Abstract Introduction A novel oral testosterone replacement therapy (TRT), testosterone undecanoate (TU, JATENZO) has been shown in 1- and 2-year studies to have durable efficacy and safety. Hypogonadal men are heterogeneous with respect to age, body mass index (BMI), and diabetic status. These factors have been shown to affect the hypothalamic-pituitary-gonadal axis. Objective The purpose of this study is to investigate the role of baseline age, BMI, and diabetic status on change in T levels, final TU dose, and safety. Methods Hypogonadal men, ages 18 – 65 y/o, were recruited into a randomized, open-label, multicenter, dose-titration trial. 222 subjects were randomized to BID TU (n = 166) or testosterone gel (n = 56). Subjects had dose adjustments based on plasma T levels (Cavg). Safety was assessed by standard clinical measures. Post hoc safety, efficacy, and dosing analyses were conducted on subjects who were stratified by age, BMI, and diabetes status. The age groups were <= 44 y/o, 45 – 54 y/o, and => 55 y/o; the BMI groups were < 30 kg/m^2, 30 – 35 kg/m^2, and > 35 kg/m^2; and the subjects were grouped as non-diabetic, pre-diabetic, or diabetic. Results Overall, serum total T Cavg for the oral TU group was 489 ± 12.6 ng/dL (mean ± SE). For all groups, the mean total T was in the eugonadal range. Age, BMI, or diabetes status did not affect key efficacy variables, such as total T or calculated free T, nor key safety variables, such as hematocrit, PSA, liver transaminases, systolic BP, diastolic BP, HDL-C, or LDL-C. There were no differences in the final TU dose among the age categories. In contrast, the final TU dose was significantly different among BMI categories (p=0.0003), and the diabetic status (p < 0.0001). The higher BMI groups need a significantly higher oral TU dose. Those in the pre-diabetic or diabetic groups needed a significantly higher dose than the non-diabetic group. Because the pre-diabetic and diabetic groups had significantly higher BMI, it is difficult to determine if it was diabetes status or BMI that influenced the final dose [baseline BMI: non-diabetic 30.5 ± 0.52 (mean ± SEM), pre-diabetic 32.7 ± 0.54 (p = 0.003 vs the non-diabetic group), diabetic 32.5 ± 0.56 (p = 0.0175 vs the non-diabetic group)]. BMI had a greater effect on the final dose in the non-diabetic group, and its effect appeared to decrease in the pre-diabetic and diabetic groups. See figure for the final mean doses. Although the final total T values were in the eugonadal range, there was also a significantly smaller change from baseline in total T comparing non-diabetics to diabetics (p=0.0042). Conclusions Regardless of age, BMI, or diabetes status, eugonadal total T levels were achieved in men administered oral TU. Age did not influence the final dose. In contrast, BMI and diabetes status influenced the final dose. Patient characteristics (BMI and diabetic status) may guide dosing of testosterone replacement with oral testosterone undecanoate to optimize T levels. Disclosure Yes, this is sponsored by industry/sponsor: Clarus Therapeutics Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Clarus Therapeutics.

ABSTRACT Introduction The diagnosis of hypogonadism (HG) in men requires both consistently low testosterone (T) levels and signs and symptoms of T deficiency. Management of HG with T replacement therapy (TRT) aims to improve both low serum T levels and patients’ symptomatic complaints. The first oral softgel formulation of testosterone undecanoate (TU) was recently approved by FDA (JATENZO®) for TRT in men with specific hypogonadal conditions and is available in 3 capsule strengths and 5 dosage combinations for necessary dose adjustments. However, dose titration may not be necessary in many patients treated with this new oral TU formulation given the wide eugonadal range. Objective Assess the ability of any given daily dosage of oral TU to restore T to eugonadal levels without dose adjustment at steady state (Css); and determine real-world dose titration experience of patients treated with oral TU. Methods Pharmacokinetic (PK) simulations were performed using a robust population PK model developed for T in 474 hypogonadal men who were treated with oral TU in prior PK studies. The model consisted of a 1-compartment model with absorption lag time and an allometric function on key allometric parameters to account for differences in body weight. This final population PK model was coded in Trial Simulator v2.3.0.6 software. T levels were simulated following oral TU BID dosing on Day 55 (i.e., at steady state) with no dose adjustments. Average T concentrations (Cavg) were derived from multiple serial blood samples collected over 24 hrs for oral TU doses of 237, 316, and 396 mg TU, BID (without dose modification). The percent of subjects with T levels within the eugonadal range (serum Cavg between 304 ng/dL-1030 ng/dL) at each of these TU dose levels was calculated. Prescription data was also accessed in the Symphony PatientSource Patient Transactional Dataset to evaluate the frequency of real-world dose titration. Results The percentage of subjects with Css T Cavg within the eugonadal range for 237, 316, and 396 mg TU, BID were 61%, 74% and 74%, respectively. These corresponded to mean [5%, 95% CI] serum T levels (ng/dL) of 398 [389, 406], 560 [549, 572] and 728 [715, 741] ng/dL, respectively. Early assessment of real-world prescribing data for JATENZO indicated 35% of patients underwent dose titration by month 5. Conclusions Simulated daily BID dosing of oral TU without dose adjustment yielded eugonadal T levels in most subjects at all 3 dose levels examined. These data are consistent with initial early real-world experience with oral TU that indicates dose titration has not been required in most patients. However, because the desired outcome of TRT therapy focuses on both T Cavg and symptomatic response, this oral TU formulation enables necessary dose adjustment when needed. Disclosure Yes, this is sponsored by industry/sponsor: Clarus Therapeutics, Inc. Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Clarus Therapeutics, Inc.

You have accessJournal of UrologyCME1 May 2022MP35-09 LINEAR RELATIONSHIP BETWEEN THE TIME OF DOSING AND 24-HOUR AVERAGE CONCENTRATION OF TOTAL TESTOSTERONE IN MEN TREATED WITH AN ORAL TESTOSTERONE UNDECANOATE CAPSULE (JATENZO®) Ronald Swerdloff, Jason Kovac, Christina Wang, Marc Gittelman, B. Woun Seo, Jay Newmark, Nestor Rohowsky, and Robert Dudley Ronald SwerdloffRonald Swerdloff More articles by this author , Jason KovacJason Kovac More articles by this author , Christina WangChristina Wang More articles by this author , Marc GittelmanMarc Gittelman More articles by this author , B. Woun SeoB. Woun Seo More articles by this author , Jay NewmarkJay Newmark More articles by this author , Nestor RohowskyNestor Rohowsky More articles by this author , and Robert DudleyRobert Dudley More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002589.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In 2019, a novel, first-in-class testosterone (T) replacement therapy (TRT), oral testosterone undecanoate (TU) was approved by the US FDA for the treatment of male hypogonadism. Concordance studies have shown that total T at 6 hrs after the morning TU dose best corresponds to the total T 24-hr average concentration (Cavg). Hence, product labeling directs clinicians to measure serum T 6 hrs after a morning TU dose. However, testing at 6 hrs may pose scheduling difficulties for some men. Therefore, the relationship between other T assay time points and Cavg was examined to see if a conversion factor could be derived to convert T values collected at earlier or later times than directed in product labeling (i.e., 6 hrs) into values that reflect true Cavg. METHODS: Hypogonadal men, age 18–65 y/o, were recruited into a randomized, open-label, multicenter, dose-titration trial. Dose titration was based on Cavg calculated from serial pharmacokinetic (PK) samples. Patients had two dose adjustments based Cavg. Because of the need for titration, there were three different PK visits. Ratio between the different timepoints and Cavg were determined for the oral TU PK samples following morning drug administration. RESULTS: With the values from all three PK days pooled, there was a linear relationship between T concentrations at 4, 6, and 9 hrs and Cavg (r2=0.35). The r2 for the three visits were similar: 1st PK visit, r2=0.33; 2nd PK visit, r2=0.36; final PK visit, r2=0.35. A factor based on the following equation was derived to enable conversion of T values assessed at a times other than 6 hrs (i.e., time of blood draw) into a close approximation of Cavg: (1.870−0.14)×(hours after AM dose). Table summarizes the conversion factors to normalize T to Cavg at various T assay time points. To illustrate, for a serum T value drawn at either 4 or 8 hrs after the morning oral TU dose, the normalized (or corrected) Cavg concentration would be approximately 75% or 133% of the drawn value, respectively. CONCLUSIONS: While dose titration for this novel oral TRT is based on a serum T level drawn at 6 hours after the AM dose, the T level can be estimated from samples obtained at other timepoints using a conversion factor. Source of Funding: Clarus Therapeutics © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e590 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ronald Swerdloff More articles by this author Jason Kovac More articles by this author Christina Wang More articles by this author Marc Gittelman More articles by this author B. Woun Seo More articles by this author Jay Newmark More articles by this author Nestor Rohowsky More articles by this author Robert Dudley More articles by this author Expand All Advertisement PDF DownloadLoading ...

ABSTRACT Introduction An oral testosterone (T) replacement therapy (TRT) would be the preferred administration route for many hypogonadal men. Until recently, the only oral TRT approved in the US was methyl-T which has been associated with hepatotoxicity. Objective The safety of a novel oral T undecanoate (TU) formulation was evaluated in hypogonadal men with two-year follow up. Methods Two open-label, multicenter, dose-titration trials were conducted in hypogonadal men (serum T ≤ 300 ng/dL) age 18-75 years. Trial I was a randomized, active-controlled, 2-arm, 12-month study. Trial 2 was a long-term extension of those who completed Trial 1. Statistical analyses were only conducted with the subjects who completed Trial 1 and continued treatment in Trial 2, thus providing up to 2 full years of data. Safety was assessed by physical exam, AE reporting, and routine clinical laboratory measurements. Results Overall, 86 subjects participated in both studies. T concentration increased from 193.75 ± 9.44 ng/dL (Mean ± SEM) at baseline (BL) to 475.5 ± 49.7 ng/dL after 24 Mo of therapy with oral TU, and 84% of men achieved T in eugonadal range (300-1000 ng/dL) after 90 days of therapy. Mean T concentrations remained in the eugonadal range throughout Trial 2. There were no clinically significant changes in liver function tests – ALP (64.05 ± 1.95 to 53.74 U/L ± 1.86 U/L), ALT (27.8 ± 1.40 to 26.7 ± 1.6 U/L), AST (21.6 ± 0.76 to 22.0 ± 1.0 U/L), and bilirubin (0.58 ± 0.03 to 0.52 ± 0.03 mg/dL) throughout the two studies. At d270, one subject had an ALT level of 227 U/L, which was > 4x the ULN (ULN for ALT = 45 U/L). Despite continued use of oral TU, ALT was measured again on d290, and the level dropped to 87 U/L, < 2x ULN. This was the only instance of an LFT elevation. There was a modest initial increase in prostate-related growth endpoints (i.e. PSA and prostate volume) that stabilized over time. Although there was a slight increase in prostate-growth related endpoints, there were no significant changes in IPSS total score (-0.06 ± 3.9 vs BL). There were significant, yet modest, increases in mean HCT (44.3 ± 0.3 to 46.6 ± 0.5%, p < 0.001) and cuff systolic BP (127.1 ± 1.2 to 131.8 ± 1.67 mmHg vs BL, p = 0.006). The change in CV endpoints, including HDL-C, hematocrit, and BP, changed initially and stabilized throughout the 2 trials. For example, systolic BP varied 3 – 6 mm Hg from BL throughout the study. Conclusions This oral TU formulation is an option for hypogonadal men and has a safety profile consistent with other approved T products, such as a rise in hematocrit and a decrease in HDL-C. Notably, no evidence of liver toxicity was observed over 2 years. The long-term efficacy and safety profile of oral TU may provide a treatment option that avoids issues associated with other TRTs, such as injection site pain or transference to partners and children. Disclosure Yes, this is sponsored by industry/sponsor: Clarus Therapeutics Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Clarus Therapeutics

Oral TU offers a safe and effective long-term treatment option for men with hypogonadism.

Abstract In 2019, a novel, first-in-class testosterone (T) replacement therapy (TRT), oral testosterone undecanoate (TU) was approved by the U.S. FDA for the treatment of male hypogonadism. During clinical trials, dose adjustments were based on 24-hr average T concentration (Cavg) because single T measurements were considered less accurate. Subsequent, concordance analyses for this oral TU product have shown that a single total T value 6-hrs after the morning oral TU dose best corresponds to Cavg. Nonetheless, a conversion factor for T values obtained at other post-dose time points would be useful for healthcare providers (HCPs) and ease potential scheduling challenges for patients. Consequently, the relationship between other T sampling time points and Cavg was examined to determine if a reliable conversion factor could be derived to help HCPs monitor a patient's serum T concentration at times other than 6-hrs after oral TU administration. Hypogonadal men, age 18–65 y/o, were recruited into a randomized, open-label, multicenter, dose-titration trial. Overall, 166 men were randomized into the oral TU arm. Dose titration was based on Cavg calculated from serial pharmacokinetic (PK) samples. There were three pre-designated PK visits, to individualize the appropriate TU dose and to achieve a eugonadal T Cavg by the final study visit. Ratios between different timepoints and Cavg were determined for PK samples following morning drug administration. Overall, 87.3% (95% CI: 81.3%, 92.0%) of hypogonadal men had a final Cavg in the eugonadal range, with a mean serum total T = 488.7 ± 154.5 ng/dL (16.95 ± 5.37 nmol/L). Pooled values from all PK days demonstrated a linear relationship between T concentrations at 4, 6, and 9-hrs and Cavg (p < 0.0001). Visit and time of sampling interaction were not statistically significant (p >> 0.50), indicating consistency in results among PK visits and among sampling timepoints. A factor was derived to enable conversion of T values assessed at a time other than 6-hrs (post oral TU dose) into a close approximation of Cavg: 1/[1.870–0.14×(hours after AM dose)]. Therefore, a sample drawn at 4-hrs after the morning oral TU dose would be multiplied by 0.75; while one drawn at 8-hrs would be multiplied by 1.33. Hence, T Cavg can be approximated after morning JATENZO administration if a blood sample cannot be collected precisely 6-hrs thereafter. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Male hypogonadism is defined by a low serum testosterone (T) concentration (e.g., < 300 ng/dL) and associated symptoms. A novel oral testosterone undecanoate (TU) formulation1 now offers hypogonadal men in the U.S. a new treatment option compared to long-standing T replacement products (e.g., intramuscular or subcutaneous injections (T-esters), subcutaneous T pellets, transdermal T-gels, buccal T patch or a nasal T-gel).

You have accessJournal of UrologySexual Function/Dysfunction: Medical, Hormonal & Non-surgical Therapy I (PD20)1 Sep 2021PD20-07 SAFETY ANALYSIS OF AN ORAL TESTOSTERONE UNDECANOATE (TU) FORMULATION FOLLOWING 2 YEARS OF ADMINISTRATION IN HYPOGONADAL MEN Ronald Swerdloff, Parviz Kavoussi, Marc Gittelman, Christina Wang, B. Woun Seo, Nestor Rohowsky, and Robert Dudley Ronald SwerdloffRonald Swerdloff , Parviz KavoussiParviz Kavoussi , Marc GittelmanMarc Gittelman , Christina WangChristina Wang , B. Woun SeoB. Woun Seo , Nestor RohowskyNestor Rohowsky , and Robert DudleyRobert Dudley View All Author Informationhttps://doi.org/10.1097/JU.0000000000002009.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: An oral testosterone (T) replacement therapy (TRT) would be the preferred administration route for many hypogonadal men. Until recently, the only oral TRT approved in the US was methyl-T which has been associated with hepatotoxicity. The safety of a novel oral T undecanoate (TU) formulation was evaluated in hypogonadal men for up to 2 years. METHODS: Two open-label, multicenter, dose-titration trials were conducted in hypogonadal men (serum T ≤300 ng/dL) age 18-75 years. Trial I was a randomized, active-controlled, 2-arm, 12-month study. Trial 2 was a long-term extension of those who completed Trial 1. Statistical analyses were only conducted with the subjects who completed Trial 1 and continued treatment in Trial 2, thus providing up to 2 full years of data. Safety was assessed by physical exam, AE reporting, and routine clinical laboratory measurements. RESULTS: Overall, 86 subjects participated in both studies. T concentration increased from 193.75±9.44 ng/dL (Mean±SEM) at baseline (BL) to 475.5±49.7 ng/dL after 24 Mo of therapy with oral TU, and 84% of men achieved T in eugonadal range (300-1000 ng/dL) after 90 days of therapy. Mean T concentrations remained in the eugonadal range throughout Trial 2. There were no clinically significant changes in liver function tests–ALP (64.05±1.95 to 53.74 U/L±1.86 U/L), ALT (27.8±1.40 to 26.7±1.6 U/L), AST (21.6±0.76 to 22.0±1.0 U/L), and bilirubin (0.58±0.03 to 0.52±0.03 mg/dL) throughout the two studies. At d270, one subject had an ALT level of 227 U/L, which was > 4x the ULN (ULN for ALT=45 U/L). Despite continued use of oral TU, ALT was measured again on d290, and the level dropped to 87 U/L, <2x ULN. This was the only instance of an LFT elevation. There was a modest initial increase in prostate-related growth endpoints (i.e. PSA and prostate volume) that stabilized over time. There were not any significant changes in IPSS total score (-0.06±3.9 vs BL). There were significant, yet modest, increases in mean HCT (44.3±0.3 to 46.6±0.5%, p<0.001) and cuff systolic BP (127.1±1.2 to 131.8±1.67 mmHg, p = 0.006). The change in prostate-related growth variables and CV endpoints changed initially and stabilized throughout the 2 trials. For example, systolic BP varied 3–6 mm Hg from BL throughout the study. CONCLUSIONS: This oral TU formulation is an option for hypogonadal men and has a safety profile consistent with other approved T products. Notably, no evidence of liver toxicity was observed. The long-term efficacy and safety profile of oral TU may provide a treatment option that avoids issues associated with other TRTs, such as injection site pain or transference to partners and children. Source of Funding: Clarus Therapeutics, Inc © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e369-e370 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ronald Swerdloff More articles by this author Parviz Kavoussi More articles by this author Marc Gittelman More articles by this author Christina Wang More articles by this author B. Woun Seo More articles by this author Nestor Rohowsky More articles by this author Robert Dudley More articles by this author Expand All Advertisement Loading ...

Treatment of male hypogonadism with testosterone (T), most profoundly with long-acting injections and pellets, have been shown to inhibit the hypogonadal-pituitary-gonadal (HPG) axis4. T injections result in a reduction in both luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations to undetectable levels as quickly as 2 weeks following initiation of therapy5. The decrease in LH and FSH impairs critical components of spermatogenesis. In a phase 3 study of an oral testosterone undecanoate (TU) capsule (JATENZO®), complete suppression of LH and FSH concentrations was not observed in all men6, although the impact on gonadotropin suppression by age was not studied.

Abstract Context A novel formulation of oral testosterone (T) undecanoate (TU) was evaluated in a phase 3 clinical trial. Objective Determine efficacy, short-term safety, and alignment of new oral TU formulation with current US approval standards for T replacement therapy. Design Randomized, active-controlled, open-label study. Setting and Patients Academic and private clinical practice sites; enrolled patients were clinically hypogonadal men 18 to 65 years old. Methods Patients were randomized 3:1 to oral TU, as prescribed (JATENZO®; n = 166) or a topical T product once daily (Axiron®; n = 56) for 3 to 4 months. Dose titration was based on average T levels (Cavg) calculated from serial pharmacokinetic (PK) samples. T was assayed by liquid chromatography–mass spectrometry/mass spectrometry. Patients had 2 dose adjustment opportunities prior to final PK visit. Safety was assessed by standard clinical measures, including ambulatory blood pressure (BP). Results 87% of patients in both groups achieved mean T Cavg in the eugonadal range. Sodium fluoride-ethylenediamine tetra-acetate plasma T Cavg (mean ± standard deviation) for the oral TU group was 403 ± 128 ng/dL (~14 ± 4 nmol/L); serum T equivalent, ~489 ± 155 ng/dL (17 ± 5 nmol/L); and topical T, 391 ± 140 ng/dL (~14 ± 5 nmol/L). Modeling/simulation of T PK data demonstrated that dose titration based on a single blood sample 4 to 6 h after oral TU dose yielded efficacy (93%) equivalent to Cavg-based titration (87%). Safety profiles were similar in both groups, but oral TU was associated with a mean increase in systolic BP of 3 to 5 mm Hg. Conclusion A new oral TU formulation effectively restored T to mid-eugonadal levels in hypogonadal patients.

INTRODUCTION AND OBJECTIVE: A new, first-in-class oral testosterone (T) replacement therapy product [T-undecanoate (TU) capsules] was recently approved by FDA to treat appropriate hypogonadal men. Two clinical trials were conducted to evaluate, in part, the impact of oral TU therapy on important secondary efficacy endpoints: a) Psycho-sexual and/or general health/well-being (Trial I and II) and; b) Body composition (Trial II). METHODS: Hypogonadal men (AM serum T ≤ 300 ng/dL) age 18 to 65 (Trial I) or 75 years old (Trial II) were randomized into open-label, active-comparator (T-gel/solution) trials. Subjects received: Trial 1: Either oral TU (n=166) or a topical T solution (Axiron®; n=55) for 4-6 mos.; or Trial II: Oral TU (n=162) or T-gel (AndroGel® 1%; n=163) for 12 mos. The starting oral TU dose (with food) was 237 mg TU, BID in Trial I and 316 mg TU, BID in Trial II; up to 2 dose-titration opportunities were available to achieve eugonadal T concentrations (Cavg; assayed by LC-MS/MS). In Trial I, Psycho-sexual Daily Questionnaires (PDQ) were completed by study subjects for 7 days at baseline and prior to final clinic visit (Day 105-180). In Trial II, the SF-36 well-being questionnaire was completed on Days 0, 30, 90, 180, 270 and 365 and PDQs were completed for 7 days prior to clinic visits on these same days. Body composition was assessed by DEXA scan on Days 0, 180 and 365. Safety was monitored by physical exam and standard clinical laboratory tests. RESULTS: Serum T Cavg in response to oral TU was 489 ± 155 ng/dL (mean ± SD) (Trial I) and 628 ± 342 ng/dL (Trial II); 84% of subjects in each trial achieved T Cavg in the eugonadal range. Mean changes from baseline for SF-36 well-being parameters increased significantly in both oral TU and topical T groups. Psycho-sexual questionnaire results also demonstrated statistically significant improvement (p<0.0001) in each parameter at Day 30 and all time points thereafter. At Day 365, oral TU was associated with a statistically significant reduction in fat mass [-2.4 ± 3.6 (SD) kg] and increase in lean mass (+3.2 ± 2.7 kg). Oral TU also significantly increased mean BMD over baseline in hip [+0.01 ± 0.04 (SD) g/cm2] and spine (+0.01 ± 0.02 g/ cm2]. Oral TU exhibited a safety profile consistent with other available T-replacement products -- including the potential to increase blood pressure in some men. CONCLUSIONS: Treatment of hypogonadal men with oral TU yielded circulating T Cavg concentrations in the mid-eugonadal range and significantly improved psycho-sexual, general well-being and body composition parameters. Source of Funding: Clarus Therapeutics, Inc.

Abstract Introduction and Objective: A new, first-in-class oral testosterone (T) replacement therapy product [T-undecanoate (TU) capsules] was recently approved by FDA to treat hypogonadal men. Clinical trials were conducted to evaluate, in part, the impact of oral TU therapy on important secondary efficacy endpoints: Psychosexual and/or general well-being (Trial I and II); and body composition and bone mineral density (BMD) (Trial II). Subject and Methods: Hypogonadal men (AM serum T ≤ 300 ng/dL) age 18 to 65 (Trial I) or 75 years old (Trial II) were randomized into open-label, active-comparator (T-gel/solution) trials. Subjects received: Trial 1: Oral TU (n=166) or a topical T solution (n=55) for 4-6 mos.; or Trial II: Oral TU (n=162) or T-gel (n=163) for 12 mos. The starting oral TU dose (with food) was 237 mg, BID in Trial I and 316 mg, BID in Trial II; up to 2 dose-titration opportunities were available to achieve eugonadal T concentrations (assayed by LC-MS/MS). In Trial I, Psychosexual Daily Questionnaires (PDQ) were completed by study subjects for 7 days at baseline and prior to final clinic visit (Day 105-180). In Trial II, the SF-36 well-being questionnaire was completed on Days 0, 30, 90, 180, 270 and 365 and PDQs were completed for 7 days prior to clinic visits on these same days. In Trial II body composition and BMD was assessed by DEXA scan on Days 0, 180 and 365. Safety was monitored by physical exam and standard clinical lab tests. Results: Mean serum T in response to oral TU was 489 ± 155 ng/dL (mean ± SD) (Trial I) and 628 ± 342 ng/dL (Trial II); 84% of subjects in each trial achieved mean T concentrations in the eugonadal range. Statistically significant mean changes from baseline (p<0.0001) for most SF-36 well-being parameters were observed in both oral TU and T-gel groups. Psychosexual questionnaire results also demonstrated statistically significant improvement over baseline (p<0.0001) in most parameters at Day 30 and all timepoints thereafter in both trials. On Days 180 and 365 (v. baseline) oral TU was associated with a significant reduction in fat mass [-1.92 ± 2.79 (SD) and -2.4 ± 3.6 kg, respectively] (p<0.0001) and an increase in lean body mass [+2.87 ± 2.73 and +3.15 ± 2.69 kg, respectively] (p<0.0001). Oral TU increased mean BMD over baseline on Days 180 and 365 in spine [+0.013 ± 0.035 and +0.018 ± 0.042 g/cm2, respectively (p<0.0001)] and hip [+0.006 ± 0.019 and +0.012 ± 0.023 g/cm2, respectively (p<0.0001)]. Oral TU exhibited a safety profile consistent with commonly prescribed topical T-comparators. Modest increases in cuff sBP of 2.8 ± 11.84 (SD) mm Hg and 1.8 ± 10.76 mm Hg were observed in Trial I for both oral TU and the comparator T-solution. Conclusions: Treatment of hypogonadal men with oral TU yielded circulating mean T concentrations in the mid-eugonadal range and significantly improved psychosexual, general well-being, body composition and BMD parameters comparable to transdermal T administration.

Background: A novel formulation of oral testosterone undecanoate (TU) was studied in a long- and short-term phase III trial to evaluate safety and efficacy. Methods: Hypogonadal men (age 18–65 years; two morning serum testosterone (T) <300 ng/dl with signs/symptoms) were recruited into a 365 day (trial I) or 105 day (trial II), randomized, multicenter trial. Patients were randomized 1:1 to oral TU ( n = 161) or T-gel ( n = 160) in trial I, and 3:1 to oral TU, twice daily (BID) JATENZO® ( n = 166) or a topical T product [Axiron® ( n = 56)] in trial II. Dose adjustments were based on average T concentrations ( C avg). Efficacy was assessed based on T levels, body composition and bone density. Safety was assessed by standard clinical measures. Results: Oral TU efficacy (% of patients with eugonadal T C avg) was 84% (serum C avg = 628 ± 343 ng/dl) and 87% (serum T equivalent C avg ≈ 489 ± 155 ng/dl) in trials I and II, respectively. Oral TU significantly ( p <0.0001) improved all Psychosexual Daily Questionnaire parameters in trials I and II. In trial I, lean mass increased 3.2 ± 2.7 kg and fat decreased by 2.4 ± 3.6 kg (both p <0.0001) and bone density improved in hip (+0.012 ± 0.0225 g/cm 2 ) and spine (+0.018 ± 0.0422 g/cm 2 ) after 365 days (both p <0.0001). Oral TU-associated adverse effects were consistent with other T-replacement therapies but oral TU patients experienced a greater number of mild gastrointestinal adverse effects. Oral TU subjects in both studies exhibited an increase in mean systolic blood pressure of about 3–5 mmHg. Oral TU was not associated with liver toxicity nor did it cause an elevation in high-sensitivity C-reactive protein or lipoprotein-associated phospholipase A 2 (cardiovascular safety biomarkers) after 365 days of therapy. Conclusion: A new oral TU formulation was safe and effective and represents a significant therapeutic advance for the treatment of appropriate hypogonadal men.

You have accessJournal of UrologySexual Function/Dysfunction: Medical, Hormonal & Non-surgical Therapy III (MP58)1 Apr 2019MP58-17 MONITORING TESTOSTERONE (T) LEVELS IN MEN RECEIVING ORAL TESTOSTERONE UNDECANOATE (TU): DEALING WITH POST-COLLECTION CONVERSION OF TU TO T Jed Kaminetsky*, Marc Gittelman, Ronald Swerdloff, James Longstreth, Robert Dudley, and Theodore Danoff Jed Kaminetsky*Jed Kaminetsky* More articles by this author , Marc GittelmanMarc Gittelman More articles by this author , Ronald SwerdloffRonald Swerdloff More articles by this author , James LongstrethJames Longstreth More articles by this author , Robert DudleyRobert Dudley More articles by this author , and Theodore DanoffTheodore Danoff More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000556709.56920.43AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: Measuring T levels during T replacement therapy is critical to guide dosing decisions. Post-collection conversion of TU to T by esterases in blood from men receiving oral TU can raise measured T levels substantially above actual levels and result in inappropriate titration decisions. We identified a method for T monitoring to address this problem. METHODS: We evaluated post-collection conversion of TU to T in blood drawn from men who had received a new oral TU and in blood spiked with TU after collection. Blood was collected in Plain, EDTA or NaF-EDTA tubes and then incubated for periods between 0 and 3 hours, at room temperature (RT) or on ice. After incubation, blood was centrifuged and the matrix (serum or plasma) isolated. T and TU concentrations were measured by LC/MS-MS. Regression analysis of rate of changes of T concentration during incubation v. TU concentration was used to develop algorithms to correct for T overestimation. Algorithm accuracy was tested using results from the Phase 3 inTUne Trial of Clarus' oral TU. RESULTS: T concentrations increase in blood samples containing TU as they await centrifugation. The rate of TU to T conversion depends on TU concentration, incubation temperature, and presence of NaF, an esterase inhibitor. Incubation temperature impacted TU to T conversion the most - rate at RT >5-fold faster than on ice; NaF had less effect than temperature. Most clinic T levels are measured in serum; however, titration in the inTUne Trial of oral TU was based on T in NaF-EDTA plasma. Equations were derived to convert the T concentration measured in one matrix to another. Based on regression analysis of T concentrations in serum and NaF-EDTA plasma, a conversion factor of 1.214 was derived to convert a NaF-EDTA plasma T value to an equivalent serum T value for samples collected 6 hours post-dose (optimal dose-titration sample point for our oral TU). When this conversion factor was tested using T data collected from the inTUne PK visit where both NaF-EDTA plasma and serum were collected, comparing measured serum T values with values derived from plasma T demonstrated a mean error of only 3.1% (N=155; 95% CI 0.4%, 5.8%). CONCLUSIONS: Post-collection conversion of TU to T can cause overestimation of circulating T levels in men dosed with oral TU. By accounting for the conversion with different tube types / handling conditions, a conversion factor was derived such that T concentrations in our oral TU patients can be monitored using serum T levels. This conversion factor was validated using in TUne data. Source of Funding: Clarus Therapeutics, Inc. New York, NY; Adventura, FL; Torrance, CA; Mundelein, IL; Northbrook, IL© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e859-e859 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jed Kaminetsky* More articles by this author Marc Gittelman More articles by this author Ronald Swerdloff More articles by this author James Longstreth More articles by this author Robert Dudley More articles by this author Theodore Danoff More articles by this author Expand All Advertisement PDF downloadLoading ...

Introduction: Measuring T levels, in addition to monitoring symptoms, during T replacement therapy is critical to guide dosing decisions. T levels in blood samples from men receiving oral TU can be elevated substantially above actual circulating T levels due to post-collection conversion of TU to T by esterases in blood. Because erroneous T values can result in inappropriate dose-titration decisions, we identified a method for monitoring T that addresses this problem. Methods: Post-collection conversion of TU to T was evaluated in blood drawn from men who had received oral TU (either JATENZO®, Clarus’s oral TU, or Andriol®) and in blood spiked with TU after collection. Blood was collected in Plain, EDTA or NaF-EDTA tubes and then incubated for selected times (up to 3 hours) at room temperature (RT) or on ice. After incubation, blood was centrifuged and the matrix (serum or plasma) was used for measurement of T and TU concentrations by LC/MS-MS. Regression analysis of rate of change of T concentration during incubation versus TU concentration was used to develop algorithms to correct for T overestimation. Algorithm accuracy was tested using results from the Phase 3 inTUne Trial of JATENZO. Results: T concentrations increase in blood containing TU as the blood sits pre-centrifugation, regardless of whether the TU is in the blood when collected or spiked post-collection. The rate of TU conversion depends on the TU concentration, incubation temperature, and presence of NaF, an esterase inhibitor. Incubation temperature had the greatest impact on conversion - rate at RT >5-fold faster than on ice; NaF had a smaller effect. Most clinic T levels are routinely measured in serum from Plain tubes; however, titration in the inTUne Trial of oral TU was based on T in NaF-EDTA plasma. Based on regression analysis of the TU to T conversion rates measured in serum and NaF-EDTA plasma and the NaF effect on measured T levels, a conversion factor of 1.214 was derived to convert a NaF-EDTA plasma T value to an equivalent serum T value for samples collected 6 hours post-dose (the optimal dose-titration sample point for JATENZO). This conversion factor was tested against T data collected during the final PK Visit of the inTUne Trial (87% of subjects attained eugonadal range based on NaF-EDTA plasma T levels) where serum T levels were also measured. Using the conversion factor to compare the measured serum T value with its matched plasma value, we observed a mean error of only 3.1% (n=155 sample pairs; 95% CI 0.4%, 5.8%). Conclusion: Post-collection conversion of TU to T can cause overestimation of circulating T levels in men dosed with oral TU. By accounting for the conversion with different tube types / handling conditions, a conversion factor was derived to allow monitoring of T concentration in JATENZO patients using serum. This conversion factor was validated for JATENZO against the Phase 3 inTUne data.

BACKGROUND:Ex vivo androgen prodrug conversion by blood esterases after oral androgen ester administration may result in an overestimation of the measured blood androgens. OBJECTIVE:We investigated whether blood collection tubes with esterase inhibitors decreased the conversion of testosterone undecanoate (TU) and dimethandrolone undecanoate (DMAU) to their active metabolites, testosterone (T), and dimethandrolone (DMA), providing a more accurate assessment of circulating T/DMA levels. METHODS:Blood was collected in tubes with/without esterase inhibitors from: (i) four healthy and four hypogonadal men receiving no androgens and spiked ex vivo with TU/DMAU; (ii) four men taking oral TU (Andriol® ); and (iii) eight hypogonadal men dosed with oral 316 mg TU and 15 healthy men with 200 mg DMAU. T/DMA levels were measured by LC-MS/MS. RESULTS:Sodium fluoride (NaF, an esterase inhibitor) decreased measured T levels by 14.2% in men not receiving TU. Increasing amounts of TU/DMAU added to blood collected into plain tubes resulted in a concentration-dependent overestimation of T/DMA that was reduced by collecting blood into NaF tubes (by 30-85%), and keeping samples at 4 °C and minimizing time prior to centrifugation. After oral TU/DMAU administration to men, when TU/DMAU levels were >15/10 ng/mL, respectively, blood collected in NaF tubes yielded lower measured T concentrations by 15-30% and DMA by 22% due to an additional inhibitory effect of NaF on blood esterases. CONCLUSION:NaF directly lowers plasma T/DMA levels measured by LC-MS/MS and also inhibits blood esterase activity. Overestimation of T/DMA in blood collected in tubes without NaF after oral TU/DMAU administration is important for pharmacokinetics studies in drug development clinical trials but may have limited impact in clinical practice/utilization because the differences between measured and true androgen values are modest and the wide therapeutic androgen efficacy ranges obviate the need for highly accurate androgen measurements during therapy.

Benefits associated with lowered serum DHT levels after 5α-reductase inhibitor (5AR-I) therapy in men have contributed to a misconception that circulating DHT levels are an important stimulus for androgenic action in target tissues (e.g., prostate). Yet evidence from clinical studies indicates that intracellular concentrations of androgens (particularly in androgen-sensitive tissues) are essentially independent of circulating levels. To assess the clinical significance of modest elevations in serum DHT and the DHT/testosterone (T) ratio observed in response to common T replacement therapy, a comprehensive review of the published literature was performed to identify relevant data. Although the primary focus of this review is about DHT in men, we also provide a brief overview of DHT in women. The available published data are limited by the lack of large, well-controlled studies of long duration that are sufficiently powered to expose subtle safety signals. Nonetheless, the preponderance of available clinical data indicates that modest elevations in circulating levels of DHT in response to androgen therapy should not be of concern in clinical practice. Elevated DHT has not been associated with increased risk of prostate disease (e.g., cancer or benign hyperplasia) nor does it appear to have any systemic effects on cardiovascular disease safety parameters (including increased risk of polycythemia) beyond those commonly observed with available T preparations. Well-controlled, long-term studies of transdermal DHT preparations have failed to identify safety signals unique to markedly elevated circulating DHT concentrations or signals materially different from T.