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FDA committees withhold approval of oral testosterone therapy
COLLEGE PARK, MD — On day 2 of a joint meeting on testosterone replacement therapies, the Bone, Reproductive and Urologic Drugs and Drug Safety and Risk Management FDA advisory committees voted 12-8, with one abstention, that a novel oral testosterone undecanoate did show efficacy as a testosterone replacement therapy.
The panel also ruled 17-4 that the overall profile for benefits and risks of the soft-gel capsule formulation oral testosterone undecanoate (TU) Rextoro, developed by Clarus Therapeutics, did not support approval of this product for testosterone replacement therapy.
“Primary efficacy endpoint just met the success threshold,” Mark S. Hirsch, MD, of Center for Drug Evaluation and Research, FDA, said during a presentation.
Mechanism and Unmet Need
At the outset, Robert Dudley, PhD, DABT, president and chief executive officer at Clarus, outlined the reasons TU and dihydrotestosterone undecanoate (DHTU) are not likely to present safety risks: the drug does not easily enter or accumulate in tissues, there is no meaningful interaction with the 87 binding targets used to assess safety risk and they do not show appreciable binding to androgen receptors.
Rextoro soft-gel capsule formulations are designed to deliver doses of either 100 mg or 150 mg twice-daily oral testosterone. The absorption of the drug, in development for more than a decade, happens primarily via intestinal pathway, Dudley explained.
Glenn Cunningham, MD, of Baylor College of Medicine, who has been treating men with hypogonadism for over two decades, advised the room that such a novel therapy would fill an unmet need, a sentiment echoed by others during the day.
“Current treatments are not patient-friendly and do carry some risks related to their methods of delivery,” Cunningham said. “My experience is most patients would prefer oral treatment to transdermal and intramuscular if it worked and if it were safe.”
Generally, the testosterone therapy adherence rate is low, Cunningham underscored, with only 24% of currently-treated patients satisfied with treatment options.
Over the 2 days, the room repeatedly heard how transdermal testosterone, in the form of gels or patches, brings with it risks and fears of transferring the hormone to a partner or children, as well as application challenges and variable absorption. Further, intramuscular injectable testosterone carries its own set of issues, including pulmonary oil micro embolisms and peak-to-trough changes in hormone levels.
Efficacy, Safety Evidence Lacking
In accordance with what has been required for current testosterone treatments, Clarus undertook one pharmacokinetics study, number 09007, then undertook a second, 12011, stacking the oral therapeutic up against Androgel (testosterone gel, AbbVie.
Results from both phase 3 trials were presented by Merrel Magelli, PharmD, senior director of medical affairs at Clarus. The 4-month 90007 looked at 161 patients with endpoint assessed at 90 days, and the 4-month 12011 a pivotal study for effectiveness and safety, included 144 patients with endpoint assessed at 114 days.
Magelli pitched the pivotal study to the panel as achieving average plasma concentration targets established for testosterone replacement approval, and presented data described as in-line with approved therapies.
“The totality of the data demonstrate that oral Rextoro is effective for serum testosterone replacement, similar to currently approved testosterone replacement therapies,” Magelli said.
She noted various sensitivity analyses to address missing data including Multiple imputation of Mixed Model Repeated Measure (MMRM), Last Observation Carried Forward and Worst Case (patients missing data considered failures).
However, outstanding concerns remained for a majority of committee members at the end of the day.
Food Effect and Drop-Out
The effect of food on dose titration was addressed in a presentation by Sayed Al Habet, RPh, PhD, senior clinical pharmacologist at FDA.
“To minimize day-to-day variability, patients should strongly be advised to eat a steady diet with relatively consistent percentage of fat content in meal,” Habet explained. “Major changes in diet must require retitration.”
Committee member Richard B. Alexander, MD, of the University of Maryland Medical Center, lauded Clarus in creating something that would fill a great need, but highlighted the metabolic requirement of the drug as very patient-dependent.
“Relying on patient behavior, particularly in the area of safety, for me is very problematic,” Alexander said.
Robin Boineau, MD, MA, medical officer at NIH, echoed the sentiment in the closing discussions, saying that “being so close to the edge with results, and having lot of variation in dietary intake, becomes just a little bit concerning.”
Michael Lincoff, MD, of Cleveland Clinic, saw the dose changes a little differently.
“This is a drug that creates a blood level of something, and you can monitor that level, and if you properly label it so monitoring is required for prescriptions and refills, you can change the dose,” he said.
Missing data also came under heavy scrutiny, in light of the 20% drop-out rate. Clarus explained the choice of MMRM as based on recommendation of the National Research Council. But the committee was not swayed.
“I’m trying to figure out if the trial is still interpretable and valuable,” John R. Teerlink, MD, of the University of California, San Francisco, said.
More Concerns and Moving Forward
Committee member Marc Garnick, MD, of Beth Israel Deaconess Medical Center, expressed concern with the safety signal seen with higher dosing. “To not be able to fully understand the very high [peak concentration] value, I think the safety has not been adequately demonstrated for this product.”
Robert A. Adler, MD, said TU needs further specific study in patients with pituitary adenomas since there was no data on how the drug would interact with their current prescriptions and relatively regimented treatment schedules.
Several committee members encouraged Clarus to find a way to reconcile the size of their study and data for safety.
In a summary, committee chair Julia Johnson, MD, said, “What I’m hearing is we need more robust data with a single pivotal trial.” — by Allegra Tiver
For more information: See the Endocrine Today Twitter feed for live updates of committee meetings: www.Twitter.com/EndocrineToday.
Or consult FDA background materials: September 18, 2014 Meeting of the Bone, Reproductive and Urologic Drugs Advisory CommitteePerspective
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The FDA Advisory meeting on testosterone was a step backwards for men’s health and for medical science. By voting to add further restrictions to the label of testosterone products, the FDA will de facto create additional challenges and costs for men currently being treated successfully and appropriately, as insurance companies are sure to follow the FDA’s lead and will use this as an excuse to deny coverage.
The insurance picture is already a major hassle for physicians and patients, and this will only make it worse. The result will be that many men receiving testosterone treatment for legitimate medical reasons will need to pay for treatment out-of-pocket, or not at all. This creates an unfair, two-tiered medical system where men of means will be able to afford treatment and those without will not.
There was no consideration of the impact of hypogonadism on men. Symptoms such as sexual dysfunction, depression and chronic fatigue were minimized and dismissed. This is a shame. This is a condition that affects men profoundly and often responds well to treatment. The FDA committee members fell prey to unsupported, unscientific assertions of overuse and inappropriate use of testosterone. For those of us in the field, it is clear that the rise in testosterone prescriptions is due to increased awareness of the benefits and reduced fear of prostate cancer.
Perspective
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The FDA was concerned about two critical issues. One was is testosterone related to cardiovascular risk and for whom is testosterone indicated?
I thought that argument was already clear there was no evidence whatsoever to link testosterone to increase risked of cardiovascular events. When you look at their vote at the end, they all said that the safety signal was weak or poor, and there just was not enough evidence. This is understandable.
It is a little frustrating, however, that the FDA took this issue and linked it to the indication. That’s a totally different issue. You cannot link them together. To me, the question of whether testosterone is related to cardiovascular risk has two answers: Yes or No. In my view, it’s a no.
Testosterone is indicated for clinical hypogonadism. How do you define clinical hypergonadism? They went through and through, talking about primary, secondary and mixed. But to include a term that has no place in clinical science — age-related hypogonadism — there is no such thing. There is no age-related hyperthyroid. There is no age-related blood pressure. There is no age-related cancer. The word age-related is nonsense.
Neither the panel nor the sponsor have the guts to come and say if you have low testosterone and you suffer from real symptoms, you have clinical hypogonadism. That’s true whether you’re 36 years old, 46 years old or 56 years old. What does it have to do with age? Either you have hypogonadism or you don’t.
Consensus is not evidence. Where’s the evidence here? Consensus is just gathering people in a room and they say “we think so.” That’s the problem with the guidelines, which were quoted over and over. The guidelines came from a group of people sitting in a room for 10 days, discussing and deciding. That’s not evidence-based; that’s consensus.
Frederick Wu (University of Manchester) presented a 3-minute discussion on hypogonadism during the public portion, he had beautiful data on primary hypogonadism, secondary hypogonadism, mixed hypogonadism and went into the idea of co-morbidities or lack thereof.
The presenters for the sponsors were disappointing, they could not make the case — either, or. The panel is a diverse group of clinicians and scientists; they come from various backgrounds; some are OBGYNs, some are men’s health, some are urologists. Their different views are understandable.
But the level of discussion was not what I would imagine among a group of scientists, coming in to inform and be informed. It was not what I would expect, but maybe I’m setting a high standard.
This is a critical issue in men’s health. We cannot deny that. Testosterone has been used since 1940; that means we have 7 decades of testosterone use. Someone should tell us what happened in these last 7 decades.
Is there any census data, scientific data, epidemiological data, anything that tells us that people are dropping dead on the street every now and then from using testosterone? I don’t see that. Every 25 to 33 year-old-male has more testosterone than five of us combined. They’re not dropping dead left and right.
There was no good, scientific discussion. The FDA has a responsibility to engage in a more vigorous and more evidence-based type of discussion, rather than consensus-based. During the discussion, after the voting, the panel shared their reasoning; it seemed no different than tossing a coin.
Consensus is in politics; you compromise. In science, you don’t compromise. You get the evidence.
Perspective
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The majority of men in the general population with “low T” have secondary hypogonadism associated with obesity, but independent of age, as described in the European Male Aging Study (Tajar et al. JCEM, 2010). These men have functional suppression of gonadotropins but under-stimulated testes. The use of the term “age-related hypogonadism” in these men is not only a misnomer which overlooks the major aetiological factor but also pathophysiological incorrect, and fails to catch important clinical management implications.
Although testosterone replacement is a well-accepted indication for the treatment of patients with classical (pathological and irreversible) primary or secondary hypogonadism, there is currently no approved therapy for the much more common (functional and potentially reversible) secondary hypogonadism associated with obesity. Exogenous testosterone treatment in these men is not only inappropriate (because of further suppression of gonadotropins) but indeed may be counterproductive, particularly in those still seeking fertility.
Restoring normal function in the hypothalamic-pituitary-testes axis through weight loss (Camacho et al. European J Endocrinol, 2013; Grossmann et al. JCEM, 2011) is a logical first-line management in obesity-related secondary hypogonadism. The use of anti-oestrogens (without the current concerns of exogenous testosterone) to reverse the gonadotropin suppression and raising endogenous testosterone may also be beneficial, although the efficacy should be confirmed in larger randomised studies.