New oral TRT exhibits favourable safety, efficacy for hypogonadal men

A novel oral testosterone replacement therapy (TRT*) formulation – testosterone undecanoate (TU) – showed favourable safety and efficacy as long-term treatment for men with low testosterone levels, according to the extension phase results of a study presented at ENDO 2021.

“For many men with low testosterone levels, an oral option is preferred to avoid issues associated with other modes of administration (ie, injection site pain) or unintended transference to women and children,” said lead researcher Dr Ronald Swerdloff from the Lundquist Research Institute at Harbor-UCLA, Torrance, California, US.

“Before TU was approved, the only [approved oral] TRT in the US was methyl-testosterone (MT), which was [tied to] significant chemical-driven liver damage,” Swerdloff continued. “Our study finds TU is an effective oral therapy [in this setting] and has a safety profile consistent with other approved testosterone products, without the drawbacks of non-oral modes of administration, [and] with no evidence of liver toxicity.”

Swerdloff and his team conducted two open-label, dose-titration trials in men aged 18–75 years with low testosterone levels (≤300 ng/dL). Participants in study 1 were followed for a year. Study 2 (extension phase) comprised trial 1 completers (n=86) who were followed for another year. [ENDO 2021, abstract P45-33]

Primary safety variables are changes in liver function tests (ie, ALP/ALT/AST and BILI**), prostate specific antigen (PSA), haematocrit, and systolic blood pressure (SBP) from baseline to year 2. Primary efficacy variable is change in baseline total testosterone concentrations.

Day 730 ALP/ALT/AST and BILI levels (53.74/26.65/22.00 U/L and 0.52 mg/dL, respectively) did not significantly change from baseline (64.05/27.81/21.58 UL and 0.58 mg/dL, respectively). Only one participant had increased ALT at day 270 (227 U/L); however, this was transient and dropped to 87 U/L after 20 days. These results reflect the lack of liver toxicity with TU as opposed to MT, noted Swerdloff.

The initial increase in PSA was also transient and stabilized throughout study 2 (overall increase in mean PSA, <0.5 ng/mL).

Despite the statistically significant increase in mean haematocrit by day 180 (2.52 percent; p<0.0001), this was deemed modest and remained stable until day 730. “Haematocrit increases were not related to either TU dose or average testosterone levels,” explained Swerdloff.

The increases in both PSA and haematocrit also correlated with those seen with other TRTs regardless of mode of administration, he added.

A small but statistically significant increase from baseline SBP was noted throughout the study (between 3 and 6 mm Hg; p<0.05).

Although the clinical significance of change in lipid parameters is unclear, triglyceride levels were significantly reduced, as were HDL-C*** levels. While this implies a reduction in the level of good cholesterol, Swerdloff noted that this is commonly observed with other TRT formulations.

Mean total testosterone concentrations across all timepoints significantly increased from baseline – falling within the eugonadal range of 300–1,000 ng/dL (p<0.0001) – and remained within this range throughout study 2. This signifies the efficacy of this new oral TU formulation in keeping testosterone levels within normal range.

“[Taken together,] this novel TU formulation offers a significant therapeutic advantage for hypogonadal men … [and] may provide a treatment option that avoids some of the administration drawbacks of other TRT products,” concluded Swerdloff.

Moreover, as opposed to other TU formulations in other territories, this new formulation has been engineered to improve its bioavailability, hence the feasibility of administering it twice daily even without a high fat meal, he added.

TU has received the FDA nod in March 2019 and has been available commercially since February 2020.