FDA Panel Votes Down Oral Testosterone Replacement Products

A US Food and Drug Administration (FDA) advisory panel has voted against approval of what would have been the first oral testosterone replacement therapy, citing concerns that ease of use — and potential for cardiovascular side effects — could expose millions to unnecessary risk.

The FDA's Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) met over 2 days this week to consider oral testosterone undecanoate formulations from two manufacturers: Lipocine (Tlando, LPCN 1021) and Clarus Therapeutics (Jatenzo).

Testosterone undecanoate, an ester prodrug of testosterone, was approved by the FDA as an injectable in 2014 (Aveed, Endo Pharmaceuticals), but came with a boxed warning on the risks of serious pulmonary oil microembolism and anaphylaxis. Aveed is only available through a risk evaluation and mitigation strategy (REMS), which restricts its use.

Several panel members suggested they'd like to see a REMS with the oral formulations, in part to curtail off-label use. Both Lipocine and Clarus were seeking to have their products approved for men with low testosterone due to hypogonadism — the only indication FDA has said is legitimate for testosterone replacement therapy.

The agency has warned against testosterone replacement therapy for aging-related low testosterone — most recently in 2015 — but off-label prescribing of already approved products has risen. BRUDAC panel members said that signals for potential heart problems with both companies' formulations were too strong to overlook in light of continuing unabated off-label use.

"I feel very strongly that there has to be a REMS, some kind of plan with real teeth," said BRUDAC panel member Tobias Gerhard, PhD, RPh, associate professor of pharmacoepidemiology, Ernest Mario School of Pharmacy, Rutgers University, New Brunswick, New Jersey, at the meeting to discuss Lipocine's Tlando.

The committee voted 10–9 against approval of Jatenzo on January 9 and 13–6 against approval of Tlando on January 10. The FDA usually follows panel recommendations.

Efficacy Not a Sticking Point

Both Salt Lake City-based Lipocine and Clarus, of Northbrook, Illinois, were on a second go-round for FDA approval. Initial applications were rejected by the FDA for a variety of issues. Both companies returned with new data that BRUDAC was asked to evaluate.

Efficacy was not a concern for the panel, with some noting that it has already been well-established for testosterone replacement therapy in general. Evidence from the manufacturers was also convincing, they said.

In one of Lipocine's new pivotal studies, 95 patients (mean age 56) were given a fixed dose of Tlando 225 mg twice daily in a 24-day open-label trial. Eighty percent of those who received Tlando met the primary endpoint — a normal testosterone C_max of 300 to 1140 ng/dL in a target of 75% or more patients. A second new pivotal study in which patients were given 150 mg three times daily did not meet the primary endpoint. Given those results, Lipocine was proposing to market the 225-mg dose.

In the Clarus pivotal study, 166 patients were randomized to receive Jatenzo, and 55 were given the comparator Axiron (testosterone topical solution, Eli Lilly). The trial also tested a titration scheme with a lower starting dose of 237 mg to address concerns about too high starting doses from previous studies. By the end of the trial, 87% of Jatenzo patients met the primary endpoint — a similar result to the Tlando trials.

Cardiovascular Effects Unclear, but Concerning

FDA reviewers noted upward shifts in blood pressure of about 4 to 5 mmHg and heart rate of 2 bpm or so in the Jatenzo and Tlando trials. In both studies, blood pressure was monitored by cuff, a method that led to insufficient data to reach conclusions, said the FDA analysts.

Panelists agreed and said they wanted to see more data, with measurements taken through ambulatory monitoring.

"As far as risks, the one still not well explained is blood pressure," said Robert A Adler, MD, chief of endocrinology and metabolism, McGuire Veterans Affairs Medical Center, Richmond, Virginia.

But "for the indicated population, the benefits outweigh the risks," he observed. Dr Adler voted for approval of both testosterone undecanoate products despite his reservations, adding that he thought further data on blood pressure could be gathered pre- or post-approval.

Other committee members insisted the question should be answered before approval.

"It's difficult to put the genie back in the bottle. It's important they get this right and gather these data before the drug is approved," said the panel's consumer representative, Sarah Sorscher, JD, MPH, deputy director of regulatory affairs, Center for Science in the Public Interest, Washington, DC, who voted against approval of both products.

Panelists were primed to look at cardiovascular effects by the FDA.

The March 2015 FDA warning required all prescription testosterone replacement products' labels to reflect a possible increased risk of heart attacks and strokes, and said it would require manufacturers to conduct trials to address the risk. Clinicians were advised to make patients aware of the possible risk.

The American Association of Clinical Endocrinologists issued a statement later that year essentially outlining the benefits of testosterone, while emphasizing the uncertainty about the FDA's advice. The statement advised clinicians to be cautious when using testosterone therapy in symptomatic elderly men with demonstrably low testosterone levels, and that treatment should be avoided in frail elderly men until better outcome data were available.

The FDA warning "was quite influential in terms of clinical practice," said Peter McCullough, MD, MPH, vice chief of medicine and cardiologist, Baylor University Medical Center, Dallas, Texas, and a Lipocine consultant, at the BRUDAC meeting, noting that prescriptions for testosterone replacement therapy have leveled off some.

Does an Oral Formulation of Testosterone Meet an Unmet Clinical Need?

Clinicians at the Tlando meeting who spoke on behalf of the company or patients, however, said that current testosterone replacement formulations are lacking.

"I believe there is an unmet need for an oral treatment option for patients," said Adrian Dobs, MD, MHS, professor of medicine and oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Dr Dobs, who was paid by Lipocine to help make its presentation to the FDA, said that an oral formulation would minimize the risks of topicals, patches, and injectables, while providing the same benefit.

Martin Miner, MD, codirector, Men's Health Center, The Miriam Hospital, Brown University, Providence, Rhode Island, who participated in the phase 3 Tlando study, and whose travel was paid for by Lipocine, said: "What we do need in this field are more products with less risk and less burden in their delivery."

Tlando's cardiovascular effects, including on blood pressure, lipids, and hematocrit, "are no greater than any other testosterone formulation and appear not to be clinically meaningful," said Dr Miner.

Panelist Glenn D Braunstein, MD, chief medical officer at Pathway Genomics, San Diego, California, who voted to approve both Tlando and Jatenzo, said he also believes there is "an unmet need for an oral agent." Speaking at the Tlando meeting, he said the therapy was no better or worse than other approved testosterone replacement products and that it wasn't fair to hold it to a higher standard.

"I do agree that there are concerns about off-label use, but I think that's a societal problem," said Dr Braunstein. When physicians prescribe off-label and patients are willing to pay out-of-pocket, "we can't really control that," he said.

The FDA is due to make an approval decision about Tlando by May 8, according to Lipocine.

Clarus has not issued any statements since the BRUDAC meeting, but resubmitted its FDA application in June 2017.

Clarus also had filed a patent infringement suit against Lipocine, which was dismissed in 2016. At the time, Clarus said it had the option to refile the suit if Lipocine received FDA approval for Tlando.

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