Future treatment modality of overactive bladder

1. Future treatment modality of overactive bladder Duk Yoon Kim Professor, Department of Urology Daegu Catholic University Medical Center(DCUMC) Daegu, Korea

2. Candidates: Pharmaceuticals Contents Approach Alternatives Summary

3. 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

4. 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

5. 3. Still hidden Disease? Yes, it is. 4. Natural history ? Symptoms fluctuate over time Company Logo

6. Candidates: Pharmaceuticals Approach Alternatives Summary

7. Neurotransmitters Understanding of Pathways, Neurotransmitters Company Logo

8. Central - Gabepentin - NK1 receptor antagonists - Tramadol - Opioids - 5-HT/Na re-uptake inhibitor • Peripheral - Mucosal signaling drugs - Myocyte signaling drugs Company Logo

9. 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. clinNeuropharm.., 2006

10. Gabapentin: Refractory OAB • Refractory OAB(tolterodine, oxy. 8 weeks)/nocturia • 100-300mg3,000mg, bedtime YT KIM et al. Int. Braz. J Urol, 2004

11. Gabapentin: Neurogenic OAB • Neurogenic OAB, 16 pts • 31 days • 300mgX 3days 600mgX 3days 900mg Carboe A. et al. Clin. Neuropharma, 2006

12. Results

13. 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

14. 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

15. Voiding and urodynamic variables

17. Adverse events

18. 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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21. Average daily micturitions Average daily urgency episodes

23. 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 Palmer J. 1983. Sprem M, et al. Croat Med J 2000 Company Logo

24. 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

25. Acetic acid model

26. 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

27. 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

28. 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

29. 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

30. 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.

31. Drugs in clinical phases of development (2007)

32. Drugs in clinical phases of development (2008)

36. Candidates: Pharmaceuticals Approach Alternatives Summary

37. Alternatives/2ndary modalities • sacral neuromodulation (SNM) • botulinum toxin (BTX) Cystoplasty /diversion: 20cm ileum Laparoscopic/robotic Medical therapy Company Logo

38. Complete Continence: treatment Success Definition by Intervention Company Logo

39. ≥50% Improvement in Incontinence episodes or Other Symptoms: Treatment Success Definition by Intervention Company Logo

40. 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

41. 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

42. 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

44. Integrated diagram of CNS and peripheral mechanisms

45. Completed A Study to Investigate the Food Effect on the Pharmacokinetics of YM178 in Healthy, Non-elderly VolunteersConditions: Healthy Volunteer;   Pharmacokinetics of YM178Intervention: Drug: YM1782 • Completed A Clinical Study to Determine the Effect of YM178 on the Pharmacokinetics of Warfarin in Healthy SubjectsCondition: 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 VolunteersCondition: Pharmacokinetics of YM178Interventions: Drug: mirabegron;   Drug: rifampin5 • Completed A Pharmacokinetic Study of YM178 in Normal Subjects and Those With Mild, Moderate, and Severe Renal ImpairmentCondition: Renal ImpairmentIntervention: Drug: YM1786 • Completed A Long-term Study of YM178 in Symptomatic Overactive Bladder PatientsCondition: Urinary Bladder, OveractiveIntervention: Drug: YM1787Active, • not recruiting A Study to Evaluate Safety and Efficacy of YM178 in Patients With Overactive BladderCondition: Urinary Bladder, OveractiveInterventions: Drug: YM178;   Drug: Placebo;   Drug: tolterodine8 • Recruiting A Study of YM178 in Subjects With Symptoms of Overactive BladderCondition: 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 BladderCondition: 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 BladderCondition: 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 BladderCondition: 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 BladderCondition: Urinary Bladder, OveractiveInterventions: Drug: YM178;   Drug: Tolterodine 4 ng • 13Completed A Study of YM178 in Patients With Symptomatic Overactive BladderCondition: 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) MirabegronConditions: Healthy;   Pharmacokinetics of MirabegronIntervention: Drug: mirabegron • 16Completed Study of the Effect of Food on the Pharmacokinetics of MirabegronConditions: Healthy;   Pharmacokinetics of MirabegronIntervention: Drug: mirabegron