madman
Super Moderator
Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety (2022)
Stanton Honig, MD, Marc Gittelman, MD, Jed Kaminetsky, MD, Christina Wang, MD, John K. Amory, MD, Nestor Rohowsky, MA, Robert E. Dudley, Ph.D., B. Woun Seo, Ph.D, Jay Newmark, MD, and Ronald Swerdloff, MD
ABSTRACT
Background: Long-term data evaluating the efficacy and safety of oral testosterone undecanoate (oral TU; JATENZO) in adult hypogonadal men provides important information for healthcare professionals who prescribe testosterone replacement therapy (TRT).
Aim: To determine the efficacy and safety of long-term oral TU therapy, including its impact on total testosterone (T) levels and psychosexual functioning.
Methods: Hypogonadal men, between 18 and 75 years old, (mean age 56.2; 87.2% white) who completed a 12- month, open-label, multicenter, randomized, active-controlled trial were given the opportunity to enroll in a 12- month extension study. Among the 129 eligible TU-treated subjects, 86 chose this option, and 69 completed 24 months of uninterrupted oral TU therapy.
Outcomes: The efficacy of oral TU was documented by measuring total serum T concentrations; sexual function was measured using the Psychosexual Daily Questionnaire (PDQ). For safety, liver function tests, cardiovascular endpoints, and prostate health were measured.
Results: Over 2 years, total serum T concentrations for patients treated with oral TU were in the eugonadal range (300−1,000 ng/dL [10−35 nmol/L]; mean § SD: 617 § 427 ng/dL [21 § 15 nmol/L]) and increased significantly from baseline (P < .0001). For sexual function, mean score changes versus baseline for all PDQ domains at all time points were significantly improved (P < .0011 for all). For the sexual activity and sexual desire components, patient scores were consistently greater than validated thresholds for clinically meaningful change. Typical Tinduced safety changes were observed, including a 3−6 mm Hg increase in systolic blood pressure (P < .05); a slight increase in hematocrit (P < .0001) that stayed <48% throughout the study; no clinically significant changes in prostate-specific antigen levels; and decreased high-density lipoprotein cholesterol (-9.8 § 0.9 mg/dL from baseline; P < .0001). There were no clinically significant changes from baseline in liver function tests.
Clinical Implications: Over 2 years of treatment, this novel oral TU formulation maintained total T concentrations in mideugonadal ranges, with improvements in sexual function and no clinically significant changes in liver function or other safety concerns previously associated with oral TRT.
Strengths & Limitations: These are the first long-term data to evaluate the efficacy and safety of a novel formulation of oral TU; the comparative long-term safety of oral TU would be strengthened by confirmatory studies versus other TRT formulations.
Conclusion: Oral TU offers a safe and effective long-term treatment option for men with hypogonadism.
INTRODUCTION
Testosterone (T) is the primary androgenic hormone responsible for the normal growth, development, and maintenance of male sex organs and secondary sex characteristics.1 Deficient production of T with associated symptoms may occur due to various etiologies including structural and genetic defects, metabolic perturbations (eg, metabolic syndrome), and disease (eg, type 2 diabetes, chronic kidney disease). To ameliorate the effects of low T production, there are a variety of different testosterone hormone replacement therapies (TRT)2 that include intramuscular injections, transdermal applications, and implantable pellets. More recently, T can be delivered by subcutaneous administration, nasal gel, and buccal mucoadhesive formulations.3,4 Each mode of administration is associated with recognized drawbacks, such as injection site pain, skin irritation, and risk of T transference. Until recently, a safe and effective oral treatment option was not available in the U.S.4 Oral T is subject to extensive first-pass metabolism in the gastrointestinal tract and the liver.5 Currently, there are 2 available oral TRT formulations approved for the treatment of hypogonadism by the U.S. Food and Drug Administration (FDA).6 The first, methyltestosterone, is a C-17 alkylated T analog that is resistant to first-pass hepatic clearance but associated with significant hepatotoxicity.4,6,7 Indeed, treatment guidelines for the management of T deficiency, published in 2018 by the American Urological Association and the Endocrine Society, recommend that clinicians avoid prescribing alkylated oral T analogs, such as methyltestosterone, due to associated liver toxicity.3,7
The second FDA-approved oral TRT is JATENZO (oral TU capsules), a recently approved (2019) prodrug formulation of T undecanoate (TU),8,9 To reduce first-pass hepatic clearance, oral TU is formulated in a self-emulsifying drug delivery system (SEDDS) that comprises a lipid and surfactant matrix designed to increase the absorption of TU- via intestinal lymphatics thus bypassing the liver. Upon dissolution of the TU SEDDS formulation in proximal gastrointestinal fluids, TU is encapsulated in lipid micelles that are exclusively absorbed into the intestinal lymphatics system which then delivers TU into the systemic circulation via the thoracic duct. The androgenic activity of TU results from the liberation of T by endogenous esterases. The improved bioavailability of this novel oral TU formulation allows for twice-daily (BID) administration with a regular morning and evening meal.8
The efficacy and safety of oral TU have been previously demonstrated in two randomized, active-controlled, open-label, phase 3 clinical trials.8,10 In the first trial (ClinicalTrials.gov identifier: NCT01403116), 161 men were treated with oral TU for up to 12 months7; in the second trial (ClinicalTrials.gov identifier: NCT02722278), 166 men received oral TU for 3−4 months.10 At the completion of both studies, 83.6−87.3% of patients treated with oral TU, respectively, had achieved mean T concentrations (Cavg) in the eugonadal range. Oral TU was also generally safe and well tolerated and yielded clinical responses consistent with the known effects of TRT. Importantly, liver toxicity was not observed. Both studies evaluated patient sexual function, utilizing the Psychosexual Daily Questionnaire (PDQ).8,10
This study presents previously unpublished 2-year efficacy, including psychosexual functioning, and safety data from the above-mentioned 12-month trial and its 12-month extension. The primary efficacy objective was to measure changes in total serum T concentrations for patients receiving long-term oral TU treatment. Another key efficacy objective was to evaluate the effect of long-term oral TU administration on changes in sexual symptoms, as measured by the PDQ. The primary safety objective was to define the long-term safety profile of oral TU, focusing on liver function, evaluated by standard liver function tests, and cardiovascular endpoints, evaluated by change in hematocrit, blood pressure, and lipid parameters, and prostate health, evaluated by change in prostate-specific antigen (PSA) and voiding function as measured by the American Urological Association International Prostate Symptom Score (AUA-IPSS).
DISCUSSION
This study summarizes the efficacy and safety of an oral TU SEDDS formulation over 2 years of treatment in hypogonadal men. Within 1 month of treatment initiation, total serum T concentrations reached the mideugonadal range, and this effect persisted over 24 months. Patients receiving oral TU reported better sexual function, evidenced by statistically significant and clinically meaningful improvements in PDQ scores that were initially observed on Day 30 and persisted over 24 months. Furthermore, oral TU exhibited a good safety profile that was both expected in context with prior research,4,10 and consistent with other TRT formulations available to treat TRT.18−21 Patients had no clinically significant changes in liver function tests, and while SBP increased slightly from baseline, this effect plateaued after several months. Additionally, oral TU did not result in a clinically meaningful increase in PSA and did not alter other prostate function parameters (consistent with the slight PSA increases observed with other TRTs, especially with intramuscular administration).19
These findings confirm the long-term efficacy of oral TU, initially established via two prior phase 3 evaluations of substantially shorter duration.4,10 Specific to sexual function, current results are consistent with existing research showing improved libido and sexual satisfaction and function in hypogonadal men treated with TRT,22,23 including research conducted using the PDQ instrument,14,15 and prior research in patients treated with oral TU.4,24 In addition to statistically significant improvements in all PDQ domains, treatment with oral TU was associated with significant and sustained clinical improvement in sexual activity and sexual desire, based on thresholds established by PDQ validation models of sexual activity (established sexual activity threshold ≥0.7: current analysis »1.0−1.2; sexual desire threshold ≥0.6: current analysis »1.5−1.8).14,15
In terms of safety, an important clinical finding from this study is the absence of liver toxicity in a continuously treated cohort over 24 months of follow-up. Oral androgens have long been associated with hepatoxicity,2,5 and although this effect is directly associated with the alkylation of T at the C-17 position (to avoid first-pass hepatic metabolism), oral administration of any TRT continues to be of potential concern.4 The current data are also consistent with those observed in a placebo-controlled trial of a different oral TU formulation administered for 15 months at a lower daily dose and at lower serum T concentrations.18
Although an increase in mean hematocrit occurred in men treated with oral TU, this remained below the ULN and stabilized after Day 180. Hematocrit increases were consistent with the TRT “class” effect. Among men undergoing TRT, T-induced hematocrit elevations are common, and the attendant risk of developing erythrocytosis is well-established. Polycythemia (defined as hematocrit >54%) is the most common dose-limiting adverse effect associated with TRT, particularly in response to parenteral TRT preparations,25 and was the second most frequently observed TEAE in the present study, affecting 7.0% (6/86) of patients receiving oral TU over 24 months. Nonetheless, no patients ceased oral TU therapy due to high hematocrit.
The effects of oral TU on lipid parameters were also consistent with the TRT class effect. Specifically, meta-analyses of hypogonadal men receiving TRT have generally shown that exogenous T lowers HDL-C and is associated with concomitant LDL-C and TC lowering.26−28 In the present study, HDL-C decreased by approximately 23% over the first 30 days of treatment and then stabilized. TC levels decreased significantly throughout the study, and LDL-C was unaffected. The absence of increases in TC and LDL-C in response to long-term oral TU therapy is noteworthy, as significant elevations in these lipid fractions (particularly LDLC) are unequivocal risk factors for cardiovascular disease.29
The modest increase in systolic blood pressure (SBP) observed in this analysis is consistent with subsequent findings from shorter-term studies of oral TU,7,13, as well as SBP findings from clinical studies for different oral TU formulations20,21 and parenterally, administered T enanthate.30 The mechanism for this pressor effect remains unclear; data from the initial 12 months of the current study were evaluated to identify factors potentially related to SBP (eg, estradiol and dihydrotestosterone concentrations, hematocrit, heart rate, hemoglobin, oral TU dose, potassium, and total and free T), but none of these correlated with increased SBP.10 Therefore, per the package insert boxed warning, healthcare practitioners who prescribe oral TU should regularly monitor patient blood pressure.9
These safety findings are consistent with the previous phase 3 studies showing that oral TU is generally safe and well tolerated.4,10 In one study, over 3−4 months of follow-up, the most common TEAEs that occurred in patients receiving oral TU were headache (4.8%), increased hematocrit (4.8%), upper respiratory tract infection (3.6%), hypertension (3.0%), decreased HDL-C (3.0%), and nausea (2.4%).10 Similarly, oral TU was found to be safe and tolerable in the first 12 months of the present study, where the most common TEAEs (occurring in ≥2% of patients) in the oral TU treatment group were elevated hematocrit (6.8%), enlarged prostate (5.6%), peripheral edema (5.5%), hypertension (3.7%), diarrhea (3.1%), elevated PSA (2.5%), and eructation (2.5%).4 The incidence of these TEAEs decreased numerically over 24 months of oral TU therapy, aside from elevated PSA, which persisted at a similar rate throughout the study.
Oral TU formulated in a SEDDS formulation represents a therapeutic advance that may promote improved patient adherence in the treatment of male hypogonadism. A U.S. retrospective claims analysis (2007−2014) conducted in men initiating topical TRT (N = 3184) showed very low medication adherence rates; at 12 months, only 17% of remained treatment-adherent (defined as ≥80% proportion of days covered).31 In contrast, a randomized controlled clinical study of an oral TU formulation (N = 237) approved in Europe found strong treatment adherence at 6 months with twice-daily dosing, with >90% of patients using ≥80% of their medication.18 There are several reasons why oral TU may promote improved patient adherence. It is more straightforward to use than injectable or transdermal T preparations, which are associated with administration site pain and T skin-to-skin transference, respectively.4 Postmarketing surveillance of T gel has captured cases of secondary exposure to children, resulting in virilization32, and has led to a boxed warning on product labeling in this regard. Furthermore, up to 12.7% of patients in clinical trials receiving T injections experience injection-site reactions (eg, bruising, hemorrhage, erythema, and induration).33,34 The benefits of treatment adherence to T therapy in hypogonadal men observed over 12 months of follow-up included improvements in fatigue, depression, sexual dysfunction, insomnia, and/or osteoarthritis.32
Strengths and Limitations
This study provides the first long-term data regarding the safety of a novel SEDDS formulation of oral TU. One potential limitation is that data in the current 2-year analysis were observational and not compared with a control or active-treatment group. However, this patient population was compared to a cohort treated with transdermal T in the initial 1-year randomized study. That analysis found similar efficacy and safety outcomes between the formulations.4 Nonetheless, the comparative long-term safety of oral TU vs transdermal T gel and other T formulations would be strengthened by confirmatory studies. In addition, while the number of patients followed for 2 years in this study was modest in size, it is sufficiently large to derive comfort that the observations regarding the safety of oral TU are accurate, and thus reassuring for medical practitioners who may prescribe oral TU for appropriate hypogonadal patients.
In addition, the PDQ was utilized to evaluate multiple parameters of sexual function, more appropriate for evaluating patients who are treated with testosterone therapy. We did not evaluate erectile dysfunction with the IIEF questionnaire in this study.
CONCLUSION
Over 2 years, a novel oral TU formulation maintained total T concentrations in mideugonadal ranges and patients showed statistically significant and clinically meaningful improvements in sexual function based on the PDQ. Treatment with oral TU did not lead to any clinically significant changes in liver function or other safety concerns previously associated with oral TRT. Oral TU may offer a safe and effective long-term treatment option for men with hypogonadism.
Stanton Honig, MD, Marc Gittelman, MD, Jed Kaminetsky, MD, Christina Wang, MD, John K. Amory, MD, Nestor Rohowsky, MA, Robert E. Dudley, Ph.D., B. Woun Seo, Ph.D, Jay Newmark, MD, and Ronald Swerdloff, MD
ABSTRACT
Background: Long-term data evaluating the efficacy and safety of oral testosterone undecanoate (oral TU; JATENZO) in adult hypogonadal men provides important information for healthcare professionals who prescribe testosterone replacement therapy (TRT).
Aim: To determine the efficacy and safety of long-term oral TU therapy, including its impact on total testosterone (T) levels and psychosexual functioning.
Methods: Hypogonadal men, between 18 and 75 years old, (mean age 56.2; 87.2% white) who completed a 12- month, open-label, multicenter, randomized, active-controlled trial were given the opportunity to enroll in a 12- month extension study. Among the 129 eligible TU-treated subjects, 86 chose this option, and 69 completed 24 months of uninterrupted oral TU therapy.
Outcomes: The efficacy of oral TU was documented by measuring total serum T concentrations; sexual function was measured using the Psychosexual Daily Questionnaire (PDQ). For safety, liver function tests, cardiovascular endpoints, and prostate health were measured.
Results: Over 2 years, total serum T concentrations for patients treated with oral TU were in the eugonadal range (300−1,000 ng/dL [10−35 nmol/L]; mean § SD: 617 § 427 ng/dL [21 § 15 nmol/L]) and increased significantly from baseline (P < .0001). For sexual function, mean score changes versus baseline for all PDQ domains at all time points were significantly improved (P < .0011 for all). For the sexual activity and sexual desire components, patient scores were consistently greater than validated thresholds for clinically meaningful change. Typical Tinduced safety changes were observed, including a 3−6 mm Hg increase in systolic blood pressure (P < .05); a slight increase in hematocrit (P < .0001) that stayed <48% throughout the study; no clinically significant changes in prostate-specific antigen levels; and decreased high-density lipoprotein cholesterol (-9.8 § 0.9 mg/dL from baseline; P < .0001). There were no clinically significant changes from baseline in liver function tests.
Clinical Implications: Over 2 years of treatment, this novel oral TU formulation maintained total T concentrations in mideugonadal ranges, with improvements in sexual function and no clinically significant changes in liver function or other safety concerns previously associated with oral TRT.
Strengths & Limitations: These are the first long-term data to evaluate the efficacy and safety of a novel formulation of oral TU; the comparative long-term safety of oral TU would be strengthened by confirmatory studies versus other TRT formulations.
Conclusion: Oral TU offers a safe and effective long-term treatment option for men with hypogonadism.
INTRODUCTION
Testosterone (T) is the primary androgenic hormone responsible for the normal growth, development, and maintenance of male sex organs and secondary sex characteristics.1 Deficient production of T with associated symptoms may occur due to various etiologies including structural and genetic defects, metabolic perturbations (eg, metabolic syndrome), and disease (eg, type 2 diabetes, chronic kidney disease). To ameliorate the effects of low T production, there are a variety of different testosterone hormone replacement therapies (TRT)2 that include intramuscular injections, transdermal applications, and implantable pellets. More recently, T can be delivered by subcutaneous administration, nasal gel, and buccal mucoadhesive formulations.3,4 Each mode of administration is associated with recognized drawbacks, such as injection site pain, skin irritation, and risk of T transference. Until recently, a safe and effective oral treatment option was not available in the U.S.4 Oral T is subject to extensive first-pass metabolism in the gastrointestinal tract and the liver.5 Currently, there are 2 available oral TRT formulations approved for the treatment of hypogonadism by the U.S. Food and Drug Administration (FDA).6 The first, methyltestosterone, is a C-17 alkylated T analog that is resistant to first-pass hepatic clearance but associated with significant hepatotoxicity.4,6,7 Indeed, treatment guidelines for the management of T deficiency, published in 2018 by the American Urological Association and the Endocrine Society, recommend that clinicians avoid prescribing alkylated oral T analogs, such as methyltestosterone, due to associated liver toxicity.3,7
The second FDA-approved oral TRT is JATENZO (oral TU capsules), a recently approved (2019) prodrug formulation of T undecanoate (TU),8,9 To reduce first-pass hepatic clearance, oral TU is formulated in a self-emulsifying drug delivery system (SEDDS) that comprises a lipid and surfactant matrix designed to increase the absorption of TU- via intestinal lymphatics thus bypassing the liver. Upon dissolution of the TU SEDDS formulation in proximal gastrointestinal fluids, TU is encapsulated in lipid micelles that are exclusively absorbed into the intestinal lymphatics system which then delivers TU into the systemic circulation via the thoracic duct. The androgenic activity of TU results from the liberation of T by endogenous esterases. The improved bioavailability of this novel oral TU formulation allows for twice-daily (BID) administration with a regular morning and evening meal.8
The efficacy and safety of oral TU have been previously demonstrated in two randomized, active-controlled, open-label, phase 3 clinical trials.8,10 In the first trial (ClinicalTrials.gov identifier: NCT01403116), 161 men were treated with oral TU for up to 12 months7; in the second trial (ClinicalTrials.gov identifier: NCT02722278), 166 men received oral TU for 3−4 months.10 At the completion of both studies, 83.6−87.3% of patients treated with oral TU, respectively, had achieved mean T concentrations (Cavg) in the eugonadal range. Oral TU was also generally safe and well tolerated and yielded clinical responses consistent with the known effects of TRT. Importantly, liver toxicity was not observed. Both studies evaluated patient sexual function, utilizing the Psychosexual Daily Questionnaire (PDQ).8,10
This study presents previously unpublished 2-year efficacy, including psychosexual functioning, and safety data from the above-mentioned 12-month trial and its 12-month extension. The primary efficacy objective was to measure changes in total serum T concentrations for patients receiving long-term oral TU treatment. Another key efficacy objective was to evaluate the effect of long-term oral TU administration on changes in sexual symptoms, as measured by the PDQ. The primary safety objective was to define the long-term safety profile of oral TU, focusing on liver function, evaluated by standard liver function tests, and cardiovascular endpoints, evaluated by change in hematocrit, blood pressure, and lipid parameters, and prostate health, evaluated by change in prostate-specific antigen (PSA) and voiding function as measured by the American Urological Association International Prostate Symptom Score (AUA-IPSS).
DISCUSSION
This study summarizes the efficacy and safety of an oral TU SEDDS formulation over 2 years of treatment in hypogonadal men. Within 1 month of treatment initiation, total serum T concentrations reached the mideugonadal range, and this effect persisted over 24 months. Patients receiving oral TU reported better sexual function, evidenced by statistically significant and clinically meaningful improvements in PDQ scores that were initially observed on Day 30 and persisted over 24 months. Furthermore, oral TU exhibited a good safety profile that was both expected in context with prior research,4,10 and consistent with other TRT formulations available to treat TRT.18−21 Patients had no clinically significant changes in liver function tests, and while SBP increased slightly from baseline, this effect plateaued after several months. Additionally, oral TU did not result in a clinically meaningful increase in PSA and did not alter other prostate function parameters (consistent with the slight PSA increases observed with other TRTs, especially with intramuscular administration).19
These findings confirm the long-term efficacy of oral TU, initially established via two prior phase 3 evaluations of substantially shorter duration.4,10 Specific to sexual function, current results are consistent with existing research showing improved libido and sexual satisfaction and function in hypogonadal men treated with TRT,22,23 including research conducted using the PDQ instrument,14,15 and prior research in patients treated with oral TU.4,24 In addition to statistically significant improvements in all PDQ domains, treatment with oral TU was associated with significant and sustained clinical improvement in sexual activity and sexual desire, based on thresholds established by PDQ validation models of sexual activity (established sexual activity threshold ≥0.7: current analysis »1.0−1.2; sexual desire threshold ≥0.6: current analysis »1.5−1.8).14,15
In terms of safety, an important clinical finding from this study is the absence of liver toxicity in a continuously treated cohort over 24 months of follow-up. Oral androgens have long been associated with hepatoxicity,2,5 and although this effect is directly associated with the alkylation of T at the C-17 position (to avoid first-pass hepatic metabolism), oral administration of any TRT continues to be of potential concern.4 The current data are also consistent with those observed in a placebo-controlled trial of a different oral TU formulation administered for 15 months at a lower daily dose and at lower serum T concentrations.18
Although an increase in mean hematocrit occurred in men treated with oral TU, this remained below the ULN and stabilized after Day 180. Hematocrit increases were consistent with the TRT “class” effect. Among men undergoing TRT, T-induced hematocrit elevations are common, and the attendant risk of developing erythrocytosis is well-established. Polycythemia (defined as hematocrit >54%) is the most common dose-limiting adverse effect associated with TRT, particularly in response to parenteral TRT preparations,25 and was the second most frequently observed TEAE in the present study, affecting 7.0% (6/86) of patients receiving oral TU over 24 months. Nonetheless, no patients ceased oral TU therapy due to high hematocrit.
The effects of oral TU on lipid parameters were also consistent with the TRT class effect. Specifically, meta-analyses of hypogonadal men receiving TRT have generally shown that exogenous T lowers HDL-C and is associated with concomitant LDL-C and TC lowering.26−28 In the present study, HDL-C decreased by approximately 23% over the first 30 days of treatment and then stabilized. TC levels decreased significantly throughout the study, and LDL-C was unaffected. The absence of increases in TC and LDL-C in response to long-term oral TU therapy is noteworthy, as significant elevations in these lipid fractions (particularly LDLC) are unequivocal risk factors for cardiovascular disease.29
The modest increase in systolic blood pressure (SBP) observed in this analysis is consistent with subsequent findings from shorter-term studies of oral TU,7,13, as well as SBP findings from clinical studies for different oral TU formulations20,21 and parenterally, administered T enanthate.30 The mechanism for this pressor effect remains unclear; data from the initial 12 months of the current study were evaluated to identify factors potentially related to SBP (eg, estradiol and dihydrotestosterone concentrations, hematocrit, heart rate, hemoglobin, oral TU dose, potassium, and total and free T), but none of these correlated with increased SBP.10 Therefore, per the package insert boxed warning, healthcare practitioners who prescribe oral TU should regularly monitor patient blood pressure.9
These safety findings are consistent with the previous phase 3 studies showing that oral TU is generally safe and well tolerated.4,10 In one study, over 3−4 months of follow-up, the most common TEAEs that occurred in patients receiving oral TU were headache (4.8%), increased hematocrit (4.8%), upper respiratory tract infection (3.6%), hypertension (3.0%), decreased HDL-C (3.0%), and nausea (2.4%).10 Similarly, oral TU was found to be safe and tolerable in the first 12 months of the present study, where the most common TEAEs (occurring in ≥2% of patients) in the oral TU treatment group were elevated hematocrit (6.8%), enlarged prostate (5.6%), peripheral edema (5.5%), hypertension (3.7%), diarrhea (3.1%), elevated PSA (2.5%), and eructation (2.5%).4 The incidence of these TEAEs decreased numerically over 24 months of oral TU therapy, aside from elevated PSA, which persisted at a similar rate throughout the study.
Oral TU formulated in a SEDDS formulation represents a therapeutic advance that may promote improved patient adherence in the treatment of male hypogonadism. A U.S. retrospective claims analysis (2007−2014) conducted in men initiating topical TRT (N = 3184) showed very low medication adherence rates; at 12 months, only 17% of remained treatment-adherent (defined as ≥80% proportion of days covered).31 In contrast, a randomized controlled clinical study of an oral TU formulation (N = 237) approved in Europe found strong treatment adherence at 6 months with twice-daily dosing, with >90% of patients using ≥80% of their medication.18 There are several reasons why oral TU may promote improved patient adherence. It is more straightforward to use than injectable or transdermal T preparations, which are associated with administration site pain and T skin-to-skin transference, respectively.4 Postmarketing surveillance of T gel has captured cases of secondary exposure to children, resulting in virilization32, and has led to a boxed warning on product labeling in this regard. Furthermore, up to 12.7% of patients in clinical trials receiving T injections experience injection-site reactions (eg, bruising, hemorrhage, erythema, and induration).33,34 The benefits of treatment adherence to T therapy in hypogonadal men observed over 12 months of follow-up included improvements in fatigue, depression, sexual dysfunction, insomnia, and/or osteoarthritis.32
Strengths and Limitations
This study provides the first long-term data regarding the safety of a novel SEDDS formulation of oral TU. One potential limitation is that data in the current 2-year analysis were observational and not compared with a control or active-treatment group. However, this patient population was compared to a cohort treated with transdermal T in the initial 1-year randomized study. That analysis found similar efficacy and safety outcomes between the formulations.4 Nonetheless, the comparative long-term safety of oral TU vs transdermal T gel and other T formulations would be strengthened by confirmatory studies. In addition, while the number of patients followed for 2 years in this study was modest in size, it is sufficiently large to derive comfort that the observations regarding the safety of oral TU are accurate, and thus reassuring for medical practitioners who may prescribe oral TU for appropriate hypogonadal patients.
In addition, the PDQ was utilized to evaluate multiple parameters of sexual function, more appropriate for evaluating patients who are treated with testosterone therapy. We did not evaluate erectile dysfunction with the IIEF questionnaire in this study.
CONCLUSION
Over 2 years, a novel oral TU formulation maintained total T concentrations in mideugonadal ranges and patients showed statistically significant and clinically meaningful improvements in sexual function based on the PDQ. Treatment with oral TU did not lead to any clinically significant changes in liver function or other safety concerns previously associated with oral TRT. Oral TU may offer a safe and effective long-term treatment option for men with hypogonadism.
