Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Univ. Prof. Dr. Dr....

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

http://www3.edumoodle.at/szo/file.php/1/_KAV-Logo_120x103_6591.gif


International Advisory Board Astellas

International Advisory Board Pfizer

International Advisory Board American Medical Systems

Consultant Johnson & Johnson



Pubmed 12.02.2013



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 2.7-20.9 [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]



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.

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

[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.



… בנים תלדי …בעצב…mit Schmerzen sollst du Kinder gebären… [Genesis 3:16]

Negev-Wüste, Israel. 1000 BCWoman giving birth in the desert

Charles-Joseph Natoire, 1740Adam et Ève chassés du Paradis terrestre



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)

GeburtsmechanikLien. AJOG 2005



Pubic bone

LA

Pubic bone

LA

Breite

Attachmentzone

68-jährige Nullipara 40-jährige Nullipara

OI

39-jährige 4p

LA

Pubic bone

Cornelia Betschart bei DeLancey



Geburt als akutes Trauma

Bis zur Menopause wenig symptomatisch.



Die Lebenserwartung nimmt seit dem 19. Jahrhundert stetig zu.

Lebenserwartung bei Geburt für FrauenÖsterreich

Altersstruktur in Österreich2010 – 2050



Prävalenz Genitaldeszensus

Nygaard. JAMA 2008. N=1961 U.S. noninstitutionalized nonpregnant women (age ≥20 years) in 2005-2006. Pelvic organ prolapse (seeing/feeling a bulge in or outside the vagina) symptoms were assessed.

[email protected]



Deszensus in Abhängigkeit vom Alter [eigene Daten]

Zystozelep=0.0001

Rektozelep=0.0001

1996 - 2009N = 6387Alter 60.1±15.3(14 - 100)

Desz. uteri/Vaginalstumpfp=0.0001



Prolapse or incontinence surgery, USA 1995 [Olson 1997]Prolapse or incontinence surgery, USA 1993 [Fialkow 2008]Prolapse surgery, Western Australia 2001-2005 [Smith 2010]

Lifetime Risk / Kumulative Inzidenzfür Operation wegen Inkontinenz oder Deszensus

[email protected]

(5-)13-17% Rezidiv[Clark 2003, Denman 2008, Kapoor 2009, Kapoor 2010, Dallenbach 2012]



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 KonsequenzRF: Ernährung, Nikotin, Alkohol, Stress…



Myogene 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. 2005

Neuronal cell adhesion molecule (NCAM) staining

NCAM-positive muscle fibers (*) next to connective tissue

(ct).

Acetylcholinesterase staining

intact neuromuscular junction.



1 Faser geht pro Tag verlustig. Perucchini. AJOG 2002

Alter

R2=0.43; p=0.0003

MUCP = 100 − AlterRud. Acta Ob Gyn Scand 1980

Trowbridge. Ob Gyn 2007

MUCP

R2=0.57; p<0.001

Histomorphologie Funktion

Urethra: Altersabhängige Abnahme der Muskelfasern

82 Nullipara21-70 jährig



0

5

10

15

20

25

30

35

40

45

50

20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85–89 90 +

EPINCONT-Studie. Hannestad. J Clin Epid 2000Belastungsinkontinenz Überaktive Blase Mischinkontinenz nicht klassifiziert

Altersabhängige Zunahme der Prävalenz der Harninkontinenz



Verlieren Sie gelegentlich Urin? D



Alter und glatte Muskulatur: mit und ohne ProlapsBoreham et al. AJOG 2002

Alter (Jahre)

Kontrolle

*) p<0.05 (vgl. mit Kontrolle)

Abnahme der Muskulatur im Alter im vorderen Kompartiment

Kollagen Typ I

Kollagen Typ III

Stage 0n=15; r=0.47

Stage 0n=15; r=0.65

Alter und KollagenexpressionLin et al. Int Urogynecol J 2007

Alter

ohne POPohne Zystozele

Stage II, III or IVn=23; r=0.58

Stage II, III or IVn=23 ; r=0.52



Histomorphologie des

Diaphragma urogenitale

Histologie Diaphragma urogenitaleGoldner 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



Abnahme der Elastizität im vorderen Kompartiment

Barbara Röhrnbauer, Edoardo Mazza, ETH Zürich



Abnahme der Dicke des

Sphinkter ani externus

Äusserer Schliessmuskel und AlterRociu. Radiology 2000

Sph

inct

er a

ni e

xern

us (D

icke

in m

m)

◦ Frauen● Männer

Innerer Schliessmuskel und AlterHuebner. Dis Colon Rectum 2007



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]



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]

Aktionspotentiale als Funktion von Alter und Geburt [Olsen. AJOG 2003]



Altersabhängige Veränderungen

an 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]



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 1.61-2.18) für SUI bei CEE+MPA‣RR 2.15 (95%CI 1.77-2.62) für SUI bei CEEConjugated 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 1.2-1.8) für OAB, wet, 12% Risiko (NNH* 8.6)‣OR 1.7 (95%CI 1.5-2.1) 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



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]



Wundheilung

Emmerson. The role of estrogen deficiency in skin ageing and wound healing. Biogerontology. 2011.



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]

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) ↓ ↑



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 0.64-0.86 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 1.17-1.49

• 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;329:753-756

p<0.001



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)



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



EU population forecast

Adapted from 2009 Ageing Report: Economic and budgetary projections for the EU-27 Member States (2008-2060) European Economy 2/2009. p.43

20000 15000 10000 5000 0 0 5000 10000 15000 20000

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

FemalesMales Age Groups2008

20000 15000 10000 5000 0 0 5000 10000 15000 20000

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

FemalesMales Age Groups2060

Population in thousands Population in thousands



Intramural facilitatory mechanisms for spontaneous contractions

Sensory collaterals

Suburothelial interstitial cellsSmooth muscle

cells

Intramural ganglia

Interstitial cellsACh

NA

ATPNOAChPGs

Urothelium-based theory

Afferent nerves

Myogenic theory

Distension

Mechanisms involved in increased afferent input from the bladder



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



Duration of solifenacin 5/10mg exposure (weeks)

4

Med

ian

perc

enta

ge

redu

ctio

n

Frequenc

y Nocturia

Urgency

-27%

-50%

-89%

8 12 16 28 40 520

-20

-60

-80

-100

-40

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



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



Time to discontinuation of medication in six chronic therapy classes

00

20

30

40

50

60

70

80

90

100

120 240 360 480 600 720

Prostaglandins

OAB Medications

ARBs*Oral Antidiabetics

StatinsBisphosphonates

10

*ARBs: angiotensin receptor blockersDays

Yeaw J, et al. J Manag Care Pharm. 2009;15:728–40



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;65:567-585



Percentage of patients remaining on each antimuscarinic over 12 months

Abstract and poster; SIU 2010, Siddiqui E, et al. BJUi 2012

01

20

30

40

50

60

70

80

90

100

10

Months9 108765432 11 12

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)



Reasons for discontinuing antimuscarinic medication for OAB

0 0.1 0.2 0.3 0.4 0.5

Advice of family/ friendDon't like taking ANY medications

Doctor didn't make right treatment decisionSwitched to previous medication

Don't like taking medications for too longChange of insurance status

Another condition/ medicationBladder symptoms stopped/ cured

Cost/ amount of copayLearned to get by without medication

Told to stop by clinician/ pharmacistHad side effects

Switched to new medicationDidn't work as expected

Conditional ProbabilityBenner JS, et al. J Urol 2009;181:2591–91



Can we achieve the optimal balance?

Efficacy TolerabilityRelieves symptoms of OAB Minimal side effects

Adherence/Persistency

Maximizes duration of therapy

Optimal Balance



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



Neurologic Innervation and Controlof Bladder Musculature

AntimuscarinicsACH

NE

M3 muscarinic receptor

detrusor smoothmuscle

(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



Non-Clinical Urology Models• Mirabegron enhances urine storage function by

stimulatingbeta3-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



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



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



Clinical Pharmacology Profile



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



Food Effect - Exposures in OAB patientsMirabegron concentration versus Time after Dose by Food condition

Red: FedGrey: Fasted

178-PK-015 Addendum 1

178-CL-046; 50 mg 178-CL-047; 50 mg

Similar exposure of mirabegron with and without food in 2 pivotal PIII trialsSimilar efficacy and safety profile with and without food

Mirabegron can be taken with or without food at the recommended dose



Clinical Profile



Mirabegron Development Program2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Phas

e 1

29

Clin

ical

Phar

mac

olog

y

Phas

e 2

6 C

linic

al

Stud

ies

Phas

e 3

6 O

AB

Clin

ical

St

udie

s

CL-002 1 SADCL-002 MAD

CL-007 MB

CL-005 PK

CL-030 PKCL-033 BA

CL-031 PK

CL-036 DDI

CL-034 PK

CL-037 TQT

CL-072 A/G

CL-066 DPCL-070 DDICL-058 DDICL-068 DDI

CL-059 DDICL-040 DDICL-064 FECL-038 Renal

CL-076 PKCL-041 FE

CL-003 POC DM

CL-069 DDICL-039 PK

CL-078 FE

CL-077 TQTCL-081 IOP

CL-080 DDI

CL-053 CI

29 PHASE 1 STUDIES1800 Volunteers

1462 mirabegron

CL-003 POC DM

CL-008 POC CL-044 DF (EU) CL-045 DF (JP)

CL-060 (LUTS/BOO)

OAB

Diabetes

LUTS/BOO 12 PHASE 2/3 STUDIES8752 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



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.



Primary Phase III design

178-CL-046 (EU), 178-CL-047 (NA), 178-CL-074 (EU/NA)

12 WEEKS

4 weeksfollow-up

2 weeksplaceborun-in

Double - Blind Treatment

Treatment -178-CL-046 NMirabegron 50 mg 497 Mirabegron 100 mg 498Tolterodine 4 mg SR 495Placebo 497

V1Week -2

V2Week 0

V3Week 4

V5Week 12

V6Week 16

START

SCREENING

END

OF STUDY

FOLLOW UP

V4Week 8

4 weeks 4 weeks 4 weeks RANDOMIZATION

Treatment – 178-CL-047 NMirabegron 50 mg 442 Mirabegron 100 mg 433Placebo 454

4 weeksfollow-up

2 weeksfollow-up

EU – Europe, NA – North America

Treatment – 178-CL-074 NMirabegron 25 mg 433 Mirabegron 50 mg 440Placebo 433



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 2.67 2.83 2.63

0.10

0.40

Khullar V. et al. Eur Urol Suppl 2011;10(2);278–279 [Abstract 886]

Mea

n nu

mbe

r of I

ncon

tinen

ce

epis

odes

per

24

hour

s

Mirabegron 100mg data not shown * Statistically significant improvement versus placebo with multiplicity adjustments



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]

num

ber o

f mic

turit

ions

pe

r 24

hour

s placebo mirabegron tolterodine

50 mg ER 4 mg (n=480) (n=473) (n=475)

Baseline 11.71 11.65 11.54

*0.25

0.60

Mirabegron 100mg data not shown * Statistically significant improvement versus placebo with multiplicity adjustments



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 12.3.5.9–12.3.5.13]

(n=479) (n=470)

p=0.005

(n=472)

p=0.50

mirabegron50 mg

tolterodine SR4 mg

Baseline 5.78 5.72 5.79

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



• 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) mirabegron50 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 12.3.5.7]

118132 142

(n=300)

tolterodine SR4 mg

Mirabegron 100mg data not shown



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



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

Impr

ovem

ent

(n=428)

Mea

n ch

ange

in t

reat

men

t sa

tisf

acti

on

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 4.11 3.95 3.87

(n=425)

Placebo (046)Mirabegron50 mg (046)

Tolterodine SR4 mg

*

Mirabegron 100mg data not shown * Statistically significant improvement versus placebo at 0.05 level



Study 046 - Common (≥2% in any treatment group)Treatment - emergent adverse eventsAdverse 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) 14 (2.8)

Dry Mouth 13 (2.6) 14 (2.8) 50 (10.1)

Headache 14 (2.8) 18 (3.7) 18 (3.6)

Influenza 8 (1.6) 11 (2.2) 7 (1.4)

Urinary tract infection 7 (1.4) 7 (1.4) 10 (2.0)

Constipation 7 (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]




Subgroup analysis: Prior OAB medicationKey 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



(n=518) (n=506) (n=360) (n=356)

Subgroup analysis: Prior OAB medicationPooled data ISE – 046/047/074: Incontinence

Previous OAB medication No previous OAB medication

2.93 2.98 2.44 2.33


Adjusted m

ean change from baseline in

mean num

ber of incontinence episodes / 24 h

-0.57 (CI -0.81, -0.33)

-0.15 (CI -0.44, 0.14)



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.



Long-term safety study178-CL-049 (EU&NA)

2 weeksRun-in

1 YearDouble-blind Treatment

Treatment -178-CL-049

Visit 1

StartScreening

tolterodine 4 mg ER (n=813)

mirabegron 50 mg (n=815)

Visit 6Month 12

Visit 5Month 9

Visit 4Month 6

Visit 3Month 3

Visit 2Week 0Week -2

mirabegron 100 mg (n=824)placebo

End ofstudy

Visit 3Month 1

Randomized n=2452

Chapple CR, et al. European Urology Supplements 2012;11(1):e683



Common (≥ 2% of patients in any treatment group) Treatment emergent adverse events

MedDRA (v9.1) Preferred Term

mirabegrontolterodineER 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




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




The BEYOND StudyThe BEYOND Study



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



Visit Schedule

12 weeks2 weeks

Placebo run-in

Mirabegron 50mg daily

Solifenacin 5mg daily

D-14 (V1) D1 (V2) W4 (V3) W8 (V4) W12 (V5)

The Study Design

Screening Randomisation End of Treatment



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



Mirabegron exposure clinical experience summary

41 clinical studies10,552 subject

OAB patients in Phase II/III8433 patients*

of which 5648 received mirabegron

29 Phase I studies1800 volunteers

of which 1462 received mirabegron

12 Phase II/III studies8752 patients

(OAB, LUTS/BOO, DM)of which 5863 received mirabegron

*622 OAB patients received mirabegron ≥ 1 year



Mirabegron clinical development programEfficacy 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



Groucho Marx, 1890 - 1977

Age is not a particularly

interesting subject.

Anyone can get old.

1960

All you have to do is All you have to do is

live long enough.live long enough.


Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus Univ. Prof. Dr. Dr....

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