Oral testosterone undecanoate safe, effective in new 2-year data
Oral testosterone undecanoate is an effective long-term therapy for men with hypogonadism, with a safety profile that is similar to other approved testosterone formulations, data from an extension study show.
In an analysis of 2-year data presented virtually at the ENDO annual meeting, researchers found no evidence of liver toxicity among men assigned oral testosterone undecanoate (Jatenzo, Clarus Therapeutics). Hepatotoxicity was a past concern with older oral testosterone medications.
“This preparation differs from methyltestosterone, which was known to be absorbed into the portal circulation and had toxic effects on the liver,” Ronald S. Swerdloff, MD, investigator with The Lundquist Institute, chief of the division of endocrinology at Harbor-UCLA Medical Center, and professor of medicine at the David Geffen School of Medicine at UCLA, told Healio. “For that reason, it was very rarely used. This preparation, the new testosterone undecanoate oral preparation, is absorbed through the lymphatic system, thus bypassing the first portal effect on the liver and is therefore free of hepatotoxicity.”
New liver, safety data
Swerdloff and colleagues analyzed data from 81 men with hypogonadism (serum testosterone 300 ng/dL) participating in two open-label, multicenter, dose-titration trials — a randomized, active-controlled, two-arm, 12-month study and a 12-month extension with participants from the first trial. Safety was assessed by physical exam, adverse event reporting and routine clinical laboratory measurements.
Researchers found that mean testosterone concentration increased from 208.3 ng/dL at baseline to 470.1 ng/dL after 24 months of treatment with oral testosterone, with 84% of men achieving a testosterone level in the eugonadal range (300-1,000 ng/dL) after 90 days of therapy. Mean testosterone concentrations remained in the eugonadal range throughout the extension phase.
There were no clinically significant changes in liver function tests. Levels of alanine transaminase (mean change, 28 U/L to 26.6 U/L), aspartate transaminase (mean change, 21.8 U/L to 22 U/L) and bilirubin (mean change, 0.58 mg/dL to 0.52 mg/dL) remained stable throughout the two studies.
The researchers observed an initial increase in prostate-specific antigen levels and prostate volume; however, these stabilized over time, and there were no changes in International Prostate Symptom Score. Researchers also noted “significant, yet modest” increases in mean hematocrit and systolic blood pressure, both of which stabilized throughout the two trials. Increases in BP have also been noted with injectable testosterone and may be a class effect, Swerdloff said.
Avoiding injections
Swerdloff said the oral formulation of testosterone offers advantages over other testosterone preparations, which include injectable, transdermal and nasal formulations.
“In the U.S. and many parts of the world, there are people who prefer to take oral medications over these other routes of administration,” Swerdloff said. “This [oral formulation] provides that option. In the past, there was a testosterone undecanoate oral preparation available in other countries, with a shorter duration of action and influenced by fat content in the diet, so it had to be taken with high-fat meals. This preparation is not dependent upon a high-fat diet. Additionally, an oral medication is free from the problems of transfer to female partners and children that can occur with the transdermal preparations.”
Swerdloff noted oral testosterone has some of the same adverse effects as other formulations, including a risk for erythrocytosis, and clinicians should monitor complete blood count in men prescribed oral testosterone. Small increases in BP have been reported with other testosterone replacements; thus, BP should be monitored.
“In addition, there is a decrease in HDL cholesterol [with testosterone therapy]; however, our present understanding is that we have to further analyze the type of HDL cholesterol that is being suppressed, and we do not have a full understanding as to whether this is a risk factor for [cardiovascular disease],” Swerdloff said.
As Healio previously reported, the FDA approved testosterone undecanoate in an oral capsule to treat men with certain forms of hypogonadism in March 2019, making it the first new oral testosterone replacement product in more than 60 years. The indication is for men with low testosterone levels due to congenital or acquired specific medical conditions, such as Klinefelter syndrome, injuries to the testes, or tumors in the pituitary gland.
In December, the FDA granted tentative approval to a second oral testosterone for testosterone replacement therapy in men with conditions associated with a deficiency or absence of endogenous testosterone (Tlando, Lipocine). That drug is not eligible for final approval and marketing in the U.S. until the expiration of the exclusivity period previously granted to Clarus Therapeutics for oral testosterone undecanoate, which expires March 27, 2022.
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Swerdloff RS, et al. P45-33. Presented at: ENDO annual meeting; March 20-23, 2021 (virtual meeting).
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