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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
International Advisory Board Astellas
International Advisory Board Pfizer
International Advisory Board American Medical Systems
Consultant Johnson & Johnson
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
Pubmed 12.02.2013
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 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]
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.
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.
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
… 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
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)
GeburtsmechanikLien. AJOG 2005
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
Geburt als akutes Trauma
Bis zur Menopause wenig symptomatisch.
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
Die Lebenserwartung nimmt seit dem 19. Jahrhundert stetig zu.
Lebenserwartung bei Geburt für FrauenÖsterreich
Altersstruktur in Österreich2010 – 2050
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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.
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
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 2001-2005 [Smith 2010]
Lifetime Risk / Kumulative Inzidenzfür Operation wegen Inkontinenz oder Deszensus
(5-)13-17% Rezidiv[Clark 2003, Denman 2008, Kapoor 2009, Kapoor 2010, Dallenbach 2012]
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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…
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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.
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
Verlieren Sie gelegentlich Urin? D
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
Abnahme der Elastizität im vorderen Kompartiment
Barbara Röhrnbauer, Edoardo Mazza, ETH Zürich
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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]
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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]
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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]
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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]
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
Wundheilung
Emmerson. The role of estrogen deficiency in skin ageing and wound healing. Biogerontology. 2011.
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]
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) ↓ ↑
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 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
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)
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
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 (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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
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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)
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
Can we achieve the optimal balance?
Efficacy TolerabilityRelieves symptoms of OAB Minimal side effects
Adherence/Persistency
Maximizes duration of therapy
Optimal Balance
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
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 beta1-AR
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 indications of arrhythmogenicity
No pre-clinical signal for hepatoxicity
Incidental increases in AST/ALT observed in PIII all reversible while still on treatment
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
Clinical Pharmacology Profile
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
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Clinical Profile
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
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.
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
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 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
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]
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
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 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
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) 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
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
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
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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]
Mirabegron 100mg data not shown
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
(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
Mirabegron 100mg data not shown
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)
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.
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Chapple CR, et al. European Urology Supplements 2012;11(1):e683
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
The BEYOND StudyThe BEYOND Study
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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
Allgemeines Krankenhaus der Stadt Wien – Medizinischer Universitätscampus
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.
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