Male hypogonadism is a clinical syndrome that

Journal of Andrology, Vol. 33, No. 4, July/August 2012 Copyright E American Society of Andrology A Novel Testosterone 2% Gel for the Treatment of Hypogonadal Males ADRIAN S. DOBS,* JOHN MCGETTIGAN,{ PAUL NORWOOD,{ JULIAN HOWELL, ELIZABETH WALDIE, AND YUSONG CHEN5 From the *Johns Hopkins University, Baltimore, Maryland; the ÀQuality of Life Medical and Research Center LLC, Tucson, Arizona; the `Valley Endocrine and Valley Research, Fresno, California; the ProStrakan, Galashiels, United Kingdom; and the 5Endo Pharmaceuticals Inc, Chadds Ford, Pennsylvania. ABSTRACT: Testosterone replacement therapy (TRT) can improve the symptoms, signs, and well being of hypogonadal men by restoring serum testosterone concentrations to physiologic levels. This multicenter, open-label noncomparative trial of men with hypogonadism evaluated the pharmacokinetic profile and safety of a novel testosterone 2% gel (Fortesta TM Gel), administered once daily to the front and inner thighs at starting doses of 40 mg/d. The metered-dose delivery system allowed dose adjustments in 10-mg increments between 10 and 70 mg/d. Of the 149 patients enrolled, 138 patients (92.6%) completed the study and 129 patients (86.6%) were included in the efficacy analysis. On day 90, mean testosterone concentration (C avg [0 24 hours] 6 SD) was 438.6 6 162.5 ng/dl. Overall, 100 (77.5%) patients achieved serum total testosterone concentrations within the normal physiologic range ($300 and #1140 ng/dl). On day 90, mean testosterone C max (6SD) was 827.6 6 356.5 ng/dl. On day 90, a total of 122 patients (94.6%) had C max levels of 1500 ng/dl or less and 2 patients (1.6%) had values between 1800 and 2500 ng/dl. Similar results for C avg (0 24 hours) and C max were observed on day 35. All enrolled patients were included in the safety analysis. Testosterone 2% gel was generally well tolerated, with the most common adverse events (AE) being mild and moderate skin reactions. There were no serious AEs related to testosterone 2% gel. Once-daily testosterone 2% gel restored levels of testosterone in more than 75% of patients, with low risk of supraphysiologic testosterone levels. Patients may find this a suitable option for TRT because of its application site and low volume. Key words: Hypogonadism, androgen, testosterone replacement, testosterone deficiency. J Androl 2012;33:601 607 This study was funded by ProStrakan Pharmaceuticals Ltd. Writing and editorial assistance was supported by Endo Pharmaceuticals. Correspondence to: Dr Adrian Dobs, Johns Hopkins University, 1830 Monument St, Suite 328, Baltimore, MD 21287 (e-mail: adobs@jhmi.edu). Received for publication May 19, 2011; accepted for publication October 6, 2011. DOI: 10.2164/jandrol.111.014308 Male hypogonadism is a clinical syndrome that results from androgen deficiency (Bhasin et al, 2010). Failure to treat androgen deficiency can have significant health consequences, including osteoporosis, decreased vitality, loss of muscle mass and function, sexual dysfunction, and increased visceral fat (Wang et al, 2009; Bhasin et al, 2010). Testosterone replacement therapy (TRT) has an important role in improving the symptoms, signs, and physiologic well being of men with hypogonadism (Bhasin et al, 2010), and there is emerging evidence that TRT might provide metabolic benefits (Wang et al, 2009). The main aim of TRT is to restore serum testosterone concentrations to physiologic levels and minimize the signs and symptoms of male hypogonadism (Seftel, 2007). Minimizing the consequences of hypogonadism might be difficult to achieve because different androgen-dependent processes have different androgen dose-response relationships (Zitzmann et al, 2006). For instance, sexual function and bone markers are restored at testosterone concentrations in the lower end of the normal male range, whereas higher concentrations of testosterone are associated with greater gains in muscle mass and strength. However, concerns exist regarding adverse effects of prolonged, markedly supraphysiologic doses of testosterone, and international guidelines recommend avoiding sustained abnormally elevated levels (Wang et al, 2009). Therefore, it is recommended that TRT should be dosed to achieve serum testosterone concentrations within the mid-normal range (Bhasin et al, 2010). Testosterone gels achieve stable serum testosterone concentrations within the normal physiologic range with a noninvasive, once-daily topical application (Swerdloff et al, 2000; Wang et al, 2000; McNicholas et al, 2003; Steidle et al, 2003). Two gels are currently approved in the United States, and both have 1% testosterone concentrations (Auxilium Pharmaceuticals, 2009; Solvay Pharmaceuticals, 2011). These gels are effective at raising testosterone levels and are generally well 601

602 Journal of Andrology N July ÙAugust 2012 tolerated but require a comparatively large weight of medication to be applied, from 5 to 10 g of gel (with 50 to 100 mg of testosterone) in 1.25, 2.5, or 5-g increments because of their 1% testosterone concentration (Auxilium Pharmaceuticals, 2009; Solvay Pharmaceuticals, 2011). Unlike the testosterone 1% gels, which are applied to the shoulders and upper arms or abdomen, a recently approved 2% testosterone topical solution is applied in the axilla (Lilly, 2011). In this study, we examined the efficacy, pharmacokinetic profile, and safety of a novel topical metered-dose testosterone 2% gel (Fortesta Gel [Endo Pharmaceuticals Inc, Chadds Ford, Philadelphia], also known as Tostran, Tostrex, and Itnogen) that was applied to the front and inner thighs with a starting dose of 40 mg testosterone (2 g/2 ml of gel) and adjusted in 10-mg testosterone increments (0.5 g/0.5 ml of gel) for dose flexibility, with a minimum dose of 10 mg and a maximum dose of 70 mg testosterone. The primary study objective was to demonstrate that 75% or more patients who received testosterone 2% gel could achieve testosterone C avg (0 24 hours) within the normal physiologic range, as defined by the central laboratory (Esoterix Clinical Trial Services, Cranford, New Jersey), for the study ($300 and #1140 ng/dl) on day 90 (63 days) and that the lower bound of the 95% confidence interval (CI) would be 65%. or greater. The secondary objective, in accordance with the US Food and Drug Administration requirements for testosterone replacement therapies, was to show that C max on day 90 (63 days) was 1500 ng/dl or less in 85% or more patients, 1800 to 2500 ng/dl in 5% or fewer patients, and more than 2500 ng/dl in no patients. Materials and Methods Study Design This was a multicenter, open-label, noncomparative trial in men with hypogonadism. All patients applied testosterone 2% gel to clean and dry skin of their front and inner thighs, avoiding areas in contact with the scrotum, once daily in the morning for approximately 90 days. Patients were educated on correct application before the first application. The testosterone 2% gel was supplied in metered-dose canisters, which delivered 0.5 g/0.5 ml gel (ie, 10 mg of testosterone) per complete depression (actuation) of the piston. In addition to testosterone, the clear, odorless gel contains propylene glycol, purified water, ethanol, 2-propanol, oleic acid, carbomer 1382, triethanolamine, and butylated hydroxytoluene. The starting dose was 40 mg testosterone/d (2 g/2 ml of gel), and the dose could be adjusted to between 10 and 70 mg testosterone/d according to predefined dose adjustment criteria. On days 14, 35, and 60 (63 days), patients applied testosterone 2% gel during a clinic visit, and dose adjustment, if indicated, was based on total serum testosterone concentrations obtained 2 hours after application. Dose adjustment occurred according to the following algorithm: for a testosterone concentration 2500 ng/dl or more, dose was decreased by 20 mg testosterone; from 1250 to 2500 ng/dl, dose was decreased by 10 mg testosterone; from 500 to 1250 ng/dl, dose was not changed; and at less than 500 ng/dl, dose was increased by 10 mg testosterone. Concomitant medication was permitted throughout the study, except for androgen treatments; androgen antagonists; application of any lotions, ointments, or steroids to the application site; and 5a-reductase inhibitors (eg, finasteride). Patients receiving prior testosterone replacement therapy needed to have gone through a washout period, ranging from 1 to 52 weeks depending on the specific therapy for instance, 1 week for 1% testosterone gels and 8 weeks for testosterone cypionate injections before a baseline total serum testosterone measurement was taken on day 0. Participants Participants were recruited from 26 centers across the United States. All study participants gave written informed consent, and the study was approved by the independent ethics committee/ institutional review board at each participating center. N Eligible participants were men aged 18 75 years with primary or secondary hypogonadism, defined as a single serum total testosterone concentration of less than 250 ng/ dl or 2 consecutive serum total testosterone concentrations of less than 300 ng/dl, which were determined at least 1 week apart during the screening period. Body mass index (BMI) had to be $22 kg/m 2 and,35 kg/m 2. N Participants were excluded from the study if they had severe concomitant illness; acute or chronic hepatic impairment; a history of or any existing clinically significant cardiac disease (New York Heart Association Class III and IV); a prostate-specific antigen level of more than 4 ng/ml, unless prostate cancer had been excluded by a biopsy; prostatic abnormality on digital rectal examination without further urological evaluation; severe symptomatic benign prostatic hyperplasia or an International Prostate Symptom Score of more than 19. Additional reasons for excluding participants included: alanine aminotransferase or aspartate aminotransferase levels of more than 2.56 the upper limit of normal (ULN); acute or chronic renal impairment with serum creatinine levels $1.5 6 ULN; sleep apnea; eczema, psoriasis, or any other clinically significant skin condition; malignancy of any type except basal cell carcinoma; or sensitivity to topical products containing alcohol. Study Assessments Samples for a 24-hour serum total testosterone pharmacokinetic profile were obtained on days 35 and 90 (63 days) at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after gel application. Additionally, serum testosterone concentrations were evaluated on days 14 and 60 (63 days) for dose adjustment 2 hours after application. All samples were tested with liquid chromatography tandem mass spectrometry. Safety was

Dobs et al N Testosterone 2% Gel for Hypogonadism 603 Figure 1. Study flowchart. monitored throughout the study by recording adverse events (AE), conducting physical examinations and 12-lead electrocardiograms on days 1 and 90, performing laboratory tests during screening and on day 90, and measuring vital signs at baseline and day 90. During clinical visits on days 1, 14, 35, 60, and 90, a standardized dermatologic examination of the thigh application site was performed, and the investigator rated dermal response with the 8-point Berger/Bowman Dermal Response Scoring Scale. Statistical Analysis Descriptive statistics were used to summarize data for continuous and categorical variables collected in the study. The primary endpoint was average serum total testosterone concentration over 24 hours (C avg, 0 24 hours) on day 90 (63 days). The secondary endpoint was the maximum serum testosterone concentration (C max ) on day 90 (63 days). A sample size of 110 was determined to provide a probability of 0.998 that the percentage of patients achieving C avg (0 24 hours) within the normal physiologic range ($300 and #1140 ng/dl) on day 90 (63 days) would be at least 75% if the true underlying percentage of patients achieving this target was 85%. For this sample size, the associated probability that the lower limit of the 95% CI would be at least 65% was calculated to be less than 0.999. Consequently, the plan was to enroll 140 patients to allow for an attrition of 20% before day 90. CIs were calculated using the normal approximation to the binomial distribution method. Safety endpoints included the frequency and severity of AEs, application site reactions, and changes in BMI and laboratory parameters. Safety analyses included all patients who had at least 1 application of the study drug, whereas efficacy analyses included those patients who received 1 dose of the study drug and had at least 2 total testosterone concentration samples on day 90. Results Patient Disposition and Characteristics A total of 406 patients were screened, of which 149 patients met the eligibility criteria and were enrolled in the study and received at least 1 application of testosterone 2% gel (Figure 1). One hundred thirtyeight (92.6%) patients completed the study. Among the 11 patients who discontinued the study, the most common reason for discontinuation was AEs (n 5 5), including contact dermatitis (n 5 1), skin reaction (n 5 1), gastric hypomotility (n 5 1), contusion (n 5 1), and dyspnea (n 5 1). Only the incident of dyspnea was a serious AE (SAE), but it was considered unrelated to the study medication. Two of the other AEs (contact dermatitis and skin reaction) were considered probably related, whereas the incident of gastric hypomotility was considered possibly related. Patient demographics and baseline characteristics are shown in Table 1. Because the washout intervals for patients on previously administered testosterone treatments before randomization into this study might not have been sufficiently long to result in an increase in serum luteinizing hormone or follicle-stimulating hormone, it was impossible to accurately categorize patients into primary vs secondary hypogonadism.

604 Journal of Andrology N July ÙAugust 2012 Table 1. Patient demographics and baseline characteristics (mean 6 SD) Patients (n 5 149) Age, y (range) 54.5 6 10.1 (29 77) Race, n (%) White 131 (87.9) Black 15 (10.1) Other a 3 (2.0) Weight, kg (range) 97.7 6 14.7 (65.3 147.6) Body mass index, kg/m 2 (range) 30.61 6 3.50 (22.1 41.5) Time since diagnosis, y (range) 2.2 6 3.3 (0 22) Prior use of TRT, n (%) 98 (65.8) Total testosterone, ng/dl b 195.4 6 65.7 Abbreviations: SD, standard deviation; TRT, testosterone replacement therapy. a Other races reported included mixed, Asian Indian, and Middle Eastern/Arabic. b n 5 138. Dosing The proportions of patients at each dose level throughout the study are shown in Table 2. Most patients required a dose change by day 35 (n 5 80; 62.0%), and by day 90, 30 patients (23.3%) remained on the starting dose of 40 mg testosterone/d. Only 1 patient (0.8%) required a dose reduction to the lowest dose (10 mg testosterone). There was a comparatively even distribution of patients at the 40 to 70-mg testosterone dose range at day 90, with more than 80% requiring 60 mg or less of testosterone per day. Primary Endpoint For the efficacy analyses, at least 2 day 90 total testosterone concentration samples were available for 129 patients (86.6% of total enrollment). Nine of the 138 patients who completed the study were excluded from the efficacy analyses because only 1 sample was available for them. On day 90, mean C avg (0 24 hours) 6 SD was 438.56 6 162.51 ng/dl, with 100 (77.5%) patients achieving mean serum total testosterone concentrations within the predefined normal physiologic range ($300 and #1140 ng/dl) with a 95% CI range of 70.3% to 84.7%. Twenty-nine patients (22.5%) had total testosterone concentrations less than 300 ng/dl on day 90. By day 35, 76.2% (95% CI: 68.8%, 83.6%) of 126 patients (n 5 96) had already reached the study s primary endpoint. Secondary Endpoint On day 90, mean maximum serum testosterone concentration (C max 6 SD) was 827.6 6 356.5 ng/dl. A total of 94.6% of patients (n 5 122) achieved testosterone C max # 1500 ng/dl, 1.6% of patients (n 5 2) had values between 1880 and 2500 ng/dl, and no patients had values or more than 2500 ng/dl. This maximum serum testosterone level was already evident by day 35 (822.98 6 391.93 ng/dl). For 126 patients analyzed at that point, 93.7% had testosterone C max # 1500 ng/dl (n 5 118), 1.6% had values between 1880 and 2500 ng/dl (n 5 2), and no patients had values greater than 2500 ng/dl. Twenty-four Hour Pharmacokinetic Profile Serum testosterone peaked at 2 4 hours after application of testosterone 2% gel at day 90 (Figure 2). The fastest increase in serum testosterone concentration was observed between 1 and 2 hours after application and fell most rapidly between 4 and 6 hours after application. Safety Among patients who received at least 1 dose and were included in the safety analysis (n 5 149), testosterone 2% gel was generally well tolerated. Although 69 patients (46.3%) reported at least 1 AE, in 35 of these patients (23.5%), the AEs were considered unrelated to the study medication. Most reported AEs were mild or moderate in severity. The most common AEs that patients experienced were skin reactions (n 5 25, 16.8%), upper respiratory infections (n 5 10, 6.7%), and sinusitis (n 5 6, 4.0%). Skin reactions were considered possibly or probably related to the study medication in 24 patients (16.1%), with the majority (n 5 19, 79.2%) being mild in severity. When thigh application sites were examined during clinical visits for Table 2. Testosterone 2% gel dose level (wt/vol) by study visit 10 mg (0.5 g/0.5 ml) 20 mg (1.0 g/1.0 ml) 30 mg (1.5 g/1.5 ml) No. (Proportion) of Patients 40 mg (2.0 g/2.0 ml) 50 mg (2.5 g/2.5 ml) 60 mg (3.0 g/3.0 ml) 70 mg (3.5 g/3.5 ml) Study Visit Visit 2 (day 1 Baseline) 0 0 0 129 (100.0%) 0 0 0 n 5 129 Visit 3 (day 14) n 5 129 0 0 0 129 (100.0%) 0 0 0 Visit 4 (day 35) n 5 129 0 1 (0.8%) 9 (7.0%) 49 (38.0%) 70 (54.3%) 0 0 Visit 5 (day 60) n 5 129 0 5 (3.9%) 11 (8.5%) 38 (29.5%) 40 (31.0%) 35 (27.1%) 0 Visit 6 (day 90) n 5 129 1 (0.8%) 6 (4.7%) 16 (12.4%) 30 (23.3%) 26 (20.2%) 27 (20.9%) 23 (17.8%)

Dobs et al N Testosterone 2% Gel for Hypogonadism 605 Figure 2. Serum testosterone pharmacokinetic profile on day 90 (n 5 129). dermal response, and the results were recorded using the Berger/Bowman Dermal Response Scoring Scale, no evidence of irritation (score 0) was reported for 146 patients (99.3%) on day 14, 139 patients (97.2%) on day 35, 134 patients (95.7%) on day 60, and 138 patients (94.5%) on day 90 (Figure 3). A slight increase in dermal response scores was observed over the course of the study. No patient received a score of greater than 3 on the 8-point scale during the study. Five patients (3.4%) experienced SAEs, but none were considered to be related to the study medication, and no deaths were reported during the study. The SAEs were rectal hemorrhage, colon cancer, dyspnea, intestinal obstruction, and cellulitis. No clinically relevant differences were observed from baseline to day 90 in laboratory values, vital signs, bodily functions, or BMI. Discussion This study demonstrated that single daily doses of a novel testosterone 2% gel restored serum testosterone levels to a normal physiologic range in male patients with hypogonadism. The primary objective of the study was met. More than 75% of patients (a total of 78%) had a day 90 average serum testosterone concentration over 24 hours in the normal physiologic range ($300 and #1140 ng/dl), and the lower bound of the 95% CI was more than 65% (95% CI: 70.3% to 84.7%). In fact, 76% of patients achieved testosterone levels within the target range by day 35. Mean maximum testosterone concentrations were within the normal range on both days (day 35: 822.98 ng/dl; day 90: 827.6 ng/dl), and 95% of patients had a maximum testosterone concentration of 1500 ng/dl or less, indicating that testosterone level excursions into a supraphysiologic Figure 3. Examination results of thigh application sites using the Berger/Bowman Dermal Response Scoring Scale. range were limited. The day 90 pharmacokinetic profile indicates that testosterone 2% gel is well suited to once-daily dosing, providing rather steady levels throughout the day. The 2% testosterone gel tested in this study was generally well tolerated. No SAEs related to the study medication were reported. The most commonly occurring AEs considered by investigators as possibly or probably related to the treatment were mild to moderate transient skin reactions in 24 patients (16.1%). Only 2 patients withdrew from the study because of skin events: 1 case each of contact dermatitis and skin reaction. Using a standardized dermal assessment tool, examination of the application site by investigators periodically throughout the study detected no signs of dermal irritation in at least 94% of patients on each occasion. The metered-dose delivery system of the testosterone gel tested in this study appeared to present a desirable dosing flexibility. The metered-dose delivery system of the testosterone 2% gel allowed doses to be titrated easily in increments of 10 mg of testosterone (0.5 g/0.5 ml of gel) across a dose range of 10 to 70 mg testosterone, and at the end of this study, patients were receiving doses throughout the permissible testosterone range (10 mg [n 5 1]; 20 mg [n 5 6]; 30 mg [n 5 16]; 40 mg [n 5 30]; 50 mg

606 Journal of Andrology N July ÙAugust 2012 [n 5 26]; 60 mg [n 5 27]; 70 mg [n 5 23]). These results showed that the testosterone 2% gel metered-dose delivery system will permit dose adjustment in small increments to provide optimal, individualized dosing for patients. Small incremental dose adjustments allow physicians to reach eugonadal concentrations, while being able to titrate downward to avoid supraphysiologic testosterone concentrations. In contrast, the smallest recommended dose by which the delivery systems of other testosterone gels can be adjusted is 25 mg of testosterone (Solvay Pharmaceuticals, 2011). The 2% testosterone topical solution, which has the same testosterone concentration as the gel tested in this study, is adjustable by 30-mg increments (Lilly, 2011). Similar to the testosterone 2% gel tested in this study, testosterone 1% gels and 2% topical solution raise serum testosterone levels into a mid-high normal adult range in a consistent, dose-dependent manner (Swerdloff et al, 2000; Wang et al, 2000; McNicholas et al, 2003; Steidle et al, 2003; Lilly, 2011). The use of testosterone 2% gel has potential implications for patient convenience and treatment regimen adherence. Because testosterone 2% gel is twice as concentrated as a testosterone 1% gel, its maximum dose of 70 mg testosterone is delivered in only 3.5 g/3.5 ml of gel, whereas the minimum dose of a testosterone 1% gel is delivered in 5 g of gel. At the end of this study, 82% of patients (n 5 106/129) were receiving 60 mg of testosterone or less. In contrast, at the end of a 120-day study testing the efficacy of another product, a 2% testosterone topical solution, 26% of patients (n 5 35/ 135) required 90 to 120 mg of testosterone to reach the same serum testosterone range, and only 74% received 60 mg of testosterone or less (Lilly, 2011). It is possible that there are differences in formulation and absorption at the application site (thighs vs under the arms) between testosterone 2% gel and 2% testosterone topical solution. Further study with testosterone 2% gel is warranted to assess how well it improves the symptoms, signs, and physiologic well being of hypogonadal men. The study drug was efficacious in this 90-day trial at raising testosterone levels to a normal range, but longer term investigation is needed to determine what effect this medication could have on sexual function, bone markers, muscle mass, and other characteristics of hypogonadism. Conclusion Once-daily testosterone 2% gel restored normal levels of testosterone in more than 75% of hypogonadal patients, with a low risk of supraphysiologic testosterone levels. The study medication was generally well tolerated, with mild or moderate skin reactions being the most common AE. The metered-dose delivery system of the testosterone 2% gel, which is adjustable in 10-mg testosterone increments (0.5 g/ 0.5 ml of gel), offers dose flexibility with the ability to fine tune exposure. The once-daily testosterone 2% gel formulation thus provides an option for men requiring TRT that is easy to apply and low in volume. Acknowledgments The authors thank Peter Budka and Catherine Jones (Watermeadow Medical) for their writing and editorial assistance. The 26 participating clinical centers were: Alabama Clinical Therapeutics, LLC, Birmingham, Alabama; Alpha Medical Research, Oviedo, Florida; Charlotte Clinical Research, Charlotte, North Carolina; The Connecticut Clinical Research Center, Middlebury, Connecticut; Cor Clinical Research LLC, Oklahoma City, Oklahoma; Diabetes and Glandular Disease Research Associates PA, San Antonio, Texas; Endocrine Research Solutions Inc, Roswell, Georgia; Grove Hill Medical Center, New Britain, Connecticut; Hudson Valley Urology, Kingston, New York; Hudson Valley Urology PC, Poughkeepsie, New York; Innovative Research of West Florida, Largo, Florida; Jacksonville Center for Clinical Research, Jacksonville, Florida; Johns Hopkins University, Baltimore, Maryland; Matrix Research LLC, Greer, South Carolina; McGuire Research Institute, Richmond, Virginia; Medical Affiliated Research Center Inc, Huntsville, Alabama; Memorial Medical Group, South Bend, Indiana; Miami Research Associates, South Miami, Florida; Panhandle Family Care Associates, Marianna, Florida; Quality of Life Medical and Research Center, Tucson, Arizona; Rapid Medical Research Inc, Cleveland, Ohio; Renaissance Clinical Research, Dallas, Texas; Troy Internal Medicine PC, Troy, Michigan; Valley Research, Fresno, California; Urology San Antonio Research, San Antonio, Texas; Volunteer Research Group, Knoxville, Tennessee. 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