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Urogynäkologie und Altern – Prävention und Therapiekonzepte

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

2 Disclosures International Advisory Board Astellas
International Advisory Board Pfizer International Advisory Board American Medical Systems Consultant Johnson & Johnson 2

3 Pubmed 12.02.2013 10‘722 "anti aging" OR "better aging“
Letzte 5 Jahre, Stichwort im Abstract: 2‘388 Artikel 233 ("age related") OR ("age-related") OR (ageing)) AND (urogyn* OR "pelvic floor" OR "pelvic organ prolapse“ Letzte 5 Jahre: 110 Artikel 18 "age related" AND ("pelvic organ prolapse" OR "pelvic floor" OR "urogyn*") 15 "anti aging" OR "better aging") AND ("urogyn*" OR "pelvic floor" OR "pelvic organ prolapse“ 11 (prevention AND aging) AND (pelvic organ prolapse OR pelvic floor) Pubmed

4 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 What to expect as you get older.
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. System What’s happening - changes with age What 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 You can't stop the aging process, but you can minimize the impact by making healthy lifestyle choices. [mayoclinic.com]

6 …בעצב תלדי בנים… …mit Schmerzen sollst du Kinder gebären… [Genesis 3:16]
Apfel (n=1) Charles-Joseph Natoire, 1740 Adam et Ève chassés du Paradis terrestre Negev-Wüste, Israel BC Woman giving birth in the desert

7 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 68-jährige Nullipara 40-jährige Nullipara 39-jährige 4p Pubic bone
LA Breite Attachmentzone Pubic bone LA OI Masson Trichrom Färbung. Bei den Nulliparen Frauen ist der Levator ani (LA) ein dicker Muskel von 3mm Durchmesser. Die Attachmentzone/Enthesis ist gut ausgebildet mit multiplen Verankerungen. OI=obturator internus Cornelia Betschart bei DeLancey 8

9 Geburt als akutes Trauma Bis zur Menopause wenig symptomatisch.
Bsp. SUI 9

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

11 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 Deszensus in Abhängigkeit vom Alter [eigene Daten]
Desz. uteri/ Vaginalstumpf p=0.0001 N = 6387 Alter 60.1±15.3 ( ) Zystozele p=0.0001 Rektozele p=0.0001

13 Deszensus in Abhängigkeit vom Alter [eigene Daten]
Desz. uteri/ Vaginalstumpf p=0.0001 N = 6387 Alter 60.1±15.3 ( ) Zystozele p=0.0001 Grad Apex Zystozele Rektozele 62 % 44 % 60 % 1 28 % 32 % 2 6 % 16 % 10 % 3-4 4 % 8 % 2 % Rektozele p=0.0001

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

15 Alterungsprozess Komplexes 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 Neuronal cell adhesion molecule (NCAM) staining
Myogene Veränderungen finden sich bereits bei jungen Frauen: Endomysiumfibrose Van Gieson staining Endomysial connective tissue proliferation (fibrosis), ventral part of the LAM Neuronal cell adhesion molecule (NCAM) staining NCAM-positive muscle fibers (*) next to connective tissue (ct). Acetylcholinesterase staining  intact neuromuscular junction. Jundt et al. Is the histomorphological concept of the female pelvic floor and its changes due to age and vaginal delivery correct? Neurourol. Urodyn. 2005

17 Urethra: Altersabhängige Abnahme der Muskelfasern
Histomorphologie Funktion MUCP 82 Nullipara 21-70 jährig R2=0.43; p=0.0003 R2=0.57; p<0.001 Trowbridge. Ob Gyn 2007 Alter 1 Faser geht pro Tag verlustig. Perucchini. AJOG 2002 MUCP = 100 − Alter Rud. Acta Ob Gyn Scand 1980

18 Altersabhängige Zunahme der Prävalenz der Harninkontinenz

19 Verlieren Sie gelegentlich Urin? D

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

21 Histomorphologie des Diaphragma urogenitale
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 Histologie Diaphragma urogenitale Goldner Färbung. Cavalieri estimator 22 Leichen. Durchschnittsalter 87 Jahre (74-101) Prozentuale Verteilung Bindegewebe und Muskulatur

22 Abnahme der Elastizität im vorderen Kompartiment
Barbara Röhrnbauer, Edoardo Mazza, ETH Zürich

23 Abnahme der Dicke des Sphinkter ani externus
Sphincter ani exernus (Dicke in mm) ◦ Frauen ● Männer Äusserer Schliessmuskel und Alter Rociu. Radiology 2000 Innerer Schliessmuskel und Alter Huebner. Dis Colon Rectum 2007

24 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 Neurologische Veränderungen im 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] N. pudendus Latenz (msec) Perineal Aktions- potential (μV) Alle (n=42) 1.94 ( ) 100.9 ( ) <40-jährig (n=20) 1.91 ( ) 118.8 ( ) 40-59 (n=16) 1.93 87.4 ( ) ≥60 (n=6) 2.10 ( ) 79.7 ( ) Aktionspotentiale als Funktion von Alter und Geburt [Olsen. AJOG 2003]

26 Altersabhängige Veränderungen an der Blase
Patchy denervation [Franklin. Am J Med 2006] Bindegewebe↑ zwischen glatten Muskelfasern Denervation Hypertrophie der glatten Muskulatur Veränderung Möglicher Einfluss Disjunction pattern Muskel-/ Axondegeneration OAB, verminderte Kontraktilität Hypotone Urethra Inkontinenz Östrogenmangel Vaginitis, HWI Nächtliche Diurese↑ Nykturie, Enuresis Neurotransmitter Dysfunktion Veränderte Immunabwehr Rez. HWI Complete Disjunction Pattern: Muskelzellen sind durch intimate cell appositions zu einer Kette verknüpft [Krengel 2006]

27 Hormonmangel 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 Wirkung 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 Wundheilung Emmerson. The role of estrogen deficiency in skin ageing and wound healing. Biogerontology

30 Sexualsteroide Hypoöstrogenismus Hormonersatz 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) 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]

31 Lokale Östrogene RCT, Placebo-kontrolliert Intravaginale Estriol-Créme
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 1-2 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. p<0.001 Raz NEJM 1993;329: RCT, Placebo-kontrolliert Intravaginale Estriol-Créme HWI-Inzidenz  p<0.001 Laktobazillen  p<0.001 Enterobakterien  p<0.005 Vaginal pH  p<0.001

32 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 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 33

34 EU population forecast
20000 15000 10000 5000 90+ 85-89 80-84 75-79 70-74 65-69 60-64 55-59 50-54 45-49 40-44 35-39 30-34 25-29 20-24 15-19 10-14 5-9 0-4 Females Males Age Groups 2008 2060 Population in thousands Population in thousands Adapted from 2009 Ageing Report: Economic and budgetary projections for the EU-27 Member States ( ) European Economy 2/2009. p.43

35 Mechanisms involved in increased afferent input from the bladder
Urothelium-based theory CNS Urothelium ATP NO ACh PGs Afferent nerves Myogenic theory Intramural facilitatory mechanisms for spontaneous contractions Distension Intramural ganglia Sensory collaterals ACh Interstitial cells Suburothelial interstitial cells NA Smooth muscle cells 35

36 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 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 Duration of solifenacin 5/10mg exposure (weeks) 4 8 12 16 28 40 52 Median percentage reduction -20 Frequency -27% Efficacy outcomes were also analysed based on total exposure to solifenacin for all patients participating in the extension study. This slide shows the mean percentage reductions in frequency, urgency episodes and nocturia episodes and urge incontinence per 24hrs. The initial efficacy benefits achieved with solifenacin therapy during the 12-week double-blind trial periods were well maintained with longer-term treatment. -40 Nocturia -50% -60 -80 Urgency -89% -100 Adapted from: Haab F, et al. Eur Urol. 2005;47:376–384 37

38 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 Time to discontinuation of medication in six chronic therapy classes
100 90 80 Percentage persistence (%) 70 60 50 40 Oral Antidiabetics ARBs* 30 Statins Bisphosphonates 20 Prostaglandins 10 OAB Medications 120 240 360 480 600 720 Days *ARBs: angiotensin receptor blockers Yeaw J, et al. J Manag Care Pharm. 2009;15:728–40 39

40 Persistence with antimuscarinic medication
35% of patients never refill their OAB medication in a non pay system1 Systematic literature review published since 1998; rate of discontinuation of treatment 43 – 83% within first 30 days2 1. Sears, et al J Urol 2010 (1) 2. Sexton, et al Int J Clin Res 2011;65:

41 Percentage of patients remaining on each antimuscarinic over 12 months
100 solifenacin (n=1,381) tolterodine ER (n=1,758) 90 tolterodine IR (n=1,758) 80 oxybutynin ER (n=482) oxybutynin IR (n=590) 70 propiverine (n=97) 60 Patients (%) trospium (n=352) 50 darifenacin (n=23) flavoxate (n=89) 40 30 20 10 1 2 3 4 5 6 7 8 9 10 11 12 Months Abstract and poster; SIU 2010, Siddiqui E, et al. BJUi 2012

42 Reasons for discontinuing antimuscarinic medication for OAB
Benner JS, et al. J Urol 2009;181:2591–91 42

43 Can we achieve the optimal balance?
Efficacy Tolerability Relieves symptoms of OAB Minimal side effects Optimal Balance Adherence/ Persistency Maximizes duration of therapy

44 Mirabegron Pharmacology
Presentation Name Presentation Name Slide Call 44 4/20/2017 Mirabegron Pharmacology Affinity for Human Beta-Adrenoceptor Subtypes Ki (nmol/L) Beta 1 Beta 2 Beta 3 mirabegron 4,200 ± 900 1,300 ± 300 40 ± 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 Structure just FYI More importantly affinity for beta3 100-fold> beta1 Presentation Name Presentation Name Slide Call 44

45 Neurologic Innervation and Control of Bladder Musculature
Antimuscarinics ACH NE M3 muscarinic receptor detrusor smooth muscle (relaxation) Norepinepherine β3 adrenergic receptor B3 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

46 Non-Clinical Urology Models
Mirabegron enhances urine storage function by stimulating beta3-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 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 beta1-AR Message: only embryofetal finding at doses where dams died 47

48 Summary of Toxicology Findings
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

49 Clinical Pharmacology Profile

50 Human Pharmacokinetic Profile
Mirabegron is rapidly absorbed; Tmax 3–4.3 hrs Absolute bioavailability increases from 29% at 25mg to 35% at 50mg Mean Cmax 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 50

51 Food Effect - Exposures in OAB patients
Mirabegron concentration versus Time after Dose by Food condition 178-CL-046; 50 mg 178-CL-047; 50 mg Red: Fed Grey: Fasted 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 178-PK-015 Addendum 1 51

52 Clinical Profile

53 Mirabegron Development Program
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 CL SAD CL-030 PK CL-069 DDI CL-002 MAD CL-007 MB CL-033 BA CL-039 PK CL-077 TQT CL-041 FE CL-081 IOP CL-005 PK CL-031 PK CL-037 TQT CL-076 PK CL-080 DDI Phase Clinical Pharmacology CL-006 DDI CL-036 DDI CL-038 Renal CL-064 FE CL-034 PK CL-053 CI CL-040 DDI 29 Phase 1 Studies 1800 Volunteers 1462 mirabegron CL-078 FE CL-059 DDI CL-066 DP CL-070 DDI CL-058 DDI CL-068 DDI CL-072 A/G CL-003 POC DM Diabetes Phase 2 6 Clinical Studies CL-003 POC DM OAB CL-008 POC CL-044 DF (EU) CL-045 DF (JP) LUTS/BOO 12 Phase 2/3 Studies 8752 Patients [8433 OAB] 5863 (OAB) mirabegron CL-060 (LUTS/BOO) CL-046 EU (SPA) 12-Weeks Studies CL-047 NA (SPA) Phase 3 6 OAB Clinical Studies CL-074 EU/NA Supportive Study CL-048 JP CL-049 EU/NA Long-term Controlled Long-term (52-Weeks Studies CL-051 JP Long-term Uncontrolled

54 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 Primary Phase III design 178-CL-046 (EU), 178-CL-047 (NA), 178-CL-074 (EU/NA)
12 WEEKS RANDOMIZATION END OF STUDY FOLLOW UP 2 weeks placebo run-in Double - Blind Treatment START SCREENING 4 weeks 4 weeks 4 weeks Treatment -178-CL-046 N Mirabegron 50 mg 497 Mirabegron 100 mg 498 Tolterodine 4 mg SR 495 Placebo 497 4 weeks follow-up 4 weeks follow-up Treatment – 178-CL-047 N Mirabegron 50 mg Mirabegron 100 mg Placebo 2 weeks follow-up Treatment – 178-CL-074 N Mirabegron 25 mg Mirabegron 50 mg Placebo V1 Week -2 V2 Week 0 V3 Week 4 V4 Week 8 V5 Week 12 V6 Week 16 EU – Europe, NA – North America 55 55

56 Mirabegron 100mg data not shown
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 episodes per 24 hours 0.10 * 0.40 * Statistically significant improvement versus placebo with multiplicity adjustments Mirabegron 100mg data not shown Khullar V. et al. Eur Urol Suppl 2011;10(2);278–279 [Abstract 886]

57 046: Co-Primary Endpoint Mean Number of Micturitions per 24 hrs
Adjusted Mean Change from Baseline to Final Visit (FAS) placebo mirabegron tolterodine 50 mg ER 4 mg (n=480) (n=473) (n=475) Baseline per 24 hours 0.25 * 0.60 * Statistically significant improvement versus placebo with multiplicity adjustments Mirabegron 100mg data not shown Khullar V et al. Eur Urol Suppl 2011;10(2);278–279 [Abstract 886]

Mirabegron 50mg significantly improved urgency episodes (grade 3 or 4) from baseline to Final Visit Mean change from baseline to Final Visit in the mean number of urgency episodes (PPIUS, grade 3 or 4) per 24 hours (FAS) mirabegron 50 mg tolterodine SR 4 mg Baseline * (n=479) (n=470) (n=472) p=0.005 p=0.50 * Statistically significant improvement versus placebo with multiplicity adjustments 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 Astellas Pharma, data on file [clinical study report, p 113 & Appendix Tables  – ] 58

Mirabegron 50 mg significantly improved nocturia episodes from baseline to Final Visit Mean change from baseline to Final Visit in the mean number of nocturia episodes in 24 hours (FAS) Mirabegron 50 mg tolterodine SR 4 mg Baseline (n=428) (n=423) (n=433) p=0.022 P=0.52 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 Astellas Pharma, data on file [clinical study report, p 113 & Appendix Tables  – ] 59

60 Number of responders with zero incontinence at Final Visit
60 Number of responders with zero incontinence at Final Visit Zero incontinence episodes at Final Visit (FAS-I) – only patients who had at least 1 incontinence episode at baseline were included placebo (046) mirabegron 50 mg (046) tolterodine SR 4 mg 142 132 118 The TS‑VAS is a visual analog scale that asks patients to rate their satisfaction with study treatment by placing a vertical mark on a line that runs from 0 (No, not at all) to 10 (Yes, completely). (n=291) (n=293) (n=300) Mirabegron 100mg data not shown 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 ] 60

61 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 PATIENT-REPORTED OUTCOME Mean change in treatment satisfaction
62 Mirabegron significantly improved treatment satisfaction at Final Visit compared with placebo Mean change from baseline to Final Visit in treatment satisfaction (TS-VAS; FAS) Placebo (046) Mirabegron 50 mg (046) Tolterodine SR4 mg Improvement * Mean change in treatment satisfaction The TS‑VAS is a visual analog scale that asks patients to rate their satisfaction with study treatment by placing a vertical mark on a line that runs from 0 (No, not at all) to 10 (Yes, completely). (n=428) (n=414) (n=425) Baseline Mirabegron 100mg data not shown * Statistically significant improvement versus placebo at 0.05 level 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] 62

63 Study 046 - 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) Hypertension 38 (7.7) 29 (5.9) 40 (8.1) Nasopharyngitis 8 (1.6) 14 (2.8) Dry Mouth 13 (2.6) 50 (10.1) Headache 18 (3.7) 18 (3.6) Influenza 11 (2.2) 7 (1.4) Urinary tract infection 10 (2.0) Constipation 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 Mirabegron 100mg data not shown Khullar V, et al. Eur Urol Suppl 2011;10(2);278–279 [Abstract 886]

64 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 64

65 Mirabegron 100mg data not shown
Subgroup analysis: Prior OAB medication Pooled data ISE – 046/047/074: Incontinence Previous OAB medication No previous OAB medication (n=518) (n=506) (n=360) (n=356) Adjusted mean change from baseline in mean number of incontinence episodes / 24 h -0.57 (CI -0.81, -0.33) -0.15 (CI -0.44, 0.14) Mirabegron 100mg data not shown

66 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. 66

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

68 Common (≥ 2% of patients in any treatment group) Treatment emergent adverse events
178-CL-049 Long term safety study MedDRA (v9.1) Preferred Term mirabegron tolterodine ER 4 mg (n=812) n (%) 50 mg 100 mg (n=820) 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 25 (3.0%) 22 (2.7%) Dry mouth 19 (2.3%) 70 (8.6%) Sinusitis 18 (2.2%) 12 (1.5%) Dizziness 21 (2.6%) Influenza 28 (3.4%) Cystitis 17 (2.1%) 11 (1.3%) Arthralgia 16 (2.0%) Diarrhoea 15 (1.8%) 24 (2.9%) Tachycardia 8 (1.0%) Chapple CR, et al. European Urology Supplements 2012;11(1):e683

69 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 The BEYOND Study

71 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 The Study Design 2 weeks 12 weeks Mirabegron 50mg daily Placebo run-in
Screening Randomisation End of Treatment 2 weeks 12 weeks Mirabegron 50mg daily Placebo run-in Solifenacin 5mg daily Visit Schedule D-14 (V1) D1 (V2) W4 (V3) W8 (V4) W12 (V5)

73 Primary & Key Secondary Endpoints
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 Mirabegron exposure clinical experience summary
41 clinical studies 10,552 subject 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 OAB patients in Phase II/III 8433 patients* of which 5648 received mirabegron *622 OAB patients received mirabegron ≥ 1 year

75 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 All you have to do is live long enough.
Groucho Marx, Age is not a particularly interesting subject. Anyone can get old. All you have to do is live long enough. 1960

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