madman
Super Moderator
Abstract
Background
Testosterone deficiency results from insufficient testosterone production. Testosterone therapy may require dose titration to reach eugonadal serum testosterone concentrations.
Objective
The primary objective was the efficacy of oral testosterone undecanoate (TLANDO; Antares Pharma Inc.) in male patients with documented hypogonadism. Secondary objectives included a comparison of oral testosterone undecanoate safety and quality-of-life assessments to 1.62% topical testosterone gel (AndroGel 1.62%;AbbVie).
Materials and methods
In this phase 3 study, 315 patients were randomized 2:1 to oral testosterone undecanoate or 1.62% topical testosterone gel (NCT02081300). Patients received 225 mg oral testosterone undecanoate twice daily, and doses were adjusted by 75 mg/dose at weeks 4 and 8 based on average serum total testosterone concentration and maximum observed serum concentration. The primary endpoint was the proportion of patients receiving oral testosterone undecanoate with serum total testosterone concentration within the eugonadal reference range (300–1140 ng/dL). Secondary endpoints included the proportion of patients with maximum serum total testosterone concentrations within predetermined limits, safety parameters, and quality-of-life endpoints including the Short Form-36v2 Health Survey, Psychosexual Daily Questionnaire, and International Prostate Symptom Score.
Results
Overall mean ± SD baseline testosterone was 205.7 ± 71.6 ng/dL. For patients receiving oral testosterone undecanoate, 87.4% demonstrated a 24-h average serum total testosterone concentration within the reference range following titration. Oral testosterone undecanoate demonstrated a nominal statistically significantly greater mean change from baseline than 1.62% topical testosterone gel for Short Form-36v2 Health Survey measures of mental health (2.91 vs. -0.10; p = 0.035), and mental component summary (3.82 vs. 0.55; p = 0.009); and Psychosexual Daily Questionnaire measure of weekly negative mood (-0.57 vs. -0.20; p = 0.021). Safety endpoints were comparable between therapies. No deaths or treatment-related serious adverse events were reported.
Discussion and conclusion
Male patients with hypogonadism receiving oral testosterone undecanoate 225 mg twice daily demonstrated improvements in libido and sexual frequency. Serum testosterone concentrations were within the reference range in 87% of patients without dose titration.
1 INTRODUCTION
Testosterone deficiency is a clinical disorder resulting from either a defect of the testes (primary hypogonadism) or failure of the hypothalamus or pituitary to produce sufficient gonadotropins (secondary hypogonadism).1–3 Diagnosis of testosterone deficiency requires measurement of two early morning total testosterone levels < 300 ng/dL with associated signs and symptoms (sexual dysfunction, delayed sexual development, loss of body hair, or small testes [< 6 mL]).2 The prevalence of symptomatic hypogonadism increases with age, and it has been estimated to be between 0.1% and 6% in the United States.4,5
Patients with testosterone deficiency who have signs and symptoms such as decreased energy, depressed mood, and reduced sexual desire should be considered for testosterone therapy, which may include intramuscular or subcutaneous injections, transdermal gels and patches, pellet implants, nasal gels, and oral capsules.2,3 Many of these approved testosterone therapies may require dose titration to reach eugonadal serum testosterone concentrations.6–8
Oral administration of natural testosterone is ineffective due to inactivation in the liver via first-pass metabolism. Methyltestosterone was the first testosterone therapy available for oral use, although itsuse has been limited due to associations with liver toxicity.9 Esterification of testosterone carbon 17-beta produced testosterone esters, such as testosterone propionate and testosterone enanthate, increasing native injectable testosterone half-life after intramuscular injection of testosterone. Further development resulted in oral testosterone undecanoate (TU) in different formulations, which predominantly circumvents the liver through absorption into the intestinal lymphatic system and avoids hepatic adverse effects seen with 17-alpha-alkyl androgens.10
A novel formulation of oral TU (TLANDO; Antares Pharma Inc.) that uses a self-emulsifying drug delivery system has been approved for the treatment of testosterone deficiency without dose adjustment.11A phase 3 study of oral TU 225 mg twice daily without dose adjustment demonstrated restoration of serum total testosterone to eugonadal ranges (300–1080 ng/dL) in 80% of men with testosterone deficiency(N = 95, NCT03242590).12
The goal of the Study of Oral Androgen Replacement (SOAR, NCT02081300) was to report the safety and efficacy endpoints of oral TU. Results of a comparison between oral TU and 1.62% topical testosterone gel for safety and quality-of-life assessments are also reported to affirm previously published findings of oral TU restoring serum total testosterone concentrations in patients with hypogonadism without dose adjustment.
3.3 Pharmacokinetics
Figure 2 displays mean serum concentrations of testosterone (Figure 2A) and DHT (Figure 2B) at weeks 3, 7, and 13 versus time for the PK set (n = 130). Mean serum concentrations of testosterone were increased > 300 ng/dL within 2 h of each oral TU dose, reached peak concentration approximately 4−6 h after dosing, and declined to pre dose levels after approximately 12 h.
At week 3, before dose titration, patients in the PK set (n = 130) receiving oral TU demonstrated mean ± SD serum total testosterone Cavg 0-24 h and Cmax 0-24 h values of 494.3 ± 192.6 and 1306.4 ± 652.2 ng/dL, respectively. At week 13, after dose titration, these patients demonstrated mean ± SD serum total testosterone Cavg 0-24 h and Cmax 0-24 h values of 446.4 ± 171.5 and 1134.1 ± 526.2 ng/dL, respectively.
Concentrations of serum total testosterone, free testosterone, and DHT are reported in Figure 3A–C, respectively, at baseline and week 52 for both treatment groups. Mean ±SD serum total testosterone levels for oral TU (full analysis set, n=193) and 1.62% topical testosterone gel (safety set, n = 314) remained within the adult male testosterone concentration range at week 26 (481.3 ± 371.2 [n = 143] vs.596.4 ± 600.7 ng/dL [n = 80]), week 39 (543.2 ± 438.2 [n = 137] vs.466.1 ± 277.8 ng/dL [n = 74]), and week 52 (538.5 ± 545.4 [n = 143] vs.456.8 ± 255.6 ng/dL [n = 77]).
3.4 Androgen-mediated laboratory parameters
The mean baseline and change from baseline for laboratory parameters commonly influenced by androgens for the safety set (n = 314) have been reported in Table 2. Mean HCT values at week 52 were comparable between patients receiving oral TU and 1.62% topical testosterone gel. Overall, HCT values ranged from 32% to 55% and demonstrated a mean ± SD change from baseline of 2.6% ± 3.4%.
All patients exhibited a mean ± SD decrease in HDL (−0.12 ± 0.22 mmol/L), LDL (−0.08 ± 0.71 mmol/L), and triglycerides (−0.16 ± 1.06 mmol/L) at week 52. Patients receiving oral TU demonstrated a greater mean ± SD decrease at week 52 in HDL (−0.15 ± 0.21 mmol/L) than those receiving 1.62% topical testosterone gel (−0.05 ± 0.23 mmol/L). Patients receiving 1.62% topical testosterone gel demonstrated a greater mean ± SD decrease at week 52 in LDL (−0.21 ± 0.74 mmol/L) than those receiving oral TU (−0.01 ± 0.68 mmol/L). Mean ± SD increases in PSA from baseline to week 52 were observed overall (0.21 ± 0.38 µg/L), and changes were similar between treatment groups. Patients receiving oral TU demonstrated a mean ± SD decrease in SHBG from baseline compared toan SHBG increase demonstrated with 1.62% topical testosterone gel (−8.91 ± 9.74 vs. 2.39 ± 7.91 nmol/L). Patients receiving oral TU and 1.62% topical testosterone gel both experienced mean decreases from baseline in FSH (−4.9 ± 9.5 vs. −3.9 ± 5.1 IU/L) and LH (−3.7 ± 7.2 vs.−2.9 ± 2.6 IU/L). For patients receiving oral TU and 1.62% topical testosterone gel, respectively, final mean ± SD (range) FSH values at week 52 were 3.97 ± 9.25 (0.15–84.90) versus 3.08 ± 4.44 (0.15–30.00) IU/L, and LH values were 2.35 ± 4.48 (0.05–37.00) versus 1.59 ± 2.42 (0.05–11.80) IU/L.
Both treatment groups demonstrated a decrease in ALT, AST, alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) from baseline at week 52. No known cases of Hy’s Law were observed.
3.6 Safety
Overall, in the safety set, 67% (210/314) of patients experienced ≥1 treatment-emergent AE (TEAE). A total of 14 patients experienced treatment-emergent SAE during the study. Overall, the treatment emergent SAEs were most frequently categorized as infections and infestations (four patients, 1.3%) and musculoskeletal and connective tissue disorders (three patients, 1.0%). Sixteen patients experienced 27 severe TEAEs, but none of these were determined by investigators to be treatment-related. The incidence of treatment-related TEAEs was similar between patients receiving oral TU compared to 1.62% topical testosterone gel (24.3% [51/210] vs. 22.1% [23/104]). Frequently reported treatment-related TEAEs for patients receiving oral TU were acne (6 [2.9%]), weight increase (5 [2.4%]), and HCT increase (4 [1.9%];Table 4). Treatment-related TEAEs led to discontinuation in 11 (5.2%) patients receiving oral TU and three (2.9%) patients receiving 1.62% topical testosterone gel. All treatment-related TEAEs of HCT level increases occurred in patients receiving oral TU. Two patients receiving oral TU and one patient receiving 1.62% topical testosterone gel were discontinued for having HCT > 54%. No patients experienced any serious cardiovascular TEAEs. Throughout this study, treatment-related AEs of hypertension occurred in one patient receiving oral TU and two patients receiving 1.62% topical testosterone gel, although no clinically meaningful trends in systolic or diastolic blood pressure change were demonstrated among patients receiving either treatment. No deaths o rtreatment-related serious AEs were reported during this study.
5 CONCLUSION
This study provides a head-to-head safety comparison of novel oral TU to a widely used testosterone gel. Concentrations of serum testosterone were similar before and after dose titration, confirming current dosing recommendations for oral TU 225 mg twice daily without dose adjustment. While the change from baseline for oral TU compared to 1.62% topical testosterone gel in most domains of SF-36 and PDQ was not significant, both therapies were beneficial in improving libido and sexual frequency. Oral TU also demonstrated comparable safety to 1.62% topical testosterone gel and, specifically, showed similar changes in HCT. The results of this study are consistent with current literature, which has found oral testosterone formulations to be well tolerated in patients with hypogonadism and effective at improving testosterone levels and sexual symptoms.32 Thus, both 1.62% topical testosterone gel and oral TU offer viable solutions, avoiding needles and dose titration, for patients with hypogonadism.
Background
Testosterone deficiency results from insufficient testosterone production. Testosterone therapy may require dose titration to reach eugonadal serum testosterone concentrations.
Objective
The primary objective was the efficacy of oral testosterone undecanoate (TLANDO; Antares Pharma Inc.) in male patients with documented hypogonadism. Secondary objectives included a comparison of oral testosterone undecanoate safety and quality-of-life assessments to 1.62% topical testosterone gel (AndroGel 1.62%;AbbVie).
Materials and methods
In this phase 3 study, 315 patients were randomized 2:1 to oral testosterone undecanoate or 1.62% topical testosterone gel (NCT02081300). Patients received 225 mg oral testosterone undecanoate twice daily, and doses were adjusted by 75 mg/dose at weeks 4 and 8 based on average serum total testosterone concentration and maximum observed serum concentration. The primary endpoint was the proportion of patients receiving oral testosterone undecanoate with serum total testosterone concentration within the eugonadal reference range (300–1140 ng/dL). Secondary endpoints included the proportion of patients with maximum serum total testosterone concentrations within predetermined limits, safety parameters, and quality-of-life endpoints including the Short Form-36v2 Health Survey, Psychosexual Daily Questionnaire, and International Prostate Symptom Score.
Results
Overall mean ± SD baseline testosterone was 205.7 ± 71.6 ng/dL. For patients receiving oral testosterone undecanoate, 87.4% demonstrated a 24-h average serum total testosterone concentration within the reference range following titration. Oral testosterone undecanoate demonstrated a nominal statistically significantly greater mean change from baseline than 1.62% topical testosterone gel for Short Form-36v2 Health Survey measures of mental health (2.91 vs. -0.10; p = 0.035), and mental component summary (3.82 vs. 0.55; p = 0.009); and Psychosexual Daily Questionnaire measure of weekly negative mood (-0.57 vs. -0.20; p = 0.021). Safety endpoints were comparable between therapies. No deaths or treatment-related serious adverse events were reported.
Discussion and conclusion
Male patients with hypogonadism receiving oral testosterone undecanoate 225 mg twice daily demonstrated improvements in libido and sexual frequency. Serum testosterone concentrations were within the reference range in 87% of patients without dose titration.
1 INTRODUCTION
Testosterone deficiency is a clinical disorder resulting from either a defect of the testes (primary hypogonadism) or failure of the hypothalamus or pituitary to produce sufficient gonadotropins (secondary hypogonadism).1–3 Diagnosis of testosterone deficiency requires measurement of two early morning total testosterone levels < 300 ng/dL with associated signs and symptoms (sexual dysfunction, delayed sexual development, loss of body hair, or small testes [< 6 mL]).2 The prevalence of symptomatic hypogonadism increases with age, and it has been estimated to be between 0.1% and 6% in the United States.4,5
Patients with testosterone deficiency who have signs and symptoms such as decreased energy, depressed mood, and reduced sexual desire should be considered for testosterone therapy, which may include intramuscular or subcutaneous injections, transdermal gels and patches, pellet implants, nasal gels, and oral capsules.2,3 Many of these approved testosterone therapies may require dose titration to reach eugonadal serum testosterone concentrations.6–8
Oral administration of natural testosterone is ineffective due to inactivation in the liver via first-pass metabolism. Methyltestosterone was the first testosterone therapy available for oral use, although itsuse has been limited due to associations with liver toxicity.9 Esterification of testosterone carbon 17-beta produced testosterone esters, such as testosterone propionate and testosterone enanthate, increasing native injectable testosterone half-life after intramuscular injection of testosterone. Further development resulted in oral testosterone undecanoate (TU) in different formulations, which predominantly circumvents the liver through absorption into the intestinal lymphatic system and avoids hepatic adverse effects seen with 17-alpha-alkyl androgens.10
A novel formulation of oral TU (TLANDO; Antares Pharma Inc.) that uses a self-emulsifying drug delivery system has been approved for the treatment of testosterone deficiency without dose adjustment.11A phase 3 study of oral TU 225 mg twice daily without dose adjustment demonstrated restoration of serum total testosterone to eugonadal ranges (300–1080 ng/dL) in 80% of men with testosterone deficiency(N = 95, NCT03242590).12
The goal of the Study of Oral Androgen Replacement (SOAR, NCT02081300) was to report the safety and efficacy endpoints of oral TU. Results of a comparison between oral TU and 1.62% topical testosterone gel for safety and quality-of-life assessments are also reported to affirm previously published findings of oral TU restoring serum total testosterone concentrations in patients with hypogonadism without dose adjustment.
3.3 Pharmacokinetics
Figure 2 displays mean serum concentrations of testosterone (Figure 2A) and DHT (Figure 2B) at weeks 3, 7, and 13 versus time for the PK set (n = 130). Mean serum concentrations of testosterone were increased > 300 ng/dL within 2 h of each oral TU dose, reached peak concentration approximately 4−6 h after dosing, and declined to pre dose levels after approximately 12 h.
At week 3, before dose titration, patients in the PK set (n = 130) receiving oral TU demonstrated mean ± SD serum total testosterone Cavg 0-24 h and Cmax 0-24 h values of 494.3 ± 192.6 and 1306.4 ± 652.2 ng/dL, respectively. At week 13, after dose titration, these patients demonstrated mean ± SD serum total testosterone Cavg 0-24 h and Cmax 0-24 h values of 446.4 ± 171.5 and 1134.1 ± 526.2 ng/dL, respectively.
Concentrations of serum total testosterone, free testosterone, and DHT are reported in Figure 3A–C, respectively, at baseline and week 52 for both treatment groups. Mean ±SD serum total testosterone levels for oral TU (full analysis set, n=193) and 1.62% topical testosterone gel (safety set, n = 314) remained within the adult male testosterone concentration range at week 26 (481.3 ± 371.2 [n = 143] vs.596.4 ± 600.7 ng/dL [n = 80]), week 39 (543.2 ± 438.2 [n = 137] vs.466.1 ± 277.8 ng/dL [n = 74]), and week 52 (538.5 ± 545.4 [n = 143] vs.456.8 ± 255.6 ng/dL [n = 77]).
3.4 Androgen-mediated laboratory parameters
The mean baseline and change from baseline for laboratory parameters commonly influenced by androgens for the safety set (n = 314) have been reported in Table 2. Mean HCT values at week 52 were comparable between patients receiving oral TU and 1.62% topical testosterone gel. Overall, HCT values ranged from 32% to 55% and demonstrated a mean ± SD change from baseline of 2.6% ± 3.4%.
All patients exhibited a mean ± SD decrease in HDL (−0.12 ± 0.22 mmol/L), LDL (−0.08 ± 0.71 mmol/L), and triglycerides (−0.16 ± 1.06 mmol/L) at week 52. Patients receiving oral TU demonstrated a greater mean ± SD decrease at week 52 in HDL (−0.15 ± 0.21 mmol/L) than those receiving 1.62% topical testosterone gel (−0.05 ± 0.23 mmol/L). Patients receiving 1.62% topical testosterone gel demonstrated a greater mean ± SD decrease at week 52 in LDL (−0.21 ± 0.74 mmol/L) than those receiving oral TU (−0.01 ± 0.68 mmol/L). Mean ± SD increases in PSA from baseline to week 52 were observed overall (0.21 ± 0.38 µg/L), and changes were similar between treatment groups. Patients receiving oral TU demonstrated a mean ± SD decrease in SHBG from baseline compared toan SHBG increase demonstrated with 1.62% topical testosterone gel (−8.91 ± 9.74 vs. 2.39 ± 7.91 nmol/L). Patients receiving oral TU and 1.62% topical testosterone gel both experienced mean decreases from baseline in FSH (−4.9 ± 9.5 vs. −3.9 ± 5.1 IU/L) and LH (−3.7 ± 7.2 vs.−2.9 ± 2.6 IU/L). For patients receiving oral TU and 1.62% topical testosterone gel, respectively, final mean ± SD (range) FSH values at week 52 were 3.97 ± 9.25 (0.15–84.90) versus 3.08 ± 4.44 (0.15–30.00) IU/L, and LH values were 2.35 ± 4.48 (0.05–37.00) versus 1.59 ± 2.42 (0.05–11.80) IU/L.
Both treatment groups demonstrated a decrease in ALT, AST, alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) from baseline at week 52. No known cases of Hy’s Law were observed.
3.6 Safety
Overall, in the safety set, 67% (210/314) of patients experienced ≥1 treatment-emergent AE (TEAE). A total of 14 patients experienced treatment-emergent SAE during the study. Overall, the treatment emergent SAEs were most frequently categorized as infections and infestations (four patients, 1.3%) and musculoskeletal and connective tissue disorders (three patients, 1.0%). Sixteen patients experienced 27 severe TEAEs, but none of these were determined by investigators to be treatment-related. The incidence of treatment-related TEAEs was similar between patients receiving oral TU compared to 1.62% topical testosterone gel (24.3% [51/210] vs. 22.1% [23/104]). Frequently reported treatment-related TEAEs for patients receiving oral TU were acne (6 [2.9%]), weight increase (5 [2.4%]), and HCT increase (4 [1.9%];Table 4). Treatment-related TEAEs led to discontinuation in 11 (5.2%) patients receiving oral TU and three (2.9%) patients receiving 1.62% topical testosterone gel. All treatment-related TEAEs of HCT level increases occurred in patients receiving oral TU. Two patients receiving oral TU and one patient receiving 1.62% topical testosterone gel were discontinued for having HCT > 54%. No patients experienced any serious cardiovascular TEAEs. Throughout this study, treatment-related AEs of hypertension occurred in one patient receiving oral TU and two patients receiving 1.62% topical testosterone gel, although no clinically meaningful trends in systolic or diastolic blood pressure change were demonstrated among patients receiving either treatment. No deaths o rtreatment-related serious AEs were reported during this study.
5 CONCLUSION
This study provides a head-to-head safety comparison of novel oral TU to a widely used testosterone gel. Concentrations of serum testosterone were similar before and after dose titration, confirming current dosing recommendations for oral TU 225 mg twice daily without dose adjustment. While the change from baseline for oral TU compared to 1.62% topical testosterone gel in most domains of SF-36 and PDQ was not significant, both therapies were beneficial in improving libido and sexual frequency. Oral TU also demonstrated comparable safety to 1.62% topical testosterone gel and, specifically, showed similar changes in HCT. The results of this study are consistent with current literature, which has found oral testosterone formulations to be well tolerated in patients with hypogonadism and effective at improving testosterone levels and sexual symptoms.32 Thus, both 1.62% topical testosterone gel and oral TU offer viable solutions, avoiding needles and dose titration, for patients with hypogonadism.
