Safety Analysis of an Oral Testosterone Undecanoate (TU) Formulation Following 2 Years of Administration in Hypogonadal Men

An oral testosterone (T) replacement therapy (TRT) would be the preferred choice 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. Subjects and 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, up to 81 subjects were available for evaluation. T concentration increased from 208.3 ± 102.4 ng/dL (Mean ± SD) at baseline (BL) to 470.1 ± 396.5 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 - ALT (28.0 ± 12.3 to 26.6 ± 12.8 U/L), AST (21.8 ± 6.8 to 22.0 ± 8.2 U/L), and bilirubin (0.58 ± 0.22 to 0.52 ± 0.19 mg/dL) throughout the two studies. At Day 270, 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 Day 290, 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 (+2.52 ± 3.7% vs BL, p < 0.001) and cuff systolic BP (+5.6 ± 15.0 mmHg vs BL, 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 consistently showed a mean increase from BL between 3 - 6 mmHg. Conclusion: This oral TU formulation is an effective long-term therapy 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.