CHICAGO, May 5, 2019 /PRNewswire/ -- Astellas Pharma Inc. today announced results from the Phase 4, 12-week PLUS trial, the first large-scale, randomized trial in North America and Europe evaluating the efficacy and safety of mirabegron vs. placebo in men with overactive bladder (OAB) symptoms receiving tamsulosin for underlying benign prostatic hyperplasia (BPH). These two conditions may cause symptoms of urinary urgency and urinary frequency.¹ The results were presented during a plenary session at the American Urological Association (AUA) 2019 Annual Meeting in Chicago (LBA-03) on Sunday, May 5.

PLUS is Astellas' second major trial specifically designed to study the effects of mirabegron in controlling OAB symptoms in men being treated for BPH. The results show that among men with OAB symptoms receiving tamsulosin for lower urinary tract symptoms (LUTS) due to underlying BPH, mirabegron was statistically superior to placebo as an add-on therapy in reducing mean number of micturitions (episodes of urination) per day, the primary endpoint of the study.² 

"Lower urinary tract symptoms are highly prevalent in men over the age of 40.³ Additionally, the overlap of symptoms in OAB and BPH can pose a treatment challenge for clinicians," said Steven Kaplan, M.D., primary researcher and director at Icahn School of Medicine at Mount Sinai in New York City. "These results show that mirabegron has the potential to reduce OAB symptoms in men with BPH currently treated with tamsulosin."

Patients receiving tamsulosin plus mirabegron experienced a greater mean change in reduction of micturitions per 24 hours from baseline to end of treatment (EOT)

(-2.00 [95% CI: -2.26, -1.74]), compared with those receiving tamsulosin plus placebo (-1.62 [95% CI: -1.88, -1.36]), with a statistically significant adjusted mean difference between groups (-0.39 [95% CI: -0.76, -0.02]. Mirabegron also showed an increase in mean volume voided (MVV) per micturition, a reduction in urgency episodes per day and improvements in total urgency and frequency score vs. placebo. No statistically signficant difference was observed in total International Prostate Symptom Scores (IPSS).²

Safety assessments included treatment-emergent adverse events (TEAEs) and changes in post-void residual volume and maximum urinary flow. Overall, 25.9% of patients taking tamsulosin plus mirabegron reported TEAEs vs. 31.4% of tamsulosin plus placebo patients. Drug-related TEAE rates were higher with tamsulosin plus mirabegron patients (11.9%), compared to the tamsulosin plus placebo patients (5.9%). Serious TEAE rates were similar in both groups. Six (1.7%) tamsulosin plus mirabegron patients and one (0.3%) tamsulosin plus placebo patient experienced urinary retention (two tamsulosin plus mirabegron patients required catheterization).²

"As a leader in urology, Astellas is focused on advancing research to identify potential new treatment approaches for urologic conditions in both men and women," said Eric Guan, M.D., Ph.D., Senior Vice President and Head of Medical Affairs Americas, Astellas. "Men in particular have remained an under-recognized patient population, though studies suggest about 90 percent of men between 50 and 80 years of age experience lower urinary tract symptoms.¹ We are encouraged by the results of the PLUS study as they enhance our understanding of urologic conditions that commonly impact men and shed light on new pathways for further research."

In the United States, mirabegron is marketed as Myrbetriq®, a beta-3 adrenergic agonist approved by the FDA as a monotherapy, or in combination with the muscarinic antagonist solifenacin succinate, for the treatment of OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency.

About PLUS Study
The Phase 4, double-blind, placebo-controlled, multi-center study (North America and Europe) randomized 715 male patients ≥40 years. The objective was to evaluate the efficacy and safety of mirabegron vs. placebo as an add-on therapy for treating OAB symptoms in men concurrently receiving tamsulosin for LUTS due to underlying BPH. Patients were randomized to receive 25 mg mirabegron or placebo at the start of the study, then were titrated at week four to 50 mg mirabegron or placebo equivalent. The primary endpoint was a mean change from baseline to week 12 (end of treatment) in average number of micturitions (episodes of urination) per day based on a 3-day diary.² For more information on the PLUS trial (NCT02757768), visit https://clinicaltrials.gov/.

About Overactive Bladder (OAB) 
Overactive bladder is a urine storage problem of urgency, with or without urge urinary incontinence (leakage), often with urinary frequency and nocturia.⁴ It has been estimated by this year, 546 million people worldwide will be affected by OAB.⁵ For people with OAB, inappropriate signals are sent to the muscles in the bladder causing them to contract before the bladder is full.⁶ These bladder contractions may cause strong, sudden urges, and a frequent need to go to the bathroom.

Indications and Usage
Myrbetriq® (mirabegron) is a beta‐3 adrenergic agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.

Important Safety Information
Do not use Myrbetriq in patients who have known hypersensitivity reactions to mirabegron or any component of the tablet.

Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in severe uncontrolled hypertensive patients (defined as systolic blood pressure ≥ 180 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg).  Worsening of hypertension was reported infrequently in Myrbetriq clinical trial patients with OAB.

In patients taking Myrbetriq, urinary retention has been reported in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB.   A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should still be administered with caution to patients with clinically significant BOO. For example, monitor these patients for signs and symptoms of urinary  retention.  Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.

Angioedema of the face, lips, tongue and/or larynx has been reported with Myrbetriq. In some cases angioedema occurred after the first dose. Cases of angioedema have been reported to occur hours after the first dose or after multiple doses. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, promptly discontinue Myrbetriq and initiate appropriate therapy and/or measures necessary to ensure a patent airway.

Since Myrbetriq is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co‐administered with Myrbetriq. Appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.

In clinical trials, the most commonly reported adverse reactions (> 2% and > placebo) for Myrbetriq 25 mg and 50 mg versus placebo, respectively, were hypertension (11.3%, 7.5% vs 7.6%), nasopharyngitis (3.5%, 3.9% vs 2.5%), urinary tract infection (4.2%, 2.9% vs 1.8%), and headache (2.1%, 3.2% vs 3.0%).

In postmarketing experience, the following events have also occurred: atrial fibrillation, nausea, constipation, diarrhea, and dizziness. 

Please see accompanying complete Prescribing Information for Myrbetriq^® (mirabegron). 

About Astellas
Astellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. For more information, please visit our website at https://www.astellas.com/en

Cautionary Notes
In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice.

¹ Mankowski C, Ikenwilo D, Heidenreich S, et al. Men's preferences for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia: a discrete choice experiment. Patient Prefer Adherence 2016;10:2407-17.
² DOF_mirabegron_ "CSR" 19-8664 Efficacy and safety of mirabegron vs. placebo add-on therapy in men with overactive bladder symptoms receiving tamsulosin for underlying benign prostatic hyperplasia (PLUS)
³ Parsons JK, Bergstrom J, Silberstein J, Barrett-Connor E. Prevalence and characteristics of lower urinary tract symptoms in men aged ≥ 80 years. Urology 2008;72(2):318-21.
⁴ Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 2003;61(1):37-49.
⁵ Irwin DE, Kopp ZS, Agatep B, Milsom I, Abrams P. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int 2011;108(7):1132-8.
⁶ Sadananda P, Drake MJ, Paton JFR, Pickering AE. A functional analysis of the influence of β3-adrenoceptors on the rat micturition cycle. J Pharmacol Exp Ther 2013;347(2):506-15.

SOURCE Astellas Pharma Inc.