of AEs. When compared with tolterodine, mirabegron was more effective in terms of mean number of incontinence episodes per 24 hours, but there were no differences between mirabegron and tolterodine in mean number of micturitions per 24 hours. Mirabegron also had a lower adverse reaction rate [odds ratio (OR) 0.9; 95% confidence interval (CI) 0.8, 1.0; p = 0.04]. Another systematic review looked at the relative efficacy and tolerability of OAB medications, specifically mirabegron 50 mg versus antimuscarinics in patients with OAB [Maman et al. 2014]. Overall, 44 RCTs involving 27,309 patients were 43

7 Therapeutic Advances in Urology 8(1) included. Bayesian mixed treatment comparison found that mirabegron 50 mg was as efficacious as antimuscarinics in reducing the frequency of urgency incontinence, with the exception of solifenacin 10 mg which was more efficacious. Mirabegron 50 mg had an incidence of dry mouth similar to placebo and significantly lower than all included antimuscarinics. Mirabegron and the complex patient A recent prospective subanalysis of individual and pooled efficacy and tolerability data showed promising results for 2 different patient populations of OAB patients aged 65 and 75 years. The prevalence of OAB rises with increasing age (15% in 65 years of age, 30 40% in 75 years of age) [Wagg et al. 2014]. Primary efficacy outcomes were the change from baseline to final visit in the mean number of incontinence episodes per 24 hours as well as the mean number of micturitions per 24 hours comparing mirabegron 25 and 50 mg with tolterodine 4 mg ER. Tolerability was assessed by the incidence of TEAEs. Mirabegron was well tolerated in both age groups. Hypertension and urinary tract infections were the most commonly noted TEAEs. Dry mouth, the most commonly reported TEAE of antimuscarinic treatment in the elderly, was found to be six times more common in those patients receiving tolterodine than those taking mirabegron. Limited selectivity of antimuscarinic medication for bladder-specific receptors and the expression of M2, M3 receptors in other systems such as the GI tract and central nervous system (CNS) are responsible for the wide side effect profile. These side effects, such as dry mouth and cognitive disturbances, play a role in the discontinuity of treatment [De Ridder, 2006; Kay et al. 2006; Kerdaron et al. 2014]. The main site of action of mirabegron is the detrusor muscle β3-ar, where it causes relaxation during bladder filling and inhibits involuntary detrusor contractions. This alternative mechanism of action may explain why mirabegron avoids the side effect profile typical of anticholinergic agents. The effects of mirabegron on cognitive functions, pharmacokinetic interactions with other drugs, and long-term adverse events have not yet been fully investigated [Caremel et al. 2012]. Mirabegron is highly lipophilic and metabolized in the liver via multiple pathways, mainly the cytochrome P450 isoenzymes CYP3A4 and 2D6. As a moderate CYP450 CYP2D6 inhibitor, mirabegron may interact with drugs that are CYP2D6 substrates. But while the potential for CYP450 interactions exists, the presence of the multiple metabolic pathways reduces the likelihood of clinical significance of each [Matthews et al. 2014]. One study on the role of CYP450 isoenzymes 3A and 2D6 in the in vivo metabolism of mirabegron deemed the effect of the CYP2D6 phenotype on mirabegron exposure to be small and likely of limited clinical importance [Krauwinkel et al. 2014; Maggiore et al. 2014]. Further studies evaluating drug interactions between mirabegron and common drugs metabolized by CYP450 isoenzymes are required, as are analyses of patients with comorbidities and those taking numerous drug therapies [Matthews et al. 2014]. Conclusion The evidence described would suggest that mirabegron is not a cure for OAB, but is as efficacious as most antimuscarinics including tolterodine ER 4 mg compared with placebo regarding: - objective measures such as reduction in number of voids per 24 hours, mean volume per void, mean number of episodes of general urinary incontinence, urgency urinary incontinence and urgency per 24 hours. - subjective measures such as severity of urgency, PPBC, ICIQ-OAB and KHQ. It is important to note however that urgency, the pathognomonic symptom of OAB, was never the primary outcome measure. With regard to tolerability, the data would suggest that patients taking mirabegron suffer a similar rate of TEAEs as those taking placebo alone, whereas the rate in those on antimuscarinics is greater. To date, mirabegron, the first and only licensed β3-ar agonist for the treatment of OAB, offers an efficacious and safe alternative to first-line treatment in adult patients poorly controlled with or intolerant to antimuscarinics. Future studies are required to provide more information regarding potential benefits of combined therapy with antimuscarinics or α-blockers and also longer term effects of β3-ar agonists. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. 44

8 G Thiagamoorthy, S Kotes et al. Conflict of interest statement The authors declare no conflicts of interest in preparing this article. References Abrams, P. (2003) Describing bladder storage function: overactive bladder syndrome and detrusor overactivity. Urology 62: 28 37; discussion Abrams, P., Cardoza, L., Khoury, A. and Wein, A. (2013) International Consultation on Urinary Incontinence, 5th edn. Plymbridge, UK: Health Publications. Abrams, P., Herzog, A., Corey, R., Stewart, W., Van Rooyen, J., Cundiff, G. et al. (2003) Prevalence and burden of overactive bladder in the United States. World J Urol 20: Abrams, P., Kelleher, C. and Staskin, D. (2015) Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study(symphony). Eur Urol 67: Andersson, K. (2004) Antimuscarinics for treatment of overactive bladder. Lancet Neurol 3: Caremel, R., Loutochin, O. and Corcos, J. (2012) What do we know and not know about mirabegron, a novel β3 agonist, in the treatment of overactive bladder? Int Urogynecol J 25: Chapple, C., Amarenco, G., Lopez Aramburu, M., Everaert, K., Liehne, J., Lucas, M. et al. (2013a) A proof-of-concept study: mirabegron, a new therapy for overactive bladder. Neurourol Urodyn 32: Chapple, C., Dvorak, V., Radziszewski, P., Van Kerrebroeck, P., Wyndaele, J., Bosman, B. et al (2013b) A phase II dose-ranging study of mirabegron in patients with overactive bladder. Int Urogynecol J 24: Chapple, C., Kaplan, S., Mitcheson, D., Klecka, J., Cummings, J., Drogendijk, T. et al (2013c) Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a beta(3)-adrenoceptor agonist, in overactive bladder. Eur Urol 63: Coyne, K., Sexton, C., Thompson, C., Milsom, I., Irwin, D., Kopp, Z. et al. (2009) The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int 104: De Ridder, D. (2006) Antimuscarinics and cognitive function. Eur Urol 50: Fowler, C., Griffiths, D. and de Groat, W. (2008) The neural control of micturition. Nat Rev Neurosi 9: Gray, S., Anderson, M., Dublin, S., Hanlon, J., Hubbard, R., Walker, R. et al. (2015) Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med 175: Haylen, B., de Ridder, D., Freeman, R., Swift, S., Berghmans, B., Lee, J. et al. (2010) An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J 21: Herschorn, S., Barkin, J., Castro-Diaz, D., Frankel, J., Espuna-Pons, M., Gousse, A. et al. (2013) A phase III, randomized, double-blind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the beta3 adrenoceptor agonist, mirabegron, in patients with symptoms of overactive bladder. Urology 82: Igawa, Y., Schneider, T., Yamazaki, Y., Tatemichi, S., Homma, Y. and Nishizawa, O. (2012) Functional investigation of β-adrenoceptors in human isolated detrusor focusing on the novel selective β3-adrenoceptor agonist KUC Naunyn Schmiedebergs Arch Pharmacol 385: Igawa, Y., Yamazaki, Y., Takeda, H., Akahane, M., Ajisawa, Y., Yoneyama, T. et al. (1998) Possible beta 3-adrenoceptor-mediated relaxation of the human detrusor. Acta Physiol Scand 164: Igawa, Y., Yamazaki, Y., Takeda, H., Kaidoh, K., Akahane, M., Ajisawa, Y. et al. (2001) Relaxant effects of isoproterenol and selective beta3- adrenoceptor agonists on normal, low compliant and hyperreflexic human bladders. J Urol 165: Jayarajan, J. and Radomski, S. (2014) Pharmacotherapy of overactive bladder in adults: a review of efficacy, tolerability and quality of life. Res Rep Urol 6: Kay, G., Crook, T., Rekeda, L., Lima, R., Ebinger, U., Arguinzoniz, M. et al. (2006) Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol 50: Kerdaron, J., Robain, G., Jeandel, C., Mongiat Artus, P., Gamé, X., Fatton, B. et al. (2014) Impact on cognitive function of anticholinergic drugs used for the treatment of overactive bladder in the elderly. Prog Urol 24: Khullar, V., Amarenco, G., Angulo, J., Cambronero, J., Høye, K., Milsom, I. et al. (2013) Efficacy and tolerability of mirabegron, a beta(3)-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur Urol 63:

9 Therapeutic Advances in Urology 8(1) Visit SAGE journals online SAGE journals Krauwinkel, W., Dickinson, J., Schaddelee, M., Meijer, J., Tretter, R., van de Wetering, J. et al. (2014) The effect of mirabegron, a potent and selective β3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol. Eur J Drug Metab Pharmacokinet 39: Kuo, H., Lee, K., Na, Y., Sood, R., Nakaji, S., Kubota, Y. et al. (2014) Results of a randomized, double-blind, parallel-group, placebo- and activecontrolled, multicenter study of mirabegron, a β3-adrenoceptor agonist, in patients with overactive bladder in Asia. Neurourol Urodyn 34: Madhuvrata, P., Cody, J., Ellis, G., Herbison, G. and Hay-Smith, E. (2012) Which anticholinergic drug for overactive bladder symptoms in adults. Cochrane Database Syst Rev: CD Maggiore, U., Cardozo, L., Ferrero, S., Sileo, F., Cola, A., Del Deo, F. et al. (2014) Mirabegron in the treatment of overactive bladder. Expert Opin Pharmacother 15: Maman, K., Aballea, S., Nazir, J., Desroziers, K., Neine, M., Siddiqui, E. et al. (2014) Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison. Eur Urol 65: Matthews, L., Shapiro, R. and Zaslau, S. (2014) Pharmacologic management of overactive bladder and urge incontinence: a review of new and old treatment options. J Androl Gynaecol 2: 4. Milsom, I., Abrams, P., Cardozo, L., Roberts, R., Thüroff, J. and Wein, A. (2001) How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 87: Nabi, G., Cody, J., Ellis, G., Herbison, P. and Hay- Smith, J. (2006) Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database Syst Rev: CD Nitti, V., Auerbach, S., Martin, N., Calhoun, A., Lee, M. and Herschorn, S. (2013) Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol 189: Notte, S., Marshall, T., Lee, M., Hakimi, Z., Odeyemi, I., Chen, W. et al. (2012) Content validity and test-retest reliability of patient perception of intensity of urgency scale (PPIUS) for overactive bladder. BMC Urol 12: 26. Sexton, C., Notte, S., Maroulis, C., Dmochowski, R., Cardozo, L., Subramanian, D. et al. (2011) Persistence and adherence in the treatment of overactive bladder syndrome with anticholinergic therapy: a systematic review of the literature. Int J Clin Pract 65: Skriapas, K., Poulakis, V., Dillenburg, W., de Vries, R., Witzsch, U., Melekos, M. et al. (2006) Tensionfree vaginal tape (TVT) in morbidly obese patients with severe urodynamic stress incontinence as last option treatment. Eur Urol 49: Takasu, T., Ukai, M., Sato, S., Matsui, T., Nagase, I., Maruyama, T. et al. (2007) Effect of (R)-2-(2- aminothiazol-4-yl)-4 -{2-[(2- hydroxy-2-phenylethyl) amino]ethyl} acetanilide (YM178), a novel selective beta(3)-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 321: Tyagi, P. and Tyagi, V. (2010) Mirabegron, a beta(3)-adrenoceptor agonist for the potential treatment of urinary frequency, urinary incontinence or urgency associated with overactive bladder. IDrugs 13: Veenboer, P. and Bosch, J. (2014) Long-term adherence to antimuscarinic therapy in everyday practice: a systematic review. J Urol 191: Wagg, A. (2012) The cognitive burden of anticholinergics in the elderly implications for the treatment of overactive bladder. Eur Urol Rev 7: Wagg, A., Cardozo, L., Nitti, V., Castro-Diaz, D., Auerbach, S., Blauwet, M. et al. (2014) The efficacy and tolerability of the β3-adrenoceptor agonist mirabegron for the treatment of symptoms of overactive bladder in older patients. Age Ageing 43: Wagg, A., Compion, G., Fahey, A. and Siddiqui, E. (2012) Persistence with prescribed antimuscarinic therapy for overactive bladder: a UK experience. BJU Int 110: Wu, T., Duan, X., Cao, C., Peng, C., Bu, S. and Wang, K. (2014) The role of mirabegron in overactive bladder: a systematic review and meta-analysis. Urol Int 93: Yamaguchi, O. (2010) Antimuscarinics and overactive bladder: other mechanism of action. Neurourol Urodyn 29: Yamaguchi, O., Marui, E., Kakizaki, H., Homma, Y., Igawa, Y., Takeda, M. et al. (2014) Phase III, randomised, double-blind, placebo-controlled study of the β3-adrenoceptor agonist mirabegron, 50 mg once daily, in Japanese patients with overactive bladder. BJU Int 113: