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Future treatment

modality of overactive

bladder

Future treatment

modality of overactive

bladder

Duk Yoon Kim

Professor, Department of Urology

Daegu Catholic University Medical Center(DCUMC)

Daegu, Korea

Contents

Summary Summary

ApproachApproach

Alternatives Alternatives

Candidates: Pharmaceuticals

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

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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

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Summary Summary

ApproachApproach

Alternatives Alternatives

Candidates: Pharmaceuticals

Neurotransmitters

Understanding of Pathways, Neurotransmitters

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Central

- Gabepentin

- NK1 receptor

antagonists

- Tramadol

- Opioids

- 5-HT/Na re-uptake

inhibitor

Peripheral

- Mucosal signaling drugs

- Myocyte signaling drugs

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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

100-300mg3,000mg, bedtime

YT KIM et al. Int. Braz. J Urol, 2004

Baseline 12 weeks

Frequency(n=31) Improved(n=11) 14.1± 2.2 10.0±2.1* p=0.01

No Improvement(n=20) 13.6±1.9 12.5±3.1

Nocturia(n=7) Improved(n=3) 4.0±1.3 1.0±0.3** p=0.03

No Improvement(n=4) 4.3±1.3 4.0±1.0

Gabapentin: Neurogenic OAB

Neurogenic OAB, 16 pts

31 days

300mgX 3days

600mgX 3days900mg

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

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Average daily micturitionsAverage 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

Company LogoCardozo LD, et al. Br Med J 1980. Cardozo LD. J Urol 1980 Palmer J. 1983. Sprem M, et al. Croat Med J 2000

Cardozo LD, et al. Br Med J 1980. Cardozo LD. J Urol 1980 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

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Vitamin D3 agonist:elocalcitol

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• 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

• 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

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• 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.

• 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.

• 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)

Summary Summary

ApproachApproach

Alternatives Alternatives

Candidates: Pharmaceuticals

Alternatives/2ndary modalities

sacral neuromodulation (SNM)

• botulinum toxin (BTX)

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Cystoplasty/diversion: 20cm ileumLaparoscopic/robotic

Medical therapy

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Complete Continence: treatment Success Definition by Intervention

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≥50% Improvement in Incontinence episodes or Other Symptoms: Treatment Success Definition by Intervention

Ways to go

Target therapy (receptor, organ, origin) possible?

Individually selectives possible?

Adequate Efficacy without AE possible?

Complete remission possible?

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Thought to ponder Take Home Point

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)

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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 !!

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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