Beta-Adrenergici: una scelta motivata?Prof. Enrico Finazzi Agrò

Dept. of Experimental Medicine and SurgeryTor Vergata University

Unit of Functional UrologyTor Vergata University HospitalS. Lucia Rehabilitation Hospital

Rome, ITALY

Beta3 Adrenergico: una scelta motivata?

Beta3gonista

• Perché il Beta3 Agonista?

Other drug classes to treat OAB?

• “Despite intensive research, few new therapeutic principles have emerged and been demonstrated to have sufficient efficacy and adverse effect profiles to be accepted for approval and clinical use”1

• Research indicated that stimulation of β3-receptors leads to bladder relaxation

• Discovery of β3-adrenoceptors, predominately present on the bladder wall development of β3-adrenoceptor agonist

1. Andersson KE. Curr Urol Rep 2013;doi:10.1007/s11934-013-0335-8; 2. Kennelly MJ Rev Urol 2010;12:12-9; 3. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202611s000lbl.pdf

First FDA-approved antimuscarinic agent2

1975

FDA-approval β3-agonist3

2012

M2 M33AC PLC

Ca2+

Ca2+

cAMP IP3

–Membr. Cell.

contraction

+

contractionrelaxation

AchNEM 2/4

M1

NE–

+

M2/4

M1

Ach+

–

+

Chapple CR. Urology. 2000;55:33-46

- -

Effects of NE e Ach on Bladder activity

Characterisation of bladder structures expressing β3 adrenoreceptors (β3AR)

• 15 human bladders from cadaveric organ donors (16-82 yr)• Immunohistochemistry with β3AR C- and N-terminal antibodies on 20 µm

cryostat longitudinal sections of the bladder dome and trigone• β3AR expression levels in mucosa and muscular layer:

• Co-expression analysis revealed:– Highest expression in cholinergic vesicular acetylcholine transporter+ nerve fibres– Less abundant expression in tyrosine hydroxylase+ nerve fibres– Occasional expression in calcitonin gene-related peptide+ fibres

β3AR expression seems to be most abundant in cholinergic nerve fibres of the human bladder, suggesting a therapeutic effect of β3AR

agonists through modulation of the bladder neural circuits

Coelho A. Eur Urol Suppl 2016;15(3):e308

Mucosa

• Nerve fibres intermingled on the connective tissue: ++

• Urothelial or sub-urothelial IC-like cells: -

Muscular layer

• Nerve fibres coursing along smooth muscle bundles: ++

• Smooth muscle cells: -

Tissue expression of the threeβ-adrenoceptor subtypes

Brain: β1 • β2 • β3 Blood vessels:

β2Lungs: β2

Kidney: β1 • β2

Pancreas: β2

GI tract: β2 • β3

Uterus: β2 • β3

Skeletal muscle: β2

Adipose: β1 • β3

Heart: β1 • β2

Liver: β2Gall bladder: β3

Bladder: β3 predominantlyAll three β-ARs are expressed in human bladder tissue but β3-AR mRNA accounts for 97% of total

β-AR mRNA8

Tissue-specific expression of human β-ARs8-20

Binding affinity (Ki) of mirabegron for human ARs1

Receptor subtype Mirabegron Ki, nmol/L*

β1-AR 4,200 + 900β2-AR 1,300 + 300β3-AR 40 + 20.2Lower Ki values represent higher affinity

* Determined in in vitro receptor binding studies using Chinese hamster ovary cells expressing human β-AR subtypes ; values are means of three replicates (+ standard error)

Beta3Agonista

• Funziona?

End-point co-primario: numero medio di minzioni per 24 h

All p values <0.05 for Mirabegron 50 and 100 mg vs placebo

Khullar V et al. Eur Urol 2013; 63: 283 – 295

Beta3Agonista

• A chi lo diamo?

Women presenting with UIEAU guidelines 2016

Men presenting with UIAUA guidelines 2014

You should be able to have mirabegron if drugs called ‘antimuscarinics’ do not work, if they are not suitable

for you, or their side effects are unacceptable

Beta3Agonista

• Funziona meglio in pazienti non responder a antimuscarinici?

Prima o seconda linea di terapia?Mean number of UI episodes/24 h

Khullar V et al. BMC Urology 2013, 13:45

Prima o seconda linea di terapia?Mean number of micturitions/24 h

Khullar V et al. BMC Urology 2013, 13:45

Beta3Agonista

Funziona meglio in pazienti non responder a antimuscarinici?

NO

Seconda linea di trattamento?

Beta3Agonista

Funziona in pazienti non responder a antimuscarinici?

Beta3Agonista

Beta3Agonista

Combination > Solifenacin 5 mgCombination <> Solifenacin 10 mg

(with less side effects)

Beta3Agonista

Funziona in pazienti non responder a antimuscarinici?

SÌ…E anche in combinazione!

Combinazione?

Beta3Agonista

In quali pazienti è particolarmente indicato?

You should be able to have mirabegron if drugs called ‘antimuscarinics’ do not work, if they are not suitable for you, or their side

effects are unacceptable

Nitti VW et al. J Urol 2013; 190: 1320-1327

Mirabegron in pazienti con BOO

Nitti VW et al. J Urol 2013; 190: 1320-1327

Bladder Contractility Index Bladder Voiding Efficiency

Beta3Agonista

E allora in quali pazienti è particolarmente indicato?

Pazienti con (rischio di) disturbo dello svuotamento…

American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults (2012)

Antihistamines Antiparkinson agents Skeletal muscle relaxantsBrompheniramine CarbinoxamineChlorpheniramine ClemastineCyproheptadine DimenhydrinateDiphenhydramine HydroxyzineLoratadine Meclizine

BenztropineTrihexyphenidyl

CarisoprodolCyclobenzaprineOrphenadrineTizanidine

Antidepressants AntipsychoticsAmitriptyline AmoxapineClomipramine DesipramineDoxepin ImipramineNortriptyline ParoxetineProtriptyline Trimipramine

Chlorpromazine ClozapineFluphenazine LoxapineOlanzapine PerphenazinePimozide ProchlorperazinePromethazine ThioridazineThiothixene Trifluoperazine

Antimuscarinics (urinary incontinence)

Antispasmodics

Darifenacin FesoterodineFlavoxate OxybutyninSolifenacin TolterodineTrospium

Atropine productsBelladonna alkaloidsDicyclomineHomatropineHyoscyamine productsPropanthelineScopolamine

Drugs with strong anticholinergic properties

Mirabegron is efficacious in the treatment of symptoms of OAB in older adults.

These data appear to show that there is no loss of efficacy with age

Mirabegron was well tolerated in older OAB patients with no difference in tolerability with age over a 1-year period.

UTI and hypertension were the most frequent AE found in the population. However, in elderly subjects, these AE were more frequent in people treated with tolterodine than those under mirabegron over 12 months

Beta3Agonista

E allora in quali pazienti è particolarmente indicato?

In pazienti anziani a rischio di sovraccarico anticolinergico…

Beta3Agonista

E la safety?

Nota Informativa Importante su mirabegron: nuove raccomandazioni relative al rischio di aumento della pressione arteriosa

Pillole dal Mondo n. 84215/09/2015 L’uso di mirabegron è ora controindicato nei pazienti

affetti da ipertensione grave non controllata, intesa come Pressione Arteriosa Sistolica ≥180 mmHg e/o Pressione Arteriosa Diastolica ≥110 mmHg. È, quindi, necessario misurare la pressione arteriosa prima di intraprendere il trattamento e monitorarla regolarmente durante lo stesso, specialmente nei pazienti affetti da ipertensione.

Pooled 12-week Phase III Studies (046, 047 and 074)CV Events Placebo

(n=1380)

Mirabegron Tolterodine ER 4mg (n=495)25mg

(n=432)50mg

(n=1375)100mg

(n=929)

Incidence, n(%) of APTC/MACE 4 (0.3) 0 0 0 1 (0.2)Relative risk of APTC/MACE (95% CI) - NE NE NE -

1-year Phase III Study (049)CV Events Mirabegron Tolterodine

ER 4mg (n=812)50mg (n=812) 100mg (n=820)

Incidence, n(%) of APTC/MACE 6 (0.7) * 0 4 (0.5) **Relative risk of APTC/MACE (95% CI) 1.50 (0.35, 7.27) NE -NE = not evaluated due to insufficient data* nonfatal stroke (3 patients), nonfatal myocardial infarction (2 patients) and CV death (1 patient)** CV death (2 patients), nonfatal myocardial infarction (1 patient) and nonfatal stroke (1 patient)

Mirabegron Tollerabilità cardiovascolare

Rosa et al., Eur Urol Eur Urol. 2016 Feb;69(2):311-23

Ipertensione

E’ stato l’evento avverso più comune registrato nell’ambito degli studi di fase III

Nell’analisi aggregata degli studi è stata rilevata rispettivamente nel : 8.7% dei pazienti in trattamento con mirabegron 50 mg 8.5% dei pazienti in trattamento con placebo

L’aumento massimo SBP/DBP associato a mirabegron 50 mg è stato ≤1 mmHg reversibile dopo interruzione della terapia

Rosa et al., Eur Urol Eur Urol. 2016 Feb;69(2):311-23

Pooled 12-week Phase III Studies (046, 047 and 074)CV Events Placebo

(n=1380)Mirabegron Tolterodine

ER 4mg (n=495)25mg

(n=432)50mg

(n=1375)100mg

(n=929)

Incidence, n(%) of: Hypertension TEAEs 117 (8.5) 52 (12.0) 120 (8.7) 58 (6.2) 48 (9.7)Hypertension SAEs 0 0 1 (0.1) 0 1 (0.2)

Discontinuations due to hypertension TEAEs 3 (0.2) 2 (0.5) 5 (0.4) 4 (0.4) 1 (0.2)Relative risk of hypertension TEAEs (95% CI)

- 1.25 (0.86, 1.80)

1.02 (0.79, 1.32)

0.78 (0.56, 1.08)

-

Beta3Agonista

E la safety?

The CV safety of mirabegron appears to be acceptable at therapeutic doses and comparable with that of antimuscarinic agents, currently first-line therapy for OAB.

Beta3Agonista

E l’aderenza alla terapia?

Persistence with antimuscarinic agents is poor

• 12-month UK study on prescription data

Wagg A et al. BJU Int 2012;110:1767-74

% of patients remaining on AM therapy over a period of 12 months

01

20

30

40

50

60

70

80

90

100

10

Patie

nts (

%)

Months9 108765432 11 12

Solifenacin (N=1,381)

Tolterodine ER (N=1,758)

Tolterodine IR (N=482)

Oxybutynin ER (N=590)

Oxybutynin IR (N=1371)

Propiverine (N=97)

Trospium (N=352)

Darifenacin (N=23)

Flavoxate (N=89)

ER: extended release; IR: immediate release

Persistence with anti-muscarinic and mirabegron treatment for OAB in daily clinical practice

• Single-centre, retrospective study in N=701 pts with OAB treated with anti-muscarinic agent (N=356) or mirabegron (N=345) according to physician’s preference

In daily clinical practice OAB pts seem to stay longer on mirabegron treatment than on anti-muscarinic treatment

Ito N. Eur Urol Suppl 2016;15(3):e999

1 yr 2 yr 3 yr0%

20%

40%

60%

27%21%

14%

63%56% 52%

Anti-muscarinicMirabegron

% o

f pts

on

ther

apy

% pts Anti-muscarinic (N=356) Mirabegron (N=345)

Symptom improvement 41.2% 68.5%

No response to treatment 24.3% 25.2%

Discontinuation due to AEs 9.4% 6.4%

P<0.001

Data from poster

Beta3Agonista

E l’aderenza alla terapia?

Potrebbe migliorare l’aderenza ad una terapia cronica

Aderenza?

Beta3Agonista: Conclusioni

Altra categoria farmacologica rispetto ad AMEfficace

Efficace in non responders ad AMAnche in combinazione con AM

Vantaggi in alcuni soggettiDisturbo di svuotamentoAnziano

Safety simileMigliore aderenza rispetto ad AM