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Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Univ. Prof. Dr. Dr. h.c. Heinz Kölbl Abteilung für Allgemeine Gynäkologie und.

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Präsentation zum Thema: "Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Univ. Prof. Dr. Dr. h.c. Heinz Kölbl Abteilung für Allgemeine Gynäkologie und."—  Präsentation transkript:

1 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Univ. Prof. Dr. Dr. h.c. Heinz Kölbl Abteilung für Allgemeine Gynäkologie und Gynäkologische Onkologie Medizinische Universität Wien Urogynäkologie und Altern – Prävention und Therapiekonzepte

2 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus  International Advisory Board Astellas  International Advisory Board Pfizer  International Advisory Board American Medical Systems  Consultant Johnson & Johnson

3 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Pubmed ‘ " a n t i a g i n g " O R " b e t t e r a g i n g “ L e t z t e 5 J a h r e, S t i c h w o r t i m A b s t r a c t : 2 ‘ A r t i k e l ( " a g e r e l a t e d " ) O R ( " a g e - r e l a t e d " ) O R ( a g e i n g ) ) A N D ( u r o g y n * O R " p e l v i c f l o o r " O R " p e l v i c o r g a n p r o l a p s e “ L e t z t e 5 J a h r e : A r t i k e l 1 8 " a g e r e l a t e d " A N D ( " p e l v i c o r g a n p r o l a p s e " O R " p e l v i c f l o o r " O R " u r o g y n * " ) 1 5 " a n t i a g i n g " O R " b e t t e r a g i n g " ) A N D ( " u r o g y n * " O R " p e l v i c f l o o r " O R " p e l v i c o r g a n p r o l a p s e “ 1 1 ( p r e v e n t i o n A N D a g i n g ) A N D ( p e l v i c o r g a n p r o l a p s e O R p e l v i c f l o o r )

4 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Lifespan Phases and a few examples of potential causal factors Phase I: Predisposing Factors (Genetic, nutritional, socialization) OR of POP in case of a pos. family history of POP 2.58 (95 % CI 2.12–3.15) [Linz IUJ 2011] Phase II: Inciting Factors Predisposing Maternal/Fetal Factors -Pelvic floor shape and size, Macrosomic Infant, Fetal Head Position Effects of Obstetrical Interventions (Prolonged 2nd stage, Occipito-posterior) -Forceps vs. Sectio: POP OR 7.5; 95% CI [Handa Ob Gyn 2011] Mechanism of injury (Muscle or nerve avulsion, nerve compression, connective tissue rupture) Phase III: Intervening Factors Variation in normal aging involving muscles, connective tissue and nerves from one individual to another Increased stresses on the pelvic floor (e.g., occupational lifting, obesity or chronic cough) Factors that lead to weakening of the support tissues (e.g. chronic steroid use or disuse atrophy of muscles) Lifestyle factors effect on symptoms (e.g., high impact aerobics, situations with restricted bathroom use) [DeLancey. AJOG 2008]

5 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus You can't stop the aging process, but you can minimize the impact by making healthy lifestyle choices. What to expect as you get older.What to expect as you get older. SystemWhat’s happening - changes with ageWhat to do Cardiovascular heart muscle less efficient, atherosclerosis, hypertension etc.physical activity, healthy diet, quit smoking Bones, joints and muscles bones tend to shrink, muscles generally lose strength and flexibility, less coordinated, trouble balancing. Calcium and vitamin D weight-bearing activities and strength training Digestive system low-fiber diet, not drinking enough, lack of exercise, medications medical conditions, including diabetes and irritable bowel syndrome Drink enough, healthy diet, physical activity Don't ignore the urge to have a bowel movement. Memory Memory becomes less efficient, number of neurons decreases. It may take longer to learn new things or remember familiar things. physical activity and healthy diet stay mentally and socially active. Eyes and ears Eyes less able to produce tears, retinas thin, lenses less clear. Focusing on objects that are close up may become more difficult. More sensitive to glare, have trouble adapting to light. Hearing may dim (high frequencies, conversation in a crowded room) Vision and hearing exams Glasses, contact lenses, hearing aids, other, sunglasses Earplugs around loud machinery or other loud noises Teeth Mouth may begin to feel drier, your gums recede from your teeth. less saliva  more vulnerable, teeth become easier to break. Brush your teeth dentist or dental hygienist Skin Skin thins, less elastic and more fragile  bruise more easily. Decreased production of natural oils  skin drier and wrinkled. Age spots, skin tags Bathe in warm water, mild soap and moisturizer. Sunscreen and protective clothing. Quit smoking Weight Maintaining a healthy weight — or losing weight is more difficult Muscle mass tends to decrease, which leads to an increase in fat. physical activity keep an eye on portion sizes Bladder and urinary tract Urinary incontinence Obesity, frequent constipation and chronic cough may contribute Urinate more often, lose excess pound, pelvic muscle exercises. Quit smoking Sexuality Sexual needs, patterns and performance may change. Illness or medication may affect ability to enjoy sex. Vaginal dryness. Share your needs and concerns with your partner. Different positions or sexual activities. Be open with your doctor. Estrogen [mayoclinic.com] Do you expect to find a few more wrinkles and gray hairs each time you look in the mirror? These are just some of the changes you're likely to notice as you get older. You're not necessarily at the mercy of Mother Nature, however.

6 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus …בעצב תלדי בנים… …mit Schmerzen sollst du Kinder gebären… [Genesis 3:16] Negev-Wüste, Israel BC Woman giving birth in the desert Charles-Joseph Natoire, 1740 Adam et Ève chassés du Paradis terrestre

7 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Pudendusschaden sub partu Injury to innervation of pelvic floor sphincter musculature in childbirth [Snooks. Lancet 1984] Pudendal nerve stretch during vaginal birth: a 3D computer simulation [Lien. AJOG 2005] Nervendehnung um bis 34% >15%  irreversible Schädigungen (Tiermodell) Geburtsmechanik Lien. AJOG 2005

8 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Pubic bone LA Pubic bone LA Breite Attachmentzone 68-jährige Nullipara40-jährige Nullipara OI 39-jährige 4p LA Pubic bone Cornelia Betschart bei DeLancey

9 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Geburt als akutes TraumaBis zur Menopause wenig symptomatisch.Geburt als akutes TraumaBis zur Menopause wenig symptomatisch.

10 Die Lebenserwartung nimmt seit dem 19. Jahrhundert stetig zu.Die Lebenserwartung nimmt seit dem 19. Jahrhundert stetig zu. Lebenserwartung bei Geburt für Frauen Österreich Altersstruktur in Österreich 2010 – 2050

11 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Prävalenz Genitaldeszensus Nygaard. JAMA N=1961 U.S. noninstitutionalized nonpregnant women (age ≥20 years) in Pelvic organ prolapse (seeing/feeling a bulge in or outside the vagina) symptoms were assessed.

12 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Deszensus in Abhängigkeit vom Alter [eigene Daten] Zystozele p= Rektozele p= N = 6387 Alter 60.1±15.3 ( ) Desz. uteri/ Vaginalstumpf p=0.0001

13 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Deszensus in Abhängigkeit vom Alter [eigene Daten] Zystozele p= Rektozele p= GradApexZystozeleRektozele 062 %44 %60 % 128 %32 %28 % 26 %16 %10 % 3-44 %8 %2 % N = 6387 Alter 60.1±15.3 ( ) Desz. uteri/ Vaginalstumpf p=0.0001

14 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Prolapse or incontinence surgery, USA 1995 [Olson 1997] Prolapse or incontinence surgery, USA 1993 [Fialkow 2008] Prolapse surgery, Western Australia [Smith 2010] Lifetime Risk / Kumulative Inzidenz für Operation wegen Inkontinenz oder Deszensus (5-)13-17% Rezidiv [Clark 2003, Denman 2008, Kapoor 2009, Kapoor 2010, Dallenbach 2012]

15 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus AlterungsprozessKomplexes Spektrum von EreignissenAlterungsprozessKomplexes Spektrum von Ereignissen Molekulare Schäden (Proteine, DNA) Zellen Organismus Freie Radikale (Oxidation) Nicht-enzymatische Glykosylierung Apoptose Zellteilung↓ und Wachstum↓ Stressantwort↓ und Homöostase↓ Erkrankungen↑ Fett↓, MMP↑, extrazelluläre Matrix↓ (Kollagen und Elastin) → Hautfalten Nervendegeneration: Geistiger Abbau bis Demenz Tod als letzte Konsequenz RF: Ernährung, Nikotin, Alkohol, Stress…

16 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Myogene Veränderungen finden sich bereits bei jungen Frauen: EndomysiumfibroseMyogene Veränderungen finden sich bereits bei jungen Frauen: Endomysiumfibrose Van Gieson staining Endomysial connective tissue proliferation (fibrosis), ventral part of the LAM Jundt et al. Is the histomorphological concept of the female pelvic floor and its changes due to age and vaginal delivery correct? Neurourol. Urodyn Neuronal cell adhesion molecule (NCAM) staining NCAM-positive muscle fibers (*) next to connective tissue (ct). Acetylcholinesterase staining  intact neuromuscular junction.

17 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus 1 Faser geht pro Tag verlustig. Perucchini. AJOG 2002 Alter R 2 =0.43; p= MUCP = 100 − Alter Rud. Acta Ob Gyn Scand 1980 Trowbridge. Ob Gyn 2007 MUCP R 2 =0.57; p<0.001 HistomorphologieFunktion Urethra: Altersabhängige Abnahme der MuskelfasernUrethra: Altersabhängige Abnahme der Muskelfasern 82 Nullipara jährig

18 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Altersabhängige Zunahme der Prävalenz der HarninkontinenzAltersabhängige Zunahme der Prävalenz der Harninkontinenz

19 Verlieren Sie gelegentlich Urin? DVerlieren Sie gelegentlich Urin? D

20 Alter und glatte Muskulatur: mit und ohne Prolaps Boreham et al. AJOG 2002 Alter (Jahre) Kontrolle *) p<0.05 (vgl. mit Kontrolle) Abnahme der Muskulatur im Alter im vorderen KompartimentAbnahme der Muskulatur im Alter im vorderen Kompartiment Kollagen Typ I Kollagen Typ III Stage 0n=15; r=0.47 Stage 0 n=15; r=0.65 Alter und Kollagenexpression Lin et al. Int Urogynecol J 2007 Alter ohne POP ohne Zystozele Stage II, III or IVn=23; r=0.58 Stage II, III or IVn=23 ; r=0.52

21 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Histomorphologie desDiaphragma urogenitaleHistomorphologie desDiaphragma urogenitale Histologie Diaphragma urogenitale Goldner Färbung. Cavalieri estimator 22 Leichen. Durchschnittsalter 87 Jahre (74-101) Prozentuale Verteilung Bindegewebe und Muskulatur Betschart C, Scheiner D, Maake C, Vich M, Slomianka L, Fink D, Perucchini D. Histomorphological analysis of the urogenital diaphragm in elderly women: a cadaver study. Int Urogynecol J Pelvic Floor Dysfunct. 2008

22 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Abnahme der Elastizität im vorderen KompartimentAbnahme der Elastizität im vorderen Kompartiment Barbara Röhrnbauer, Edoardo Mazza, ETH Zürich

23 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Abnahme der Dicke desSphinkter ani externusAbnahme der Dicke desSphinkter ani externus Äusserer Schliessmuskel und Alter Rociu. Radiology 2000 Sphincter ani exernus (Dicke in mm) ◦Frauen ●Männer Innerer Schliessmuskel und Alter Huebner. Dis Colon Rectum 2007

24 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Wirkt sich das Alter auf den Levator und Obturatormuskel aus?Wirkt sich das Alter auf den Levator und Obturatormuskel aus? MRI bei gesunden 21- bis 25-j. (N=15) und über 63-j. Frauen (N=12). Keine stat. sign. Unterschiede beim Levator. Sign. Abnahme M. obturator int. (CSA 24.5%, Vol. 28.2%, P < 0.001). M. levator ani zeigt bei gesunden Nulliparae keine Evidenz für signifikante altersabhängige Atrophie. Wenn Alter einen geringeren Einfluss auf den Levator hat, dann muss geklärt werden, wie Alter andere Gewebeeigenschaften ändert und wie diese Änderungen mit Schwangerschaft und Geburt interagieren und letztlich im Versagen der Beckenbodenaufhängung führen. Location 1 nahe Symphyse, 9 Spina Location 1 nahe Sympyhse, 9 iliococcygeal/ coccygeus Ansatz. [Morris et al. Neurourol. Urodynam. 2012]

25 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Neurologische Veränderungenim AlterNeurologische Veränderungenim Alter Zentralnervöse Veränderungen Miktion Überaktive Blase AChE-pos. Nerven↓ Axone im M. detrusor vesicae ↓ [Gilpin. BJU 1986] EMG-Aktivität↓ [Aukee. Maturitas 2003] Denervation↑ nach Geburt [Allen. BJOG 1990] Aktionspotentiale als Funktion von Alter und Geburt [Olsen. AJOG 2003]

26 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Altersabhängige Veränderungenan der BlaseAltersabhängige Veränderungenan der Blase Patchy denervation [Franklin. Am J Med 2006] Bindegewebe↑ zwischen glatten Muskelfasern Denervation Hypertrophie der glatten Muskulatur Complete Disjunction Pattern: Muskelzellen sind durch intimate cell appositions zu einer Kette verknüpft [Krengel 2006]

27 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Hormonmangel ist mitverantwortlich für Beckeninsuffizienz im AlterHormonmangel ist mitverantwortlich für Beckeninsuffizienz im Alter Östrogenrezeptoren ‣ Plattenepithel Urethra (proximal und distal), Vagina, Trigonum ‣ M. pubococcygeus… WHI (Women‘s Health Initiative) [Hendrix. JAMA 2005] ‣ 27‘347 Frauen  Pz vs CEE+MPA vs Pz vs CEE ‣ RR 1.87 (95%CI ) für SUI bei CEE+MPA ‣ RR 2.15 (95%CI ) für SUI bei CEE Conjugated equine estrogen alone and conjugated equine estrogen plus medroxyprogesterone acetate increased the risk of UI among continent women and worsened the characteristics of UI among symp- tomatic women after 1 year. Conjugated equine estrogen with or without progestin should not be prescribed for the prevention or relief of UI. HERS (Heart Estrogen/progestin Replacement Study) [Steinauer. Obstet Gynecol 2005] ‣ 1‘208 Frauen ohne UI  Pz vs CEE+MPA ‣ Wöchentliche Inkontinenz bei 64% mit HRT vs 49% ohne HRT ‣ OR 1.5 (95%CI ) für OAB, wet,12% Risiko (NNH* 8.6) ‣ OR 1.7 (95%CI ) für SUI,16% Risiko (NNH* 6.2) In conclusion, oral estrogen plus progestin therapy increased the risk for stress and urge urinary incontinence in postmenopausal women. Women who are using or considering hormone therapy should be informed about this increased risk. *) NNH, number needed to harm

28 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Wirkung von Östrogen auf die HautWirkung von Östrogen auf die Haut 17b Estradiol und Antioxidantien (Resveratrol, Genistein, S-equol) sind effektive Substanzen zur Verminderung der Hautalterung. Hauptmechanismus der Antioxidantien ist die Aktivierung des b-Östrogen-Rezeptors. [Jackson. Experimental Dermatology. 2011]

29 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Wundheilung Emmerson. The role of estrogen deficiency in skin ageing and wound healing. Biogerontology

30 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Sexualsteroide Kein Benefit bei bereits prämenopausaler oder ausgeprägter Inkontinenz oder bei fortgeschrittenem Deszensus. Inkontinenz ↓, die postmenopausal beginnt und wenn kein Deszensus Adjuvant perioperativ/-therapeutisch: verbesserte Vaskularisation Brennen, Jucken, Dyspareunie, Dysurie oder Urgency ↓ Harnweginfektionen ↓ (pH ↓, Lactobacilli ↑) [Sartori et al. Sexual steroids in urogynecology. Climacteric. 2011] HypoöstrogenismusHormonersatz Mukosa im Harntrakt↓↑ Urogenitale Zellreifung↓↑ Vaskularisaton von Blase, Mm. periurethrales und Levator ani↓↑ Muskularis von Urethra und Blase↓↑ Kollagen in Muskularis von Urethra und Blase↑↓ Sulfat-Glycosaminoglycane und Hyaluronsäure im Harntrakt+++ b2-Microglobulin, Cyt-c-Oxidase, VEGF↓↑ Muskarinrezeptoren (Dichte)↓↑

31 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus  RCT, Placebo-kontrolliert  Intravaginale Estriol-Créme  HWI-Inzidenz  p<0.001  Laktobazillen  p<0.001  Enterobakterien  p<0.005  Vaginal pH  p<0.001 Lokale Östrogene Cody et al. Oestrogen therapy for urinary incontinence in post-menopausal women. Cochrane 2012: 33 Studien mit 19’313 inkontinenten Frauen Lokales Östrogen kann Harninkontinenz verbessern. RR 0.74, 95% CI weniger Miktionen/24h, weniger Drang Wenig Evidenz über Erfolg nach Abschluss der Östrogenisierung Systemische HRT mit konjugiertem äquinem Östrogen kann die Inkontinenz verschlechtern. RR 1.32, 95% CI Zu wenig verlässliche Daten zu Art des Östrogens, Dosierung und Galenik Risiko von Endometrium- und Mammakarzinom nach langer systemischer Östrogeneinnahme suggeriert eine zeitlich beschränkte Östrogenapplikation, v.a. bei Frauen mit Uterus. Kein sicherer Benefit bei Deszensus (Sharif. Cochrane 2010) Ev. orales Raloxifen mag Notwendigkeit für Deszensuschirurgie bei Frauen > 60 reduzieren. Raz NEJM 1993;329: p<0.001

32 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Führt nun der aktuelle Wissensstand zu einer wirksamen Prophylaxe? Derzeit steht praktisch keine eigentliche Prävention altersbedingter Veränderungen zur Verfügung. Beckenbodenschwäche begünstigt durch wenig oder schlecht beeinflussbare Faktoren: Schwangerschaft, Geburten Voroperationen Neurologische Schäden, Neuropathie Mögliche Beeinflussung und allgemeine Massnahmen Verbesserung der Kognition Vermeiden resp. Behebung von Risikofaktoren: Adipositas (Kudish. Ob Gyn 2009), Diabetes, chronische Belastung Lokal Östrogen Uro-Vaxom, Cranberry etc. Anti-Aging, Substanzen wie Ghrelin (Rizk 2007)? Lavy et al. Int Urogynecol J (2012)

33 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Overactive Bladder Syndrome ‘Urinary urgency usually accompanied by frequency and nocturia with or without urgency urinary incontinence in the absence of UTI or other obvious pathology’ Haylen BT et al. Neurourology and Urodynamics. 2010; 29:4-20

34 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus EU population forecast Adapted from 2009 Ageing Report: Economic and budgetary projections for the EU-27 Member States ( ) European Economy 2/2009. p FemalesMalesAge Groups FemalesMalesAge Groups 2060 Population in thousands

35 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Intramural facilitatory mechanisms for spontaneous contractions Sensory collaterals Suburothelial interstitial cells Smooth muscle cells Intramural ganglia Interstitial cells ACh NA ATP NO ACh PGs Urothelium-based theory Afferent nerves Myogenic theory Distension Mechanisms involved in increased afferent input from the bladderMechanisms involved in increased afferent input from the bladder

36 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Antimuscarinics Antimuscarinics are the mainstay pharmacological treatment for OAB They are effective in the short term as well as long term Antimuscarincis improve HRQoL in OAB patients

37 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Duration of solifenacin 5/10mg exposure (weeks) 4 Median percentage reduction Frequency Nocturia Urgency -27% -50% -89% Adapted from: Haab F, et al. Eur Urol. 2005;47:376–384 Antimuscarinic drug therapy improves OAB symptoms 40-week open-label extension trial with patients completing treatment in the two previous randomised, double-blind, 12-week studies

38 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus The challenge with antimuscarinics Despite being the main pharmacological treatment option for OAB, persistence with antimuscarinics can be a challenge Patients may stop medication either due to an insufficient response to treatment or intolerable side effects

39 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Time to discontinuation of medication in six chronic therapy classes Prostaglandins OAB Medications ARBs* Oral Antidiabetics Statins Bisphosphonates 10 Percentage persistence (%) *ARBs: angiotensin receptor blockers Days Yeaw J, et al. J Manag Care Pharm. 2009;15:728–40

40 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Persistence with antimuscarinic medication 35% of patients never refill their OAB medication in a non pay system 1 Systematic literature review published since 1998; rate of discontinuation of treatment 43 – 83% within first 30 days 2 1. Sears, et al J Urol 2010 (1) 2. Sexton, et al Int J Clin Res 2011;65:

41 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Percentage of patients remaining on each antimuscarinic over 12 months Abstract and poster; SIU 2010, Siddiqui E, et al. BJUi Patients (%) Months solifenacin (n=1,381) tolterodine ER (n=1,758) tolterodine IR (n=1,758) oxybutynin ER (n=482) oxybutynin IR (n=590) propiverine (n=97) trospium (n=352) darifenacin (n=23) flavoxate (n=89)

42 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Reasons for discontinuing antimuscarinic medication for OAB Benner JS, et al. J Urol 2009;181:2591–91

43 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Can we achieve the optimal balance? EfficacyTolerability Relieves symptoms of OAB Minimal side effects Adherence/ Persistency Maximizes duration of therapy Optimal Balance

44 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Mirabegron Pharmacology Affinity for Human Beta-Adrenoceptor Subtypes Ki (nmol/L) Beta 1Beta 2Beta 3 mirabegron4,200 ± 9001,300 ± ± 20.2 Ki values are expressed as the mean ± SE; receptor binding study using membrane fractions from Chinese hamster ovary (CHO) cells expressing human β-AR subtypes

45 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Neurologic Innervation and Control of Bladder Musculature Antimuscarinics ACH NE M3 muscarinic receptor detrusor smooth muscle (relaxation) Norepinepherine β 3 adrenergic receptor B 3 agonist – + Acetylcholine (contraction) Activation of parasympathetic pathway causes detrusor muscle contraction and micturition. Activation of sympathetic pathway inhibits detrusor contraction and contracts the bladder outlet Activation of parasympathetic pathway causes detrusor muscle contraction and micturition. Activation of sympathetic pathway inhibits detrusor contraction and contracts the bladder outlet

46 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Non-Clinical Urology Models Mirabegron enhances urine storage function by stimulating beta 3 -ARs in the bladder Mirabegron showed relaxation of isolated rat and human bladder smooth muscle and increased cAMP in rat bladder tissue Mirabegron decreased the frequency of rhythmic bladder contractions without affecting the force of the rhythmic bladder contractions in rats Mirabegron decreased the frequency of non-voiding contractions, without affecting the voiding pressure in rats

47 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Summary of Toxicology Findings Genotoxicity and Carcinogenicity Mirabegron demonstrated no genotoxic or carcinogenic potential Reproduction No effect on fertility or teratogenic potential Embryo-fetal toxicity at doses causing maternal toxicity in rats (reversible wavy ribs; systemic exposures 95-fold the human exposure at MRHD) and rabbits (dilated aorta and cardiomegaly; systemic exposure 36-fold the human exposure at MRHD) These animal observations are thought to be due to cross activation of beta 1 -AR

48 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Summary of Toxicology Findings No direct indications of central effects Effect of mirabegron on cognition has not been studied in humans No direct indications of central effects Effect of mirabegron on cognition has not been studied in humans No indications of arrhythmogenicity No pre-clinical signal for hepatoxicity Incidental increases in AST/ALT observed in PIII all reversible while still on treatment No pre-clinical signal for hepatoxicity Incidental increases in AST/ALT observed in PIII all reversible while still on treatment

49 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Clinical Pharmacology Profile

50 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Human Pharmacokinetic Profile Mirabegron is rapidly absorbed; T max 3–4.3 hrs Absolute bioavailability increases from 29% at 25mg to 35% at 50mg Mean C max and AUC increase more than dose proportionally after oral administration Plasma effective half-life 19 hrs Steady state concentrations attained within 7 days Mirabegron is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided or crushed One dose level for young and elderly, and gender Mirabegron is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided or crushed One dose level for young and elderly, and gender

51 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Food Effect - Exposures in OAB patients Mirabegron concentration versus Time after Dose by Food condition Red: Fed Grey: Fasted 178-PK-0 15 Addendum CL-046; 50 mg 178-CL-047; 50 mg Similar exposure of mirabegron with and without food in 2 pivotal PIII trials Similar efficacy and safety profile with and without food Mirabegron can be taken with or without food at the recommended dose Similar exposure of mirabegron with and without food in 2 pivotal PIII trials Similar efficacy and safety profile with and without food Mirabegron can be taken with or without food at the recommended dose

52 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Clinical Profile

53 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Mirabegron Development Program Phase 1 29 Clinical Pharmacology Phase 2 6 Clinical Studies Phase 3 6 OAB Clinical Studies CL SAD CL-002 MAD CL-007 MB CL-005 PK CL-030 PK CL-033 BA CL-031 PK CL-036 DDI CL-034 PK CL-037 TQT CL-072 A/G CL-066 DP CL-070 DDI CL-058 DDI CL-068 DDI CL-059 DDI CL-040 DDI CL-064 FE CL-038 Renal CL-076 PK CL-041 FE CL-003 POC DM CL-069 DDI CL-039 PK CL-078 FE CL-077 TQT CL-081 IOP CL-080 DDI CL-053 CI 29 P HASE 1 S TUDIES 1800 Volunteers 1462 mirabegron CL-003 POC DM CL-008 POCCL-044 DF (EU)CL-045 DF (JP) CL-060 (LUTS/BOO) OAB Diabetes LUTS/BOO 12 P HASE 2/3 S TUDIES 8752 Patients [8433 OAB] 5863 (OAB) mirabegron Supportive Study 12-Weeks Studies Long-term (52-Weeks Studies CL-046 EU (SPA) CL-047 NA (SPA) CL-074 EU/NA CL-048 JP CL-049 EU/NA Long-term Controlled CL-051 JP Long-term Uncontrolled CL-006 DDI

54 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Mirabegron – Can it fulfil the unmet need? Mirabegron may be able to provide the optimal balance between efficacy and tolerability? Mirabegron may be able to improve the persistence with OAB therapy with currently is low.

55 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Primary Phase III design178-CL-046 (EU), 178-CL-047 (NA), 178-CL-074 (EU/NA)Primary Phase III design178-CL-046 (EU), 178-CL-047 (NA), 178-CL-074 (EU/NA) 12 WEEKS 4 weeks follow-up 2 weeks placebo run-in Double - Blind Treatment Treatment -178-CL-046N Mirabegron 50 mg497 Mirabegron 100 mg498 Tolterodine 4 mg SR495 Placebo497 V1 Week -2 V2 Week 0 V3 Week 4 V5 Week 12 V6 Week 16 START SCREENINGSTART SCREENING ENDOF STUDYENDOF STUDY FOLLOW UPFOLLOW UP V4 Week 8 4 weeks RANDOMIZATION RANDOMIZATION Treatment – 178-CL-047N Mirabegron 50 mg 442 Mirabegron 100 mg 433 Placebo weeks follow-up 2 weeks follow-up EU – Europe, NA – North America Treatment – 178-CL-074N Mirabegron 25 mg 433 Mirabegron 50 mg 440 Placebo 433

56 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus 046: Co-Primary Endpoint Mean Number of Incontinence Episodes per 24 hrs * Adjusted Mean Change from Baseline to Final Visit (FAS Incontinence) placebo mirabegron tolterodine 50 mg ER 4 mg (n=291) (n=293) (n=301) Baseline Khullar V. et al. Eur Urol Suppl 2011;10(2);278–279 [Abstract 886] Mean number of Incontinence episodes per 24 hours Mirabegron 100mg data not shown * Statistically significant improvement versus placebo with multiplicity adjustments

57 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus 046: Co-Primary Endpoint Mean Number of Micturitions per 24 hrs Adjusted Mean Change from Baseline to Final Visit (FAS) Khullar V et al. Eur Urol Suppl 2011;10(2);278–279 [Abstract 886] number of micturitions per 24 hours placebo mirabegron tolterodine 50 mg ER 4 mg (n=480) (n=473) (n=475) Baseline * Mirabegron 100mg data not shown * Statistically significant improvement versus placebo with multiplicity adjustments

58 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Mirabegron 50mg significantly improved urgency episodes (grade 3 or 4) from baseline to Final Visit ADDITIONAL SECONDARY RESULTS  Mean change from baseline to Final Visit in the mean number of urgency episodes (PPIUS, grade 3 or 4) per 24 hours (FAS) Astellas Pharma, data on file [clinical study report, p 113 & Appendix Tables – ] (n=479) (n=470) p=0.005 (n=472) p=0.50 mirabegron 50 mg tolterodine SR 4 mg Baseline Data are least squares mean adjusted for baseline, gender and geographical region; FAS-I = all FAS patients who had at least one incontinence episode at baseline; SR=slow release; mirabegron 100mg data not shown * * Statistically significant improvement versus placebo with multiplicity adjustments

59 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Mirabegron 50 mg significantly improved nocturia episodes from baseline to Final Visit ADDITIONAL SECONDARY RESULTS  Mean change from baseline to Final Visit in the mean number of nocturia episodes in 24 hours (FAS) Astellas Pharma, data on file [clinical study report, p 113 & Appendix Tables – ] (n=428)(n=423) p=0.022 (n=433) P=0.52 Mirabegron 50 mg tolterodine SR 4 mg Baseline Data are least squares mean adjusted for baseline, gender and geographical region; FAS-I=all FAS patients who had at least one incontinence episode at baseline; SR=slow release; Mirabegron 100mg data not shown

60 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Zero incontinence episodes at Final Visit (FAS-I) – only patients who had at least 1 incontinence episode at baseline were included 60 (n=291) ZERO INCONTINENCE (n=293) placebo (046) mirabegron 50 mg (046) Number of responders with zero incontinence at Final Visit A responder is defined as a subject who becomes continent during the treatment period as each visit is defined. Only subjects who have at least one incontinence episode at baseline are included. Astellas Pharma, data on file [clinical study report,table ] (n=300) tolterodine SR 4 mg Mirabegron 100mg data not shown

61 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Quality of life results (046/047/074) HEOR questionnaires demonstrated that mirabegron had a statistically significant improvement compared to placebo at Final Visit for: OAB-q (100 mg, 50 mg except for sleep and social) Patient Perception of Bladder Condition (50 mg, 100 mg) TS-VAS (25 mg, 50 mg, 100 mg) Improvement demonstrated but no data on statistical significance Work and Activity Impairment EQ-5D

62 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Mirabegron significantly improved treatment satisfaction at Final Visit compared with placebo Mean change from baseline to Final Visit in treatment satisfaction (TS-VAS; FAS) 62 Improvement (n=428) Mean change in treatment satisfaction PATIENT-REPORTED OUTCOME (n=414) Data are least squares mean adjusted for baseline, gender and geographical region; Nitti V, et al. J Urol 2011;11(4):e784 [Abstract 1959]; Astellas Pharma, data on file [clinical study report] Baseline (n=425) Placebo (046) Mirabegron 50 mg (046) Tolterodine SR4 mg * Mirabegron 100mg data not shown * Statistically significant improvement versus placebo at 0.05 level

63 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Study Common (≥2% in any treatment group) Treatment - emergent adverse events Adverse events n (%)placebo (n=494) mirabegron 50 mg (n=493) tolterodine SR 4 mg (n=495) Hypertension38 (7.7)29 (5.9)40 (8.1) Nasopharyngitis8 (1.6)14 (2.8) Dry Mouth13 (2.6)14 (2.8)50 (10.1) Headache14 (2.8)18 (3.7)18 (3.6) Influenza8 (1.6)11 (2.2)7 (1.4) Urinary tract infection7 (1.4) 10 (2.0) Constipation7 (1.4)8 (1.6)10 (2.0) Data are for the safety analysis set. Adverse events, defined according to the Medical Dictionary for the Regulatory Activities (MedDRA version 9.1), were reported after the first dose of double-blind study drug and no more than 30 days after the last dose of double-blind study drug. Patients with one or more adverse events within a level of the MedDRA term were counted only once in that level Khullar V, et al. Eur Urol Suppl 2011;10(2);278–279 [Abstract 886] Mirabegron 100mg data not shown

64 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Subgroup analysis: Prior OAB medication Key Queries: Is there a difference in treatment effect of mirabegron between patients previously treated with antimuscarinics versus treatment naïve patients? Evaluations of pooled data pre-specified in integrated analysis plan Is there a difference in treatment effect of mirabegron versus tolterodine in patients previously treated with antimuscarinics? Evaluations of 178-CL-046 study data post-hoc to further assess tolterodine performance

65 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus (n=518) (n=506) (n=360) (n=356) Subgroup analysis: Prior OAB medication Pooled data ISE – 046/047/074: Incontinence Previous OAB medication No previous OAB medication Mirabegron 100mg data not shown Adjusted mean change from baseline in mean number of incontinence episodes / 24 h (CI -0.81, -0.33) (CI -0.44, 0.14)

66 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Insights from subgroup analyses: Prior OAB medication Mirabegron is effective in antimuscarinic treatment naïve patients and in patients who discontinued prior OAB antimuscarinic treatment. Mirabegron is effective in patients who discontinued prior OAB antimuscarinic treatment due to insufficient efficacy. Tolterodine demonstrated a response similar to placebo.

67 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Long-term safety study 178-CL-049 (EU&NA) 2 weeks Run-in 1 Year Double-blind Treatment Treatment -178-CL-049 Visit 1 Start Screening tolterodine 4 mg ER (n=813) mirabegron 50 mg (n=815) Visit 6 Month 12 Visit 5 Month 9 Visit 4 Month 6 Visit 3 Month 3 Visit 2 Week 0Week -2 mirabegron 100 mg (n=824) placebo End of study Visit 3 Month 1 Randomized n=2452 Chapple CR, et al. European Urology Supplements 2012;11(1):e683

68 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Common (≥ 2% of patients in any treatment group) Treatment emergent adverse events MedDRA (v9.1) Preferred Term mirabegron tolterodine ER 4 mg (n=812) n (%) 50 mg (n=812) n (%) 100 mg (n=820) n (%) Hypertension 75 (9.2%)80 (9.8%)78 (9.6%) Urinary tract infection 48 (5.9%)45 (5.5%)52 (6.4%) Headache 33 (4.1%)26 (3.2%)20 (2.5%) Nasopharyngitis 32 (3.9%)35 (4.3%)25 (3.1%) Back pain 23 (2.8%)29 (3.5%)13 (1.6%) Constipation 23 (2.8%)25 (3.0%)22 (2.7%) Dry mouth 23 (2.8%)19 (2.3%)70 (8.6%) Sinusitis 22 (2.7%)18 (2.2%)12 (1.5%) Dizziness 22 (2.7%)13 (1.6%)21 (2.6%) Influenza 21 (2.6%)25 (3.0%)28 (3.4%) Cystitis 17 (2.1%)11 (1.3%)19 (2.3%) Arthralgia 17 (2.1%)19 (2.3%)16 (2.0%) Diarrhoea 15 (1.8%)24 (2.9%)16 (2.0%) Tachycardia 8 (1.0%)19 (2.3%)25 (3.1%) 178-CL-049 Long term safety study Chapple CR, et al. European Urology Supplements 2012;11(1):e683

69 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Conclusion from long term safety study 178-CL-049 This study supports the long-term safety and tolerability of mirabegron for OAB. Mirabegron was well tolerated over a 12 month period AEs typical of antimuscarinics, incidence of dry mouth was 3-fold higher with tolterodine than mirabegron Mirabegron demonstrated improvement from baseline for key OAB symptoms with an efficacy similar to that observed with tolterodine ER Chapple CR, et al. European Urology Supplements 2012;11(1):e683

70 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus The BEYOND Study

71 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Population OAB subjects who have had ≥1 antimuscarinic in past 6 months ● Includes lapsed or those currently receiving an antimuscarinic treatment Must have taken the last antimuscarinic for at least 4 weeks Subject is dissatisfied with last antimuscarinic due to lack of efficacy Last antimuscarinic cannot be solifenacin

72 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Visit Schedule 12 weeks 2 weeks Placebo run-in Mirabegron 50mg daily Solifenacin 5mg daily D-14 (V1 ) D1 (V2) W4 (V3)W8 (V4)W12 (V5 ) The Study Design ScreeningRandomisation End of Treatment

73 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Primary & Key Secondary Endpoints Primary: Change from baseline in the mean number of micturitions per 24 hours, based on a 3-day micturition diary Key Secondary: Proportion of subjects reporting at least one treatment-emergent adverse event of dry mouth, constipation or blurred vision during double-blind treatment period

74 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Mirabegron exposure clinical experience summary 41 clinical studies 10,552 subject OAB patients in Phase II/III 8433 patients* of which 5648 received mirabegron OAB patients in Phase II/III 8433 patients* of which 5648 received mirabegron 29 Phase I studies 1800 volunteers of which 1462 received mirabegron 12 Phase II/III studies 8752 patients (OAB, LUTS/BOO, DM) of which 5863 received mirabegron 12 Phase II/III studies 8752 patients (OAB, LUTS/BOO, DM) of which 5863 received mirabegron *622 OAB patients received mirabegron ≥ 1 year

75 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Mirabegron clinical development program Efficacy and safety conclusions The global development program provides robust data to support the efficacy and safety of mirabegron in the treatment of overactive bladder Efficacy established through subjective and objective endpoints Effect established across multiple studies Efficacy evident in both antimuscarinic treatment naïve patients and patients who discontinued prior OAB antimuscarinic therapy Safety and tolerability in both short term and long term studies

76 Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Groucho Marx, Age is not a particularly interesting subject. Anyone can get old All you have to do is live long enough.


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