Mirabegron 50 mg once-daily for the treatment of symptoms of overactive bladder: An overview of efficacy and tolerability over 12 weeks and 1 year

bs_bs_banner International Journal of Urology (2014) 21, 960 967 doi: 10.1111/iju.12568 Review Article Mirabegron 50 mg once-daily for the treatment of symptoms of overactive bladder: An overview of efficacy and tolerability over 12 weeks and 1 year Christopher R Chapple, 1 Steven A Kaplan, 2 David Mitcheson, 3 Mary Beth Blauwet, 4 Moses Huang, 5 Emad Siddiqui 5 and Vik Khullar 6 1 Department of Urology, Royal Hallamshire Hospital, Sheffield, UK; 2 Institute of Bladder and Prostate Health, Weill Medical College of Cornell University, New York, New York, 3 St Elizabeth s Medical Center, Brighton, Massachusetts, 4 Astellas Pharma Global Development, Northbrook, Illinois, USA; 5 Astellas Pharma Europe Ltd, Chertsey, Surrey, and 6 Urogynaecology Department, St Mary s Hospital, Imperial College, London, UK Abbreviations & Acronyms AE = adverse events ANCOVA = analysis of covariance APTC/MACE = Antiplatelet Trialists Collaboration/Major Adverse Cardiovascular Events AUR = acute urinary retention BP = blood pressure CV = cardiovascular DBP = diastolic blood pressure ECG = electrocardiogram FAS = full analysis set FAS-I = full analysis set-incontinence HRQoL = health-related quality of life MVV = mean volume voided OAB = overactive bladder OAB-q = overactive bladder questionnaire PPBC = Patient Perception of Bladder Condition PRO = patient reported outcomes QD = once daily QTcF = QT interval corrected for heart rate using Fridericia s formula SAE = serious adverse events SAF = safety analysis set SBP = systolic blood pressure TEAE = treatment-emergent adverse events TS-VAS = Treatment Satisfaction Visual Analog Scale UTI = urinary tract infection Correspondence: Christopher R Chapple M.D., Department of Urology, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK. Email: c.r.chapple@shef.ac.uk Received 30 April 2014; accepted 17 June 2014. Online publication 4 August 2014 Abstract: The aim of the present review article was to summarize the efficacy and tolerability for mirabegron 50 mg over 12 weeks and 1 year versus placebo (SCORPIO) or tolterodine ER 4 mg (SCORPIO and TAURUS). After a 2-week placebo run-in, adults with overactive bladder symptoms for 3 months were randomized if, during a 3-day micturition diary period before baseline, they had an average of 8 micturitions/24 h and 3 urgency episodes. Efficacy end-points were change from baseline to each study visit and final visit in incontinence, micturitions, volume voided/micturition, urgency incontinence, urgency (grades 3 or 4), level of urgency and nocturia. Additional secondary efficacy variables included patient-reported outcomes. Safety variables included changes in treatmentemergent adverse events and vital signs. For SCORPIO, statistically significant improvements from baseline in efficacy variables and patient-reported outcomes were seen with mirabegron versus placebo from week 4, and were maintained over time. For TAURUS, numerical improvements in efficacy were evident from month 1, and were maintained throughout 12 months. Treatment-emergent adverse events incidence was similar between groups, except for dry mouth, which was reported by fourfold (SCORPIO) and threefold (TAURUS) more patients taking tolterodine than mirabegron. Mirabegron 50 mg for 12 weeks was associated with statistically significant improvements in objective measures of efficacy and patient-reported outcomes. At final visit, improvements with mirabegron 50 mg were statistically greater versus placebo. The efficacy profile of mirabegron 50 mg appears to be maintained over 12 months. Key words: agonist. Introduction efficacy, mirabegron, overactive bladder, tolerability, β 3-adrenoceptor Mirabegron is a β 3-adrenoceptor agonist approved for treatment of OAB in Europe, the USA, Canada, Japan and Australia. It is the first in a new class of compounds, with a mechanism of action different to antimuscarinics, 1 and is available in two oral doses 25 and 50 mg. Product labeling differs between countries, with a recommended starting dose of 25 mg QD in the USA, Canada and Australia, with an option to increase to 50 mg, and a recommended dose of 50 mg QD in Japan and Europe, with the 25 mg dose reserved for special populations (e.g. patients with severe renal impairment or moderate hepatic impairment). No dose adjustment is required with respect to age or sex. SCORPIO, a large, randomized, placebo-controlled, phase III trial (Study 178-CL-046; NCT00689104) was carried out to evaluate efficacy, safety and tolerability of mirabegron, 50 and 100 mg QD, over 12 weeks, in patients with OAB. 2 TAURUS, a 1-year, randomized, double-blind, parallel-group, active-controlled, safety study (Study 178-CL-049 [NCT00688688]), 3 was carried out to evaluate safety, tolerability and efficacy of mirabegron 50 and 100 mg QD over 1 year. Both studies incorporated a tolterodine ER 4 mg active control arm to enable efficacy and safety of mirabegron to be placed in context with a commonly used antimuscarinic. The studies were carried out in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki (1996). Study protocols and the 960 2014 The Japanese Urological Association

Mirabegron 50 mg over 12 weeks and 1 year informed consent form were reviewed and approved by the local independent ethics committees before study initiation. Patients provided written informed consent. This present paper presents an overview of efficacy and tolerability data for the 50 mg dose (recommended starting dose in the EU) over 12 weeks and 1 year versus comparator placebo (SCORPIO) or active-control, tolterodine ER 4 mg (SCORPIO and TAURUS). Data for the 100 mg dose are not presented, as this is not a licensed dose. Methods Study design Both SCORPIO and TAURUS enrolled men and women aged 18 years with OAB symptoms for 3 months. Naïve patients and patients who had completed previous 12-week phase III studies (SCORPIO, ARIES [178-CL-047, NCT00662909] 4 ) could be enrolled in TAURUS, but non-naïve patients required 30 days wash-out. After a 2-week placebo run-in to determine baseline symptoms, patients were randomized if, during a 3-day micturition diary period before baseline, they had an average of 8 micturitions/24 h and 3 urgency episodes (Patient Perception of Intensity of Urgency Scale grade 3 or 4) with/without incontinence. Key OAB-related exclusion criteria included stress incontinence or mixed stress/urgency incontinence where stress was predominant at screening, or average total daily urine volume of >3000 ml, recorded in a 3-day micturition diary. Eligible patients were randomized in a 1:1:1:1 ratio to 12-week, double-blind treatment (SCORPIO) or 1:1:1 to 1-year, doubleblind treatment (TAURUS); all treatments were administered orally, QD (Fig. 1). Efficacy assessments Efficacy end-points were change from baseline to each study visit (SCORPIO: weeks 4, 8, 12; TAURUS: months 1, 3, 6, 9, 12) and final visit (end of treatment) in the mean number of incontinence episodes/24 h and micturitions/24 h. For SCORPIO, change from baseline to final visit in both outcomes were co-primary end-points. For TAURUS, efficacy end-points were secondary. Other efficacy end-points included change from baseline to each study visit and final visit in MVV/ micturition; number of urgency incontinence episodes/24 h; number of urgency episodes (grades 3 or 4)/24 h; level of urgency; and number of nocturia episodes/24 h. Responder analyses based on incontinence episodes were carried out at each study visit and the final visit. Responder definitions were: zero incontinence episodes (responder = patient with no incontinence episodes post-baseline at study visit or final visit [dry rate]); and reduction in incontinence episodes (responder = patient with 50% decrease from baseline in mean number of incontinence episodes/24 h). Additional secondary efficacy variables were PRO. These included change from baseline to final visit in the symptom bother score (level of bother associated with OAB symptoms assessed using the 8 items comprising the symptom bother scale of the 33-item OAB-q); total HRQoL, measured using the remaining 25 items of the OAB-q; subscales of the HRQoL measuring coping, concern, sleep and social interaction; the PPBC scale; and the TS-VAS. (a) BASELINE SCREENING* (randomization) 2-week 12-week treatment period placebo run-in : n=497 Visit 1 Week 2 (b) SCREENING* Visit 1 Week 2 Visit 2 Week 0 2-week placebo run-in Safety assessments Safety variables included extent of exposure, and incidence and severity of TEAE (defined as AE starting or worsening in the period from the first dose of the double-blind study drug until 30 days after the last dose). Changes in laboratory parameters and vital signs (pulse rate, BP and ECG data) were summarized. Urinary AE of interest were UTI and AUR. CV-related events of interest were hypertension and cardiac arrhythmia (including atrial fibrillation and tachycardia). Hypertension was reported as an AE if any of the following criteria were met, or at the investigator s discretion: average SBP 140 mmhg and/or average DBP 90 mmhg at two consecutive post-baseline visits for patients without hypertension at baseline; average SBP increased by 20 mmhg and/or average DBP increased by 10 mmhg at two consecutive post-baseline visits for patients with hypertension at baseline; initiation or increase in dose of an antihypertensive. For TAURUS, safety assessments were primary end-points. Statistical analyses Mirabegron 50 mg/day: n=497 4 mg/day: n=495 Visit 3 Week 4 BASELINE (randomization) Visit 4 Week 8 12-month treatment period END OF TREATMENT (final visit) Mirabegron 50 mg/day: n=815 4 mg/day: n=813 Visit 2 Visit 3 Visit 4 Week 0 Month 1 Month 3 Visit 5 Month 6 FOLLOW UP Visit 5 Visit 6 Week 12 + 30 days END OF TREATMENT (final visit) Visit 6 Visit 7 Month 9 Month 12 Fig. 1 Overview of design of (a) SCORPIO and (b) TAURUS. Data for the 100-mg dose are not presented here, as this is not a licensed dose. *Screening from weeks 3 to 2. Evaluation of adverse events and concomitant medication by telephone contact or visit for a period of 30 days after the final visit in SCORPIO; n, number of patients randomized. Safety was evaluated in the SAF (all randomized patients receiving 1 dose of double-blind study drug). The FAS comprised SAF patients recording 1 micturition measurement in 2014 The Japanese Urological Association 961

CR CHAPPLE ET AL. the 3-day baseline diary and 1 post-baseline diary. The FAS-I population comprised FAS patients recording 1 incontinence episode in the 3-day baseline diary. For SCORPIO, inferential analyses for change from baseline in incontinence episodes were carried out using a separate stratified rank ANCOVA for mirabegron 50 mg versus placebo. The stratified rank ANCOVA was used for hypothesis testing and calculating pairwise P-values. The least squares mean estimates and two-sided 95% confidence intervals for mean changes from baseline within treatment groups, and mean change from baseline in the difference between mirabegron 50 mg and placebo and between tolterodine and placebo were derived from the corresponding ANCOVA model using treatment, sex and geographic region as fixed factors, and baseline as a covariate. All other change from baseline efficacy end-points and vital sign variables were analyzed using ANCOVA. Responder end-points were analyzed using a logistic regression model that included treatment, sex, geographic region and baseline. For TAURUS, two models were used to analyze efficacy and vital sign variables. A repeated-measures model analyzed change from baseline to study visits (time) for efficacy and vital sign variables to obtain adjusted means by treatment group and time. Factors in the repeated-measures model included previous study history, sex, geographic region, treatment group, time, treatment by time interaction and sex by time interaction with baseline, and baseline by time interaction as covariates. Change from baseline to final visit was analyzed using an ANCOVA model to obtain adjusted means for each treatment group. Factors in the ANCOVA model included previous study history, sex, geographic region and treatment group with baseline as a covariate. All other safety variables were analyzed descriptively. Results Study populations In each study, patient demographics and baseline characteristics were similar across treatment groups (Table 1). In TAURUS, 81.3% of patients had been previously treated in mirabegron phase III trials; similar proportions (21 22%) had previously received placebo or mirabegron 50 mg, and 14.1% had previously received tolterodine. Baseline values for OAB parameters were similar across groups. In TAURUS, 77.2% and 76.4% of patients randomized to mirabegron 50 mg and tolterodine, respectively, completed double-blind treatment. The most common reasons for discontinuation were withdrawal of consent (8.0% and 7.9%, respectively) and AE (6.4% and 6.0%, respectively). Mean duration of exposure was 311.3 days and 308.7 days, respectively (Table 2). In SCORPIO, 91.1%, 88.5% and 89.9% of patients randomized to placebo, mirabegron 50 mg and tolterodine completed the study. The most common reason for discontinuation was AE (2.6%, 5.0% and 4.8%, respectively). Study drug exposure was similar across treatment groups; mean duration of exposure was 80.8 days, 79.5 days and 80.6 days, respectively. Efficacy SCORPIO Baseline value: n: Mean change (SE) from baseline 0.5 1.5 2.67 291 FAS-I 2.83 293 * 2.63 300 11.71 480 FAS 11.65 473 Statistically significant improvements from baseline to final visit in mean numbers of incontinence episodes and micturitions were seen with mirabegron 50 mg versus placebo over 12 weeks (Fig. 2; P < 5). Improvements were seen from week 4, the earliest time-point assessed, and were maintained over time. Improvements from baseline to final visit in both co-primary end-points were also seen with tolterodine, but were not statistically significant versus placebo. Mirabegron 50 mg showed statistically significant improvements from baseline versus placebo at weeks 4, 8 and 12, and final visit in MVV/micturition, urgency incontinence episodes/ 24 h, urgency episodes/24 h and mean level of urgency (P 5; Fig. 3). Although tolterodine also showed statistically significant improvements from baseline versus placebo at weeks 4, 8 and 12, and final visit for MVV/micturition and urgency episodes/24 h, the difference versus placebo was not statistically significant after week 4 for urgency incontinence episodes/24 h, or at the final visit for mean level of urgency. For nocturia, the adjusted mean change from baseline was statistically significantly different versus placebo for mirabegron 50 mg, but not for tolterodine at week 12 and the final visit (P < 5). As early as week 4, the percentage of responders with 50% reduction in incontinence episodes was greater for mirabegron 50 mg and tolterodine than for placebo, and both groups showed a statistically significant difference versus placebo, which was maintained at the final visit (Table 3). At the final visit, 72.0% of patients on mirabegron 50 mg were responders, versus 68.3% on tolterodine. The percentage of responders who were incontinent at baseline and became dry post-baseline was numerically (although not statistically significantly) higher for mirabegron 50 mg and tolterodine than for placebo; this difference was maintained or increased from week 4 to the final visit. For OAB-q symptom bother, PPBC and TS-VAS, both mirabegron 50 mg and tolterodine showed statistically significant differences in improvement from baseline to final visit versus placebo. Mirabegron 50 mg also showed statistically significant differences versus placebo in the increase in HRQoL total score, and coping and concern subscales (all P < 5). * 11.55 475 Fig. 2 Adjusted change from baseline to final visit in mean number of incontinence episodes/24 h (FAS-I) and mean number of micturitions/24 h (FAS); SCORPIO. *Statistically significantly superior compared with placebo at the 5 level with multiplicity adjustment., placebo;, mirabegron 50 mg;, tolterodine ER 4 mg. 962 2014 The Japanese Urological Association

Mirabegron 50 mg over 12 weeks and 1 year Table 1 Demographic and baseline characteristics in SCORPIO and TAURUS Demographics (SAF) SCORPIO (12 weeks) TAURUS (1 year) Mirabegron 50 mg 4 mg Mirabegron 50 mg 4 mg n = 494 n = 493 n = 495 n = 812 n = 812 Sex, n (%) Male 138 (27.9) 136 (27.6) 134 (27.1) 210 (25.9) 212 (26.1) Female 356 (72.1) 357 (72.4) 361 (72.9) 602 (74.1) 600 (73.9) Age (years) Mean (SD) 59.2 (12.3) 59.1 (12.4) 59.1 (12.9) 59.2 (12.6) 59.6 (12.5) n (%) by age group 65 years 181 (36.6) 178 (36.1) 192 (38.8) 289 (35.6) 303 (37.3) 75 years 44 (8.9) 46 (9.3) 37 (7.5) 75 (9.2) 83 (10.2) Race, n (%) White 490 (99.2) 488 (99.0) 490 (99.0) 778 (95.8) 780 (96.1) Black or African American 2 (0.4) 1 (0.2) 3 (0.6) 22 (2.7) 20 (2.5) Asian 0 2 (0.4) 2 (0.4) 8 (1.0) 5 (0.6) Other 2 (0.4) 2 (0.4) 0 4 (0.5) 7 (0.9) Body mass index (kg/m 2 ) Mean (SD) 27.8 (5.0) 27.5 (4.9) 27.8 (5.0) 29.0 (6.3) 28.5 (5.7) Type of OAB, n (%) Urgency incontinence 204 (41.3) 200 (40.6) 190 (38.4) 296 (36.5) 317 (39.0) Frequency 184 (37.2) 180 (36.5) 194 (39.2) 284 (35.0) 285 (35.1) Mixed stress/urgency incontinence 106 (21.5) 113 (22.9) 111 (22.4) 232 (28.6) 210 (25.9) Prior OAB surgery, n (%) Yes 22 (4.5) 34 (6.9) 20 (4.0) 75 (9.2) 68 (8.4) Used OAB drug previously, n (%) 239 (48.4) 252 (51.1) 241 (48.7) 446 (54.9) 447 (55.0) Reason for previous OAB drug discontinuation, n (%) Insufficient effect 159 (66.5) 168 (66.7) 162 (67.2) 297 (66.6) 283 (63.3) Poor tolerability 69 (28.9) 69 (27.4) 59 (24.5) 97 (21.7) 122 (27.3) Duration of OAB symptoms, months Mean (SD) 76.0 (91.4) 79.6 (87.1) 75.5 (92.2) 87.4 (96.3) 83.8 (87.3) Range 3 688 3 637 3 711 3 653 3 642 OAB parameters (FAS) n = 480 n = 473 n = 475 n = 789 n = 791 No. micturitions/24 h, mean (SD) 11.71 (3.14) 11.65 (2.97) 11.55 (2.78) 11.13 (2.80) 10.94 (2.62) Volume voided/micturition, mean (SD) 156.7 (52.5) 161.1 (58.4) 158.6 (54.1) 160.1 (58.63) 160.1 (56.65) Urgency episodes (grade 3 or 4)/24 h, mean (SD) 5.76 (3.99) 5.69 (3.65) 5.77 (3.45) 5.66 (3.57) 5.45 (3.45) Mean level of urgency 2.37 (0.56) 2.40 (0.54) 2.41 (0.56) 2.45 (0.54) 2.44 (0.52) Nocturia episodes/24 h, mean (SD) 1.98 (1.41) 1.87 (1.29) 1.95 (1.41) 1.83 (1.36) 1.77 (1.35) OAB parameters (FAS-I) n = 291 n = 293 n = 300 n = 479 n = 488 No. incontinence episodes/24 h, mean (SD) 2.67 (2.40) 2.83 (2.83) 2.63 (2.56) 2.66 (2.63) 2.42 (2.37) No. urgency incontinence episodes/24 h, mean (SD) 2.36 (2.18) 2.46 (2.60) 2.28 (2.28) 2.43 (2.40) 2.20 (2.23) n = 493 for placebo in SCORPIO, n = 811 for mirabegron 50 mg in TAURUS, n = 809 for tolterodine ER 4 mg in TAURUS. Predominant types of OAB were defined as follows: urgency incontinence = urge incontinence only; mixed = mixed stress/urge incontinence with urge as a predominant factor; frequency = frequency/urgency. Patients could choose more than one reason for discontinuation of previous OAB drug. n = 472. n = 474. TAURUS TAURUS was primarily a safety study; not designed to show statistically significant differences in efficacy between treatment groups. Nevertheless, numerical improvements in efficacy variables were evident with mirabegron 50 mg from the first measured time-point (month 1), and were maintained throughout 12 months. These included similar reductions versus tolterodine in the adjusted mean change from baseline in the mean number of micturitions/24 h, incontinence episodes/24 h and MVV/micturition (Fig. 4). At the final visit, the percentage of responders with 50% decrease from baseline in the mean number of incontinence episodes/24 h was 63.7% and 66.8% in the mirabegron 50 mg and tolterodine groups, respectively, and responders for zero incontinence episodes were 43.4% and 45.1%, respectively. Mirabegron 50 mg showed numerical improvements from baseline on other secondary efficacy variables including the number of nocturia episodes, OAB-q symptom bother, HRQoL, PPBC and TS-VAS. Safety/tolerability Overall incidence of TEAE in SCORPIO was similar across treatment groups: 42.8% of patients receiving mirabegron 50 mg experienced 1 TEAE compared with 43.3% and 46.7% 2014 The Japanese Urological Association 963

CR CHAPPLE ET AL. Table 2 Exposure to study drug and incidence of TEAE (number of patients reporting event [as % of total number in treatment group]) by preferred term; SAF SCORPIO (12 weeks) TAURUS (1 year) (n = 494) Mirabegron 50 mg (n = 493) 4mg(n = 495) Mirabegron 50 mg (n = 812) 4mg(n = 812) Exposure to study drug (days), mean (SD) 80.8 (15.6) 79.5 (18.4) 80.6 (17.3) 311.3 (109.9) 308.7 (111.5) Any TEAE 214 (43.3) 211 (42.8) 231 (46.7) 485 (59.7) 508 (62.6) Most common (reported by 2% of patients in any treatment group in SCORPIO or 3% of patients in any treatment group in TAURUS by preferred term) Hypertension 38 (7.7) 29 (5.9) 40 (8.1) 75 (9.2) 78 (9.6) Headache 14 (2.8) 18 (3.7) 18 (3.6) 33 (4.1) 20 (2.5) Nasopharyngitis 8 (1.6) 14 (2.8) 14 (2.8) 32 (3.9) 25 (3.1) Dry mouth 13 (2.6) 14 (2.8) 50 (10.1) 23 (2.8) 70 (8.6) Influenza 8 (1.6) 11 (2.2) 7 (1.4) 21 (2.6) 28 (3.4) UTI 7 (1.4) 7 (1.4) 10 (2.0) 48 (5.9) 52 (6.4) Constipation 7 (1.4) 8 (1.6) 10 (2.0) 23 (2.8) 22 (2.7) Drug-related TEAE 89 (18.0) 100 (20.3) 131 (26.5) 213 (26.2) 224 (27.6) Most common (reported by 2% of patients in any treatment group in SCORPIO or 3% of patients in any treatment group in TAURUS by preferred term) Hypertension 23 (4.7) 20 (4.1) 30 (6.1) 43 (5.3) 42 (5.2) Headache 6 (1.2) 13 (2.6) 11 (2.2) 18 (2.2) 14 (1.7) Dry mouth 9 (1.8) 9 (1.8) 47 (9.5) 20 (2.5) 67 (8.3) Maximum TEAE severity Mild 135 (27.3) 116 (23.5) 129 (26.1) 222 (27.3) 251 (30.9) Moderate 67 (13.6) 76 (15.4) 85 (17.2) 212 (26.1) 218 (26.8) Severe 12 (2.4) 19 (3.9) 17 (3.4) 51 (6.3) 39 (4.8) Deaths 0 0 1 (0.2) 3 (0.4) 2 (0.2) SAE 8 (1.6) 14 (2.8) 11 (2.2) 42 (5.2) 44 (5.4) Drug-related SAE 4 (0.8) 3 (0.6) 6 (1.2) 10 (1.2) 5 (0.6) TEAE leading to permanent discontinuation of study drug 13 (2.6) 24 (4.9) 22 (4.4) 48 (5.9) 46 (5.7) Most common (reported by 0.4% of patients in any treatment group in either SCORPIO or TAURUS by preferred term) Nausea 2 (0.4) 1 (0.2) 0 3 (0.4) 1 (0.1) Chest pain 2 (0.4) 0 0 0 0 Fatigue 0 0 3 (0.6) 1 (0.1) 1 (0.1) Constipation 1 (0.2) 0 1 (0.2) 7 (0.9) 0 Headache 0 1 (0.2) 2 (0.4) 5 (0.6) 3 (0.4) Hypertensive crisis 0 2 (0.4) 0 0 0 Hypertension 1 (0.2) 0 1 (0.2) 4 (0.5) 3 (0.4) Urinary retention 0 1 (0.2) 3 (0.6) 0 1 (0.1) Viral infection 2 (0.4) 0 0 0 0 Dry mouth 0 0 1 (0.2) 3 (0.4) 4 (0.5) Upper abdominal pain 0 0 1 (0.2) 1 (0.1) 3 (0.4) Vision blurred 0 0 0 3 (0.4) 1 (0.1) UTI 0 0 0 3 (0.4) 1 (0.1) Tachycardia 0 2 (0.4) 0 0 0 Dizziness 0 1 (0.2) 1 (0.2) 4 (0.5) 0 Drug-related TEAE leading to discontinuation 9 (1.8) 18 (3.7) 20 (4.0) 35 (4.3) 31 (3.8) Treatment relatedness was based on investigator assessment. Includes any death that occurred at any time after the first dose of study drug, regardless of time after the last dose of study drug. of patients receiving placebo and tolterodine, respectively. The corresponding values for TAURUS were 59.7% for mirabegron 50 mg and 62.6% for tolterodine (Table 2). In SCORPIO, hypertension and headache were the only TEAE occurring with an incidence 3% in the mirabegron 50 mg group. However, the overall incidence of hypertension TEAE was higher for tolterodine and placebo than for mirabegron 50 mg. In TAURUS, hypertension, headache, nasopharyngitis and UTI occurred with an incidence of 3% for mirabegron 50 mg. In general, the incidence of most TEAE was similar for mirabegron 50 mg, placebo (in SCORPIO) and tolterodine, except for dry mouth, which was reported by approximately fourfold (SCORPIO) and threefold (TAURUS) more patients taking tolterodine than mirabegron 50 mg. Constipation occurred with a similar incidence in all treatment groups in SCORPIO and in TAURUS (Table 2). The majority of TEAE were mild. The incidence of SAE and discontinuations as a result of TEAE was low and similar across treatment groups, and most SAE were not considered related to the study drug. The frequency of UTI was similar for all treatment groups in SCORPIO, and in TAURUS (where three mirabegron patients and one tolterodine patient discontinued as a result of UTI). In SCORPIO, two patients receiving placebo, one receiving mirabegron and three receiving tolterodine reported urinary retention. TEAE of AUR were reported by one patient receiving placebo, one receiving mirabegron and three receiving tolterodine. The mirabegron patient and the three tolterodine 964 2014 The Japanese Urological Association

Mirabegron 50 mg over 12 weeks and 1 year (a) Mean (SE) change from baseline (c) 30 20 10 * 0 Baseline 4 8 12 Final Week Visit (b) Mean (SE) change from baseline (d) 0.2 0.4 0.6 0.8 1.2 1.4 1.6 1.8 Baseline 4 8 12 Final Visit Week Fig. 3 Adjusted change from baseline at each visit in (a) MVV/micturition (FAS), (b) mean number of urgency incontinence episodes/24 h (FAS-I), (c) mean number of urgency episodes (grade 3 or 4)/24 h (FAS) and (d) mean level of urgency (FAS); SCORPIO. Statistically significantly superior compared with placebo at the 5 level *with and without multiplicity adjustment., placebo;, mirabegron 50 mg;, tolterodine ER 4 mg. Mean (SE) change from baseline 3.0 Baseline 4 8 12 Final Visit Week Mean (SE) change from baseline 0.1 0.2 0.3 0.4 Baseline 4 8 12 Final Week Visit Table 3 Results of responder analyses at final visit based on incontinence episodes for SCORPIO (FAS-I) (n = 291) Mirabegron 50 mg (n = 293) P-value 4mg(n = 300) P-value Percentage of patients with a 50% reduction from baseline to final visit in mean number of incontinence episodes/24 h 60.1 72.0 68.3 Odds ratio versus placebo (95% CI) 1.75 (1.23, 2.49) 02 1.44 (1.02, 2.03) 37 Percentage of patients with zero incontinence episodes at final visit 40.5 45.1 47.3 Odds ratio versus placebo (95% CI) 1.23 (0.86, 1.76) 0.26 1.35 (0.95, 1.92) 97 Mean (SE) change from baseline (a) 0.2 0.4 0.6 0.8 1.2 1.4 1.6 1.8 Baseline 1 3 6 9 Month 12 Final visit Mean (SE) change from baseline (b) 0.2 0.4 0.6 0.8 1.2 1.4 1.6 1.8 Baseline1 3 6 9 Month 12 Final visit Mean (SE) change from baseline (c) 30 20 10 0 Baseline1 3 6 9 Month 12 Final visit Fig. 4 Adjusted change from baseline at each visit in (a) mean number of incontinence episodes/24 h (FAS-I), (b) mean number of micturitions/24 h (FAS) and (c) MVV/micturition (FAS); TAURUS., mirabegron 50 mg;, tolterodine ER 4 mg. patients permanently discontinued treatment. In TAURUS, urinary retention was reported for one patient receiving mirabegron and three patients receiving tolterodine. There was no AUR in the mirabegron 50 mg group. AUR requiring catheterization was reported by one patient receiving tolterodine (a 65-year-old man with chronic history of lower urinary tract symptoms). In SCORPIO, small increases were observed at the final visit in AM and PM pulse rate with mirabegron versus placebo, but these changes were similar to, or less than, after tolterodine administration. In TAURUS, pulse rate changes seen with mirabegron were approximately 1 b.p.m. from baseline to final visit, but were less than with tolterodine (Table 4). In SCORPIO, BP increases for mirabegron were similar to or less than placebo. In TAURUS, adjusted mean changes from baseline to final visit for SBP for mirabegron and tolterodine were 0.2 and 0.5 mmhg for AM and 0.3 and mmhg for PM measurements. Adjusted mean changes for DBP were 0.3 and 0.1 mmhg for AM and and 0.6 mmhg for PM measurements. The overall incidence of arrhythmia TEAE in SCORPIO was 1.0%, 2.2% and 3.2% for placebo, mirabegron and tolterodine, respectively. In TAURUS, the incidence of cardiac 2014 The Japanese Urological Association 965

CR CHAPPLE ET AL. Table 4 Summary of vital sign data (SAF) SCORPIO (12 weeks) TAURUS (1 year) (n = 494) Mirabegron 50 mg (n = 493) 4mg(n = 495) Mirabegron 50 mg (n = 812) 4mg(n = 812) Vital sign data Adjusted mean difference from baseline to final visit (95% CI) in: n AM 481 474 476 791 793 PM 479 474 476 789 793 SBP (mmhg) AM 0.7 ( 0.1, 1.4) 0.6 ( 0.2, 1.3) 0.1 ( 0.6, 0.9) 0.2 ( 0.4, 0.9) 0.5 ( 1.1, 0.2) PM 1.2 (0.4, 2.0) 0.3 ( 0.5, 1.1) 0.4 ( 0.4, 1.2) 0.3 ( 0.9, 0.3) ( 0.7, 0.6) DBP (mmhg) AM 0.4 ( 0.1, 0.9) 0.3 ( 0.2, 0.8) 0.9 (0.1, 1.4) 0.3 ( 0.7, 0.1) 0.1 ( 0.3, 0.5) PM 0.3 ( 0.2, 0.8) 0.3 ( 0.2, 0.8) 1.3 (0.8, 1.8) ( 0.4, 0.4) 0.6 (0.2, 1.0) Pulse rate (b.p.m.) AM 0.8 (0.2, 1.3) 1.6 (1.0, 2.1) 1.6 (1.0, 2.1) 0.9 (0.5, 1.4) 1.5 (1.1, 2.0) PM 0.1 ( 0.5, 0.7) 0.8 (0.2, 1.4) 2.0 (1.4, 2.5) 0.4 ( 0.1, 0.8) 1.9 (1.4, 2.4) Adjusted mean difference versus placebo (95% CI) in: SBP (mmhg) AM 0.1 ( 1.2, 1.0) 0.5 ( 1.6, 0.6) PM 0.9 ( 2.1, 0.2) 0.8 ( 1.9, 0.4) DBP (mmhg) AM 0.1 ( 0.8, 0.6) 0.5 ( 0.2, 1.2) PM ( 0.8, 0.7) 1.0 (0.2, 1.7) Pulse rate (b.p.m.) AM 0.8 (, 1.6) 0.8 (, 1.6) PM 0.7 ( 0.1, 1.5) 1.9 (1.1, 2.7) ECG data QTcF interval Patients, n (%) meeting threshold criteria, maximum value of: n 446 434 435 736 733 >450 ms 9 (2.0) 4 (0.9) 17 (3.9) 36 (4.9) 32 (4.4) >480 ms 1 (0.2) 1 (0.2) 3 (0.7) 5 (0.7) 6 (0.8) >500 ms 0 0 1 (0.2) 2 (0.3) 1 (0.1) Patients, n (%) with increase from baseline from: n 425 418 418 729 724 30 ms to <60 ms 21 (4.9) 28 (6.7) 22 (5.3) 73 (1) 74 (10.2) 60 ms 1 (0.2) 1 (0.2) 2 (0.5) 3 (0.4) 3 (0.4) Total ( 30 ms) 22 (5.2) 29 (6.9) 24 (5.7) 76 (10.4) 77 (10.6) CV TEAE Incidence, n (%) of: n 494 493 495 812 812 Tachycardia 2 (0.4) 4 (0.8) 0 8 (1.0) 25 (3.1) Tachycardia SAE 0 0 0 0 0 Discontinuations due to tachycardia 0 2 (0.4) 0 0 0 ECG QT corrected interval prolonged 0 0 2 (0.4) 1 (0.1) 1 (0.1) Based on Medical Dictionary for Regulatory Activities (MedDRA) preferred term. arrhythmias was higher in the tolterodine group (6.0%) than the mirabegron group (3.9%), and the frequency of tachycardia TEAE was less for mirabegron than for tolterodine. In SCORPIO, only one patient the tolterodine patient who died as a result of a ruptured cerebral aneurysm 10 days after the last dose had a TEAE adjudicated as APTC/MACE. In TAURUS, overall incidence of APTC/MACE was 0.7% in the mirabegron group and 0.5% in the tolterodine group. No consistent trends in ECG changes were identified, and categorical outliers for QTc interval assessments were unremarkable across treatment groups. In both studies, mean changes from baseline to final visit in hematology laboratory parameters were small and similar between treatment groups. There were five deaths in TAURUS: three on mirabegron 50 mg (one as a result of cardiac failure judged unrelated to the study drug; one suicide possibly related to the study drug; one from a number of non-cv causes judged unrelated to the study drug and pneumonia possibly related to the study drug); and two on tolterodine (one as a result of coronary artery disease, one as a result of cerebrovascular accident, both unrelated to the study drug; however, these patients had prior exposure to 12 weeks of mirabegron). 966 2014 The Japanese Urological Association

Mirabegron 50 mg over 12 weeks and 1 year Discussion Treatment with mirabegron 50 mg for 12 weeks in patients with OAB was associated with statistically significant improvements in objective measures of efficacy, mirrored by statistically significant improvements in PRO. At the final visit, improvements with mirabegron were statistically greater than seen with placebo. Although the 1-year study was designed as a safety study, evaluation of efficacy outcomes suggests that the efficacy profile of mirabegron 50 mg is maintained over 12 months. In SCORPIO, the change from baseline in pulse rate after administration of mirabegron 50 mg QD was, in general, similar to, or less than, after tolterodine administration. Hypertension, the most common TEAE in the mirabegron group in SCORPIO, occurred with a lower incidence than placebo. In TAURUS, pulse rate changes seen with mirabegron 50 mg were less than with tolterodine. Changes in vital signs did not result in more CV-related AE in mirabegron-treated patients versus placebo- or tolterodine-treated patients in either study. Mirabegron 50 mg was well tolerated over both 12 weeks and 1 year. Typical anticholinergic side-effects, such as dry mouth, occurred with a similar incidence with mirabegron as placebo. Dry mouth occurred with a three- or fourfold lower incidence with mirabegron than with tolterodine. As noted in a metaanalysis, antimuscarinic drugs are associated with an incidence of dry mouth of 29.6%. 5 As dry mouth is reported to be an important factor determining persistence, the favorable tolerability profile of mirabegron might result in improved treatment adherence compared with antimuscarinics, with important implications for patient outcomes. Clinical trial data suggest that mirabegron provides efficacy similar to that of antimuscarinics, with an improved tolerability profile. Further use of this new class of agent in clinical practice will inform us if mirabegron can offer an improved efficacy tolerability balance for patients with OAB. Acknowledgments The authors thank Aideen Young and Sue Cooper of Envision Scientific Solutions Ltd, who provided medical writing assistance for this work, supported by Astellas Pharma. Conflict of interest Christopher R Chapple is an investigator, consultant and speaker for Astellas, Pfizer and Recordati, and a consultant for Ono and Lilly. Steven A Kaplan is an investigator for Astellas. David Mitcheson is a consultant for Astellas. Vik Khullar is an investigator, consultant and speaker for Astellas, Allergan and Pfizer. Mary Beth Blauwet, Moses Huang and Emad Siddiqui are employees of Astellas. References 1 Takasu T, Ukai M, Sato S et al. Effect of (R)-2-(2-aminothiazol-4-yl)-4 -{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective β 3-adrenoceptor agonist, on bladder function. J. Pharmacol. Exp. Ther. 2007; 321: 642 7. 2 Khullar V, Amarenco G, Angulo JC et al. Efficacy and tolerability of mirabegron, a β 3-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur. Urol. 2013; 63: 283 95. 3 Chapple CR, Kaplan SA, Mitcheson D et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a β 3-adrenoceptor agonist, in overactive bladder. Eur. Urol. 2013; 63: 296 305. 4 Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J. Urol. 2013; 189: 1388 95. 5 Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein D. The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur. Urol. 2008; 54: 543 62. 2014 The Japanese Urological Association 967