Article Title: FDA Panel Rejects New Oral Testosterone Replacement Drug

Author: Larry Hand

Date of Publication: September 18, 2014

A combined US Food and Drug Administration (FDA) advisory committee has voted against recommending approval of oral testosterone undecanoate (TU) gel capsules as testosterone-replacement therapy (TRT).

In a joint session today of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, panelists voted 12 to 8, with 1 abstention, that there is insufficient evidence to conclude that the testosterone prodrug is effective. They voted 18 to 3 that the overall benefit/risk profile was not acceptable to support approval.

While most panel members consistently called for more data on efficacy and safety, others contended that the drug’s manufacturer, Clarus Therapeutics, of Northbrook, Illinois, had proved its case for the brand-name drug Rextoro and that a definite need exists for an oral formulation.

The meeting followed the previous day’s hearing by the same group concerning label changes of all testosterone-replacement products because of widespread use of TRTs for natural age-related hypogonadism or for signs or symptoms of men with “low T” who often may not need the drug or weren’t even tested.

Glenn D. Braunstein, MD, vice president for clinical innovation at Cedars-Sinai Medical Center, in Los Angeles, California, characterized a prime issue for panelists voting yes on effectiveness, addressing FDA staff members: “If you applied the same criteria to other [TRTs] on the market, most of them would fail.”

Keith Gordon, PhD, the industry representative and a nonvoting panelist, added, “I’m concerned this is being judged today rather than yesterday.”

“There is a level of concern regarding higher standards,” panel chair Julia V. Johnson, MD, of the University of Massachusetts Memorial Medical Center, in Worcester, conceded. “However, study data were not sufficient to give us the assurance we need regarding safety. I hope the company will continue to look at safety data.”

Throughout the proceedings, Clarus officials maintained that the efficacy and safety profile of TU was highly similar to the profiles of currently marketed TRTs. That includes gels, patches, and other skin applications, as well as intramuscular injections. The only other oral TRT, methyltransferase, has a risk profile including liver toxicity.

Phase 3 Trials

Clarus requested new drug approval based on 2 phase 3 trials. In a 12-month, open-label phase 3 trial, researchers compared results of treatment with TU or Androgel 1% (AbbVie), a topical gel applied to the skin. Both treatments met the primary efficacy end point. Of patients randomized to TU, 83% met a prespecified average normal range of 300 to 1000 ng/dL of testosterone.

However, for a secondary end point regarding maximum serum testosterone, a number of TU patients had unacceptably high values.

Of 325 patients enrolled in the study, 262 completed it.

Clarus then conducted a 4-month pivotal phase 3 trial involving TU only, in which researchers modified the dosages and titration regimen to try to control more for maximum serum testosterone levels. In that trial, 75% of patients (the least-specified end point) achieved average normal range, and few had unacceptably high levels of maximum serum testosterone.

Of 148 patients enrolled, 116 completed the 6 visits specified.

That analysis covered only those patients who completed the study.

Post Hoc Studies

FDA researchers, however, conducted post hoc sensitivity analyses trying to account for patients who did not complete the study. They noted a higher-than-expected dropout rate in the pivotal trial of 19.4%. That process reduced efficacy results to 70.8% in a last-observed-clinical-finding analysis and to 60.4% in a worst-case-scenario analysis.

FDA researchers also presented safety issues uncovered in the trials, including worse cardiovascular risks in TU compared with AndroGel 1%, larger decreases in HDL cholesterol, and greater increases in blood pressure.

FDA staff members noted that bioavailability of TU increases as the amount of fat in the diet increases. They recommended that, if the drug were approved, patients should be informed that they should maintain regular diets and restrain from daily diet deviations.

That recommendation, however, fell flat on panelists.

“Compliance with a controlled-fat diet would be fair to poor,” said panelist Stuart S. Howards, MD, professor of urology at the University of Virginia, in Charlottesville. “It’s an impractical recommendation.”

“I’m concerned that the drug benefits are dependent on patient behavior,” said Richard B. Alexander, MD, professor of urology at the University of Maryland Medical Center, in Baltimore.

Unmet Need

In Clarus presentations, Glenn Cunningham, MD, professor of medicine and molecular and cellular biology at Baylor College of Medicine, in Houston, Texas, detailed the need for an orally administered TRT.

The 6 modalities approved often result in complications, he said. “Each of these treatments comes with issues. Patients need options to improve long-term adherence. We need an oral testosterone option.”

An oral dosage might just be a “double-edged sword,” however, Dr. Howards said. While an oral dose is “obviously a benefit” for patients who don’t get satisfactory results with topicals, “I think it will increase inappropriate use of testosterone preparations because it’s so easy.”

Overall, panel members encouraged Clarus to continue to develop the drug.

Toby C. Chai, MD, professor and vice chair of research in urology at Yale School of Medicine, in New Haven, Connecticut, summed it up: “Although I think this is a valuable product and there’s a need for it, I think it can be cleaned up on what we’ve heard today.”

Panelist Marc Garnick, MD, of Beth Israel Deaconess Medical Center, in Boston, Massachusetts, received a waiver of conflict of interest because he disclosed owning stock in a competing company; no other panel members reported any relevant financial relationships.

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