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New England Section of the American Urological Association

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Safety Analysis of an Oral Testosterone Undecanoate (TU) Formulation Following 2 Years of Administration in Hypogonadal Men
Ronald Swerdloff, MD1, Ricardo M. Munarriz, MD2, Stanton C. Honig, MD3, Christina Wang, MD1, B. Woun Seo, PhD4, Nestor Rohowsky, MA5, Robert E. Dudley, PhD4.
1Lundquist Institute at Harbor-UCLA, Torrance, CA, USA, 2Boston University School of Medicine, Boston, MA, USA, 3Yale School of Medicine, New Haven, CT, USA, 4Clarus Therapeutics, Inc., Northbrook, IL, USA, 5Integrated Data Consultation Services, Inc., LaGrange, IL, USA.

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. The objective of this study was to evaluate the safety and efficacy of a novel oral T undecanoate (TU) formulation with 2 year follow up. 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, 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 increase in PSA (0.26 0.28 ng/mL vs BL @ d730). 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 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 varied 3 - 6 mm Hg from BL throughout the study. CONCLUSION: 2 year follow up data with 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 at 2 years 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.


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