IC351 (tadalafil, Cialis): update on clinical experience

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1 (2002) 14, Suppl 1, S57 S64 ß 2002 Nature Publishing Group All rights reserved /02 $ IC351 (tadalafil, Cialis): update on clinical experience 1 * 1 Urological practice, Hamburg, Germany IC351 (tadalafil, trade name Cialis) is a new representative compound of the second generation of selective phosphodiesterase 5 (PDE-5) inhibitors. The selectivity ratio vs PDE-5 is more than for PDE-1 through PDE-4 and PDE-7 through PDE-10 and 780 for PDE-6. In the European dailydosing trial, the efficacy rates were up to 93% for successful intercourses with completion in the 50-mg dose in patients with mild to moderate erectile dysfunction (ED). In two different doseranging studies with 2 25 mg taken as needed, efficacy rates of up to 88% improvement in erections and up to 73% successful intercourses with completion were achieved. In a placebocontrolled, fixed-dose (10- and 20-mg) trial in diabetic patients, improved erections of 56% and 64% were reported compared with 25% after placebo. Drug-related adverse effects, with headache in up to 23% of patients (placebo, up to 17%), dyspepsia in up to 11% (placebo, up to 7%), back pain in up to 4.7% (placebo, 0%), and myalgia in up to 4.1% (placebo, up to 2.4%), were mostly mild to moderate. Neither drug-related serious cardiovascular adverse events nor color vision disturbances were encountered. The long half-life ( > 17 h), with a comfortably long window of opportunity, releases couples from the need to plan sexual activities and therefore provides the highest amount of spontaneity for sexual activities. (2002) 14, Suppl 1, S57 S64. DOI: = sj=ijir= Keywords: erectile dysfunction; pharmacotherapy; phosphodiesterase 5 inhibition; IC351; tadalafil; cyclic guanosine monophosphate Introduction Comprehensive basic research has considerably enlarged our knowledge of and insight into the biological and biochemical mechanisms of erectile function and erectile dysfunction (ED), focusing the interest of both physicians and the pharmaceutical industry on new attractive target enzymes and ion channels. In this context, it has been proven that the nitric oxide-guanylylcyclase-cyclic guanosine monophosphate (cgmp)-phosphodiesterase pathway is of utmost interest in the development of new compounds that attack the generation or cleavage of cgmp. These general considerations are supported by the impressive success of sildenafil, the first oral phosphodiesterase 5 (PDE-5) inhibitor in the management of male ED, which was made available in March 1998 and has since been prescribed to more than 15 million patients. The first publications of this new compound provided evidence on the attractiveness of the approach to PDE-5 inhibition, with success rates of up to 84% in terms of improved erections after *Correspondence:, Neuer Jungfernstieg 6a, Hamburg, Germany. Porst20354@aol.com 100 mg of sildenafil compared with only 25% vs placebo and successful intercourse rates of 69% compared with only 22% for those receiving placebo. 1,2 On the other hand, these incredibly high success rates (for an oral compound) were adversely compromised by drug-related adverse effects of headaches in up to 30% of patients, flushing in 20%, dyspepsia in 16%, rhinitis in 11%, and, of special importance, visual disturbances in 9%, all of which were due to the fact that this PDE-5 inhibitor also attacks the PDE-5 in the general vascular system and other PDEs, such as the retinal PDE-6. PDE-5 inhibition has proven the concept of efficacy in the management of male impotence, and the major attention in terms of this approach is now paid to more selective PDE-5 inhibitors to prevent or lower the drug-related adverse effects mentioned herein. IC351 (tadalafil, trade name Cialis) represents a new compound of the PDE-5 inhibitor class, which has proven in in vitro trials to have a clearly higher selectivity to the PDE-5 enzyme than sildenafil, which was the first representative of this new compound class (Table 1). 3 The most important pharmacokinetic data of the three PDE-5 inhibitors, sildenafil, tadalafil, and vardenafil, are summarized in Table 2. 4 This article is, therefore, devoted to the present experiences and knowledge of this new, highly selective PDE-5 inhibitor, including personal

2 S58 Table 1 PDE isoform Table 2 The pharmacokinetics of the three PDE-5 inhibitors sildenafil, tadalafil (IC351), and vardenafil a Parameter Overall selectivity of IC351 Sildenafil, Tadalafil, Vardenafil, 100 mg b 20 mg c 20 mg d t max, h ( ) t 1=2, h C max,ng=ml AUC, ng 6 h=ml a t max, indicates times of occurrence for maximum drug concentration; t 1=2, half-life time of drug; and C max, maximum concentration of drug. b Viagra product monograph. c B Pullman, IC351 (Cialis) Symposium, Indianapolis, Ind, June 7, d Klotz et al. 4 experiences of 178 patients in six different IC351 trials. Clinical human experiences with IC351 (tadalafil, Cialis) Selectivity ratio a 1a > 10,000 1b > 10,000 1c > 10,000 2 > 10,000 3a > 10,000 3b > 10,000 4 > 10, > 10,000 a Selectivity ratio vs PDE-5. diabetes, condition after radical prostatectomy or spinal cord injury, hypogonadism, and alcoholism. Before entering the double-blind protocol, a singleblind placebo run-in phase was conducted to exclude extreme responders, ie, more than 80% rigidity for more than 10 min or inability to achieve at least some kind of erection of more than 20% rigidity for 2 min or more. End points in this trial were change in duration of penile rigidity of more than 55%, change in area under the curve (AUC) of rigidity over time, and change in maximum rigidity. In addition, patients were asked to assess the degree of erection according to an erection score from 1 (none) to 5 (full and rigid erection). Mean age of patients was 47.6 y (range, y), and mean IIEF score was 18.5 (range, 15 24). The final results of this trial, determined as changes from baseline, were as follows (Table 3). For the base of the penis, (1) increase in duration of erection of more than 55% rigidity of minutes for placebo and minutes for 100 mg of IC351 (P < 0.001) (Figure 1); (2) mean change from baseline in AUC of rigidity over time of for placebo and for IC351; and (3) mean increase in maximum rigidity of 2.6% for placebo and 15.2% for IC351 (P < 0.008). Total improved erections over baseline were 86% for IC351 and 41% for placebo. The results for the tip of the penis were similar, with P < for all the aforementioned parameters. The median change in patient assessment of rigidity was 0 for placebo and 2 for IC351. In this RigiScan study, there were no serious adverse events or dropouts. Most common drug-related adverse events were headache and back pain. Electrocardiogram, vital signs, and clinical laboratory values remained unchanged. Phase 2A: RigiScan study In a double-blind, placebo-controlled, single-crossover RigiScan study, efficacy and safety of 100 mg of IC351 were investigated in 44 men after visual sexual stimulation. 5 Inclusion criteria for patient enrolment were an age of y and mild to moderate ED, according to the definition of the International Index of Erectile Function (IIEF), 6 for at least 6 months. Major exclusion criteria were Figure 1 IC351 phase 2A RigiScan study. Data are from Meuleman et al 5 *P < Table 3 IC351 (tadalafil, Cialis) clinical update: phase 2A RigiScan study results a Parameter (base of penis) Placebo IC351 P-value Increase duration of erection > 55% rigidity, min < Mean change from baseline in AUC of rigidity over time curve < Mean increase in maximum rigidity, % < Change in patient assessment of rigidity 0 2 < a Data are from Meuleman et al. 5

3 Phase 2B: European daily-dosing study S59 In a European, multicenter, randomized, doubleblind, parallel study, efficacy and safety of IC351 in doses of 10, 25, 50, or 100 mg given once daily for 3 weeks were assessed vs placebo. 7 Patients with mild to moderate ED for more than 6 months, according to the IIEF, and living in a stable heterosexual relationship could be enrolled. Major exclusion criteria were diabetes, conditions after radical prostatectomy or spinal cord injury, severe cardiovascular events of less than 6 months, hypogonadism, and any nitrate or nitric oxide-donor medication. Patients were requested to take one pill of the allocated study medication every morning and to engage in sexual activities whenever they were in the mood. Efficacy end points were the Global Assessment Question (GAQ), changes from baseline in the Erectile Function Domain of the IIEF, and the Sexual Encounter Profile (SEP), with final results as follows (Table 4): for the GAQ: placebo, 38%; 10 mg of IC351, 90%; 25 mg of IC351, 85%; 50 mg of IC351, 86%; and 100 mg of IC351, 81% (P < , Figure 2); for SEP questions 3 and 4 (successful vaginal penetration and completion of sexual intercourse with ejaculation (Figure 5): placebo, 40%; 10 mg of IC351, 82%; 25 mg of IC351, 80%; 50 mg of IC351, 93%; and 100 mg of IC351, 86% (P < , Figure 3); mean score for IIEF question 3 (penetration ability): placebo, 3.3; 10 mg of IC351, 4.4; 25 mg of IC351, 4.3; 50 mg of IC351, 4.7; and 100 mg of IC351, 4.6 (P < ); the mean changes for question 3 ranged from 1.33 to 1.66 for IC351 vs 0.25 for placebo (P < ); mean score for IIEF question 4 (maintenance ability): placebo, 2.9; 10 mg of IC351, 4.2; 25 mg of IC351, 4.2; 50 mg of IC351, 4.5; and 100 mg of IC351, 4.4 (P < ); the mean changes for question 4 ranged from 1.79 to 2.10 for IC351 vs 0.51 for placebo (P < ); and mean IIEF Erectile Function Domain score (questions 1 5 and 15): placebo, 19; 10 mg of IC351, 26; 25 mg of IC351, 25; 50 mg of IC351, 27; and 100 mg of IC351, 26 (P < ). All IC351 doses significantly increased all domain scores of the IIEF (P ¼ 0.002) for every domain vs placebo. The most common drugrelated adverse events in this daily-dosing study Figure 2 Results of the European IC351 phase 2B dailiy-dosing study GAQ. Data are from Porst et al. 7 *P < vs placebo. { Has the treatment you have been taking during the past study interval improved your erections? Figure 3 Results of the European IC351 phase 2B daily-dosing study successful intercourses with completion. Data are from Porst et al. 7 *P < vs placebo for mean baseline score. { Positive responses to both SEP question 3 (were you able to insert your penis into the vagina of your partner?) and SEP question 4 (did your erection last long enough for you to complete intercourse with ejaculation?). were headache, back pain, myalgia, and dyspepsia, with a considerable decrease in frequency with continued treatment (Figure 4). Phase 2B: US and Canadian dose-ranging studies After the successful outcome of both the cited phase 2 RigiScan and daily-dosing IC351 studies, two large dose-ranging studies in the United States and Canada were launched and the results published. 8,9 Table 4 Results of the IC351 European Multicenter Daily-Dosing Study a IC351 dose Efficacy end point Placebo 10 mg 25 mg 50 mg 100 mg P-value GAQ (improved erections), % < SEP questions 3 and 4 (intercourses with completion), % < Final scores IIEF question < IIEF question < IIEF erectile function domain < a Data are from Porst et al. 7

4 S60 Figure 4 Results of the European IC351 phase 2B daily-dosing study decrease of adverse events with time. Data are from Porst et al. 7 Figure 5 Results of the US IC351 (taken as needed) phase 2B dose-ranging study successful intercourse with completion (SEP questions 3 and 4). Data are from Padma-Nathan et al. 8 For mean baseline scores, *P ¼ 0.01 vs placebo, **P ¼ vs placebo and ***P ¼ vs placebo. { Positive responses to both SEP question 3 (were you able to insert your penis into the vagina of your partner?) and SEP question 4 (did your erection last long enough for you to complete intercourse with ejaculation?). Table 5 Results of the US IC351 (taken as needed) Phase 2B Dose-Ranging Study a IC351 dose Efficacy end point Placebo 2 mg 5 mg 10 mg 25 mg P-value GAQ (improved erections), % < SEP questions 3 and 4 (intercourses with completion), % < Final scores IIEF question < IIEF question < IIEF erectile function domain < a Data are from Padma-Nathan et al. 8 Table 6 Adverse events of the US IC351 Phase 2B Dose-Ranging Study reported in 3% of all patients a IC351 dose Adverse event Placebo (n ¼ 35) 2 mg (n ¼ 35) 5 mg (n ¼ 37) 10 mg (n ¼ 36) 25 mg (n ¼ 36) Headache 5.7 (2) 5.7 (2) 2.7 (1) 16.7 (6) 13.9 (5) Dyspepsia (3) 2.8 (1) 8.3 (3) Back pain (1) (3) 2.8 (1) a Data are from Padma-Nathan et al. 8 Data are percentage (n) of patients.

5 Table 7 Results of the Canadian IC351 Phase 2B Dose-Ranging Study a S61 IC351 dose Efficacy end point Placebo (n ¼ 41) 2mg (n ¼ 42) 5mg (n ¼ 44) 10 mg (n ¼ 42) 25 mg (n ¼ 43) P-value GAQ (improved erections), % < (5 25 mg) SEP questions 3 and 4 (intercourses with completion) < (5 25 mg) Final scores IIEF question < (5 25 mg) IIEF question < (10=25 mg) IIEF erectile function domain < (5 25 mg) a Data are from Brock et al. 9 In a US, multicenter, double-blind, placebo-controlled phase 2B study, 179 men (mean age, 56 y) with mild to moderate ED were randomized to take placebo or IC351 in doses of 2, 5, 10, or 25 mg as needed during a 3-week period. 8 Similar to the preceding IC351 trials, patients with radical prostatectomy and diabetes mellitus were excluded. Efficacy end points were changes from baseline for questions 3 and 4 and for the Erectile Function Domain score of the IIEF and the results of the GAQ and the SEP. The outcomes of this study in terms of the aforementioned end points are summarized in Table 5 and show statistically significant efficacy results for all doses of IC351 compared with placebo, with the only exception being the lowest dose of 2 mg of IC351 in question 4 of the IIEF. Regarding the safety profile of IC351 in this takenas-needed trial, no drug-related serious adverse events were reported and no relevant changes in electrocardiogram or laboratory values were observed. Study medication-related adverse effects of more than 3% were headache in up to 16.7% of patients for active drug vs 5.7% for placebo, dyspepsia in up to 8.3% for active drug vs 0% for placebo, and back pain in up to 8.3% for active drug vs 0% for placebo (Table 6). Overall drug-related adverse events reported on at least one occasion were observed in 25.7% after IC351 treatment compared with 8.6% after placebo. In two patients in the 10-mg dose arm, drug-related adverse effects resulted in early discontinuation due to headache or back pain. A multicenter, randomized, double-blind parallel phase 2B study was also conducted in Canada. In this trial, 212 men with mild to severe ED of all etiological categories, including diabetes mellitus and radical prostatectomy, were involved and treated for 8 weeks with placebo or IC351, 2, 5, 10, and 25 mg, taken as needed. 9 A summary of the results is outlined in Table 7 and Figures 6 and 7. For all end points, such as GAQ, SEP, questions 3 and 4 of the IIEF, and Erectile Function Domain of the IIEF, the doses of 5, 10, and 25 mg of IC351 showed a statistically significant superiority to placebo. This was not true for all end points for the 2-mg IC351 dose. Orgasmic function, intercourse satisfaction, and overall satisfaction of the IIEF were also statistically significantly changed after IC351. The adverse event percentages in this trial were similar to those in the US trial and are summarized in Table 8. Phase 3A Spanish study taken as needed in diabetic patients In a 12-week, randomized, double-blind, parallel study 216 patients (mean age, 56 y; range, y) Figure 6 Canadian IC351 (taken as needed) phase 2B dose-ranging study. Data are from Brock et al. 9 *P ¼ vs placebo; **P < vs placebo. ***P < vs placebo; { Has the treatment you have been taking improved your erections?

6 S62 Figure 7 Canadian IC351 (taken as needed) phase 2B dose-ranging study. Data are from Brock et al. 9 *P ¼ vs placebo; **P < vs placebo. { Positive responses to SEP question 3 (did your erection last long enough for you to complete intercourse with ejaculation?). Table 8 Drug-related adverse events in the Canadian IC351 Phase 2B Study a Adverse event Placebo, % (n ¼ 41) All IC351, % (n ¼ 171) Headache Dyspepsia Back pain Myalgia a Data are from Brock et al. 9 Data are adverse events reported in more than 3% of patients. with diabetes and ED of more than 3 months were treated with 10 or 20 mg of IC351 vs placebo. 10 Approximately 9% experienced type 1 and 91% type 2 diabetes. Baseline IIEF Erectile Function Domain score was The results of this study were as follows: GAQ (improved erections Figure 8): placebo, 25%; 10 mg of IC351, 56%; and 20 mg of IC351, 64%; Erectile Function Domain score (mean change): placebo, 0.1; 10 mg of IC351, 6.4; and 20 mg of IC351, 7.3; and SEP question 3 (percentage of patients with > 25% increase in yes response): placebo, 16%; 10 mg of IC351, 44%; and 20 mg of Figure 8 Results of the Spanish phase 3A IC351 (taken as needed) study in diabetes. Data are from Saenz de Tejada et al. 10 *P < 0.01 vs placebo. { Has the treatment you have been taking improved your erections? IC351, 51%. All the cited efficacy end points resulted in statistical significance for the 2 IC351 doses vs placebo. Adverse events of more than 3% are summarized in Table 9 and did not exceed the 11% boundary. Conclusions The various trials presented in this overview on IC351 (tadalafil, trade name Cialis) bear witness that this new compound in the class of so-called PDE-5 inhibitors is very effective in the broad-spectrum population of patients with ED. Major differences compared with sildenafil (Viagra), currently the only officially approved PDE-5 inhibitor for treatment of male impotence, are the higher selectivity to PDE-5, especially in terms of PDE-6, resulting so far in avoidance of visual disturbances and the considerably longer half-life time, leading to a distinctly longer window of opportunity than sildenafil has. Moreover, all the trials with IC351 taken as needed showed a favorable adverse effect profile, with headaches, flushing, and dyspepsia exhibiting approximately half of the frequency than was reported in the first large sildenafil trial, in which a patient population similar to that in the presented IC351 trials was investigated. 2 In the on-demand dose-ranging studies, this new selective PDE-5 inhibitor yielded success rates of up to 88% in terms of improved erections and up to 73% in terms of successful intercourse rates with completion. 8,9 Even in diabetic patients with a high likelihood of an organic origin of ED, the 20-mg dose of the new market formulation of IC351 (Cialis) yielded success rates of 64% relating to improved erections. 10 The results of the first daily-dosing trial with IC351 deserve special consideration, since successful intercourse rates with completion (SEP questions 3 and 4) of up to 93% were reported in doses of 50 mg of the previous formulation. These

7 Table 9 Drug-related adverse events in the Spanish Phase 3A IC351 (taken as needed) study in diabetic patients a Adverse event Placebo, % Tadalafil, 10 mg, % Tadalafil, 20 mg, % Dyspepsia Headache Myalgia Flushing Back pain a Data are from Saenz de Tejada et al. 10 Data are adverse events reported in more than 3% of patients. impressively high efficacy rates in ED populations with mild and moderate cases resemble the convincing efficacy rates of the varied trials in selfinjection therapy with alprostadil in the past. 11,12 These data once more emphasize the outstanding importance of the cgmp molecule in inducing a rigid erection and the attractiveness of the PDE-5 inhibition approach in the management of male impotence. These data may open up new perspectives in the pharmacological approach of male impotence, which may be principally possible with compounds with reasonably long half-life times. The considerably longer half-life time of IC351 compared with the other two PDE-5 inhibitors, sildenafil and vardenafil, frees the couples from the need to plan sexual activities, providing a maximal degree of spontaneity, which is highly desirable and should therefore not be underestimated. After successful completion of the phase 2 program, IC351 is currently in the advanced phase 3 clinical studies, and market approval of this promising drug may be expected in the second half of References 1 Boolell MA et al. Sildenafil: an orally active type 5 cyclic GMP specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996; 8: Goldstein I et al. Oral sildenafil in the treatment of erectile dysfunction. New Engl J Med 1998; 338: Angulo I et al. IC351 enhances NO-mediated relaxation of human arterial and trabecular penile smooth muscle. Eur Urol 2001; 39(Suppl 5): 106, abstract Klotz T et al. Vardenafil increases penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study. World J Urol 2001; 19: Meuleman E et al. Effect of IC351 on erectile response to visual sexual stimulation. J Urol 1999; 161(Suppl): 212, abstract Rosen RC et al. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: Porst H et al. Daily IC351 treatment of ED. Int J Impot Res 2000; 12(Suppl 3): S76, abstract B13. 8 Padma-Nathan H et al. For the IC351 on demand dosing study group: on demand IC351 (Cialis TM ) enhances erectile function in patients with erectile dysfunction. Int J Impot Res 2001; 13: Brock G et al. Efficacy and safety of IC351 treatment for ED. Eur Urol 2001; 39(Suppl 5): 106, abstract Saenz de Tejada I et al. The effect of on-demand IC351 treatment of erectile dysfunction in men with diabetes. Eur Urol 2001; 39(Suppl 5): 16, abstract Linet OJ, Ogrinc FG, and Alprostadil Study Group. Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. New Engl J Med 1996; 334: Porst H et al. Intracavernous alprostadil Alfadex-an effective and well tolerated treatment for erectile dysfunction: results of a long-term European Study. Int J Impot Res 1998; 10: S63 Appendix Open discussion following Dr Porst s presentation Dr Montorsi: You have experience with both the old and new formulations of IC351. With the old formulation, it looks like the 10-mg dose is able to give you results that are very similar to the 25-mg dose. My question is, which new formulation dose is similar to the effect of the old 10-mg dose? Dr Porst: From my personal experience, you can translate the results from the 25-mg dose to the 20- mg dose of the new formulation. It s more or less comparable from the point of efficacy. The difference in the efficacy is only from daily dosing to taking as needed. Dr Hatzichristou: Do you mean that the 20-mg dose of the new formulation can be translated into the 25-mg dose of the old one? Dr Porst: We don t know exactly if there is a big difference in a broad spectrum of ED patients except the diabetics. There was a difference between the 10- and the 20-mg dose in the diabetics. When you are excluding the diabetics and focusing on all the other ED etiologies, my personal feeling is that there is not a big difference, but we have no exact data about this. Dr Althof: Was there an escalating pattern in dose effect that you saw? Dr Porst: I do not have these data, but from my personal experience with the patients, within 1 week you can differentiate between the responders and the nonresponders with this drug. Dr Meuleman: At the American Urological Association meeting, there was some concern about IC351 selectivity for PDE-11. Dr Porst: In that paper, they were addressing PDE-11 in the testicle in an in vitro study. We have no clinical signs in humans that there is any impact on spermatogenesis with this drug. Dr Nehra: A recent publication by Tom Lue suggests that prolonged half-life may result in up-regulation of PDE-5. If patients are going to be on this

8 S64 medication with that kind of a half-life, is that something that we should be aware of on a chronic basis? Dr Andersson: They have the basis for suggesting that there is an up-regulation, but I don t think that that up-regulation will be of clinical importance. There will still be sufficient inhibition of the enzyme to make clinical impact. Dr Porst: So when you translate this up-regulation, it would mean that we see patients after 6 months or 12 months in whom the drug is not working? Dr Nehra: Or who may need a higher dose. Dr Porst: But that s not the case, from my personal experience. I have had patients up to 18 months now in whom the response to this drug was very stable. So I don t think that there s an impact on the clinical efficacy in the long term. Dr Giuliano: I have the same experience. With a long period of treatment, we do not need to increase the dose.