1. SILODOSIN: THE DIFFERENTIAL EFFECTS OF A NOVEL ALPHA BLOCKER

2. What we have learned about LUTS…. 1.It is a multifactorial disease 2.It has a complex pathophisiology 3.We have predictive factors available 4.There are 3 types of symptoms 5.Not all patients should be treated with the same drugs 6.New drug therapies 7.New surgical options 2

3. EAU Guidelines on the Treatment of Male Non-neurogenic LUTS LUTS SEVERE LUTS (IPSS ≥20) MEDICAL/ SURGICAL THERAPY MILD LUTS (IPSS <8) WACHTFUL WAITING MODERATE LUTS (IPSS 8 – 19) MEDICAL THERAPY EAU, 2014: http: /www.uroweb.org AUA,2010:http://www.aua.net.org/ NICE, 2010:http://www.guidance.nice.org.ukdeline

4. CCurrently available drugs for LUTS α-blockers 5-ARIs Anticholinergics β 3 - adrenergics PDE5-I Combinations –α-blockers + 5-ARIs –α-blockers + Anticolinergics 4

5. 5 CHOOSING TREATMENT: Set the goals of therapy. Categorize patients according to symptoms. Asses predictive factors of progression. Discuss adverse effects

6. Available α- blockers Doxazosine Terazosine Alfuzosine Tamsulosine Silodosine Quick symptoms relief

7. WHY SILODOSIN …?

8. WHY SILODOSIN – the 3S 1.Selectivity 2.Sustained efficacy 3.Safety

9. α 1A Primary subtype expressed in the prostate. Regulates contraction of the smooth muscle in the prostate, bladder base and neck, urethra, seminal vesicles, and vas deferens. 1-5 α 1D Primary subtype expressed in the bladder, spinal cord, and nasal passages. Thought to play a role in bladder symptoms and nasal secretions. 1,6 α 1B Primary subtype expressed in the blood vessels. Regulates contraction of arterial blood vessels in response to postural redistribution of blood volume. 4-7 1.Schwinn DA, et al. Int J Urol. 2008;15:193-199. 2.Kaplan SA. Urology. 2004;63:428-434. 3.Nasu K, et al. Br J Pharmacol. 1996;119:797-803. 4.Murata S, et al. J Urol. 2000;164:578-583. 5.Carbone DJ, et al. Int J Impotence Res. 2003;15:299-306. 6.Stafford-Smith M, et al. Can J Anesth. 2007;54:549-555. 7.Townsend SA, et al. Hypertension. 2004;44:776-782. α 1 Adrenoreceptor Distribution & Function

10. Pharmacologic Selectivity Profiles of α 1 -Blockers  α 1 -Blocker  α 1 -Receptor Selectivity  Doxazosin 1  α 1A = α 1D = α 1B  Terazosin 1  α 1A = α 1D = α 1B  Alfuzosin 1  α 1A = α 1D = α 1B  Tamsulosin 1,2  α 1A = α 1D >α 1B  Silodosin 3  α 1A >α 1D >α 1B 1.Schwinn DA, et al. Mayo Clin Proc. 2004;79:1423-1434. 2.Kenny BA, et al. Br J Pharmacol. 1996;118:871-878. 3.Akiyama K, et al. J Pharm Exp Ther. 1999;291:81-91. Results based on in vitro data

11. α 1 -Blocker Selectivity Profiles Results based on in vitro studies Ratio expressed as the relative concentration. Tatemichi S, et al. Yakugaku Zasshi. 2006;12:209-216. Data on file, Watson Laboratories, Inc. KMD-0005 Study Report. IN VITRO DIFFERENCES IN ALPHA-BLOCKER SELECTIVITY MAY NOT CORRELATE TO DIFFERENCES IN ACTUAL CLINICAL OUTCOMES.  α 1 -Blocker  Receptor Selectivity  α 1A : α 1B  Silodosin  162:1  Tamsulosin  10:1  Alfuzosin  1:1

12. α 1A Adrenoreceptor Expression Increases in BPH vs Non-BPH Prostate Tissue Nasu K, et al. Br J Pharmacol. 1996;119:797-803. Non-BPH Tissue BPH Tissue α 1A 63% 85% α 1D 31%14% α 1B 6% 1%

13. α 1B Adrenoreceptor Expression in the Vasculature Increases with Age Rudner XL, et al. Circulation. 1999;100:2336-2343. Age <55 yearsAge ≥65 years Adrenoreceptor Expression α 1A >α 1B α 1B >α 1A

14. Yamagishi et al Eur J Pharmacol 315;73, 1996 Akiyama et al., JPET 291;81, 1999 Akiyama et al Int J Urol 8; 177, 2001 Silodosin is tissue-selective Silodosin reduces phenylephrine-contraction of the rabbit prostate at low concentrations with a “window” to effects on the aorta

15. Yamagishi et al Eur J Pharmacol 315;73, 1996 Akiyama et al., JPET 291;81, 1999 Akiyama et al Int J Urol 8; 177, 2001 Silodosin exhibits functional selectivity Silodosin reduces rat or dog urethral pressure in vivo at doses that have little effect on blood pressure dog rat

16. SILODOSIN: A Uniquely Selective Alpha-Blocker  Highly receptor-subtype selective –Binds with much higher affinity to α 1A receptors than α 1D or α 1B receptors in in vitro studies  Highly tissue selective –Silodosin has ~200 times higher affinity for prostatic tissue than aortic tissue Shibata K, et al. Mol Pharmacol. 1995;48:250-258.

17. SILODOSIN – the 3S 1.Selectivity 2.Sustained efficacy 3.Safety

18. Silodosin is efficacious within 2 - 6 hours… …..with sustained efficacy during 12-weeks treatment (8mg o.d) versus placebo (p<0.0001 – p<0.005) in two phase III trials in the USA Marks et al J Urol 181, 2634, 2009

19. SILODOSIN: Combined IPSS Subscale Analysis † Analysis based on last observation carried forward. IPSS, International Prostate Symptom Score. Marks LS, et al. J Urol. 2009;181:2634-2640. *P≤0.0002

20. *Statistically significant superiority vs placebo in patients with at least 2 episodes of nocturia at baseline (not for tamsulosin) Chapple et al, Eur Urol, 2011 Montorsi F, Eur Urol Suppl 2010 Silodosin and tamsulosin: comparison in the subgroup of patients with nocturia (IPSS) at baseline

21. Schneider et al – World J Urol – in press

22. Simultaneous improvement in symptoms Montorsi F., Eur. Urol. Suppl. 2010; 9: 491-495. Statistically significant superiority vs tamsulosin on simultaneous improvement of frequency, nocturia and incomplete emptying (EU study - post hoc analysis) % of patients with a simultaneous improvement in 3 of the most bothersome symptoms

23. Changes in Urodynamic Parameters Before and at 3 Months After Silodosin Treatment Before (n=35)After (n=29)P values a First desire to void (ml)193.1± 105.5230.3± 99.90.0974 Maximum cystometric capacity (ml)356.1± 139.6409.1± 122.20.0027 Bladder compliance (ml/cm H 2 O)40.5± 51.945.0 ±34.20.3806 Detrusor overactivity (DO)Before (n=23)After (n=20)P valuesa Amplitude of the largest DO contraction (cm H 2 O) b 85.3± 35.337.4± 42.90.0003 Bladder volume at FIC (ml) c 285.34 ±112.8380.6± 136.870.0003 Pressure flow studyBefore (n=35)After (n=27)P values a Detrusor opening pressure (cm H 2 O)77.8± 42.952.2± 20.70.0010 Detrusor pressure at Q max 80.6± 37.848.6 ±25.3<0.0001 Bladder outlet obstruction index70.2 ±38.132.6 ±29.2<0.0001 Schäfer’s linear passive urethral resistance relation obstruction class 4.5 ±1.52.6 ±1.5<0.0001 Watts factor at Q max (µW/mm 2 )9.9 ±6.68.8 ±6.00.7784 SILODOSIN: EFFICACY Statistically significant improvement of almost all urodynamic parameters - 44% of the patients avoided invasive surgery, due to the improvement of LUTS obtained with silodosin Yamanishi et. al, Neurourol. Urodynam. 29:558–562, 2010

24. 1.Selectivity 2.Sustained efficacy 3.Safety SILODOSIN – the 3S

25. Silodosin has no effect on ECG parameters Morganroth et al Clin Pharm Ther 87, 609, 2010 QTc intervalHeart Rate In 139 healthy male subjects, placebo, silodosin 8 or 24 mg once daily for 5 days did not affect heart rate, QTc interval, PR-interval or QRS-complex and did not cause any deviations of the ECG morphology

26. Safety data At normal (8mg) and supra-therapeutic (24mg) doses no meaningful effects on heart rate, PR and QRS interval duration (study S105014) Does not affect cardiac repolarization MacDiarmid et al Urology 75;l, 520-25, 2010

27. Silodosin exhibits cardiovascular safety in efficacy trials Kawabe et al. Marks et al BJU Int98, 1019, 2006 Marks et al. J Urol 181, 2634, 2009 Chapple et al Eur Urol 59, 342, 2011 Silodosin is similar to findings with placebo reported with low frequencies of cardiovascular adverse events baselineendpoint Heart-rate baselineendpoint Systolic BP baselineendpoint Diastolic BP *Data from Kawabe et al BJU Int 2006 § No episodes to orthostatic test. Chapple et al Eur Urol 2011.

28. Montorsi F., Eur. Urol. Suppl. 2010; 9: 491-495 Supine blood pressure

29. Low Incidence of Orthostatic Hypotension in All Age Groups RAPAFLO ® (silodosin) Capsules full Prescribing Information. November 2009.  Age Group  No. of Patients  Incidence of Orthostatic Hypotension <65 years  259  2.3%  ≥65 years  207  2.9%  ≥75 years  60  5.0%  All patients  466  2.6%

30. Silodosin lacks clinically relevant interaction with sildenafil or tadalafil MacDiarmid et al Urology 75;l, 520, 2010 Heart-rateSystolic BPDiastolic BP

31. SILODOSIN: SAFETY & TOLERABILITY Most common adverse reactions (all studies) Placebo controlled studiesAll studies Preferred TermSilodosin 8mg (n=931) Placebo (n=733) Silodosin (n=1,581) Total No. of patients with drug related AE 268 (28.8%)66 (9.0%)502 (31.8%) Retrograde ejaculation200 (21.5%)6 (0.8%)373 (23.6%) Dizziness17 (1.8%)6 (0.8%)33 (2.1%) Orthostatic hypotension11 (1.2%)6 (0.8%)20 (1.3%) Nasal Congestion9 (1.0%)1 (0.1%)20 (1.3%) Headache10 (1.1%)9 (1.2%)20 (1.3%) Diarrhoea6 (0.6%)2 (0.3%)16 (1.0%) Data on File, Recordati- Summary of safety; Capitanio et al: Int.J.Clin.Pract. E-publ.doi:10/1111/ijcp.12135, 2013

32. SILODOSIN: SAFETY & TOLERABILITY Discontinuations due to adverse reactions In controlled studies 40/931 (4.3%) patients discontinued with silodosin, as compared to 14/733 (1.9%) patients on placebo Overall (controlled + long term extension), only 148/1,581 (9.4%) subjects discontinued the study due to TEAE The most frequent cause was retrograde ejaculation (3.9%) Dizziness was a cause of discontinuation in 8/1,581 patients (0.5%) Orthostatic hypotension in only 3/1,581 patients (0.2%) Data on File, Recordati- Summary of safety; Capitanio et al : Int.J.Clin.Pract.,e-publ. doi:10.1111/ijcp.12135, 2013

33. Understanding Retrograde Ejaculation  Orgasm with reduced or no semen  Due to reduced contraction of smooth muscles of vas deferens and seminal vesicles, mediated via α 1A receptor 1-4 –Expected side effect of α 1A -selective antagonists  Not true RE but reduced seminal expulsion 2  Not a serious side effect  Reversible on discontinuation 5 1.Hisasue S, et al. Int J Urol. 2006;13:1311-1316. 2.Noguchi Y, et al. Eur J Pharmacol. 2008;580:256-261. 3.Kobayashi K, et al. J Sex Med. 2008;5:2185-2190. 4.Moriyama N, et al. Br J Pharmacol. 1997;122:1009-1041. 5.RAPAFLO ® (silodosin) Capsules full Prescribing Information, November 2009.

34. Ejaculation disorder was associated with a significantly improved change in total IPSS at all time points from weeks 1-12 vs no ejaculation disorder or placebo Homma Urology76:1446 2010 SILODOSIN: EFFICACY & SAFETY *** * ** † ††† †† Change from baseline (IPSS) Observation period (week) -15 -10 -5 -0 Pre-dose 124812LOCF Placebo No-EjD Sil-EjD

35. RE= retrograde ejaculation Roehrborn et al,Prost.Ca.Prost.Dis.2011:143-8. 9.2 12.9 20.9 23 27.5 34.4 0 5 10 15 20 25 30 35 40 ≥30% IPSS and Qmax≥3 Units IPSS and Qmax Placebo (n=457)No RE (n=335)RE (n=131) Percent Silodosin Post-hoc Responder Analysis by Ejaculation Status  RE associated with improvement in IPSS response with silodosin

36. CONCLUSIONS - Selectivity, Sustained efficacy and Safety (1) Highly selective α1A-adrenoreceptor antagonist Significantly more effective than placebo and at least as effective as tamsulosin (0.4 mg once a day) in improving IPSS score, storage sub-score and voiding sub-score Post-hoc analyses have shown that is significantly more efficacious than tamsulosin in improving the triad of symptoms including incomplete emptying, frequency and nocturia

37. CONCLUSIONS - Selectivity, Sustained efficacy and Safety (2) Minimal cardiovascular effects The most common adverse reaction is retrograde ejaculation (drug discontinuation only in less than 4% of patients) Can co prescribe silodosin and PDE-5 inhibitors

38. 38 Nocturia as main complaint Prostate <30-40 gr; PSA< 1.5 Quick improvement of symptoms Avoidance of CV effects; Not-ejaculation focused Categorize patients according to symptoms1 Asses predictive factors of progression2 Set the goals of therapy 3 Discuss adverse effects1 4

39. 39 Nocturia main complaint