1. Terapia medica dell’IPB: focus su Silodosina Dr. Umberto Capitanio Department of Urology San Raffaele Scientific Institute, Milan, Italy

2. EpiLUTS 14,139 men ≥ 40 years old 71% reported LUTS Adapted from Sexton CC et al. BJU Int. 2009;103(Suppl3):12-23 Voiding + storage symptoms Storage symptoms only Voiding symptoms only Post micturition symptoms only (3.0%) Post micturition + storage symptoms (2.0%) Voiding + storage + post micturition symptoms Voiding + post micturition symptoms 12.1% 10.4% 24.3% 10.3% 9.1% 46% storage symptoms Male LUTS

3. LIFESTYLE ADVICE LUTS: Treatment modality SURGICAL TREATMENT DRUG TREATMENT

4. 1991199219931994199519961997199819992000 0.0 5.0 10.0 15.0 20.0 25.0 30.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 PHARMACOLOGICAL THERAPY SURGERY Souverein, Eur Urol 43:528, 2003 Drug Treatment: Evolution In The ‘90s

5. EAU guidelines 2013 on conservative treatment of non neurogenic male LUTS, available at www.uroweb.org RecommendationsLEGR Combination treatment with α-blocker together with 5α- reductase inhibitor should be offered to men with moderate to severe LUTS, enlarged prostates, and reduced Q max (men likely to develop disease progression). Combination treatment is not recommended for short- term therapy (< 1 year) 1bA Combination treatment with α-blocker and muscarinic receptor antagonist might be considered in patients with moderate to severe LUTS if symptom relief has been insufficient with the monotherapy of either drug 1bB RecommendationsLEGR α-blockers should be offered to men with moderate to severe LUTS 1aA Alpha-blockers in daily practice 1 2 3

6. 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. α 1D Primary subtype expressed in the bladder, spinal cord, and nasal passages. Thought to play a role in bladder symptoms and nasal secretions. α 1B Primary subtype expressed in the blood vessels. Regulates contraction of arterial blood vessels in response to postural redistribution of blood volume. Alpha-blockers

7. α 1 -Blockerα 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 Silodosin is an  -adrenoceptor antagonist with high selectivity for the  1A receptors relative to  1B receptors

8. 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 -BlockerReceptor Selectivity α 1A :α 1B Silodosin 162:1 Tamsulosin 10:1 Alfuzosin 1:1

9. 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%

10. Efficacy Safety data Who may benefit the most? SILODOSIN

11. 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

12. Capitanio et al. Int J Clin Pract, June 2013, 67, 6, 544–551 More than 2,500 pts included in 5 RCTs Silodosin: 68% of responders (delta IPSS ≥25%)

13. Pharmacokinetics and Safety data does not inhibit cytochrome P450 enzyme systems at normal (8 mg) and supra-therapeutic (24 mg) doses had no meaningful effects on heart rate, PR, and QRS interval duration does not affect cardiac repolarization Marks et al J Urol 181, 2634, 2009 SILODOSIN

14. Silodosin has no effect on ECG parameters Morganroth et al Clin Pharm Ther 87, 609, 2010 QTc interval Heart 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

15. Chapple et al. Eur Urol 2011 Virtually no effect on blood pressure

16. SILODOSIN: SAFETY & TOLERABILITY Most common adverse reactions (all studies) Placebo controlled studiesAll studies Preferred TermSilodosin 8 mg (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%)7 (1.0%)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%) Silodosin Integrated Summary of Safety (September 2008)

17. 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 extensions), only 148/1,581 (9.4%) subjects discontinued the study due to TEAE The most frequent cause was retrograde ejaculation (3.9%) SILODOSIN: SAFETY & TOLERABILITY

18. SILODOSIN: EFFICACY Placebo Sil-EjD Sil+EjD 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 Y et al., Urology 2011

19. Forte correlazione tra una importante riduzione nel volume dell’eiaculato e la gravità dei LUTS n = 11,063 (uomini con erezioni) % 88 9 13 14 19 16 25 43 62 31 44 58 73 36 57 67 69 0 10 20 30 40 50 60 70 80 90 100 Aneiaculazione Netta riduzione dell’eiaculato 18 27 45 64 38 50 63 78 45 70 81 IPSS=0 IPSS  7 7<IPSS  19 IPSS>20 IPSS=0 IPSS  7 7<IPSS  19 IPSS>20 IPSS=0 IPSS  7 7<IPSS  19 IPSS>20 50 – 59 anni60 - 69 anni70 - 79 anni 22 2 2 7 6 55 DIMINUZIONE DEL VOLUME DELL’EIACULATO Rosen et al. Eur.Urol. 44(2003) 637-649

20. Terapia medica dell’IPB: focus su Silodosina A novel alpha blocker: Silodosin A novel alpha blocker: Silodosin Who are the best candidates? Who are the best candidates?

21. Silodosin: who are the best candidates 1- Patients suffering from moderate-severe nocturia Post-hoc analyses: statistically significant superiority vs placebo, while tamsulosin not, in a subgroup of patients with at least 2 episodes of nocturia at baseline Michel et al. EAU Annual Meeting Vienna 2011 Montorsi et al. Eur Urol Suppl 2010; 9: 491-5

22. Silodosin: who are the best candidates 1- Patients suffering from moderate-severe nocturia Michel et al. EAU Annual Meeting Vienna 2011 Montorsi et al. Eur Urol Suppl 2010; 9: 491-5 Statistically significant superiority vs tamsulosin and placebo on the simultaneous improvement of nocturia, frequency and incomplete emptying 1.Nocturia 2.Frequency 3.Incomplete emptying

23. Silodosin: who are the best candidates 2 – Patients with low blood pressure levels and patients concomitantly treated with antihypertensive medications Agency EM. CHMP ASSESSMENT REPORT FOR Silodyx. Doc.Ref.: EMA/72316/2010. Procedure No. EMEA/H/C/001209. 2010. http://www.ema. europa.eu/docs/en_GB/document_library/EPAR_Public_assessment_report/human/001209/WC500074188. pdf (accessed October 2012). Dizziness was cause of discontinuation in 8/1,581 pts (0.5%) and orthostatic hypotension in only 3/1,581 pts (0.2%) Virtually no risk of orthostatic hypotension One third of the patients included in clinical trials received concomitant antihypertensive agents

24. Silodosin: who are the best candidates 3 – Patients concomitantly treated with PDE5-I 24 MacDiarmid et a Urology 75;l, 520, 2010 Heart-rateSystolic BP Diastolic BP

25. Silodosin: who are the best candidates 4 – Patients with ureteral stone EAU Guidelines 2014

26. The density of α 1 receptors (especially α 1A and α 1D ) in the ureteral smooth muscle has been shown to be greater than other adrenoceptors Park et al. Urol Res 2007 Silodosin: who are the best candidates 4 – Patients with ureteral stone

27. 55 male Sprague-Dawley rats (250-300gr) Saline infusion in the ureter through a PE-10 catheter at a speed 0.4ml/hour The psoas muscle was sutured around the distal part of the ureter to cause a partial distal obstruction. Carotid artery and femoral vein were cannulated in order to register mean arterial pressure and to administer drugs, respectively.

28. α – BLOCKERS EFFECT IN VIVO α – BLOCKERS EFFECT IN VITRO - Silodosin reduces ureteral pressure with less systemic side effects than tamsulosin and prazosin - Silodosin exhibits better inhibitory efficacy on EFS-induced contraction of human and rat isolated ureters than tamsulosin and prazosin Villa et al. BJP 2013

29. Silodosin: who are the best candidates 5 – Chronic prostatitis/chronic pelvic syndrome-related symptoms 6 – Patients not satisfied (for efficacy or tolerability) with previous treatment with other alpha-blokers 7 – Brachytherapy-related symptoms 8 – After Acute Urinary Retention for TWOC success Tsumura H et al. IJROBP 2011; 81: e385-92 Nickel JC et al. J Urol 2011. 186: 125-31 Miyakita et al. IJU 2010; 17: 869-75 Kumar et al. Urology 2013

30.  I LUTS sono molto frequenti nella popolazione generale  I farmaci antagonisti dei recettori α1A-adrenergici rappresentano la terapia di prima linea nel trattamento dei LUTS  La Silodosina ha dimostrato una selettività mai riscontrata per i recettori adrenergici α1A rispetto a α1B e α1D in studi di legame e funzionali. CONCLUSIONI - 1

31.  La Silodosina ha un’efficacia pari a quella della tamsulosina, addirittura superiore in alcuni scenari clinici (e.g. nocturia)  Grazie alla sua elevata uroselettività gli effetti collaterali a livello dell‘apparato cardiovascolare sono risultati minimi.  Silodosina puo’ essere somministrata in concomitanza di PDE5-I  Dati preliminari suggeriscono un ruolo determinante di silodosina nell’espulsione di calcoli ureterali, nei sintomi secondari a brachiterapia e nella CP/CPPS CONCLUSIONI - 2