Injectable and gel versions of testosterone replacement therapy have long been considered cumbersome by both patients and providers, for a litany of reasons from being difficult to administer to an overwhelming insurance burden. However, research from ENDO 2024 revealed that a new oral therapy could potentially eliminate these barriers and be a safer option.
By Kelly Horvath
Although testosterone replacement therapy (TRT) has been around for decades, a recent survey jointly undertaken by pharmaceutical company Tolmar, Inc. and the online physician community Sermo found that many patients who could benefit from TRT may not be effectively treated, for a variety of reasons.
The survey polled more than 300 physicians in February, seeking their perspectives on barriers to effective treatment, among other points of interest including prescribing preferences and unmet patient needs. The results from this survey were presented at ENDO 2024 in June by Adrian Dobs, MD, professor of medicine and oncology at The Johns Hopkins School of Medicine, in Baltimore, Md., and Sandeep Dhindsa, MBBS, director of the Division of Endocrinology, Diabetes and Metabolism at the St. Louis University School of Medicine in Missouri.
Tolmar is the maker of Jatenzo®, an oral TRT approved by the U.S. Food and Drug Administration in 2019. “Tolmar wanted to understand the current landscape of TRT among physicians who write a lot of TRT prescriptions a month,” Dhindsa says, “and they wanted a good representation of endocrinologists and urologists, the two relevant specialties. In the end they had 100 endocrinologists, 100 urologists, and 103 other specialties. To disseminate the findings of this comprehensive survey, they chose to do so at ENDO 2024, and they contacted Dr. Dobs and me who are both interested in clinical andrology to present at the product theater.”
Jatenzo® is testosterone undecanoate (TU) unlike the previous formulation of oral TRT, methyltestosterone, which was found to cause liver damage. “TU is a different kind of esterified testosterone, and it is absorbed through the lymphatic system, where it goes directly into the peripheral circulation,” Dobs explains. “The oral preparation that was available many years ago had a methylated group to improve absorption. But the problem was, it was directly absorbed through the portal vein into the liver, and that caused abnormal liver function.” This pharmacokinetic profile of this drug has shown that liver monitoring is not required, and TU’s safety has been rigorously tested.
Barriers to Treatment and Unmet Patient Needs
The importance of having a new oral TRT available cannot be overstated. This is where the unmet patient needs and barriers to treatment comes in as well as, as Dobs puts it, “how physicians make prescribing decisions and what they think is important in making recommendations to patients.” Moreover, the barriers and unmet needs are inextricably intertwined, thus compounding each other.
One barrier to treatment is insurance. Despite the number of TRT products now on the market, including injections, gels, patches, and (now) oral, as well as various routes of administration, insurance generally covers inexpensive generic formulations, which, in the realm of TRT, usually means injectables or, more recently, gels. “Intramuscular injections are painful, and they have some limitations, specifically the peaks and the troughs,” Dhindsa says. The associated pain and the highs and lows can lead to patient nonadherence. Although gels do not have the same administration challenges, some patients and physicians nevertheless would not opt for them either, given the choice.
“As physicians, sometimes we’re really quite blinded to the fact that there are obstacles to patients. In reality, there are several problems that cause them to switch to other testosterone products. Sometimes, its insurance, sometimes its tolerance — injectables are painful; gels are messy. That was an important finding.” — Adrian Dobs, MD, professor of medicine and oncology, Johns Hopkins School of Medicine, Baltimore, Maryland
Dhindsa explains: “In the survey, we asked physicians what they prescribe and why. They responded that injections and gels are lot of what they prescribe, and the number one reason is to avoid insurance hassles. When, in a follow-up question, we asked what they would prescribe if insurance was removed completely, their preference for gels and injections went way down.” Moreover, when asked if they thought their patients would prefer an oral option, 70% not only said yes, but also that adherence would improve dramatically.
Dhindsa and Dobs both found something surprising in the survey related to barriers and unmet needs: that so many patients switch TRT formulations. “As physicians, sometimes we’re really quite blinded to the fact that there are obstacles to patients,” Dobs says. “In reality, there are several problems that cause them to switch to other testosterone products. Sometimes, its insurance, sometimes its tolerance — injectables are painful; gels are messy. That was an important finding.”
Dhindsa explains it this way: “we typically would not expect that switching from one TRT product to another would improve compliance because it’s just a different testosterone product. But clearly administration makes a difference in this case. We were surprised to know that 25% of patients don’t take the TRT prescribed to them, and 17% don’t even come back to the doctor to follow up. They give up because it’s just too cumbersome for them to do.”
Insurance creates other problems besides restricting patient/provider choices (again, leading to nonadherence), namely, the hoops the provider and their staff have to jump through to ensure that coverage. Dhindsa says the survey asked how much time staff spend on obtaining prior authorizations as well as on following up with insurance companies when a particular formulation is not serving a patient, and it’s on the order of 11 hours per month — just for paperwork — none of that time is reimbursable to the physician.
Another physician perspective that is pertinent here relates back to the TRT switching already described. Physicians would prefer to be able to start a patient on the TRT that is going to work for them, not to have to work up to that status by trial and error, both because that is obviously better for the patient, but it’s better for the physician trying to provide care for that patient also. “When I start a patient on TRT, I do a blood test to see what the levels are, then titrate the dose and get them where they need to be to have symptomatic benefit,” Dhindsa says. “If I have to change it and start the process all over again, we are losing weeks if not months in the process, and it may be six months before the patient can expect any benefit. Some of them may give up at that time because they don’t think it is worth the hassle. So, we lose patients.” The implication is clear: an oral TRT would circumvent many of these issues (e.g., administration challenges, burdens associated with TRT switching) for many patients.
So, if oral TU is both safe and well tolerated, why aren’t more patients using it? Perhaps the most surprising finding to come out of the survey for both Dobs and Dhindsa was the lack of physician (and patient) awareness about oral TRT — its existence in some cases, its safety profile in others. “Many physicians did not realize that there was an oral preparation available. Even though patients wanted to use an oral preparation, they didn’t know that it was available,” Dobs says. “This really suggests to me as well that physicians don’t do a good job of explaining to patients what options are out there and their pros and cons.”
Says Dhindsa: “Although there has been no liver toxicity, this point has to be made again and again, because one of the findings in our survey is that there were some physicians still concerned about toxicity with oral testosterone because of the baggage from the prior version of oral testosterone. This was one of the key points we really focused on during the presentation at ENDO 2024.”
Need for Education
Dobs and Dhindsa agree that education is needed on this score. “It takes a long time for patients and for physicians to understand a new product, how it’s given, and how to make sure that the patient is obtaining a sufficient level,” Dobs says. “So some of that is general to all medications, and some specific for testosterone, which has had a sort of a bumpy course altogether. There have always been lots of discussions about who should be treated and when should they be treated, and that has created controversy in the field. So put this all together, and it’s not easy for physicians to discuss this with patients and really be impartial on one of the various options that they have.”
“We typically would not expect that switching from one TRT product to another would improve compliance because it’s just a different testosterone product. But clearly administration makes a difference in this case. We were surprised to know that 25% of patients don’t take the TRT prescribed to them, and 17% don’t even come back to the doctor to follow up. They give up because it’s just too cumbersome for them to do.” — Sandeep Dhindsa, MBBS, director, Division of Endocrinology, Diabetes and Metabolism, St. Louis University School of Medicine, St. Louis, Missouri
Physicians can also help dispel myths surrounding testosterone, Dhindsa says. Patients are lured by promises that over-the-counter TRT supplements will boost their levels, for example. “So, it is necessary to make sure that doctors are well educated because they are the number one resource for patients.”
Then again, further physician training is still needed, given that the surveyed physicians themselves still expressed so many reservations about the safety of oral TRT. Both Dobs and Dhindsa mentioned concerns about blood pressure and hematocrit elevations with oral TU, but Dobs says evidence suggests this is a class effect and not specific to TU. They recommend blood pressure and hematocrit monitoring with oral TU treatment.
Improving Patient Care
Ultimately, improving patient care is at the heart of this matter, and having various formulations and routes of administration will increase the ability of patients to adhere to one or the other. Oral TU that is taken twice daily with meals, explains Dobs, will likely work well for a patient with a regular daily routine, for example, while it might not be the best choice for a patient who does not keep regular mealtimes. “But that’s we what we want — compliance with the medication because if they’re not adhering to the treatment, it’s hard to determine whether or not the patient is improving. We have to make sure that patients need to be treated, that they adhere to treatment, that they’re getting better with treatment, and that it’s safe over time,” she says. Dhindsa adds that oral TU’s multiple dosing options also may improve adherence and therefore care.
But, continuing to get the word out about oral TU is the first step because, as Dobs says, “the key takeaway is really talking to patients, making sure that they’re aware of the various options that are out there, and that oral therapy is available.” In order to accomplish that aim, says Dhindsa, “we have to continue the work that has started with the Endocrine Society presentation and disseminate these findings,” Dhindsa says. “There was good involvement from the audience, and quite a few people came up to us after the presentation to discuss their experiences.” He believes the survey of physicians was probably the first in an annual series of surveys and hopes that he and Dobs we will be presenting further iterations in future meetings.
Horvath is a freelance writer based in Baltimore, Md. In the September issue, she wrote about some of the women’s health research presented at ENDO 2024 in Boston.