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Once-a-Day Tadalafil for the Treatment of Erectile Dysfunction. Summary Slide Set. Tadalafil under the name of Cialis is only approved for the treatment of erectile dysfunction. Tadalafil for Erectile Dysfunction. Elimination half-life ( t 1/2 ) : ~17.5 hours 1,2

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  1. Once-a-Day Tadalafil for the Treatment of Erectile Dysfunction Summary Slide Set Tadalafil under the name of Cialis is only approved for the treatment of erectile dysfunction

  2. Tadalafil for Erectile Dysfunction • Elimination half-life (t1/2 ): ~17.5 hours1,2 • Steady state attained by Day 5 of once-dailyadministration1-4 • Accumulation (1.6-fold) consistent with t1/21,3-4 • Protein binding: 94%1-4 • Metabolism: P450 CYP3A4 (primary)1-4 • Metabolite: methylcatechol glucuronide conjugate1-4 (13,000-fold less potent)2 • Food: no effect on absorption1-3 • Hepatic impairment (mild/moderate): area under the curve (AUC) comparable for 10 mg,1-2,4 trend toward longer t1/2 with increasing impairment4 • Renal disease: approximately doubled AUC,1-2,4 and higher Cmax4 pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12ahexahydro-2-methyl-, (6R,12aR)-1 1. Cialis [US Package Insert] 2010. 2. Cialis [EU Summary of Product Characteristics] 2010. 3. Forgue S et al. Br J Clin Pharmacol 2006;61:280-8. 4. Forgue S et al. Br J Clin Pharmacol 2007;63:24-35.

  3. Introduction – Erectile Dysfunction • Erectile dysfunction (ED) is characterized by the consistent inability to attain or maintain an erection sufficient for satisfactory sexual intercourse1 • ED affects ~50% of men between 40 and 70 years of age, with prevalence increasing with age2 • ED often3-5: • Reduces motivation for sexual activity • Creates a conscious focus on ED by the affected man • Inhibits partner initiation of sexual activity 1. NIH Consensus Conference. JAMA 1993;270(1):83-90. 2. Feldman H et al. J Urol 1994;151:54-61. 3. Perelman M et al. J Sex Med 2005;2:397-406. 4. Fisher W et al. J Sex Med 2005;2:675-84. 5. Cameron A et al. J Sex Marital Ther 2005;31:229-42.

  4. Factors Important in ED Treatment • Patients define ED treatment success as: cure, pleasure, partner satisfaction, reproduction, and naturalness1 • Planning sexual activity around taking a pill is burdensome to some patients and their partners1,2 • Taking an ED medication once a day may be one way for patients to be ready for sexual activity when they choose2 ED=erectile dysfunction 1. Hanson-Divers C et al. J Urol 1998;159:1541-7. 2. Dunn M et al. Int J Impot Res 2007;19:119-23.

  5. Introduction – Why the Once-Daily Option • Oral PDE5 inhibitors successfully treat ED1; however, • Ameliorating the full psychological impact of ED remains a challenge2 • One complication is the lack of a clear pattern of timing of sexual activity for many couples2 • Once-daily dosing would offer an alternative for couples who prefer spontaneous instead of scheduled sexual activities, or for those who anticipate frequent sexual activities ED=erectile dysfunction; PDE5=phosphodiesterase 5 1. Eardley I et al. J Sex Med 2010;7:524-40. 2. Fisher W et al. J Sex Med 2005;2:675-84.

  6. Introduction – Why the Once-Daily Option • Dosing paradigms that eliminate coordinating dosing with sexual activity are desirable to accommodate individual patterns and spontaneity of sexual intimacy1-3 • Tadalafil is suited for use as a once-daily ED therapy, owing to its long half-life (17.5 hours)4 ED=erectile dysfunction; PDE5=phosphodiesterase 5 1. Carson C et al. BJU Int 2004;93:1276-81. 2. Rajfer J et al. Int J Impot Res 2007;19:95-103. 3. Dunn M et al. Int J Impot Res 2007;19:119-23. 4. Forgue S et al. Br J Clin Pharmacol 2006;61:280-8.

  7. Tadalafil Pharmacokinetics and Once-Daily Dosing • The mean half-life of tadalafil is 17.5 hours1,2 • Steady-state plasma concentrations are attained within5 days of daily dosing • Exposure is approximately 1.6-fold greater than after a single dose3: • Daily tadalafil 10 mg  16 mg at steady state • Daily tadalafil 5 mg  8 mg at steady state • This duration of efficacy may permit men with ED and their partners to disconnect sexual activity from dosing ED=erectile dysfunction 1. Cialis [US Package Insert] 2010. 2. Cialis [EU Summary of Product Characteristics] 2010. 3. Forgue S et al. Br J Clin Pharmacol 2006;61:280-8.

  8. Tadalafil Pharmacokinetics and Once-Daily Dosing: pK/pD Modeling • Pharmacokinetic/pharmacodynamic modeling used as part of the rationale for developing tadalafil for daily use are described in a recent publication • Predictions based on plasma concentrations after single-dose oral simulations were used to simulate plasma concentrations for once-daily tadalafil pD=pharmacodynamic; pK=pharmacokinetic Wrishko R et al. J Sex Med 2009;6:2039-48.

  9. Predicted Tadalafil Concentration-Versus-Time Profiles Tadalafil Plasma Concentrations Over 1 Week 400 350 Tadalafil 5 mg OAD 300 Tadalafil 20 mg single dose 250 200 Tadalafil Plasma Concentration (ng/mL) 150 100 50 0 0 24 48 72 96 120 144 168 Time (hours) OAD=Once-a-Day or Once-Daily Wrishko R et al. J Sex Med 2009;6:2039-48.

  10. Once-a-Day Tadalafil Efficacysummary Tadalafil under the name of Cialis is only approved for the treatment of erectile dysfunction

  11. Once-Daily Tadalafil for ED: Efficacy Introduction • Tadalafil OAD is an effective treatment for patients with ED1-3 • Significant improvements in primary study endpoints1-3 • IIEF EF • SEP2 (insertion) • SEP3 (successful intercourse) • Longterm effectiveness (1- and 2-year)4 • Efficacy that is numerically similar to that with tadalafil on-demand analyses1-6 ED=erectile dysfunction; IIEF EF=International Index of Erectile Function Erectile Function Domain; OAD=Once-a-Day or Once-Daily SEP2=Sexual Encounter Profile Question 2: “Were you able to insert your penis into your partner’s vagina?”; SEP3=Sexual Encounter Profile Question 3: “Did your erection last long enough to have successful intercourse?” 1. Porst H et al. EurUrol2006;50(2):351-359. 2. Rajfer J et al. Int J Impot Res 2007;19(1):95-103. 3. Hatzichristou D et al. Diabet Med 2008;25(2):138-146. 4. Porst H et al. J Sex Med 2008;5(9):2160-2169. 5. Brock GB et al. J Urol 2002:168(4):1332-1336. 6. Carson CC et al. BJU Int 2004;93(9):1276-1281.

  12. Overview of Once-Daily Tadalafil Clinical (Registration) Studies ED=erectile dysfunction; OAD=Once-Daily/Once-a-Day 3. Hatzichristou D et al. Diabet Med 2008;25:138-146. 1. Porst H et al. Eur Urol 2006;50:351-359. 2. Rajfer J et al. Int J Impot Res 2007;19:95-103.

  13. Tadalafil OAD Clinical Registration Studies: Basic Trial Design Run-In Period Treatment Period Open-Label Extension Follow-Up Placebo Daily Tadalafil Once-Daily Study 1: 5 mgStudy 2,3: 2.5 mg • Tadalafil 5 mg Once-Daily • Study 1: 1 year • Study 2: 2 years Study 1:No StudyDrug Tadalafil Once-Daily Study 1: 10 mgStudy 2,3: 5 mg -4 Weeks 0 Weeks Every 4 Weeks Study 1,3: 12 Weeks Study 2: 24 Weeks Every 3-4 Months Study 1: 1 Yr Study 2: 2 Yr 4 Weeks IIEF GAQ (Study 2) InformedConsent Randomization Baseline IIEF Baseline SEP IIEF SEP PAIRS (Study 2) IIEF, SEP GAQ, Labs, ECG PAIRS (Study 2) IIEF IIEF Patients were asked to take one dose at approximately the same time each day ECG=electrocardiogram; GAQ=Global Assessment Question; IIEF=International Index of Erectile Function; OAD=Once-a-Day or Once-Daily; PAIRS=Psychological and Interpersonal Relationship Scales; SEP=Sexual Encounter Profile 3. Hatzichristou D et al. Diabet Med 2008;25:138-146. 1. Porst H et al. Eur Urol 2006;50:351-359. 2. Rajfer J et al. Int J Impot Res 2007;19:95-103.

  14. 12-Week Study 1 (General ED Population)Co-Primary Endpoint: IIEF EF Placebo Tadalafil 5 mg OAD *22.8 *22.8 Tadalafil 10 mg OAD *p<0.05 vs placebo 15.0 Mean IIEF EF Domain Score Baseline Placebo(n=54) Tadalafil 5 mg OAD(n=107) Tadalafil 10 mgOAD(n=105) IIEF EF=International Index of Erectile Function Erectile Function Domain Porst H et al. Eur Urol 2006;50:351-359.

  15. 24-Week Study 2 (General ED Population)Co-Primary Endpoint: IIEF EF Placebo Tadalafil 2.5 mg OAD Tadalafil 5 mg OAD * 20.8 *p<0.001 vs placebo * 19.1 14.6 Mean IIEF EF Domain Score Baseline Tadalafil 5 mg OAD(n=96) Tadalafil 2.5 mg OAD(n=93) Placebo(n=93) IIEF EF=International Index of Erectile Function Erectile Function Domain Rajfer J et al. Int J Impot Res 2007;19:95-103.

  16. Study 2 Additional Co-Primary Endpoints: SEP2 (Penetration) and SEP3 (Successful Intercourse) Placebo Tadalafil 2.5 mg OAD 100 Tadalafil 5 mg OAD 90 * 70.7% *p<0.001 tadalafil vs placebo * 65.3% 80 * 56.9% 70 * 50.0% 60 51.1% Mean Per-Patient % “Yes” 50 31.3% 40 30 Baseline 20 10 0 (n=92) (n=96) (n=92) (n=92) (n=96) (n=92) SEP2 SEP3 SEP2=Sexual Encounter Profile Question 2: “Were you able to insert your penis into your partner’s vagina?”; SEP3=Sexual Encounter Profile Question 3: “Did your erection last long enough to have successful intercourse?” Rajfer J et al. Int J Impot Res 2007;19:95-103.

  17. Historical Comparison: IIEF EF DomainPooled Once-Daily and Integrated On-Demand Placebo Tadalafil 2.5 mg OAD Tadalafil 5 mg OAD Tadalafil 10 mg On-Demand Tadalafil 20 mg On-Demand *p<0.001 vs placebo *23.2 *21.9 *21.1 *19.2 15.3 14.9 Mean IIEF EF Domain Score Baseline (n=147) (n=93) (n=203) (n=638) (n=321) (n=1143) Once-Daily1 (12-week data from a 12-2 and 24-week3 study) On-Demand4 (11 pooled 12-week studies) IIEF EF=International Index of Erectile Function Erectile Function Domain; OAD = Once-Daily/Once-a-Day 1. Donatucci et al. Curr Med Res Opin 2008; 24:3383-3392. 2. Porst H et al. Eur Urol 2006;50:351-359 3. Rajfer J et al. Int J Impot Res 2007;19:95-103. 4. Carson et al. BJU Int 2004;93:1276-1281.

  18. Historical Comparison: SEP3Pooled Once-Daily and Integrated On-Demand Placebo Tadalafil 5 mg OAD Tadalafil 2.5 mg OAD Tadalafil 10 mg On-Demand Tadalafil 20 mg On-Demand *p<0.001 vs placebo *68% *62% *58% *50% Mean Per-Patient % SEP3 “Yes” 31% 33% Baseline (n=144) (n=92) (n=201) (n=638) (n=321) (n=1143) Once-Daily1 (one 12-2 and one 24-week3 study) On-Demand4 (11 pooled 12-week studies) SEP3=Sexual Encounter Profile Question 3: “Did your erection last long enough to have successful intercourse?” 1. Donatucci et al. Curr Med Res Opin 2008; 24:3383-3392. 2. Porst H et al. Eur Urol 2006;50:351-359 3. Rajfer J et al. Int J Impot Res 2007;19:95-103. 4. Carson et al. BJU Int 2004;93:1276-1281.

  19. Once-a-Day Tadalafil Efficacy in ED in Menwith Diabetes, summary Tadalafil under the name of Cialis is only approved for the treatment of erectile dysfunction

  20. Tadalafil OAD Efficacy in ED in Men with Diabetes: ED and Diabetes Introduction • The prevalence of ED in diabetic men is ≥50%1 • ED in patients with DM is frequently more severe, and studies support an association between poor glycemic control and ED severity2 • Men with DM have an age-corrected risk of developing ED that is 1.3-2 to 3-fold3 greater than those without DM • ED and diabetes have a high co-prevalence3,4 DM=diabetes mellitus; ED=erectile dysfunction; OAD=once-daily/once-a-day 1.Thorve VS et al. J Diabetes Complications 2010; May 10 [Epub]. 2. Bacon CG et al. Diabetes Care 2002;25(8):1458-1463. 3. Grover SA et al. Arch Intern Med 2006;166:213-219. 4. Sun P et al. JUrol 2006;176(3):1081-1085.

  21. PDE5 Inhibitors in Diabetic Men • While PDE5 inhibitors are a common, effective treatment for ED, they are less effective in men with ED and diabetes1 • Possible reasons for the lower efficacy include: • Impaired endothelium-derived factors in penile arteries2 • Underlying endothelial dysfunction1,3 ED=erectile dysfunction; PDE5 =phosphodiesterase 5 1. Nehra A. Mayo Clin Proc 2009 Feb;84(2):139-48. 2. Angulo J et al. J Sex Med 2005;2(3):341-346. 3. Billups KL et al. CurrUrol Rep 2005;6(6):439-444.

  22. Once-Daily Tadalafil 2.5 mg and 5 mgin Diabetes: Baseline Characteristics *p≤0.005 vs placebo ACR=albumin-creatinine ratio; HbA1c=hemoglobin A1c; OAD=once-a-day/once-daily. Hatzichristou D et al. Diabet Med 2008;25:138-146.

  23. Once-Daily Tadalafil 2.5 mg and 5 mg in Diabetes Co-Primary Endpoint: IIEF EF *p≤0.005 vs placebo Placebo Tadalafil 2.5 mg OAD 30 Tadalafil 5 mg OAD 25 *p≤0.005 vs placebo *18.3 *17.2 20 14.7 Mean IIEF EF Domain Score 15 Baseline 10 5 0 Placebo(n=98) Tadalafil5 mg OAD(n=97) Tadalafil 2.5 mg OAD(n=97) All Patients IIEF EF=International Index of Erectile Function Erectile Function Domain Hatzichristou D et al. Diabet Med 2008;25:138-146.

  24. Once-Daily Tadalafil 2.5 mg and 5 mg in Diabetes: Additional Co-Primary Endpoints SEP2 and SEP3 Placebo Tadalafil 2.5 mg OAD Tadalafil 5 mg OAD *61% *p≤0.005 vs placebo *62% *46% *41% Mean Per-Patient % “Yes” 43% 28% Baseline Placebo(n=95) Tadalafil2.5 mg OAD(n=96) Tadalafil5 mg OAD(n=95) Placebo(n=98) Tadalafil 2.5 mg OAD(n=97) Tadalafil5 mg OAD(n=97) SEP2 SEP3 SEP2=Sexual Encounter Profile Question 2: “Were you able to insert your penis into your partner’s vagina?”; SEP3=Sexual Encounter Profile Question 3: “Did your erection last long enough to have successful intercourse?” Hatzichristou D et al. Diabet Med 2008;25:138-146.

  25. Once-Daily Tadalafil 2.5 mg and 5 mg in Diabetes Subgroup Analyses: IIEF EF by ED Severity Placebo 30 Tadalafil 2.5 mg OAD 24.7 24.4 Tadalafil 5 mg OAD 25 22.1 *18.3 *17.2 *p≤0.005 vs placebo 18.7 17.8 20 16.1 14.7 13.6 Mean IIEF EF Domain Score 12.2 15 7.8 10 Baseline 5 0 (n=98) (n=97) (n=97) (n=33) (n=28) (n=27) (n=25) (n=28) (n=28) (n=40) (n=41) (n=42) All Patients Mild ED(22-30) Moderate ED(17-21) Severe ED(1-10) Baseline ED Severity (IIEF EF) Statistical comparisons not made within severity subgroups due to small sample size ED=erectile dysfunction; IIEF EF=International Index of Erectile Function Erectile Function Domain Hatzichristou D et al. Diabet Med 2008;25:138-146.

  26. Once-Daily Tadalafil 2.5 mg and 5 mg in Diabetes: IIEF EF by Glycemic Control Placebo Tadalafil 2.5 mg OAD 30 Tadalafil 5 mg OAD 25 21.1 *p≤0.005 vs placebo *18.3 *17.2 19.3 18.8 20 17.5 16.0 15.5 14.7 14.6 12.8 Mean IIEF EF Domain Score 15 11.5 Baseline 10 5 0 (n=98) (n=97) (n=97) (n=34) (n=49) (n=32) (n=53) (n=36) (n=51) (n=11) (n=12) (n=14) All Patients Good Control ( <7.0% ) Fair Control ( 7.0 to ≤9.5% ) Poor Control ( >9.5% ) Glycemic Control by Hemoglobin A1c (HbA1c) at Baseline Statistical comparisons not made within glycemic control subgroups due to small sample size ED=erectile dysfunction; IIEF EF=International Index of Erectile Function Erectile Function Domain Hatzichristou D et al. Diabet Med 2008;25:138-146.

  27. Historical Comparison: IIEF EF in DiabetesOnce-Daily and On-Demand • First study to examine once-daily tadalafil in this population1 • Daily and on-demand dosing were not directly compared • Historical comparison of ED dosing regimens in diabetic men: • Once-daily tadalafil 2.5 mg and 5 mg1 • Change in IIEF EF domain score, 4.5 and 4.8 • 41% and 46% mean per-patient SEP3 • On-demand tadalafil 20 mg2 • Change in IIEF EF domain score, 7.4 • 53% mean per-patient SEP3 ED=erectile dysfunction; IIEF EF=International Index of Erectile Function Erectile Function Domain; SEP3=Sexual Encounter Profile Question 3: “Did your erection last long enough to have successful intercourse?” 1. Hatzichristou D et al. Diabet Med 2008;25:138-146. 2. Fonseca V, et al. Diabetologia 2004; 47(11):1914-1923.

  28. Once-Daily Tadalafil in Diabetic Men: Efficacy Conclusions / Discussion In men with diabetes and ED, tadalafil 2.5 mg OAD as well as 5 mg OAD for 12 weeks improved erectile function (by IIEF EF, SEP2 and SEP3; p≤0.005 vs placebo) Multiple secondary efficacy measures supported improvement in both tadalafil OAD dose groups vs placebo. Reason for lack of dose response not clear Study’s baseline characteristics may indicate “sicker” 5-mg group: Duration of diabetes longer (12.3 vs 9.9 years) Smaller proportion of patients with good glycemic control (33% vs 49%) Urinary ACR worse (115.2 vs 76.8 mg/g) 28 ACR=albumin-creatinine ratio; IIEF EF=International Index of Erectile Function Erectile Function Domain; SEP2=Sexual Encounter Profile Question 2: “Were you able to insert your penis into your partner’s vagina?”; SEP3=Sexual Encounter Profile Question 3: “Did your erection last long enough to have successful intercourse?” Hatzichristou D et al. Diabet Med 2008;25:138-146.

  29. Once-Daily Tadalafil: Longterm Effectiveness

  30. Once-Daily Tadalafil Open-Label Extensions ofOAD Studies (General ED Population) • 1-year, open-label extension (once-daily tadalafil 5 mg)3following Study 1 (12-week double-blind, placebo-controlled of once-daily tadalafil 5 mg or 10 mg (N=234)1 • 2-year, open-label extension (once-dailytadalafil 5 mg)3following Study 2 (24-week double-blind, placebo-controlled of once-daily tadalafil 2.5 mg or 5 mg (N=238)2 ED=erectile dysfunction; OAD=Once-Daily/Once-a-Day • Porst H et al. Eur Urol 2006;50:351-359. • Rajfer J et al. Int J Impot Res 2007;19:95-103. 3. Porst H et al. J Sex Med 2008;5:2160-2169.

  31. Once-Daily Tadalafil:Open-Label Extension Studies 1 and 2 Treatment Free Run-In Period Study 1 Open-Label Extension* *Extension primary endpoints: AEs, ECGs, labs †PAIRS and GAQ only measured in Study 22 AE=adverse event; ECG=Electrocardiogram; GAQ=Global Assessment Question; IIEF=International Index of Erectile Function; PAIRS=Psychological and Interpersonal Relationship Scales; SEP=Sexual Encounter Profile 12-Week Placebo- Controlled Tadalafil 5 mg OAD (N=234) Study 11 Treatment Free Week: -4 0 12 Month: 4 8 12 13 IIEF Labs ECG IIEF Labs ECG IIEF Labs ECG IIEF Labs ECG Randomization Treatment Free Run-In Period Study 2 Open-Label Extension* 24-Week Placebo- Controlled Study 22 Tadalafil 5 mg OAD (N=238) Week: -4 0 24 Month: 3 6 9 12 15 18 21 24 IIEF SEP IIEF GAQ† Labs ECG IIEF IIEF GAQ† Labs ECG IIEF GAQ† Labs ECG IIEF, SEP, PAIRS† Every 4 Weeks Every 3-4 Months: SEP and PAIRS • Porst H et al. Eur Urol 2006;50:351-359. • Rajfer J et al. Int J Impot Res 2007;19:95-103. 3. Porst H et al. J Sex Med 2008;5:2160-2169.

  32. Studies 1 and 2 Open-Label Extensions Tadalafil 5 mg OAD: Objectives • Primary Objective: Safety • AEs • ECGs • Clinical laboratory measures • Secondary Objectives: Effectiveness* • IIEF EF • IIEF IS • IIEF OS • GAQ1 • GAQ2 * “effectiveness” used rather than “efficacy” as there was no placebo arm during these study extensions **GAQ administered only in the 2-year open-label extension study AEs=Adverse Events; ECG=electrocardiogram; GAQ=Global Assessment Question; IIEF=International Index of Erectile Function; IS=Intercourse Satisfaction; OAD=Once-a-Day or Once-Daily; OS=Overall Satisfaction • Porst H et al. Eur Urol 2006;50:351-359. • Rajfer J et al. Int J Impot Res 2007;19:95-103. 3. Porst H et al. J Sex Med 2008;5:2160-2169.

  33. Once-Daily Tadalafil 5 mg Longterm Effectiveness and Patient Disposition: Studies 11 and 22 12-wk once-daily controlled study/1-yr open label in orange Completed second year of open-label phase: 24-wk once-daily controlled study/2-yr open label in green Completed one year of open-label phase: 139 Completers enrolling in open-label phase: 208 162 Randomized in controlled phase: Discontinued, during year 2 of open-label phase: Perceived lack of efficacy Adverse event* Patient decision Lost to follow-up Protocol violation Death Discontinued, during year 1 of open-label phase: Perceived lack of efficacy Adverse event* Patient decision Lost to follow-up Protocol violation Personal conflict Sponsor decision Physician decision Death Protocol violation/FU 234 238 268 287 35 8 4 10 8 Newly added to open-label phase: 13 Discontinued: 0 4 8 5 34 49 7 6 2 4 0 3 51 3 2 0 1 1 0 1 0 1 1 *Excluding those patients who died. FU=follow-up visit • Porst H et al. Eur Urol 2006;50:351-359. • Rajfer J et al. Int J Impot Res 2007;19:95-103. 3. Porst H et al. J Sex Med 2008;5:2160-2169.

  34. Once-Daily Tadalafil 5 mg Longterm Effectiveness: IIEF EF 34 2-Year Extension 1-Year Extension Mean IIEF EF Domain Score 229 229 217 213 205 204 170 153 139 Baseline 4-mos 8-mos 12-mos Baseline 6-mos 12-mos 18-mos 24-mos In the 1-year extension, patients were washed out for 1 month following the open-label extension At the end of this washout period, the mean IIEF EF Domain score was 16.0 IIEF EF=International Index of Erectile Function Erectile Function Domain; mos = months’ study visit Porst H et al. J Sex Med 2008;5(9):2160-2169.

  35. Once-Daily Tadalafil 5 mg Longterm Effectiveness: Percentage of Men Achieving IIEF EF ≥26 35 1-Year Extension Study 2-Year Extension Study % of Patients with NormalIIEF EF Domain Score N=202 N=135 Patients with IIEF EF <26 at Baseline IIEF EF=International Index of Erectile Function Erectile Function Domain Porst H et al. J Sex Med 2008;5(9):2160-2169.

  36. Once-Daily Tadalafil Longterm Effectiveness: IIEF EF in 1- and 2-yr Open-Label Extensions 1-Year Open-Label Extension 2-Year Open-Label Extension 30 24.8 24.1 25 20 14.0 15 Mean IIEF EF Domain Score 16.0 13.7 10 5 N= N= 229 205 229 --- --- 204 213 170 206 --- --- 153 --- 139 217 --- 0 Baseline 4 8 12 16 20 24 Month of Open-Label Extension IEF EF=International Index of Erectile Function Erectile Function Domain; N=number of evaluable patients Porst H et al. J Sex Med 2008;5(9):2160-2169.

  37. Once-Daily Tadalafil 5 mg Longterm Effectiveness: IIEF EF in Clinically Relevant Subgroups Data shown as mean (SD); ED=erectile dysfunction Porst H et al. J Sex Med 2008;5(9):2160-2169.

  38. Once-Daily Tadalafil Longterm Effectiveness: Additional Measures *GAQ administered only in the 2-year open-label extension study. EF=erectile function; GAQ=Global Assessment Question; IIEF=International Index of Erectile Function; IS=intercourse satisfaction; OS=overall satisfaction Porst H et al. J Sex Med 2008;5(9):2160-2169.

  39. OAD Longterm Effectiveness: Conclusions Efficacy improvements observed after 12 and 24 weeks in the placebo-controlled study periods1,2 were maintained as effectiveness improvements after 1 and 2 years ofopen-label treatment3 There was no evidence of tolerance or treatment resistance (tachyphylaxis) after up to 2 years of tadalafil 5 mgonce-daily dosing3 Longterm, once-daily tadalafil treatment provides a viable treatment alternative to on-demand dosing of tadalafil for men with ED3 39 ED=erectile dysfunction; OAD=once-daily/once-a-day 1. Porst H et al. Eur Urol 2006;50:351-359. 2. Rajfer J et al. Int J Impot Res 2007;19:95-103. 3. Porst H et al. J Sex Med 2008;5(9):2160-2169.

  40. Tadalafil OAD Durability of Response: Retrospective Analysis of the 4-WeekTreatment-Free Period1 of an OAD Study2After Its 1-Year Open-Label Extension3 • Porst H et al. J Sex Med 2010 [In Press]. • Porst H et al. EurUrol2006;50(2):351-359. • Porst H et al. J Sex Med 2008;5:2160-2169.

  41. Once-Daily Tadalafil Durability: What Happens After Treatment Ceases? • PDE5is improve erectile function in men with ED during active treatment; however, research on durability of response to PDE5is following discontinuation of therapy is limited3 • One placebo-controlled OAD registration trial1 of tadalafil for men with ED with a 1-year open-label extension2 included a 4-week, treatment-free, follow-up period2,3 • A retrospective analysis based on IIEF EF domain data from this study3 examined durability of response – defined as change in ED severity category – in men with ED treated with longterm tadalafil 5 mg OAD ED=erectile dysfunction; IIEF EF=International Index of Erectile Function Erectile Function Domain; OAD=Once-a-Day or Once-Daily; PDE5i=phosphodiesterase type 5 inhibitor 1. Porst H et al. Eur Urol 2006;50(2):351-359. 2. Porst H et al. J Sex Med 2008;5:2160-2169. 3. Porst H et al. J Sex Med 2010 [In Press].

  42. Tadalafil 5 mg OAD Durability of Response:Change in ED Severity Category by IIEF EF (Retrospective Analysis) Run-In Period Treatment Period1 Open-Label Extension2 Follow-Up3 Placebo Daily Tadalafil OAD 5 and 10 mg Tadalafil OAD 5 mg No Study Drug -4 Weeks 0 Weeks 12 Weeks 1 Year 4 Weeks InformedConsent Randomization Baseline IIEF Baseline SEP IIEF, SEP GAQ, Labs IIEF IIEF Every 4 Weeks Every 3-4 Months IIEF, SEP IIEF The IIEF is a validated, multidimensional, self-administered questionnaire commonly employed to assess therapeutic efficacy of erectile dysfunction therapy. It is a questionnaire of 15 questions arranged into five domains. The erectile function (EF) domain includes questions 1 to 5 and 15. Scores on the IIEF EF domain are interpreted as follows: Severe (1–10); Moderate (11–16); Mild (17–25); Normal (26-30)4 ECG=electrocardiogram; GAQ=Global Assessment Question; IIEF=International Index of Erectile Function; SEP3=Sexual Encounter Profile Question 3: “Did your erection last long enough to have successful intercourse?” 1. Porst H et al. Eur Urol 2006;50(2):351-359. 2. Porst H et al. J Sex Med 2008;5:2160-2169. 3. Porst H et al. J Sex Med 2010 [In Press]. 4. Rosen RC et al. Int J Impot Res 2002;14(4):226-244.

  43. Changes in ED Severity Category from Baseline to End of Treatment-Free Follow-Up Period Pre-DB Baseline (n=158 Post-OL Completers) End of Open-Label End of Follow-Up N=38 Durable Response Improved/Maintained (n=136) N=25 Baseline ED Severity Category Same as Baseline (n=15) N=50 No Durable Response N=23 Worse than Baseline (n=7) DB=Double-Blind; ED=erectile dysfunction; OL=Open-Label Porst H et al. J Sex Med 2010 [In Press].

  44. Durability of Once-Daily Tadalafil 5 mg Off Drug 4 Weeks After Longterm Treatment by Baseline ED Severity Durability of Response to Longterm Tadalafil 5 mg OAD by ED Severity at Baseline Yes re: durability of response 40 No 35 Durability of Response: Maintaining ≥1 ED severity category improvement compared with baseline by end of 4-week, treatment-free period. Only calculated for 151 men who improved one ED severity category (or stayed the same) during 1-year open-label extension with tadalafil 5 mg OAD. 30 25 Durability of Response: % of Patients 20 15 10 5 0 Yes=63, No=73; 63 of 136 n= 23 26 21 23 17 18 2 6 Severe Moderate Mild Normal 46.3% of patients with durable response to tadalafil 5 mg OAD ED Severity at Baseline re: = regarding Porst H et al. J Sex Med 2010 [In Press].

  45. Tadalafil 5 mg OAD Durability of Response: Conclusions • Durability of response (maintaining ≥1 IIEF EF domain severity category compared with baseline, 4 weeks after treatment cessation) with once-daily tadalafil 5 mg by a retrospective analysis1 of a 12-week, double-blind, placebo-controlled trial2 that continued with a 1-year, open-label extension3, and concluded with a 4-week, treatment-free period1,3 demonstrated the following: • Out of 136 patients, 63 (46.3%) experienced a durable response to tadalafil treatment1 ED=erectile dysfunction; IIEF EF=International Index of Erectile Function Erectile Function Domain 1. Porst H et al. J Sex Med 2010 [In Press]. 2. Porst H et al. Eur Urol 2006;50(2):351-359. 3. Porst H et al. J Sex Med 2008;5:2160-2169.

  46. Once-Daily Tadalafil: Tolerability and Safety

  47. Historical Comparison: Adverse Events – Once-Daily (Studies 1 and 2) vs. On-Demand Randomized Trials *All once-daily and on-demand trials were randomized and placebo-controlled AE=Adverse Event; OAD=Once-A-Day; TEAE=Treatment-Emergent Adverse Events 1. Porst H et al. Eur Urol 2006;50:351-9. 2. Rajfer J et al. Int J Impot Res 2007;19:95-103. 3. Donatucci et al. Curr Med Res Opin 2008; 24:3383-92. 4. Carson CC et al. BJU Int2004;93:1276-81.

  48. Historical Comparison: Patient Disposition Once-Daily (Studies 1 and 2) vs. Integrated On-Demand Randomized Trials* *All once-daily and on-demand trials were randomized and placebo-controlled OAD=Once-Daily/Once-a-Day Porst H et al. EurUrol 2006;50:351-9 2. Rajfer J et al. Int J Impot Res 2007;19:95-103. 3. Carson CC et al. BJU Int2004;93:1276-81.

  49. Longterm Safety: Adverse Events in Once-Daily Open-Label Extensions *Observed in ≥5% of the patients during the first year of either open-label extension. ED=Erectile Dysfunction; OAD=Once-A-Day; SAE =Serious Adverse Event; TEAE =Treatment-Emergent Adverse Event Porst H et al. J Sex Med 2008;5:2160-9.

  50. Historical Comparison (Long-Term Safety):Adverse Events at 24 Months * One 24-month extension trial of tadalafil 5 mg OAD ** Pooled 24-month extension data from five 8- or 12-week double-blind, placebo-controlled on-demand tadalafil studies OAD=Once-Daily/Once-A-Day Porst H et al. J Sex Med 2008;5:2160–9. Montorsi F et al. Eur Urol 2004;45:339-45.

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