Mirabegron in overactive bladder: A review of efficacy, safety, and tolerability

Authors


  • Karl-Erik Andersson led the peer-review process as the Associate Editor responsible for the paper.
  • Conflicts of interest: Christopher R. Chapple is a Consultant or Researcher for Allergan, Astellas, BioCSL, Lilly, Ono, Pfizer, and Ranbaxy. Linda Cardozo is a Consultant or Researcher for Astellas and Pfizer, and an Advisor for Allergan, Astellas, Ethicon, Merck, Pfizer, and Teva. Victor W. Nitti is a Consultant or Researcher for Allergan, American Medical Systems, Astellas, Coloplast, Medtronic, Ono, Pfizer, Ipsen, Serenity and Theracoat; a Speaker for Allergan and Astellas; and has Equity Interests in Serenity. Emad Siddiqui is an employee of Astellas Pharma Europe Ltd. Martin C. Michel is a Consultant or Researcher for Astellas, AltheRX, Boehringer Ingelheim, Pfizer, Bayer, and Apogepha; a Speaker for Astellas, Pfizer, and Allergan; a Director of Boehringer Ingelheim; and has Equity Interests in AltheRX.

ABSTRACT

Aims

Mirabegron, the first β3-adrenoceptor agonist to enter clinical practice, has a different mechanism of action from antimuscarinic agents. This review presents data on the efficacy, safety, and tolerability of mirabegron in studies conducted to date.

Methods

All clinical data on mirabegron that are currently in the public domain are included, including some in-press manuscripts.

Results

In Phase III clinical trials in patients with overactive bladder (OAB), mirabegron at daily doses of 25, 50, and 100 mg demonstrated significant efficacy in treating the symptoms of OAB, including micturition frequency, urgency incontinence, and urgency. Significant improvements in micturition frequency, urgency incontinence, and mean volume voided/micturition were seen as early as the first assessment (week 4) for mirabegron 50 and 100 mg, and were maintained throughout treatment. Responder analyses showed a significant improvement with mirabegron 50 and 100 mg in terms of dry rates, ≥50% reduction in mean number of incontinence episodes/24 hr, and the proportion of patients with ≤8 micturitions/24 hr at final visit. The benefit of mirabegron 50 and 100 mg was also evident in patients ≥65 years of age, and in both treatment-naïve patients and those who previously discontinued antimuscarinic therapy. These data therefore demonstrate a clinically meaningful benefit with mirabegron in the objective endpoints of OAB. Assessment of measures of health-related quality of life and treatment satisfaction showed that patients perceived treatment with mirabegron as meaningful. In OAB clinical trials of up to 12 months mirabegron appeared to be well tolerated. The most common adverse events (AEs) observed with mirabegron in clinical trials of up to 12 months were hypertension, nasopharyngitis, and urinary tract infection. The incidence of dry mouth was similar to placebo, and was between three and fivefold less than for tolterodine extended release 4 mg. Since dry mouth is the most bothersome AE associated with antimuscarinic drugs and often a reason for treatment discontinuation, mirabegron may be a valuable treatment option for these patients.

Conclusions

In Phase III clinical trials, mirabegron at daily doses of 25, 50, and 100 mg demonstrated significant efficacy in treating symptoms of OAB and, at doses of 50 and 100 mg, demonstrated significant improvements versus placebo on key secondary endpoints, as early as the first assessment (week 4), and these were maintained throughout treatment. In OAB clinical trials of up to 12 months, mirabegron appeared to be well tolerated. Neurourol. Urodynam. 33:17–30, 2014. © 2013 Wiley Periodicals, Inc.

INTRODUCTION

Overactive bladder (OAB) is a prevalent, chronic symptom complex that can impair quality of life (QoL).[1] Treatment goals are to reduce the occurrence of bothersome symptoms, and provide benefits that are perceived by patients as meaningful.[2] Antimuscarinics are well established as pharmacotherapy for reducing OAB symptoms[3] and improving QoL.[4] However, their use is limited in some patients by insufficient response to treatment,[5] or intolerable side effects such as dry mouth, blurred vision, constipation, and cognitive impairment.[6] A recent UK study found that 12 months after the initial prescription, persistence rates on antimuscarinics were ≤35% in patients with OAB.[7] In the search for alternative OAB treatments with a novel target and an improved efficacy/tolerability profile to existing treatments, β3-adrenoceptor agonists have emerged as a promising class of drugs; the first novel OAB medication for many years.

Recent advances in the understanding of the physiopathology of OAB have identified three subtypes of β-adrenoceptor (β1, β2, and β3) in the detrusor muscle and urothelium;[8-10] β3-adrenoceptors predominate, accounting for 97% of total β-adrenoceptor messenger (m)RNA,[11] and are thought to be the main subtype mediating relaxation of the detrusor in humans.[12] Stimulation of β3-adrenoceptors elicits direct relaxation of detrusor smooth muscle; the underlying cellular mechanisms are not fully clear but may involve activation of adenylyl cyclase and subsequent increases in the intracellular levels of cyclic adenosine phosphate (cAMP) and BK Ca channels.[13] In addition to their presence in the urinary bladder, β3-adrenoceptors are distributed in adipose tissue, the heart, and the vasculature in rodents. Their expression in humans appears to be much more restricted, but requires further characterization.

Mirabegron is the first β3-adrenoceptor agonist to enter clinical practice, and has been approved for the treatment of symptoms of OAB in Japan, the USA, Europe, and Canada. Product labeling differs between countries, with a recommended starting dose of 25 mg once daily (QD) in the US and Canada (Myrbetriq®, Astellas Pharma Inc, Northbrook, IL), with an option to increase to 50 mg, and a recommended dose of 50 mg QD in Japan (Betanis®, Astellas Pharma Inc, Chuo-ku, Tokyo, Japan) and Europe (Betmiga™, Astellas Pharma BV, Leiden, the Netherlands), with the 25 mg dose reserved for special populations (e.g., those with severe renal impairment or moderate hepatic impairment).

Mirabegron shows high intrinsic activity for β3-adrenoceptors and very low intrinsic activity for β1 and β2 adrenoceptors. In Chinese hamster ovary cells expressing human β3-adrenoceptors, the half-maximal effective concentration (EC50) value was 22.4 nM compared with EC50 values of >10,000 nM for β1 and β2 adrenoceptors.[14] Mirabegron improves the storage capacity of the bladder, without impairing bladder contraction during voiding.[15] Further detail can be found in the review by Igawa and Michel.[16]

Mirabegron is rapidly absorbed after oral administration and circulates in plasma as the unchanged form, its glucuronic acid conjugates and other metabolites, which are pharmacologically inactive.[17] Mirabegron is metabolized in the liver via multiple pathways, and is recovered in urine (55%) and faeces (34%) mainly as the unchanged form (see Table I for other pharmacokinetic [PK] parameters).[18-20] Since mirabegron is metabolized by cytochrome P450 (CYP) 3A4,[21] and to a minor extent by CYP2D6 in humans,[22] it may be subject to clinically relevant drug–drug interactions and should therefore be used with caution in patients who are taking ketoconozole or other potent CYP3A inhibitors.

Table I. Summary of Mirabegron Pharmacokinetics[17-20]
Absorption
Tmax
  • 3–4 hr
T1/2
  • ∼40 hr
Bioavailability
  • ∼29% at a 25 mg dose
 
  • 35% at a 50 mg dose
 
  • Higher in women (20–30% higher exposure when normalized for body weight)
 
  • Reduced when given with food; with low-fat food having greater effect on the absorption than high-fat food
Distribution
Plasma protein binding
  • 71%
Volume of distribution
  • ∼1,670 L
Metabolism
  • Metabolized via multiple pathways involving dealkylation, oxidation, glucuronidation, and amide hydrolysis
 
  • Mirabegron is the major circulating component following a single dose of 14C-mirabegron
 
  • Two major metabolites were observed in human plasma (phase 2 glucuronides representing 16% and 11% of total exposure—not pharmacologically active toward β3-adrenoceptors)
 
  • The 8 mirabegron metabolites identified in human plasma do not contribute to the pharmacological activity
 
  • In-vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, but in vivo results indicate that they play a limited role in overall elimination
Terminal elimination half-life
  • ∼50 hr
Excretion
  • Mirabegron is recovered in urine and faeces mainly as the unchanged form
Special patient populations
  • Mirabegron AUC and Cmax increased 118% and 92%, respectively, in subjects with severe renal impairment, and 65% and 175%, respectively, in subjects with moderate hepatic impairment
 
  • PK changes in subjects with mild or moderate renal impairment or mild hepatic impairment were of small magnitude and likely to be without clinical importance
Drug–drug interaction
  • Performed with compounds affecting CYP3A and P-glycoprotein (P-gp), with substrates for CYP3A, CYP2D6 and P-gp and with other urological products, for example, ketoconazole, rifampin, oral contraceptive, metformin, metoprolol, warfarin, desipramine, digoxin, solifenacin, and tamsulosin
 
  • Although changes in mirabegron plasma exposure were seen in several of these studies, changes were less than twofold and no dosage adjustment or precaution is necessary
 
  • Drugs that are CYP2D6 substrates are not expected to require dose adjustment, except for drugs with narrow therapeutic indices that are significantly metabolized by CYP2D6; caution is advised if mirabegron is coadministered with CYP2D6 substrates with narrow therapeutic indices
 
  • From a PK point of view, the interaction between mirabegron and solifenacin is not expected to be clinically relevant[54]

Other selective β3-adrenoceptor agonists are currently in development. Phase II results have been reported for solabegron in incontinent female patients with OAB,[23] and preclinical studies have been reported for ritobegron[24, 25] and TRK-380.[26] The FDA has also recently approved onabotulinumtoxinA injection, acting independently of β3-adrenoceptors, for treatment of OAB in adults who have an inadequate response to or who are intolerant of antimuscarinics.[27, 28]

Clinical Efficacy

Mirabegron has been studied extensively in more than 10,500 subjects over approximately 10 years. Over 5,500 OAB patients have received mirabegron in Phase II and III studies, sponsored by Astellas. The studies shared similar designs, although the doses of mirabegron and inclusion of placebo and/or an active-control arm with tolterodine extended release (ER) 4 mg varied across trials (Table II). Men and women ≥18 years of age with OAB symptoms for ≥3 months were enrolled into the trials. Following a 2-week, single-blind, placebo run-in period to determine baseline symptoms and patient eligibility, patients were randomized if, during a 3-day micturition diary period, they recorded ≥8 micturitions/24 hr and ≥3 urgency episodes—based on urgency grade of three or four according to the Patient Perception of Intensity and Urgency Scale (PPIUS), [29] with or without urgency incontinence.

Table II. Overview of Studies
 BLOSSOM[30]DRAGON[31]SCORPIO[32]ARIES[33]CAPRICORN[34]TAURUS[39]
  • BLOSSOM is Study 178-CL-008 (NCT01604928), DRAGON is Study 178-CL-044 (NCT00337090), SCORPIO is Study 178-CL-046 (NCT00689104), ARIES is Study 178-CL-047 (NCT00662909), CAPRICORN is Study 178-CL-074 (NCT00912964), TAURUS is Study 178-CL-049 (NCT00688688).
  • BID, twice daily; QD, once daily; ER, extended release.
  • aImmediate release (IR) formulation.
Patients enrolledN = 314N = 1,108N = 2,336N = 2,149N = 2,030N = 2,801
Patients randomizedN = 262N = 928N = 1,987N = 1,329N = 1,306N = 2,444
Mirabegron dose100 mg or 150 mg BIDa25, 50, 100 or 200 mg QD50 or 100 mg50 or 100 mg25 or 50 mg QD50 and 100 mg
Placebo controlYesYesYesYesYesNo
Active comparatorTolterodine 4 mg ER QDTolterodine 4 mg ER QDTolterodine ER 4 mg QDNoNoTolterodine ER 4 mg QD
Study duration (double-blind treatment period)4 weeks12 weeks12 weeks12 weeks12 weeks12 months
OAB history at baseline
Urge incontinence43%42%40%30%36%38%
Mixed incontinence26%31%23%38%33%27%
Frequency/urgency without incontinence31%27%38%32%32%35%
Primary endpoint(s)Micturitions/24 hrMicturitions/24 hrMicturitions/24 hr, Incontinence episodes/24 hrMicturitions/24 hr, Incontinence episodes/24 hrMicturitions/24 hr, Incontinence episodes/24 hrMicturitions/24 hr, Incontinence episodes/24 hr

Chapple et al.[30] reported results from a proof-of-concept, randomized, double-blind, parallel-group, Phase IIA study (BLOSSOM [Study 178-CL-008; NCT01604928]) of mirabegron at doses of 100 or 150 mg twice daily (BID), placebo (BID), or tolterodine 4 mg ER QD for 4 weeks. Mirabegron 100 and 150 mg BID showed statistically significant improvement versus placebo in mean change from baseline to final visit (End of Treatment; EOT) in the primary endpoint of micturition frequency (P ≤ 0.005).[30, 31] In terms of secondary endpoints,[30, 31] mean volume voided/micturition was dose-dependently increased in the mirabegron groups, with a significant difference versus placebo for mirabegron 150 mg (P ≤ 0.05). Urgency episodes/24 hr decreased significantly for both mirabegron groups versus placebo (P ≤ 0.05). Mirabegron 100 mg also showed statistically significant improvements versus placebo in change from baseline to final visit in incontinence episodes, urgency incontinence episodes, and nocturia episodes (P ≤ 0.05). Of note, BLOSSOM used a different mirabegron formulation than subsequent studies (Table II), which may have resulted in different drug exposure over time and hence somewhat different efficacy and tolerability.

Following the BLOSSOM trial, Chapple et al. carried out a 12-week European Phase IIB dose-ranging study (DRAGON [Study 178-CL-044; NCT00337090]) of mirabegron at doses of 25, 50, 100, or 200 mg QD versus placebo. Analysis of the primary efficacy measure showed dose-dependent decreases in mean number of micturitions/24 hr, which were statistically significant versus placebo for the mirabegron 50, 100, and 200 mg dose groups (P ≤ 0.05; Table III).[31] In addition, mean baseline to final visit improvements were statistically significant for mirabegron versus placebo for mean volume voided/micturition (P ≤ 0.001 for mirabegron 50, 100, and 200 mg); incontinence episodes (P ≤ 0.05 for mirabegron 25 and 50 mg); urgency incontinence episodes (P ≤ 0.05 at all mirabegron doses studied); urgency episodes (P ≤ 0.05 for mirabegron 25, 100, and 200 mg); level of urgency (P ≤ 0.05 for mirabegron 100 and 200 mg); and nocturia episodes (P ≤ 0.05 for mirabegron 50 mg).[31]

Table III. Primary Efficacy Endpointsa (Change from Baseline to Final Visit [EOT])
 Mirabegron (total daily dose)Tolterodine ER 4 mg
25 mg50 mg100 mg
  • DRAGON is Study 178-CL-044 (NCT00337090), SCORPIO is Study 178-CL-046 (NCT00689104), ARIES is Study 178-CL-047 (NCT00662909), CAPRICORN is Study 178-CL-074 (NCT00912964), TAURUS is Study 178-CL-049 (NCT00688688).
  • BLOSSOM data (Study 178-CL-008 [NCT01604928] for mirabegron at doses of 200 mg and 300 mg are not shown, as these doses were not progressed.
  • EOT, end of treatment; ER, extended release; CI, confidence interval; SE, standard error.
  • aEfficacy results are considered secondary endpoints for the TAURUS study. Safety was the primary endpoint.
  • bEstimates, 95% CIs, and P-values are based on an ANCOVA model, which included treatment group and country as fixed factors and baseline as a covariate.
  • cEstimates, 95% CIs, and P-values are based on an ANCOVA model, which included treatment group, gender, and geographical region as fixed factors and baseline as a covariate.
  • dEstimates and 95% CIs are based on an ANCOVA model, which included treatment group, gender, and geographical region as fixed factors and baseline as a covariate. P-values are derived using a corresponding stratified rank ANCOVA.
  • eEstimates and 95% CIs are based on an ANCOVA model, which included treatment group, gender, geographical region, and previous study history as fixed factors and baseline as a covariate.
  • *P ≤ 0.05 without multiplicity adjustment.
  • #P ≤ 0.05 with multiplicity adjustment.
DRAGON[31]
Micturitions/24 hrbN = 167N = 167N = 168N = 85
Adjusted mean−1.9−2.1−2.1−2.0
Treatment difference versus placebo (SE)−0.5 (0.3)−0.6 (0.3)*−0.7 (0.3)*−0.5 (0.3)
95% CIs(−1.0, 0.1)(−1.2, −0.1)(−1.2, −0.1)(−1.2, 0.2)
SCORPIO[32]
Micturitions/24 hrc N = 473N = 478N = 475
Adjusted mean (SE) −1.9 (0.1)−1.8 (0.1)−1.6 (0.1)
Treatment difference versus placebo (SE) −0.6 (0.2)#−0.4 (0.2)#−0.3 (0.2)
95% CIs (−0.9, −0.3)(−0.7, −0.1)(−0.6, 0.1)
Incontinence episodes/24 hrcd N = 293N = 281N = 300
Adjusted mean (SE) −1.6 (0.1)−1.5 (0.1)−1.3 (0.1)
Treatment difference versus placebo (SE) −0.4 (0.2)#−0.3 (0.2)#−0.1 (0.2)
95% CIs (−0.7, −0.1)(−0.6, 0.0)(−0.4, 0.2)
ARIES[33]
Micturitions/24 hrc N = 425N = 412 
Adjusted mean (SE) −1.7 (0.1)−1.8 (0.1) 
Treatment difference versus placebo (SE) −0.6 (0.2)#−0.7 (0.2)# 
95% CIs (−1.0, −0.2)(−1.1, −0.3) 
Incontinence episodes/24 hrd N = 312N = 296 
Adjusted mean (SE) −1.5 (0.1)−1.6 (0.1) 
Treatment difference versus placebo (SE) −0.3 (0.2)#−0.5 (0.2)# 
95% CIs (−0.7, −0.0)(−0.8, −0.2) 
CAPRICORN[34]
Micturitions/24 hrcN = 410N = 426  
Adjusted mean (SE)−1.7 (0.1)−1.6 (0.1)  
Treatment difference versus placebo (SE)−0.5 (0.2)#−0.4 (0.2)#  
95% CIs(−0.8, −0.1)(−0.8, −0.1)  
Incontinence episodes/24 hrdN = 254N = 257  
Adjusted mean (SE)−1.4 (0.1)−1.4 (0.1)  
Treatment difference versus placebo (SE)−0.4 (0.2)#−0.4 (0.2)#  
95% CIs(−0.7, −0.1)(−0.8, −0.1)  
TAURUS[39]
Micturitions/24 hre N = 789N = 802N = 791
Adjusted mean (SE) −1.3 (0.1)−1.4 (0.1)−1.4 (0.1)
95% CIs (−1.4, −1.1)(−1.6, −1.3)(−1.6, −1.2)
Incontinence episodes/24 hre N = 479N = 483N = 488
Adjusted mean (SE) −1.0 (0.1)−1.2 (0.1)−1.3 (0.1)
95% CIs (−1.2, −0.8)(−1.4, −1.1)(−1.4, −1.1)

Three pivotal, large-scale, 12-week, multicenter, randomized, double-blind, parallel-group, Phase III studies of mirabegron conducted in Europe, Australia, and North America featured the co-primary endpoints of change from baseline to final visit in mean number of micturitions/24 hr and mean number of incontinence episodes/24 hr (Fig. 1). Khullar et al. reported on results from Europe and Australia (SCORPIO [Study 178-CL-046; NCT00689104]), Nitti et al. presented results from North America (ARIES [Study 178-CL-047; NCT00662909]), and Herschorn et al. presented results from Europe and North America (CAPRICORN [Study 178-CL-074; NCT00912964]).

Figure 1.

Overview of design of SCORPIO,[32] ARIES,[33] and CAPRICORN.[34] This figure has been adapted from Figure 1 from Nitti et al.[35]

© Astellas Pharma Europe Ltd. International Journal of Clinical Practice published by John Wiley & Sons Ltd.

For SCORPIO, ARIES, and CAPRICORN, statistically significant improvements from baseline to final visit were seen for both doses of mirabegron versus placebo in both co-primary endpoints (P ≤ 0.05; Table III). Improvements were seen from week 4, the earliest timepoint assessed, and were maintained over time. In SCORPIO, statistically significant improvements from baseline to final visit were seen for both mirabegron doses versus placebo in mean volume voided/micturition and mean number of urgency incontinence episodes/24 hr (P ≤ 0.05).[32] The mirabegron 50 mg group also achieved a statistically significant improvement from baseline to final visit in the mean number of urgency episodes (grade 3 or 4) per 24 hr (P ≤ 0.05).

These secondary efficacy results were confirmed by ARIES, which showed statistically significant improvements from baseline to final visit for both mirabegron groups versus placebo in mean volume voided/micturition, level of urgency, number of urgency incontinence episodes, urgency episodes and nocturia episodes/24 hr, and from baseline to week 4 in number of incontinence episodes and micturitions/24 hr versus placebo (all P ≤ 0.05).[33]

In the third Phase III trial, CAPRICORN, mirabegron 50 mg demonstrated significantly greater improvements versus placebo in change to final visit in mean volume voided/micturition (P < 0.001).[34] As regards observations at earlier timepoints, mirabegron 50 mg demonstrated significantly greater improvements versus placebo in change to week 4 in mean number of incontinence episodes/24 hr (P < 0.001). Both mirabegron groups demonstrated statistically significant improvements versus placebo at week 8 in mean number of incontinence episodes and micturitions/24 hr. Mirabegron 50 mg demonstrated statistically significant improvements versus placebo at weeks 4 and 8 in mean volume voided/micturition; however, statistically significant differences were not observed for mirabegron 25 mg at weeks 4 and 8 for mean volume voided. Mirabegron 50 mg also demonstrated statistically significant improvements versus placebo, at these timepoints, in mean level of urgency and number of urgency incontinence episodes/24 hr, and for urgency episodes (grades 3 or 4). Mirabegron 25 mg demonstrated numerically greater improvements on the 3 urgency assessments versus placebo; however, reduction from baseline to weeks 4 and 8 in mean urgency incontinence episodes/24 hr was the only urgency assessment achieving statistical significance.[34]

Primary and secondary efficacy data from a prespecified pooled analysis of these three studies are presented in Figures 2-4.[35] A total of 2,542 patients were included in the pooled efficacy analysis. Additional secondary endpoints included two responder analyses based on incontinence episodes at final visit (patients who were incontinent at baseline who recorded zero incontinence episodes at final visit [“dry rate”], and patients with a ≥50% decrease from baseline in mean number of incontinence episodes/24 hr), and a post hoc analysis of the proportion of patients with ≤8 micturitions/24 hr at final visit. In all cases, the percentages of patients were significantly higher in the mirabegron 50 and 100 mg groups compared with placebo (Table IV; P < 0.05).

Figure 2.

Adjusted mean change from baseline (±SE) by time point in mean number of micturitions/24 hr for the pooled placebo, mirabegron 25, 50, and 100 mg groups (FAS) in SCORPIO,[32] ARIES,[33] and CAPRICORN.[34] This figure has been adapted in part, from Figure 4 from Nitti et al.[35]

© Astellas Pharma Europe Ltd. International Journal of Clinical Practice published by John Wiley & Sons Ltd.

Figure 3.

Adjusted mean change from baseline (± SE) by time point in the mean number of incontinence episodes/24 hr for the pooled placebo, mirabegron 25, 50, and 100 mg groups (FAS-I) in SCORPIO,[32] ARIES,[33] and CAPRICORN.[34] This figure has been adapted, in part, from Figure 3 from Nitti et al.[35]

© Astellas Pharma Europe Ltd. International Journal of Clinical Practice published by John Wiley & Sons Ltd.

Figure 4.

Adjusted mean change from baseline to final visit (SE) in key secondary endpoints: A mean volume voided/micturition (FAS), B mean level of urgency (FAS), and C number of urgency episodes/24 hr (FAS) and number of urgency incontinence episodes/24 hr (FAS-I) in SCORPIO,[32] ARIES,[33] and CAPRICORN.[34] This figure has been adapted, in part, from Figure 5 from Nitti et al.[35]

© Astellas Pharma Europe Ltd. International Journal of Clinical Practice published by John Wiley & Sons Ltd.

Table IV. Results of Incontinence Episodes and Micturition Frequency Responder Analyses of Pooled SCORPIO, ARIES and CAPRICORN Data[35]
 Mirabegron 50 mgMirabegron 100 mgPlacebo
  • SCORPIO is Study 178-CL-046 (NCT00689104), ARIES is Study 178-CL-047 (NCT00662909), CAPRICORN is Study 178-CL-074 (NCT00912964), TAURUS is Study 178-CL-049 (NCT00688688). Odd ratios and associated P-values are from a logistic regression model including treatment group, gender, and study as factors and baseline as a covariate.
  • CI, confidence interval.
  • **P ≤ 0.01 without multiplicity adjustment.
  • ***P ≤ 0.001 without multiplicity adjustment.
Percentage of patients with zero incontinence episodes at final visit44.146.437.8
Odds ratio (95% CI)1.3 (1.1, 1.6)**1.6 (1.3, 2.0)*** 
Percentage of patients with a ≥50% reduction from baseline to final visit in mean number of incontinence episodes/24 hr69.570.559.6
Odds ratio (95% CI)1.5 (1.3, 1.9)***1.6 (1.3, 2.1)*** 
Percentage of patients with ≤8 micturitions/24 hr at final visit31.634.024.6
Odds ratio (95% CI)1.6 (1.3, 1.9)***1.7 (1.4, 2.1)*** 

To investigate the benefit of mirabegron in elderly OAB patients, these pooled data were analyzed in the OAB population aged ≥65 years. Mirabegron 50 and 100 mg were effective in reducing the mean number of incontinence episodes/24 hr from baseline to final visit for patients ≥65 years of age, with improvements of −1.6 for both groups. A similar benefit was observed for the reduction in the mean number of micturitions/24 hr for patients aged ≥65 years, with improvements of −1.7 and −1.8 for the mirabegron 50 and 100 mg groups, respectively.[36]

The response in treatment-naïve patients and those who had previously discontinued antimuscarinic treatment was also examined for the pooled data.[37] Approximately, 50% of the patients included in the pooled full analysis set (FAS) population (n = 3,542) and the patients in the FAS-I population (n = 2,317) had previously used antimuscarinics (tolterodine, solifenacin, oxybutynin, trospium, darifenacin, propiverine, fesoterodine, or emepronium). Mirabegron 50 and 100 mg demonstrated improvements from baseline to final visit versus placebo in the co-primary endpoints in patients who had received prior OAB medication, as well as in those who were treatment-naïve (Table V). The adjusted mean difference versus placebo in patients who discontinued previous antimuscarinic therapy was of a greater magnitude than in treatment-naïve patients, possibly due to the higher placebo response in treatment-naïve patients. In addition, in a post-hoc analysis of SCORPIO, mirabegron at a dose of 50 or 100 mg QD demonstrated improvements in the frequency of micturitions or incontinence episodes in OAB patients who had discontinued prior antimuscarinic therapy due to insufficient efficacy (66.9% of patients). In such patients, the response to tolterodine was similar to placebo.[38]

Table V. Improvements in Mean Number of Micturitions/24 hr and Mean Number of Incontinence Episodes/24 hr from Baseline to Final Visit (EOT) with Mirabegron 50 mg, Mirabegron 100 mg and Placebo in Patients who had Received Prior OAB Medication and in those who were Treatment-Naïve: Pooled SCORPIO, ARIES and CAPRICORN Data[37]
 Patients who had received prior OAB medicationTreatment-naïve patients
 Mirabegron 50 mgMirabegron 100 mgPlaceboMirabegron 50 mgMirabegron 100 mgPlacebo
  • SCORPIO is Study 178-CL-046 (NCT00689104), ARIES is Study 178-CL-047 (NCT00662909), CAPRICORN is Study 178-CL-074 (NCT00912964), TAURUS is Study 178-CL-049 (NCT00688688).
  • EOT, end of treatment.
  • aAdjusted mean change from baseline to final visit. Estimates and 95% CIs are based on an ANCOVA model, which included treatment group, gender, study, subgroup, and subgroup by treatment interaction as a fixed factor and baseline as a covariate.
Micturitions/24 hr (95% CI)a−1.7 (−1.9, −1.5)−1.6 (−1.9, −1.4)−0.9 (−1.1, −0.7)−1.8 (−2.0, −1.6)−1.9 (−2.1, −1.6)−1.5 (−1.7, −1.3)
Incontinence episodes/24 hr (95% CI)a−1.5 (−1.7, −1.3)−1.4 (−1.6, −1.2)−0.9 (−1.1, −0.8)−1.5 (−1.7, −1.3)−1.6 (−1.9, −1.4)−1.4 (−1.6, −1.1)

A 12-month, multinational, randomized, double-blind, parallel-group, active-controlled, Phase III trial (TAURUS [Study 178-CL-049; NCT00688688]), assessed mirabegron 50 and 100 mg and tolterodine ER 4 mg QD.[39] Although the study was not designed to demonstrate a statistically significant difference in efficacy between treatment groups, mirabegron 50 and 100 mg and tolterodine ER 4 mg showed numerical improvements from months 1–12 in mean number of micturitions/24 hr, incontinence episodes/24 hr, and mean volume voided/micturition. Similar findings were evident for responder analyses based on incontinence episodes. At final visit, the percentage of responders for zero incontinence episodes was 43.4%, 45.8%, and 45.1%, respectively, in the mirabegron 50 mg, mirabegron 100 mg, and tolterodine ER 4 mg groups, and the percentage of responders with ≥50% decrease from baseline in mean number of incontinence episodes/24 hr was 63.7%, 66.3%, and 66.8%, respectively.

Patient-reported outcomes

Since OAB is a symptom complex, subjective patient-reported outcomes (PROs) are an important means of assessing treatment efficacy. Health-related quality of life (HRQL) and treatment satisfaction were assessed in the mirabegron trials using validated OAB-specific scales (the overactive bladder questionnaire [OAB-q],[40] the patient perception of bladder condition [PPBC],[41] and the treatment satisfaction visual analog scale [TS-VAS]). The minimally important difference (MID), the smallest change that would be considered meaningful to the patient, has been estimated at 10 points for all OAB-q scales and domains.[42] As can be seen from Table VI, changes in all OAB-q scales and domains exceeded the MID for all the mirabegron trials that utilized the OAB-q, with the exception of the OAB-q Social Interaction domain for ARIES, CAPRICORN, and TAURUS.

Table VI. Efficacy Endpoints Assessing Patient-Reported Outcomes (Change from Baseline to Final Visit [EOT])
 Mirabegron (total daily dose)Tolterodine ER 4 mg
 25 mg50 mg100 mg
  • DRAGON is Study 178-CL-044 (NCT00337090), SCORPIO is Study 178-CL-046 (NCT00689104), ARIES is Study 178-CL-047 (NCT00662909), CAPRICORN is Study 178-CL-074 (NCT00912964), TAURUS is Study 178-CL-049 (NCT00688688).
  • Data for mirabegron at doses of 200 mg and 300 mg are not shown.
  • EOT, end of treatment; ER, extended release; CI, confidence interval; SE, standard error; NA, not applicable; PPBC, patient perception of bladder condition.
  • aEstimates, 95% CIs, and P-values are based on an analysis of covariance (ANCOVA) model, which included treatment group and country as fixed factors and baseline as a covariate.
  • bEstimates, 95% CIs, and P–values are based on an ANCOVA model, which included treatment group, gender and geographical region as fixed factors and baseline as a covariate.
  • cEstimates and 95% CIs are based on an ANCOVA model, which included treatment group, gender, geographical region, and previous study history as fixed factors and baseline as a covariate.
  • *P ≤ 0.05 without multiplicity adjustment.
  • **P ≤ 0.01 without multiplicity adjustment.
  • ***P ≤ 0.001 without multiplicity adjustment.
DRAGON[31]N = 167N = 167N = 168N = 85
ICIQ-OABa
Adjusted mean−2.4−2.5−2.7−2.2
Treatment difference versus placebo (SE)−0.6 (0.3)*−0.7 (0.3)*−0.9 (0.3)**−0.4 (0.4)
95% CI(−1.1, −0.0)(−1.2, −0.1)(−1.5, −0.3)(−1.1, 0.3)
ICIQ-OABqola
Adjusted mean−17.1−20.4−20.6−17.4
Treatment difference versus placebo (SE)−1.0 (2.5)−4.3 (2.5)−4.5 (2.5)−1.3 (3.1)
95% CI(−5.9, 3.9)(−9.1, 0.6)(−9.4, 0.5)(−7.3, 4.7)
Improvement ≥1 category on patient perception of treatment benefit
Percentage of responders59656655
SCORPIO[32]
OAB-q symptom botherb N = 465N = 473N = 469
Adjusted mean (SE) −19.6 (0.9)−19.9 (0.8)−18.4 (0.9)
Treatment difference versus placebo (SE) −4.7 (1.2)***−5.0 (1.2)***−3.5 (1.2)**
95% CI (−7.1, −2.4)(−7.3, −2.6)(−5.9, −1.2)
HRQL Totalb N = 468N = 472N = 470
Adjusted mean (SE) 16.1 (0.8)17.0 (0.8)14.8 (0.8)
Treatment difference versus placebo (SE) 2.3 (1.1)3.3 (1.1)1.1 (1.1)
95% CI (0.2, 4.5)(1.2, 5.4)(−1.1, 3.2)
OAB-q copingb N = 468N = 473N = 470
Adjusted mean (SE) 18.5 (0.9)19.9 (0.9)17.8 (0.9)
Treatment difference versus placebo (SE) 2.9 (1.3)*4.3 (1.3)***2.3 (1.3)
95% CI (0.4, 5.5)(1.8, 6.9)(−0.3, 4.8)
OAB-q concernb N = 469N = 474N = 470
Adjusted mean (SE) 18.4 (0.9)19.0 (0.9)16.2 (0.9)
Treatment difference versus placebo (SE) 2.6 (1.2)*3.2 (1.2)**0.4 (1.2)
95% CI (0.2, 5.0)(0.8, 5.6)(−2.0, 2.8)
OAB-q sleepb N = 469N = 474N = 470
Adjusted mean (SE) 15.1 (0.9)15.8 (0.9)13.9 (0.9)
Treatment difference versus placebo (SE) 1.9 (1.2)2.6 (1.2)*0.7 (1.2)
95% CI (−0.5, 4.3)(0.2, 5.0)(−1.7, 3.1)
OAB-q socialb N = 469N = 472N = 470
Adjusted mean (SE) 10.1 (0.7)10.9 (0.7)8.8 (0.7)
Treatment difference versus placebo (SE) 1.4 (1.0)2.2 (1.0)*0.1 (1.0)
95% CI (−0.5, 3.3)(0.3, 4.1)(−1.7, 2.0)
PPBCb N = 416N = 429N = 426
Adjusted mean (SE) −1.0 (0.1)−1.1 (0.1)−1.0 (0.1)
Treatment difference versus placebo (SE) −0.2 (0.1)*−0.2 (0.1)***−0.2 (0.1)*
95% CI (−0.3, −0.0)(−0.4, −0.1)(−0.3, −0.0)
Improvement ≥1 category on PPBC N = 416N = 429N = 426
Percentage of responders 616265
Improvement ≥2 categories on PPBC N = 416N = 429N = 426
Percentage of responders 293432
TS-VASb N = 414N = 427N = 425
Adjusted mean (SE) 2.6 (0.1)2.7 (0.1)2.4 (0.1)
Treatment difference versus placebo (SE) 0.7 (0.2)***0.8 (0.2)***0.6 (0.2)**
95% CI (0.3, 1.1)(0.4, 1.2)(0.1, 1.0)
ARIES[33]
OAB-q symptom botherb N = 350N = 344 
Adjusted mean (SE) −17.0 (1.0)−20.2 (1.0) 
Treatment difference versus placebo (SE) −6.2 (1.4)***−9.3 (1.4)*** 
95% CI (−8.9, −3.5)(−12.1, −6.6) 
OAB-q HRQL Totalb N = 350N = 344 
Adjusted mean (SE) 14.8 (0.9)17.3 (0.9) 
Treatment difference versus placebo (SE) 4.1 (1.3)***6.5 (1.3)*** 
95% CI (1.6, 6.6)(4.1, 9.0) 
OAB-q copingb N = 350N = 344 
Adjusted mean (SE) 16.9 (1.1)19.1 (1.1) 
Treatment difference versus placebo (SE) 4.1 (1.5)**6.3 (1.5)*** 
95% CI (1.1, 7.1)(3.4, 9.3) 
OAB-q concernb N = 350N = 344 
Adjusted mean (SE) 18.0 (1.0)20.5 (1.1) 
Treatment difference versus placebo (SE) 5.3 (1.5)**7.7 (1.5)*** 
95% CI (2.4, 8.2)(4.8, 10.6) 
OAB-q sleepb N = 350N = 344 
Adjusted mean (SE) 14.6 (1.1)17.5 (1.1) 
Treatment difference versus placebo (SE) 4.9 (1.5)***7.8 (1.5)*** 
95% CI (1.9, 7.9)(4.8, 10.8) 
OAB-q socialb N = 350N = 344 
Adjusted mean (SE) 7.4 (0.8)9.6 (0.8) 
Treatment difference versus placebo (SE) 1.4 (1.1)3.7 (1.1)*** 
95% CI (−0.7, 3.6)(1.5, 5.8) 
PPBCb N = 388N = 377 
Adjusted mean (SE) −0.7 (0.1)−0.8 (0.1) 
Treatment difference versus placebo (SE) −0.2 (0.1)*−0.3 (0.1)*** 
95% CI (−0.3, −0.0)(−0.4, −0.2) 
Improvement ≥1 category on PPBC N = 388N = 377 
Percentage of responders 5157 
Improvement ≥2 categories on PPBC N = 388N = 377 
Percentage of responders 1927 
TS-VASb N = 387N = 373 
Adjusted mean (SE) 1.6 (0.2)2.1 (0.2) 
Treatment difference versus placebo (SE) 0.9 (0.2)***1.4 (0.2)*** 
95% CI (0.4, 1.3)(1.0, 1.8) 
CAPRICORN[34]
OAB-q symptom botherbN = 407N = 422  
Adjusted mean (SE)−17.9 (0.9)−18.8 (0.9)  
Treatment difference versus placebo (SE)−1.8 (1.3)−2.8 (1.3)*  
95% CI(−4.3, 0.7)(−5.3, −0.3)  
HRQL totalbN = 408N = 419  
Adjusted mean (SE)14.3 (0.8)14.2 (0.8)  
Treatment difference versus placebo (SE)1.3 (1.1)1.2 (1.1)  
95% CI(−0.9, 3.5)(−1.0, 3.4)  
OAB-q copingbN = 408N = 419  
Adjusted mean (SE)16.9 (1.0)16.4 (1.0)  
Treatment difference versus placebo (SE)2.2 (1.4)1.7 (1.4)  
95% CI(−0.5, 4.9)(−0.9, 4.4)  
OAB-q concernbN = 408N = 421  
Adjusted mean (SE)15.8 (0.9)16.2 (0.9)  
Treatment difference versus placebo (SE)1.0 (1.3)1.5 (1.3)  
95% CI(−1.5, 3.6)(−1.0, 4.0)  
OAB-q sleepbN = 408N = 421  
Adjusted mean (SE)14.3 (1.0)14.5 (1.0)  
Treatment difference versus placebo (SE)0.3 (1.4)0.4 (1.4)  
95% CI(−2.4, 2.9)(−2.2, 3.1)  
OAB-q socialbN = 409N = 420  
Adjusted mean (SE)8.2 (0.7)7.7 (0.7)  
Treatment difference versus placebo (SE)1.1 (1.0)0.6 (1.0)  
95% CI(−0.8, 3.0)(−1.3, 2.5)  
PPBCbN = 391N = 395  
Adjusted mean (SE)−0.8 (0.1)−0.7 (0.1)  
Treatment difference versus placebo (SE)−0.1 (0.1)−0.0 (0.1)  
95% CI(−0.2, 0.1)(−0.2, 0.1)  
Improvement ≥1 category on PPBCN = 391N = 395  
Percentage of responders5355  
Improvement ≥2 categories on PPBCN = 410N = 426  
Percentage of responders2326  
TS-VASbN = 389N = 388  
Adjusted mean (SE)1.5 (0.2)1.9 (0.2)  
Treatment difference versus placebo (SE)0.5 (0.2)*0.8 (0.2)***  
95% CI(0.1, 0.9)(0.4, 1.3)  
TAURUS[39]
OAB-q symptom botherc N = 779N = 795N = 781
Adjusted mean (SE) −13.1 (0.7)−14.8 (0.7)−14.3 (0.7)
OAB-q HRQL totalc N = 779N = 798N = 783
Adjusted mean (SE) 10.7 (0.6)11.7 (0.6)11.4 (0.6)
OAB-q copingc N = 780N = 798N = 783
Adjusted mean (SE) 12.2 (0.7)13.6 (0.7)13.3 (0.7)
OAB-q concernc N = 781N = 799N = 784
Adjusted mean (SE) 11.8 (0.7)13.3 (0.7)12.5 (0.7)
OAB-q sleepc N = 781N = 799N = 784
Adjusted mean (SE) 10.7 (0.7)10.8 (0.7)11.2 (0.7)
OAB-q socialc N = 780N = 798N = 785
Adjusted mean (SE) 6.5 (0.5)7.2 (0.5)7.2 (0.5)
PPBCc N = 655N = 673N = 673
Adjusted mean (SE) −0.8 (0.0)−0.9 (0.0)−0.8 (0.0)
Improvement ≥1 category on PPBC N = 671N = 688N = 684
Percentage of responders 536054
Improvement ≥2 categories on PPBC N = 671N = 688N = 684
Percentage of responders 262827
TS-VASc N = 654N = 676N = 676
Adjusted mean (SE) 2.1 (0.2)2.1 (0.2)2.3 (0.2)

While an MID for the PPBC has not been established, a validation study of the PPBC by Coyne et al.[41] evaluated responsiveness to treatment using four categories: major improvement (≥2-category decrease), minor improvement (≥1-category decrease), no change, and deterioration (≥1-point increase). According to these categories, minor and major improvement on the PPBC at final visit compared with baseline was seen for mirabegron 100 mg versus placebo in SCORPIO and ARIES;[32, 33] in SCORPIO, the percentage of patients with minor improvement on the PPBC was also significantly higher for mirabegron 50 mg versus placebo (Table VI). In CAPRICORN, the percentage of patients with minor or major improvement on the PPBC was higher for mirabegron 50 and 100 mg versus placebo, but these differences were not significant (Table VI).

Statistically significant improvements from baseline to final visit on the TS-VAS were seen in SCORPIO and ARIES (P < 0.001 for mirabegron 50 and 100 mg versus placebo groups);[32, 33] and in CAPRICORN (P < 0.05 for mirabegron 25 and 50 mg versus placebo; Table VI).[34]

In DRAGON, OAB symptoms and HRQL were also assessed using the International Consultation on Incontinence Questionnaire-Overactive Bladder (ICIQ-OAB) and ICIQ-OABqol questionnaires.[31] Patients' assessment of treatment benefit was evaluated, with the question “has the treatment been of any benefit to you?” (possible responses: “no,” “yes, a little,” or “yes, very much”). Responders were defined as those patients with an improvement of ≥1 category from baseline. The positive effect of mirabegron on the ICIQ-OAB increased with mirabegron dose; in addition, the change from baseline to final visit for all mirabegron groups was statistically significant versus placebo (P ≤ 0.05). Improvements from baseline to final visit were also observed with the ICIQ-OABqol questionnaire, although only the comparison between the mirabegron 200 mg group and placebo was statistically significant (P ≤ 0.05). No statistically significant differences between tolterodine ER 4 mg and placebo were noted for scores obtained on either the ICIQ-OAB or ICIQ-OABqol. A statistically significant treatment effect in favor of mirabegron 200 mg compared with tolterodine ER 4 mg (P < 0.05) was seen on the ICIQ-OAB.

Although the 12-month TAURUS study did not include a placebo arm and was not designed to demonstrate a statistically significant difference in efficacy between treatment groups, mirabegron 50 and 100 mg showed numerical improvements in OAB-q Symptom Bother, HRQL Total scores and subscores, and on the TS-VAS and PPBC (Table VI).[39]

The consistent pattern of significant results in favor of mirabegron over placebo on the PRO measures suggests that mirabegron provides positive and meaningful changes in symptom-specific bother, HRQL, and patients' perception of their bladder condition; in parallel with the improvements reported for diary-based endpoints.

Safety

Cardiovascular safety

Since β3-adrenoceptors may be present in tissues outside of the bladder, such as cardiac and vascular tissue, a thorough cardiovascular safety evaluation of mirabegron was performed. This randomized, placebo, and active- (moxifloxacin 400 mg) controlled, parallel, crossover heart rate corrected QT interval (QT/QTc) study in 352 healthy subjects found that mirabegron at doses of 50 or 100 mg did not cause QTc prolongation.[43] Only at a supratherapeutic dose (200 mg) was the QTc interval prolonged (upper one-sided 95% CI); this was seen in women, but not in men. PK interactions upon add-on of mirabegron or tamsulosin to existing tamsulosin or mirabegron therapy did not cause clinically relevant changes in cardiovascular safety.[17]

Heart rate/pulse rate

In the above-mentioned QT/QTc healthy volunteer study, mirabegron increased heart rate on ECG in a dose-dependent manner (maximum mean increases in heart rate from baseline versus placebo: 6.7, 11, and 17 bpm for the 50, 100, and 200 mg dose groups, respectively).[17, 43] These findings were not, however, replicated in the clinical studies. A plausible explanation is that in healthy volunteers the increase in heart rate is due to a relatively higher sensitivity of the cardiac response to β-adrenoceptor agonists.[44]

Results from BLOSSOM showed that mirabegron 150 mg BID caused a small (5 bpm) mean increase from baseline in pulse rate, but this was not associated with a clinically significant increase in cardiovascular adverse events (AEs) such as tachycardia and palpitations.[30] The effects of mirabegron 100 mg BID and tolterodine ER 4 mg QD on pulse rate (observed increases of −0.7 to 1.4 bpm vs. −0.7 to −0.8 for placebo) were not clinically relevant. While there was a small but significant (P < 0.05) increase from baseline in pulse rate in the mirabegron 100 and 200 mg groups in DRAGON (1.6 and 4.1 bpm for AM measurements; 2.7 and 4.7 bpm for PM measurements, respectively, vs. placebo), this was not associated with an increased incidence of cardiovascular AEs.[31]

In the pooled population from SCORPIO, ARIES, and CAPRICORN, there were small, dose-dependent increases from baseline in adjusted mean difference versus placebo for both AM and PM pulse rate measurements, but these changes were reversible on treatment discontinuation. Specifically, the adjusted mean difference versus placebo for change from baseline to final visit in pulse rate in the group receiving mirabegron 25, 50, and 100 mg and tolterodine ER 4 mg was 0.9, 1.0, 1.9, and 1.0 bpm for AM measurements, respectively, and 0.6, 1.0, 2.3, and 2.1 bpm for PM measurements, respectively. Low proportions of patients receiving mirabegron reported tachycardia: the overall occurrence of tachycardia events, either based on treatment-emergent adverse events (TEAEs) and/or observations of pulse rate ≥100 bpm captured by patient diary, was: 21/432 (4.9%) mirabegron 25 mg, 52/1,375 (3.8%) mirabegron 50 mg, 43/929 (4.6%) mirabegron 100 mg, 43/1,380 (3.1%) placebo, and 16/495 (3.2%) tolterodine ER 4 mg. ECG findings revealed no overt trends in central tendency or categorical outliers for QTc interval assessment across treatment groups.[35]

Across the 12 months of TAURUS, adjusted mean change from baseline pulse rates showed a small increase in each group; this was similar in the mirabegron 100 mg and tolterodine ER 4 mg groups and less in the mirabegron 50 mg group (0.9, 1.6, and 1.5 bpm for AM measurements for the mirabegron 50, 100 mg, and tolterodine ER groups, respectively, and 0.4, 1.3, and 1.9 bpm for PM measurements).[39] The change from baseline to final visit for pulse rate in patients receiving mirabegron 50 mg was approximately 1 bpm.

Blood pressure

In the QT/QTc healthy volunteer study, the maximum mean increase in supine systolic blood pressure/diastolic blood pressure (SBP/DBP) at a mirabegron dose of 50 mg was ∼4.0/1.6 mm Hg greater than placebo.[17, 43] The 24-hr average increases in SBP versus placebo were 3.0, 5.5, and 9.7 mm Hg for the 50, 100, and 200 mg dose groups. Increases in DBP were also dose dependent, but were smaller than SBP.[17] However, there were no clinically relevant effects on SBP/DBP, ECG, laboratory parameters, or physical examination findings in the BLOSSOM study,[30] and no drug effect on SBP, DBP, or ECG parameters, including QTcF, was observed in DRAGON.[31]

When the pooled population from SCORPIO, ARIES, and CAPRICORN was examined, mirabegron was associated with an increase of ≤1 mm Hg in blood pressure versus placebo. Specifically, the adjusted mean difference versus placebo for change from baseline to final visit in SBP for mirabegron 25, 50 and 100 mg, and tolterodine ER 4 mg was −0.5, 0.6, 0.4, and −0.1 mm Hg for AM measurements, respectively, and −1.0, 0.5, 0.9, and 0.0 mm Hg for PM measurements, respectively. The adjusted mean difference versus placebo for change from baseline to final visit in DBP in mirabegron 25, 50 and 100 mg and tolterodine was −0.1, 0.4, 0.2, and 0.7 mm Hg for AM measurements, respectively, and −0.3, 0.4, 0.5, and 1.0 mm Hg for PM measurements, respectively. The overall occurrence of tachycardia events, either based on TEAE and/or observations of pulse rate ≥100 bpm captured by patient diary, was: 43/1,380 (3.1%) placebo, 21/432 (4.9%) mirabegron 25 mg, 52/1,375 (3.8%) mirabegron 50 mg, 43/929 (4.6%) mirabegron 100 mg, and 16/495 (3.2%) tolterodine ER 4 mg. ECG findings revealed no overt trends in central tendency or categorical outliers for QTc interval assessment across treatment groups.[35]

In the 12-month TAURUS study, adjusted mean changes from baseline to final visit for SBP for patients receiving mirabegron 50 and 100 mg and tolterodine were 0.2, 0.4, and −0.5 mm Hg for AM measurements and −0.3, 0.1, and −0.0 mm Hg for PM measurements. Adjusted mean changes for DBP were −0.3, 0.4, and 0.1 mm Hg for AM measurements and −0.0, 0.1, and 0.6 mm Hg for PM measurements.[39] No consistent trends in ECG changes were identified, and categorical outliers for QTc interval assessments were unremarkable across treatment groups.

General safety

No patients in BLOSSOM reported serious AEs (SAEs),[30] and SAEs were reported in <2% of patients across treatment groups in DRAGON.[31] In the 12-month TAURUS study, incidence of treatment-emergent SAEs was similar in the mirabegron 50 mg (5.2%), mirabegron 100 mg (6.2%), and tolterodine ER 4 mg (5.4%) groups. Most SAEs were considered unrelated to study drug. A blinded independent data safety monitoring board (DSMB) inspection of SAEs, discontinuation rates, overall AEs and treatment-emergent AEs, clinical laboratory assessments, vital signs, and ECG readings concluded that there were no relevant safety concerns across the treatment groups during or at the end of the study.[39]

There were no clinically relevant effects on post-void residual (PVR) volume in BLOSSOM.[30] When the safety set for the pooled population from SCORPIO, ARIES, and CAPRICORN was analyzed (n = 4,611 patients), the mean change from baseline to final visit in PVR volume was unremarkable across treatment groups: mirabegron 25 mg (−3.0 ml), mirabegron 50 mg (−0.9 ml), mirabegron 100 mg (−0.7 ml), placebo (−1.6 ml), and tolterodine ER 4 mg (+0.1 ml). The proportion of patients experiencing ≥150 ml change from baseline in PVR volume was lower in the mirabegron groups compared with placebo and tolterodine: mirabegron 25 mg (0%), mirabegron 50 mg (0.3%), mirabegron 100 mg (0.4%), placebo (0.7%), and tolterodine ER 4 mg (0.8%).[35]

No episodes of acute urinary retention were reported in DRAGON.[31] In the pooled population, the incidence of urinary retention was low, and less in mirabegron-treated patients than in placebo or tolterodine-treated patients: total mirabegron (n = 1; <0.1%), placebo (n = 7; 0.5%), and tolterodine (n = 3; 0.6%).[35] In the 12-month TAURUS study, no SAEs of urinary retention were reported. One patient in each of the mirabegron 50 and 100 mg groups and three patients in the tolterodine ER 4 mg group reported urinary retention (confounded by a prior lumbar stenosis procedure in the mirabegron 100 mg group). Acute urinary retention requiring catheterization was reported by 0, 1, and 1 patients in the mirabegron 50 mg, mirabegron 100 mg, and tolterodine ER 4 mg groups, respectively.[39]

In addition, 12 weeks' treatment with mirabegron 50 and 100 mg did not adversely affect voiding urodynamics (Qmax and PdetQmax) versus placebo in male patients with lower urinary tract symptoms (LUTS) and significant bladder outlet obstruction (BOO). The adjusted mean difference (95% CI) versus placebo was 0.40 ml/sec (−0.63, 1.42) and 0.62 ml/sec (−0.43, 1.68), respectively, for Qmax, and −5.94 cmH2O (−13.98, 2.09) and −1.39 cmH2O (−9.73, 6.96) for PdetQmax.[45] Although antimuscarinics may increase ocular pressure, making them unsuitable for treatment of patients with uncontrolled narrow-angle glaucoma, mirabegron 100 mg orally QD for 8 weeks did not increase intraocular pressure (IOP) in healthy volunteers, and was generally safe and well tolerated.[46]

Tolerability

As noted previously, antimuscarinics are currently first-line pharmacotherapy for OAB but are associated with AEs such as dry mouth, blurred vision, and constipation, which affect tolerability and persistence with treatment.[3] In general, treatment with mirabegron was well tolerated. In BLOSSOM, treatment-related AEs were reported with an incidence of 18.5% and 24.6% for the mirabegron 100 and 150 mg BID groups, respectively, versus 24.2% for placebo and 26.6% for the tolterodine ER 4 mg group.[30] The rate of discontinuation due to AEs was low at 4.6% (mirabegron 100 mg BID), 7.7% (mirabegron 150 mg BID), 1.5% (placebo), and 3.1% (tolterodine ER 4 mg QD). In DRAGON, the incidence of treatment-related AEs was comparable for the mirabegron and placebo groups (20.1%, 22.5%, 21.4%, and 22.2% for the mirabegron 25, 50, 100, and 200 mg groups versus 15.4% for placebo).[31] Discontinuation due to AEs was low at 2.4–5.3% for the mirabegron groups versus 3.0% for placebo and 1.2% for tolterodine ER.

Pooled safety data from SCORPIO, ARIES, and CAPRICORN showed that the overall incidence of TEAEs was similar across treatment groups and there was no evidence of a dose–response relationship across the mirabegron treatment groups for overall rates of TEAEs: mirabegron 25 mg (48.6%), mirabegron 50 mg (47.1%), mirabegron 100 mg (43.3%), total mirabegron (46.0%), placebo (47.7%), and tolterodine ER 4 mg (46.7%).[35] The most common TEAEs, reported in ≥3% of the total mirabegron group were hypertension (7.3%), nasopharyngitis (3.4%), and urinary tract infection (3.0%). The incidence of hypertension and urinary tract infection decreased with increasing mirabegron dose. The most common drug-related TEAEs in the mirabegron groups were hypertension and headache, which occurred at a similar incidence in the placebo and tolterodine groups, and dry mouth, occurring at a similar incidence in the mirabegron and placebo groups but ∼fivefold higher for the tolterodine group (2.0% for the total mirabegron groups vs. 2.1% for placebo and 10.1% for the tolterodine group). The majority of AEs were of mild or moderate severity across treatment groups. The proportion of patients discontinuing study drug due to TEAEs was low and similar across each group: mirabegron 25 mg (3.9%), mirabegron 50 mg (3.9%), mirabegron 100 mg (3.7%), total mirabegron (3.8%), placebo (3.3%), and tolterodine ER 4 mg (4.4%). The incidence of SAEs was also low and similar between mirabegron and placebo groups: mirabegron 25 mg (1.6%), mirabegron 50 mg (2.1%), mirabegron 100 mg (2.8%), total mirabegron (2.3%), placebo (2.1%), and tolterodine ER 4 mg (2.2%).

In the 12-month TAURUS study, the incidence of TEAEs was similar across the mirabegron 50 mg (59.7%), mirabegron 100 mg (61.3%), and tolterodine ER 4 mg (62.6%) groups. Most TEAEs were of mild or moderate severity.[39] The most frequent TEAEs included hypertension, dry mouth, constipation, and headache, occurring at a similar incidence across treatment groups, except for dry mouth, which was highest in the tolterodine group (8.6%) versus mirabegron 50 mg (2.8%) and 100 mg (2.3%). Discontinuations due to AEs were comparable across treatment groups, occurring in only 6.4%, 5.9%, and 6.0% of patients receiving mirabegron 50 mg, mirabegron 100 mg, and tolterodine ER 4 mg, respectively.

When combined safety data for studies SCORPIO, ARIES, and CAPRICORN were examined, AEs most commonly associated with antimuscarinics were similar across treatment groups, with the exception of dry mouth and pruritus which occurred with ∼fivefold higher incidence in the tolterodine group versus mirabegron or placebo groups (Table VII).[47] The incidence of dry mouth and pruritus for tolterodine in this trial was markedly lower than the incidence reported in a recent meta-analysis,[3] where the incidence was 29.6% and 15.4%, respectively.

Table VII. Adverse Events (AEs) Associated with Antimuscarinic Agents:[3] Incidence with Mirabegron, Placebo and Tolterodine ER 4 mg in a Pooled Analysis of Data from SCORPIO, ARIES, and CAPRICORN[47]
AE (MedDRA preferred term) number of patients (%)Placebo (n = 1,380)MirabegronTotal mirabegron (N = 2,736)Tolterodine ER 4 mg (N = 495)Systematic review and meta-analysis[3]
25 mg (N = 432)50 mg (N = 1,375)100 mg (N = 929)Antimuscarinic therapya (%)Placebo (%)
  • SCORPIO is Study 178-CL-046 (NCT00689104), ARIES is Study 178-CL-047 (NCT00662909), CAPRICORN is Study 178-CL-074 (NCT00912964), TAURUS is Study 178-CL-049 (NCT00688688).
  • aAEs significantly higher with tolterodine ER versus placebo were constipation, dry mouth, vision blurred and fatigue; AEs significantly higher with other antimuscarinic agents versus placebo included erythema, hyperhidrosis (increased sweating), pruritus and urinary retention.
Any AE658 (47.7%)210 (48.6%)647 (47.1%)402 (43.3%)1,259 (46.0%)231 (46.7%)53.439.9
Dry mouth29 (2.1%)8 (1.9)23 (1.7%)23 (2.5%)54 (2.0%)50 (10.1%)29.67.9
Pruritus5 (0.4%)1 (0.2%)3 (0.2%)3 (0.3%)7 (0.3%)7 (1.4%)15.45.2
Constipation20 (1.4%)7 (1.6%)22 (1.6%)15 (1.6%)44 (1.6%)10 (2.0%)7.73.9
Erythema2 (0.1%)01 (0.1%)1 (0.1%)2 (0.1%)1 (0.2%)6.92.0
Vision blurred3 (0.2%)02 (0.1%)4 (0.4%)6 (0.2%)03.82.6
Fatigue14 (1.0%)6 (1.4%)17 (1.2%)7 (0.8%)30 (1.1%)9 (1.8%)1.60.6
Urinary retention6 (0.4%)01 (0.1%)01 (<0.1%)3 (0.6%)1.10.2

DISCUSSION

In Phase III clinical trials patients with OAB, mirabegron at daily doses of 25, 50, and 100 mg demonstrated significant efficacy in treating the symptoms of OAB, including micturition frequency, urgency incontinence, and urgency; which are recognized as important outcome measures for OAB treatment by International guidelines.[48] Mirabegron, at doses of 50 and 100 mg, also demonstrated significant improvements versus placebo on key secondary endpoints, as early as the first assessment (week 4), and these were maintained throughout treatment. In OAB clinical trials of up to 12 months, mirabegron appeared to be well tolerated. Although there are some disparities between clinical trial data and data from cardiovascular studies in healthy volunteers, this is possibly because in healthy volunteers the increase in heart rate is due to a relatively higher sensitivity of the cardiac response to β-adrenoceptor agonists. Data from healthy volunteers showed a mirabegron related dose–response elevation in heart rate of 6.7, 11, and 17 bpm for the 50, 100, and 200 mg dose groups, respectively, and 24-hr average increases in SBP versus placebo of 3.0, 5.5, and 9.7 mm Hg, respectively.[43] However, in the pooled Phase III clinical studies with a large number of patients, the change in mean pulse rate for mirabegron was approximately 1 bpm compared with placebo, similar to the change from baseline pulse rate described for antimuscarinics such as tolterodine,[49] fesoterodine,[50] and trospium,[51] and was reversible upon treatment discontinuation. In addition, the increase in blood pressure associated with mirabegron was ≤1 mm Hg, and the incidence of hypertension was similar between the total mirabegron group, placebo and tolterodine ER 4 mg.

Patients with neurogenic LUTS may also benefit from mirabegron therapy; however, such trials are awaited. Trials on head-to-head comparisons with solifenacin are also awaited.[52] Considering their different mechanisms of action, there is also potential for β3-adrenoceptor agonists to be used in combination with anticholinergic therapy. The Symphony trial investigated 1 of 6 combinations of mirabegron (25 or 50 mg) with solifenacin (2.5, 5, or 10 mg), or placebo QD for 12 weeks in comparison with monotherapy with mirabegron or solifenacin. Combination therapy demonstrated greater efficacy than solifenacin 5 mg alone on change from baseline to EOT in mean volume voided/micturition (all dose combinations) and in the frequency of micturitions/24 hr (10 + 25 mg, 5 + 50 mg, 10 + 50 mg).[53] Further results from the Symphony trial and future combination trials are keenly awaited.

Mirabegron is the first in a new class of agent and is the first new class of oral therapy for the pharmacological therapy of OAB for more than 30 years. Although the inclusion and exclusion criteria in these trials limit the ability to extrapolate the results beyond the populations studied, the outcomes of the use of this therapy both alone and in combination with other pharmacotherapeutic agents in real life clinical practice are awaited with interest.

ACKNOWLEDGMENTS

Sue Cooper from Envision Scientific Solutions provided medical writing assistance for this work, which was supported by Astellas.

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