Antares: Approval of Xyosted is a Matter of When, Not If (ATRS, $2.12, Buy)
The Issue
Antares received a complete response letter for Xyosted that did not cite any questions relating to efficacy, manufacturing, quality control or the device used to deliver testosterone. Surprisingly, the FDA raised concerns that Xyosted could cause a clinically meaningful increase in blood pressure and might also be linked to depression and suicidality. Let me try to put this in perspective.
Testosterone replacement therapy is well established as testosterone injections and gels are currently being used by millions of men. Based on historical experience the FDA has determined an upper level for testosterone levels in the blood; excursions above this level can cause side effects. Also, excursions below a lower bound can reduce efficacy.
Xyosted is being developed under the 505 (b) 2 regulatory pathway in which clinical trials had to show that it does not (or only rarely) result in blood levels of testosterone levels above an upper or below a lower bound during the course of therapy. These levels have been established by the FDA based on experience with numerous other testosterone formulations. There was no control arm in the Xyosted clinical trials. Xyosted showed that it results in consistent blood levels of testosterone within the desired range better than any of the currently marketed gels or injections. I think I am in the consensus in considering it as being best in class for this pharmacokinetic parameter.
What is the FDA concerned about then? Are the side effect issues cited in the CRL unique to Xyosted or are they a class effect? An increase in blood pressure and link to depression and suicidality are known side effects of testosterone replacement therapy so this would be an issue not only for Xyosted, but also for all other testosterone replacement therapies; this is a class effect.
Importantly, testosterone side effects can be exacerbated if the blood levels surge above the upper blood level bound. Because Xyosted is less subject to excursions above the upper bound, one would expect that class side effects would be less. Put another way, Xyosted would be subject to side effects associated with testosterone replacement therapies as a class, but the side effects would be expected to be less pronounced. I cannot really imagine a scenario in which the better pharmacokinetic profile of Xyosted would somehow cause a greater risk for high blood pressure, depression or suicidality. Common sense would suggest no greater and perhaps a lesser risk than with other marketed products.
My conclusion is that the FDA has decided to put more emphasis on these potential side effects and language to this effect will be included in the labeling of all testosterone formulations and it is in the process of doing so. I mentioned an FDA action like this as a possibility in my last note “FDA Action to not Approve Xyosted on its October 20, 2017 PDUFA Date is Perplexing”
Investment Thinking on Antares
The question is how does Antares resolve this issue with the FDA and when? The FDA has no questions with Xyosted’s efficacy, manufacturing, quality control or the device so there would seem to be no reason to request more clinical trials dealing with these issues.
Doing a large clinical trial to determine the extent and risk of high blood pressure, depression and suicidality would require a large and lengthy clinical trial that would be prohibitive for Antares and other manufacturers. It seems to me that the course of action for the FDA will be one of deciding on new wording that would be a class effect warning on the label for Xyosted and all current testosterone replacement products.
The FDA almost certainly has all of the information available to it to determine what, if any, class labeling changes will be necessary. If we were not dealing with the FDA, I would predict that the issue could be resolved quickly in a matter of a few weeks or months. However, the FDA moves at its own glacial pace and there is the risk that this could take longer. The agency might call for industry comments which could drag on and Xyosted approval could be caught up in this.
I think that the issue of Xyosted approval is a matter of when and not if. As a pure guess, I would think that Xyosted could be approved within a range of two to twelve months. I continue to be a buyer of the stock.
Tagged as Antares Pharma Inc., ATRS, Xyosted CRL + Categorized as Company Reports, LinkedIn
Larry, your comment: “Are the side effect issues cited in the CRL unique to Xyosted or are they a class effect? An increase in blood pressure and link to depression and suicidality are known side effects of testosterone replacement therapy so this would be an issue not only for Xyosted, but also for all other testosterone replacement therapies; this is a class effect.”
My $.02 is the CRL had everything to do with labeling. What the FDA wanted included on the label vs. Antares asking(?) for maybe otherwise.
>From the Antares STEADY subcataneous testosterone trial results<
From page 8 of that study: 3 SAE's (Vertigo, Depression, Suicide) were reported but not considered drug related by investigators.
The known class effect vs. Antares trial results showed that that their drug, per the conclusion of independent investigators, didn't have the typical class effects of depression and suicide. Did Antares ask the FDA to have those removed from their label in spite of it being a class effect?
From page 15 of that study: Systolic and diastolic BP barely, and I mean barely increased at the 13 week level, then stayed the same at 26 weeks, then retraced at 52 weeks for systolic and stayed on plane for diastolic. In other words, a miniscule increase in BP that's well within the class criteria. Maybe this area is one of framing the wording. Whatever it was the FDA didn't like it. Again, as Larry mentioned, an increase in BP is typical for this class of drug.
Labeing between the FDA and the filing company is a negotation that happens in the last two weeks of a trial. Time ran out. CRL. Fixing labeling is a class 1 resubmission. We'll learn soon enough next steps to resolve.
It’s my understanding that Antares was conservative on the labeling and included common class effects including the named in the CRL and showed to be very low in their trial data (BP), plus the other two elements which showed not the result of the drug per the independent investigator who reviewed the trial results.
A face to face meeting will come next with the FDA.
Larry, you said:
“Xyosted is being developed under the 505 (b) 2 regulatory pathway in which clinical trials had to show that it does not (or only rarely) result in blood levels of testosterone levels above an upper or below a lower bound during the course of therapy. These levels have been established by the FDA based on experience with numerous other testosterone formulations. There was no control arm in the Xyosted clinical trials. Xyosted showed that it results in consistent blood levels of testosterone within the desired range better than any of the currently marketed gels or injections. I think I am in the consensus in considering it as being best in class for this pharmacokinetic parameter.”
So for the XYO trials, is it correct to say the ‘control arm’ (so to speak) was the acceptable range of testosterone levels established by the FDA based on experience with numerous other testosterone formulations. Antares had to show results within that range, not exceeeding the highs or lows for a certain percentage of patients as established by the FDA.
Thanks