Apomorphine: an Update of Clinical Trial Results

Apomorphine: an update of clinical trial results

JPW Heaton1*

1Queen's University, Kingston General Hospital, Kingston, Ontario, Canada

Apomorphine SL (TAP Holdings, Deer®eld, IL) is a centrally acting treatment for erectile dysfunction (ED) that has been undergoing phase III trials. Over 3000 men have received apomorphine SL and over 75,000 doses have been taken. In the ®rst three phase III parallel arm cross-over double-blind studies 854 patients were given a total of 8263 tablets of apomorphine SL in 2 and 4 mg doses. The patients were between 18 and 70 y old and outcome measures included per attempt rates of intercourse and erections ®rm enough for intercourse as well as psychometric instruments and partner responses. The majority (74.1%) had moderate and severe grades of ED on admission to the studies, 31% had hypertension, 16% had documented coronary artery disease, 16% had dyslipidemia and 16% had diabetes. Erections occurred rapidly (10 ± 25 min) and in 54.4% of attempts at 4 mg (vs 33.8% placebo). A majority of the attempts at intercourse (50.6%) were successful at 4 mg in patients when recorded on a per-attempt basis. The most common but infrequent and mild side effect of nausea decreases with use. The phase III trials of apomorphine SL show that there is a clinically important restoration of erectile function from this new formulation of apomorphine. It has a rapid and safe effect through action in the central nervous system. Apomorphine SL brings a new choice to the management of ED that will further bene®t the millions of couples affected. International Journal of Impotence Research (2000) 12, Suppl 4, S67±S73.

Keywords: apomorphine; erection; central nervous system; dopaminergic

Introduction medical intervention. Gone are test injections, ultrasounds for everyone, and the immediate threat of surgery. Still, after evaluation, education, risk Apomorphine has been in phase III clinical testing reduction, lifestyle modi®cation and medication as a sublingual (SL) preparation (TAP Holdings Inc., assessment, it is important that a choice of therapies Deer®eld, IL) for about 4 y. This period of time has is available for the patient and the couple. been a momentous one for patients with erectile The development of new agents for ED has dysfunction (ED). Long time sufferers ®rst saw their accelerated over the last decade. There is still a ad hoc intracavernous injection preparations sup- focus on the rigid penis as a reasonable and planted by fully authorized, carefully prepared kits achievable pharmacological goal, but there is also 1 of prostaglandin E1 (PGE1). At that time, despite awareness that, while erections enable intercourse, the efforts of the National Institutes of Health, only they do not treat the whole relationship. Better the patients and a few experts knew about ED and erections help just one aspect of sexual contact and the disorder was not yet widely understood by the a medical intervention for ED must provide bene®t medical community.2 In 1996, ViagraTM was a in an acceptable way. developing reality, but it was MUSE that made the The clinical development program for apomor- next appearance.3 The approval of ViagraTM in 1998 phine SL was initiated when physiological outcome raised public awareness about the condition and, criteria were giving way to increasingly sophisti- following this milestone, many patients received cated patient diaries and psychometric instruments. their ®rst effective oral therapy for ED.4 There were then, and are now, no fully accepted Patients arriving at the critical point of needing universal metrics to de®ne the diagnosis of ED, to help with the erectile component of their relation- identify patients for inclusion into ED trials or to ships are now experiencing a wholly new type of assess the results of treatment. This paper will not restate the results for apomorphine SL, trial by trial, through all measures of outcome. It will, however, *Correspondence: JPW Heaton, Queen's University, Kingston detail a selection of issues that are particularly General Hospital, 76 Stuart Street, Kingston, Ontario, Canada relevant to the experience of all patients undergoing K7L 2VL. therapy for ED. Apomorphine: update of clinical trials JPW Heaton S68 Methods relaxed and free from distractions and interruptions. When you and your wife=partner are ready you should place the tablet under your tongue until More than 3000 men have received apomorphine SL dissolved ... Proceed with sexual intercourse when and over 75,000 doses have been taken. In the ®rst you feel ready. When you have ®nished having three phase III parallel arm cross-over double blind intercourse or at least 2 hours have passed ...You studies, 854 patients were given a total of 8263 should complete the patient diary.' The diary entries tablets of apomorphine SL in 2 and 4 mg doses. The included the date, time, `Did you have intercourse general trial design is shown in Figure 1 and with wife=partner after taking the tablets?' and `How includes, in this example, additional higher than long did it take to achieve the erection?' The adverse recommended doses of drug that will not be further event data was also recorded in the diaries at or reported on here. Patients admitted to the trials were immediately after any event. men with a diagnosis of ED, between 18 and 70 y Hemodynamic data was obtained in one of the of age, who were suited to pharmacotherapy and studies in which patients underwent measurements consented with their partners to attempt intercourse of standing and supine heart rate and blood pressure approximately twice a week for the duration of their prior to dosing and at 10, 20, 30, 40, 50, 60, 75, 90, participation. Diary entries documenting the re- 105 and 120 min after the ®rst (in-of®ce) dose in a sponses were completed after every tablet taken. study period. Patients were included in the studies that had stable organic medical diseases (as evidenced by concur- rent medical therapy for hypertension, diabetes and Results coronary artery disease). Evidence was required of susceptibility to ED pharmacotherapy by means of baseline assessments that documented the presence The IIEF scores were used to judge the baseline of erections not suf®cient for intercourse Ð this was severity of the ED in men admitted to the studies. It taken as presumptive evidence of the presence of is possible to assess the severity of the disease at some viable cavernosal tissue. presentation from two phase III crossover studies Baseline documentation of erectile status was by where men received doses of 2 and 4 mg. Severe ED means of a medical and sexual history and the Brief (IIEF < 10) was found in 37.3% of the men (n 208), Sexual Function Inventory (BSFI)5 for the ®rst study moderate ED (IIEF 11 ± 16) in 36.8% (n 205) and and the International Index of Erectile Function lesser grades in the remainder. Thus, the majority (IIEF)6 for subsequent studies. This change was a (74.1%) had moderate and severe grades of ED on function of instrument availability at the time the admission to the studies. The pro®le of organic co- studies were initiated. morbidities in the phase III patients was 31% with Timing of drug effect was established by means of hypertension, 16% with documented coronary patient diary entries. The patients were instructed to artery disease, 16% with dyslipidemia and 16% `plan times when you and your wife=partner will be with diabetes.

Figure 1 Schematic of general trial design for phase III clinical trials of apomorphine SL.

International Journal of Impotence Research Apomorphine: update of clinical trials JPW Heaton S69 The ef®cacy for the primary outcome variable Table 1. There was no signi®cant change in the (`yes' to the question: `Was your erection ®rm pattern and timing of sexual response as measured enough for intercourse?') was assessed on a per in these studies except in the increase in likelihood attempt basis. The combined results from three of gaining a satisfactory erectile response. phase III crossover studies are shown in Figure 2. The safety of apomorphine in the phase III trials In patients who received doses of 4 mg, 54.6% was, in part, documented by the absence of any (45.6% at 2 mg) were able to have erections reports of death, myocardial infarction, cerebrovas- suf®cient for intercourse compared with a baseline cular accident, priapism or unprovoked erection value of 26.8% and a placebo value of 33.8% thought, by the investigator, to be related to drug. (P < 0.001). Baseline values were consistent Nausea occurred at least once in 2.1% of patients throughout the trials. The response from the part- taking 2 mg apomorphine and in 20.4% at 4 mg the ners, with reference to this and other questions, was three crossover studies as documented in patient virtually identical to the responses given by the diaries. When nausea did occur it was most often patients. mild. Nausea was found to have no impact on The most relevant outcome is the ability of the ef®cacy and resulted in infrequent anti-emetic use men to have intercourse. The combined response on or trial drop-out. Three types of information demon- a per attempt basis is shown in Figure 3. The rate of strate that the incidence of nausea declines with intercourse was 50.6% at 4 mg compared with a continued use. Firstly, usage of optional, at hand, baseline rate of only 25.7% and a placebo rate of antiemetics declined with the number of doses used. 30.8% (P < 0.001). Secondly, the long-term studies with all dosage The timing of intercourse following administra- strengths (including doses higher than recom- tion of the tablet was documented as indicated mended) show an approximate halving of the above. The median times to erection can be seen in number of patients reporting any degree of nausea

Figure 2 Percentage of `yes' responses to the question `was your erections ®rm enough for intercourse?' Ð combined data from the crossover studies (all differences P < 0.001 for drug).

Figure 3 Percentage of `yes' responses to the question `did attempt result in intercourse' Ð combined data from the crossover studies (all differences P < 0.001 for drug).

International Journal of Impotence Research Apomorphine: update of clinical trials JPW Heaton S70 Table 1 The median time to erection in the phase III crossover ences in systolic and diastolic blood pressures, but trials for patients experiencing an erectile response there were no trends or changes that were of any Apomorphine clinical signi®cance. Median time to Placebo (IQR) SL (IQR) erection in minutes (% erection) (% erection)

2 mg apomorphine 16.7 (10 ± 25) 17.5 (10 ± 25) SL (n 245) (33.8%) (45.6%*) 4 mg apomorphine 15.0 (9 ± 25) 16.0 (10 ± 28) Discussion SL (n 246) (33.8%) (54.4%*)

IQR, interquartile range. *P < 0.001. Apomorphine SL is the ®rst drug for the management of ED that has a central site of action.7 The action is through dopaminergic effects in the hypothalamus at serum concentrations of less than in the last 4 weeks of a trial (12.2% of patients) 2ng=ml.8 This low level of effective serum concen- compared with the ®rst 4 weeks (24.9%). Thirdly, an tration combined with ef®cient absorption across analysis of the frequency of reports of nausea by the sublingual mucosa produces a rapid onset of dose revealed a declining histogram with no nausea action. The action in man is enhanced by a pro- after 20 doses (see Figure 4). sexual context, as has been noted for other therapies Vasovagal syncope has been reported with apo- of ED. morphine and occurs in less than 1 in 800 patients No prolonged or unwanted erections were noted when apomorphine SL is taken as directed in a in the apomorphine SL phase III studies. It is dose-optimized way. Overall, the rate of syncope for probable that apomorphine SL works centrally to the optimized 2 and 4 mg doses in the phase III trials enhance pro-erectile signaling through decreasing has been 0.6% (4=690). The reported syncopal inhibitory signals and augmenting the normal path- episodes were brief and self-limited and generally ways including effects on spinal integrating cen- followed a prodrome of autonomic symptoms. ters.9 The net effect at the level of the corporal Over 1700 Holter monitor recordings demonstrated smooth muscle is enhanced vasodilatory and sup- that arrhythmias are no more common after pressed vasoconstrictive activity. It has previously apomorphine SL than after placebo. been shown that penile tissue from impotent men Vital signs were recorded for apomorphine SL in commonly has signi®cant residual vasodilator po- one of the phase III crossover trials. No statistically tential.10 This dysfunctional tissue may be im- signi®cant changes in heart rate were observed proved by increasing the message to the smooth following either 2 or 4 mg doses of apomorphine muscle cell, as with apomorphine SL, increasing the SL at any time-point in both standing and supine intracellular message,11 or by improving smooth pulse measurements. At various time points, there muscle cell contractility Ð a strategy that has not yet were a few sporadic statistically signi®cant differ- been employed clinically. Apomorphine SL is the

Figure 4 Percentage of patients experiencing any degree of nausea by dose number.

International Journal of Impotence Research Apomorphine: update of clinical trials JPW Heaton S71 ®rst effective clinical example of a drug that restores attempt basis at 4 mg Ð these rates are in line with erectile function through central mechanisms. previous studies using comparable endpoints. There The phase III studies on apomorphine SL were was no period or sequence bias detected in this or conducted in men with disease pro®les typical of any other outcome measure for apomorphine SL. patients in clinical practice including wide-ranging The rate of successful intercourse, an intuitively documented co-morbidities. Baseline characteristics relevant and clinically meaningful outcome, was were consistent across studies and demonstrated shown to improve by a substantial margin. severe to moderate degrees of ED (IIEF criteria based The issue of how apomorphine SL impacts on the on the previous 4 weeks) in the majority (74.1%) of timing of intercourse is complex. To some extent, the patients. Despite the possible uncertainty raised the design of the study and the instructions given to by the inclusion of men with some ability to have the patients will blur the precision of any such erections, the average baseline rate of successful measurements. However, the crossover design and intercourse was only 25.8% when measured on a the placebo values provide a benchmark for the per attempt basis. This is in keeping with published chronology of pharmacologically unaided inter- rates in other clinical trials. As expected, co-morbid course. It can be observed from the records that organic disease or medication use was documented natural erections, under study conditions and in a majority of patients. The pro®le of co-morbid recorded in the diaries, occur between 15 and disease is similar to that recorded for previous 17 min after taking a sublingual dose of placebo, studies of patients with ED including community- and 50% of patients have an erection within a 9 ± based evaluations of men with ED (Table 2). 25 min time frame. Time points for patients achiev- Inclusion criteria were applied uniformly ing an erection after apomorphine SL administration throughout all the studies of apomorphine SL. In were 16 ± 17.5 and 10 ± 28 min, respectively. These the study population, age, medical status and are overlapping time courses but many more erectile status appeared to be representative of a patients experience erections on drug (54.4%) than typical ED clinic population. The exception to that on placebo (33.8%). In other words, the erection was the exclusion from these studies of patients induced by the addition of apomorphine SL is with ED related to radical surgery. natural in that it mimics the pattern of the unaided The use of `erection ®rm enough for intercourse' erection under study conditions where a sublingual as the primary outcome variable was based on an tablet is taken before intercourse. agreed study design and methodology from the mid The overall safety of the 2 and 4 mg doses of 1990s and a desire to record clinically relevant apomorphine SL has been demonstrated by the endpoints. The endpoint is particular in that it is absence of any deaths, myocardial events, strokes based on a diary record made at each attempt and and priapisms judged to be due to the study drug. does not generalize events over a period of recall. There were a small number of random events in both With this measure, patients experienced a rate of treated and untreated groups as be®ts a series this success per attempt, whether judged by themselves size in a population of men with this health status. or their partners, of about 54% overall with 4 mg No investigator associated any of these events with doses. taking apomorphine SL. The predictable appearance The ultimate test of a therapy for ED is the of mild nausea as the most frequent adverse event achieved rate of successful intercourse. This is also a was not associated with a signi®cant drop-out rate measure of drug activity that admits more extrinsic nor did it have a measurable effect on ef®cacy. As interference because it inherently involves major has been noted before with dopaminergic agents, the unquanti®able factors such as the quality of the non- rate of nausea decreases with the usage.12 Data from pharmacological components of the stimulus. It also the present trials shows that three different mea- involves external factors such as timing, conveni- sures of nausea indicate the same phenomenon. ence and judgement on the part of the couple. Even with intermittent administration, there is Again, the data are derived from immediate diary accommodation to the side effects of the drug. entries not subject to recall averaging or bias. The Syncope has been documented in these trials but rate of intercourse was 50.6% vs 25.7% at baseline is controlled to below 0.6% of patients when (P < 0.001) or 30.8% for placebo (P < 0.001) on a per patients are informed and a dose-optimization strategy is used. Comparable ®gures for syncope can be found regarding drugs in common use from Table 2 A comparison of co-morbidities for patients and the package inserts, eg 0.6% for terazosin, 1.2% for populations with ED bupropion and 0.9% for intraurethral PGE1. The intrinsic effects on blood pressure and apomorphine SL, Phase III MMAS17 cardiac health are critical issues in drugs designed Hypertension 31% 33% to treat ED. There is wide acceptance of the Coronary artery disease 16% 16% important overlap between cardiac risk factors13 Dyslipidemia 16% 14 Diabetes 16% 9% and the risk factors for ED. The common issue of vascular health has become accepted and there is

International Journal of Impotence Research Apomorphine: update of clinical trials JPW Heaton S72 reason to believe that, in some men, the onset of ED Acknowledgements may actually precede clinically evident systemic cardiovascular disease and be the ®rst indicator of declining vascular function.15 Myocardial events The clinical team at TAP Holdings and the apomor- have been recorded for sex with and without phine SL Study Group are gratefully acknowledged pharmacological assistance.16 At the doses of apo- for help with the data. morphine SL used to promote erection, peak serum levels recorded (< 1.5 ng=dl) are several times lower than those required for direct vascular effects. References There is, therefore, no mechanistic basis to expect systemic vasodilation from apomorphine SL admin- 1 Linet OI, Ogrinc FG. Ef®cacy and safety of intracavernosal istration or interaction with cardiovascular medi- alprostadil in men with erectile dysfunction. The Alprostadil cations, especially nitrates. It is not surprising that Study Group. New Engl J Med 1996; 334: 873 ± 877. there is no signi®cant pattern of blood pressure drop 2 NIH Consensus Development Panel on Impotence. JAMA or heart rate rise after apomorphine administration. 1993; 270: 83 ± 90. Subgroup analyses of patients with known cardio- 3 Padma-Nathan H et al. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Ure- vascular disease and those on antihypertensive thral System for Erection (MUSE) Study Group. New Engl J agents have shown no increase in the rate of general Med 1997; 336: 1±7. adverse events, nor is there evidence of arrhythmo- 4 Goldstein I et al. Oral sildena®l in the treatment of erectile genesis. Taken together with the overall record of no dysfunction. Sildena®l Study Group. New Engl J Med 1998; 338: 1397 ± 1404. cardiac events, the pro®le of this drug in the patient 5 O'Leary MP et al. A brief male sexual function inventory for with known cardiovascular disease appears not to urology. Urology 1995; 46: 697 ± 706. present any special considerations. 6 Rosen RC et al. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: 822 ± 830. 7 Heaton JP et al. Recovery of erectile function by the oral Conclusion administration of apomorphine. Urology 1995; 45: 200 ± 206. 8 Data on ®le, TAP Holdings Inc. (http:==www.fda.gov= ohrms=dockets=ac=00=transcripts=3602bld.pdf). These data taken from the phase III trials show that 9 McKenna KE. Central control of penile erection. Int J Impot Res 1998; 10(Suppl 1): S25 ± 34. there is a clinically useful effect on erectile function 10 Rajfer J et al. Nitric oxide as a mediator of relaxation of the from this new formulation of apomorphine and that a corpus cavernosum in response to nonadrenergic, noncholi- majority of patient attempts at intercourse (50.6%) nergic neurotransmission. New Engl J Med 1992; 326: 90 ± 94. will be successful at 4 mg. The drug has been shown to 11 Boolell M et al. Sildena®l: an orally active type 5 cyclic GMP- support a normal pattern of intercourse and it makes speci®c phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996; 8: 47 ± 52. intercourse more possible. Apomorphine SL has a 12 Szechtman H et al. Sensitization and tolerance to apomor- rapid action and permits erection suf®cient for phine in men: yawning, growth hormone, nausea, and intercourse in a majority of attempts. The data support hyperthermia. Psychiat Res 1988; 23: 245 ± 55. the ef®cacy of apomorphine in patients with moderate 13 Wilson PW, Culleton BF. Epidemiology of cardiovascular disease in the United States. Am J Kidney Dis 1998; 32(5 Suppl to severe degrees of ED when they have some inherent 3):S56 ± 65. residual capacity for pharmacological response. Ef®- 14 Johannes CB et al. Incidence of erectile dysfunction in men cacy has been shown in a group of patients with a 40 ± 69 y old: longitudinal results from the Massachusetts Male baseline rate of organic disease typical for the ED Aging Study. J Urol 2000; 163: 460 ± 463. population in the community. Nausea is infrequent, 15 Feldman HA et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male usually mild, and a decrease in the rate of nausea over Aging Study. Prev Med 2000; 30: 328 ± 338. serial administrations of apomorphine SL has been 16 Muller JE et al. Triggering myocardial infarction by sexual demonstrated. In general, the study of consistent, activity. Low absolute risk and prevention by regular physical identi®able and relevant inclusion criteria and out- exertion. Determinants of Myocardial Infarction Onset Study come measures in phase III studies should provide a Investigators. JAMA 1996; 275: 1405 ± 1409. 17 Feldman HA et al. Impotence and its medical and psychoso- basis for understanding the bene®ts of new treatments cial correlates: results of the Massachusetts Male Aging Study. for ED in a clinic population. J Urol 1994; 151: 54 ± 61.

International Journal of Impotence Research Apomorphine: update of clinical trials JPW Heaton S73 Appendix Dr Porst: What is the reason for syncope and dizziness when the blood pressure is not changing?

Open discussion following Dr Heaton's presentation Dr Heaton: There are episodic syndromal presyn- copal occurrences that a few patients, some of the time, will experience. In a properly administered Dr Wagner: When did syncope occur in relation to format, where patients are dose optimized and are at intake? home, you see 1 in 800 for the completed syndrome. The numbers for the incomplete syndrome, ie mild Dr Heaton: The average time was about 40 min and hypotension, would be slightly higher than this, but the average duration was 4 ± 10 s; it's classical these numbers have not been documented. vasovagal. Dr Eid: What is it about your study design that Dr Porst: We heard at an investigator's meeting produces a placebo rate of 33% vs the other previous that the syncope rate is much higher, and from de studies that show a placebo rate around 18, 20%? Tejada's work that syncope is about 1%, not one per 800. Thirteen percent of our patients experience Dr Heaton: Placebo rates in ED have been docu- dizziness, which means you must have an impact on mented anything from 10 to 40. the blood pressure. Dr Wyllie: You presented data on nausea, which is Dr Heaton: Syncope occurs after a prodrome which either mild to moderate and in the long term, it will includes dizziness, mild hypotension and nausea. If be attenuated. That could be classical tachyphy- patients lie down, they will not experience any laxis. Are there any long-term data that show a blood pressure changes. If they get up suddenly, this gradual reduction in ef®cacy over time? is when the syncopes have occurred. There have been approximately 20 syncopal episodes for these Dr Heaton: Long-term data are obtained in safety trials with doses of 2 and 4 mg. studies where ef®cacy is a secondary endpoint. The clinical trials show clearly that ef®cacy is main- Dr Porst: But they do not measure blood pressure tained and the actual percentage of patients at home, and therefore, we have no idea about these dropping out for lack of ef®cacy is extremely small. blood pressure changes.

Dr Heaton: Blood pressure changes in crossover studies measured every 10 min, supine and standing, amounted to 2 mm of Hg.

International Journal of Impotence Research