Vibegron 50 mg n = 118. Completed n = 102. Safety analysis set (SAF) Full analysis set (FAS)

Transcription

1 International Journal of Urology (218) 25, doi: /iju Original Article: Clinical Investigation Long-term safety and efficacy of the novel b 3 -adrenoreceptor agonist vibegron in Japanese patients with overactive bladder: A phase III prospective study Masaki Yoshida, 1 Hidehiro Kakizaki, 2 Satoru Takahashi, 3 Shinji Nagai 4 and Takafumi Kurose 4 1 Department of Urology, National Centre for Geriatrics and Gerontology, Obu, Aichi, 2 Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, 3 Department of Urology, Nihon University School of Medicine, Tokyo, and 4 Kyorin Pharmaceutical, Tokyo, Japan Abbreviations & Acronyms AE = adverse event AR = adrenoreceptor BMI = body mass index CI = confidence interval DBP = diastolic blood pressure ECG = electrocardiogram EOT = end of treatment FAS = full analysis set KHQ = King s Health Questionnaire LDA = longitudinal data analysis LS mean = least squares mean Max = maximum Med = median Min = minimum OAB = overactive bladder PGI = Patient Global Impression PVR = post-void residual urine volume QoL = quality of life SAE = serious adverse event SAF = safety analysis set SBP = systolic blood pressure SD = standard deviation TEAE = treatment-emergent adverse event Objectives: To evaluate the long-term safety and efficacy of vibegron 5 mg and 1 mg, a novel b 3 -adrenoreceptor agonist, in Japanese patients with overactive bladder. Methods: This was a 1-year, multicenter, open-label, non-controlled study. After a 1- week observation phase, patients were treated with vibegron for 52 weeks. When the efficacy was insufficient after an 8-week treatment with 5 mg, the dose was increased to 1 mg and maintained for an additional 44 weeks. Results: Among a total of 169 patients receiving one or more doses of vibegron, 118 (69.8%) received vibegron 5 mg for 52 weeks, and the dose was increased to 1 mg in 51 (3.2%) patients. The incidence of drug-related adverse events was 18.1% (21/116) in the vibegron 5 mg group and 11.8% (6/51) in the vibegron 1 mg group. Most frequent drug-related adverse events were dry mouth (3.%), residual urine volume increased (3.%), constipation (2.4%) and cystitis (1.8%). Statistically significant changes in overactive bladder symptom variables (daily means of micturitions, urgency episodes, urgency incontinence episodes, incontinence episodes and night-time frequency) from baseline were observed at week 4 and maintained until week 52. The condition of patients who did not respond well to vibegron 5 mg was much improved by increasing the dose to 1 mg. Vibegron improved the quality of life, and the proportion of patients satisfaction after the treatment with vibegron was high. Conclusions: Long-term (52-week) treatment with vibegron is safe, well-tolerated and effective in patients with overactive bladder. Key words: b 3 -adrenoreceptor agonist, long-term study, overactive bladder, safety, vibegron. Correspondence: Masaki Yoshida M.D., Ph.D., Department of Urology, National Centre for Geriatrics and Gerontology, 7-43 Morioka-cho, Obu, Aichi , Japan. akko-maki@umin.net This is an open access article under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is noncommercial and no modifications or adaptations are made. Received 6 November 217; accepted 3 April 218. Online publication 11 May 218 Introduction OAB is defined by the International Continence Society as urinary urgency, usually with urinary frequency and nocturia, with or without urgency urinary incontinence, in the absence of any other pathology. 1 In the general adult population, the prevalence of OAB is 1 2% in Japan, Europe and the USA, 2 4 but OAB has a significant negative impact on the healthrelated QoL of patients. 5,6 Anticholinergics have been the first-line treatment for OAB over the past decades. 7 However, many patients discontinue long-term anticholinergic therapy because of limited efficacy and undesired class-related AEs. 8,9 Much attention has been directed toward b 3 -AR agonists as a new and alternative target of OAB, as the human bladder expresses a high level of b 3 -AR mrna and b 3 -AR agonist relaxed detrusor smooth muscle Mirabegron was approved first as a b 3 -AR agonist for the treatment of OAB and is currently used widely in the world. 13 However, mirabegron is known to inhibit CYP2D6, a cytochrome P45 enzyme; a source of drug drug interactions. 14 Vibegron is a novel, potent and selective b 3 -AR agonist, and possesses favorable preclinical pharmacokinetic, pharmacological and toxicological profiles in vitro and in vivo as a candidate drug for OAB. 15,16 Especially regarding drug metabolism, vibegron did not show any induction and inhibitory effect on cytochrome P45 enzymes, suggesting a low risk of The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.

2 Safety and efficacy of vibegron drug drug interaction. 15 In a phase 2b placebo-controlled randomized clinical trial, treatments with vibegron 5 mg and 1 mg for 8 weeks in patients with OAB were generally well-tolerated and showed improvements in OAB symptoms (NCT : results/nct ). These efficacies were comparable or favorable to those of an active comparator, anticholinergic tolterodine. The objective of the present study was to evaluate the safety and efficacy of vibegron for long-term treatment of Japanese patients with OAB as a phase 3 study (JapicCTI- 1528). Methods Study design and patients This was a 1-year (52-week), multicenter, open-label, noncontrolled study in patients with OAB carried out at 25 sites in Japan. The study consisted of a 1-week observation phase and 52-week treatment phase with vibegron. The primary end-point of this study was the safety of vibegron, which was comprehensively evaluated. Male and female patients aged 2 years with OAB symptoms for 6 months were enrolled. The key exclusion criteria were concurrent diabetes insipidus, urinary tract stone, interstitial cystitis, pelvic organ prolapse, neurogenic bladder, clinically important lower urinary tract obstruction, enuresis, urinary tract infection or a history of recurrent urinary tract infection ( 3 during the past 6 months before screening); a history of pelvic surgery, or neurodegenerative diseases that could affect the lower urinary tract or its nerve supply; indwelling catheter or practiced intermittent self-catheterization; surgery within 6 months before screening to correct stress urinary incontinence or pelvic organ prolapse; bladder training, electrostimulation, magnetic stimulation, biofeedback procedure or pelvic floor muscle training; daily total volume of urine voided 3 ml; or PVR 1 ml. Patients who took smooth muscle-relaxant drugs, b 2 - or b 3 -AR agonists, or synthetic antidiuretic hormones were excluded. Concomitant medication with anticholinergics was allowed in this study, but the same regimen was to be maintained during the study. After evaluation for inclusion and exclusion criteria, patient were enrolled in the 1-week observation phase. At the end of the observation phase, once patients met the inclusion criteria related to OAB symptoms (mean frequency of micturitions/day 8, either urgency episodes/day 1 or urgency incontinence episodes/day 1 and the number of urgency incontinence episodes > half of incontinence episodes), patients entered into the treatment phase with vibegron 5 mg. After treatment with 5 mg for 8 weeks, if the investigator judged the efficacy as insufficient without any safety concern and patients agreed with the dose increase, the daily vibegron dose was increased from 5 mg to 1 mg. If the investigators judged no need for a dose increase, patients continued to receive vibegron 5 mg for an additional 44 weeks. After dose adjustment, a dose reduction from 1 mg to 5 mg was allowed only when clinically significant AEs were observed. The study protocol, informed consent form and other relevant study documentations were approved by the institutional review board at each participating study site. All patients gave written informed consent before initiation of any studyspecific procedure. The study was carried out in accordance with the ethical principles originating in or derived from the Declaration of Helsinki, International Council for Harmonization Good Clinical Practice Guidelines, and locally applicable laws and regulations. The study was designed and carried out by the sponsor (Kyorin Pharmaceutical, Tokyo, Japan) in collaboration with the principal investigators. The study is registered with Japan Pharmaceutical Information Center, number JapicCTI Safety and efficacy assessments Safety was assessed according to the incidence and severity of AEs, clinical test (hematology, biochemistry and urinalysis), vital signs, 12-lead ECG and PVR. The effect of the concomitant use of anticholinergics on safety was assessed. TEAE was defined as an event that first appeared after the Enrollment n = 169 Vibegron 5 mg n = 169 n = 169 Vibegron 5 mg n = 118 Vibegron 1 mg n = 51 Discontinued n = 16 Consent withdrawn: 8 Adverse events: 5 Others: 3 Discontinued n = 3 Consent withdrawn: 3 Completed n = 12 Completed n = 48 Fig. 1 Patient disposition. Safety analysis set (SAF) Full analysis set (FAS) The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association. 669

3 M YOSHIDA ET AL. start of treatment with vibegron, which was absent before or which worsened relative to the observation phase. For the assessment of efficacy, a 3-day micturition diary was used. Patients were advised to record the precise time and volume of each voided urine. The times of waking up and going to bed, urgency episodes, and incontinence episodes were also recorded. The evaluated efficacy parameters were daily means of micturitions, urgency episodes, urgency incontinence episodes, incontinence episodes and night-time frequency, and mean voided volume per micturition. Changes from baselines (week and week 8) in OAB symptom variables were analyzed at each visit. QoL was evaluated using the KHQ, 17 which was completed at weeks, 8, 24 and 52. In addition, patients satisfaction was assessed at the end of treatment using a self-administered PGI: very much improved, much improved, minimally improved, no change, minimally worse, much worse and very much worse. 18 Patient satisfaction levels were defined as satisfied, consisting of very much improved, much improved and minimally improved, and very much satisfied consisting of very much improved and much improved. Statistical analysis Safety analysis was carried out for patients in the SAF, which consisted of patients who took one or more dose of vibegron and had a safety measurement. Efficacy was analyzed in the FAS, which included all patients who took one or more dose of vibegron and had at least an efficacy measurement after the first treatment. AEs were coded using the Medical Dictionary for Regulatory Activities Japanese Edition version Changes in continuous variables from baseline were Table 1 Patients demographics and clinical characteristics at baseline (FAS) Variables All n = 166 Vibegron 5 mg (dose-retained) n = 115 Vibegron 1 mg (dose-increased) n = 51 Sex Female, n (%) 146 (88.) 11 (87.8) 45 (88.2) 1. Male, n (%) 2 (12.) 14 (12.2) 6 (11.8) Age (years) Mean SD (Min, Med, Max) (32, 61., 86) (35, 62., 86) (32, 57., 79) <65, n (%) 93 (56.) 62 (53.9) 31 (6.8) 65, n (%) 73 (44.) 53 (46.1) 2 (39.2) BMI (kg/cm 2 ) Mean SD (Min, Med, Max) (15.3, 22.32, 4.5) (15.3, 22.32, 35.2) (16.4, 22.35, 4.5) Type of OAB Wet, n (%) 113 (68.1) 72 (62.6) 41 (8.4).3 Dry, n (%) 53 (31.9) 43 (37.4) 1 (19.6) Duration of OAB symptoms (months) Mean SD (Min, Med, Max) (7, 54.5, 437) (8, 52., 437) (7, 78., 34) Previous therapy for OAB within 1 year before screening No, n (%) 17 (64.5) 71 (61.7) 36 (7.6).297 Yes, n (%) 59 (35.5) 44 (38.3) 15 (29.4) Anticholinergics, n (%) 49 (29.5) 35 (3.4) 14 (27.5).854 b 3 Adrenergic agonists, n (%) 19 (11.4) 16 (13.9) 3 (5.9).187 Herbal medicines, n (%) 2 (1.2) 2 (1.7) (.) 1. Non-pharmacological therapy, n (%) 3 (1.8) 3 (2.6) (.).553 Baseline characteristics Mean SD (Min, Med, Max) Micturitions/day <.1 (8., 11., 23.7) (8., 1.33, 15.7) (8., 12.67, 23.7) Urgency episodes/day <.1 (1., 3.67, 15.) (1., 3., 12.) (1., 4.33, 15.) Urgency incontinence episodes/day (., 1.33, 13.7) (., 1., 7.) (., 1.67, 13.7) Incontinence episodes/day (., 1.33, 13.7) (., 1., 7.3) (., 1.67, 13.7) Night-time frequency/day (., 1.33, 4.7) (., 1., 4.7) (., 1.33, 4.3) Voided volume/micturition (ml) (55.6, 145.9, 265.4) (79.6, , 265.4) (55.6, , 224.8) Student s t-test or Fisher s exact test (two-sided significance level of 5%) between the vibegron 5 mg and 1 mg groups. Daily mean urgency incontinence episodes 1 at baseline. Daily mean urgency incontinence episodes <1 at baseline. P-value The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.

4 Safety and efficacy of vibegron summarized using the descriptive statistics including mean, SD, Min, Med and Max, and categorical variables were described using absolute and relative frequency. The LS mean and the two-sided 95% CI of changes in the response variables from baseline to time of assessment in each group were estimated using a LDA model including adjustment factors: sex, prior treatment for OAB (use/no use of anticholinergics and b 3 -AR agonist) and urgency incontinence (OAB wet and dry). OAB wet was defined as patients with one or more mean urgency incontinence/day at baseline, and OAB dry as patients with less than one mean urgency incontinence/day at baseline. Statistical tests were carried out under the null hypothesis that the change difference was zero () using the LDA model. Baselines were defined as week and week 8. P-value <.5 was considered statistically significant. A sample size of 16 was selected to allow the assessment of 1 patients or more completed for 52 weeks treatment. All analyses were carried out using SAS software version 9.4 for Windows (SAS Institute, Cary, NC, USA). Results Patient disposition and baseline characteristics The study was carried out at 25 sites in Japan from March 215 to June 216. A total of 169 patients received one or more doses of vibegron (Fig. 1). The number of patients of the vibegron 5 mg (dose-retained) group was 118 (69.8%) and vibegron 1 mg (dose-increased) group was 51 (3.2%). The proportion of patients who completed the study was 86.4% (12/118) in the vibegron 5 mg group and 94.1% (48/51) in the vibegron 1 mg group. The SAF population consisted of 167 patients after excluding two patients because of double entries in different study sites. The FAS consisted of 166 patients after excluding one patient in the SAF due to unavailability of efficacy data (n = 1). Patient characteristics and baseline of the efficacy variables at week in the FAS population are presented in Table 1. There were no significant differences in patient characteristics between the two groups. However, the baseline of OAB symptom variables including daily means of micturitions, urgency episodes, urgency incontinence episodes and incontinence episodes, and the proportion of OAB wet in the vibegron 1 mg group were significantly higher than those in the vibegron 5 mg group. Anticholinergics, such as solifenacin, fesoterodine, imidafenacin and propiverine, were used in combination with vibegron in 34 (2.5%) patients: 25 (21.6%) patients in the 5 mg group and nine (17.6%) patients in the 1 mg group. Adherences of all patients to the treatment were 75% and mean SD exposure duration to vibegron was days (range days). Safety The overall incidence of any TEAEs was 55.1% (92/167), and drug-related TEAEs was 16.2% (27/167; Table 2). The Table 2 Number and percentage of patients with TEAEs classified by primary system organ class and preferred term (preferred term incidence 2%; SAF) All TEAE Drug-related TEAE System organ class Preferred term All Vibegron 5 mg (dose-retained) Vibegron 1 mg (dose-increased) All Vibegron 5 mg (dose-retained) (n = 167) (n = 116) (n = 51) (n = 167) (n = 116) (n = 51) n (%) n (%) n (%) n (%) n (%) n (%) Vibegron 1 mg (dose-increased) All 92 (55.1) 67 (57.8) 25 (49.) 27 (16.2) 21 (18.1) 6 (11.8) Gastrointestinal disorders 16 (9.6) 7 (6.) 9 (17.6) 8 (4.8) 4 (3.4) 4 (7.8) Constipation 5 (3.) 2 (1.7) 3 (5.9) 4 (2.4) 2 (1.7) 2 (3.9) Diarrhea 4 (2.4) 2 (1.7) 2 (3.9) (.) (.) (.) Dry mouth 8 (4.8) 4 (3.4) 4 (7.8) 5 (3.) 3 (2.6) 2 (3.9) Infections and infestations 46 (27.5) 38 (32.8) 8 (15.7) 3 (1.8) 3 (2.6) (.) Cystitis 11 (6.6) 1 (8.6) 1 (2.) 3 (1.8) 3 (2.6) (.) Gastroenteritis 3 (1.8) 3 (2.6) (.) (.) (.) (.) Influenza 3 (1.8) 3 (2.6) (.) (.) (.) (.) Nasopharyngitis 27 (16.2) 2 (17.2) 7 (13.7) (.) (.) (.) Pharyngitis 3 (1.8) 3 (2.6) (.) (.) (.) (.) Injury, poisoning and procedural complications 3 (1.8) 3 (2.6) (.) (.) (.) (.) Contusion 3 (1.8) 3 (2.6) (.) (.) (.) (.) Investigations 9 (5.4) 9 (7.8) (.) 5 (3.) 5 (4.3) (.) Blood triglycerides increased 4 (2.4) 4 (3.4) (.) (.) (.) (.) Residual urine volume increased 5 (3.) 5 (4.3) (.) 5 (3.) 5 (4.3) (.) Musculoskeletal and connective tissue disorders 3 (1.8) 3 (2.6) (.) 1 (.6) 1 (.9) (.) Arthralgia 3 (1.8) 3 (2.6) (.) 1 (.6) 1 (.9) (.) Respiratory, thoracic and mediastinal disorders 4 (2.4) 3 (2.6) 1 (2.) (.) (.) (.) Upper respiratory tract inflammation 4 (2.4) 3 (2.6) 1 (2.) (.) (.) (.) Skin and subcutaneous tissue disorders 4 (2.4) 2 (1.7) 2 (3.9) (.) (.) (.) Eczema 4 (2.4) 2 (1.7) 2 (3.9) (.) (.) (.) AEs were coded using the MedDRA/J version The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association. 671

5 M YOSHIDA ET AL. incidence of any AEs was similar between the vibegron 5 mg (dose-retained) and 1 mg (dose-increased) groups, although the incidence of cystitis and residual urine volume increased in the vibegron 5 mg group were numerically higher than in the 1 mg group. Common drug-related TEAEs were residual urine volume increased (4.3%, 5/116), dry mouth (2.6%, 3/116), cystitis (2.6%, 3/116) and constipation (1.7%, 2/116) in the vibegron 5 mg group, and dry mouth (3.9%, 2/51) and constipation (3.9%, 2/51) in the vibegron 1 mg group. Almost all the TEAEs were mild or moderate in intensity. Severe TEAEs, which only occurred in the vibegron 5 mg group, were angina pectoris, Prinzmetal angina, fall and cerebral infarction, but these were not considered related to vibegron, except cerebral infarction. One-third of TEAEs (32.9%) were reported during the first 12 weeks after the start of treatment and decreased time-dependently after week 12. One death due to fall was reported in the present study. Five SAEs other than death were reported in five patients in the vibegron 5 mg group: angina pectoris, Prinzmetal angina, cerebral infarction, intervertebral disc protrusion and vertigo positional, but were not reported in the vibegron 1 mg group. The investigator considered that all SAEs, except cerebral infarction, had no relationship with vibegron because of a non-correlation between the AE onset and the administration of the drug. All SAEs became less severe or recovered with appropriate treatments, except death. TEAEs leading to permanent discontinuation of the treatment occurred in six events in six patients: fall, Prinzmetal angina, cerebral infarction and angina pectoris (each one), and residual urine volume increased (n = 2). There were no notable differences in the incidence of drug-related TEAEs between combination with (23.5%) and without (14.3%) anticholinergics. However, dry mouth, increased residual urine volume and constipation, which are TEAEs related to anticholinergics, are relatively higher in patients with concominant use of anticholinergics. The incidence of dry mouth, increased residual urine volume and constipation was 5.9% (2/34), 11.8% (4/34) and 2.9% (1/34) in patients taking anticholinergic, and 2.3% (3/133),.8% (1/133) and 2.3% (3/133) in patients not taking anticholinergic, respectively. No clinically significant changes in vital signs were observed over time, as shown in Figure 2. Abnormal ECG was found in 3.% (5/166) of patients, but the investigator reported no relationship with vibegron. No notable changes in clinical tests (hematology, biochemistry and urinalysis) and PVR were observed during the study. The two patients who discontinued due to the increased residual urine volume (TEAE) were women with the concomitant use of anticholinergics. The increased PVR volumes were 365 ml (baseline 69 ml) and 184 ml (baseline 72 ml), respectively. In patients with the concomitant use of anticholinergics, PVR slightly increased from baseline at week 4 (9.1 ml); however, the increase was not clinically significant and no further increase was observed thereafter. The increase of PVR at week 52 was just 4.1 ml. Efficacy Significant changes from baseline (week ) at week 52 were observed in all OAB symptom variables (Table 3). These significant changes from baseline (week ) were found at week 4 and continued through the study (Fig. 3). Even in patients whose dose was increased due to insufficient efficacy judged by the investigators, the OAB symptom variables including micturition, urgency, urgency incontinence, incontinence and night-time frequency were significantly improved by treatment with vibegron 5 mg at week 8. In addition, the vibegron dose increase to 1 mg resulted in significant improvement (changes from week 8 to week 12; Fig. 3). In QoL assessments, treatment with vibegron significantly reduced the LS mean of the KHQ domain scores from baseline at week 52, except for general health perception (Table 4). The proportions of patients that reported satisfied and very much satisfied in the PGI were 91.% (151/166) and 71.1% (118/166), respectively (Table 5). Discussion The present 1-year long study showed that long-term vibegron 5 mg and 1 mg treatments were safe, well-tolerated and clinically useful in patients with OAB. In this study, the (a) SBP (mmhg) (b) DBP (mmhg) (c) Pulse (b.p.m.) EOT EOT EOT Fig. 2 Mean change (SD) of vital signs from baseline at each visit in: (a) SBP (mmhg), (b) DBP (mmhg) and (c) pulse (b.p.m.). ( ), Vibegron 5 mg/day (dose-retained); ( ), vibegron 1 mg/day (dose-increased) The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.

6 Safety and efficacy of vibegron Table 3 Changes from baselines (week and week 8) in OAB symptom variables at week 52 (FAS) Change from week at week 52 Change from week 8 at week 52 Variable Group n LS mean 95% CI P-value LS mean 95% CI P-value Micturitions/day All ( 3.26, 2.43) <.1.54 (.83,.26) <.1 Vibegron 5 mg (dose-retained) ( 3.21, 2.21) <.1.19 (.52,.14).258 Vibegron 1 mg (dose-increased) ( 3.9, 2.41) < ( 1.8,.82) <.1 Urgency episodes/day All ( 3.5, 2.64) <.1.52 (.78,.26) <.1 Vibegron 5 mg (dose-retained) ( 3.43, 2.39) <.1.19 (.49,.11).27 Vibegron 1 mg (dose-increased) ( 4.2, 2.65) < ( 1.67,.8) <.1 Urgency incontinence episodes/day Incontinence episodes/day Night-time frequency/ day Voided volume/ micturition (ml) All ( 2.7, 1.51) <.1.3 (.46,.14) <.1 Vibegron 5 mg (dose-retained) ( 1.88, 1.22) <.1.6 (.24,.12).515 Vibegron 1 mg (dose-increased) ( 2.76, 1.81) <.1.8 ( 1.5,.54) <.1 All ( 2.16, 1.58) <.1.33 (.5,.16) <.1 Vibegron 5 mg (dose-retained) ( 1.97, 1.26) <.1.9 (.28,.1).348 Vibegron 1 mg (dose-increased) ( 2.9, 1.89) <.1.81 ( 1.9,.54) <.1 All (.87,.59) <.1.19 (.3,.8) <.1 Vibegron 5 mg (dose-retained) (.88,.54) <.1.12 (.25,.2).85 Vibegron 1 mg (dose-increased) ( 1.4,.53) <.1.37 (.56,.17) <.1 All (39.86, 54.51) < (.88, 14.2).27 Vibegron 5 mg (dose-retained) (41.66, 59.36) < ( 6.61, 9.22).745 Vibegron 1 mg (dose-increased) (26.58, 52.5) < (9.38, 32.45) <.1 Statistical test under the null hypothesis that the change from week to week 52 was. Statistical test under the null hypothesis that the change from week 8 to week 52 was. The number of episodes at baseline was not. (a) (b) (c) Micturitions/day Urgency episodes/day (d) (e) (f) Incontinence episodes/day Nocturia episodes/day Urgency incontinence episodes/day Volume/micturition(mL) Vibegron 5 mg/day (dose-retained) Vibegron 1 mg/day (dose-increased) Fig. 3 LS mean change (95% CI) from baseline at each visit in the daily mean of the following: (a) micturitions; (b) urgency episodes; (c) urgency incontinence episodes; (d) incontinence episodes; and (e) night-time frequency and (f) the mean voided volume/micturition (ml). P-value <.5, statistical test under the null hypothesis that the change from week at each visit was. P-value <.5, statistical test under the null hypothesis that the change from week 8 at each visit was. ( ), Vibegron 5 mg/day (dose-retained); ( ), vibegron 1 mg/day (dose-increased). most frequent drug-related TEAEs were dry mouth, residual urine volume increased, constipation and cystitis. These are well known as class-related AEs of anticholinergics, but the incidence of AEs of vibegron was much lower than those reported for anticholinergics. 19 No novel, clinically significant AEs were seen in this long-term treatment with vibegron, referring to the phase 2b study. AEs observed after the dose increase to 1 mg were 37.3% (19/51), whereas in the vibegron 5 mg group, AEs were 47.3% (52/11), suggesting no noteworthy differences in safety profiles between the 5 mg and 1 mg groups of vibegron. Because four severe TEAEs were observed only in 5 mg, the possibility of an ordering 218 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association. 673

7 M YOSHIDA ET AL. Table 4 Changes from baselines (week and week 8) in the KHQ domain scores at week 52 (FAS) Variable Group n Domain 1: general health perception Domain 2: incontinence impact Domain 3: role limitations Domain 4: physical limitations Domain 5: social limitations Domain 6: personal relationships Change from week at week 52 Change from week 8 at week 52 LS mean 95% CI P-value LS mean 95% CI P-value All ( 6.47,.36) ( 1.96, 4.28).463 Vibegron 5 mg (dose-retained) ( 9.68, 1.53) ( 2.42, 5.12).481 Vibegron 1 mg (dose-increased) ( 3.44, 8.64) ( 4.94, 6.21).822 All ( 34.89, 25.45) < ( 6.82,.11).43 Vibegron 5 mg (dose-retained) ( 35.81, 24.4) < ( 5.14, 2.9).582 Vibegron 1 mg (dose-increased) ( 38.72, 21.74) < ( 14.58, 2.75).4 All ( 32.35, 23.52) < ( 9.59, 2.7).1 Vibegron 5 mg (dose-retained) ( 32.42, 21.76) < ( 7.72,.5).85 Vibegron 1 mg (dose-increased) ( 37.79, 21.94) < ( 17.96, 5.82) <.1 All ( 31.47, 22.56) < ( 9.98, 3.28) <.1 Vibegron 5 mg (dose-retained) ( 3.35, 19.65) < ( 7.67,.28).69 Vibegron 1 mg (dose-increased) ( 39.47, 23.57) < ( 19.8, 7.36) <.1 All ( 22.26, 14.15) < ( 7.46, 1.79).2 Vibegron 5 mg (dose-retained) ( 21.16, 11.42) < ( 5.44, 1.27).222 Vibegron 1 mg (dose-increased) ( 29.79, 15.26) < ( 15.3, 5.35) <.1 All ( 9.8, 4.28) < ( 3.76,.24).84 Vibegron 5 mg (dose-retained) ( 9.74, 3.2) <.1.81 ( 3.24, 1.62).512 Vibegron 1 mg (dose-increased) ( 13.35, 3.61) ( 7.34,.35).32 Domain 7: emotions All ( 29.3, 2.17) < ( 7.26,.83).14 Vibegron 5 mg (dose-retained) ( 28.68, 18.) < ( 5.95, 1.77).288 Vibegron 1 mg (dose-increased) ( 35.35, 19.48) < ( 14.14, 2.77).4 Domain 8: sleep/energy Domain 9: severity measures All ( 28.66, 2.7) < ( 8.4, 2.41) <.1 Vibegron 5 mg (dose-retained) ( 28.98, 19.36) < ( 6.44,.7).115 Vibegron 1 mg (dose-increased) ( 32.99, 18.72) < ( 16.39, 5.9) <.1 All ( 23.18, 16.82) < ( 6.2, 1.75).1 Vibegron 5 mg (dose-retained) ( 23.11, 15.44) < ( 4.7,.58).126 Vibegron 1 mg (dose-increased) ( 27.32, 15.92) < ( 12.16, 4.4) <.1 Statistical test under the null hypothesis that the change from week to week 52 was. Statistical test under the null hypothesis that the change from week 8 to week 52 was. Table 5 Patient global impression Patient satisfaction by treatment with vibegron (FAS) All n = 166 Vibegron 5 mg n = 115 Vibegron 1 mg n = 51 Satisfied n (%) 151 (91.) 16 (92.2) 45 (88.2) 95% CI (85.6, 94.4) (85.8, 95.8) (76.6, 94.5) Very much satisfied n (%) 118 (71.1) 86 (74.8) 32 (62.7) 95% CI (63.8, 77.4) (66.1, 81.8) (49., 74.7) Patient global impression: very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse since the initiation of treatment. Very much improved + much improved + minimally improved. Very much improved + much improved. effect was not completely ruled out. However, causal relationships with the study drug were denied in three cases. Therefore, we considered that it was not due to an ordering effect. Furthermore, there were no differences in safety between combination with and without anticholinergics. This suggests that vibegron can be safely used with the combination of anticholinergics. Significant improvement changes from baseline in all OAB symptom variables were seen by the 8th week of the treatment with vibegron 5 mg, and were maintained throughout the study. The investigators judged that the efficacies of vibegron 5 mg in 51 patients were insufficient and a dose increase to 1 mg resulted in significant improvement. It should be noted that the baselines of OAB symptoms at week in the vibegron 1 mg group were significantly more severe than those of the vibegron 5 mg group, suggesting that vibegron 1 mg might be useful for treatment of patients with severe OAB. Significant improvement in urgency incontinence episodes would be a determining cause of improvement in the KHQ domain scores, as reported in other studies. 2,21 OAB is a chronic condition and typically requires long-term treatment, and high persistence and adherence to therapy are essential for the management of OAB. 22 Although anticholinergics are the first-line pharmacological treatment for OAB, persistence with prescribed therapy is very low due to poor efficacy and tolerability. 23 Objective measures in clinical trials have poorly correlated with patient-related outcome measures, therefore the improvement in patient-related outcome is thought to be important for the evaluation of clinical significance. 19 In the present study, vibegron treatment for week 52 significantly improved OAB symptoms and improved the patients satisfactions in PGI measurement. It is noteworthy that long-term treatment with vibegron satisfied not only the objective, but The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.

8 Safety and efficacy of vibegron also the subjective measurements for the patients with OAB. In addition, high satisfactions were obtained when the dose was increased to 1 mg in patients who did not respond well to the 5 mg dose, suggesting that dose escalation of vibegron is beneficial for achieving further satisfaction of the patients together with improvement of OAB symptoms. The present study had some limitations. The first was the lack of placebo control. A marked placebo effect on treatment outcomes in OAB symptoms has been reported in many double-blind, placebo-controlled, randomized trials. 24 The true effectiveness and safety profile could not be determined in the present study, and particularly, the efficacy outcomes might be overestimated. Meanwhile, the robust effectiveness of vibegron for the treatment of OAB has been elucidated in the previous placebo-controlled study. Second, the proportions of elderly patients and male patients in the present study were lower than those in the real world. 1 Finally, the number of patients, particularly the number of concomitant use of anticholinergics, was relatively small to assess safety. Further long-term studies, including a postmarketing study in routine clinical practice evaluating the safety and effectiveness of vibegron in a large number of patients, are required. In conclusion, vibegron 5 mg and 1 mg have favorable safety profiles for the 52-week treatment. Vibegron improved OAB symptoms and QoL, and a dose increase to 1 mg improved OAB symptoms without increasing AEs in those patients who did not respond well to vibegron 5 mg. Vibegron could provide a promising treatment for OAB using monotherapy with the usual dose of 5 mg, with dose escalation to 1 mg if efficacy is insufficient. Acknowledgments We thank all participating patients and their families, the study investigators, study nurses, study monitors, data manager, and all other members of the study team. The study was funded by Kyorin Pharmaceutical and Kissei Pharmaceutical. The study was designed by Kyorin in collaboration with the authors. Kyorin had a role in conduct of the study; monitoring, data management and analysis. The authors received medical writing assistance from Tetsuji Asao (SunFlare, Tokyo, Japan) for preparation of the initial and final drafts of the manuscript, which was funded by Kyorin Pharmaceutical and Kissei Pharmaceutical. Conflict of interest Masaki Yoshida has received consultancy fees from Kyorin, grants from Astellas, and speaker fees from Kyorin, Astellas, Kissei, Daiichi-Sankyo, Ono and Pfizer. Hidehiro Kakizaki has received consultancy fees from Kyorin and Astellas, and speaker fees from Kyorin, Astellas, Kissei, Pfizer and Taiho. 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