Thank you for the opportunity to speak today. I am Dr. Danielle Shapiro, I am a physician and senior fellow at the National Center for Health Research. Our research center scrutinizes scientific and medical data and provides objective health information to patients, providers and policy makers. Those are the perspectives I bring with me today. We do not accept funding from device companies and therefore I have no conflicts of interest.
Prescriptions for testosterone replacement drugs are on the rise. In 2013, it was estimated that over 2 million men in the United States were on a testosterone drug, commonly receiving their prescriptions during a primary care visit. As men age, testosterone levels decline, and doctors figure–what’s the harm? And, as you know, for many of those men, the risks have outweighed the benefits. That is not the indication we are here to discuss today. For men who have hypogonadism, replacing testosterone could provide a chance of living a normal life. However, this first-of-its-kind oral testosterone drug could also be misused, which could harm millions.
Jatenzo met its narrowly defined efficacy endpoints. However, the trial did not demonstrate efficacy of relevant patient-related outcomes and the results raised concerns of potential harms.
We have the following concerns:
#1. The measures of drug efficacy are based solely on pharmacokinetics, such that the intended drug replaces the missing or deficient testosterone. While this outcome is important, it is not a patient-centered outcome. Outcomes of interest to patients may include psychological parameters, such as behavior and mood; physiological parameters, such as muscle strength and bone density; and global parameters such as overall health and well-being. Other meaningful measures may include activities of daily living, social impairment, emotional distress, self-satisfaction, and resilience. These types of psychosexual dimensions are the patient-centered outcomes, and although some of them improved on the drug, there were no significant differences between the drug and the active comparator. Therefore, the important issue is how well the risks of Jatenzo compares to other treatments.
#2. We have concerns about the cardiovascular safety of Jatenzo, which seem even more significant than others in its class. The data indicate that blood pressure parameters exceeded clinically dangerous thresholds. In addition, hypertensive patients had even more significant climbs in blood pressure. Furthermore, the trends suggest that over time the blood pressure measurements may continue to rise without an apparent plateau.
It must be noted, that subjects were grouped according to outdated clinical guidelines. The new guidelines define stage 1 hypertension at systolic pressure of 130-139 and stage 2 at 140 and up. With these lowered thresholds in mind, the trends in the data are even more clinically significant and concerning. Although the sponsor contends that these effects are “not correlated,” there is a clear cardiovascular safety signal that cannot be ignored. These safety concerns may be further compounded in the population that is likely to misuse this drug off label.
#3. We have concerns about the adrenal effects of this drug. We agree with the endocrinology consultant that the data are insufficient. We urge the FDA to require the sponsor to assess the effects on adrenal function in a well-powered study with standardized methodology. Adrenal insufficiency can have many life-altering and life-threatening consequences. Therefore, before this drug is approved, we need data to establish safe use.
#4. Last, we need additional information on drug-drug interactions. The sponsor promised separate analysis of subjects taking lipid lowering drugs, including statins, fibrates, niacin, and omega-3 oils; however those analyses were not provided. Given the drug’s pharmacology, lipid lowering drugs could affect efficacy. Such information would be useful for patients and prescribers and should be included on the label.
In conclusion, testosterone replacement can help patients with hypogonadism live a normal life. A new oral drug might be beneficial, but this drug raises concern of potential harms. On a chemical level, the drug works, but we don’t know whether it meaningfully helps patients in the long run. Long term studies with patient-centered outcomes may provide more certainty. In addition, the data do not provide reasonable assurance that this drug is safe. We need additional safety data and drug interaction data before this drug is approved. Furthermore, if we consider potential misuse as part of the risk/benefit evaluation, then the potential for harm surely exceeds the drug’s benefits. Therefore we cannot recommend approval at this time. Thank you for the opportunity to share our perspective.
The Bone, Reproductive, and Urological Drugs Advisory Committee (BRUDAC) voted against Jatenzo with a close 10 no’s-9 yes’s-0 abstains. Read more coverage of the 2-day testosterone meetings here.