New Class of Treatment for Overactive Bladder Demonstrates Efficacy and Tolerability Across Three Separate Studies

Paris (ots/PRNewswire) -

ASTELLAS PHARMA EUROPE Ltd., European subsidiary of Tokyo-based
Astellas Pharma Inc. today announced results from three separate
clinical trials that further support the efficacy and tolerability of
mirabegron. Mirabegron, a beta3 adrenoceptor agonist, is the first in
a new class of treatment to be submitted for regulatory approval,
using a novel mode of action for the treatment of OAB.[1,2,3]

The results, presented for the first time at the 27th annual
congress of the European Association of Urology (EAU) in Paris
demonstrate:

- Efficacy and tolerability of mirabegron in patients who have previously
discontinued antimuscarinics - the current standard of care for OAB[1]
- Safety and efficacy of mirabegron in OAB patients over a 1 year period[2]
- Ocular safety of mirabegron with chronic use[3]

In a sub-group, post-hoc analysis of the Phase III
European-Australian trial, patients were randomised to mirabegron 50
or 100mg, tolterodine ER 4mg (a licenced antimuscarinic therapy) or
placebo. Mirabegron was found to be effective in reducing the mean
number of incontinence episodes/24 hours and micturitions/24 hours in
antimuscarinic-naive patients as well as those who had discontinued
prior antimuscarinic therapy, regardless of the reason for
discontinuation.[1] However, in patients who had discontinued prior
antimuscarinic therapy due to lack of efficacy, only mirabegron
demonstrated improvement in OAB symptoms - efficacy of tolterodine ER
4mg was similar to placebo.[1] For more information on the data,
please see the 'notes to editors' section later in this release.

The results of a large physician / patient survey also presented
at the EAU support the findings that mirabegron could be an important
development for patients who have failed on previous antimuscarinic
therapy due to lack of treatment response. In this survey of 519
physicians, (regarding 5,316 patients), pooled data across France,
Germany, Spain and the UK found that the most common reason for
switching antimuscarinics was lack of efficacy alone, accounting for
36% of 1,067 patients who switched therapy.[4]

"We have waited 30 years for a completely new mechanism of drug
action to treat OAB," commented Dr Vik Khullar, head of the
Department of Urogynaecology at St. Mary's Hospital, London, United
Kingdom, and Principal Investigator of the European-Australian Phase
III trial. "These results demonstrate that mirabegron can benefit
many patients, but in particular, will offer hope to those patients
who have discontinued antimuscarinic therapy due to lack of efficacy,
who currently have no other treatment options."

As a first-in-class drug, long term safety and tolerability is
important to establish. In a 12 month Phase III safety and
tolerability study 2,444 patients were randomised to receive
mirabegron 50mg, mirabegron 100mg or tolterodine ER 4mg. The study
found that both mirabegron and tolterodine improved key symptoms of
OAB, with improvements in efficacy from the first measured time point
(month 1) and maintained throughout the one year treatment period.[2]
Overall reported adverse events were similar across all groups;
mirabegron 50mg (59.7%), mirabegron 100mg (61.3%) and tolterodine ER
4mg (62.6%).[2] However, the incidence of dry mouth, the most common
and bothersome side effect associated with antimuscarinics, was
considerably higher with tolterodine ER 4mg than with mirabegron 50mg
or mirabegron 100mg (8.6%, 2.8% and 2.3% respectively).[2]

"Dry mouth is a very common and troublesome side effect for
patients on treatment with antimuscarinics, which often leads to
problems with eating, speaking and general quality of life,"
commented Professor Christopher Chapple, Consultant Urological
Surgeon at Sheffield Teaching Hospitals and Lead Investigator of the
12 month safety and tolerability study. "In fact, a number of
patients find that this leads to them wishing to discontinue therapy.
This study confirms that mirabegron, which represents a new class of
oral agents, offers similar potential efficacy to an antimuscarinic,
but without the same burden of dry mouth seen with antimuscarinics.
This therefore provides an alternative potential option for patients
who are unable to achieve the right balance of efficacy and
tolerability with currently available antimuscarinic therapy for
overactive bladder."

Antimuscarinics are not recommended for OAB patients with
uncontrolled narrow-angle glaucoma because of their potential for
mydriasis (prolonged dilatation of the pupil). Mydriasis may increase
intraocular pressure (IOP).[3] Results of a Phase Ib study of 305
healthy volunteers presented at the EAU demonstrated that mirabegron
100mg was non-inferior to placebo with regard to effect on IOP. This
was based on a non-inferiority margin of 1.5mmHg.[3] The adjusted
mean change in IOP from baseline to day 56 was -0.3 mmHg for patients
taking mirabegron and -0.2 mmHg for patients taking placebo [95% CI
-0.4 to 0.3].[3] Clinically, these results demonstrate that
mirabegron does not increase IOP after chronic administration in
healthy volunteers over 8 weeks and supports the ocular safety and
tolerability of mirabegron.[3]

Astellas Pharma Europe Ltd. is an established leader in urology
in Europe, committed to improving the lives of patients with
urological conditions. Its current urology portfolio includes
treatments for benign prostatic hyperplasia (BPH) and overactive
bladder (OAB). With a strong emphasis on research and development,
Astellas is dedicated to finding new treatments to meet unmet medical
needs and has a number of treatments for urological conditions in
late stage development. As part of its ongoing commitment to the
field, Astellas also provides and supports a wide range of
educational opportunities for those working in the field of urology,
designed to progress professional expertise and improve patient
outcomes.

Notes to editors

Sub-group post-hoc analysis of the Phase III European-Australian
trial: results breakdown[1]

A post-hoc analysis of a randomised, double-blind,
parallel-group, placebo- and active-controlled trial in OAB patients
receiving once-daily placebo, mirabegron 50 or 100 mg, or tolterodine
ER 4 mg for 12 weeks. The analysis evaluated efficacy of mirabegron
in patients with and without prior OAB antimuscarinic therapy,
including the reason for discontinuation (lack of efficacy or poor
tolerability). Treatment effects on the original co-primary efficacy
endpoints were evaluated using analysis of covariance (ANCOVA).

In patients who discontinued due to lack of efficacy, adjusted
mean difference versus placebo in change from baseline in mean number
of incontinence episodes/24 h was -0.76 (95% CI -1.32 to -0.19) for
mirabegron 50 mg , -0.62 (95% CI -1.16 to -0.07) for mirabegron 100
mg and -0.06 (95% CI -0.63, 0.50) for tolterodine ER 4mg. Difference
versus placebo in change from baseline in mean number of
micturitions/24 h was -0.59 (95% CI -1.15 to -0.04) for mirabegron 50
mg, -0.58 (95% CI -1.13 to -0.02) for mirabegron 100 mg and -0.08
(95% CI -0.64 to 0.47) for tolterodine.

About mirabegron

Mirabegron is a once daily oral selective beta3-adrenoceptor
agonist discovered and developed by Astellas. It is the first
compound to be submitted for regulatory approval in this new class of
treatment, using a novel mechanism of action to antimuscarinics, the
current treatment standard.[1] Antimuscarinics work by binding to
muscarinic receptors in the bladder and inhibiting involuntary
bladder contractions. Mirabegron works by stimulating the beta3
receptors in the detrusor muscle of the bladder[5] causing relaxation
of the bladder muscle during the storage phase of the micturition
cycle. This improves the storage capacity of the bladder without
impeding bladder voiding.[6]

Astellas submitted a New Drug Application and Market
Authorisation Application for mirabegron to the U.S. Food and Drug
Administration and the European Medicines Agency on August 24 and 26,
2011 (US and Europe, respectively). Astellas is seeking approval for
the indication of overactive bladder (OAB) associated with symptoms
of urgency, urinary frequency, and urge urinary incontinence. In
Japan, Astellas was granted marketing approval under the trade name
of Betanis(R) tablet in July 2011. Additionally, there is an on-going
multiregional Phase 3 study in China, Korea, Taiwan, and India.

About Astellas Pharma Europe Ltd.:

Astellas Pharma Europe Ltd., located in the UK, is a European
subsidiary of Tokyo-based Astellas Pharma Inc. Astellas is a
pharmaceutical company dedicated to improving the health of people
around the world through the provision of innovative and reliable
pharmaceuticals. The organisation is committed to becoming a global
company by combining outstanding R&D and marketing capabilities and
continuing to grow in the world pharmaceutical market. Astellas
Pharma Europe Ltd. is responsible for 21 affiliate offices located
across Europe, the Middle East and Africa, an R&D site and three
manufacturing plants. The company employs approximately 4,200 staff
across these regions. For more information about Astellas Pharma
Europe, please visit http://www.astellas.eu.

References

1) Khullar V et al. Efficacy of mirabegron in patients with and without
prior anti-muscarinic therapy for overactive bladder (OAB): Post-hoc analysis of a
prospective, randomised European-Australian phase III trial. EAU 2012 Abstract
AM12-2389: 684
2) Chapple CR et al. Randomised, double blind, active controlled phase III study
to assess the long-term safety and efficacy of mirabegron in overactive bladder. EAU
2012 Abstract AM12-1967:683
3) Martin N et al. Randomised, double-blind, placebo-controlled study to assess
ocular safety of mirabegron in normotensive IOP research subjects. EAU 2012 Poster
AM12-1928: 686
4) Compion G et al. Reasons for switching antimuscarinic therapy: Results from a
European cross-sectional survey of physicians and patients with OAB. EAU 2012 Abstract
AM12-2068: 691
5) Takasu T et al. Effect of (R)-2-(2-aminothiazol-4-yl)-4?-{2-[(
2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective
beta3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 2007; 321: 642-7
6) Tyagi P et al. Mirabegron: safety review Expert Opin. Drug Safety
2011;10.2:287-294.

ots Originaltext: Astellas Pharma Europe Limited
Im Internet recherchierbar: http://www.presseportal.de

Contact:
For further information please contact: Julia Holt, Red Door
Communications, jholt@rdcomms.com, Tel: +44(0)20-8392-8052; Mindy
Dooa,
Astellas Pharma Europe Ltd.,
Mindy.Dooa@eu.astellas.com, Tel: +44(0)1784-419-408