Astellas Pharma Europe Limited

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. 

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


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