Oncternal Therapeutics Inc (ONCT) 2012 Q1 法說會逐字稿

Welcome to your Q1 2012 GTx Incorporated earnings conference call, hosted by Dr. Mitchell Steiner, Chief Executive Officer. My name is Chris, and I'll be your conference coordinator for today. Throughout today's conference, lines will remain on listen-only until the question and answer session begins. (Operator Instructions). Thank you. At this stage, I would like to turn the call over Dr. Steiner to start. Please go ahead.

Thank you, Operator. I will be making forward-looking comments today during our call, and I direct you to the two press releases we filed today and the annual report on form 10-K we filed March 2 with the SEC where we discussed the risks and uncertainties that affect our business.

Early this morning, we announced that the US Food and Drug Administration has removed its full clinical hold on Capesaris to allow GTx to continue the clinical development of Capesaris in a Phase II clinical trial to evaluate three lower doses of Capesaris for the indication of secondary hormonal therapy in men with metastatic castration resistant prostate cancer. This announcement comes just 30 days following our early April press release stating that we have filed our complete response to FDA's full clinical hold.

Capesaris has a unique mechanism of action compared to other drugs in development for advanced prostate cancer by raising SHBG and lowering free T testosterone levels below to what's typically seen with other hormonal therapies. At the same time, as an estrogen-based therapy, we believe Capesaris will improve the estrogen deficiency side effects related to castration, such as hot flashes and bone loss.

Also having received FDA's input on the protocol for our new Phase II clinical study, GTx plans to initiate during the third quarter a clinical trial to test lower doses of Capesaris in 75 men with metastatic castration resistant prostate cancer. This will be an open label clinical study which will be staggered with 25 subjects, each being randomized sequentially to 125 milligrams, 250 milligrams, and 500 milligram doses of Capesaris.

The study is designed to assess the effect of Capesaris on serum PSA levels and prostate cancer progression in men with metastatic castration resistant prostate cancer who are maintained on androgen deprivation therapy. The primary endpoint is the proportion of men who have achieved a serum PSA response by 90 days. In addition, we will be evaluating serum PSA progression, time to progression, and progression-free survival.

The study will further confirm Capesaris' mechanism of action to increase SHBG and to reduce free testosterone to levels lower than what can be achieved by LHRH agonist alone, which we have already observed in three Phase II studies in men with advanced prostate cancer and in a Phase II study in healthy male subjects. Since a drug with this mechanism of action may also affect the production of adrenal androgen precursors, DHEA and DHEAS levels will also be measured.

Data from our terminated Phase II clinical studies demonstrate to us that the drug is effective,And data from earlier Phase I and Phase II clinical studies and pre-clinical studies and pre-clinical models give us comfort that Capesaris will continue to be effective at lower doses we will be testing in men with metastatic castration resistant prostate cancer.

We do have clinical data in about 190 subjects from our previous clinical trials who have received less than 1,000 milligrams per day of Capesaris. Based on these data, we expect that the 500 milligram and the 250 milligram daily dose of Capesaris should raise SHBG and lower free T. The 125 daily milligram dose may also work on these patients, especially as they have already castrate levels of testosterone from their primary ADT.

Evidence from our studies show that lowering free T matters, as almost twice as many Capesaris-treated patients in our Phase II maintenance dose clinical study as those receiving Lupron had an undetectable PSA. That is, the PSA was less than 0.2 nanograms per ml which we believe was attributable to the ability of Capesaris to lower free testosterone.

As for safety, we expect that patients taking Capesaris will have an improvement in bone loss and in the incidence and frequency of hot flashes, both of which are common estrogen deficiency side effects in men with castrate levels of testosterone. The safety signal, which was responsible for FDA's full clinical hold, was the increased incidence of venous thromboembolic events.

At the higher doses tested in the maintenance dose arms of our previous Phase II studies, the 1,000 milligram and 2,000 milligram per day, the VTE rate was 5.8%. As a benchmark, LHRH agonists have reported VTE rates of up to 4%.

We believe that we can reduce the Capesaris' VTE rate by one, valuating lower doses of Capesaris; two, better patient selection by excluding patient with a history of VTEs or screen positive for bloodclotting factors, mutations or deficiencies; and three, monitoring patients who develop new VTE risk factors while on study and where appropriate, consider VTE prophylaxis. With these additional requirements added to the protocol, we believe the incidence for VTEs will be shown to be similar to that of primary ADT achieved by LHRH agonists, LHRH antagonists, or surgical orchiectomy.

In men with metastatic prostate cancer who have failed androgen deprivation therapy, lowering free T by increasing SHBG offers a unique way to treat their advanced prostate cancer. As it has been shown that advanced prostate cancer can continue to be suppressed by different hormonal therapies, the prostate cancer field is evolving to be more like the breast cancer field, where several secondary hormonal therapies will be used sequentially and in combination before cytotoxic chemotherapy is attempted. The main question in prostate cancer of how these agents will be used is not whether they'll be used prior to chemotherapy. They all will be used prior to chemotherapy. But instead, which secondary hormonal therapy has the preferred efficacy and safety profile.

Since this will be an open label study, we'll be receiving data as the trial is being conducted and we look forward to sharing efficacy and safety data with you during December of 2013. We're excited about the potential of Capesaris in men with advanced prostate cancer.

Next, I would like to update you on the progress of Enobosarm, previously known as Ostarine, which is a first-in-class selective androgen receptor modulator agent. Enobosarm is being developed for the prevention and treatment of muscle wasting, an important cancer-related symptom in patients with advanced non-small cell lung cancer, in two pivotal Phase III clinical studies called POWER 1 and POWER 2.

An independent Data Safety Monitoring Board, DSMB, was established to review the unblinded safety data from these pivotal Phase III clinical trials. This morning, we also announced, in the clinical update of our financial press release, that the DSMB recently met and completed its first review of the safety data from our two ongoing Enobosarm studies and determined that the clinical trials can continue as planned.

The POWER trials are now enrolling subjects from clinical sites located in the US, Europe, and South America. If we meet our goal of fully enrolling these studies by the end of the summer, we should have top-line data from these two clinical trials during the first half of 2013.

This morning, we also released our financial results for the first quarter of 2012. While I won't review the financial results in detail, let me point out that we ended the quarter with $64 million in cash and short-term investments. Marc Hanover and I will be happy to answer any questions you might have about our function results during the Q&A.

Operator, we're now ready for our first question.

Thank you very much. Okay. So ladies and gentlemen, your question and answer session will now begin. (Operator Instructions). Our first question today is from the line of Joel Sendek from Stifel Nicolaus. Please go ahead.

Great. Thanks a lot. Let's see. I guess two questions. Could you go over, if you have the data, 190 patients with Capesaris that were dosed at less than 1,000,what the VTE rate was? And then I have a follow-up after that. Thanks.

Yeah, so of the 190 patients dosed with less than 1,000 milligrams per day, there were zero VTEs.

Oh, okay, great. And then, with regard to how you're structuring the new Phase II study, in order to prevent the safety signal that the FDA was worried about with regard to the VTEs, does that in a way create a non-real world situation that the FDA could then come back later and say is a problem? How do you deal with that? And/or is that the way that patients are treated with Lupron today?

Right. So if you look at Lupron today, you'll see, it already has a VTE warning on it in the label, and that was actually placed there this past year, October. And the reason for that is because Lupron and drugs, hormonal therapies in prostate cancer do increase the rate of VTEs. So the labels for any hormonal therapy that's related to the Lupron class, and certainly for the estrogen class, will already have that.

So the real-life situation is that the agency is going to require that people with a history of VTEs, certainly you should have an increased vigilance in terms of whether you put them on a hormonal therapy. At least you discuss with the patient those options. If we do not believe that we're creating an artificial environment, people with VTEs should be careful when they start hormonal therapies.

In terms of some of the more specific criteria, for example, monitoring patients while on drug -- well, for example in our Phase II studies that we terminated, we had some patients that were hospitalized with prolonged immobilization or ICU visits that were not VTE prophylax, and I would argue somebody with metastatic prostate cancer, regardless whether they're on our drug, if they're going to be known to be hospitalized, most hospitals have a VTE prophylaxis program. And so I think it's very realistic to insist that patients that we monitor that develop a VTE risk factor while on study that we consider VTE prophylaxis.

Whether or not they're on our drug or not is irrelevant. They just picked up another VTE risk. As far as screening for blood clotting mutations, if you go back and look at the studies, especially in hormone replacement therapy in women, it was fascinating to me that over 80% of women that end up getting a VTE on hormone replacement therapy, which is primarily an estrogen-based therapy, that these women had at least one identifiable factor related to blood clotting mutations and/or deficiencies. In other words, you can actually measure things like protein C and protein S and prothrombin mutations and something called Factor V Leiden mutations very commonly.

It's not a big percentage of the population, just like VTEs isn't a big percentage of our trial. However, the patients that do get VTEs, most of them, at least in this study, 80% of them have at least one of these contributing factors. If we screened those patients out of our study, then it's not going to affect the real life where 85% of the patients to 90% of the patients are still going to be eligible for our drug. It's all we're trying to do is make sure that the patients that have a known risk factor are not subjected to the increased risk.

So we think that that's still a large market and it's still getting a large piece of that market and again, the data they're suggesting is that if we had a 80% reduction in the VTE rate, we'll be well below the target to be similar to ADT like Lupron and LHRH antagonist. Interestingly, because this is a secondary hormonal therapy approach, a lot of our patients would have been on Lupron for three years or more, and as you know, the Lupron rate for VTE is about 4% per year.

The patients that would get into trouble, screening by treatment, if you will, are going to be screened out. So the patients that we'll end up seeing in our study will already have gone through sort of the first round of hormone therapy and screened out. So I do think we're setting ourselves up for success in this Phase II study, and that what we're asking in our screening and inclusion/exclusion criteria will be pretty much what real life should be doing with these compounds anyway.

Okay. Thanks. That's great.

Thank you for your question. Our next question is from the line of Biren Amin from Jefferies. Please go ahead.

Thanks for taking my questions. Just wondering, with the Phase II trial, what is the treatment period for Capesaris?

In the new Phase II trial?

Correct.

Okay, so the treatment period in the new Phase II trial, for PSA response, the primary endpoint is 90 days. Which is typical, based on the prostate cancer, Working Group 2 for Phase II trials in prostate cancer. So we're looking for a PSA response greater than 50% in over half the patients by Day 90. And the patient response, they stay on the study until they have progression,so the study will continue longer than that. It's just the primary endpoint being PSA response will be at 90 days.

That's an important endpoint, because right now we know from two large Phase III study programs -- one drug that was approved and the other drug we just saw data this past February -- that the only data they had to go forward into Phase III post-chemo in this setting was the PSA response data, which definitely correlates with survival. So that's the endpoint that we're using. One additional point to be made is that we did run a study similar to the one we're about to run, which is the Phase II, what we call the 707 study in patients with castrate resistant metastatic prostate cancer.

And in that study, 25 patients were to be randomized. Eleven were randomized. We had data on seven, and of those patients, by Day 30, not by Day 90, almost 100% of those patients had greater than a 50% reduction in PSA. Granted, the dose was a 2,000 milligram dose per day, but the point is the drug is very active.

And if I read the press release correctly, it seems that the initial 25 patients will go on the 125 milligram dose. And so what's the threshold to progress to the next cohort of 250 milligram dose in enrolling those 25 patients?

Right. So we do have stopping rules, just like we had in our other trials, for VTEs, and the threshold is pretty liberal, quite frankly. With that said, if we have to stop the trial, it's going to be stopped because we clearly have a VTE signal that is unacceptable. So our expectation is the 125 patients will come on. We have never seen a VTE in anything quite less than 1,000, and those patients will be enrolled.

And then each cohort is staggered so that instead of being a one-to-one-to-one, it's one to the 125. You fill that up, then you go to the 250. You fill it up and you go to the 500. You fill it up and you follow all the patients. So there are stopping rules, but the stopping rules are much more liberal than, for example, the 5% that you're thinking about because every patient counts quite a bit. But there are stopping rules to follow these patients.

And in terms of your patient selection in the study, why no patients on background primary ADT therapy versus patients that have progressed with their disease and have progressed the after ADT?

So make sure I understand the question. So what is the patient population that we'll be studying?

Why select patients on background primary ADT versus patients that already have castrate resistant prostate cancer and have progressed past ADT therapy?

So really the answer is if somebody has progressed, they stay on ADT, okay? So you don't take them off ADT. So you may be reading too much into it. So if somebody is on ADT and they progress, they stay on ADT. All right. So all we're saying is a criteria is that if you progress, by definition you have castration resistant prostate cancer. You can't take the ADT away because testosterone will act like kerosene on fire, so you leave the ADT in the background. All right. So that's all we're saying. It's not a distinction in those populations.

Great. Thanks. Thanks for taking my questions.

Sure, thank you.

Thank you for your question. Our next question is from the line of David Nierengarten from Wedbush Securities. Please go ahead.

Hi, guys. Thanks for taking the questions. Just a quick question. Do you have any idea or what the usual timeframe is for a patient to go off Lupron and progress on to a different therapy, and of course differences in timing of that impacts the VTE rate? Thanks.

So make sure I understand the question. What is sort of the average time that somebody with metastatic prostate cancer that's put on Lupron or other kinds of primary ADT, how long do they typically stay on ADT?

Yes, and if differences in that correlate to differences in VTE rates.

Right. The literature, that number is different depending on the series. The one that we can refer to is the one for Toremifene 80 where we actually ran a 1400-patient study in patients on ADT, and at the time they started the study, most of them were about three-and-a-half to four years on ADT.

So I think a typical patient on ADT is probably going to be on ADT for three to five years which if you look at the literature, in that time period, even at four years, going like four-and-a-half years, the VTE rate is like 15% and that includes PEs, DVTs and arterial embolism. So it's pretty high. People just don't realize it, and the literature is starting to show more and more that these Lupron and primary ADT therapies do carry substantial risk of VTEs. So if you imagine now that an average patient that fails Lupron or primary ADTs is probably going to be somewhere between three and five years.

That's plenty of time to select out those patients that have genetic reasons or protein, clotting factor protein reasons for developing VTEs. The other interesting fact for estrogen-based therapies is that once you get past that early period -- and early periods are defined as less than six months -- patients who do not develop trouble within that first six months, they don't develop trouble after that six months. So this is not like they have this prolonged risk or increased risk with time. They basically go back to baseline risk.

And this is true for hormonal replacement therapy in women. This is true for serums like Raloxifene and other drugs in osteoporosis, and it's also true for oral contraception, and it's also true for DES, which has been used in this patient population.

Great. And you probably won't answer this question, but I was wondering if you to tell us how far you were in enrollment with Enobosarm where you had the DSMB review?

Right. I can't answer that question, only because what happens then is how many patients did you give me this week? But I will tell you, it was a substantial number of patients and that we're on track and we feel comfortable that the trial will be fully involved by end of summer. And so all those things are there. The DSMB meets on a regular basis based on time and not number of patients, but I hate to say I'm not surprised, because Enobosarm has been in eight clinical studies, over 600 patients, and I think we feel pretty good about the dose and safety profile. so I would have been surprised if the DSMB said anything other than that.

All right. Thanks.

Thank you.

Thank you for your question. Our next question is from the line of Ryan Martins from Lazard Capital Markets. Please go ahead.

I came in late, so I apologize, but can you talk about your experience with the lower doses that they're going to be testing in terms of the PSA levels? And maybe even if you've seen something in terms of progression, just on the lower doses you're using. And if not, if you can talk through that as to what your expectations might be?

Yeah. So the answer is the doses that we tested less than 1,000 milligrams were all in healthy patients, and so about 190 of them, and in these lower doses, we were able to map out SHBG levels, free T levels, and PSA. What I can tell you is that the liver is extremely sensitive to this compound and that SHBG levels go up quite substantially and even in patients that did not castrate, their free T levels really dropped and their PSA levels dropped. So they would have a total testosterone that appeared normal, but their PSA dropped because their free T went down.

And so we were able to actually look at the doses in this patient population and say, well, the 500 milligram dose is like a one to two in terms of where we were before with the 1,000 milligram, the 250 is like one to four, and then the 125 was almost one to 10. So we've got a nice range in there, and what makes this a little different, though, is in those intact males, many of them did not become castrate, but they did drop their free T, their PSA, and increase their SHBG. In this patient population, it's different. Why? Because these patients are already castrated on Lupron or LHRH agonist or antagonist. So you're starting out with a total T level that's very low. Now you add in our drug -- I'm not suggesting the liver is more or less sensitive in that environment, but even if it's the same sensitivity, the SHBG, when it goes up, it's looking for testosterone.

It will remove it out of the circulation, so if the patients are castrate and now you raise SHBG, I do believe that our lower doses are going to be able to pull down that free T to levels that you're going to see activity. So we have a lot of data. To put it into perspective, we have something like 230 patients that we have tested with prostate cancer and understand the mechanics of SHBG and free T, and we have 190 patients that have less than that dose and we understand the SHBG and the free T. So we've got a good handle, I believe, on the SHBG/free T relationship, which is pretty -- I mean, this is what this drug does.

Okay. Thanks for that color. And are you going to be presenting that data from the second line trial before the clinical hold was put and how long were those patients on the drug in the second line study?

In the second line study, as I mentioned earlier, we were supposed to have 25 patients. Eleven patients were randomized. At the time of the clinical hold, only seven patients we got data on. And of those seven patients, they all became greater than 50% reduced -- PSA response of greater than 50% was in all of the patients, and our plan is to present that data. In that second line study, there were no VTEs, but we will present that data in the future. With the clinical hold activity and with the complete response letter that we had to quickly pull together,we made the determination that we're going to miss ASCA and we'll miss the AUA, but we do have meetings later in the year that we'll target to present those data.

Thanks. And then one final one. In terms of data disclosure from the trial you're planning to start in Q2, is that going to be on a cohort-by-cohort basis?

Yes. Cohort-by-cohort. What's the question? For news? I'm sorry. So in terms of news, no, it won't be cohort-by-cohort. I will be honest with you, I think the first thing we need to do is start the study, start enrolling the study, and it will be open label and we're targeting next year when we'll have the 125 to 250 and the 500 milligram efficacy rates, as well as the VTE rates. And if we enroll faster, we'll have news sooner and we're just giving ourselves time to get the study going and move forward.

The important point here is that when we filed the complete response to address the clinical deficiencies, we also submitted a protocol at the same time. And so we were very fortunate that within 30 days, we answered the questions and we had a protocol with full input by FDA and so there's not even really a delay. What we're doing now is literally get through the IRB and do all the usual mechanics of starting a trial is our only rate-limiting step, and that's why we believe we're going to turn around and start this thing quickly. If we start this thing quickly, it will impact when we'll have the data.

Okay. Thanks.

Thank you for your question. Our next question is from the line of Jonathan Eckard from Leerink Swann.

My first question, just so I'm clear, the full clinical hold is lifted but the program is still under a partial clinical hold; is that correct.

No. we got a removal full clinical hold. We still can go after first line, we can still go after second line. What we did is we proposed the study that we believe will answer the questions we need, so for example, my thinking is that we do the Phase II, we do the lower doses, we understand the VTE rates, and then based on that, then we come back and we propose what we want to do for first line. No, this is removal of full clinical hold on the IND.

Okay. And then just so I'm clear also, with the sequential enrollment for this planned trial. Do you have to enroll, treat, get results from the lowest first dose before you can start enrolling the second dose? Or can the second cohort enroll before the first cohort has reached the 90 days?

Right. No. It's staggered by one cycle, which is defined as 30 days. So you enroll 125 patients. When that last patient hits day 30, you start the next one.

Okay.

You're not waiting the full 90 days, no.

Okay. So it's not that this is going to be a nine-month trial per se?

No, it's going to be a lot shorter than that. By adding the two-cycle delay, you only delay by two months, you're really not delaying by two months because these patients don't need to be "immediately treated." So the trial just continues and you just stagger it by one cycle.

And then I guess the next question is has that data that you were referring to earlier about the healthy volunteers treated below doses of 1,000 and the effects of their PSA, was that data ever published?

No. I have to go back and look and see. I think the answer is yes. I think we've put an abstract out on a Phase II study, and it appeared in the Society of Urologic Oncology in December of not this year but last year. And in that study, we do talk about a solution study where we did a 600 milligram, 1,000 milligram, and a 1,500 milligram daily solution of Capesaris, and I believe there's free T, SHBG, and PSA data in that abstract.

Very good. I heard your comments earlier that in this trial, most of these patients will have had ADT for quite a long time. So you may be screening out those who are more susceptible to VTEs from, say, Lupron or androgen deprivation therapy. Is there any concern from your side that you're adding now Capesaris that had a clinical hold because of increased VTE on top of another agent that has a labeled warning of increased rate of VTE? I know they're lower doses.

To me it's not the lower doses. It's the fact that whatever hormonal mechanism that set these patients off so they developed a VTE usually means that unlike -- I don't know your blood clotting profile, but if you're normal, most patients will be doing just fine. It's those patients that already have one or two strikes against them because they have a blood clotting disorder that they don't know about or they do know about. I'll give you an example. Bruce Montgomery published a paper looking at treating patients with DES and docetaxel and in this paper, he had five VTEs and I can't remember the number of patients, but it was like an 8% rate or something like that. Of the five VTEs -- remember, these patients were also on Lupron -- four of the five had a Factor V Leiden mutation, and that's one of the ones that we're testing.

Our thinking is we had a VTE rate of 5.8%. Even if we say the VTE rate was 5.8% -- we call it 6% to make the math easy -- that means 94% of the patients were fine, okay? So if you go back to the world of estrogens and hormone therapies, in the old days you really didn't know how to get these patients out of the study or to consult them because you were screening by treatment. I do believe, based on a better understanding of the clotting factors and the fact that patients that do have one or more of these clotting factor deficiencies, whether it's a mutation or a lower protein level, you can pick them out of very simple well-established blood tests.

And so our feeling is that this is such a large market, 100,000 patients, they're going to e through different secondary hormone therapies before they even touch chemotherapy, and even if we had a 5% to 10% rate of patients that could not come on to the study because they have one of these clotting mutations, that's still a lot of patients that could benefit and not have the same VTE risk.

Very good. Thanks. If I could just ask one more question.

Sure.

Since there appears to be no limits or clinical holds so to speak at all on the program, is there potentially an alternative trial design that you could do that may more expedite the development of getting Capesaris to the next stage, maybe something more like a randomized? Or is that option not really opportune?

Well, our thinking was that in order to move forward and understand the VTE rate better, that the sequential design is a safer way for patients and a better way for us to get a handle on the VTE rate. Our expectation is that the VTE rate, given the things that we're doing, is going to be acceptable. Otherwise we wouldn't be starting this study.

And so I do think that this is probably the next smartest study to do, because what we want to be able to do once we've done this study is not only to continue as a secondary hormone therapy approach, where we think our safety profile will be superior to what's in development now, but more importantly it gives us the opportunity to go back and say, hey, look, our VTE rates similar to Lupron and these other drugs. And so we're coming right back into first line but we can do that with data in our hands. So I do think that there really isn't an alternative approach where you want to stay ahead. I mean, if the drug does have a safety issue, then it shouldn't be developed. But we don't believe that.

Very good. Thank you very much for taking the questions.

Thank you.

Thank you for your question. We have no further questions in the queue. So I would like to hand the call back to Dr. Steiner. Thank you.

Thank you, Operator. We would like to thank you all for your interest in GTx and we look forward to updating you in the future. Good morning.

Thank you, sir. Ladies and gentlemen, that does now conclude your conference call for today and you may now disconnect your lines. Have a great day. Thank you very much for joining.