Oncternal Therapeutics Inc (ONCT) 2011 Q4 法說會逐字稿

Good day ladies and gentlemen, and welcome to this morning's GTx conference call. My name is Ann, and I will be your coordinator for today's call. As a reminder, this conference is being recorded for replay purposes. At this time all participants are in listen-only mode. (Operator Instructions). We will be facilitating a question and answer session following the presentation. I would now like to turn the presentation over to Dr. Steiner. Please proceed, sir.

Thank you, Operator. I will be making forward-looking comments during today's call, and I will direct you to the two press releases we filed today, and the quarterly report on Form 10-Q we filed November 4 with the SEC, where we discussed the risks and uncertainties that affect our business. Earlier this morning we announced that the US Food and Drug Administration notified the Company in a telephone conversation last Friday that the Agency has placed a clinical hold on our clinical trials evaluating Capesaris for first line androgen deprivation therapy for advanced prostate cancer, and in secondary hormone therapy.

As these trials were open label, we were able to monitor efficacy and safety of these patients. In the loading dose study we raised the doses of Capesaris to induce castration by 28 days. These doses were indeed successful in achieving castration in greater than 95% of the subjects by 28 days, at both the 1,500 milligram bid and 1,000 milligram bid doses. However, the higher loading doses also had a greater rate of VTEs.

After receiving reports of an increase in VTEs in the loading dose study over the prior ten days, we requested a conference call with FDA to express our concern with the current loading doses, and to discuss whether there may be a possibility of discontinuing the loading doses and suggesting an alternative approach. During our call with the FDA on Friday the Agency told GTx that it was placing the current program on clinical hold, until we can better understand the relationship of our current doses to the potential for VTEs. We will be receiving written communication from FDA detailing the steps required to have the clinical hold lifted, and to resume clinical development. To date, we have not received the written communication. The clinical hold affects GTx's Phase 2 loading dose finding clinical trial, and its Phase 2b maintenance dose finding clinical trial, as well as the Phase 2 clinical trial in men with castration resistant prostate cancer.

We believe there is a path forward to develop Capesaris at lower doses to treat men with metastatic hormone sensitive prostate cancer as primary ADT, as well as castration resistant prostate cancer as secondary hormone therapy. We intend to work with FDA to determine the appropriate course of action to evaluate Capesaris in these patient populations. Capesaris was demonstrating significant efficacy in both our primary ADT and our secondary hormone therapy clinical trials. In the primary ADT Phase 2 clinical studies of Capesaris, the rates of induction and maintenance of castration were consistent with our expectations, with over 95% of patients achieving castration by day 28, and over 95% maintaining castration.

The testosterone escapes were similar to the LHRH agonist treatment. Furthermore, Capesaris also demonstrated the ability to increase SHBG, which resulted in a reduction of serum free testosterone to levels below what can be achieved with LHRH agonist therapy. Evidence from this study shows that lower free T matters, as almost twice as many Capesaris treated patients in this maintenance dose clinical study as those receiving Lupron had an undetectable PSA defined as a PSA less than 0.2 nanograms per mil, which we believe was attributable to the ability of Capesaris to increase SHBG and lower free T.

Regarding improving upon the estrogen deficiency side effects of ADT, subjects treated with Capesaris reported a very low rate of hot flashes around 5%. There were no significant changes in insulin resistance, which if it were increased would lead to diabetes, and there were striking reductions in bone turnover markers consistent with preventing bone loss. Capesaris' target product profile for efficacy and the avoidance of estrogen deficiency side effects, met our expectations for primary ADT or first line hormone therapy.

There were two safety issues that we needed to sort out in our Phase 2 clinical studies in prostate cancer patients, based on known class effects of estrogens and what we observed in our previous Capesaris clinical studies. These safety issues are an increase in hepatic enzymes and an increased risk of VTEs. We have discussed both of these concerns many times publicly.

In regard to the hepatic enzyme elevation, specifically ALT and AST, in over 168 patients treated in our three Phase 2 clinical studies with some patients being treated for as long as nine months, we have not observed any significant changes in hepatic enzymes. As for VTEs, we know that the potential for VTEs is an estrogen class effect and is related to dose. We were not concerned about arterial embolism, because we know that Capesaris as an ER alpha agonist does not affect platelets, and clinically this appears to hold true. We believe that if VTEs occurred they would have occurred at or below the rate of VTEs observed in patients treated with other standard medical primary ADTs, as well as in surgical orchioectomy for advanced prostate cancer.

We felt that Capesaris could successfully be developed for primary ADT for advanced prostate cancer with a favorable benefit risk profile, including a reduction in estrogen deficiency side effects. With VTEs now having been observed at doses of 1,000 milligrams and higher tested in our clinical studies, and especially even the higher exposure from doses designed to achieve castration by day 28, we are in agreement with FDA that dosing should be modified.

We need to reassess our approach as we try to understand the reason for these VTEs, and how we can develop Capesaris as a primary ADT perhaps by inducing castration by an alternative method followed by Capesaris, or by selecting a more appropriate patient population, such as men with metastatic hormone sensitive prostate cancer, or both. Capesaris also was performing well as a potential second line therapy in our Phase 2 clinical study of men with castration resistant prostate cancer. Current data at the 2,000 milligram dose showed promising results, with serum PSA reductions occurring in all patients randomized into the study. The mechanism of this activity appears to be related to increasing SHBG and further lowering free T.

We have a good deal of clinical data collected from several of our clinical trials involving in excess of 400 patients, where we examined the relationship of SHBG increases and Capesaris dose. These data suggest to us that Capesaris can be developed as a secondary hormonal treatment at doses lower than those tested to date in our Phase 2 clinical studies of men with castration resistant prostate cancer. More specifically, at lower doses Capesaris has been shown to increase SHBG significantly, thereby reducing serum free testosterone and serum PSA. Consequently, for patients who develop castration resistant prostate cancer, we believe Capesaris has a unique efficacy profile as secondary hormonal therapy at doses that are both effective and safe, and with the added benefit of treating the estrogen deficiency side effects associated with LHRH agonist treatment.

This is a large market with over 80,000 patients that have castrate resistant prostate cancer in the US alone, and physicians would rather have patients undergo multiple secondary hormone therapies before choosing chemotherapy for prostate cancer. We hope to receive the written notification from FDA soon. We plan to work promptly with FDA to clarify a path forward for Capesaris. We will update investors after we have discussed the matter further with FDA. and have more information to report.

Before we begin the Q&A portion of the call, I would like to update you on the progress of our SARM program. Many of you have known our lead SARM by the names of Ostarine or GTx024. From now until the drug is approved with its own brand name, we will refer to the compound as Enobosarm, which is the generic name officially given to the compound by the USAN Council and the World Health Organization. This is the first molecule to receive the SARM stem from USAN, recognizing it as a first in class.

Last summer after receiving input from FDA on the design of our pivotal Phase 3 clinical studies, we commenced two Phase 3 clinical trials, POWER1 and POWER2 evaluating Enobosarm for the prevention and treatment of muscle wasting in patients with advanced non-small cell lung cancer. In the fourth quarter, we met with regulatory representatives at the Medicines and Healthcare Products Regulatory Agency of the United Kingdom, and also with the Medical Products Agency of Sweden, two key agencies represented at the EMA. We reviewed with them the design of these studies including the end points being assessed.

Assuming Enobosarm is found to be sufficiently effective and safe for its intended use, these European representatives have indicated that the Phase 3 studies are appropriately designed to support the indication of prevention and treatment of muscle wasting, and allow for a central filing for marketing approval in Europe. The POWER1 and POWER2 studies are enrolling now, and if we meet our goal of fully enrolling these studies by the end of summer, we should have top line data from POWER1 and POWER2 Phase 3 clinical studies in the first quarter of 2013.

This morning we also released our financial results for the fourth quarter and full year 2011. While we won't review the financial results in full at this time, let me point out that we ended the year with $74 million in cash and short-term investments. Mark Hanover and I will be happy to answer any questions you may have about our financials during the Q&A. Operator, we are now ready for our first question.

Thank you. (Operator Instructions). And our first question comes from the line of Mike King with Rodman & Renshaw. Please proceed.

Good morning. Thanks for taking my question. Can you guts hear me okay?

Yes, Mike, we can.

Hi, Mitch. I guess a couple of questions. I don't know how much more detail you can get into as far as the rates of VTE are concerned, but I guess my overarching concern is that the clinical hold was placed on both arms of the Phase 2 in both ADT, as well as the CRPC population, and sometimes clinical holds can be put on molecules where the patient population might not, it may not be appropriate from a risk benefit standpoint, but the fact that you guys got hit with a clinical hold in the metastatic patient population is a bit concerning. I am wondering if you can say any more about that?

Yes, I would be happy to. First thing I will tell you is that in the metastatic population, which is we were testing the 2,000 milligram dose versus, just the 2,000 milligram dose. There were no VTEs in that study. The FDA didn't look at that study and say well, you have got VTEs and now you are in trouble. They did a complete clinical hold because we wanted to understand our doses better. But to give you the more specific rate and the reason why they kind of just generalize, is when we did the VTEs, and I will be happy to give you the rates. We had 55 patients randomized to our loading dose study. We had 164 patients randomized to our maintenance dose study, which were two arms, the 1,000 milligram and 2,000 milligram. Originally we had a 500 milligram arm, but because we didn't see efficacy in the 1,000 milligrams we didn't waste our time or money with the 500. It was just two arms and 164 patients. And actually the 500 milligram arm would have been in the loading dose study. We just never did the 500 milligram. So it is 55 in the loading dose, and 164 in the Phase 2b.

Now the VTEs, I will give you data from our trials, and I am going to give you data from the other studies that we have done, so you can see what I mean by being dose related. The loading dose phase to achieve castration by 28 days, as you know we achieved castration in 28 days but we had to use higher exposure which is 1,500 milligrams bid, and 1,000 milligrams bid and that rate was 5.5%. Grade greater than, equal or greater than 3 was 3.6%. The maintenance dose phase, okay, so the maintenance dose are going to be the patients that were in the maintenance dose, either in the loading dose study or maintenance dose study, and some of these patients were treated for as long as nine months, and then greater than or equal to a 1,000 milligrams the rate was 5.7%, and the grade greater than 3 was 2.1%.

If you ask the question, not these studies but other studies that we have done in similar populations, other Phase 2 studies where we looked at doses less than 1,000 milligrams, we have 180 subjects and we saw no VTEs. So the take home here is that we picked up a higher VTE rate when we pushed the dose to get to castration by day 28, which as you know is the requirement to lower your testosterone level, regulatory requirement to lower your testosterone less than 15 nanograms per deciliter by day 28, and then to maintain that from day 28 to day 360. So the maintenance portion of it was splendid. The loading portion of it was the reason why we called the FDA, and said to the FDA that we wanted to change the loading doses and move to either lower doses, and actually our recommendation is an alternative approach, and at that point it was felt that we need to kind of examine the doses that we have plus consider lower doses, and that is kind of where we ended up.

We prompted the call, FDA was gracious to give us the telephone call, and they verbally told us at that point there is a clinical hold, and that we would get a letter to tell us based on that report what to do. The only point I can make right now is I wouldn't generalize much more than that, except that we do believe there is a path forward. We do believe there is a path forward in castrate resistant prostate cancer, and we also believe there is a path forward in first line, especially when you consider potential for patient selection and dose.

Okay. But I mean it sounds like you have got a very narrow therapeutic window here. I am trying to think of an appropriate patient population for ADT?

You are talking about for first line?

For first line.

The first line most of that is going to be a discussion about the relationship of VTEs to dose, not necessarily saying that we may not continue with the same doses. So I wouldn't read much more into that than saying well, oh my gosh that is your rate and our job is to figure out what is the appropriate, our rate that we want to see is going be a rate that is similar to Lupron, and Lupron has been out for 30 years, and has got lots and lots of data that shows that Lupron's rate is about 3.8% VTEs, and what we are hoping we are able to do is to figure out a way to get our rate in that range, and on top of that to have the estrogen deficiency related side effects treated, so you are actually improving upon the profile for first line.

Right, I understand the idea there but again --

I guess I am saying is that we are going to talk to the FDA and understand that. I would say that the current doses is fully loaded with all kinds of patients that went on the study. And including nonmetastatic cancer patients, and as you know that is a group of patients the FDA has great concern about.

Yes.

And so there is some, we just need to do our work and then come back and tell you how we want to move forward in first line and second line. The second line as you mentioned is the low hanging fruit, because in second line which is castrate resistant prostate cancer, we have confidence, I would tell you that the therapeutic window here is not narrow. We can drop the dose and still see the efficacy.

Okay. Just I will ask one more question about that population, and then get back in queue. Can you say what other agents patients in the CRPC subgroup had been exposed to?

Right. The only agents that they have been exposed to would have been LHRH agonist plus or minus an antiandrogen. They are truly patients who have failed Lupron, or we would say first systemic therapy.

Okay. So no docetaxel or no medvation, or no--?

No. This is not post chemo. This is prechemo and there are patients that developed castrate resistant prostate cancer as demonstrated by a rising PSA in spite of castration.

Okay. Thanks very much.

Thank you, Michael.

And our next question comes from the line of Biren Amin with Jefferies. Please proceed.

Thanks for taking my questions. I just want to get some clarification on the loading dose. What loading dose achieved the 95% castration at day 28?

Both did.

Okay. And I guess you are potentially going to contemplate a lower dose, lower loading dose strategy, and what would give you I guess confidence in the effectiveness of this type of a strategy?

I will tell you exactly what our strategy we are thinking about. Of course, we have to discuss this with the Agency and all of the disclaimers but what we were going to propose to the Agency, and we still want to propose to the Agency is that we feel confident. The issue here is that you have to castrate over 90% of your patients by day 28. We saw in our maintenance dose study that we can achieve that by day 60. So do you really need to have an emergency castration, and get everybody down to day 28, castrated by day 28.

The answer is that is the regulatory requirement, okay. We know that our drug at the lower doses can maintain castration, and maintain castration means that once you are castrated your testosterone escapes, and looks just like the Lupron escapes, 95.5% by Kaplan-Meier estimates. If that is the case why not consider giving the patient a one month Lupron injection, and then you give them Capesaris going forward.

What that does you don't pick up the VTE rate of a higher dose, and then you are down to your maintenance doses, which I believe through patient selection we will get it down to standard of care, other standard of care VTE rates plus the estrogen deficiency related side effects can be ameliorated, and actually improving on the profile, and all you would be doing that would change is that you hit the regulatory requirement of day 28 by giving a shot of Lupron one month, and then the patient would remain on your drug the rest of the time they are on primary ADT. That was the thinking versus dropping the dose down to a level where your VTE rate would be acceptable for 28 days, because I think to castrate you need a higher dose, and this may be a way around that.

Just to confirm were there any VTEs observed in the castrate resistant Phase 2?

No.

Okay, great. Thanks.

The next question from the line of David Nierengarten with Wedbush Securities.

Hi, thanks for taking the question. Interesting that you didn't see any VTEs in the higher dose second line study where as you did in the primary ADT population. Were there differences in the patients entering either trial outside of the cancer, such as were one group of patients on blood thinners or other background therapies, that would maybe explain the differences in VTEs?

Let me tell you that, first of all, these trials are small which means every patient counts for a lot, okay. And so our thinking is that we need to go back, this is the reason why we are not taking the current doses off the table necessarily, we just have to go back and understand the relationship of VTEs and the patient population. I would argue to go the other way, and that is that there are going to be factors that if the inclusion/exclusion criteria was changed, I am talking about for first line right now, that you would have a group of patients that would be the right patients for Capesaris at the right VTE rate. So we know, and the good news is that the literature is filled with that kind of information, and plus we now have information ourselves. What we need to do at least for first line, is go back and try to understand better what is happening with the VTEs versus the kinds of patients that went on the study.

If the patients were all metastatic prostate cancer patients, the original indication for Lupron was the palliative treatment of metastatic or advanced prostate cancer, not for patients with a rising PSA. Not for patients that are going to get radiation therapy and they want to downsize their prostate. There is room there for us to evaluate that. Back to the question about why we didn't see any VTEs at the higher doses, that is what I am saying, there are some inconsistencies here that we need to sort out. The only thing I would say is consistent is that the loading dose had a higher VTE rate, and the VTEs were higher grade. That tells you that higher dose you want to stay away from. But the other doses we need to understand them better, and understand how we want to go forward.

With that said, for second line hormone therapy, we know now you with the SHBG levels and the free T levels and the effects on PSA, that we could get away from the 2,000 milligram dose and go down for example to a 500 milligram dose, and get pretty much the same efficacy if it is anything similar to what we saw in the other patients, i.e. the SHBG levels and their free T levels. We really do think that is the low he hanging fruit from the standpoint of a path going forward, but it doesn't take off the table how we want to handle Capesaris going forward for first line.

Alright. Thanks.

And our next question comes from the line of Ryan Martin with Lazard Capital. Please proceed.

Hi, thanks for taking the questions. Just wanted to ask you on the maintenance dose finding study you have the 1,000 mg and 2,000 mg QID. I think you mentioned there was a about a 95% castration rate by 60 days. Was wondering if you had an idea what the castration rate was at 28 days?

Yes. So both of those drugs are not efficacious at day 28 if efficacious means you have to hit 90%. I don't have the exact numbers in front of me, but the 2,000 milligram was more in the 75% range for 28 days. And that is why we knew going in that would be our maintenance dose, because the goal there was to maintain, first get castrate by a higher dose, and then we made our endpoint there day 60 and beyond, because we knew that would not be high enough based on our previous data, and that is exactly what happened. I mean barring the VTE issue, the rest of the trials both first line and second line hit exactly as we would hope.

Okay. And just on the loading dose study, I know you said there was obviously a higher VTE rate there with both of the loading doses, but then the patients went on to receive three different maintenance doses versus the loading dose. Were there any differences that you could, I know it is a small patient number but you any differences between --?

First let me make a correction, and I will let you finish the question. We did not do the 500 milligram dose in the loading study because when we looked at the 1,000 milligram dose in the maintenance study, it became clear that was not going to be our best maintenance dose. So the maintenance doses that we used in the loading dose were 2,000 milligrams and 1,000 milligrams. The question you are asking is did we see any differences in VTEs up there, compared to the maintenance dose.

Yes. Comparing the maintenance doses post the loading dose?

Yes. I think it is fair to say that post the loading dose, again small numbers. This is just my impression from reviewing the data and it is small numbers. And all of these numbers quite frankly are small, if every patient counts a lot. But our job in Phase 2 is to develop a trial that in Phase 3 will be successful both from an efficacy and safety standpoint. But my impression is that if you have a loading dose that is higher and then go to a lower dose, that you will pick up the baggage of that higher dose. I really do believe to meet castration by day 28 with a higher dose affects not only the loading dose VTE rate, but also the post-loading dose VTE rate. That is why I am more in favor of avoiding a loading dose, and considering a one month Lupron shot for example, followed by Capesaris. We know we can maintain castration, and now we just have to make sure we understand the dose versus VTE relationship.

And then maybe just in terms of the timeline for onset of the VTEs. It was all in the first 28 days?

Talking about for the loading dose?

I guess in both studies.?

The loading dose was the one that was all within the first, practically all in the first 28 days so you can only blame the loading dose. And the maintenance dose it was, and the maintenance dose it was kind of scattered about. What we do know about estrogens is that they tend to, the VTEs tend to occur early. The reason they occur early is because there is really no good way to screen these patients, and so you are really screening by treatment. And when you screen by treatment the patients that get into trouble get into trouble early, and then the patients that remain on the study continue to do fine. I mean the other way to look at it is 95% of the patients continue to do fine up to nine months, and so it is really an issue of how do you get that rate down to at least standard of care, i.e. orchioectomy or LHRH agonist which have a known VTE rate.

I know you have some good data on free testosterone. How does the FDA look at free testosterone?

Well, we have not had that direct discussion with FDA on free testosterone. We do think that free testosterone is our trump card here, because it is not just free testosterone it is all of the clinical effects of free testosterone. And so by seeing, I mean to be more specific when we looked at free testosterone, the levels really go down, and what is interesting is you asked, I kind of said it during my call, prepared comments during the call, but more specifically if you look at patients that are on Capesaris, their serum PSA, the percent of patients that had the serum PSA less than 2 nanograms per mil, which we call in urology undetectable was 73%, and on Lupron that number was 44%. Even if total Ts are the same, your free T was almost reducing the number of patients, or I should say definitely increasing the number of patients with an undetectable PSA by almost double. So free T matters.

So one approach is to say well, we can show that through a metastatic prostate cancer population, number one. Number two, it must matter because in your second line study when you take castrate resistant prostate cancer patients on Lupron, and they fail, we were able to show by adding Capesaris we lowered free T and we increased SHBG which was the mechanism and guess what, everybody had a reduction in PSA, and interestingly, about two-thirds of those patients had a reduction in PSA greater than 50% by day 15. So it is, I mean the drug is working. It is an efficacious drug, and now the question is how do you take an efficacious drug, and make sure that you pick the appropriate patients both in first line, and then second line I think will be a lot easier to move forward.

Okay. Thank you.

Our next question comes from the line of Eric Schmidt with Cowen and Company. Please proceed.

Good morning. Thanks for taking my question. Mitch, in terms of the mechanism here, I thought we were optimistic that via selective agonist of the ER alpha receptor we might avoided VTEs. At the higher doses are you hitting ER beta, or is the selectivity not what it is trumped up to be in terms of the associated risk?

The answer was that we thought that by, thank you for your call, Eric, the question. This is the thinking behind it. By having an ER alpha selective agent that you wouldn't have sticky platelets. If you don't have sticky platelets then you are more likely not to have any arterial events. As you know what killed DES was not just the VTE rate, but also the MIs and strokes and all of the other things related to the arterial side, okay. So far we are not seeing the arterial side issues, and we have known from our studies with P-selectin and platelet aggregation studies in both the human and the monkey, that we don't make platelets sticky like DES. So platelets are part of the story.

The other part of the story is whether or not you induce procoagulants and decrease anticoagulants from the liver. That is not an ER alpha and ER beta effect. That is more sort of an ER alpha effect. So we knew we were going to have a certain VTE rate, and our hope was that VTE rate will be more like standard of care because you are castrating these patients, and not higher like DES. I believe if you go to doses like we did in the loading dose study, it may be you lose selectivity when you get to those higher, higher doses, or exposure I should say. I believe it is a combination answer, and there is no question that the VTE rate at the loading dose is very different in character and in speed, with the very, very high doses. And whereas the maintenance dose was more classic from a standpoint of what we were expecting from the VTE rate for something that was working on liver only. So I do think it is kind of a combination of both.

Our biggest concern was from arterial side, like DES where you see edema, and you see all of these other off target effects, we didn't see anything like that. With DES, which is diethylstilbestrol and having effects on glucocorticoid receptors, mineral corticoid receptors, progesterone receptors, a lot of off target stuff, did not see that with Capesaris. So the selectivity is playing out but from this side effect, the VTE side effect which as you know Eric we were concerned about, and trying to make sure we understood that, I do think the higher doses is where we need to avoid.

Okay. And then it sounded like you had at least a couple of higher grade cases of VTEs. Could you remind us what a grade four or higher VTE is, and whether you had any deaths associated with them?

Right. The higher AEs grade means whether they are hospitalized or not. And if you are like a grade two or less, then you are not hospitalized with it. That is really part of that. And also if you have a PE, then the PE is considered a high grade automatically, okay. In terms of the question about deaths, we had two deaths in the Lupron arm in the maintenance dose study. We had one death in the 1,000 milligram arm in the maintenance dose study. And we had one death in the maintenance arm of the loading dose study. So there were a total of four deaths, two for Capesaris and two for Lupron.

And were the deaths on Capesaris, were they VTE related?

At this point, all we can say is that there were deaths there and all that is being sorted out. But I don't have that in front of me, quite frankly. I don't know.

Okay. Thanks for the added info.

Sure.

Our next question comes from the line of Joel Sendek from Stifel Nicolaus. Please proceed.

Hi, Mitch. Thanks for taking the questions. I am wondering if in your discussions with the FDA so far that they share your view of the threshold DVT rate being that of standard of care or Lupron, or if they are hoping for something better? Are they giving you any guidance on that front?

The only thing I can tell you, and this is consistent with their public comments, is that they do not like primary ADT to be a choice for patients with nonmetastatic advanced prostate cancer, okay. And that really sets the tone for clinical benefit versus risk. And so if the patient population was a metastatic prostate cancer population versus a nonmetastatic prostate cancer population, that certainly affects their clinical benefit versus risk ratio. We heard that loud and clear, and we have heard that loud and clear in the September 14 advisory panel meeting, and we heard that loud and clear in the February 8 Amgen panel meeting. So the FDA has been very consistent that they view primary ADT to be a choice for patients with metastatic hormone sensitive disease, and that will be the standard in my opinion for products being developed going forward. So I wouldn't take anything from the VTE rate approaching standard of care as meaning that is a line in the sand. I think the line in the sand is that the primary ADT should be for patients with metastatic hormone sensitive prostate cancer, not nonmetastatic.

Okay. And then two other questions. One is, do you have to potentially go back to the drawing board here and start with another study in healthy volunteers in lower doses, to rule out or really get a full or a fuller appreciation for the rate of VTEs, or can you actually use this data and move forward?

In my comments I made the comment that we do have 180 patients in, we have 180 patients, the first question is do we have data to talk about what we need to do. First of all, I haven't seen what the FDA wants, okay, let's start there. But my assumption, my belief is that they are not going there. I think that my belief is, and this is Mitch talking, that they are going to want to understand how we want to use lower doses going forward when you look at efficacy and safety.

With that said, we do have about 180 patients in other Phase 1s and Phase 2s that we have conducted with doses less than 1,000 milligrams and have not seen VTEs. 180 subjects is plenty of subjects to see at least a signal. We do have that. We do have information on SHBG and free T, so we can know from the efficacy side since that is the beauty of this system is that SHBG is telling us how the free T is going to act, so we have a real nice biomarker if you will that will be a biomarker for activity. And on the safety side, we have these data. So I do not believe this is a go back to the drawing board. I do believe this is a pose a path forward where we can for second line lower the dose, and for first line come up with a better understanding of patient population and dose and its relationship to VTEs, as opposed to starting from the drawing board.

Again with all of this efficacy data, and being where we are today versus where we were even six months ago, now we have an oral tablet that does what we said, which is to castrate and to treat the side effects of estrogen deficiency, the side effects related to ADT, and like I said, being an oral drug we have got more efficacy data and a better understanding of the drug in over 400 patients today, and being Phase 2 studies where you do lots of them, and you push doses it is not unusual to drop doses when you want to go forward. So we are doing good drug development, and as we see things we are dealing with it. And one of the things that we saw was the VTE rate, and now we are dealing with it.

And just in the second line setting, I mean that was on a standalone basis that was a successful trial?

Absolutely.

With no VTEs.

With no VTEs.

So you really have to change that on the basis of what you saw in the other studies, is that true?

Or you justify. But again, I would take it a different way, and that is that because we saw such success in the second line approach with 2,000 milligrams, and we know what SHBG levels you get with 2,000, we believe we can achieve pretty close to that with 500. And whereas 500 doesn't castrate, in a castrate patient 500 milligrams would be fine. So there is a way to kind of make the FDA happy from the standpoint of lowering the dose, getting the low hanging fruit, which is the castrate resistant prostate cancer group, recognizing we have a unique mechanism of action in a prechemo setting, where doctors and patients are more likely to now that we know the hormone therapies work, more likely to undergo many secondary hormone therapies trying to push chemo off as far as possible, we do believe there is a place for Capesaris in that continuum of care. From again having to wait for the correspondence from a practical standpoint going forward, we do believe that is going to be the easiest way forward, and then we just need to better understand how we about want to go forward in first line.

Okay. Thanks, Mitch.

And our next question comes from the line of Howard Liang with Leerink Swann. Please proceed.

Thanks very much for taking the question. Mitch, if you could go over the data on the lower dose, why the lower dose has lower rate of VTE. Were those in healthy volunteers or prostate cancer patients?

They were in, you are talking about for less than 1,000 milligrams. Some of it was in healthy volunteers. Some of those doses were in volunteers that were the same age as prostate cancer patients. None of those lower doses were in prostate cancer patients.

Can you talk about what were the rates that we are seeing and at what dose?

I haven't broken up the rates per dose. But what I did say is in aggregate for the maintenance dose study, which means the maintenance dose study in the loading dose and the maintenance dose study, maintenance dose arm of the loading dose arms of the loading dose, and the maintenance does arms of the maintenance dose study, the aggregate was 5.7%. Okay. And that is in 190 subjects. And then the loading dose was 5.5%, and that all happened within 28 days. And that is 55 patients we randomized to that study.

I was wondering about the lower doses?

You are talking about the 1,000 versus the 2,000.

Okay. So what was the rate of below 1,000?

We did not do anything lower than 1,000. What I said during the call was that because we didn't see efficacy at the 1,000 milligrams for maintaining castration in the Phase 2b maintenance dose study, we did not start the 500 milligram dose maintenance in the loading dose finding study. Does that make sense?

Right. I was wondering about the rate in healthy volunteers?

Oh, in healthy volunteers it was zero, no VTEs. I missed the question. We had 180 subjects and zero, none.

Okay. I think the prostate cancer patients I guess inherently have a higher rate of VTEs. Is that correct? And what was the rate in the trial on the Lupron comparator arm?

In Lupron the comparator arm at 9 months there were no VTEs.

Okay. I guess do you think of VTEs as exposure related, or is it purely the peak effect?

I think it is actually the peak effect, you mean like the CMAX?

Yes.

So CMAX, I would start by saying I don't know, okay. But it is our impression is that the trough is more important than the CMAX.

Okay. I guess my question is how do we know that maintenance dosing after long exposure VTE will be less of a problem than the lower doses?

Right. Well, the answer is because if you look at the, well it as combination of things. One is what we know from the literature. That always helps us because lots of people have been treated with estrogens, so we go back and look at that. Second, we even see here with higher exposure, or use the word trough that we have, it is a very different character. There is definitely a dose-related effect to VTE. We do believe if you go lower you should see a lower VTE rate. We also know with estrogens, that you tend to see them earlier, and then the rate goes back down. Has been shown over and over in post menopausal women with osteoporosis, it has been shown in men on DES. It has been shown in all kinds of populations including advanced prostate cancer populations. So we do believe, I mean the dose relationship that we are trying to understand here we do believe going lower will be helpful. Now, the problem is if you go lower for second line where the patients are already castrated, I think you are okay. In first line, I think going lower you are not going to be able to maintain castration. So the question there becomes well, are there patient populations where quote the rate that we are seeing now or less if we work with patient selection will be acceptable for the metastatic first line setting and not do a loading dose where we got into trouble.

Thanks very much for taking my questions.

Thank you.

Our next question is a follow-up from the line of Mike King with Rodman and Renshaw. Please proceed.

Thanks for taking the follow-up. And I think Howard just asked most of my question, but can you give us a number of the average duration of therapy, Mitch, in the maintenance arm in serum PC?

I don't have that I am sorry. I can tell you because the study was started in July, and it filled pretty quickly most of these patients are more toward the nine month area.

More towards the nine month area. Okay. So alright, I think I get that. Were these patients on prophylaxis--?

Did you ask castrate resistant prostate cancer?

I did.

I am wrong. My team just told me I didn't hear. No. That was for the maintenance dose study. For the castrate resistant prostate cancer group I would say that is shorter, that is like 45 days.

Okay. Okay.

Sorry, I misunderstood the question.

But nine months for the loading?

For the maintenance dose.

Loading and yes.

Right.

Okay. And then were the patients on thromboprophylaxis at all?

No, no, no one was put on VTE prophylaxis.

No aspirin?

I think some patients took aspirin. Aspirin we always find in clinical trials about 40% of patients are on aspirin. That is because doctors say take it, it is good for your heart so they take it and we don't exclude it. I couldn't tell you whether the VTEs occurred in patients on aspirin or not.

Okay. And then have you also, pardon me for forgetting, but as far as drug/drug interaction studies are concerned, have you seen any interaction with Capesaris and any other commonly used--?

Good question. Turns out Capesaris is glucoronidated, which means that the potential for drug/drug interactions is minimal.

But formal DDI studies have or have not been done?

We have done all the studies we need to do at this point which is basically cytochrome P450 work, and we understand very well how the drug is metabolized which is through glucoronidation. We so the potential for drug/drug interaction should be low.

Great. I have got other questions but we can take them off line. Thank you.

Thank you.

The next question from David with a follow-up as well from Wedbush Securities. Please proceed.

Hi, just wanted to follow up. I am still just a little curious on any other background differences between the patient populations. I mean with the initial ADT I mean obviously the patients are first seeing the therapy and with the second line ADT they have already seen it. Do you think it is a background medication effect that we don't see VTEs in the other one, a dose effect with Capesaris, or kind of a survivor bias where patients who didn't get VTEs with front line hormone therapy continue on and get second line ADT, and aren't going onto other maybe different or more exotic agents?

Yes, yes, yes, I don't have an answer, I am sorry.

Okay.

I don't have an answer. I just don't know. I mean the empirical facts are that they are different, and we just going forward it will be part of our evaluation, and we just need to understand that.

Okay. Thanks.

Ladies and gentlemen, with no further questions, this concludes today's question and answer session, and I would now like to turn the call back to Dr. Steiner for closing remarks.

There is Dr. Steiner. Dr. Weiner couldn't be here today. We would like to thank you all for your interest in GTx, and we look forward to getting and evaluating the FDA correspondence, and updating you on our next steps. Thank you again for joining us on today's call.

I do apologize. Ladies and gentlemen, we thank you for your participation in today's conference. This concludes the presentation. And you may now disconnect. Have a good day.