HYATTSVILLE, MD. – In an 18-3 vote, the majority of a Food and Drug Administration advisory panel agreed that the overall risk-benefit profile of an oral formulation of testosterone undecanoate did not support approval at this time, citing issues with the pivotal trial, safety, and wide dietary-dependent variations in absorption, at a meeting on Sept. 18.
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The results of two phase III pharmacokinetic studies in hypogonadal adult men, whose mean age was about 55 years, with a total serum testosterone of 300 ng/dL or less, were reviewed at a joint meeting of the FDA’s Bone, Reproductive, and Urologic Drugs Advisory Committee, and Drug Safety and Risk Management Advisory Committee. The manufacturer, Clarus Therapeutics, has proposed that testosterone undecanoate capsules be approved for replacement therapy in men for conditions associated with a deficiency or absence of endogenous testosterone, primary hypogonadism (congenital or acquired), and hypogonadotropic hypogonadism (congenital or acquired), the standard indication for testosterone replacement therapy (TRT). For approval of TRT products, the FDA requires a pharmacokinetic study.
Because of excessive testosterone spikes in the first study, a less aggressive dosing algorithm was evaluated in the pivotal open-label study of 116 patients, evaluating a starting dose of 200 mg twice a day, titrated in increments of 50 mg twice a day based on the serum testosterone levels at least 7 days after the initial or adjusted dose, with a minimum dose of 100 mg twice a day and a maximum dose of 300 mg twice a day.
The study just met the prespecified primary endpoint, which was that at least 75% of patients achieve a “Cavg” of testosterone (a measure that divides total exposure to testosterone, based on pharmacokinetic sampling over 24 hours, by 24) in the eugonadal range (300-1,000 ng/dL) at the end of treatment, at 114 days. However, almost 20% of patients were lost to follow-up, a major issue cited by the FDA and panelists. In this study, four patients had a testosterone measurement that exceeded 2,500 ng/dL, and one patient (less than 1%) had a serious cardiovascular event. But in the initial study with the higher dose, the rate of adverse CV events was almost 4%, and there were increases in CV biomarkers, such as C-reactive protein and blood pressure.
The panels voted 12-8, with 1 abstention, that these data did not provide sufficient evidence that oral testosterone undecanoate was effective, for reasons that included concerns about the effect the high dropout rate had on the results, and the failure to meet any of the secondary endpoints in the study. The panelists also cited concerns about the effect dietary changes had on systemic absorption, particularly increased fat content.
Like other panelists, Dr. Richard Alexander, a professor in the urology division at the University of Maryland, Baltimore, agreed there was a great need for an oral formulation of testosterone, but he voted against approval because the way the drug works is ”highly dependent on patient behavior ... which is very problematic.” Referring to a marked increase in bioavailability with a high-fat diet, he said, “I’m afraid that in the real world,“ men would be at a heightened risk of overdoses with this product.
Another concern mentioned by several panelists was the increased likelihood that the availability of an oral TRT that is easier to administer than currently available topical and injectable formulations could further increase the widespread off-label use among men with age-related low testosterone, the most common use of TRT products, despite no conclusive data TRT is effective in this population and some concerns about safety – the topic of the panel meeting the previous day.
If the product is approved, the company would market it as Rextoro, and it would the first oral testosterone product available, other than the rarely used oral methyltestosterone formulation.
The FDA usually follows the recommendations of its advisory panels. In a statement issued by Clarus after the meeting, Dr. Robert Dudley, the chief executive officer, said that the company “will work closely with the FDA to respond to the panel’s concerns, and remain committed to bringing Rextoro to the market as soon as possible.” The FDA is expected to make a decision on approval by Nov. 3, 2014.
Usually, members of advisory panels have no financial conflicts, but in some cases, a panelist is granted a waiver, and at this meeting, one panelist who owned stock in an affected company was granted a waiver.