Curis, Inc. (NASDAQ:CRIS)
R&D Day Conference
October 03, 2013 8:00 am ET
Ali Fattaey - President and Chief Operating Officer
Jaye Viner - Chief Medical Officer and Executive Vice President
Anas Younes - Advisor
Mani Mohindru - Vice President of Corporate Strategy and Investor Relations
Jesus G. Berdeja - Director of Leukemia Research
Anthony W. Tolcher - Managing Director
Daniel R. Passeri - Chief Executive Officer and Director
Adnan S. Butt - RBC Capital Markets, LLC, Research Division
Edward A. Tenthoff - Piper Jaffray Companies, Research Division
Good morning, and welcome, everyone, to this very first Curis R&D Day with the colleagues here as well as those listening in the audience. I also -- I'd like to thank everyone for coming and being in the room. And just to assure you that the security you had to go through was not for Curis.
So I also want to thank our panel of investigators and experts who've joined us here, and not only joining us for the discussion today, but the investigators continuing to trust patients, enrolling them into our clinical trials and examining our drug candidates.
So we have a fairly full agenda for you today, and I'll begin that. My name is Ali Fattaey, the President and Chief Operating Officer of the company. We will be discussing certain forward-looking statements regarding Curis' future prospects, and that's already in the presentation.
I'd like to start off by indicating to you that we are, as a company and as a team, dedicated to develop the next generation of targeted cancer therapeutics for treatment of human cancer. And the -- we, in this case, is the entire Curis team, which I'll introduce and really want to draw attention and focus to the fact that this is a new vision and direction for Curis, to focus on the development of cancer drugs and, in particular, targeted cancer drugs that are -- we develop for treatment of certain cancer patient populations.
In the case of the we, as I mentioned, I'd like to also introduce and thank Dan Passeri and Mike Gray, who many of you know, and I want to thank them for their vision and stewardship of the organization and also recognize Mani Mohindru, who has recently joined us as the Vice President of Investor Relations and Corporate Strategy, thank her for making this day possible here today and also for the strategic perspective that she brings to the organization.
There are also new team members that I'd like to introduce on the next slide. First and foremost, Jaye Viner, who has recently joined us as Chief Medical Officer and she'll be doing some of the presentation later on; and also, Tania Chander, who has joined us as the Vice President of Product Development in the organization. And Jaye and Tania have been very busy with the short period of time that they've been here to recruit and put in place a very professional team in terms of clinical operations and product management and project management in the organization. I also want to acknowledge the -- all of the Curis team who's not here but busily working in Boston, which makes everything that we discuss here possible for us today.
In addition to the internal team that's involved in the operations and the conduct of our work, I also would like to acknowledge a new advisory team that we have recruited to support, in conjunction with our investigative experts, not only to make sure and continue to maintain our scientific rigor in the organization but help and support us as we chart and navigate our course in this ever evolving landscape for the treatment and regulatory landscape for cancer drug development. So I'd like to acknowledge those individuals and, first and foremost, Lori Kunkel, who many of you may know in the field, most recently retired from Pharmacyclics, and Lori has joined us as an adviser in the organization; as well as other members who, of course, couldn't be here today for prior commitments outside of the country.
So with that introductions and the appreciation of everyone being here, I wanted to start by showing you the pipeline of the organization. As I indicated, we are now dedicated to developing cancer drugs. And when you look at the drug candidates that we're working on, we're going to focus much of today on the proprietary targets that we are involved in developing and -- namely the CUDC-427 IAP antagonist that is now in clinical development, as well as CUDC-907 dual PI3 kinase and HDAC inhibitor that is also in clinical development. And there will be investigators that are involved in the conduct of those trials, which we'll present those to you as well
Later on in the -- during the session in the later part of the morning, we will also discuss our partner programs, namely Erivedge with Roche and Genentech that is already approved in basal cell cancer, and Dan will describe some of the additional clinical development opportunities and market expansion with that drug as well. And finally, Debio 0932, the Hsp90 inhibitor that is in partnership with Debiopharm that is being tested in non-small cell lung cancer and other potential indications as well.
So our agenda for today is the presentation of the CUDC-907 in the morning -- in the early part of the morning session. Dr. Anas Younes will give us a sense of the lymphoma landscape and some of the aspects of the drug candidate; as well as Dr. Jesus Berdeja, who will present some of the landscape around multiple myeloma and the opportunities for our drug candidate, CUDC-907, in that indication.
After a short break, we will come back and discuss our second our candidate, CUDC-427 IAP antagonist and, in particular, our thoughts around the clinical development and some of the clinical data being presented by Dr. Tony Tolcher.
Then we'll end this morning session at the end with Dan Passeri describing our partner programs and closing the session. And there will be ample time for question-and-answer session after the speakers. And then again, at the end when we close, we can have an open question-and-answer session and discussion as well.
So without further ado, I'd like to turn the introductions over to Jaye Viner, who's going to introduce our speakers and begin the process here. thank you.
Thank you. Well, hello, everyone, and welcome to Curis' First R&D Day. It's a privilege to be here today with [indiscernible] with clinical researchers who'll be talking about their own work as well as the foundation for some of the novel agents that are currently under investigation at Curis. It was this pipeline as well as the existing and growing team that enticed me to join the company a few weeks ago. And I think you'll understand our enthusiasm as the program progresses.
Our first speaker is Dr. Younes, who is Chief of the Lymphoma Service in the Division of Hematologic Oncology at Memorial Sloan-Kettering Cancer Center in New York City. Prior to this, he served as Director of Clinical Investigation and Translational Research in the Department of Lymphoma/Melanoma at the University of Texas in the Anderson Cancer Center in Houston. Dr. Younes' many clinical and research accomplishments include leadership at one of the National Cancer Institute's Specialized Programs of Research Excellence in lymphoma, service on the Scientific Advisory Board at the Lymphoma Research Foundation and membership on the National Cancer Institute's Lymphoma Steering Committee.
He played an instrumental role in the development of rituximab, the first targeted drug approved by the U.S. Food and Drug Administration for the treatment of patients with Hodgkin's lymphoma in more than 3 decades. Dr. Younes has served as the principal investigator for more than 60 clinical trials, including Curis' Phase I trial testing of CUDC-907, which he will be describing now. Dr. Younes?
Yes, thanks for the [indiscernible] invitation, and good morning, everyone. I have a few slides I prepared, and they're really not [indiscernible] here and -- but just to give you a flavor of why I'm interested in doing this trial and then where is the field at right now and where would this drug fit in, in the development in terms of other agents being developed for non-Hodgkin lymphoma and Hodgkin lymphoma.
These are not my slides, but -- okay, all right, okay.
So the most important reason for me -- and again, this drug has broader potential applications, but it's the idea that most recently, there's a subset of patients with diffuse large B-cell lymphoma identified by 2 immunohistochemistry biomarkers, MYC and bcl-2 expression. And if you think about diffuse large B-cell lymphoma, so there's about 75,000 patients who have non-Hodgkin lymphoma per year. About 1/3 is diffuse large B-cell lymphoma. So we're talking about probably 25,000 patients per year. And about 1/3 of these patients, which is about 8,000 to 9,000 patients, would fit into this category, which is a biomarker-defined subset of diffuse large B-cell lymphoma, which is the MYC, bcl-2.
And if you look at the outcome with these patients treated with the current standard treatment, which is R-CHOP chemotherapy, you can see 2 curves, one do better than the other. The lower curve is the one that has this MYC and bcl-2, which is clearly now represent an unmet medical need for a good chunk of patients with diffuse large B-cell lymphoma, that, again, we have a biomarker that can define and simple biomarker immunohistochemistry done in any diagnostic hematopathology lab. But it's also giving opportunity to look at treatment based on this biology, based on this biomarker. Can you target these 2 proteins, MYC and bcl-2? And if so, can you improve treatment outcome? And then, all of a sudden, this drug popped up because it can potentially hit both targets, and I'll show you how.
So there's a lot of mouse models in the past that showed that there is an oncogenic cooperation, at least in the pathogenesis of lymphoma. The most famous one is MYC plus bcl-2. MYC by itself is oncogenic transgenic mice for make -- induces a high proliferative lymphoid malignancy that looks like Burkitt’s lymphoma. If you add to this bcl-2, then the mice have a much faster growth of tumor cells and die much faster. And then conversely, if you do MYC plus PI3 kinase in a mouse, again you can accelerate tumor growth and the mice die faster.
So the clear genetic cooperation between MYC and 2 oncoproteins, bcl-2 and PI3 kinase pathway, so PI3 kinase or Akt or mTOR pathway. And there's a lot of preclinical models showed you that if you hit this oncogenic cooperation, you can potentially cure these mice from the lymphomas.
So that's how I see it at least. And this is again not unique for this subset. This is applicable for other types of malignancies where you can see cooperation between a PI3 kinase pathway and MYC pathway. And these are -- the yellow boxes are the boxes that can potentially pharmacologically inhibit it in one way or the other. You can inhibit the protein function expression for phosphorylation and so forth.
So if you look at the PI3 kinase pathway, there's drugs that can inhibit PI3 Kinase, different isoforms. And there's drugs that inhibit Akt, drugs that inhibit mTOR, drugs that inhibit bcl-2. For MYC, we don't have a drug that inhibits MYC itself per se, but we can modulate MYC expression at the RNA level or at the protein translation either by extract inhibitors, now bromodomain inhibitor inhibitors can do that, or by mTOR inhibitors that can control MYC translation. So you can modulate this cooperation in different levels using different drugs. And of course, the -- this Curis drug hits both PI3 Kinase and HDAC, and you can see where it fits into this cartoon, how it works potentially in this model.
Then so when we look at patients with diffuse large lymphoma that has MYC and bcl-2, was there justification then to hit them with a PI3 kinase inhibitor? So we look at biomarker that reflects PI3 kinase pathway activation, which is the phosphorylated form of p70 S6 kinase. We can see that 89% of these patients also have evidence of activated PI3 kinase pathway. So again, this then jumped up to my radar screen. I said, "Whoa, this could be like a nice drug to test in this -- with this model because it has activated PI3 kinase pathway and has MYC overexpression.
Again, to oversimplify this in this cartoon, and if you look at the PI3 kinase pathway in MYC, how they interact, they interact at different levels. And they are regulated at different levels, of course. And then how do they work? One hypothesis is that MYC has dual functions. It can induce cell death and survival. It inhibits the sort of the cell death function by something else. Then you're promoting [indiscernible] survival and growth mechanism, and it can inhibit this cell death induced by MYC either by bcl-2 or by PI3 kinase pathway, and that's how it works. Of course, this is also something in -- by cooperation from metabolism and so forth, but this is beyond having this presentation.
So we'll just skip into the landscape. And I just put just -- this is the leading compounds right now. And for lymphomas, there's, of course, more drugs in development. But these are the drugs at least that are making news, the PI3 kinase pathway inhibitors, and the leading compound is -- right now is idelalisib, which is a PI3 kinase delta-specific isoform inhibitor. You've heard the news. They have a high response rate. And mantle cell lymphoma then small small lymphocytic, CLL most likely will be approved. Actually, CLL, just to be updated, it should be 65%.
And then for B-cell receptors' signaling pathway inhibitor, the ibrutinib. Again, you've heard the news, the high response rate in both CLL, SLL, mantle cell lymphoma and also in other types of the non-Hodgkin Lymphomas. And now the ABT-199, small number of patients but at least making also like good impression in large lymphomas with 38% response rate. Small number of patients, but it's an impressive response rate for single agent in the relapse setting.
And just to show you like how these 2 pathways cooperate, this a very simple combination, I have to say, looking at combination index between a PI3 kinase inhibitor, in this example Akt inhibitor, which is MK-2206 from Merck, and then SAHA, which is vorinostat, which is an HDAC inhibitor. And then you can see the blue is the SAHA, the green is an MK. And if you combine both, you can have more than double the antiproliferative effect. And you can show at a certain level that this is associated with decrease in Akt phosphorylation and MYC expression and down-regulation, and they can do it by different ways. So proves what we're trying.
So the drug is, as you'll hear in more detail, this is actually chemically sort of like engineered to combine both the PI3 kinase inhibitor and then HDAC inhibitor, both in one drug. So it's not 2 pills, it's one pill that hits both of them. And if compared to other drugs by an antiproliferative assay, it really gets -- it kills cells at very low concentrations, in nanomolar concentrations compared to other drugs like, say, JP1, which is a bromodomain inhibitors, which is people using it to down-regulate. You can see you need more than one micromolar concentration to kill the same cell [indiscernible].
I think this will -- you'll -- the -- you'll go over some details when they describe the drug to you. I'll skip these things. I'll just go to the clinical trials.
So the clinical trial is then, as -- I think at the Phase I right now. It's an oral drug given initially as daily dosing. And then subsequently, the product was amended to allow for twice a week or 3x a week dosing at 3 x 3 dose escalation design standard Phase I trial. The cycle is defined as 21-day cycles. It includes both relapse and refractory lymphoma and multiple myeloma after at least 2 prior treatments, 18 years or older. Good [indiscernible] function and, of course, allogeneic transplant allowed [indiscernible] after 3 months and have no evidence of [indiscernible]. So it's a very inclusive trial.
I guess that's it. It's ongoing trial. We're now at the twice-a-week schedule and a 3x-a-week schedule. We'll be starting after we enroll the last -- the third patient on a twice-a-week schedule, so hopefully, we'll be done soon.
Thank you, Dr. Younes. And actually, just in terms of the order of the presentation, I wanted to make sure that you hear the perspective of the disease and the drug and the clinic from Dr. Younes. Now I'd like to go back to the slide, especially Slide #10, to just introduce the drug for you and then open the question for Dr. Younes...
You want me to -- this one?
Actually, if you go through the very beginning of the presentation.
Thank you. As Dr. Younes indicated, the drug CUDC-907 is specifically designed really to incorporate and integrate 2 different inhibitory activities, namely an HDAC inhibitor motility [ph], which is very potent into the same molecule as in the PI3 kinase inhibitor motility [ph], and the whole premise behind this, which is really a platform that Curis initiated a number of years ago, was to generate a single molecule that can provide a strong synergy and anticancer activity associated with it.
Now when we discuss and describe synergy in this regard, the dual inhibitors strategy can provide synergy in many, many different -- from many different ways and angles. One of which is the potential -- I apologize, the potential to inhibit other compensatory pathways or resistant mechanisms that arise as one mechanism of synergy. Other possibility is to hit the same individual target, for example, on the right-hand side, if you look at a canonical receptor tyrosine kinase pathway, signaling one of the targets that we focus on quite a bit, as Dr. Younes indicated as well, as the Akt kinase itself downstream of the PI3 kinase, a very important effector of that signaling molecule, not only would we inhibit that potentially through PI3 kinase inhibition, but also the HDAC activity having an effect on it.
Well, finally, the last bullet point, potentially synergy by inhibition of the multiple parts of the same pathway. And in this case, for example, the effect on the other arm of the receptor tyrosine kinase pathway namely MEK and ERK, synergizing with the inhibition of the Akt.
And we have examples of all of those in the following slide. On the top left-hand side, if you look in this dual inhibition strategy slide, you could note that the drugs, in this case CUDC-907, we are testing it in a cell line -- multiple cell lines, in this case a Daudi cell line, where you can see as compared to control treated cells, we get very potent induction of acetylation of histone H3 and tubulin, which is a mark of HDAC activity, as shown here, using the economical HDAC inhibitor. Or as compared to a canonical PI3-Kinase inhibitor, we get very, very potent inhibition of the Akt activation as noted in the absence of phospho-Akt protein itself.
Interestingly, also, this drug, CUDC-907, has a profound effect on the MEK-ERK pathway, arm of the pathway as well and this is shown here. Not because of the PI3 kinase only inhibition, but as you can see, because of the potent HDAC inhibitory activity, we lose the activation of the MEK and ERK in the context of CUDC-907.
So this really illustrates how the one drug combining both activities of PI3 kinase and HDAC can provide, not only the inhibition of the PI3 kinase pathway and marker, but also other arms of the pathway, namely phospho-MEK and ERK, which are very important. And that's one of the contents of synergy that we find with our drug in this case.
What's important, of course, as you can see on the left-hand side, we can follow a lot of markers, but how does that translate into an anticancer effect and the potency, that's really shown on the right-hand side of this slide with the gel. I'll just draw your attention to the fact that as compared to a pure HDAC inhibitor in the middle or a pure PI3 kinase inhibitor that we've used, in this case, in the middle, as you can see, the CUDC-907 is able to very potently induce apoptosis as marked by caspase-3 activation in this case, whereas the individual drugs themselves don't do a very good job of that or the control. In this case, we're testing this in 2 different cell lines. One being a multiple myeloma model and also down below, the RPMI model, you can see a very potent inhibition of the markers but as well induction of apoptosis as marked by caspase gene -- caspase protein activation as well.
So this really gives us a concept of, not only is a molecule in one single entity has dual activity, it can inhibit multiple parts of the arms of the pathway here and result in potent anticancer activity, as shown in terms of synergistic apoptosis induction as well.
So the drug candidate itself, the CUDC-907, as Dr. Younes indicated, has both activities in one molecule. CUDC-907 is a very potent HDAC inhibitor and, in particular, HDAC, the Class I, enzymes 1, 2 and 3, as well as Class IIB, 6 and 10 enzymes, and does affect other HDAC enzyme. And on the right-hand side table, as you can see, it's a very potent inhibitor of PI3 kinase alpha and delta. And we carry inhibitor PI3 kinase beta and no significant inhibition of PI3 kinase gamma.
One of the things, of course, as we find -- and this is specific to this particular drug, that not only is the drug as a single entity has these activities, but we're very closely monitoring the metabolism of the drug. And one of them metabolized as a drug namely M2 shown here at the bottom right-hand side of this slide. You can see that has very potent -- maintained or continues to have very potent PI3 kinase activity but loses the HDAC activity as part of the metabolism. So in a patient, we get both the parent compound dual active, as well as ample quantities of the M2 metabolizing and that is what is really being worked up through the clinical trial at this point, as well.
So with that, introduction around the drug and the lymphoma landscape and how the drug is behaving in the clinic, I'd like to open it up for questions regarding CUDC-907 or for Dr. Younes and the clinic as well.
Great, thanks. So Dr. Younes, just a question on sort of the landscape and the role of, you see potentially, 907 sitting in? And this is, obviously, with such high response rates and, fortunately, so many drugs now being addressed at these different cancers, is the need really -- and really long-term duration is starting to be seen, is the need really for another compound to be added at the end of life for at least these patients? Or what we're really looking for a more potent compound that can be substituted into the armamentarium to increase of the -- and what is the role, really, of combination in this, in particular, as you start to look at hitting the pathway at multiple points such as PI3K and maybe in combination with an mTOR inhibitor, so maybe you can comment a little bit more on those 2 thoughts?
So it's a good question. So I think most people believe that a single agent drug, and no matter how good it is, eventually will fail for one reason or the other, or for feedback and mechanisms or because of acquiring the mutation of a mixed drug, less potent and loses efficacy. So the trend is to move beyond the single agent and do combination strategies but this has to be mechanism-based not just like throwing drugs and then see what happens. And this drug provides this potential strategy of mechanism-based combination, fashion designed combination that hits multiple pathways that are applicable, not just for lymphoma, that I just focused in front, because that's my area of expertise but there's a lot of examples where it's the cooperation between MEK and PI3 kinase, that even solid tumors and another types of cancers, that can benefit from this combo strategy.
Can you talk a little bit about resistance mechanisms? And has there been any mutational analysis that's done on patients after being exposed to PI3K inhibitors? And what the potential could be if suddenly you're exposing them in second or third line [indiscernible] effect?
So for lymphoma, this still evolving in emerging science. For the CAL101, or idelalisib, which is a delta specific. There's data now in mantle cell lymphoma to show that with multiple relapsed patients. You not only have a delta activation, you have also alpha activation, meaning that you may not as responsive to a delta-specific. You need a drug that inhibits both and this happens to have activity against delta and alpha. So this goes one step beyond, of course, say, idelalisib, but also it's a combined the drug with an HDAC inhibitor, which adds value to a PI3 kinase inhibitor that has put delta on there and gamma. Not much known about mutations that would lead to resistance in lymphoid malignancies. This is more frequently in more solid tumors.
Just a follow-up to Ted's [ph] question on using combination, you have single agent activities that are very strong and the preference of position may have to using combination products versus one pill that has 2 activities, right, there's the ability to modulate one versus the other, see an advantage to one or the other?
So that needs to be tested and I hear what you're saying and what's the advantage of -- to have 2 pills that way you can modulate both or have one pill that combines both. I mean, with -- so, let's say, the triple combo for HIV therapy, they're all in one pill, you don't modulate each subset, right? So you have to strike a balance and if you can, then it's more convenient to have both drugs in one formulation, whether it's both put in one capsule or the drug itself hits both pathways. This needs to be tested but from a convenience point of view, I think it makes a lot of sense to have it in one pill.
Okay. If I can just pick up Len's [ph] questions really quick and this is more probably because when it comes to kind of looking at the combined HDAC and PI3K inhibition, talk to us a little bit then about the safety side of that equation for a 907 if you could?
Yes. So, as we indicated, obviously, the clinical study is continuing to move forward. And Jaye will describe some of that coalesce efforts [ph] later as she goes through it and later on in the morning as well. But the things that we find commonly with these drugs, namely HDAC inhibitors in particular and, also, PI3 kinase inhibitors, some of the things that are common between us, for example, with HDAC inhibitors, is the drop in platelet numbers. But the fortunate part of it is that these are very transient, very manageable introduction of drug holiday, short or brief drug holidays is very applicable and in fact, that is how these patients are managed once they show that. The second effect that is seen can be attributed to either PI3 kinase activity or the HDAC activity is the gastrointestinal effect and in particular, the potential for diarrhea onset. These are, again, the side effects that have been known for these drugs, including the PI3 kinase's and HDAC. And very manageable. And one of the things that, obviously, we are testing now is continuing to look at different regimens of administration of the drug and, in particular, for CUDC-907, as I described, not only following the drug, but also the metabolize of the drug that potentially provide very good activity for us. And at the same time, we need to continue to monitor the safety of the drug. Again, there are no unexpected side effects that we observed with administration of CUDC-907 versus what we would have expected by administering a PI3-Kinase or an HDAC inhibitor. And at this point, we don't see anything that overlaps in that regard. But again, this is clearly in a Phase I clinical study and as we all know, safety is the #1, and determining what the safety profile and side effect profile of the drug is the very key. But for us, of course, as well, we would like to observe any of the clinical benefits that are there as well. But nothing that's unexpected at this point, and fairly the potential for continued enrollment and the development is ongoing with the study.
Adnan S. Butt - RBC Capital Markets, LLC, Research Division
This is Adnan from RBC. A question on the landscape again. In terms of the evolution of compounds for the space, do you see other compounds that are dual mechanism as well? So I know mTORs are out there but why isn't there more? And in terms of history, what have those combinations shown both in terms of safety or efficacy that you kind of focus on?
So as I said, the trend is not to do combination strategies. There's lot of combinations going on, mainly investigated and initiated studies, some are like company-sponsored trials, especially the companies that have average 5 plan where they combine their products. And that's the trend. And if you look at single-agent activity in lymphoma, yes, there are some of these agents that produce higher response rate in subset of patients. These are the durable responses. But in more subsets, the response rate is either low or the duration of response is short and that's why you need the combination to improve the CR rate and duration of response.
Adnan S. Butt - RBC Capital Markets, LLC, Research Division
What about depth of response?
Right. So, again, in most of these responses with single-agent are partial. Yes, some of them are durable but they're not complete. Complete response rate is usually not high with a single agent and that's the idea behind the combination. So improve the depth of response, improve the CR rate, hoping that CR rate would translate into prolonged duration of remission.
Question for Ali. Can you comment on the halflife for 907 and the 2 metabolize. It looks like M1 and the M2 lose their HDAC activities, is that a concern for you?
That's a very good question. We've described some of these in the past in our public presentations as well. Just to set the stage with regard to that question, when we administer CUDC-907, which is a dual-active drug PI3-Kinase and HDAC, as I indicated on -- I'll go back to that slide, here, that's Slide 12 for those listening on the webcast, when we administer the drug in either -- in certain animal models and in particular rodents, but not canine animal models, and also in patients, what we find, the predominant metabolites of the drug are the M1 and M2. The M2 in particular is of interest for us simply because it has -- it's retained its PI3-Kinase activity in particular. At the moment, the data that we have with the drug is that when we look at the plasma, the concentration of the drug or the metabolites in plasma, CUDC-907 parent drug has -- appears fairly early. It's got a short duration of stay, within a few hours. Whereas the M2 metabolites is present in plasma for longer period of time, and at least during a 24-hour period, continues to increase. Obviously, that M2 metabolite is not being generated on its own, but it is obvious that the drug is somewhere in the patient's body that's generating the M2 metabolites, at much higher levels that are then what we saw in plasma of the parent drug alone itself. Those are some of things that, in addition to testing different regimens of the drug, we have implemented now, to allow us to look at not only the patient's plasma, but also potentially access the patient's tissue to look for the drug and the metabolite and also better address this topic of the half-life, as you mentioned. So far, the M2 metabolite, for example, appears to have a residence time longer than 24 hours, hence, the ability for us to integrate noncontinuous dosing of the drug. With regard to whether this is a concern for us, it actually is not a concern, and we think that's one of the attributes of the drug that's working towards that. Simply because HDAC activity, this historically a short duration of HDAC treatment or the short presence of HDAC, the pharmacokinetic or the pharmacodynamic profile of an HDAC inhibitor tends to be fairly durable and long lived and doesn't show up until later on. So the short duration of HDAC is something that's actually used currently clinically. As opposed to PI3-Kinase, which is traditionally and generally at the moment not approved, but in the clinical development is maintained throughout the treatment cycle for the patient. In a sense, the combination of the parent, which is -- appears to be short-lived in plasma, and the M2 metabolite, which is a pure PI3-Kinase active, if you will, metabolite of the drug, sustaining itself for the duration of the period seems to be something that will actually work for us, so it's not a concern at this...
Just curious about the selectivity of the PI3 kinase inhibitors. So we are looking at alpha, beta, delta and then, gamma, you don't have much activity, did you design the drug that way? Was there any biological basis for those? And what you think this particular property will lead to?
A good question. I think the design of the drug from the beginning was to target more than one single component of the PI3-Kinase and there was a -- by design and by selection of the structure activity relationship, to select the compound that does not have gamma and focus much more of it on the PI3-Kinase alpha and delta, which is where we knew there was, at least for the PI3 kinase alpha, mutations in various solid human tumors, not in the hematologic malignancies. And with regard to PI3-Kinase delta, the known potential of the importance of the -- the importance of PI3-Kinase delta in hematologic density. So it's somewhat by design but you don't always get exactly what you want. So this profile was sought after in that regard. And with respect to what it means for the drug in terms of the PI3 kinase side, clearly, I mean, the PI3 kinase delta, we would love to show that in the clinic that we are affecting PI3-Kinase delta and potentially have benefit for that types of patients that we're treating, and Dr. Younes and Dr. Berdeja are treating in terms of the lymphoma patients. And in terms of the PI3-Kinase alpha, I think Dr. Younes indicated very elegantly how, in some, even in the lymphoma settings, for example, in the mantle cell lymphoma, not only are they driven by PI3-Kinase delta early, but on relapse, they could potentially be driven and express high levels of PI3-Kinase alpha. And we think that suites a drug that has both PI3-Kinase alpha and delta activity in this case. So we think it's an advantage as well.
Have you seen any hypoglycaemia in the treatment setting?
That was Dr. Viner indicating that we have not seen that in the clinic thus far. And I think with just in the context of the logistics, keeping it on time, I think there's one last question. If there's no question, we would move on with the schedule. Excellent.
So, thank you Dr. Younes who is now running off to clinic. So our next speaker is Dr. Berdeja, he is a director of multiple myeloma research and a senior investigator in hematologic malignancies research at the Sarah Cannon Research Institute in Nashville, Tennessee. Serving as principal investigator, and in some cases, study chair on 40 Phase I to III clinical trials in patients with various hematologic malignancies, Dr. Berdeja has established himself as an authority on the management of hematologic malignancies, a topic he is invited to lecture on at major international conferences.
A key contributor to Curis' Phase I trial testing CUDC-907, in addition to Dr. Younes, he will now describe the therapeutic landscape for multiple myeloma. Thank you.
Jesus G. Berdeja
Thank you for having me. Unlike Dr. Younes, I came from Nashville, so I can't -- I get to skip clinic today. It's all right, I guess. So I'm going to change gears a little bit because I was asked to sort of describe multiple myeloma, which is a little bit of a different disease. And if you're not used to actually myeloma, it's a little bit more difficult. It's not as simple as making a biopsy and making a diagnosis. It's actually more of a clinical disease. And so because of that, it's sort of had these nuances that become important in how we actually approach this disease. So I'm going to concentrate more on sort of myeloma itself and sort of how we approach it and also where we are in the treatment. We have not been as successful as we have in lymphoma, so I think the need is especially higher in this disease.
So just to put into context, there's about 20,000 new cases of myeloma diagnosed each year. It accounts for about 10% of all blood cancers. About 11,000 people will actually die per year of myeloma. It's a disease that -- of people that are in their 60s, although we are more and more seeing patients in their 40s and 50s with this disease. The median survival has improved, I'll show you some graphics, but it still remains 4 to 5 years. So not fantastic. Only about 1/3 of patients will live out 5 years. And it's more common in African-Americans. We're still not sure exactly why, and it remains an incurable illness. So unlike lymphoma, where there are subsets of patients who are cured, nobody is cured with myeloma.
So Dr. Younes didn't go into this in detail, but most lymphomas arise out of the B-cell. And the B-cell is of the cells in our immune system. Myeloma is also a disease of the B-cell. So as the B-cell sort of progress, they mature. The mature B-cells are the ones that can mutate and become lymphomas. Some of those B-cells will continue to mature further and differentiate into plasma cells. And plasma cells as the cells that are in your immune system, are making the antibodies to fight infections, to fight foreign bodies. And so these are cells tend to produce a lot of proteins and antibodies. So patients with myeloma actually often will produce in excess of these proteins that we can actually detect in the blood and the urine, that help us sort of kind of alert to potential diagnosis. These proteins themselves can cause damage to patients, which essentially leads to the clinical diagnosis.
I changed my slides a little bit, I wasn't going to go to this one yet. But I'll actually start here. With noncancerous disease, double-hit hypothesis, that I think it's very appropriate in myeloma itself. As you start with the normal cells, there seems to be something that occurs in mutation that actually leads to some patients developing this propensity to make this excess protein. So there's this development of these cells that mutate, become malignant potentially, create this protein, but just seems to sit there. It doesn't do anything. It just is part of you, you're normal. You wouldn't know you have it until something else happens along the way that them causes these cells to continue to proliferate and become more malignant and eventually start leading to clinical problems.
So the reason this is important is because we don't have a cure for myeloma, and we know that the treatments for myeloma have potential side effects. So we need to define who the patients are that need treatment. So there are 3 main groups of patients that are in this sort of scope. And one is, you'll be hearing a lot about a monoclonal gammopathy of uncertain significance, and the name tells you basically everything. We basically -- this is a patient that goes to their doctor, they find an the elevation in their protein, they feel fine, they go and see a hematologist and would detect this clonal protein. We look and look for potential myeloma or lymphoma and we can't find a thing. And so these patients have the protein, you may be able to find some of the cells but they're not symptomatic.
Then there's this other patient and has that protein. We actually check a bone marrow biopsy and you detect plasma cells and you detect myeloma cells, and they truly have a diagnosis of multiple myeloma, but they're not having any symptoms whatsoever. They actually feel perfectly fine, and these are small smoldering myeloma patients, as opposed to the patient that have myeloma but also has all the classic symptoms of myeloma.
Myeloma doctors are not very smart. So we needed mnemonic in terms to figure out what of symptoms do we expect. And so these are the so called CRAB symptoms. And so each letter stands for the more common problems that we see in patients with myeloma. So patients with myeloma will often have an elevation with calcium, we call that hypercalcemia. That leads to many medical problems, including the next problem, which is renal dysfunction or kidney disease. And so kidney dysfunction is a very big problem in myeloma, both from the elevated calcium and from the elevated proteins that deposit in the kidneys. Anemia is very common, and bone disease.
So this used to be bone cancer by a lot of patients. Because people would come into the clinics and they would -- I had a patient that went and actually tried to hit the light switch and broke the wrist. So patients came in with very fragile bones and broken bones, so it was associated with bone disease. So that's the B part. There's a lot of other symptoms, but those are the main ones that we usually think of with myeloma.
So, clearly, once the patient has -- is having these complications, this is no longer a benign disease that is just sitting there. This is something that requires attention.
We've been trying to sort of get more sort of trying to break groups of myeloma patients once diagnosed into who is more likely to do better versus worse. And so we have these prognostic factors, and Dr. Rajkumar nicely kind of set this out for us. And so there's obviously, clearly, a host of factors that impact if you're older, if you're sicker, you're likely to do worse. If you're a higher stage, you're likely to do worse. If you have certain mutations that we can detect and the cells from the bone marrow, you tend to do worse. But the truth is that we're at a point where even the best group doesn't do so well. So that even though we have all these attempts of sort of trying to break up the patients with myeloma, we approach them very similarly.
So I borrowed this from Dr. Anderson, who -- Ken Anderson, who published this in terms of sort of where are in myeloma treatment. So until 1962, the only -- or beginning in '62, the only treatment we have for myeloma was melphalan and prednisone. And this is a low-dose, very old chemotherapy that you get patients and obviously a steroid. It worked pretty well but it didn't last very long and it's very toxic to the bone marrow. We didn't have anything else for about 20 years. In the '80s, started playing with higher doses of chemotherapies, but it wasn't until the mid-90s when we actually started doing high-dose melphalan chemotherapy and autologous stem cell rescue or the so called old bone marrow transplant. And after the advent of [indiscernible], these are drugs that actually strengthen bones -- that actually not only strengthen bones in patients with myeloma, but decrease bone disease formation.
So that was a big breakthrough. But then there was really nothing until thalidomide came into view. And if you all recall, thalidomide from the '60s and all the problems that it had in the past, well, it turns out that thalidomide actually is a very potent drug against myeloma, and so that kind of revived the field a little bit. And that was the first so-called IMiDS or immunomodulating drug. In the 2000s, we started getting the proteasome inhibitors, particularly bortezomib and [indiscernible] second-generation IMiDS. And those really revolutionized the way we approach myeloma.
So a nice sort of survival graph that Dr. Kumar published. Looking at sort of these different time points in the history of myeloma. You can see that the top 2 curves correspond to when we started doing stem cell transplant in the advent of the proteasome inhibitors and the IMiDS. So the treatment has improved. The survival has improved. It's almost doubled, but it still remains less than 5 years.
So you we a patient with newly diagnosed multiple myeloma. We usually talk about, and this is a patient with active myeloma, they have bone disease, they have all these different things, clearly, a malignant process. We talked about whether they can get a transplant or not, and that's when initially approach them. If they're not a transplant candidate, we go a certain route. If they're a transplant candidate, we go a different route. But if you look at sort of the NCCN-recommended treatments for myeloma, you see that basically it's 3 drugs that are being used for the most part. It is the steroid, bortezomib or lenalidomide. So an IMiD, a proteasome inhibitor or a steroid, either 2 of them together or all 3 at ones, and different combinations with some oral chemotherapies, is how we approach every patient with myeloma.
Unfortunately, all of these patients, regardless of what we start with, eventually would relapse. And this is actually a graph that I took from the International Myeloma Foundation and it's been adapted a little bit with some sheer data and some market research data. And basically, it shows nicely -- I think I have a pointer, so this is sort of the state where you have this MGUS or the smoldering myeloma, people are sort of living with but are not really suffering from it.
And then at some point something happened. So we're using the M protein, which is the protein that we can detect in the blood as a surrogate for disease progression. So eventually, this gets -- this regulated people start having problems and they need treatment. So it's about 16,000 patients at any one time will initiate treatment for active myeloma. And these patients will mostly respond, patients respond very well. But unfortunately, they will only stay in remission for so long before they progress again, require therapy and eventually, they will stop responding. And at any one time, sort of people who are going through treatment or are in that remission phase of their treatment, I'm probably thinking about 60,000 patients with myeloma.
This is sort of a graph looking at sort of the duration of that remission. And just kind of looking at -- sort of taking from different papers, patients who are treated first line with lenalidomide-based therapies or bortezomib-based therapies and sort of how long we think they stay in remission. And so the average remission is about 2 years for most of these patients. They then progress and they get treatment again. Again, the treatment tends to be, again, bortezomib or lenalidomide base. That remission tends to last for about a year. And then once you get into third line, the remissions become very short.
And so Dr. Kumar actually looked at this and a very [indiscernible] statistic. This is a graph of patients who have failed bortezomib or lenalidomide -- or an IMiD. And basically, if you have been exposed to both and you failed, this is the overall survival, and it's only 9 months. And these are patients who are alive and still in remission of their disease, only 5 months. And then patients who are truly refractory, meaning that they're growing through bortezomib or lenalidomide treatment, or they've progressing within 6 months of treatment, the event -- the event-free survival is only 2 months.
So, clearly, a huge need in myeloma in terms of our therapies. So once the patient progresses from their initial treatment, these are the NCCN recommendations in terms of salvage therapies. And again, they're very similar to the ones that I showed you for front line. The 2 main things that have occurred is obviously, in July 2012, carfilzomib was approved, and that's a second-generation proteasome inhibitor.
And pomalidomide was approved just this year. That's third-generation IMiD. Both of these drugs were improved with overall response rates in the 20%.
So it's great to have them, but clearly, not a huge jump. Where I think they really will help is that these drugs are -- as the new generations come along, they're becoming less toxic. So one of our main concern with the treatment of myeloma patients is neuropathy. So patients with myeloma already can have neuropathy. These proteins can actually deposit in peripheral nerves and cause that as a side effect, both the proteasome inhibitors and the IMiD can also cause neuropathy so it gets augmented. And so in the early days of using this drug, people are having a really difficult time. People are actually having difficult time writing, buttoning their shirts, even walking, because toxicity was so bad. So these newer drugs are much better. The toxicity is much less, and so I think that will help significantly. Ultimately, we'll see better results. But nonetheless, they're still the same type of drugs. I think we will still see improvements, but just not dramatic changes, in my opinion.
So despite all this progress, myeloma still remains uniformly fatal. We talked about the toxicities. The median of survival has almost doubled since the advent of proteasome inhibitors and IMiD, but it still remains about 4 years. So clearly, we need to improve on that. All patients in myeloma eventually will go through all these medicines. It's -- I mean, I don't think I have seen a patient that died from myeloma that hasn't sort of exhausted all the current treatment options. So clearly, we need some changes. We need new medicines. We need medicines that have additive or synergistic properties with the current medicines that we have, that may be bypass resistent mechanisms or completely different medicines that offer novel targets. And also that -- where they don't have additive toxicities. So we don't want to obviously add something that is going to have the same toxicity to what we currently use.
So I think we have a solid backbone of therapy in myeloma. We've moved away from the chemotherapy and steroid by itself to more of the proteasome inhibitor and IMiD backbone, and we have several new generations coming along that are getting better at -- with improved toxicity and also ease of giving the medications. So bortezomib, of course, and carfilzomib, we talked about. They are oral formulations of both drugs that are being developed that are looking very promising which will also help with sort of how -- carfilzomib, for example, requires that you give it intravenously twice weekly, 3 weeks on, 1 week off. So patients are coming into the clinic 6 visits out of each month and potentially forever. At this point, the indication is until progression. So it's a lot of visits. It's testing on the patient. So the oral medication, I think, will make an impact on this.
The IMiDS, pomalidomide, which is recently approved. There's others in development as well. So I think we're pretty solid with those 2, and eventually, will become easier to give it, but I think that's still just the backbone of therapy. I don't predict that this will cure myeloma.
So I don't have the nice pictures that everyone else did. But I put a list of sort of some of the interesting agents and pathways that we're seeing in myeloma. Everyone's very interested in getting the Rituxan for myeloma, Rituxan, I'm sorry, for myeloma. So an antibody-based therapy make sense here. So there's several in development, some sort of later phase and others. We have elotuzumab, tabalumab, daratumumab, all are sort of monoclonal antibodies that are targeting cell surfaces, although, tabalumab is a little bit different.
But there's also antibody drug conjugates. So lorvotuzumab mertansine, for example, sort of -- it's a sort of the smart drug, sort of like PDM1 breast cancer where you have the antibody that is down to chemotherapy. The antibody binds, it's internalized, and chemotherapy is released killing the cells. So those are in development.
We talked about HDAC inhibition. HDAC inhibition, in particular, I think, in myeloma, there's been a lot of interest because of what was stated earlier, but also because there's a lot of synergism with proteasome inhibitors and with the IMiD. So there's a lot of interest in the HDAC pathways as an additive to some of the stack point that we already have. And obviously, CUDC-907, it's not only HDAC inhibitor, but also a PI3 kinase. We don't have as much information with the PI3 kinase inhibitors in myelomas with lymphomas, but there clearly is a pathway in the B-cell signaling, and obviously, myeloma cells are B-cells as well. So there is definitely some synergies in the myeloma cell lines with the PI3 kinase and HDAC inhibitors. So that is actually very interesting.
Some of the other pathways that are of interest, there are drugs that are being developed and all these other pathways are listed there as well.
So I don't think any one drug will cure myeloma. I think we need to start thinking about combinations. If you look at sort of -- this has been touched upon. Any time you approach any one pathway, you have sort of this compensatory mechanism that arises that requires to hit it somewhere else. And so I think we're seeing that not only with the targeted therapies, but also with the sort of broader therapies. So if you have proteasome inhibitor that is hitting at the proteasome [ph], you see an increase of the [ph], which basically bypasses the proteasome. And so the HDAC inhibitors can inhibit the So that makes sense to me that you want to hit sort of -- both. So drugs like this, make a lot sense to me. You asked that we're worried about the fact that, that you have this -- that we lose the HDAC activity so quickly from the -- in the pharmacokinetics data they presented. Actually, I'm actually -- I was actually very happy when I saw that because we started giving it orally and where we're seeing the toxicities with a lot of the HDAC inhibitors when we're seeing them in Phase I. And so what we learn from the pure HDAC inhibitors is that you actually need to give it break and so most of them are being given intermittently every other day or twice a week. And so I actually like to see those pharmacokinetics. I like the idea that we're going to have continuos PI3 kinase inhibition and intermittent HDAC inhibition. So I'm actually very excited about moving forward with the amendment. And I think I'll stop there.
We can open the floor for questions.
I just had a quick question, Doctor. And again, I totally agree watching this field over the last 17 years. It's really amazing the part -- that occurred and it's great for patients. How do you decide what you use first? Are you usually -- using myeloma treatments [ph] going to [ph] because of toxicity? Does it depend on age? Does it depend on health? What do you go with -- do other doctors have a favorite [indiscernible]or is there a one that's used first over the others? And how do you see the new agents sort of fitting in? So is this really a situation where I think they're going to come to the back line and then find a moving forward in combination?
Sorry, I said yes. It's true though. So there's no standard of care in myeloma. So unlike -- if its used by patients that's going to get chopped [ph] rituximab has a base in this clinical trial or something. There is no such thing in myeloma. So it -- you bring in all those different sort of reasons as too why to approach someone. I think most of us want to approach people aggressively and what we're finding is that we need to be more aggressive with our therapies where we'll use to be treating myeloma like we did others solid tumors where you had a finite number of cycles of therapy and then you kind of stopped. And we're finding that actually is the -- that there's several stages in the treatment of myeloma that you actually approach the patient to try and sort of release the bulk as much as you can. But if you continue therapy and even if you pull back somewhat, you actually continue to see improvement in response over time. So I think most of us are moving towards finding sort of less toxic combinations that can be given more for longer duration. We're potentially finding sort of stepwise sort of treatments where you might start with [indiscernible] and then come in with something else that may sort of serve as the maintenance type of modality. And so what I foresee is that we will probably start using of the less toxic potent proteasome inhibitors in this. Earlier on, we're seeing quite good responses in the ongoing trials. But I think we're all looking to add those therapies that will be complimentary and that will allow us to sort of continue that without the continued toxicity of the triplets [indiscernible]. But just to go back to one of your questions. So someone has kidney disease for example, you can't really give an IMiD. So that patient is someone who would just get bortezomib steroids for example. So there are sort of nuances that kind of prevent this from going full flex [ph].
All right just a basic [indiscernible] of questions. What's the rational for evaluating the PI3K inhibitor along with HDAC in multiple myeloma there? Is there an over expression of what you think is the norm or you're just kind of looking for a home [ph]?
So actually, the -- so there is some over expression of mutated kinase kind in some myeloma. But what's really interesting is actually more -- in cell lines, if you actually look at inhibiting the PI3 kinase, there is cell death. So there is some -- even -- myeloma are still B-cells after all. And even though they're not as dependent B-cell receptor as of less therapy [ph] cells, I guess. There -- it still is the mechanism that is activated. And so there is, actually, for example, with the PI3 kinase and the HDAC there is some synergism with -- blocking both in myeloma. So you're right. There's definitely -- there's -- there hasn't been as a clear cut sort of mechanism as it is in lymphoma. But I think most of us is trying to kind of go back and rethink the PI3 kinase. I think one of the things that is interesting to me and that is so much fun when you're sort of in this day and age in terms that we find out so much more about different pathways is that what we thought was going to be important in a certain disease and not in another one is completely wrong. And so we're always like surprised that actually this makes -- does it make sense. So for example, like bortezomib [ph], for example, actually, PTK was actually under expressed in plasma cells. But if you actually look at activated myeloma cells, it's actually over expressed. So we had completely disregarded that drug and now it's sort of being revived. So it's -- there's always room for us to go back and rethink.
And so I'll make comments then with regards to that question. Obviously, we've -- to a great extent, inclusion of multiple myeloma patients into the Phase I clinical study was predicated based on the preclinical evidence that we've had and published at Curis looking at CUDC-907's effect, not only in the cell lines, but multiple -- or a number of multiple myeloma models as well that were observed. And so that's juxtapose very nicely with the comments that Dr. Berdeja is making here. It's not obvious as you would have expected but we definitely see benefits of pre-clinically and as Dr. Berdeja had mentioned, they're potentially clinically in that regard as well. One other nonscientific comment I wanted to make with regards to multiple myeloma is just realize it's just kind of a humbling position to be right next to 3 individuals who -- in the case of Dr. Berdeja, dedicating to treatment of multiple myeloma patients with approved and experimental therapeutic, but also standing right next to Jaye, Dr. Viner who's -- before joining Curis, was developing the oral proteasome inhibitor at Millenium pharmaceuticals in the Phase III set A. And of course, right next to Dr. Berdeja, Lori Kunkel, who developed carfilzomib for the treatment of multiple myeloma. So it is humbling for me to recognize the expertise as a panel in this particular setting and the focus that 907 at the moment is getting in the clinic as well.
Adnan S. Butt - RBC Capital Markets, LLC, Research Division
It's Adnan from RBC again. So in terms of multiple myeloma, what's sort of development strategy that you see here? Is it -- are there any specific agents that you see it being -- being combinable with? And are there others that may or may not be combinable with based upon the mechanism or side effects of this?
So I mean, personally, I think that's where it needs to go. I think we need to, first, find out how to give it and how safe it's going to be. And I think, hopefully, we'll attenuate some of the early toxicities by following these other schedules. But the truth is that if you look at sort of the HDAC inhibitors on their own, there's not -- there's single-agent activity, but it's actually not overwhelming. So really, where I see this happening -- if we see a significant activity and even just [indiscernible] disease, that's actually quite impressive in myeloma with just these compounds. But really where I see it going is that as long as it looks to be hitting its targets and is a tolerable therapy, it's in combination.
And another comment on that. From the preclinical side of it, again, at Curis as well, we certainly demonstrated the effects of the monotherapy with the single agent and multiple myeloma cell lines as I showed, as well as in the in vivo xenograft models that we've tested. But also beginning to address some of the questions of other agents, and in particular, agents that treat multiple myeloma that we can think about, I'd also like to go back to the comment that Dr. Younes made. We also want to be rationally led. We can certainly test many different combinations and there are certain excellent choices for multiple myeloma treatments to look out here, but we also would like to go at it rationally, so some of them make sense from combination. And then secondly, as you point out very nicely, Adnan, is make sure that we're not having any overlapping side effects that we have to address. All of those are also getting their attention at the preclinical level. And -- but Dr. Berdeja and Jaye indicated, at the moment, our focus is to look at the drug as a monotherapy first. It is in the Phase I clinical study and we want to establish the drug itself both its potential benefit, but also its safety profile in those clinical patients. And then progress towards potential combination strategies in multiple myeloma and other settings as well.
Any other additional comments from the audience? If not, I believe this is a good opportunity to give a brief break. Coffee and other items are right down the hall here, and we'll be right back at -- in about 10, 15 minutes. Thank you.
Okay. We'll go ahead and get the second half of the session started. Very good. So what we'd like to do in this half of the session is draw the focus and our attention around the second proprietary program at Curis, CUDC-427, which is an antagonist of the IAP proteins or inhibitor of apoptosis proteins. In this case, as my colleagues always tell me, it's a double negative. We're inhibiting an inhibitor of apoptosis. Therefore, we are inducing apoptosis. And what we -- what I'll do is provide an introduction, both on the drug and some of its mechanisms. And then Dr. Tolcher will present his thoughts on the IAP antagonist and some of the data from the clinical trial that is sponsored by Genentech and [ph]. And then finally, Dr. Julia will also be presenting to you around the landscape in breast cancer. And then Dr. Viner will close this out with some of the plans in clinical development around both programs, CUDC-907 and 427 to you.
So CUDC-427 is an IAP antagonist. It is an oral small molecule. It's a monovalent inhibitor as opposed to being bivalent. There are other bivalent inhibitors that are also in clinical development and it is a SMAC mimetic. And I'll describe what SMAC is and what's the importance of inhibiting the IAPs with fine SMAC. Its drug target is the -- the drug target itself is the IAP proteins. There are multiple IAP proteins that you can see on the graphic on the right-hand side. The 4 that have a common domain or BIR domains are the c-IAP1 and 2, as well as the XIAP protein, which I'll illustrate on the following slide, as well as the ML-IAP or the melanoma-specific IAP proteins. All 4 gets targeted relatively the same by a SMAC mimetic molecule and CUDC-427.
The mechanism of action of the drug really is by inhibiting the IAP protein. They affect the way that cells process apoptosis signaling either through intrinsic signal, those are the signals that go through the mitochondria, and I'll show you that again in the next slide; or through extracellular signals or extrinsic signaling towards apoptosis, which is usually affected to the TNF and TNF receptor family.
The concept behind IAP antagonism is really to synergize with other apoptosis-inducing agents, which we'll describe as well, and these include, of course, potentially TNF, tumor necrosis factor, itself and other chemotherapeutic agents.
So when we look at the pathway for apoptosis induction, and also, how the apoptosis induction is inhibited within the cell by IAP proteins, the drug is relatively simple in diagram.
If you look at the left-hand side of it, extrinsic signaling through the TNF receptor family. Really, majority of that either through the canonical or the non-canonical pathway is targeted towards activation of the NF-kappa B transcription factor, which is involved with cytokine release and survival of the cell. There are IAP proteins, the cIAPs that ensure that the apoptosis machinery of the cell, and namely caspase-8 is not activated in response to TNF receptor signaling. That's one of the places that the cIAP proteins serve and function to inhibit apoptosis induction.
Separately, if you look on the right-hand of the slide, intrinsically, for example, through chemotherapy or other signals, the cell can also induce apoptosis induction which is a common mechanism through the mitochondrial pathway by induction of caspase-9. Either caspase-9 or caspase-8 induction through the extrinsic with caspase-8 or caspase-9 induction through the intrinsic pathway really leads to activation of the common caspase protease that initiates the apoptosis process itself, and that's caspase-3. So these -- all of these caspases, 8, 9 and 3 or 7, are easily monitored within cells. And I'll show you some of those data as well in response to -- and not only with CUDC-427 inhibition of the IAPs, but that's also where the IAP proteins, in this case, XIAP protein, for example, is an inhibitor of caspase-9, as well as potentially binding to the SMAC proteins that initiate the caspase induction process as well. Part of the reason that I put the caspase-8, -9 and -3 in bold letters here because those are some of the enzymes and caspases that we can follow as markers to look at the activity of our drug. And also, we can follow the presence or absence of the IAP proteins, themselves, namely cIAP protein, and I will walk's you through that.
On the next slide, you'll see that our drug, CUDC-427, shown here as a capsule really inhibits the IAP proteins, whether it's the cIAP protein through the extrinsic signaling pathway for caspase-8 induction or the intrinsic apoptosis inhibition pathways XIAP and ML-IAP that results in caspase-9 activation. The drug is able to inhibit both of those.
What this results in is really shown on the next slide. In this case, it's cell line -- a breast cancer cell line that's relatively sensitive to the presence of the drug. The thing that we do see are that 2 markers that I've described. One is the degradation of the IAP protein itself. On the left-hand side, either at 3 hours or 24 hours, you can see that in different concentration of the drug added all the way from 200 nanomolar to 5 micromolar inhibit -- addition of the drug. You can see very, very robust inhibition of the IAP protein as designated by this degradation, loss of the protein. But more importantly, what we find -- shown here as caspase-8 and caspase-9, you can see that's very early on upon the addition of the drug. We get good caspase-9 activation that lasts and get better at 24 hours post administration of the drug. And importantly later on, after treatment, we see very good activation of the caspase-8 and conversion of pro-caspase in active form of the enzyme to a caspase-8 which is active.
And that's all the same hallmarks that I mentioned, reduction of the IAP protein, activation of caspase-9 and activation of caspase-8, which are the hallmarks of apoptosis induction. And also shows that the drug can induce and inhibit both arms of the pathway, extrinsic and intrinsic signaling. What we're showing here on the right-hand side is one of the things that really distinguishes CUDC-427 as a monovalent oral small molecule away from some of the other drugs that are also in development. In this case, in the blue line showing or the purple line showing a timer, bivalent inhibitor; and the other 2, the green and the purple or blue line here, showing the other 2 oral inhibitors that are also in clinical development. And in particular in red, of course, showing CUDC-427.
On the right-hand side, what this assay is trying to look at is, in fact, the caspase-3 activation. As I mentioned, the common caspase underneath or downstream of caspase-8 and 9. When we look for activation of this caspase in the cell, you can see that CUDC-427, very, very potently have low, low nanomolar concentration when added to the cell result in activation of caspase-3. Unlike some of the other oral inhibitors that are in clinical development, CUDC-427 is very potent at doing this. And in fact, it's nearly as potent as the bivalent drug that's currently in development as well, but as will -- Dr. Viner will allude -- or indicate later as well the monovalent drug appears to be better tolerated so far in the clinic as an oral agent than the bivalent drug that is intravenously administered the drug.
So this is one of the first time that we see a distinguishing feature of CUDC-427 in the sense separating it away from the rest of this field in terms of its potency and caspase activation, and yet, it is a monovalent oral small molecule drug that is very well tolerated as -- Dr. Tolcher will show you that as well.
So following on the same thing that we saw in the cell line in terms of inhibition and reduction in the cIAP protein levels as a marker of the drug, as well as induction of caspases, which is the apoptosis induction. Those are the 2 hallmarks that we look for in a cell. If we follow that into the animal models and away from cell lines, on this slide, you can see very much the same thing. These are again -- this is the same breast cancer model, MDA-MB-231, that's implanted in animals and then treat it with the CUDC-427 inhibitor. As you can see here, untreated animals and these are multiple tumors from different animals, untreated animals have very high levels of cIAP protein very rapidly after one administration of the drug. You can see the loss of the cIAP protein that lasts for longer than 24 hours in the animal -- in the tumor that's planted and analyzed.
And at the bottom of the slide, as you can see, unlike vehicle untreated animal tumors, tumors that are growing in animals, very rapidly after administration of the CUDC-427 orally to these animals, you can see very robust activation of caspase-3 again as shown by the staining of the cells with the brown staining. Again, 2 hallmarks, degradation of the cIAP protein, as well as induction of the caspases very rapidly in this particular animal model when given as a single agent, CUDC-427. I should point out that this particular breast cancer model is one that's used by other IAP antagonists as a model. It happens to be very sensitive to the single administration of the drug as well in this set.
And if we follow that, of course, into the clinic now, and Dr. Tolcher will address some of this in his presentation as well, we see the same thing in a -- the clinical setting in patient. At the top, you can see we're monitoring the levels of the cIAP protein. And here, we show 2 patients, for example, that are treated with the CUDC-427 at cycle 1 day 1. Before dosing, you have this cIAP level at 100% at day 11 or -- to 18 treatment -- I'm sorry, day 11-18 sort of 24 hours treatments, you can see that very ample reduction in the cIAP protein in these patients. And of course, in some of these patients, when we look directly within their tumor tissue prior to treatment, there is no cleaved caspase-8 -- sorry, caspase-3 present. After treatment, fairly rapidly, you can see again the hallmarks of apoptosis induction in response to the drug as shown with caspase-3 staining in this tissue. So the same hallmarks that we see in cell lines as a mechanism of the drug is followed in vivo in animal models, and of course, we're very fortunate to see that in the patient following through as well, definitely establishes the drug and its mechanism of actions very nicely as we go through it.
In the last slide that I wanted to show here was to show or show you some of the data preclinically in terms of how the drug actually combines with other agents. What I showed you so far was the drug as a monotherapy. This happens to be a relatively complex slide, but let me just walk you through it in this regard.
Here's the case where now we try to combine the drug with other agents and look at mechanistically why is it that the drug can, in some cases, combine with agents, in particular, cancer types. This slide is looking at different breast cancer models. There are 6 of them that are tested here. On the left-hand side, 3 of these models happen to be very sensitive to the combination of fluoropyrimidine drug, in this case, 5-FU, in combination with CUDC-427. All 3 of the cell line models shown on the left-hand side have a very high S score or Synergy score as we described it in the hundred into the relative markup being seeing how well the cells are killed when the 2 drugs are given as opposed to individually. You can see that all of them have a very high S score or Synergy score as opposed to 3 other breast cancer cell lines that don't have a very good Synergy score are not killed by the combination of the drug, they have a negative S score as shown in the right-hand side panel. So one of the things that we wanted to find out is what is it that mechanistically makes certain cancer cells -- these all happened to be breast cancer cell lines, what makes some of them very sensitive to the synergistic effects of the -- of CUDC-427 plus the fluoropyrimidine, in this case, 5-FU, versus others that are not synergistic. What we find is really, again, comes back to the IAP protein itself. On the left-hand side, all 3 of the cell lines, so line 1, 2 and 3, had very high induction of the XIAP protein in response to the 5-FU. When you look at 0 hours compared to 24, all 3 cell lines had very good induction of XIAP in response to 5-FU, indicating that, that is how they tried to overcome those cell lines and how they tried to overcome the inhibition of 5-FU. That's how they protect themselves against apoptosis, therefore, setting themselves up very nicely to combination with a CUDC-427, which inhibits anxiety. And that's the reason we find the synergy in these breast cancer models as opposed to on the right-hand side. None of those models are sensitive to the synergy between 5-FU and CUDC-427. And in neither of those cases, you see any induction of the XIAP in response to the drug.
Now these breast cancer cell lines don't fall into the traditional categories of what we think about breast cancer, whether they're heard to status [ph] or the hormone receptor status. They don't very nicely fall into those categories. But this is an area of intense research for us. So we really try and identify -- can we really take out signatures that allow us to say which tumor types in this clinic can actually be treatable, in this case, in the combination of our drug with other chemotherapeutic engine versus other cancer.
And this is an area of very high interest for us simply because we do know, and this is one of the basis, that the drug, in combination with the fluoropyrimidine, in the case of the clinic, it would be cytidine in the setting of breast cancers that we do have a very, very nice synergy with it in certain breast cancer going forward. And this is the basis of our development plan in the breast cancer setting or at least one of the basis for it.
So with that introduction, really describing the drug and its mechanism both as a single agent and its ability to synergize with other anticancer agents, and in particular, a fluoropyrimidine, in the case of the preclinical 5-FU as I showed you here. The drug seems to behave very nicely. We can understand the mechanism of it. And at the moment, we're eagerly searching for markers of selection of patients for this type of synergy and treatment of the cancer. This is -- this theme will also be followed very nicely by Dr. Tolcher who'll describe other studies that are -- that he's conducting to analyze in a different cancer setting as well.
So with that, I'd like to turn the podium over to Dr. Tolcher. And he will walk you through the -- his presentation, then we'll come back and address questions after that.
So while the podium is getting set up, I'll share with you that Dr. Tolcher is Director of Clinical Research in South Texas Accelerated Research Therapeutics also known as START. And this is the world's largest Phase I clinical trial program. He previously served as the Director of Clinical Research at the Cancer Therapy and Research Center, CTRC, also, in San Antonio, Texas. Dr. Tolcher's anti-cancer research has a special focus on molecular genetic targets for cancer therapy and his work has been published in more than 200 peer-reviewed publications conference proceedings and book chapters. He's been a major contributor to studies testing the therapeutic potential of CUDC-427 and the earlier -- also in this earlier forum and currently leads Curis' ongoing Phase I trial testing this novel molecule. He'll be sharing this [ph] with us now.
Anthony W. Tolcher
Thank you, Jaye. Thank you, Ali. So what I'd like to do is review in next the 20 minutes or so the clinical experience with this drug and also a strategy moving forward to try to identify the optimal population. And so I wanted to outline a bit about what I'm going to speak on. And Ali has done wonderful a job talking about the background of IAP inhibitor that I'm just going to give a little bit of color commentary from the standpoint of medical oncology.
I'm going to talk about the Phase I study that was completed and presented last -- or this past summer at ASCO. I'm talking about the "2 weeks on 1 weak off" schedule. I'm going to discuss the rational why we're re-exploring schedule and dose, and then finally, talk a little bit about moving forward.
So as Ali nicely presented, there's a number of good reasons why you would want to target the IAP. So first and foremost is that diminished cell death or diminished apoptosis is a hallmark of cancer. It's one of the fundamental alterations that happened. And there are certain malignancies that are associated not so much with increased proliferation but just absence of death and clonal expansion, things chronic lymphocytic leukemia and so on and so forth. And we've tried to develop a number of drugs to the apoptotic pathway, Bcl-2 inhibitors, [ph] inhibitors, for example, tumor necrosis factor trail receptors. All of these have been problematic in their development. But a fundamental theme, again, is the fact that you are -- the cells no longer have that beautiful harmony of proliferation and cell death. And so if you have decreased cell death, you have this accumulation, you might say, of cell.
One of the unique features about targeting the IAPs, they're the final common pathway to cell death. So they're downstream of many different alterations. And if you can see some of the targets, we've spent a lot of time looking at the surviving [ph] in which actually targets SMAC/Diablo, the tumor necrosis factor family. The pre-mitochondrial members of the Bcl-2 family such as Bcl-2, which is over expressed. And the lesion of BAD [ph], which is also a common feature in certain types of breast cancer.
So if you are able to target these sort of at the end level, the final common pathway, you may be able to overcome abrogated apoptosis.
So I'm going to begin by talking about the Phase I study GDC-0917. This is the same agent as CUDC-427, and I'm going to use this intermittently. And this is the data that was presented in ASCO last year.
So this was a standard Phase I dose escalation trial of GDC-0917, and then this one we used actually a modified continuous reassessment method for dose escalation. And it was performed in patients with refractory solid tumors and lymphoma. We chose -- or was chosen -- a schedule of once daily was chosen and it was based on 14 days on, 7 days off; so 2 weeks on, 1 weak off. And then at least, initially, in day 1, it have a single dose and then pharmacokinetics were performed in the period up to day 3, and then patients would continue out through the entire 2-week period and receive the drug daily. They'd have a break for 1 week and then restart. And the cycles were every 21 days.
At the conclusion of the study, we had entered a total of 42 patients. They were the typical age of patients going into Phase I studies, a median of 61 with a range from 36 to 86 relatively well balanced between men and women. All good performance at it. You'll see that 0 and 1, a wide spectrum of different diseases and indications. And as you can see, most of these patients were quite heavily pretreated with a median number of prior chemotherapy regimens of 3, ranging from 1 to 9.
Initially, we started off at the very safe dose based on the preclinical toxicology. As you can see, we were down at 5 milligrams. Cohorts of 3 patients were included, dose doubling continued up until 60 milligrams. We then went all the way up to 600 milligrams. At one point, we did have the appearance of some dose-limiting toxicity that may have been related to a particular molecular genetic abnormality in 1 patient. So you can see we went to over an extensive dose range in this particular study. I might add that we stop dose escalation once we reached the IC90 that was predicted from Genentech's preclinical data. So we did not determine the maximum tolerated dose in this particular study.
Actually, I want to go back. One other point, and this came up a lot at ASCO. As opposed to most of the other agents that are going through development, we actually didn't see any patients who had Bell's palsy. And so this was unique feature of this particular agent. And if you see, what were the side effects that we did see? There was 1 grade 3 fatigue. We had fatigue which is very common in Phase I study for almost any agent; mild nausea, most of which is actually grade 1; rash that was seen in some patients; vomiting that was present in only 6 patients throughout the entire study. There was an elevation of transamnate [ph] in some patients. And overall, the rest of them were generally mild and really not contributory to anything that were not accustomed to in oncology Phase I study.
If you look at the pharmacokinetics from this first study, you'd see that with the Tmax when -- the first sign that you had a peak concentration after an orally administered drug, it was about 2 to 3 hours after the patient dose. The elimination half-life was between 4 and 8 hours, averaging about 6 hours. It was clear that it performed well. It was dose proportional. There was no evidence of accumulation. And so as a Phase I doctor, this is actually what you look for. You want to make sure that you're seeing linear pharmacokinetics. So there's nothing that's unpredictable and that those generally reflects plasma concentration.
The drug was active. We had a number of -- we had 2 responses that were important to discuss. The first one was a patient with ovarian cancer who responded at 450 milligrams. This is the woman that was a platinum refractory ovarian cancer. She actually had a biopsy prior to going on to study that confirmed recurrent and viable ovarian cancer. After cycle 2, she had a complete response. And this patient actually remained alive today in a complete response now, 14 months out since her last treatment. She continued on with the treatment, but interesting, she had a very specific molecular and genetic abnormality that we're currently pursuing. She discontinued after a few courses and has remained off treatment but at the same time in a complete response since that time. And as you can see, as much as typical for ovarian cancer, you get this mesenteric and peritoneal metastases. This is the actual one that was biopsied, so we know that is indeed was a disease. We've looked multiple times with PET scans to see if there's any viable disease when she comes for follow-up and there is none.
Another patient with a MALT lymphoma.
MALT lymphoma is especially interesting from a standpoint of a cIAP inhibitor because there's a characteristic translocation associated with many of the MALT lymphomas that lead to Anacapa B [ph] and cIAP over expression. This patient, interestingly enough, didn't have that translocation, but did have something equivalent, which was a cIAP amplification based on array-CGH that was performed. After a cycle of 5, because you follow these patients with PET scans, because they are a gastric-like malignancy that involve the lining of the stomach, you'll see that she had a marked reduction in the uptake of FDG in the PET scans. And this woman actually remains live off treatment now, more than a year as well. She's somewhat lost the follow-up because one of the natures about this particular patient was she was a little bit ornery and she didn't want to continue after cycle 5.
So in summary, GDC-0917 had a favorable safety profile. We didn't actually determine the maximum tolerated dose, had, what we consider, a reliable PK profile. We stopped at a dose of 600 milligrams once daily for 14 days, every 21 days, based on the dose that portended the effective concentration for 90% inhibition. We saw, as Ali showed, that you can actually down-regulate cIAP in tumor biopsies, and we saw encouraging antitumor activity. Now this agent then subsequently was in-licensed by Curis. And so, we had an opportunity, like, say -- to say, okay, what needs to be done to explore this and try to find and determine what is the optimal dose, what is the optimal schedule, what are the optimal patient populations? So the first point. In the studies that we did in-house in start, we tried to determine, with the help of Curis, whether indeed there's dose-dependent antitumor activity in preclinical model.
Since the elimination of half-life range between 4 and 8 hours on averaging about 6 hours, the question arose: Can you deliver the drug twice daily and hence, improve the antitumor effectiveness? Is it possible to give the drug continuously? The 2 weeks on, 1 week off, dose would base somewhat empirically, and so one wanted to see, can you give the drug safely on a continuous daily dosing? And finally, if you saw antitumor activity in ovarian cancer patients, can we actually try to determine what might separate those patients who respond versus those that don't?
So let me address first and foremost, the dose-dependent nature of CUDC-427. And this is the same cell line that's a triple negative breast cancer model. And this is actually performed independently in our lab, not in Genentech or at Curis. And as you can see, we examined the dose schedule. This is a dose that was actually recommended by -- for preclinical studies, by Genentech, 10 milligrams per kilogram every day for 28 days. And we examined both increase of dose 20 30 and also a BID schedule. And I'll bring your attention to the fact that the recommended dose from Genentech was actually 10 milligrams, which is the blue line. But we found that as you increase the dose, you were then more able to improve upon the antitumor activity.
If you compare BID to once-daily dosing in the animal model, it's not quite so apparent because, of course, the overlapping error bars that are present. But what this really suggests, first and foremost is, that we can't be content with just a dose at the ED 90. We really need to explore how high we can go to try to get maximum antitumor activity out of this molecule.
So to address this, we've launched a Phase I study right now where we give the agent twice daily to patients with advanced malignancies, and the cycles are every 21 days. And so schematically, this is how this new schedule appears.
Now I've addressed dose, and I've addressed schedule. The most important question in targeted therapies is how do you identify the right patient? Because if you can get the right dose and right schedule, but you don't have the right patient, the whole system falls down.
So this is a strategy that we have taken along with Curis. And that is that if you look in representative models that might better reflect the disease in question, can you identify the molecular signature of responders versus nonresponders? Now this is just regorafenib, this is a currently approved drug. And this has been gone through our patient-derived explant screening model system that we have to start.
And let me tell you, if you don't know what about patient-derived explant, they're a pain at the time of surgery from patients who planted right away. They're a novel way of trying to develop more representative models. The models themselves have the architecture and the phenotype, consistent with the patient's disease, which is very different from cell lines, which tend to be monomorphic sheets of cells. And so, you try to get a model that is more representative of what the disease is that we treat in the clinic.
In this situation, this is an example, on our colon models, we have close to 40 models here. And all those models are then screened with regorafenib. And you can see a beautiful spectrum of antitumor response to this drug, regorafenib, with some of these responding, actually, 2, that actually met the criteria that we think of as responsive, and those on the extreme that are completely resistant to regorafenib.
Now this is particularly important because this is not by design. This represents about 5% responsiveness in our models, which actually reflects the 5% responsiveness in regorafenib for colorectal carcinoma. Most patients who receive regorafenib have a slowing of the growth, but no tumor shrinkage. And what it really means is that you have the opportunity then of comparing those that aren't going to respond to those that are, and see if you can use those -- that molecular signature as a point to selecting clinical studies.
There also has a time efficiency because if you can do that, you don't need to have a Phase II study where you do it and take it into a particular indication, you can actually try to screen. There's also one additional advantage, because if you can't define who is ultimately going to respond, because this pattern might be similar to those that get some benefit, but not complete benefit, at least, you could eliminate those that have no chance of benefiting because at any randomized study, that is the group that's going to diminish your effect of your drug additive to standard chemotherapy.
So we're currently carrying that out in ovarian cancer models, PDX models. We have about 36 models, and we're going through screening right now. And this is some of the data that's being performed today. And you can see, much like the colon model, you have some where you're actually seeing tumor regressions, some where you're having tumor growth inhibition, and some where you're really not seeing any inhibition at all. And once this screening process is complete, we intend to actually compare those responsive versus those who are not responsive, particularly in this ovarian cancer population, as well as the breast cancer population. Because if you can find that signature, then by the time of Phase II, and hopefully well before Phase III, you can identify the optimal population for CUDC-427.
So with that, I would like to acknowledge all the people on our side, as well as the people at Sarah Cannon and Curis, who've actually helped support us in these clinical studies. Thank you.
Go ahead and open the floor for questions?
Adnan S. Butt - RBC Capital Markets, LLC, Research Division
It's Adnan again. So in terms the developing strategy in breast cancer, have you found any marker? What's the plan to keep continuing the drug, to -- developing the drug in breast cancer, specifically?
I think we'll come back and address that once [indiscernible] gets up and discusses it as well. So perhaps, Adnan, we'll wait, if you don't mind. So as [indiscernible] gets up and describes some of our development plans and specifically, around breast cancer as well. Okay.
Adnan S. Butt - RBC Capital Markets, LLC, Research Division
And just -- so maybe you can just discuss the safety profiles that you've seen to date of the patient and then combination with whatever drugs you've applied to them.
Anthony W. Tolcher
Well, right now, it's a single agent in clinical development, so the combination studies, I believe are planned. I don't know if they're active at this point, but...
Adnan S. Butt - RBC Capital Markets, LLC, Research Division
And the single agent activity -- does anything stand out or is it clean safety?
Anthony W. Tolcher
No, on the -- so on the once-a-day dosing, 2 weeks out of 3 weeks, it was a relatively clean drug with those modest side effects that I showed before, mostly gastrointestinal, some nausea, some fatigue and the like. In the twice-daily, so far, it seems to be performing well, but there is -- there are toxicities associated with -- accumulated toxicities associated with the daily -- the twice-daily dosing, but we're trying to find the right schedule at this point.
Dr. Tolcher, just a little bit more on the [indiscernible]. It sounds really interesting. Are you able to extract out [indiscernible] and almost do -- kind of induce [indiscernible] modeling to actually look at the genome cap normalities. Is that what you're talking about here? Because that's a really interesting application of some of that technology, to really get pretty deep on the biology around those patients?
Anthony W. Tolcher
Right. So the -- once the models are implanted and then you grow them out to about the third passage, you try not to grow them much beyond 4 to 5 to 6 passages, otherwise, you lose what they -- what we really are doing to them to be reflective of the clinic. So we recently signed a strategic agreement with BGI because one of the key aspects is you want to be able to harvest the cell from the model that's in question, you then do whole genome sequencing. And the added parts in those skill set that BGI brings to the table is they've been able to remove any contaminating mouth DNA. And so then, you actually have data sets where you can look at also the models and do a comparative analysis because that's the key point. And so, we work with many large and small pharma in the model system and have done so for quite a few years.
I have a good general question with what you're doing at START. Why do labs like -- everybody's assuming doctors send the biopsies out and they get them tested. And through the course of activity of people in studies and in actual giving the drug, you would think that they'd have biopsies, they'd have drugs for working against biopsies. Then the people relapse, they try another drug. If they kept the genetic markers of the biopsies, people would actually be able to follow what drugs work in what genetic markers. And this is something I would think that the cancer labs would be keeping track of and getting -- then you'd know what drug to use against what marker.
Anthony W. Tolcher
Well, it's not quite as straightforward as you're describing because as you can imagine, we developed rituximab and that was developed, but we didn't recognize who didn't respond. It only came out later in large clinical studies that K-RAS mutations and B-RAS mutations predicted that you'd get no benefit from [indiscernible]. We still actually don't know who benefits because we haven't been able to sort that out. And it's due to a limited ability, until very recently, of actually having the genetics. So in the last few years, we've had the ability of doing sequenom, which is looking at a multiplex number of genes that are altered and array-CGH. And it's only been in the last few years that the cost of, say, doing whole genome sequencing, has come down. It is still not used routinely, still not, because our desires are actually to do that, but our ability to pay for it is not there yet. But that will come. It's just we're not there yet. It's like everything else. And it also raises an important question is that once you have essentially 3 terabytes of data, how do you make sense of that in clinical trials? And that's a whole area that is yet to be explored.
I'd also like to ask the members of the audience who are here, try to contain the questions more towards the topics and the drug candidates as we're going through. We'll have a panel available here as well later on who can discuss some of these more -- questions around patient treatments and strategies for both selection and continuous monitoring of the genetic profiles of the patients as well. Dan [ph] ?
Okay. So I'm just curious about the [indiscernible] comment on the competitive landscape of IAB [indiscernible] and monorated surveillance [ph] and how you differentiate from the field?
Dr. Viner will describe some of that in terms of where, at the moment, in development, the various drugs are and how we fit into it. And I'd try to articulate, at least, from a profile perspective and the drug properties perspective, how our drugs candidates differentiate from the others, mechanistically, potency, and its ability to affect key markers of doses as we described. Again, Dr. Viner will describe some of the effective trial landscape as well.
Dr. Tolcher, my impression is that IAP [indiscernible] most likely to be in these combination agents. Could you also cite your perspective about the Phase I results that you saw currently in the [indiscernible]?
Anthony W. Tolcher
Yes, so from our standpoint, the one thing that we would say that was very encouraging, as you know, with most of the IAP, is that there's not ever been reports of single-agent antitumor activity. So that was quite satisfying. This one, we saw evidence of that. Two, one of the biggest dangers when you look at combinations is, if you haven't yet really understood where -- which population is going to get benefit, you can sometimes have great difficulty sorting that out afterwards when you combine it. And so, in this circumstance, a number of people are pursuing, say, with other agents, the ovarian population, but it's just in ovary, it's not in certain select population of ovarian cancer. And I think to some degree, that's a mistaken development strategy largely due to the fact that, as I showed you, there's going to be a spectrum of those that are responsive to IAP inhibitors and there are going to be those that don't. And those ones that don't are not going to add to your success.
Dr. Tolcher, can you talk a little bit about the genetics of the ovarian cancer patient? You mentioned very specifically if there is a patient, but not mutation, and then can you just expand on why we're having such a long and profound benefit?
Anthony W. Tolcher
Yes. So I think the decision has been made, and I think it's the right decision, is that, that will not publicly be disclosed. And there's -- I think in the world that we live in, there's a competitive advantage to find out to -- what was observed. So I would just say that it's a very discrete molecular alteration.
I guess a more PK question, you're going to twice-daily, but at least based on the half-life, I would've thought that maybe 3x daily with the holiday would be better, but what am I missing?
Anthony W. Tolcher
Well, first and foremost, 3x daily is not usually feasible in the real world. Think of antihypertensive, how often do you have 3x daily antihypertensive? Two, we don't even know if twice-daily is going to be superior to once-daily. Because in many times with oncology agents, it sometimes -- the peak dose can have the maximal effect. And as Ali showed, the pharmacodynamic effect may persist well beyond the pharmacologic half-life. And so, you need to examine that question to make sure you're not missing something, but it doesn't necessarily mean that twice-daily is going to be superior to once-daily.
I guess just a basic science follow-up,make it Ali. You mentioned that there are different family members right out of IAPs. And so, just going on that, do we know what the feedback mechanisms are? So when you're inhibiting one family member, what's -- are the members that are coming on? And is there an effect on the de novo or natural stem cells, where I would imagine that you have a suppression of IAP in order for them to continue to function? And do you see that in the cumulative talks profile in the current Phase I study?
That's several good questions, Reni [ph], thank you. With respect to potential differential expression and/or -- because our multiple family members did a bypass one another or not, and the -- although they all share a common reason before IAPs that we've described and loosely all categorized and it's the cIAPs which really function more for the extrinsic and geno-preceptor family member signaling. And the ones that worked more closely on the intrinsic signaling, such as XIAP and MLIAP and loosely [ph] categories and those 2 categories, they do have different functions and they have other functional units beyond -- functional activities beyond the apoptosis inhibition, but they happen to do that very well. But I want to draw your attention to one thing that Dr. Tolcher elegantly introduced in this set. The IAP proteins are really the end stage or the almost penultimate protection of the cells before apoptosis induction, which is really initiated by the activation of the caspases. So very difficult to see how cells can try to bypass one of these mechanisms. It is a very finite threshold for cells. Once that threshold is reached, they commit to apoptosis and cell death halfway induction. It's a nearly impossible form to come back. Having said that, we do, as we mentioned, XIAP. For example, I showed you in a certain setting, that it is a common mechanism of up regulating it in order to overcome apoptosis. And as Dr. Tolcher indicated, at least for the one MALT lymphoma patient, that's a patient that -- their tumor was selected or had selected based on amplifying the cIAP gene, and they seem to be very distinct. So different family members are used, but again, I think we -- we have the fact that we're hitting strategically almost the last step of protection for the tumor cells, the IAPs. We have not, at this point, identified resistance mechanism or bypass mechanism to go active. Having said that, it is a fairly young field as well, so this is, again, one of the places we're here to talk in the court. As what happened in the case of the Hedgehog, the inhibitors had been well discussed. With regards to stem cells, no evidence of interaction at this point. We've not really dealt into that at this stage. Yes?
Dr. Tolcher, for the IAP inhibitors on the device, I was wondering whether there is a contact toxicity for this kind of drug. And also, how should we be thinking about that pneumonia case that went back in the [indiscernible]?
Anthony W. Tolcher
Yes, so we didn't think the pneumonia was associated with the drug per se, so we don't think that it was drug-related. We record all the deaths, but these are patients with advanced cancer who have a number of other things that are going on. The issue about what is a -- what are the planned side effects. So far, one of the most important class effects we can see, but not seen with this particular agent, is Bell's palsy. And it's been associated with both the TetraLogic agents, as well as the other agents in development. Now I don't think I'm doing that, but anyway, a key aspect is that it's not been seen with this particular agent, and so there is no other sort of overwriting class effects that we've seen.
I have a question, a little bit more about the pharmacokinetics and the characteristics of the drug. What is the mechanism, the inhibition of the drug? Is it closed infinity? Does it go on and off quickly? And as it goes off, is the inhibitor, again, active as an inhibitor? Or is it chaperone to degradation? And what's the tissue distribution? I mean, is it accumulated tumors?
Anthony W. Tolcher
So let me address the parts that I know, and I'm going to pass over to JV the parts that I don't know. So the [indiscernible] is essentially a CAT-based binding portion of the IAPs and so that part inhibits the actual binding of IAPs to CAT bases, so that's really the target. So it's a direct inhibitor. It's not having an effect on chaperones and the like. From the standpoint of the distribution, of course, you don't do distribution so easily in clinical studies. There are preclinical studies where they look at the distribution, and Jaye can probably address that. But the one other question in that -- that you've mentioned?
Would the inhibition, does it then lead to degradation? Or is it just -- it falls off the IAP today and then it becomes an active inhibitor again?
Anthony W. Tolcher
Right. So as you saw in the work that Ali presented, there was actually a true downward regulation of the IAPs associated with the drug, but I'll let other people clarify that. They might know a little bit more.
Yes. The drug itself, as we said, is a monomer pneumatic that binds the same portion of the IAP proteins as they bind either to smac or to the caspases. So it's a symmetric binding, so it has to bind to that region and inhibit the interaction of the protein with the smac or the caspases. In the case of the cIAP protein, it says when the drug compound binds those, it results in a degradation of the protein or autocatalytic degradation of the protein. Our assumption is that the drug comes off and is able to, then, bind another molecule. We have not identified any degradation of the small molecule drugs itself or its elimination. In terms of the tissue distribution, as far as we know, it doesn't necessarily accumulate in any specific tissue including the tumors. So it's readily distributed throughout the body.
And I forgot to ask, bioavailability, pretty good early?
Nearly 100% has been measured by Genentech. So data is very, very orally viable. Any additional questions? Great. We'd move on to the next presentation. I have to make an admission. I continue to say Julia. And I don't say Julia Lawrence, because every time I think about Julia, I think about Julia Donaldson, one of the favorite authors of my young daughter who I read books to every night. And I have to hold myself from it frankly.
[indiscernible] I'll introduce Dr. Lawrence, a former colleague of mine, an Associate Professor in the Section of Hematology and Oncology of Wake Forest University Health Sciences in Winston-Salem, North Carolina, where she served in the Breast Cancer Center of Excellence. Her work there was recently recognized with the New Investigator in Women's Health Clinical Research award. Prior to this, Dr. Lawrence conducted a sense of clinical research for the National Cancer Institute [indiscernible], where she had a joint appointment in the Women's Cancer section in the laboratory of technology. She has worked extensively in the area of cancer protection research and published broadly in the development of chemotherapeutics for breast cancer, the topic of today's presentation.
Okay, thank you, Jaye, and the other organizers. So I've been asked to present somewhat of the landscape of breast cancer. And I know you're all eager about questions about these particular compounds. And I'm going to present where we are clinically in breast cancer today and unmet needs.
Breast cancer is common. 12% of American women are going to be affected by breast cancer. And importantly, the disproportionate number of women who die, in comparison to those who are diagnosed. So in fact, we do -- I am lucky to be treating a disease that is primarily curable. And worldwide, the breast cancer is a common problem and this is -- it is the most common cancer in women worldwide.
So the most important molecule for breast cancer has been estrogen, and that has driven pretty much all aspects of breast cancer biology and epidemiology. A woman's exposure to estrogen during her lifetime is associated with risks. The number of cells that is sensitive to estrogen is associated with the biology in the prognosis. And drugs that have effectively blocked estrogen like the estrogen receptor with tamoxifen have made the most significant impact on breast cancer treatments systemically.
Important things that have really caused a major change in breast cancer recently is, one is that -- sorry, maybe I'm going to take that water. That we have more traditionally thought of breast cancer as 2 distinct subtypes. Those that are the estrogen receptor positive or sensitive and those that are estrogen receptor independent. More recently, with the benefit of molecular biology, we now have this recognition of multiple breast cancer subtypes. And probably, that's going to be continuing to expand as far as the recognition of different breast cancer subtypes.
And furthermore, that we do traditionally treat patients or women based on stage. How many lymph node involvement, the tumor type? How that's clearly shifting as well is that we are trying -- we are thinking more and more about biology and potentially late-stage presentation with favorable biology behaves well.
So what has really led to some of these changes is the seminal paper that was reported in 2001 by Perel and Shoreley [ph], which used a group of tumors that had long-term prognostic data with actually a relatively small group of tumors. But they looked at 1,400 genes within those tumor types. And from this, they were able to subclassify breast cancers. And this is what I'm referring to as the different breast cancer subtypes.
From this emerged our different terminology essentially, and that one of them -- subtypes that has been quite significant binding is that of the basal-like breast cancer, which is often termed the triple negative. The ERBB2, which is the Her-2 positive breast cancer. And then there is this relatively large group of the luminal-type breast cancers. And the luminal type breast cancers are, by and large, those that are the estrogen receptor-positive. But within there, there seems to be a spectrum of different estrogen-receptor positivity different proliferation.
So when we landed this news and we all have our individual laboratories that can't do molecular biology on a daily basis, so we're left with who within our clinic population are we looking at that is represented by this basal-like breast cancer. And as a result, we saw that estrogen receptor and progesterone receptor and Her-2 are absent in the basal-like breast cancer. And that is where the terminology, triple negative, emerged from. Although there are some fallacies within that, which I'll talk about later. And then the Her-2 positive breast cancer, Her-2, are to be determined by immunohistochemistry and FISH. And I'm going to be talking about the different subtypes, but not particularly about the Her-2 positive breast cancer. We give a mine view. In fact, Her-2 positive breast cancer is actually getting a lot of attention, a lot of new drugs are coming down the pipe for that. Luminal B breast cancer and Luminal A breast cancer are distinctly different in that Luminal A is very estrogen-rich, low proliferation and therefore, most likely to benefit from just purely hormonal therapy and not likely to benefit from chemotherapy. Or is the luminal B are more of that mixed tumor that has lower estrogen receptor and higher proliferation within it.
So this is the long-term prognostic data that came out of that. These tumors were based on older specimens, so therefore, the Her-2 positive group were not the group that received Herceptin because this cohort preceded the Herceptin. So now, of course, the lowest pink line is doing much better because of the advent of Herceptin in the adjuvant setting.
The blue line is the Luminal A breast cancers that, at 5 years, have an 80% survival. And their survival is not necessarily greatly -- potentially not impacted by their breast cancer. The Luminal B breast cancers in contrast are doing considerably worse. Although they are treated -- were treated fairly similarly to estrogen-receptor positive, some got chemotherapy and some didn't. And then the red line represents the basal-like breast cancer where you could see that early recurrences within the basal-like breast cancer, which is the most unfortunate scenario.
So in my view, those are the 2 biggest unmet needs where there's the greatest degree of activity as far as clinical research. So just to start with that luminal group, of luminal-type breast cancer, about 85% have been -- have no lymph node involvement and will not recur with tamoxifen in 10 years. And just deciding who amongst that group are we able to select out to give chemotherapy. Because they are highly curable, exposing them to chemotherapy early in their lifetime could cause late-term, long-term effects, which we're all becoming more increasingly aware of with greater breast cancer survivorship. And there is a challenge, the challenge is how do we select these women who need more than just hormonal therapy at diagnosis.
So the validated breast cancer markers that we have are nodal status, type or grade, and that is the pathologic determination of the degree of the cell morphology, the differentiation of the cells, the rate of mitotic activity. And tumor size, which is N, patient age, lymphal vasal invasion, again, a pathologic diagnosis. The extent of estrogen receptor positivity and progesterone receptor positivity, which we have more traditionally been thought of as a qualitative marker and more and more we're thinking of it as a quantitative marker, as the extent is important for our prognosis rather than just whether it's positive or negative. And Her-2 new status, which has now been more and more clearly, a prognostic marker rather than just a predictive marker. And then the latter 2 are Oncotype DX and PEM 50. And I think it's important that the difference in how breast cancer is viewing molecular markers and that, rather than just going for -- rather than thinking of different targets and looking for specific mutations, which is occurring amongst other tumors, there is these 2 prognostic markers that are now looking at panels of genes. So the first one with Oncotype DX, which has been available to us in the clinic, I think for almost a decade, and this is an example of a score that's reported to us on a woman with breast cancer. At this point, the state-of-the-art is that we send our specimens to [indiscernible] and they send back the results to our individual labs. So there's no way for us to do these at our individual labs, because of the proprietary information. And we get back from them a score of low, intermediate or high risk. And the low risk scores are those women who don't benefit from chemotherapy. Those women who have an intermediate risk are somewhat of an unknown about the benefit of chemotherapy, and the high-risk group was a group that truly benefited from chemotherapy in our long-term prognostic, our long-term cohort study using older chemotherapy regimens.
So of these newer prognostic tools, the Oncotype DX was primarily based the score that to us is reflective of perforation. And there's another score that's more recently -- or another prognostic tool that has more recently become available that's more based on the breast cancer subtype. Both of these tools are essentially complementary of each other. But it gives you an idea of where this field is going as I go through it. So the proliferation, as I said, we are really focused on that because we know chemotherapy is working on perforation and breast cancer that is estrogen-receptor positive and has this low growth rate really responds quite poorly to chemotherapy. So deciding who has the most perforating cells or subpopulations of perforation is inherently important. The ways that we already determine proliferation are just immunohistochemistry markers of Ki-67 and MIB-1, which is same for some proteins within the S phase of proliferation. And then, also grayed, the histologic gray that is reflective of proliferation.
So the Oncotype DX, that is the gene signature that we've performed on paraffin-embedded specimens, and they do a 21-gene signature. But what is important to the score that is determined is that the proliferation group, all those genes that reflect proliferation, are weighted the heaviest. So voted the 21-gene signature, we know that most of genes that are really given the most quantitative value are those related to proliferation.
And this score, the Oncotype DX, is associated with long-term outcomes. The green line is the low-risk group, and the red line is the high-risk group. Again, the intermediate risk group, although it has been shown to be a continuous variable, that is a little bit of a debate about how continuous a variable it is.
And then more recently, we've had the approval, although not really in our hometown laboratories yet, of PAM50. And so PAM50 was developed more in line with that initial molecular signature, and the scientists who were involved in that are the ones who developed this. So that is essentially then using the same signature that defined luminal A and luminal B initially to determine who is, in fact, luminal A and luminal B. Right now, it was just approved for post-menopausal women only, and that was because they went to a clinical trial that was for anastrozole and tamoxifen, in comparison to ATAC trial, which was just combined to post-menopausal women. So that's not a subject, really, as a biology of it but more as a clinical data that was utilized.
Right now, that tool is really for the benefit of -- one of the decision points we have now with women with breast cancer is that long-term hormonal therapy is beneficial. And who is a candidate for that? That Prosigna has been approved for that indication, who benefits after 5 years of tamoxifen or 5 years of AI. But those tools are also available and a benefit to who's -- deciding who's at risk for recurrence and who is likely to benefit from chemotherapy in early-stage disease or adjuvant therapy.
So now, switching to the other unmet need. Now, as I said, that this is a new classification: Luminal A, Luminal B, HER2-positive and the basal-like, in contrast to ER-positive versus AR-negative.
And the recognition of basal-like breast cancer was very important that we don't see the markers of the estrogen receptor, progesterone receptor and HER2. And it affects about 20 -- it occurs in about 20% of the breast cancer cases. It is associated with a poor prognosis. And also, the cell of origin seems to be in distinct contrast to what we've really previously thought about for cells of origin for breast cancer. And that it seems to be originating from a basal-like breast cancer cell. And here is that -- in a cartoon figure is that the breast cancer is really a cancer of a ductal unit. And so the luminal cells are those cells that line the ducts. They are the active cells. They're the cells that respond to estrogen during a woman's lifetime. They're the cells that evolve in lactation. So they're more of the glandular metabolically changing cells. Whereas the basal-like breast cancer includes the basement membrane and the myoepithelial cells. And those are the cells that are -- they are more thought of as the origin for basal-like breast cancer.
So as I said, we do have this disconnect though currently that we have this definition from a molecular signature that we're trying to deal within the clinic, and there's an inherent acceptance that we're misclassifying women who are truly triple-negative, who are basal-like and not triple-negative or vice versa. And that overlap is somewhere between 10% to 40% of women are being misclassified based on just using immunohistochemistry alone.
Our adjuvant chemotherapy currently for triple-negative breast cancer are -- is still standard agents. So although this new insight has emerged, we haven't really been having an advantage of changing our clinical approaches to them because we just don't have the insight to do so. So right now, adjuvant therapy really does consist of what we use classically for breast cancer and the adjuvant setting meaning to prevent breast cancer recurrence after surgery. And that is an anthracycline plus or minus a taxane.
However, some of the clues for biologic insights for what would work in a triple-negative breast cancer come from the overlap of hereditary breast cancer or BRCA1 breast cancers with triple-negative. And as a result, there's been a lot of focus on platinum compounds. However, right now, those are not used in an adjuvant setting. The reason to focus on platinum compounds is that there is thought to be some DNA repair default within the basal-like breast cancers and platinum compounds to be specifically important for that.
So the other area that is -- so adjuvant is giving chemotherapy after surgery. However, one great opportunity we have in breast cancer is that it is just the availability of imaging the organ and feeling it or a clinical exam. We have the ability to treat cancer before surgery. And there is no -- that isn't really clinical practice, but it's emerging as a very important tool for clinical research. And the reason for that is that this finding that if we bring a person to surgery after chemotherapy and they have no evidence of disease in their breast whatsoever, we call that a complete pathologic response. And that finding has been so significant that we've seen women who are a stage III, and that's why they got their new adjuvant chemotherapy, who we can induce the pathologic complete response and their prognosis almost turns down to that of a stage I. So the prognostic value of pathologic CR is very important.
And for triple-negative breast cancer, this has also become a very important area. This is MD Anderson's published experience with triple-negative in contrast to other cancers. And what you could see is the pathologic complete response to chemotherapy amongst the triple-negative breast cancers far away outweighs the pathologic complete response in non-triple-negative breast cancers. Again, I said that this is a poor prognostic tumor. However, it does seem like it's a very chemo-sensitive tumor, if we could figure out how to tailor our therapies better. And again, on the survival curves, you could see that, that pathologic CR turned out to be a highly important prognostic sign. This is, again, survival curves when other study looking at all [ph] new adjuvant clinical trials, those that achieved a pathologic complete response versus not.
So as a result, at our last national meeting, and I don't believe this is in publication yet, one of the FDA investigators brought the table, well, can we use pathologic complete response as a surrogate marker? And could that be used for drug approval eventually? And this is important because, as I showed you, that -- women with breast cancer largely do survive. And to get answers for breast cancer does take a lot more time. So if we had some faster mechanism of determining a efficacy of a drug, that would be really important to getting drugs to women quicker.
So she -- Dr. Pordesar [ph] had looked at all the women who are enrolled in neoadjuvant clinical trials. There's variable definitions of how pathologic complete response is defined. In fact, some people, they consider if there's some premalignant cancer remaining, that's considered a pathologic response. So she kind of [indiscernible] all that and said that absence of any pre-cancer will be considered a pathologic complete response, as well as absence of lymph node involvement and, in fact, looked at that, yes, pathologic complete response was clearly associated with event-free survival and overall survival. And the difficulty though now stands at, by and large, we probably see on average, about a 20% pathologic complete response in a nonselective breast cancer population. And what degree of increase over that would be -- lead to a clinically meaningful, significant end point? And that's where she left the question open.
But this is a summary of the 13,000 women who are on the clinical trials. And as you could see, those women who have -- who are triple-negative, by and large, had a 34% pathologic complete response. Those that are the high-grade estrogen receptor-positive, they had the poorest pathologic clinical response, which wouldn't be surprising because we're kind of expecting them to get more of the benefit from estrogen receptor-positive, estrogen-directed therapy. The HER2-positive group had the highest pathologic CR rate. However, admittedly, this was a population that the most neoadjuvant clinical trials has really been done on with the newest therapies. And then that group of HER2-positive, as well as estrogen receptor-positive, had a little less pathologic CR rate. And I'm not sure if that was based on who was entered into the HER2-positive trials.
So I focus mostly on adjuvant chemotherapy and adjuvants -- what we think when we are initially diagnosing breast cancer. However, metastatic breast cancer is most women who are diagnosed or diagnosed early-stage. It's rare for somebody to be diagnosed with metastatic at presentation. But when we talk about recurrence, there are patients who are shifting to a diagnostic approach to metastatic breast cancer, where a lot of our clinical trials and drug development is at present. The most common signs of metastasis for breast cancer are those listed. And when somebody has a newly diagnosed metastatic breast cancer patient, our initial approach is a biopsy to confirm that it is, in fact, metastasis rather than something else and post-staging evaluation, including imaging. And then also, we reassay for HER2, ER and PR in the metastatic site. We don't really yet do anything else beyond that as far as prognostic indicators, although those are being looked at in various clinical trials, looking at that, if some of those assays can be used as predictors of drug response. And our treatment decisions are based on hormonal therapy, if they're ER-positive, it's usually the first line, and then chemotherapy for those who are ER-low or who are absent of estrogen receptor.
So triple-negative breast cancer is a very difficult situation at present because, although they are chemo-sensitive initially, that's not what they're looking at like when they recur or metastasize. A median survival after metastasis is about 9 to 12 months. Unfortunately, this is a disease that's tending to affect younger women, more commonly amongst minority women. And the opportunity here is that any compounds that do effectively get developed in a metastatic setting do have the potential to then move to the adjuvant or neoadjuvant setting.
So in this slide, I summarized some of the triple-negative breast cancer studies to date, which, in some ways, have been largely disappointing. Because of the evidence of need for DNA repair, you'll see that the platinum compounds tend to be the backbone of the -- of testing a new drug, carboplatin and cisplatin, because they affect DNA and repair and were thought on early insight to be important to this disease.
The PARP inhibitors were the one that got the most attention, Dr. O'Shaughnessy's study that was reported in New England Journal, and then tended to be a disappointment in the Phase III setting. However, I think one -- and I put my own study at the bottom here, which has -- is the only one that's not published. And I think that it was humbling to, for the first time, really separate out beyond that -- that was done for HER2-positive disease. This was the first setting for breast cancer doctors to be separating out these distinct subtypes and putting them -- entering into a metastatic breast cancer study. And that, really, before that, we really had pooled patients. And I think quite alarming was the rapid rate to tumor progression, which is a progression-free survival and time to progression I pooled just for the sake of demonstrating that it really was between 1 and up to 5 months before patients were progressing. And that's -- for some diseases, that's not surprising, but as a breast cancer oncologist, it was very surprising. And being one of the principal investigators in one on these trials, it was very heartening to see these very young women presenting with very clinically rapid disease.
And so I just wanted to -- on these studies, so the -- all the entries for this was estrogen receptor with immunohistochemistry markers. However, the current 2 studies, Dr. Carey and Dr. Ma, went back and then did molecular subtyping of those. And one thing that was shown was the -- again, what we're seeing -- knowing we're doing in clinical practice. But only probably about 40%, maybe up to 50%, of the patients within these studies are really turning out to be basal-like breast cancer when we're selecting them for just triple-negative markers immunohistochemistry. So that's clearly a limitation in that we're letting the biology kind of drive this. And then when we get to clinical trial enrollment, we have this limitation that we're not exactly selecting the patients as well as we would like to. And so from that has emerged even more further defining of what constitutes triple-negative breast cancer. We know that about 30% of them are clearly having some of these markers we're very familiar with. ER PR and HER2 are probably represented on these trials. And then there's further subclassification of what basal-like breast cancer and a new -- yet a new subtype has emerged, which is claudin-low. And just watching this field, I have no doubt if we are back here a year from now, this diagram will be further expanding just because I think that, that's where we're headed. It is just understanding the great heterogeneity within breast cancer.
And that was my landscape of breast cancer.
Thank you, Julia. We are going to close by merging Julia's session with mine so that all of the questions can be answered together. I trust that based on the presentations thus far, you perhaps understand why we're encouraged by the noncritical data generated by Curis and also with regard to these compounds in general and why we're optimistic that we have an opportunity now to capitalize on our experience to date in order -- in our quest to identify better therapeutic options for patients with cancer.
So just speaking broadly about the IAP antagonists, obviously, this has more evolved than what we have going with our PI3 kinase/HDAC inhibitor. Just to orient us, as stated earlier, there are no approved agents to date in this space. And as it's been shown in a rather compelling fashion, IAPs have been implicated in tumor survival, in drug resistance. And elevated expression has been demonstrated across multiple tumor types. We've also shown data showing cooperative efficacy or synergy with other anticancer agents, which explains our eagerness to move in a rather aggressive way towards combinatorial testing. So the mechanistic rationale for coadministration with the agents has been amply discussed. And while it's encouraging to see what we can achieve with our own agent in our lab and the labs of independent investigators as well, it's also heartening to see that mutually and confirmatory data has been demonstrated across IAP targeting agent -- IAP antagonists with different agents in class.
So in terms of differentiation, you saw a slide that showed that we can achieve potentially more potent activity than other monovalent competitors. And as was described earlier, there's -- we -- based on the data that we have so far, it appears that CUDC-427 is better tolerated in the bivalent competitor. We have an oral schedule, and this enables sustained inhibition of XIAP. And I trust that you appreciate that the sustained inhibition potentially is an important feature of this targeting. And the oral schedule, of course, permits dosing flexibility.
So we only have published data on the first-in-human trial, the data that Tony presented earlier today. And just as a quick reminder, it was gratifying to see that the pharmacokinetic and pharmacodynamic profile confirmed preclinical data and modeling that had been conducted before the study, and the rapid down-modulation of cIAP1 at all dose levels in the peripheral mononuclear blood cells suggested that we are hitting our target. As described, the drug was well-tolerated in 42 heavily pretreated patients, with only 1 dose limiting toxicity, which was a grade 3 fatigue, and the maximum tolerated dose was not found. The absence of Bell palsy, again, Bell's palsy was encouraging, and the etiology of this toxicity is not well-understood. We don't know if this is a class effect or perhaps something that's exclusive to the dimers. Nevertheless, importantly, we have demonstration of potential to administer CUDC-427 at clinically relevant doses. And the encouraging efficacy signals in ovarian and MALT lymphoma, of course, are signals that we'd like to further explore.
So we have this ongoing monotherapy study that's trying to determine whether a more intensive schedule might enhance target inhibition, and by that, I mean tumor efficacy. So by exploring promising findings from the first-in-human study, we're trying to lay a foundation for optimizing dosing schedule for higher phasing combinatorial testing, and that's the work that we're aggressively moving towards now. We're delighted to say that the Phase I twice-daily dosing study is moving at a very nice clip. And so we will continue to exploit mechanistic signals emerging from nonclinical studies, as well as any efficacy and other translational or translational signals that come off of the twice-daily dosing schedule to inform our combination study. And as you can see here, there's a strong interest in testing in combination with capecitabine in the approved tumor types in breast cancer. We're going to be comparing the safety and clinical benefit of the combination to that of standard of care prior to initiating higher phase testing. The intent here is to gain early insights into toxic signals that are attributable to the investigational agent or the investigational in combination with capecitabine, in this case, as well as to determine whether or not there's an efficacy signal that would be attributable to the investigational agent or the investigational in combination with the standard of care early, so that we can feel as though we're on a more solid foundation in higher phase testing and not inadvertently attributing efficacy to what is, in fact, something that could be expected with the standard of care alone.
So the CUDC-427 activity in breast cancer models has been described both in terms of the extrinsic and intrinsic pathways that appear to be engaged in breast cancer. The high expression of TNF, I think, has been amply demonstrated and the IAP induction as a potential mechanism of drug resistance as well. The sensitivity of breast cancer cell lines to CUDC-427 in the presence of TNF and the potential for synergy is extremely exciting to us, and this has been demonstrated in multiple cell lines that have been examined. The [indiscernible] advantages of the combinatorial -- combination therapy is -- has been supported by the data from our breast cancer animal models, as well as demonstration that fluoropyrimidine induce XIAP and TNF in some of these breast cancer models and the demonstration that CUDC may overcome chemo resistance mediated by XIAP up regulation.
Now this slide is simply -- okay. Sorry. I'm going to ignore this because I can't work it. But on the left side of this slide, what you'll see here is simply a nice visual showing that TNF-alpha sensitizes breast cancer cell lines to CUDC-427, and this is a synergy that was alluded to before. On the left side of the left graph that you see here is TNF-alpha without, and on the right is plus TNF-alpha. On the right side of the slide, what you'll see here is the TNF-alpha levels are high in breast tumors -- higher in breast tumors and in cell lines. This is encouraging because, obviously, as mentioned earlier, our cell line data, these are nice tools, but they have their limitations. And the closer that we can get to the human clinical experience, the more we hope that this will reflect what we have to look forward to when we actually test in the clinic.
So this next slide here is simply a reminder that both CUDC-427 and 5-FU induce TNF-alpha in a breast xenograft model. On the left, you see the CUDC-427 graph. On the right, you see the 5-FU.
And a question earlier today related to the competitive landscape. So to orient you to this slide, the yellow boxes are the monovalent oral SMAC mimetic, which includes our drug, the font of which is in the blue, just to make it jump out at you a little bit more. The blue boxes are the bivalent, the intravenous SMAC mimetics. And the green box is an oral non-SMAC mimetic. As you can see, there are a few agents that are currently in the discovery phase. And then in the Phase I space, which is where we currently are, well, we're not entirely sure we know what the future holds for the bivalent SMAC mimetic immediately below ours. You can see that, again, this is not a dense competitive landscape. And the highest testing right now is being done by the 2 molecules that you see in the right in the Phase II space, and we expect to join them in the not-too-distant future.
So now it's part of a -- just to try to close things down a bit, I realize that there may be questions specifically about the breast and the IAP antagonists. I'll just -- because we have very few slides now on 907, just the developmental landscape for this molecule, as mentioned, this is currently in a first-in-human study. It is a novel proprietary approach. We've had some questions about the combination approach. It is an approach, it is not the only approach. As mentioned earlier, this combination targeting has worked very well at other therapeutic areas such as anti-infectives. Whether or not that is -- we can expect that sort of success. Well, this remains to be seen. It's still quite early. What we do know is the HDAC moiety has been validated as a target for cancer therapy. They're 2 approved agents in the lymphoma space. And for the PI3 kinase pathway, well, it's active across a broad range of hematologic malignancies. There are no approved agents in that area. We have -- the nonclinical data that were presented earlier today showed that dual targeting achieves synergistic effects.
And we hope to see hints of this activity in our first-in-human study that is ongoing. Again, we're aggressively trying to move -- test this hypothesis in the preliminary clinic studies in order to really do what is the foundational work of a Phase I study, which is to determine the MTD and recommended Phase II dose. In this case, we're tailoring our population of patients with advanced or refractory lymphoma or multiple myeloma for the reasons described by Dr. Berdeja and Dr. Younes earlier today and the necessary drill of characterizing the safety, tolerability, PK and preliminary activity. And we have a number of nonclinical studies that are trying to identify whether or not therapeutic potential in solid tumors might be something we could expect with this agent as well.
So in the interest of being true to what -- doing what I said we were going to do, I did say that I was going to give people an opportunity to ask questions to Dr. Lawrence and myself jointly, if you want to, around the breast issue. And I'll put this on hold now.
Open the floor for questions.
I understand the preclinical rationale for the combination and the valuation of the IAP inhibitor in breast, but there's something from the Phase I study because we see a great response in ovarian, we see a great response in MALT and then the Phase II is in breast. And so was there anything else from the Phase I that would suggest that breast cancer is [indiscernible]?
You're correct. We did not see the extensive response in breast cancer that was seen in the Phase I with the ovarian and the MALT. But we need to, again, be mindful of the fact that in Phase I studies, it's not at all uncommon to really just look for evidence of efficacy. Some suggested efficacy and then use the mechanistic rationale that's being described earlier today to determine whether or not, if we were to tailor in other populations, this might be meaningful. I don't know if Tony wants to talk about this as well.
Anthony W. Tolcher
So the trouble awaits in Phase I, that the tyranny of small numbers so we didn't have that many patients with breast cancer. We have some patients with breast cancer now, and I think that plan is to be led by the biology. And as I showed, that MDA-231 and MB-231 is a triple-negative breast cancer. There's also evidence of cIAP amplifications in a number of other things that make it an attractive area. But again, it really comes down to decision-making amongst the sponsors as to which areas they want to pursue.
And just with the ongoing Phase II breast cancer study and based on the landscape that was reviewed for us, is there a particular niche within triple-negative? Is there a particular patient population that you want to try to enrich your focus on or the trial design could potentially, if you start being responsive [indiscernible]?
So I think, again -- so it's always a bit of a fine line because, well, I think we can sometimes get a little too smart by half. We get an early signal. And we decide if there's potential and people do this all the time, you narrow very quickly down, thinking that you've got the answer. We're really trying to have a very data-driven approach where we draw off of mechanistic signals in rational science and at least allow an opportunity that maybe what we've seen preclinically may not be all there is to see. And I think this speaks somewhat to what Tony has described as well. Obviously, breast cancer, we're not looking at HER2-positive, because as Julia described in great detail, there's other options for that population that may not be the best niche. It's just important to figure out where not to go as it is to say where to go but to narrow too quickly. And what's nice about these trials, and I realize that they can be challenging, is, as these signals emerge, we will be nimble. We will adapt our trials and hopefully exploit the positive signals so that we can enrich in whatever way we can. But right now, we're at a relatively early stage, and we're optimistic. But we're also poised to take advantage of any new signals that we haven't seen yet that might help direct some of our designs.
If I may make a comment around that as well. The depreciation that's from Julia's presentation, recognizing the complexity of the different types of the disease and how -- in breast cancer and how you can potentially not only select the patients but figure out how you treat them in terms of what they may respond to or not, what they may benefit to or not, marrying that for the first time to CUDC-427 as an IAP antagonist, in combination with one of those therapies, so I think this is the depth of the design of the study that we're trying to do. As Jaye indicated, we're not looking at HER2-positive patients. That would be the HER2-negative population. But for the very first time and, again, from a scientifically rational perspective, we have chosen capecitabine as the selection. So the question really comes, how do you answer those 2 questions in 1 study, both the ability to select patients that may benefit some of the combination and also, at the same time, for the very first time, combine those 2 agents as one? I think this is what's really taken much of our attention and, in fact, of course, Jaye's attention, plus Julia and other breast cancer specialists [indiscernible] the design of this study to give us those meaningful answers in terms of how to combine our drug with capecitabine and, also, how to tailor the study to be able to not eliminate patients too early and get a meaningful randomized answer from that study. We would love to be able to present to you the exact design of that study, but I have to say, I'm heartened by the amount of attention that the study is getting internally for us, with Jaye and her team, as well as many of our expert advisers, to really design the study absolutely correctly to allow us patient selection and, also, a meaningful answer from the combination side.
Anthony W. Tolcher
I might also just add that there are also -- Curis is also screening in our breast cancer triple-negative PDX models as well to, again, try to clarify what might be a sensitive population.
In that regard, are you planning to use the archetype of the PAM in each -- in the study to stratify participation [ph].
It's a very good question, and -- I think that Julia got through that. It's not only what we test but what are of the prospective information that we want to get from those patients, and this is, of course, on that situation. A very important question.
Just a quick follow up on line of question. So I'm looking at Slide 54 where is this the [indiscernible] looks like. There were 10 patients with breast cancer in 2 sites [indiscernible] and you have 2 ovarian patients, and 1 CR. So I don't understand why the company is not pursuing any additional studies of ovarian cancer.
[indiscernible] So we -- I would just like to mention that in the BID schedule Phase I study, we are in fact, encouraging enrollment of patients with ovarian cancer specifically to follow up on that signal, as well as other tumor types that may be of particular interest. So we're not ignoring them but we're trying to take advantage of an open Phase I study in order to get more information, including some of the correlative studies.
And I think to add to that, Toni's [ph] group is also collecting samples from the patients to make sure that not only do we encourage the inclusion of ovarian cancer patients, but also to type all of those patients genetically. So it's quite a bit of information to come from that particular clinical study.
So just a quick follow-up. So how many more patients are you expecting to enroll in the Phase I study, and how many ovarian cancer patients are you expecting to enroll?
This is what [indiscernible] doctors do when there's breast cancer.
Tom, so we haven't set a fixed number and that we have some latitude in the Phase I study that we will be able to enroll additional patients based on the signals that are coming out of the study. So I can't remember if that answered everything, or if I forgot some questions while this is getting passed down.
[indiscernible], when would we see more with that data about the patient study?
Right. So the Phase I -- that's a good entree because I realized I neglected to mention something important. So we don't have any abstracts that we expect to be published this year but we certainly do next -- we expect that we'll have data but will be made public next year in the standard setting. And this gives me a good opportunity. And I thank you, because -- Dr. Guinness isn't here, but he deserves this. For 907, there will be data presented at ASH. He has an abstract that will be presented there. So that's when the CUDC-907 molecule. And I noticed that Dr. Lawrence [ph] had something to say. I'm going to walk this to her, because I'm not going to point.
I'm just going to make a comment about the ovarian cancer. And I'm not privy to any of the insight of the particular mutation. But it is interesting from a breast cancer standpoint because the overlap between ovarian and breast, all women with ovarian cancer are tested for the BRCA1 gene because we see more BRCA1 biology amongst ovarian cancer than amongst breast cancer. And so again, with triple negative breast cancer, BRCA1 biology is really important. So I don't -- as I said, I don't know what was so intriguing in the findings of the ovarian cancer patient, but there could actually be some really good insights to breast cancer, they are triple negative breast cancer.
Any additional questions? Great. We will proceed with the next section. And just as a way of transition, really, as described for the fun part of the session, we have focused the majority of our time and the extra time to discuss the proprietary program, CUDC-427 and 907. As you've heard very elegantly from our experts, investigators and our internal team. But we'd would want to make sure that you recognize that the business model and the whole assets within Curis is not only the proprietary programs which we focus on and are fully owned by us, but also, in a number of partner programs that are very strategically important to us, namely, the Erivedge, Hedgehog antagonist that's commercialized and marketed by Roche and Genentech, as well as a clinical investigational agents Debio 0932, partnered with Debiopharm that is in Phase I/II clinical testing in non-small cell lung cancer at this point.
So I'd like to turn it over to Dan to present our partnered programs as well. Thank you, Dan.
Daniel R. Passeri
All right, thanks. Okay, first, I want to thank everyone for your attention. It's been a long morning and a productive morning. The 2 concepts I want to start off with, before I get into the partnered programs, is emphasize the concept of evolution, continue evolution in that context, and those 2 go hand-in-hand. First, I think the fact that we're putting the partnered programs at the back of the presentation is evidence that we've evolved as a company. But these partnerships have helped us evolve also in terms of corporate competencies. I think as evidenced by the team we've been able to pull together today and the quality of the underlying research and the thoughtfulness of how to proceed, and that's the context. And I think on a philosophical level, I've been involved in the oncology sector for almost my entire career in some form, hence, the color of my beard of lack of. But we're really in the midst of a transforming revolution in oncology. This is an exciting time in this space. We're starting to be able to make sense out of molecular aberrations and tailor therapeutic approaches to address those aberrations. And that's what you're hearing a lot of today from the experts is, being able to subtype patients, stratify and select patients for all particular aberrations that your drug will likely work against in a much, much more robust manner, combinations of drugs, and this is really the first time over the past several years in the oncology sector that we're able to actually have this type of help going forward. So what I want to underscore there is that we've been taking our time, particularly after in licensing IAPS to really make sure that we have proper context and an understanding of how to position these assets to maximize the probability of success both with 427 and 907. And I think that's really important to underscore randomized trials as opposed to single arm. And then, before going into a randomized, making sure you're selecting the right patient population with the right context. So I'm going to switch now to our partnered programs. Again, both of these programs have been core to allowing Curis to evolve, not only in terms of subsidizing the company partially on a financial basis, but particularly with Genentech and Roche, but also with Debiopharm. The partnership has afforded us an opportunity to engage in ongoing dialogue with our counterparts. And particularly with Genentech, that turned out to be really critical in our corporate evolution.
With Genentech, Roche, we have a partnership for the Hedgehog pathway. Erivedge is now an approved drug. It's first-in-class and only-in-class Hedgehog Pathway Inhibitor, and I'll be touching upon that briefly here. First is it has an involvement in tumor biology in a number of different mechanisms. The one I'm going to be focusing on is mutation-driven. This is a ligand-independent where there's a mutation. That is the nexus of basal-cell carcinoma. This actually is a form of precision medicine. It just turns out that, fortunately, you don't have to actually use a diagnostic because greater than 90%, 95% of all BCCs have a mutation in this pathway. So the drug is designed to block at the level of smooth and which gets activated when patch is mutated. So basically, it emulates what occurs when the ligand binds to patch. Instead of requiring the ligand, patch is mutated typically through UV radiation. Sometimes, in Gorlin Syndrome, patients are born heterozygous where 1 copy is already mutated, so a high propensity for BCCs. So you don't need the ligand to disassociate from patches -- permanently dissociated from patch. So the compound binds to smoothen and therefore, shuts the signaling cascade off. So I'm going to be focusing on this type 1 mechanism, which now, has an approved drug and we're seeing good market expansion. But also, I want to touch upon this type 3B reversed paracrine signaling. There is a trial that is now sponsored by Genentech and Roche that is on clinicaltrials.gov and it is meant to explore the prospects of looking at Erivedge in its application for AML and MDS. So we look forward to giving you updates on that one if it becomes available. I think our take-home message is Genentech and Roche is continuing to look on how they can expand applications of Hedgehog integration.
Regarding its application to BCC, we have an approval in 2012 for advanced basal cell carcinoma. The market potential is indicated for advanced BCC, is approximately 40,000 patients looking at the U.S. and top 5 EU territories. And I just want to underscore that for this restrictive reading here, which is metastatic, substantial deformity and inoperable. We also are still optimistic that we have the prospects of expanding that market into poor surgical candidates, albeit still classified as operable. The label is very attractive. It provides for treatment of patients with metastatic BCC, recurrent disease after surgery, and we believe that could also encompass the 4,000 to 5,000 patients prevalence in Gorlin Syndrome and not amenable to surgery or radiation and again, that appears to be under the doctor's discretion. So we believe that in the existing label, we may get market expansion into poor surgical candidates.
And that could be predicated on the data emerging from this Phase II trial, which has been completed in an operable study. We're expecting the second and third cohorts from that trial to read out at a conference in Q1 of 2014. Just to give our recent contacts, Genentech was aiming for a Q4 conference, they do not get the abstract submitted in time, so rather than go to a suboptimal forum, they've opted for waiting until the American Association of Dermatology in March. So we are pleased with the fact that they're going to be rolling that out in that quality of a conference.
Just to give you some context in terms of the data around the launch. It was approved in 2012 but I will remind everyone that this was predicated on Phase II data, so there was not a tremendous amount of data. Dermatologists are on average, much more conservative than oncologists, so this has been an education process. I think the data that's been emerging in 2013 is certainly encouraging. Roche recorded 30 million in the first half of 2013, representing a 22% sales growth, Q2 over Q1. Starting to trigger royalties coming in and we expect this growth to continue over the next several years. Through Roche arm, they have expanded global marketing. We have now, have approval in a number of significant territories. Genentech has approximately 100 dedicated sales reps just to Erivedge for educating the dermatology market. I think as a conservative group, the key is to overcome any initial resistance. It appears that once they write a prescription for the drug, just by looking at the responses that the patients are experiencing, you're seeing a second, third, fourth prescription from that physician. So we think we should see a nice trajectory and growth based on what we're seeing today. And again, the operable Phase II study, we're expecting Q1 of 2014.
Now, I'm going to switch to Hsp90. Debio 0932. What I want to underscore here, this is a second-generation oral Hsp90 inhibitor. And again, this has to do with the oncology space in context. Hsp90 has held on so have a lot of promise. Clearly, it's associated with providing tumor cells with a buffering mechanism from stress. It chaperones and protects mutated proteins that may be involved in tumor genecity itself. Tumor cells are chronically stressed, hypoxic, et cetera. So Hsp90's clearly play a role in helping to buffer instability. However, we have not seen to date, any really overwhelming clinical data. And I think that's important for context.
So this is a second-generation, non-geldanamycin small molecule. It inhibits HSPs that basically are needed to stabilize proteins required for cancer maintenance. It has a broad range of oncologic client proteins. Preclinical studies have clearly demonstrated the advantage of this target. Our drug crosses the blood brain barrier that has extended tumor retention versus plasma clearance, which is very attractive. And we saw antitumor activity preclinically as a single agent or in combination. Most importantly here, it's a differentiating feature, we saw no ocular toxicity so far in a significant number of patients in Phase I. This is exclusively licensed to Debiopharm. Now, they certainly have taken more time than we would have opted for in the early part of this relationship. But I think what's come out of that, again, this has to do with context, is a much more robust understanding of how to potentially exploit the drug in proper context.
In the Phase I, they treated 45 patients. They saw our partial responses as a single agent observed in 2 patients and this is what one would have predicted. We saw a response in a K-RAS mutant, lung -- non-small cell lung cancer patient. So K-RAS was involved in tumor genecity in this context. Take the chaperoning away of Hsp90 and you got a PR effect as a monotherapy. So that has, I think, Jaye used the term data-driven, which is what we're trying to do with all of our trials that has guided Debiopharm in how to potentially exploit this asset going forward. They also saw our PR in breast cancer. Then out of 8 non-small cell lung cancer patients, we had 1 PR and 4 stable disease. The drug is relatively well tolerated. Again, no ocular tox, it is presently in a, what we call a HALO study. It's a Phase I/II clinical trial, Phase I portion is ongoing and again, having to do with context, they're looking at a broad survey with several combinations of the drug with standard of care for non-small cell lung frontline, using the drug which is cisplatin and premetrexed, or cisplatin/gemcitabine and then treatment experienced using Debio 0932 along with docetaxel.
So out of this Phase I survey, trying to then find proper context and the right combination for going forward. Also it includes advanced non-small cell lung patients, which squamous or non-squamous histology without known EGFR mutation, we'll also will also be looking at retrospective K-RAS mutation analysis for a potential patient stratification going forward.
All right, So that wraps up our 2 programs. I think what I want to summarize in terms of where Curis is right now. First of all, it has the term evolution, has been a continual evolution as a company. We are clearly now well-established for conducting high-quality professionalized clinical development of oncology assets. Right now, we're focusing on 427 and 907. That's come to building a new team and the experience that we've had through these partnerships. And then this allows us to focus on development of our proprietary programs. And we have 2 partnered programs that's basically stabilized the business model, give us greater capacity. We should have in increasing revenue sources on an ongoing basis over the next several years both with Erivedge and Debio 0932.
Also, this pipeline that continues to grow gives us the prospect of multiple milestones over the coming 6, 12, 18 months. Starting with 427, you heard a lot of the anticipated clinical trials strategies and again, this is all very well thought out with context of molecular aberrations that we may want to be focusing on. As monotherapy, we have a Phase I presently pending at the start what Tony told you. Emphasis on ovarian cancer, that was initiated July of this year and this is a subpredicated on the observations of the Phase I, seeing a monotherapy response in ovarian patients. We'll be launching a Phase Ib/II breast cancer in combination with [indiscernible] by the end of this year. Again, I want to emphasize bringing Jaye on in building the team. We're looking at conducting our trials in a randomized fashion so that the data is far more meaningful for investors. And then a Phase II monotherapy in indolent and aggressive lymphoma, obviously, MALT will be one of the subsets we'll be following and that will be late end of this year, early next year. And then with 907, we have an ongoing Phase I pending. We've been encouraged by what we're seeing to date. This is a novel compound with 2 activities, so we want to make sure we do it right. So we just recently amended the protocol. So we have flexibility and dosing regimens so that we can maximize the prospects of achieving the optimum benefits with this combination approach.
And then as I stated with Erivedge, we have continued growth in the U.S. market, recent launch in Europe, Australia, other approved territories should start contributing to the revenue trajectory and then the read out of the operable Phase II data in Q1, we believe, can add to the market potential of this drug and in a significant way. And in Debio 0932, the Hsp90 inhibitor, again, there's been some disappointment in this space. But we're very pleased with the way Debio has been going about this, very methodically, and making sure that the following data and trying to find proper context on the way to exploit this asset to maximize the probability that we're going to see a demonstrable clinical benefit to patients.
So on that, I will end and open up to, in general, questions. Thank you very much.
Edward A. Tenthoff - Piper Jaffray Companies, Research Division
Great, and thank you so much for -- and all of you for taking the time today. Because this is really helpful to put in perspective and also to meet some new people and see some interesting faces and understand the expense of the team. So I guess I have a question on the high level. We've seen Curis in the past partner and use, as you said, to evolve the company for, we're now sitting at a point where we got 2 pretty exciting promising compounds. What's the partnering strategy now? Since the intention to take these further yourselves, what is the kind of game plan here around 907 and the IAP inhibitor? And are there intentions to do earlier stage deals or is it just a more keep the rights to maybe deal with overseas alliances?
Daniel R. Passeri
Yes, it's an important question, Ted. So just to clarify. So we have had ongoing inquiries on both assets from both midsized and large companies. We have no intention to just outline since either asset the way we did with Erivedge. I want to underscore, at the time we outlicensed Erivedge, we are in no position to conduct clinical trials. So had we not partnered with Genentech, we would not have Erivedge as an approved drug today. So our intention on the partnering side is to look at it creatively. We're open-minded but we will only partner if, one, we gain access to competences and capacities we ourselves can't and we'll demonstrably benefit the drug's development, or access to capital resources, et cetera. Our territory. So we're not concluding the partnership plays no role going forward, but it will be a different function or a different structure than we've engaged in, in the past. Other questions? Adnan?
Adnan S. Butt - RBC Capital Markets, LLC, Research Division
So Curis has recently added new blood to the team. I think Jaye is there. The advisers are there. What do you expect to get from the -- how much input will the advisers have in trying to have in terms of developing plans, clinical trials, and when do we see that input team coming more to right yet?
Daniel R. Passeri
It's an important question so I'll give you a generic answer to that, and I'm going to hand it to Ali since he's the individual overseeing that and possibly Jaye. So strategically, we have put in place a team of advisers to give us their knowledge and input into our own strategies looking at the data. We want basically an objective review of the data that we're looking at and their insight and perspective on whether we're seeing things the proper way or we should make adjustments. So on an ongoing basis, we are seeking the input of some of these external advisers that we have to complement and supplement our own capabilities. And I think we're going to continue using that in that manner, probably expanding it. Do you want to add anything to that?
Yes. And thank you, Adnan, for the question. Both from the context of expanding the internal team and then with Jaye and Tania joining that, and the [indiscernible] of the teams that you see there, I have to say that part of the reason that we -- I think my mic has a problem. I mean, we spent quite an amount of time since me joining, actually, earlier this year, in the organization, wooing and recruiting Jaye to come and join us for very specific reasons. A, she's an extremely critical and rigorous clinical developer. Secondly, she's very scientifically-oriented and the key part of this is, translationally, how do we take our drugs forward. And lastly, the importance she puts on meaningful answers out of clinical studies, namely, charts that have a comparator arm so that we can ascertain that the results that we see are geared towards our drugs. I think Jaye is obviously -- the team that she has now assembled and recruited, fully capable of doing that. As you can see, the advisers that we've also brought on for the company, including Laurie [ph] and Coppell [ph] and Klaus Wagner [ph] and Frank McCormick [ph], not only bring expertise only in their specific areas, but we should really look at them as advisers for the company from a corporate strategic perspective as well. Certainly, they'll have inputs in supporting the team in terms of the design of the studies, so that's really not the main place or the only place where we look at interacting with them. But how do we position our drugs? And maybe to the extent that the questions were asked, at what point do we think a partner will be more helpful for us versus continuing to take our drug forward. Look at the landscape of both development and regulatory and competitive, which we do internally but get supplemented with the expertise that Laurie [ph], Coppell [ph] and others bring on, to position our drugs. So I think it's really the advisers are much more corporate and strategic advisers. And in terms of the development plans coming forward. In terms of timelines. I think one of the great disciplines and strength that I actually mentioned, with regards to Jaye, very critical. And she's also an extremely good drug developer who wants to ensure that any study that we enroll -- that we initiate and any single patient that we enroll into the trial, there's meaningful answers coming out of that. And I think this is part of the reason we spent a little bit more time around the design of and the initiation of our breast cancer study, to base them on the complexity that we saw. I want to assure everyone that this is getting a maximum attention, any of the clinical trials are getting maximum attention at Curis to ensure the results that we get on the back end of them are extremely meaningful for us. I hope that answered, at least added color to that for you.
Dan, it seems to me the company is implementing heavily on the --using a biomarker strategy. But it appears that CUDC-427, the biomarkers are not quite obvious. So what might be the realistic timeline to use the strategy for your regulatory path going forward?
Daniel R. Passeri
I couldn't hear it [indiscernible] Ali for that one.
Dr. Berdeja [indiscernible] he couldn't pass the microphone. No, it's a very good question. And I shouldn't say we're so rapid to conclude that we're not -- although the markers or selection strategies may not be obvious, they definitely exist, simply because we see the differences in the context of why some tumors and why some patients respond to the drug, either at monotherapy or in the case of a preclinical setting in combination with another. We're just saying it's going to take us a little bit more time to identify the exact selection strategy. We didn't directly try to tie the types of things we look at, preclinically, either at Curis or with the studies that Dr. Tolcher mentioned as far as with the PDX models. But they tie in very nicely to the descriptions that Dr. Julie Lawrence [ph] was presenting to you. So how do we go about sub-categorizing breast cancer patients, for example. These are the very same things that we look at preclinically. As I mentioned, for example, in the preclinical models that we tested in breast cancer with the combination of CUDC-427 and capecitabine, they don't fall along the original classifications of patients as the Her2 positive, ER positive or triple negative. But there are classifications that we're looking the other day are likely to fall into and may fall into the [indiscernible] identifier. The same thing goes for the ovarian cancer patients that Dr. Tolcher identified as well. It means for us to, if there's not a clear genetic alteration to choose for patient selection, that means they are there for us to genetically characterize the patients to find out. I do want to draw one distinction though, in the context of the MALT lymphomas, which we described a little bit earlier, as Dr. Tolcher mentioned, a high proportion of, for example, most lymphoma products that have a very common translocation that involves the target of our drug. The IAP gene, the CIAP gene or, in the case our patients that we treated, as Dr. Tolcher mentioned, has an amplification. That's a direct marker, if you will, not an indirect marker, that we can look at. And those are the things that we're trying to fit in place in the context of our potential studies, starting in the lymphoma center.
Dan, I got a question regarding your Debiopharm collaboration. They're pretty much in full control, do you have any input in how the trials are going? And what's going to happen? You mentioned you're a little bit disappointed about the progress and I'm wondering perhaps that might reflect the [indiscernible] with their agency but I don't know whether that department is sort of trying to learn from some of the experience.
Daniel R. Passeri
Yes. I think the disappointment was in the early phase of our relationship, sort of the classic conservative statistics-based approach that we're using. I think it was fortuitive, but that gave them an opportunity to readjust and learn from the landscape. More recent discussions with them have actually been very promising in terms of their focus on molecular characterization, looking at the data very carefully in the way they are approaching trial design. So I think your comment about the central trials, so they're all watching the landscape very carefully and trying to learn in terms of context, on how they may be able to alter their own thinking.
Are they -- I'm not that familiar with the number, they're pretty well capitalized?
Daniel R. Passeri
Yes, they were very well-capitalized because they specialize in clinical development through late preclinical through Phase III.
Dan, can you talk or give us a little bit more detail [indiscernible] you may be expecting at ASH for 907 in terms of the preliminary data?
Daniel R. Passeri
Yes, our emphasis will be preliminary. That it's -- this is going to be the first few patients that we've been treating with the drug in the Phase I. We expect to give an update on the safety profile that we're seeing. We've made an amendment to the protocols that we have right now, 3 dosing schedules. So an overview of those 3 dosing schedules, any data that may be available at that time that we can tease out from what we're seeing between those 3 dosing schedules and obviously, any signs of efficacy will be discussed as well.
I think we've mentioned in the past, everything that Dan indicated with regards to the ASH presentation, there will be the data that's available from the 3 different dosing regimens and schedules and any patient benefit associated with the treatments. We have described 2 of the patients early on that came on to this study and have continued at the moment since the early enrollment of them, continued to benefit with disease stabilization, one being a multiple myeloma patient and one being a lymphoma patient that continued to receive the drug. Additional patients that may have clinical benefit as well in the nature of their disease, the nature of the benefit will be described at the ASH presentation as well.
Just going back to the biomarker analysis that you're conducting, and I think you mentioned that you have to direct the biomarker, the IAP. Why not just focus on that, right? So why did it suddenly become prohibited -- did the patient population become prohibitively small, or has there been a broad analysis done across multitudes of cancers just looking at over-expression of IAPs, whether that's a viable project or not?
Yes, good question. I'll give my own perspective and then ask colleagues. They're going to comment on it as well. In terms of genetic alterations of the IAP, there are mutations, amplifications and translocations, probably the most prevalent, as we've described in the setting of the multi-lymphoma, has a fairly high percentage of those patients having a common translocation that involve the target of these genes. Outside of that, there is also genetic alterations, they don't reach to the level of prevalence in a specific population of cancer patients to address it. Therefore, looking at 4 additional markers or the genetic signatures. Other mutations that may cooperate or other biomarkers that we can look at, all of those are being looked at, at this point. In terms of why not just follow that one, I think, the context of the common genetic alterations in the lymphoma setting is one that we will look at and plan to look at. But outside of that, we would like to mechanistically, again, look for markers that synergize with our specific drug and potentially the other drugs in combination and go after that.
Just a follow-up on 907, you're on your second or third cohort? I think you may have mentioned it [indiscernible].
Actually, we did not mention. The trial is ongoing with multiple schedules and I should say cohort -- several cohorts have been treated. We did not associate.
No problem, we got you.
Daniel R. Passeri
Okay, great. So we'll conclude. First, I want to thank everyone for your attention. This has been a very productive morning. I want to thank the panel. Very, very good presentations and we very much appreciate your participation. I primarily want to thank the patients that are involved in the studies and our investors, who give us the ability to investigate these very important and promising drugs. Thank you very much for your attention.
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