Salvage of Sildenafil Failures with Bremelanotide: a Randomized
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Salvage of Sildenafil Failures With Bremelanotide: A Randomized, Double-Blind, Placebo Controlled Study Mohammad Reza Safarinejad* and Seyyed Yousof Hosseini From the Urology and Nephrology Research Center, Shaheed Modarress Hospital, Shaheed Beheshti University of Medical Sciences, Tehran, Iran Purpose: We evaluated the safety and efficacy of intranasal bremelanotide in men with erectile dysfunction who did not respond to sildenafil. Materials and Methods:A total of 342 married men (28 to 59 years old) with erectile dysfunction who did not respond to sildenafil were randomly assigned to receive 10 mg bremelanotide as an intranasal spray (group 1, 172) 45 minutes to 2 hours prior to sexual stimulation, or a similar regimen of placebo (group 2, 170). Patients were asked to use at least 16 doses/attempts at home. They underwent preliminary assessment, including medical and sexual history, and self-administered International Index of Erectile Function. The efficacytreatments o f 2 was assessed every 4 attempts during treatment and at the end of study, using responses to International Index of Erectile Function, and evaluation of mean intercourse satisfaction domain, mean weekly coitus episodes and adverse drug effects. Results: Positive clinical results were seen in 51 (33.5%) patients in the bremelanotide group compared with 13 (8.5%) patients in the placebo groupϭ 0.03). (p Patients in the bremelanotide group reported significantly greater intercourse satisfaction than those in placebo groupϭ 0.03). (p More drug related adverse effects occurred in the bremelanotide group (p ϭ 0.01). Conclusions: Bremelanotide can be an alternative treatment for erectile dysfunction with a potentially broad patient base. Further studies with different dosages and treatment regimens are necessary to draw final conclusions on the efficacy of this drug in erectile dysfunction. Key Words: receptors, melanocortin; erectile dysfunction; drug therapy; sildenafil; PT-141 rectile dysfunction has been estimated to affect,Most to of the research efforts toward the treatment of ED some degree, 52% of men 40 to 701 Theyears haveold. targeted the peripheralmechanisms of penile erec- E launch of orally administered phosphodiesterase tion.type The administration of apomorphine for the treat- 5 inhibitors has had a revolutionary effect on the menttreatment of ED has demonstrated the possibility of enhancing of ED. Sildenafil citrate, a PDE-5 inhibitor, selectivelypenile in-erection by acting elsewhere than on corpus caver- hibits cyclic guanosine monophosphate specific PDE typenosum 5, smooth muscle cells.7 Melanocyte stimulating hor- leading to increased cyclic guanosine monophosphate monelevels and related melanocortins regulate a diversity of 2 which result in muscle relaxation and penile tumescence.functions as mediated through a multitude of MC recep- Results of extensive multicenter international clinical tors.trials Most interesting was the relatively recent discovery have demonstrated superior efficacy of sildenafil to thatplacebo a MC regulates sexual function in8 PT-141humans. 3 with an overall dose dependent response rateIt ofhas 78%(bremelanotide),. a cyclic, heptapeptidemelanocortin ana- been determined that, up to 50% of subjects who log,receive is anthe active metabolite of Melanotan-II.9 It is erectogenic 4 sildenafil do not respond adequately to Marketingtherapy. in men by an action believed to occur C3-Randat central M data worldwide showed that dropout rates for sildenafil are10 5 MC4-R. Diamond et al reported that the erectile re- as high as 50% of patients Amongtreated. other factors, sponse induced by co-administration of PT-141 and silde- side effects such as severe headache, flushing, and visual nafil is significantly greater than the response elicited by disturbances contribute to the reasons for discontinuation. administration of sildenafil alone.11 In another study PT- In addition, in a study by El-Galley et al, there was a 141 was evaluated following intranasal administration12 . possible tachyphylaxis effect with sildenafil.6 Of the patients Erectile response induced by PT-141 was statistically sig- who were followed for 2 years 20% had to increase the nificant, compared to placebo. This new chemical entity sildenafil dose to have the same effect and 17% discontinued has been evaluated in phase II clinical trials studying the use due to loss of efficacy. efficacy and safety profile of varying doses of in men experiencing ED. Doses ranging from 0.3 to 10 mg were administered to healthy male subjects without visual sex- Submitted for publication July 1, 2007. ual stimulation, resulting in a statistically significant * Correspondence: P.O. Box 19395-1849, Tehran, Iran (telephone: 13 0098 21 22454499; FAX: 0098 21 22456845; e-mail: safarinejad@erectile response at doses greater than 1 mg. In addi- urologist.md). tion, administration of either 4 or 6 mg subcutaneous See Editorial on page 819. bremelanotide, in association with visual sexual stimula- 0022-5347/08/1793-1066/0 1066 Vol. 179, 1066-1071, March 2008 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.10.063 BREMELANOTIDE FOR TREATMENT OF SILDENAFIL FAILURE 1067 tion, to patients with moderate or severe ED who report Inclusion/Exclusion Criteria an inadequate response to sildenafil, resulted in a signifi- None of the patients had received other treatment for male cant erectile response compared to the placebo response.13 ED for at least 4 weeks before the start of the study. Patients Therefore PT-141 is a promising candidate for further were eligible for inclusion in the study if they were aged 18 evaluation as a treatment for male ED. In March 2006 the years or older, were nonresponders to sildenafil mono- United States Adopted Names (USAN) Council and the therapy and had medically documented ED of at least 6 WHO have approved the generic name bremelanotide for months duration. The patients had to be in a stable relation- PT-141. To our knowledge this is the first large scale, ship with his wife for at least the previous 6 months. at-home evaluation of bremelanotide. Exclusion criteria were penile anatomical defects; a pri- mary diagnosis of another sexual disorder; use of psy- chotropic and antidepressant medication, and serious rela- MATERIALS AND METHODS tionship problems; poorly controlled diabetes mellitus; un- Study Design controlled congestive or ischemic heart disease, or renal or From March 2004 to December 2006 a total of 446 married liver impairment; history of alcohol or drug abuse; spinal men (28 to 59 years old) with ED and their wives were cord injury; history of prostate cancer; neurological disor- enrolled in this study (without sponsorship). They were re- ders that cause ED; and those unlikely to be available for ferred to 1 urologist (MRS) from primary care physicians or followup. addressed themselves disappointed by the results of silde- nafil. The diagnosis of ED was established according to the National Institutes of Health statement on ED.14 All sub- Medical Treatment jects gave their written informed consent in accordance with Eligible patients were randomly assigned to double-blind, the Declaration of Helsinki. The Human Ethics Committee fixed dose treatment with either bremelanotide or placebo. approved the study protocol. All patients were given a silde- Assignment to treatment group was performed using an nafil instruction/safety sheet prior to including the study. interactive voice response system, which followed a random- The instruction sheet emphasized the timing of sildenafil ization table generated by the method of random permuted administration (45 minutes to 2 hours prior to sexual stim- blocks. Group 1 (172) was given 10 mg bremelanotide as an ulation) as well as the absolute need for sexual stimulation, intranasal spray 45 minutes to 2 hours prior to sexual stim- such as visual stimulation, foreplay and hugging. In addi- ulation. Group 2 (170) received a similar regimen of placebo. tion, the instruction sheet stressed that sildenafil should be Patients were asked to use at least 16 doses/ used 2 to 3 hours after a low fat meal. Finally, the sheet also attempts at home, but not to exceed more than 1 attempt per emphasized that outcomes tend to get better after 6 to 8 day. All of the men were asked not to consume alcoholic attempts and success is often dose dependent. The starting drinks within 6 hours of sexual activity. dose in all patients was 50 mg. They were instructed to rapidly increase the dose from the 50 mg to 100 mg after 1 attempt if the initial treatment was not satisfactory and Outcome Measures there were no adverse reactions, but not to exceed more than All patients were seen with their wives and interviewed 1 tablet per day. Patients were asked to use at least 12 about sexual activity and erectile function. The effect of tablets/attempts at home. Outcome measures were assessed treatment was assessed every 4 attempts during treatment, using a global assessment questionnaire (“Did this treat- evaluating changes in IIEF and responses to the questions ment improve your erections?”). The effect of treatment was from the IIEF question 3, “When you attempted sexual in- assessed every 2 weeks during a 16-week treatment period. tercourse, how often were you able to penetrate your part- Of the 446 patients reeducated 58 (13%) responded to silde- ner?” and question 4, “During sexual intercourse, how often nafil and were therefore excluded from the study. A total of were you able to maintain your erection to completion of 388 men who were nonresponders to sildenafil entered the intercourse?” Responses to the 2 questions were rated on a study (mean age 42.5 years, range 28 to 59) with a mean scale ranging from 1 to 5, with 5 response options 1—almost duration of penile ED of 2.4 years (range 1.5 to 6). The study never/never, 2—a few times (much less than half the time), was not advertised, and no remuneration was offered.