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BRIEF REPORT/PHARMACODYNAMICS |
From Merck & Co Inc, Whitehouse Station, New Jersey (Dr Krishna, Dr Wong, Ms Stevens, Dr De Lepeleire, Dr Van Dyck, Mr Gendrano III, Dr Wagner, Dr Herman); New England Research Institutes Inc, Watertown, Massachusetts (Dr Rosen); SGS Life Science Services, Antwerp, Belgium (Dr Peeters); GlaxoSmithKline Biologicals, Rixensart, Belgium (Dr Peeters); and the Department of Clinical Pharmacology, Merck Research Laboratories, Rahway, New Jersey (Dr Krishna).
Address for reprints: Rajesh Krishna, PhD, FCP, Department of Clinical Pharmacology, Merck Research Laboratories, Mailstop RY34-A500, 126 East Lincoln Avenue, Rahway, NJ 07065-0900; e-mail: rajesh_krishna{at}merck.com.
Key Words: Melanocortin • erectile dysfunction
Erectile dysfunction (ED) is a prevalent but likely significantly underreported health problem that impacts overall mental health.1 The pathophysiology is likely multifactorial but involves decreased blood flow to the corpus cavernosum, possibly related to decreased nitric oxide–mediated smooth muscle relaxation, in response to sexual stimuli. Phosphodiesterase (PDE5) Type 5 inhibitors sildenafil, tadalafil, and vardenadil are approved drugs of the same class for the treatment of ED.2 Because many patients with ED do not respond to these drugs or are either not satisfied with results (estimates of 46% to 70%), or cannot take PDE 5 inhibitors because of cardiovascular risk factors, several investigative drugs with a distinct mechanism of action are in development.3,4
One potential new mechanism for ED is the melanocortin 4 receptor (MC4R) mediated agonism.5-10 The nonselective melanocortin receptor peptide agonist (recognizing all of the melanocortin receptor subtypes, including MC4R), melanotan II (MT-II), and its derivative, PT-141, has been shown in clinical studies to induce transient, nonpainful erections in men with ED.11-16 However, considerable uncertainty remains on the plausibility of this mechanism with selective agonists of the MC4R.
MK-0493 is a novel selective MC4R agonist that, in healthy human subjects and patients with obesity, was generally well tolerated, with nausea and vomiting being the predominant dose-limiting findings. An increase in spontaneous erections has not been observed with MK-0493 in healthy male subjects to date. MK-0493 did not alter food intake in healthy subjects.17 The proerectile effects of MK-0493 studied in anesthetized mice indicated that while it failed to directly influence intracavernosal pressure (ICP), the compound dose-dependently increased electrically evoked increases in ICP.18,19 MK-0493 was ineffective at 0.3 mg/kg intravenous (iv), whereas significant increases (P < .05, paired t test) in ICP normalized to mean arterial pressure (MAP) were evident at 1 mg/kg iv (16%), 3 mg/kg iv (23%), and 10 mg/kg iv (29%) 15 minutes postdose. We, therefore, endeavor to assess the erectogenic potential of a novel selective MC4R agonist in a clinical experimental model using the PDE5 inhibitor sildenafil, an erectile facilitator, as a positive control in patients with ED.
Experimental medicine aims to design short-term but more innovative clinical investigations to guide the preliminary assessment of new molecular entities.20,21 Initial studies with sildenafil showed enhanced penile rigidity, as assessed by the RigiScan methodology (Dacomed Corporation, Minneapolis, Minn), in the presence of audiovisual sexual stimuli (VSS), and this phenomenon has been replicated with other PDE5 inhibitors.22-25 The increase in base rigidity has been correlated with clinically meaningful increases in sexual functioning in patients with ED.26-30
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METHODS |
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 TOP METHODS RESULTS AND DISCUSSIONREFERENCES |
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This was a randomized, double-blinded, placebo-controlled, 4-period crossover study during which 20 patients with ED received each of 4 treatments (placebo; 200 mg single oral dose of MK-0493; 500 mg single oral dose of MK-0493; and 50 mg single oral dose of sildenafil), according to a randomized allocation schedule. Study periods were separated by at least a 7-day washout interval. At approximately 3 hours postdose (relative to the time of MK-0493 or matching placebo administration), patients were exposed to VSS (ie, sexually explicit video material) for 
60 minutes. Patients underwent RigiScan monitoring beginning 30 minutes predose through 2 hours following the VSS session (approximately 5 hours postdose). Patients were allowed to preview brief clips of the video selection (prior to each period) and were allowed to select the video for each VSS session (the same video was to be selected only twice during the study). Safety and tolerability assessments were conducted at pre- and postdose time points.
Assuming a within-subject standard deviation of 1.405 on the log scale (log minutes) for the total duration of base penile rigidity >60%, there was 80% power (
= 0.05; 2-tailed; n = 20) to detect a ratio shift of 3.561.30 Thus if the placebo mean total duration of penile base rigidity >60% was 2.8 minutes, there was 80% power to detect an increase of 9.97 minutes (9.97/2.8 = 3.561) or between-treatment difference of approximately 7.17 minutes. Similarly, there was approximately 92% power to detect a ratio shift of 4.57 ( = 0.05; 2-tailed; n = 20) in the mean total duration of penile base rigidity >60%.
Base and tip rigidity data were analyzed using an analysis of variance (ANOVA) model appropriate for a 4-period, crossover design with terms: subject, period, and treatment. Since the data were not normally distributed, the RigiScan data were Tukey rank-normalized for the ANOVA to assess the between-treatment comparison.
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RESULTS AND DISCUSSION |
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TOPMETHODSRESULTS AND DISCUSSIONREFERENCES |
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Published literature, albeit with nonselective melanocortin agonists, have suggested a role for MC4R in the neural regulation of erectile activity.8-16 In the present study, at the 2 doses tested, there was no evidence that selective MC4R agonist MK-0493 produced any clinically meaningful increases in erectogenic activity, as compared to placebo. The highest dose of MK-0493 evaluated in the study represented the maximum tolerated single dose (doses higher than 500 mg were found to be associated with higher incidence of nausea and vomiting in a rising single-dose study in healthy subjects). At both doses, plasma MK-0493 concentrations exceeded the pharmacokinetic exposures attained in the mouse ICP study. However, sildenafil administration was associated with increases in erectogenic activity that were significantly different from placebo, qualifying the clinical experimental model presented here.
Assessment of male sexual function presents a complex challenge in human experimentation given interplay between physiological and subjective processes. Several physiological or laboratory-based methods have been used, which include the RigiScan device (Dacomed Corporation), volumetric and circumferential plethysmography, penile Doppler ultrasound (PDU) and the erectiometer.27,28 Self-report methods are also available.26 RigiScan studies, however, are routinely used as proof-of-concept measure in phase II studies. Such an investigation, employing a very small patient sample size, could be initiated soon after a single, rising-dose escalation, first-in-man study is completed, wherein the maximum tolerated dose is established. This allows decisions on the further progression of a drug candidate in the development cycle to be made in as early as the second clinical trial as compared to those that are completed in the phase II development space, wherein significant resources are expended.
Our results indicate that MK-0493 does not exhibit the desired level of erectogenic effects to warrant development resources to be expended further. Our study, however, also raises some important questions on the melanocortin hypothesis for ED.
The test of melanocortin hypothesis in ED has been probed previously by nonselective melanocortin agonists melanotan-II (MT-II) and PT-141.11-15 Whereas MT-II is a potent peptide agonist of all of the melanocortin receptor subtypes, PT-141 is an active metabolite of MT-II that is being developed as an intranasally administered treatment for ED. In limited investigations in males with ED with no underlying organic cause with either candidate, there were observations of increased erectile activity detected by RigiScan monitoring.12,13 Although observed effects were noted to be statistically significant, the effects appeared relatively lower in magnitude than those shown by approved PDE5 inhibitors. Such effect raises the level of uncertainty on drug development efforts, deferring decisions on the candidate's likelihood of success to late-stage clinical development such as phase III.
In the context of the role of MC4R in sexual function, our results further add to the uncertainty why a selective MC4R agonist appears to have no effect compared to reported effects seen with nonspecific MT-II and PT-141.8 Although preclinical data suggested proerectile effects in mice, this finding did not translate into meaningful effect in humans. Since plasma MK-0493 exposures that were associated with these effects in mice were exceeded at the doses of MK-0493 tested in this study, we believe our study adequately tested the concept in ED.
Single doses of 200 mg and 500 mg MK-0493 and sildenafil were generally well tolerated in this study. There was one serious AE of intentional drug overdose (with painkillers, not MK-0493) at 5 days postdose. There were no clinically significant abnormalities observed in routine blood and urine chemistry panels, complete blood count (CBC), EKG, vital signs, and physical examinations. All adverse events were generally mild in intensity and resolved without treatment. There were no discontinuations.
In summary, the selective MC4R agonist MK-0493 did not provide clinically meaningful effects in this study, questioning the validity of the melanocortin pathway for ED. Based on these results, we believe that selective MC4R agonists will not be effective in ED. Our study also rationalizes that a well-controlled small patient phase I study performed early in clinical development could be used as a decision-making tool to assist in the prioritization of development candidates.
Financial disclosure: This study was funded by Merck & Co Inc. Dr Krishna, Dr Wong, Ms Stevens, Dr De Lepeleire, Dr Van Dyck, Mr Gendrano III, Dr Wagner, and Dr Herman are employees of Merck.
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REFERENCES |
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TOPMETHODSRESULTS AND DISCUSSIONREFERENCES |
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