Mitchell S. Steiner – Vice Chairman and Chief Executive Officer
Phil Kantoff – Solid Tumor Oncology, Dana-Farber Cancer Institute
Evan Yu – Faculty-Medical Oncology, University of Washington
Thomas Flaig – Faculty-University of Colorado
GTx, Inc. (GTXI) Analyst Day Conference Call February 15, 2013 9:00 AM ET
Mitchell S. Steiner
Good morning. Welcome to the GTx-758 Analyst Presentation. Today, there may be forward-looking comments made during today’s webcast and GTx directs your attention to the Quarterly Report filed on Form 10-Q November 8, 2012, with the SEC where there is a discussion of the risks and uncertainties that can affect GTx’s business.
I want to thank everybody for being here today. The purpose of today’s discussion is to take advantage of where we are now with our Capesaris program. We’ve been in over 500 patients within our fifth Phase II clinical study. We have a better understanding today about the indication and taking advantage of the regulatory pathway for a compound and its novel and our compound has a novel mechanism.
The program for today is that we have very fortunate to have three of our Steering Committee members: Dr. Phil Kantoff, Dr. Evan Yu, and Dr. Thomas Flaig. They’re going to be presenting different aspects of this story and the story is exactly what it is, because we witnessed a remarkable change in prostate cancer, where we’re having a lot more alternatives, but at the same time, the alternatives are being used for very, very specific indications.
And as you pick away at a different unmet medical need, it becomes clear that new unmet medical needs that cannot be treated with the current therapies including the ones that have been recently approved and have to think through not only that patient population, what’s clinical benefit, but more importantly, how do you bring that drug forward, both in the clinical development and regulatory pathway.
But to begin, I’m going to, and then just going over the agenda, and then we will come back and introduce the individual speakers, and then we’re going to save time for a discussion at the end. as to begin with the changing landscape of the management of advanced prostate cancer, I can remember a year ago after enzalutamide announced their data, there were actually people and the audience that said well, we’re done, prostate cancer is cured, and we don’t have to worry about any other therapies. And in fact, the opposite has quite frankly happened and that raises the question now with multiple alternatives, what does the landscape look like? How we’re going to manage advanced prostate cancer? What are some of the parallels to some of the other cancer types after like breast cancer, for example?
So Dr. Phil Kantoff, who is the Director of the Solid Tumor Oncology, Dana-Farber Cancer Institute, Professor of Department of Medicine and Harvard Medical School, Director of the Lank Center for Genitourinary Oncology, also Dana-Farber Cancer Institute, and also an individual that participated in the Phase III for enzalutamide, as well as serving on the steering committees, all three of the abiraterone Phase III studies is uniquely positioned to talk about the changing landscape and the management of the advanced prostate cancer and where does Capesaris fit in.
Followed by that, Dr. Evan Yu, who has been very, very busy during this meeting; we had four abstracts that were presented. One of the abstracts was about the mechanism of Capesaris based on the Phase IIs that we’ve done, and the other three were on the side effect amelioration if you will of using estragon-based therapy to treat these patients.
And I’m very busy yesterday and then today again another presentation. And he is going to talk about what have we learned from our previous Phase II studies on GTx-758 and in particular putting into focus whether this is mean again in the credit landscape of prostate cancer therapy and the right patient population that an agent life is could be useful.
Dr. Evan Yu is Associate Professor at Department of Medical Oncology University of Washington School Medicine. He is Associate Member with the Fred Hutchinson Cancer Research Center, and he was involved in Phase II studies with enzalutamide, and I think Phase III/II with enzalutamide and abiraterone.
And then Dr. Thomas Flaig and other member of our steering committee will talk to us about the current Phase II study and this is the 712 study we are running now in metastatic castration resistant prostate cancer to allow us to understand better lower doses of Capesaris.
And what is the next step with GTx-758, in particular to clinical development pathway and some of his thoughts on the regulatory pathway. And more importantly, he is going to talk to you about his experience with estrogens, because this is the class of compounds just like ketoconazole and AR blockers have been around for a while, and it’s making them better and more potent and more selective that allows us to use them again round two. And Thomas Flaig is Associate Professor, Department of Medicine, University of Colorado, he is involved also with the enzalutamide and abiraterone Phase III studies, and also make some uniquely qualified to comment about our program, and how it relates to what's out there and what’s the patient population.
So with that I’m going to ask Dr. Phil Kantoff to come up and he’s going to talk about the changing landscape in the management of the advanced prostate cancer, and where this Capesaris fit in. Thank you, Phil.
Thank you, Mitch. I’m honored to be here this morning. So my job is to really set the stage for the discussion about Capesaris, and as you all know a lot things have changed over the past couple of years in the treatment of advanced prostate cancer, and I want to bring everybody up to speed and sort of talk about some of the unanswered questions and then introduce some thoughts about Capesaris.
So these are the nutations on the block that have been approved over the past couple of years, and I would start with going back about a decade ago with the introduction of docetaxel patients with advanced prostate cancer, that was the first agent to prolong survival, and then with metastatic castration resistant prostate cancer.
And then over the past couple of years, as you know there are number of other studies and drugs that have come along including Sipuleucel-T, Provenge the IMPACT study in men with asymptomatic or symptomatic prostate cancer, abiraterone, COU-AA-302 demonstrated a progression free survival, and a trend toward improved survival in men, pre-chemotherapy, AFFIRM trial in post-docetaxel treated men with castration resistant prostate cancer, prolonged lungs survival. The ALSYMPCA study with Radium 223 prolong survival in men, who had either not been treated or have been treated with docetaxel, not yet approved, but likely to be approved; cabazitaxel and the TROPIC study in men, within previously treated with docetaxel prolonged survival, and the COU-AA-301 study in men post-docetaxel prolonged survival.
And as you can in all these phases a median prolongation survival are comparable hazard ratios seen in the 60 to 70 range of significant, all of these drugs are approved with the exception of Radium 223, where Radium 223 and are being used currently.
So this is what the landscape looks like right now, there is really been little change within the context of men with non-metastatic castration resistant prostrate cancer. No drug yet has been approved in this setting. There are bunch of changes as you know in metastatic chemotherapy naïve. There is the introduction of Sipuleucel-T Provenge, abiraterone. We still use second line hormonal therapies in this context including estrogens, some people use docetaxel, taxotere, in this context, but most taxotere use is in the symptomatic setting.
And then there is the anti-resorb divisions, zoledronic acid and more recently denosumab, the RANK ligand inhibitor which both inhibits and delay the onset is still related events with which you use (inaudible). The patients with metastatic disease that are symptomatic, we have docetaxel for a decade now Radium-223 likely to be approved in the next year or so. And as I mentioned before, a bunch of new drugs that have been introduced in the post-docetaxel setting, including Enzalutamide, Abiraterone, Docetaxel and eventually Radium-223.
So a lot of new drugs as Mitch mentioned and there is still tons of questions. I’ve been to multiple meetings at this conference, where we are still sorting out what’s the correct order, what’s the correct combinations that should be used? So I’m just listing some of the questions here that remain in men with, were being treated for metastatic castration-resistant prostate cancer, what’s the proper sequencing? So one question that arises is, when should Provenge or sipuleucel-T be used? Can it be used in conjunction with another agent like Abiraterone or Enzalutamide? If and when Enzalutamide is approved in the pre-docetaxel space which will probably find out about in the next year or two.
Which patients should move directly from primary androgen deprivation therapy to Abiraterone? What is the proper sequencing of Abiraterone and then Enzalutamide? When and if Enzalutamide gets approved, one of the issues is there going to be cross resistance between these agents. If you use Abiraterone, will Enzalutamide still work as well? If you use Enzalutamide first, will Abiraterone work as well? Can these hormonal agents be given together? And will there be synergy between these two rather than just an added factor in more toxicity.
Are there patients who should go from primary hormonal therapy right to Chemotherapy and skip over secondary hormonal therapies like Enzalutamide and Abiraterone. And I think there probably are some, but we’ve really haven’t yet identified them.
What’s the role of the (inaudible) the current indication to these drugs are in patients with metastatic castration resistant prostate cancer to prevent skill related events. But should these drugs be used the same as they have been given the fact that we have a bunch of agents now that are treating prostate cancer, and diminishing the rates of skill related events.
And these agents in addition to the agents I mentioned before half their own sets of toxicities, so we haven’t sorted that out yet. What agents to be used in the non- metastatic castration resistant space, so that, that space was empty in the diagram that I showed before. Denosumab was tested in that context, they try to prevent metastatic disease in patients at high-risk development of metastatic disease, but the prolongation in the time to event was only four months. And the FDA felt that that was not sufficient for approval of denosumab in that context. But that’s a wide-open space as well for the introduction of new agents.
The patients with hormone-sensitive disease, little has changed in my mind. We learned at this meeting, I think I learned, I don’t know if others learned, but would agree with me that we now have a better handle on the duration of androgen deprivation therapy for men with local events prostate cancer who are being treated with radiation plus hormonal therapy, where we don’t have to use three years of hormonal therapy, we may be able to get by with 18 months of hormonal therapy. So patients with high-risk disease, we use either surgery and if its organ confined or combination of radiation plus androgen deprivation therapy. And then there is a huge space of patients would relapse after a local therapy with rising PSA for eventually development of stag disease, where androgen deprivation therapy is used.
Patients in this space live for many years, 10 years, 15 years, and they are treated either continuously or intermittently with the current agents, which have been around for many, many years, the LHRH analogs or orchiectomy is still used which are obviously cannot be used intermittently.
So that as you can see here, this area has really not changed very much, and there are questions here as well. And I think one of the most exciting questions to me right now is given the development of all these new agents, can we cure more patients with high-risk localized disease? Most patients present that who ultimately die at prostate cancer with localized prostate cancer, high-risk localized disease, and may live 10 or 15 years without at least common disease, I think it’s conceivable that we will be able to increase the cure rates as we combine some of these agents and combine them with local therapies like surgery and radiation.
Can we improve on the efficacy of primary home alone therapy? A little has changed in this arena in the past 50 years. We had estrogens, we had orchiectomy, then we develop LHRH analogs, a little has changed combined engine blockade is sometimes used, but it probably provides very little benefit over using a single agent. And I think there is an opportunity here for improvement on primary androgen deprivation therapy.
Now, the flip side of that is that patients being a physician that cares the patient, the burden of therapy is enormous and that is – there are acute and cumulative side effects are associated with androgen deprivation therapy. These men live in the androgen deprivation stage for many years and suffer the consequences of that. And I don’t think it could be underestimated. It hasn’t been well studied, but other than the side effects, the psychological impact of it and all the side effects can be understated.
So along comes our drug, Capesaris and the question is as you hear from my other speakers much more about it, but I just want to introduce the concept here that this is quite a unique agent, and it’s really not in the category of LHRH analogs, it’s not in the category of why is inhibitors like Abiraterone and it’s not a ARN agonist like MDV3100 or Enzalutamide or ARN-509, it’s an estrogen and it’s a selective estrogen in alpha and ER alpha antagonist, which is more specific than the estrogens we’ve used in the past like (inaudible) Premarin, which were much more promiscuous and multifunctional, so this is a targeted agent.
So the estrogens arguably and I don’t know that there is a great data on this, but I would argue that historically estrogens could have been the best therapeutic for primary hormonal therapy. However, they suffered from the side effects that were associated with them and fell into this that were associated with high rates of thromboembolic events, much higher than with LHRH analogs and also associated with chronic amnesia, enlargement of breasts, and they fell in this favor over the past 20 to 30 years, because of the side effects. So Capesaris has the advantages of being an estrogen, but has mitigated some of the side effects that’s associated with some of the other estrogens. So it has the bone-sparing effects that estrogens do.
So unlike agents that diminish androgens like LHRH analogs and orchiectomy, the estrogen is bone-sparing, it will not cause loss of bone mineral density. It also being an estrogen would mitigate a troubling side effect that men have with androgen deprivation therapy and that is hot flashes.
And interestingly, as I’ve learned from our other speakers who have done the studies, it appears that it mitigates the insulin resistance associated with androgen deprivation therapy, which is a subtle-effect. so some people get diabetics, some people have subtle insulin insensitivity and is a tendency with androgen deprivation therapy to develop metabolic syndrome and there’s now data to suggest that men who do develop metabolic syndrome may have a shortened duration of effect of androgen deprivation therapy.
So Capesaris mitigates as you’ll see from our other speakers, this insulin insensitivity, so it is conceivable that by doing it, it may mitigate the metabolic syndrome and may in fact improve the efficacy of androgen deprivation therapy.
So as you’ll hear from our other speakers, it raises steroid hormone binding globulin and in turn lowers free testosterone. We’ve always looked for many years at total testosterone and we haven't really understood what that all means because we pulled cash flow levels of testosterone below 50 nanograms and no leader but what we probably should be looking at is, free T levels and you'll here about this from our other speakers and in fact Capesaris lowers free T better than the other agents than that we have been using.
So where could this fit into this complicated evolving paradigm of treatment of advanced prostate cancer or in early disease. Well it is conceivable to me that it could be used as part of this thing that I am very excited about and that is improving the cure rate of men with localized high risk prostate cancer by more effectively lowering free T levels, it’s conceivable that it will add something to the next in treating these high risk men.
And another area I think probably the most important first area of investigation is using it in conjunction with an LHRH analog and possibly with other new agents like Enzalutamide or Abiraterone, and the advantages once again will be first of all, it lowers free T levels better than LHRH analog. It may mitigate the side effects of – it appears to mitigate and probably will mitigate the side effects associated with androgen deprivation therapy for men who are remaining on the androgen deprivation therapy for many years. And including the hot flashes, resorptive effects.
It may in fact if it is used along with androgen deprivation therapy. It may make us question whether we need to use antiresorptive agents, like zoledronic acid or denosumab, which have their own sets of side effects. Though there are some potential real advantages to using this in conjunction with an LHRH analog.
And as I mentioned before finally in the space of men with non-metastatic castration resistant prostate cancer where there has been no approved agent so far. Denosumab as I mentioned before was tried there but the duration of prolongation to a event which is metastatic disease was not long enough to gain approval by the FDA it is conceivable that Capesaris could be tested there and it is conceivable that it may reach the bar of prolonging the time to metastatic disease by greater than six months which the FDA seems to hold as the bar right now for radiographic progression.
So as I think about where it could fit in, these are the three areas I think that are most exciting going forward and as you get from others they are beginning to be investigating the setting. So I thank you very much, I’m happy to answer questions at the end.
Mitchell S. Steiner
Thank you, Phil. Our next speaker is Dr. Evan Yu. He is going to talk about what we have learned from the previous Phase II studies of GTx-758 Capesaris. Evan?
Thank you very much, Mitch. Yes, exactly I’m going to talk today about some of the previous work that’s being done with Capesaris, and as you can see on the slide, there have been multiple studies performed both in Phase I and in Phase II. At this meeting, we are presenting data from 705 and 707, which I want to focus in on, before that I just want to separate out the differences between the 710 study and the 705 study. The 710 study was really meant to be a loading study. So starting with 1500 milligram t.i.d. or 1000 milligrams t.i.d, then followed by maintenance dosing about 1000 milligrams a day or 2000 milligrams a day in those 55 patients. What that demonstrated is that, the castration rate was very significant, greater than 90% for both arms and that it did biologically increase sex hormone binding globulin or SHBG as Phil mentioned earlier and also decreased free testosterone.
So however the data that we’ll focus on today is really from this Phase II open label maintenance dose finding study which really is just the dosing at 1000 milligrams a day or 2000 milligrams a day and just doesn’t have the loading doses. With that again and also maintain castration estimates greater than 95% with a similar testosterone escapes. But it also did increase SHBG as well as decreasing free T and I’ll also show you some interesting data in regards to some of the side effects of antigen deprivation therapy, hot flashes, no internal remarkers, insulin resistance, how Capesaris actually has some good effect in those areas.
Just to say also that there was VTE incidence rate as well and that was increased to doses of 1000 milligrams a day or greater 4000 milligrams and 2000 milligrams doses and we will talk a little more about that later. But to get to the efficacy data and how this drug works is really to first look at total testosterone. Okay and total testosterone has been the standard that we look at, at this duration of time. But as (inaudible) mentioned earlier the question is really what’s biologically relevant testosterone. Free testosterone is the testosterone that binds the androgen receptor and I think we need to think about this in a different way. But first let’s talk about total testosterone.
And what this drug actually did is it did lower total testosterone not as fast as Lupron did, but over time it did catch up and it certainly lowered it to less than 15 nanograms per deciliter, which is considered castrate testosterone level. And the interesting thing is when you look at PSA is, it lowered it just as well and actually better than Dupont did. On this graph as you can see at all time point, you really kind of lowered PSA percentage wise from baseline to a lower depth. And so one might actually ask, why is that? Is the testosterone initially would lower faster by Lupron, but then caught that with Capesaris.
But the PSA levels seem to be even very early on going to drop into greater depth. So what’s driving this reduction in PSA? And so one thing that was looked at is the free testosterone as I mentioned, and a percentage free testosterone versus time as you can see with both the 1,000 and 2,000 milligram dosing of Capesaris is dropped much lower than it is with Lupron here. So it’s certainly possible that this might be the reason why you’re seeing PSA dropping at greater depth at all time point, and it drops very quickly the free testosterone.
Now, to move on again, there are two trials here that data being present from the 705 trial was for hormone naive patients. The 707 trial was for patients that were receiving a secondary hormonal therapy. So this is patients with castration resistant prostate cancer. Patients that are not yet received chemotherapy and this required a few basic inclusion and exclusion criteria that we use is PSA have to be greater than two.
We have to have a rising PSA. So these were not patients that had stable disease. These were patients who were progressing by PSA criteria and then started on this drug. Of course, they had to have castrate testosterone levels, less than testosterone at 50 to go on to the study and they had to stay on primary androgen deprivation therapy within LHRH agonist.
So the endpoint was looking PSA response greater than 50% that was a primary endpoint and obviously also looking at PSA progression and Biomarkers of Serum free T, SHBG, bone and soft tissue metastases as well. And as you can see here, nine patients were enrolled on this initially. Seven patients were valuable by PSA and as you can see all seven patients are mapped out here by PSA response, and all of them had some decline in PSAs. The serum PSA response is greater than 50%. It looks like there patients or four patients met that bar. And as you can see, mean SHBG was elevated about 400%, which fits with the proposed mechanism of action.
Now geographically show free testosterone, PSA and SHBG together, mind you this is SHBG times 10. You could show that there seems to be a relationship there. So again the mechanism of action here, one of the mechanisms of action I’ll say is up-regulation of SHBG and it’s certainly possible that SHBG may be soaking up free testosterone and as you increase SHBG levels, you see a drop in free testosterone in the corresponding drop in PSA as well.
Now to go back to the original 705 study, the initial castration study to look at some of the side effect profile data from that. And actually one of the things to think about is hot flashes and in fact Dr. Kantoff mentioned earlier estrogenic agents can certainly diminish the effects of hot flashes.
So what these bar graphs show is that, baseline interestingly a very small percentage of patients were reporting from hot flashes anyhow at baseline. But when you go to day 28 and you go to day 90, you could see that the hot flash rate reported by patients is certainly much higher for Lupron, that is for Capesaris either at 1,000 milligrams a day or at 2,000 milligrams a day.
Now what about bone affect. Again, Dr. Kantoff mentioned that that’s a well-known side effect of androgen deprivation therapy is increased in bone turnover markers, increased osteoclast activity and risk of osteoporotic fractures. While these waterfall plots basically look at each individual patient on the study. And as you can see here, bone specific alkaline phosphatase, which is an osteoblastic marker, and c-telopeptide, which is an osteolytic marker here with – at Capesaris, you can see significant declines in both of these markers on the waterfall plot, whereas with Lupron, rather significant increases in most of the patients.
And again Dr. Kantoff alluded to the metabolic syndrome is something that we are paying a lot of attention to in the field with prostate cancer, it makes certainly may induce resistance to standard therapies IGF or insulin-like growth factor 1, is up regulated generally in patients with metabolics syndrome. So this is not an unreasonable marker to look at to see whether an agent like this might mitigate some of the metabolics syndrome effect.
And as you can see here, IGF-1 from baseline today, 60 to day 90 and the day 180 generally with Capesaris you see significant decreases in IGF-1 much less so, with Lupron and actually a reasonable month number of patients probably about half the patients or so have increased in IGF-1. So there are a lot of biologic effect here that seem very promising.
Now, under the SAE, so of course, with every drug there is always with benefit, there is always risk, and so in these two studies combined, when you look at the SAE risk, atrial fibrillation was seen in three patients with Capesaris, and thromboembolic events or overall venous thromboembolic events was seen in 4.2% of patients would appear by DDPs and by pulmonary embolism, two patients had myocardial infarction and there was one death, but likewise there was one death in the big pharma as well.
So to summarize I think that there is plenty of data now in this field with agents like enzalutamide with abiraterone and others to show that maximum suppression or blockade of this pathway with testosterone really does matter. Estrogens have been around for a long time, but this agent does have unique properties, unique from standard estrogens or older estrogens such as DES. But these agents can induce primary androgen deprivation therapy as well acting on the LHRH pathway. Certainly, they may have proapoptotic effects as well as directly against the tumor, and in this instance, it looks like it up regulates SHBG.
So this is certainly more selective than DES and also as shown that it may abrogate some of the side effects of androgen deprivation therapy. Other advantages is certainly it’s not cytotoxic chemotherapy and one thing we look at, and it was emphasizing the COU-AA-302 abiraterone trial is the time until chemotherapy for our patients’ quality of life to use an agent that has fewer side effects and cytotoxic chemotherapy is always applied, and unique from some of the drugs out there that require prednisone to aggregate the mineralocorticoid excess, this certainly does not require steroid.
So with that, I’ll close. And Dr. Flaig will talk about the current Phase II study in the next step.
Well. Good morning, looking ahead in terms of the current Phase II study and do that by looking back, it’s a little bit of difficult perspective, now DES or estrogen is a general mind around in part of prostate cancer care for a long time.
So, I’m somewhat still used that estrogen as these non-selective agents that are historic at this point, because of the value I see them added to our patient care. And really as you’ve had, just I think a wonderful overview that feels right now where things are going. Those different oral agents that we’re using, so those we have used bicalutamide, we now get enzalutamide, much more selective pro-inhibitor, we’ve used ketoconazole again, fairly non-selective adrenal special agent, we’re now going to have abiraterone, I think the agonist where I’ve used DES, and many of us have used DES for decades. We now have the opportunity to look at more selective agents, and I think there’s a unique and a real role to that.
So if we just take a couple of minutes to look at DES and those 10 estrogens have been using the non-selective sense in prostate cancer. DES for example, which is I mentioned several times, when we studied back in the 1960s and 1970s largely to the VA Cooperative Group, and unlike Capesaris, this was a non-selective ER alpha and beta agonist. So it had unselected properties. I think insights into the use of Capesaris and how it moves forward, that can be gained by understanding the history of this drug. And so the DES is an active drug, but there’s several limitations, which I mentioned today.
If you go way back and look at these data largely from the 1960’s and 1970’s, we understood that there is a dose response with DES, that’s non-selective estrogen in terms of cardiovascular disease. So this particular graph shows that depending on the dose of DES used, there is a fall off in terms of survival based on cardiovascular disease. In this case, once the dose was pushed to 5 milligrams, we saw a clear cutoff in terms of both in this case arterial and venous thrombotic event there’s non-selective agent. And it’s clearly dose related, and that’s drove my practice as well.
Looking at this side effect in terms of activity, again in 1966, you could look at PSA or SHBG you’re looking outside, that’s simply the progression from Stage III to metastatic disease. But again, there was a dose response in terms of prostrate cancer efficacy as well in moving up to 5 milligram and even 1 milligram; there is relative delay in the progression of this disease whereas placebo low dose, there is a more rapid progression.
So both the side effects and the efficacy appear to be dose related. Putting all up together for these agents again, DES something that I use, 1 milligram seem to be the one that gave the advantage in terms of prostate cancer efficacy without staying the cardiovascular disease as shown here.
It’s a trial, we published a few years ago, this was retrospective from our institute to look at the use of again, these unselected DES 63 patients with castrate resistant prostate cancer who had gone through anti-androgens trials in most of all cases that was at Casodex. We had to use our 1 milligram of DES, which seem to best mitigate the side effects, but still give efficacy in terms of prostate cancer health. So we had as a general practice includes a low-dose aspirin as to again mitigate the arterial events that have been seen with this agent.
So for this side, let’s say 63 patients. We saw that nearly 40% of the patients had a PSA response reduction of 50%, and the duration of medium time to progression is 30 weeks, so more than six months. I'll say one of the reasons I’ve used these drugs and you can see long-term responses. So you have some patients that run for year and more. No response in the quarter of the patients roughly and then about a third that had a reduction in PSAs response was less than 50%. So but it is a clearly an active agent.
As I noted there are side effects to estrogens, what I see in practice that DES is going to come as almost all men get it and you could do prophylactic breast radiation to prevent that from occurring or minimize it. Relatively low rate of DVT in this particular series we get two out of 63, about 3% rate, if you look at other people use these dose ranges 3% to 8%, but there is certainly (inaudible) kind of come after you assist the largest more significant event I think in patients.
If you look at the waterfall part of PSA responses again, not unlikely the fastest team, but these are active agents and large number of the patients are having PSA reduction some with PSA responses. This is a particular cohort about 50% patients were pre-chemotherapy, so that castration resistant metastatic without, metastatic again on the metastatic without previous chemotherapy response.
So if I would summarize looking back part of this, DES is a drug it’s known for decades a long time. There is clearly favorable clinical responses and PSA responses to the one milligram dose is some long-term responses. Clearly, there are some patients that have mitigation or hot flashes and if you see patients in clinic, that's a major complaint that they have. They have – some men has severe hot flashes, that’s a life altering. Many of those patients that used DES that certainly have a reduction in the hot flashes, with the limitations though, clearly DVT is not selective agent, in our series of 3%, you will see this series between 5% to 8%, there is a baseline increase in DVT with these nonselective agents.
Gynecomastia most men have that, it has been addressed in most men either through radiation or some other mean. And frankly DES is just difficult to obtain, it looks through a compound in pharmacy, it’s hard to indicate the cost or the size that you’re going play, is it outside of your local location, you have to find different company pharmacies and so forth, so just a mere limitations to obtaining DES going forward.
Just shift gears now and I'll just talk about the current state of the ongoing Phase II trial with 712 by looking back and then look forward just over that. This is a three cohort study of patients with metastatic castration resistant prostate cancer. They have been maintained an androgen deprivation therapy, so LHRH analogs. There is three cohesive patients, 25 patients in each cohort. The doses looked at here are lower than the doses been talked about by doctor, you and others here, so looking at 125 a day, 250 and 500.
So primarily looking at PSA, but also certainly look at Free T testosterone, the SHBG levels as well as the effects of this dose on patients, I can say that clearly about half of the 125 milligram armed has been randomized or it’s been screened. We're anticipating complete enrollment of this dose group in March of this year, the 250 milligram group will be instead 30 days latest, so there is a 30-day wait from the last patient to look at side effects before going to the next cohort.
Enrollment should increase significantly with the addition of sites in Hungary and screening activity is picking up in the U.S., although the numbers are small and outpatients who have observed increases in the SHBG at the 125 milligram dose in a range similar to the 2,000 dose with an average increase in patients reaching at 60-day mark or greater at 420% of baseline, so I’ll put that in perspective in a different slide.
so it’s at a 60-mark in the 420 range increase. So although, these patients are maintained on primary ADT, the 125 dose of GTx-758 or Capesaris, because of these increases in SHBG result in reductions in free T and PSA. We’ve also observed improvements in long turnover and a lowered dose at least preliminary looks to be well tolerated.
So if you look at the different doses here, I think this is a nice summary slide on the lower axis you see the different doses of the Capesaris going from 125 up to 1,500 twice a day. The yellow indicates the trough levels of the drug in the blood. so you can see that goes up, it’s very dose related.
Up in contrast that the SHBG levels, you get most of the (inaudible) rest of that, you see a significant increase in the 300 range roughly going to the right now looking. And even though you increase the Serum levels of drugs substantially with those increases, the SHBG level, I would say, increases just modestly, there’s some increase. The question is that the lower doses of 125 and 250, 500, we get most of the cancer efficacy without seeing the side effects. The purple boxes in the right corner here show that VTE rates of 1.8 for the 1,000, 2,000, and then 5.45 at the higher doses.
So again, does that correlate with the dose levels and can you have the a little bit of the side effects at the lower doses, and that’s primarily this study is looking at.
My experience of using DES with estrogen, what I do see clot is typically the early defense. This is the work published by one of the British groups that uses the drug frequently, (inaudible) and others. They show it’s peaking at the 3 to 4 month range, I would say my experiences is that or even a bit earlier, this is an early event for patients, it's not a late or a random event. It tends occur in the first few months of my experience for those that do have VTE.
So what are the ways to address the issues of venous thromboembolic event rate and to get that rate down to an acceptable level moving forward. So one thing is certainly patient selection, at this current study these are patients with meta state castrate resistant prostate cancer. Any history of VTE is exclusionary as our major risk factors. It’s also an aggressive approach in terms of using a screening test to look for mutations and the factors that my previous, those who might having that clot of this nature.
Further line the doses, as I suggest that will make it effective, going back to DES data it was very much dose related, so these are significant dose reductions, but again that SHBG increase appears to happen at a very low dose level. So lowering the dose is one way to address this and also prophylactic. So we are typically with the DES use to low dose aspirin and clearly the patients without the risk factor have decreased mobility for some unrelated events, so forth with the prophylactic as well.
So at the lower dose again looking at the study of efficacy, the SHBG levels if we try to project this based on some of the preliminary Phase I data, based on Phase II data, it's predicted that increase is by the 60 and the 300-400 range. So again I will give you some of the update on the current Phase II study. So even at low doses I think in terms of what this marker is, the SHBG you've seen substantial increases in that level.
And looking forward the Phase II study of the 712 is shown here, this is a secondary hormonal therapy primary Ps3 response for those who look in to the bio markers that I mentioned here, that's under way. From there we would select the best dose based on efficacy and the VTE rates to have these three different cohorts and then moving to the Phase III. So as it's been pointed out, there's been a lot of development later in the field once refractory disease is developed, this all kind of new agents.
Looking at an earlier application for those that are hormone naïve and starting this ADT and using in combination. So can GTx-758 combined with Lupron castrate better than Lupron alone, so using it with very early application. Endpoints would be biomarker driven to start an free testosterone.
I think the secondary end points, which I think in terms of the patient experience would be hot flashes and these sort of things won’t turn over. Clearly patients can live longer with the castration resistant disease around castration and that’s a good think but some of these long term side effects, long side effects, metabolic side effects I think are going to come into play clinically and worse we have seen in the past.
Secondary doses is based on the non-metastatic castrate resistant disease, endpoints in that space would be radiographic progression survival and also VTE levels, so just a glimpse of this steering committee. You have met a few of us here today, others represented here both in medical oncology, urology as well as the advocacy.
So just probably a shift back to Steiner.
Mitchell S. Steiner
Thank you, so a couple of questions, I have a few questions with the panel, then we’ll let the audience ask questions, again if you write it down on the card and give it to me, that will be great, in this way I can say the question on the microphone, and the panel can come in.
The first question has to do with one of the things that became clear from our studies is that it is a dose dependent relationship between VTE’s and drug. And one of the things that was unknown is, if you go down to 125 milligram, which is almost 120th of the 2000 milligram dose that we gave in another castration resistant prostate cancer group. We were able to show the concept was, it will be able to show the VTE rates would be lower in fact the VTE rates that we’re shooting for should be similar to Lupron. But we would lose efficacy. And so Tom just – Dr. Flaig just told you that no, we’re seeing a 420% increase in SHBG and with that follows reductions in free T and reductions in PSA.
So we’re pretty excited from that standpoint, because that now tells you that lower dose is possible for efficacy and we put all the things in place for safety. And now you’ve got potentially active, your alpha agonist that the question becomes, how they develop it? The question for the panel is that all these other agents have been looking in the post-chemo setting and the pre-chemo setting for metastatic castrate resistant prostate cancer, so the drugs only going to be useful, if you can get it to the regulatory bodies. and so what is your feeling about the right patient population to put an agent like this and will overall survival be required? And I’ll start with Phil.
I think, Tom mentioned I think the study that needs to be done, which is in conjunction with Lupron and demonstrating that firstly, you can lower testosterone levels to the same degree, where free testosterone levels to a greater degree than Lupron, but from a regulatory standpoint, if you demonstrate that the addition of Capesaris to Lupron diminishes side effects. I think that would be a good regulatory path to pursue, if you demonstrate equivalents at the same time, which I think is likely to be the case.
Mitchell S. Steiner
Sure. I think I more or less agree with Phil there. My kind of standpoint is with an agent like this, the earlier the better, and the reason that is a point that I made earlier is quality of life, better with these types of agents than it is with chemotherapy, and not only it’s a better with hormonal agents but with this hormonal agent and actually Steve alluded to at least in early studies, improve some of the quality of life, detriment that you might get with standard androgen deprivation therapy, Lupron. So my point of view, earlier is better, as long as the lower dose, it’s a good biologic effect, clinical efficacy, and as I say probably.
Unidentified Company Representative
I just say that I recently said it’s a prednisone in the medical therapy of breast prostate cancer; it has been so much changed here. I think if the question is overall survival is an endpoint going forward. I think this has changed in our best, not going to be particularly in earlier study.
I can echo the comments just made about the quality of life. Those patients, I treat with ES or whatever reason they have to come off with that therapy, they typically are not happy because the hot flash returns so forth, which again in terms of quality life as a major impact.
Unidentified Company Representative
Okay. And so one of the things that’s happening now to the late public and many people looking at this field is, there are lot of drugs for prostate cancer right now. And Capesaris is coming along and you can’t be compete with TAK-700 compete with Aragon’s product, you got enzalutamide out there, you got abiraterone out there, I mean how is an agent like this going to compete with those drugs.
Unidentified Company Representative
I think as I just said, I think that the places start is early, so those drugs are getting in late in the post-dose of taxol setting first and in the pre-dose of taxol setting and there really no studies with those drugs yet in conjunction with primary hormonal therapy. So I think there is open field. We try to introduce it in that setting and look at quality of life endpoints as we mentioned.
So I don’t look at this as competition at the different mechanism of action. The goals are different. Looking at the survival endpoint at this point in time with almost any agent is going to be extremely hard given the number of agents that are out there, particularly if you’re looking in early disease.
So quality of life and I think it’s a very meaningful issue for patients, being a clinician and caring for patients who are on androgen deprivation therapy for a long period of time. If you can improve the quality of life I think it can be very important. So I think getting in early with primary hormonal therapy is the place to go and that’s a space that is not competitive right now. It hasn’t been competitive for many, many years. Evan?
Yeah, I think two simple issues. I agree I don’t look at it as a competition, but compared to the other agents that you’ve mentioned, I think number one is mechanism action you need; and number two is the quality of life potential benefits versus detriment. So I think those are the two things.
Unidentified Company Representative
Thankfully with the evidence of these new agents and our ability to really target the AR access, and they can live longer with this and that’s really a great step for us in the field. I think my question is as these formal agents all moved forward, which is the one that’s going to give the best long-term combination therapy?
Don’t help to something I think about as we annihilate the ER by reducing testosterone block into the affect, what’s the long-term impact that don’t help? And clearly there are some advantages here that I think can be interesting in the future, and that’s can become a larger issue both in terms of costs and as was mentioned the side effects of these entries are debated, which are not insignificant right now.
Unidentified Company Representative
I think VTE issue is minimized antagonist mask – is looks promising, I think the anti-resorptive properties of this could avert the need to use agents like Enobosarm or Zoledronic acid, which would be from a financial standpoint very, very advantageous. From a side effect profile also very advantageous. There is lot of men have to remain on those agents for a long time.
Unidentified Company Representative
Questions from the audience, David?
Unidentified Company Representative
Any of your experiences Lupron of course, as a background of VTE rates, that study been done or in your experience, by what degree do you decrease the VTE rates (inaudible).
Mitchell S. Steiner
Tom, you want to take a stab at that as you look to that?
Yeah. So in terms of just using Lupron in standard practice, I don’t think the most people are doing the screening procedures right now. there’s a variety of different epidemiologics study showing there is likely some increases VTE references adding the ADT in there. In terms of using estrogen, we’ve used the aspirin low dose in the patients just as the standard practice with that un-selected DES I talked about. And that’s been more of an arterial prophylaxis in the VTE, but in terms of standard Lupron therapy, I don’t think most people are doing screening right now.
Mitchell S. Steiner
Now the real question there is that if people did screening, what would they find, and we do know that Lupron has its own VTE rate. and the VTE rate based on some of the Scandinavian studies, is about 3.8% to 4%. and so it’s real, but it’s very, very different than the VTE rate that occurs with estrogens, because for some reason, this is true in hormone replacement therapy that women that get into trouble, and you go back and ask the question, whey they got into trouble? 85% of them have some sort of a functional mutation, functional attribute or a mutation in one of the clotting proteins.
And so Factor V Leiden mutation, prothrombin mutations, some of the other immune antibodies that can be measured protein C deficiency, protein S deficiency. But 85%, you could have picked that up, okay. But that’s not a big number with the women, it’s just that once they got into trouble, got into trouble and what’s weird, I’d call it, a treatment by screening in some ways and that only you’re going to find out who is in trouble, is you’re treating with an estrogen and they get into trouble, they get into trouble early, and then everybody else is fine. and this has been shown over and over in both males and females with estrogens and the selective estrogen receptor modulator world like the raloxifene and the tamoxifen and the termifin has shown the same.
So we’re taking the position that if we screen, it should affect not only the estrogen risk, but also, may help with the Lupron risk. But again, this has to all play out, the first positive step for us is to see that 125 milligrams a day, which is almost 20 fold lower than the dose we used in our 707 study that we see efficacy.
So now, it’s all up to safety in this group. If the safety is where we wanted to be, we can move very much early and as Tom said, the two places we would go is one is primary combination primary ADT, and as Phil said, there’s nothing there right now. And we do believe, the whole controversy now is, do you need to be less than 50 nanograms per deciliter. I think people feeling that that 50 was certainly arbitrary, and we’ve used it to be lower than 20, while the consensus groups are saying that total T less than 20 is probably where you need to be, but there’s a whole another group that’s saying, well, you’re measuring the wrong thing, I mean that’s 98% of the testosterone in the bloodstream is not what’s getting into the cancer cells that 2% that free unbound testosterone.
so maybe we should be introducing new sign. In the non-metastatic castrate resistant prostate group, no drugs approved that we at least have some indication that if you can do better than four months, then there’s some, and there’s progression-free survival, not overall survival, you have the way forward. So I do believe in closing here that the area in prostate cancer is going to get a lot more fun, a lot more exciting. There are a lot of me-too drugs, they’re going to struggle to figure out, how to fit in with the drugs that are already out there that they’re similar too. But this one is by itself right now, and it’s one of the three pillars of prostate cancer hormonal monotherapy, you had liase inhibitor, you have an AR blocker, and an estrogen working through SHBG and VTE.
So I want to thank everybody for being on the webcast. I want to thank our panel, our distinguished panel for being part of the presentation today. And we look forward to updating you on Capesaris in the future. Have a great afternoon. Thank you.
[No Q&A session for this event]
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