Tag: mirabegron

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May Editorial: The Current Hot Topics in Functional Urology

April 18, 2016/by Marcus Drake

For some time, the challenge represented by managing the overactive bladder (OAB) has been dominant in functional urology research. The introduction of new therapies has galvanised the area, with mirabegron showing strong promise for many patients as a monotherapy. In addition, the potential for combined therapy using mirabegron with established antimuscarinics has recently been reported for urgency urinary incontinence [1]. Now that the place of onabotulinum-A injections in refractory cases is firmly established, management options have clearly taken a step forward in recent years. However, there remain people for whom even the more comprehensive current options are inadequate or intolerable. The need for basic science research remains a priority, in the hope of translation into clinical options. In this month’s BJUI, Aizawa et al. [2] report responses in an animal model to an inhibitor of fatty acid amide hydrolase, showing how exploiting the endocannabinoid pathway might be a translational focus for entirely new approaches in OAB. They consider an issue that is very important in developing clinical options, which is that the systems regulating bladder function are also fundamental in other organs, such as the CNS. As the compound they studied does not cross the blood–brain barrier, the potential generation of CNS adverse effects is reduced, which would be important for its potential as a new therapy.

OAB is a symptom syndrome based on storage-type LUTS [3]. Increasingly the field of functional urology is recognising the large number of people who present with voiding and post-micturition LUTS yet do not have BOO. Currently, there are no satisfactory treatment options for affected people and the symptoms can have considerable impact. Frustratingly, current diagnostic methods rely on urodynamic testing to establish whether the presence of detrusor underactivity explains voiding LUTS in an individual patient. Recently, the profession has established a move towards using symptoms to categorise the clinical need in patients [4]. Accordingly, the International Continence Society has established a working group to generate terminology for underactive bladder (UAB), which will report this year, including a symptom-based definition. A symptomatic diagnosis would be very helpful to enable therapy development to proceed without the need for urodynamic testing. Also, in this month’s BJUI, Kajbafzadeh et al. [5] report a clinical trial in UAB using transcutaneous interferential electrical stimulation in children. The treatment was delivered in the context of the rather laborious process currently required for managing this difficult problem, namely diet and fluid manipulation, scheduled voiding, toilet training, and pelvic floor and abdominal muscles relaxation training. The electrical stimulation was demonstrably beneficial, and included responses for the highly troublesome symptom of nocturnal enuresis. The comparatively straightforward nature of this therapeutic approach potentially makes it a valuable tool for dealing with a notoriously difficult problem.

Marcus J. Drake, Senior Lecturer

School of Clinical Sciences, University of Bristol, Bristol, UK

References

1 Drake MJ, Chapple C, Esen AA et al. Efﬁcacy and safety of mirabegron add-on therapy to solifenacin in incontinent overactive bladder patients with an inadequate response to initial 4-week solifenacin monotherapy: a randomised double-blind multicentre phase 3B study (BESIDE). Eur Urol 2016; [Epub ahead of print]. DOI: 10.1016/j.eururo.2016.02.030

2 Aizawa N, Gandaglia G, Hedlund P et al. URB937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E2-induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve ﬁbres in rats. BJU Int 2016; 117: 821–8

3 Abrams P, Cardozo L, Fall M et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub- committee of the International Continence Society. Neurourol Urodyn 2002; 21: 167–78

4 Chapple CR, Osman NI , Birder L et al. The underactive bladder: a new clinical concept? Eur Urol 2015; 68: 351–3

5 Kajbafzadeh AM, Shariﬁ-Rad L, Ladi-Seyedian SS, Mozafarpour S. Transcutaneous interferential electrical stimulation for the management of non-neuropathic underactive bladder in children: a randomised clinical trial. BJU Int 2016; 117: 793–800

Article of the Month: Safety and efficacy of mirabegron as add-on therapy in patients with solifenacin-treated OAB (MILAI study)

September 30, 2015/by admin Z.9

Every Month the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Prof. Osamu Yamaguchi discussing his paper.

If you only have time to read one article this week, it should be this one.

Safety and efficacy of mirabegron as add-on therapy in patients with overactive bladder treated with solifenacin: a postmarketing, open-label study in Japan (MILAI study)

Osamu Yamaguchi, Hidehiro Kakizaki*, Yukio Homma†, Yasuhiko Igawa‡, Masayuki Takeda§, Osamu Nishizawa¶, Momokazu Gotoh**, Masaki Yoshida††, Osamu Yokoyama‡‡, Narihito Seki§§, Akira Okitsu¶¶, Takuya Hamada¶¶, Akiko Kobayashi¶¶ and Kentarou Kuroishi¶¶

Division of Bioengineering and LUTD Research, School of Engineering, Nihon University, Koriyama, *Department of Urology, Asahikawa Medical University, Asahikawa, †Department of Urology, University of Tokyo Graduate School of Medicine, Tokyo, ‡Department of Continence Medicine, University of Tokyo Graduate School of Medicine, Tokyo, §Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, ¶Department of Urology, Shinshu University, Matsumoto, **Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, ††Department of Urology, National Centre for Geriatrics and Gerontology, Obu, ‡‡Department of Urology, University of Fukui Faculty of Medical Sciences, Fukui, §§Department of Urology, Kyushu

Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, and ¶¶Astellas Pharma Inc., Tokyo, Japan

Read the full article

OBJECTIVE

To examine the safety and efficacy of mirabegron as ‘add-on’ therapy to solifenacin in patients with overactive bladder (OAB).

PATIENTS AND METHODS

This multicentre, open-label, phase IV study enrolled patients aged ≥20 years with OAB, as determined by an OAB symptom score (OABSS) total of ≥3 points and an OABSS Question 3 score of ≥2 points, who were being treated with solifenacin at a stable dose of 2.5 or 5 mg once daily for at least 4 weeks. Study duration was 18 weeks, comprising a 2-week screening period and a 16-week treatment period. Patients meeting eligibility criteria continued to receive solifenacin (2.5 or 5 mg once daily) and additional mirabegron (25 mg once daily) for 16 weeks. After 8 weeks of treatment, the mirabegron dose could be increased to 50 mg if the patient’s symptom improvement was not sufficient, if he/she was agreeable to the dose increase, and the investigator judged that there were no safety concerns. Safety assessments included adverse events (AEs), laboratory tests, vital signs, 12-lead electrocardiogram, QT corrected for heart rate using Fridericia’s correction (QTcF) interval and post-void residual (PVR) volume. Efficacy endpoints were changes from baseline in OABSS total score, OAB questionnaire short form (OAB-q SF) score (symptom bother and total health-related quality of life [HRQL] score), mean number of micturitions/24 h, mean number of urgency episodes/24 h, mean number of urinary incontinence (UI) episodes/24 h, mean number of urgency UI episodes/24 h, mean volume voided/micturition, and mean number of nocturia episodes/night. Patients were instructed to complete the OABSS sheets at weeks −2, 0, 8 and 16 (or at discontinuation), OAB-q SF sheets at weeks 0, 8 and 16 (or at discontinuation) and patient voiding diaries at weeks 0, 4, 8, 12 and 16 (or at discontinuation).

RESULTS

Overall incidence of drug-related treatment-emergent AEs (TEAEs) was 23.3%. Almost all TEAEs were mild or moderate. The most common TEAE was constipation, with similar incidence in the groups receiving a dose increase to that observed in the groups maintained on the original dose. Changes in PVR volume, QTcF interval, pulse rate and blood pressure were not considered to be clinically significant and there were no reports of urinary retention. Significant improvement was seen for changes in efficacy endpoints from baseline to end of treatment (EOT) in all groups (patients receiving solifenacin 2.5 or 5 mg + mirabegron 25 or 50 mg).

CONCLUSIONS

Add-on therapy with mirabegron 25 mg once daily for 16 weeks, with an optional dose increase to 50 mg at week 8, was well tolerated in patients with OAB treated with solifenacin 2.5 mg or 5 mg once daily. There were significant improvements from baseline to EOT in OAB symptoms with combination therapy with mirabegron and solifenacin. Add-on therapy with mirabegron and an antimuscarinic agent, such as solifenacin, may provide an attractive therapeutic option.

Read more articles of the week

Editorial: Combining solifenacin and mirabegron for OAB management

September 30, 2015/by Jean-Nicolas Cornu

Overactive bladder (OAB) is one of the most frequent LUTS in both sexes, and is associated with significant bother and impact on quality of life [1]. In many cases, no underlying cause is found and OAB is stated as being ‘idiopathic’. Until recently, the first-line management of idiopathic OAB has been based on the use of antimuscarinics, solifenacin being one of the most prescribed drugs; however, the long-term adherence to antimuscarinics has been shown to be rather low because of lack of efficacy, treatment switch or adverse events, or for mixed reasons [2].

A few years ago, β₃-adrenergics were successfully introduced as an alternative to antimuscarinics for OAB management. The efficacy of β₃-adrenergics has been shown and they are associated with a new safety profile that differs from that of antimuscarinics [3]. Mirabegron, the most widely used β₃-adrenergic drug, has thus gained popularity in clinical practice. Given that β₃-adrenergics and anticholinergics have a distinct mechanism of action, the combination of both drugs has been seen as a possible option and has been tested through a huge randomized controlled trial [4].

In the present issue of BJUI, Yamaguchi et al. [5] report the results of the MILAI study, an open-label phase IV trial assessing the effects of mirabegron as an add-on therapy in patients treated for OAB with solifenacin. They found that the addition of mirabegron to solifenacin generated only mild to moderate adverse events, and led to promising efficacy results; however, this study, which the authors call a preliminary study, raises a number of questions that remain completely unanswered.

First, even if seen as fluctuant, idiopathic OAB is considered to be a chronic disease. Long-term results must be seen as a critical issue in the field, and there is no guarantee that the short-term data presented in the MILAI study will stand the test of time in terms of efficacy and adherence.

Second, the study raises an important question about the optimum use of mirabegron in idiopathic OAB. Should it be a first-line option, a secondary option after antimuscarinics (available for treatment switch), or an add-on therapy, as it is presented in the present trial? There might be some room for each of these pathways depending on the patient history and characteristics, and the results obtained under antimuscarinics. From that point of view, the MILAI study is probably too weak to identify factors associated with failure of the combination therapy. Further studies should better detail patient inclusion criteria (because ‘failure’ of antimuscarinics is a heterogeneous concept), as well as characteristics of non-responders. In the present study, these two points are not detailed, and the study provides only a global statistically significant improvement, paving the way for additional research. A better understanding of the mechanism of action of the treatment combination would be of great value to move forward and enable better patient selection.

Finally, one of the upcoming challenges will be to integrate mirabegron as an add-on therapy in the world of male LUTS, including benign prostatic obstruction, where β₃-adrenergics probably have an important role to play. As underlined by the authors, several studies are on the way, and their results (in a male population) are urgently awaited.

After having been successfully introduced in most countries in the western world, the new life of mirabegron has begun (including post-marketing studies, extensions of market authorizations, potentially new indications, combination therapy). The future will tell us whether this success story will continue.

Read the full article

Jean-Nicolas Cornu

Department of Urology, Tenon Hospital, Hopitaux Universitaires Paris-EST, Assistance publique Hopitaux de Paris, Universite Pierre et Marie Curie Paris 6, Paris, France

References

1 Agarwal A, Eryuzlu LN, Cartwright R et al. What is the most bothersome lower urinary tract symptom? Individual- and population- level perspectives for both men and women. Eur Urol 2014; 65: 1211–7

2 Veenboer PW, Bosch JL. Long-term adherence to antimuscarinic therapy in everyday practice: a systematic review. J Urol 2014; 191: 1003–8

3 Maman K, Aballea S, Nazir J et al. Comparative efﬁcacy and safety of medical treat ment s for the management of o veractive bl adder: a syste matic literature review and mixed treatment comparison. Eur Urol 2014; 65: 755–65

4 Abrams P, Kelleher C, Staskin D et al. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efﬁcacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony). Eur Urol 2014; 67: 577–88

5 Yamaguchi O, Kakizaki H, Homma Y et al. Safety and efﬁcacy of mirabegron as add-on therapy in patients with overactive bladder treated with solifenacin: a post-marketing, open-label study in Japan (MILAI study). BJU Int 2015; 116: 612–22

Video: Safety and efficacy of mirabegron as ‘add-on’ therapy in patients with OAB treated with solifenacin

September 30, 2015/by admin Z.9