Future
treatment
modality of
overactive
bladder
Duk Yoon Kim
Professor, Department of Urology
Daegu Catholic University Medical Center(DCUMC)
Daegu, Korea
LOGO
Contents
Approach
Candidates: Pharmaceuticals
Alternatives
Summary
OAB Management: where we stand?
1. Terminology
-Symptom complex of storage symptoms
≠ urodynamically proven detrusor overactivity (DO)





OAB syndrome
LUTS/OAB
OAB in male (men)/female (women)
Idiopathic/Neurogenic OAB
OAB wet/dry
 Multifactorial
Company Logo
2. Epidemiology
- NOBLE(National Overactive Bladder Evaluation)
-
16%:16.9% (M:W)
Japanese survey
12.4%(>40), 20%(>70), 35%(>80)
EPIC: 11/13 % (M:W)
K-EPIC: similar
Overall: 8.0-13.9%
Cartwright R. et al. Current opinion in OB & GY 2008
3. Still hidden Disease?
Yes, it is.
4. Natural history ?
Symptoms fluctuate over time
Company Logo
Approach
Candidates: Pharmaceuticals
Alternatives
Summary
Neurotransmitters
Understanding of Pathways, Neurotransmitters
Company Logo
Central
-
Gabepentin
- NK1 receptor
antagonists
Peripheral
- Mucosal signaling
drugs
- Tramadol
- Opioids
- 5-HT/Na re-uptake
inhibitor
- Myocyte signaling
drugs
Company Logo
Centrally acting:Gabapentin
 Anticonvulsant
 Peripheral neuropathic pain relieve
 Action mechanisms in bladder
: Inhibitory activity on afferent C-fibers activity
High affinity to the ɑ-2- σ subunit Ca channels
reduce L-type current(A-, σ-fibers)
reduce detrusor contraction after submucosal receptor
stimulation
- Modify afferent input from periphery
- Decreases the glutamate release modulated by
substance-P facilitated effect
Carbnone A. clin Neuropharm.., 2006
Gabapentin: Refractory OAB
 Refractory OAB(tolterodine, oxy. 8 weeks)/nocturia
 100-300mg3,000mg, bedtime
Frequency(n=31)
Improved(n=11)
No Improvement(n=20)
Nocturia(n=7)
Improved(n=3)
No Improvement(n=4)
Baseline
12 weeks
14.1± 2.2
10.0±2.1* p=0.01
13.6±1.9
12.5±3.1
4.0±1.3
1.0±0.3** p=0.03
4.3±1.3
4.0±1.0
YT KIM et al. Int. Braz. J Urol, 2004
Gabapentin: Neurogenic OAB
 Neurogenic
OAB, 16 pts
 31 days
 300mgX
3days
600mgX 3days
900mg
Carboe A. et al. Clin.
Neuropharma, 2006
Results
Before Treatment
After Treatment
Micturition/day
7±4
5±1.2
Urgency/day
13±3
8±0.7
Incontinence/day
3±2
1±0.3
Pad use/day
2±0.76
1±0.5
Centrally acting:Tramadol
 Analgesic drug
 Action on IDO
 Inhibit the function of M1, M3 Rc
 Inhibit serotonin, noradrenalin reuptake
: bladder relaxation through
ß-Rc,
dopamine activation,
stimulation of µ- & delta-opioid
 Rat: inhibit micturition below analgesic level
suppress apomorphine-induced IDO (dopaminergic)
Grond S. Clinical Phramcokinet. 2004
Iran Study
 Double-blind, placebo-controlled, randomized
study in efficacy and safety of tramadol
 IDO 76>18
 100mg SR bid X 12 weeks
Safarinejad MR J Clin Pharmacol. 2006
Voiding and urodynamic variables
 Adverse events
Tramadol (%)
Placebo (%)
P-value
Adverse events
13(34)
6(15.8)
<0.05
Nasea
7(18.4)
2(5.3)
<0.05
Vomiting
3(7.9)
2(5.3)
NS
Dizziness
2(5.3)
1(2.6)
NS
Constipation
1(2.6)
0
NS
Centrally acting: Aprepitant
 Selective, CNS penetrating NK-1-Rc antagonist
 Originally, agents for chemotherapy-induced N/V
 double-blind, randomized, placebo controlled, parallel group
pilot study
 postmenopausal women with urge urinary incontinence or
mixed incontinence (with predominantly urge urinary
incontinence)
 160 mg capsule of aprepitant (61) or placebo (64) once daily
for 8 weeks.
Stewart AG et al. J Urol 2006
Company Logo
Average daily micturitions
Average daily urgency episodes
Peripheral-mucosal
Inhibitors/Antagonists of COX/Prostanoid
Receptors
 Clinical evidence: scare
 Non-selective: flurbiprofen, indomethacin
urodynamically, clinically- effective
N/V/GI, headache- high
: Ketoprofen, intravesical, oncex4weeks
18/30 women, IDO symptom free
Cardozo LD, et al. Br Med J 1980. Cardozo LD. J Urol 1980
Company Logo
Palmer J. 1983. Sprem M, et al. Croat Med J 2000
Transient Receptor Potential (TRP)
channel subfamily
 TRPV1: essential for the generation of noxious input, bladder
reflex overactivity
 GRC-6211, TRPV1 antagonist: highly effective
for decreasing the bladder reflex overactivity,
noxious input (Capsaicin/LPS model)
Ana C et al. J Urol 2009
Acetic acid model
Peripheral-myocyte
β3-Rc: detrusor>urothelium
Trp 64 Arg polymorphism in the
β3-AR gene is associated with
idiopathic OAB symptom
Relaxation of detrusor muscle
β3-adrenoceptor agonists
:YM-178(14/16), GW427353, KUC7483
Yamaguchi, Neurourol. 2007
PDE5 inhibitors
 Relaxation effects on urethral smooth muscles in
afferent signal
 PDE5i
-Sildenafil, suppress smooth muscle spontaneous
activity
-Vardenafil, sig. reduced nonvoiding contractions
-DA8159, decreased urethral pressure
 PDE4i
- IC485, reduce bladder overactivity
- rolipram, decreased amplitude/frequency of
contractility
Company Logo
Vitamin D3 agonist:elocalcitol
• Development by BioXell SpA
• Synthetic derivative of vitamin D3
• Regulates cell proliferation, apoptosis via its binding to the
vitamin D receptor
• Preclinical studies: inhibited the androgen-dependent and
androgen-independent proliferation of benign prostatic
hyperplasia (BPH) cells more potently than finasteride
Company Logo
• phase IIb trial, BPH: a significantly reduced prostate
volume compared with placebo;
irritative urinary symptoms (frequency, urgency and nocturia)
and urodynamic parameters- comparable to tamsulosin.
• phase IIa trial in patients with prostatitis: significantly
reduced levels of IL-8 in semen, improved quality and
forward motility of sperm.
Company Logo
• phase IIb trial data, overactive bladder (OAB): failed to
meet the primary endpoint
• BioXell: decided to terminate all further clinical
development of elocalcitol, including an uncompleted phase
IIa trial in patients with male infertility.
• Given the novel mechanism of action, efficacy profile and
improved tolerability of elocalcitol over existing classes of
drugs, the compound could have potentially added to the
armamentarium in the expanding therapeutic markets of
BPH, OAB and male infertility.
• This possibility appears to have been negated by BioXell's
recent decision to terminate all further development of
elocalcitol.
Drugs in clinical phases of development
(2007)
Drugs in clinical phases of development
(2008)
Approach
Candidates: Pharmaceuticals
Alternatives
Summary
Alternatives/2ndary modalities
Cystoplasty
/diversion:
20cm ileum
Laparoscopic
/robotic
Medical
therapy
sacral
neuromodulation
(SNM)
• botulinum toxin
(BTX)
Company Logo
Complete Continence: treatment Success
Definition by Intervention
Company Logo
≥50% Improvement in Incontinence episodes or Other
Symptoms: Treatment Success Definition by Intervention
Company Logo
Ways to go
Thought to ponder
Take Home Point
Target therapy (receptor, organ,
origin) possible?
Individually selectives possible?
Adequate Efficacy without AE
possible?
Complete remission possible?
Company Logo
Summary & Conclusion
 Development of therapeutic options of
OAB is complicated.
 Future promising drugs
-phosphdiesterase inhibitors
-GnRH antagonists
-VitD3 analogs
-EP-1-receptor antagonists
-TRPV1-receptor antagonists
-Central-acting drugs (gabapentin)
Company Logo
 Selective targeting of receptors/ion
channels or a disease–specific form of
the receptor may represent a viable
therapeutic target.
감사합니다.
교실의 무궁한 발전을 기원합니다.
그리스전 승리와 함께!!
Company Logo
Integrated diagram of CNS and peripheral
mechanisms
















Completed A Study to Investigate the Food Effect on the Pharmacokinetics of YM178 in Healthy, Non-elderly
Volunteers Conditions: Healthy Volunteer; Pharmacokinetics of YM178Intervention: Drug: YM1782
Completed A Clinical Study to Determine the Effect of YM178 on the Pharmacokinetics of Warfarin in Healthy
Subjects Condition: Overactive BladderInterventions: Drug: warfarin; Drug: YM1783
Completed A Study of YM178 in Men With Lower Urinary Tract Symptoms (LUTS) and Bladder Outlet
Obstruction (BOO) Conditions: Lower Urinary Tract Symptoms; Bladder Outlet ObstructionInterventions:
Drug: YM178; Drug: Placebo4
Completed Pharmacokinetic Interaction Study to Assess the Effect of Repeat Doses of Rifampin on
Mirabegron (YM178) in Healthy Volunteers Condition: Pharmacokinetics of YM178Interventions:
Drug: mirabegron; Drug: rifampin5
Completed A Pharmacokinetic Study of YM178 in Normal Subjects and Those With Mild, Moderate, and
Severe Renal Impairment Condition: Renal ImpairmentIntervention: Drug: YM1786
Completed A Long-term Study of YM178 in Symptomatic Overactive Bladder Patients Condition:
Urinary Bladder, OveractiveIntervention: Drug: YM1787Active,
not recruiting A Study to Evaluate Safety and Efficacy of YM178 in Patients With Overactive Bladder
Condition: Urinary Bladder, OveractiveInterventions: Drug: YM178; Drug: Placebo; Drug: tolterodine8
Recruiting A Study of YM178 in Subjects With Symptoms of Overactive Bladder Condition:
Urinary Bladder, OveractiveInterventions: Drug: YM178; Drug: Placebo; Drug: tolterodine ER9
Completed Study to Test the Efficacy and Safety of the Beta-3 Agonist YM178 in Patients With Symptoms of
Overactive Bladder Condition: Urinary Bladder, OveractiveInterventions: Drug: YM178; Drug: Placebo
10Completed A Study to Test the Efficacy and Safety of the Beta-3 Agonist YM178 in Subjects With
Symptoms of Overactive Bladder Condition: Urinary Bladder, OveractiveInterventions:
Drug: YM178; Drug: Placebo
11Completed Study to Test the Efficacy and Safety of the Beta-3 Agonist YM178 in Subjects With Symptoms
of Overactive Bladder Condition: Urinary Bladder, OveractiveInterventions:
Drug: YM178; Drug: Tolterodine 4 mg; Drug: Placebo
12Active, not recruiting Study to Test the Long Term Safety and Efficacy of the Beta-3 Agonist YM178 in
Patients With Symptoms of Overactive Bladder Condition: Urinary Bladder, OveractiveInterventions:
Drug: YM178; Drug: Tolterodine 4 ng
13Completed A Study of YM178 in Patients With Symptomatic Overactive Bladder Condition:
Urinary Bladder, OveractiveInterventions: Drug: YM178; Drug: Placebo
14Completed A Study of YM178 in Patients With Symptomatic Overactive Bladder (DRAGON) Condition:
Overactive BladderIntervention: Drug: YM178
15Completed Pharmacokinetics of Oral Mirabegron With Different Release Rates Versus Intravenous (IV)
Mirabegron Conditions: Healthy; Pharmacokinetics of MirabegronIntervention: Drug: mirabegron
16Completed Study of the Effect of Food on the Pharmacokinetics of Mirabegron Conditions:
Healthy; Pharmacokinetics of MirabegronIntervention: Drug: mirabegron