Study Update

Dec 3, 2018

Slides

So, welcome everyone to our ASH 2018 data review. I'm Troy Wilson, Kura Oncology's President and CEO, and really a pleasure to have so many of you here tonight to walk through the data with us. In today's presentation, we're going to be making some forward looking statements and want to just refer you to both the information on the SEC's website as well as our website for more information about the company and about the risks of an investment in the company. Go through this very, very quickly. I know a number of you are quite familiar with the company, but we may have some new folks here less familiar with Kura. Our focus is the discovery and development of targeted therapies for the treatment of cancer. Along with a number of our precision medicine peers, we are working hard to try to identify biomarkers that will allow us to enrich for clinical activity and to identify those patients most likely to benefit from treatment with our drug candidates. Our most advanced drug candidate is a compound called tipifarnib, which is really going to be the focus of tonight's discussion. As many of you may be familiar, we've been pursuing tipifarnib in HRAS mutant solid tumors and just last month initiated the 1st registration directed trial in HRAS mutant head and neck cancer. We have an ongoing Phase II trial as well in other HRAS mutant squamous cell carcinomas. So we're quite excited about that. In parallel, we've been working on really a second major thrust for the development of tipifarnib related to a pathway called the CXCL12 pathway, which is the focus of what Antonio is going to talk to you about tonight. And the goal of tonight's discussion is really to walk you through the data that was presented this evening in the poster session at ASH and to put that data in the context of how we think about the development of tipifarnib. So without further ado, let me just introduce just a few members of the leadership team here with me. Antonio Gilberto is our Head of Development and Chief Medical Officer. He's going to take you through the slides and most of the presentation. Mark Grasso, our Chief Financial Officer and Chief Business Officer and John Farnam, our Chief Operating Officer are here this evening as is Pete De Spain, our Vice President of Investor Relations and Corporate Communications. I'll just leave you this is the last slide I have before I turn it over to Antonio, but I just want to help you sort of frame the slides that are to come. So recall that we out licensed this drug from Janssen in 2014 really around a hypothesis that we could drive antitumor activity in HRAS mutant solid tumors. That's played out, I think, as well or better than we had expected. We've been very fortunate to have 2 additional clinical proof of concepts, 1 in chronic myelomonocytic leukemia that we disclosed last year at ASH and now a second one in the angioimmunoblastic T cell lymphoma subtype of PTCL. And we've moved the compound now just in a few short years to a first registration directed trial in HRAS mutant head and neck. And then the question is, what's next? How do you think about the development of tipifarnib in both hematologic tumors and solid tumors? And how do we as much as possible leverage the strategy that we've used, I think, quite successfully to date in HRAS mutant head and neck so that we can drive toward smaller trials with a higher likelihood of clinical success and everything lines up nicely as I think we should hold ourselves to that standard with targeted therapeutics. So that's really going to be the focus of tonight's discussion, this initial data in AITL and the significance of CXCL12 as a biomarker. We're going to hold questions until the end of the presentation. This presentation is being webcast. And so I'm going to let Antonio walk you through these slides and then we'll pause at the end and take as many questions as there are interest. So with that, let me introduce Antonio Calberto, our Head of Development and Chief Medical Officer. Thank you, Tore. So thank you for the opportunity to discuss Tipifarnib with you. So we are I'm going to start with the data that was presented at ASH today. And then all the potential opportunities that the association of CXCL12 expression with tipifarnay activity open for us. I'm going to start for a very important question and is that as many of you know by the mid-90s like every single major company will have a financial transfers inhibition program. By 2005, 2,006 all those problems have disappeared. And the Aesop one of the potential reasons for that failure is that the actual mechanism of such was not completely known. And with that I means that obviously, farnesyltransferase inhibitors inhibit the farnesyltransferase. That's what known. But for a clinician like me, what is important is how inhibition of farnesylation translate to clinical activity. And that question was never answered. Now since we licensed Tipifarnib, we were able to determine that the SRAS mutation in Ketanik provided evidence or selection of patients. So provide evidence that the SRAS mutation drive a portion of esquemocetanec and by inhibiting financialization of SRAS we can see clinical activity. But the issue is that in many tumors that in which there is anecdotal evidence of activity from prior studies to most like breast cancer, acute myeloid leukemia, TB cell lymphoma, pancreatic cancer. You can go back some of these old programs. They are fairly large programs. In the case of Tipifarnel Johnson and collaborator conducted more than 70 trials. So you can see multiple cases of activity, but you cannot explain it. You cannot explain it because SRAS mutation is really uncommon. SRAS mutation is not present in those tumors. So the big question is what are the determinant of activity in those tumors in which you can go back and you can look at the cases and you can see that there was a LAMP patient that received Tipifarnib for 13 years, where Hodgkin lymphoma patient that received Tipifarnib for 6.5 years, what was the determinant of activity? That's actually not an easy question as many people have tried before and there have been multiple hypotheses and unfortunately none of them translated to proof of concept in the clinic. So in order to address that question, you need a disease model. You need technologies that now they are viable. You have RNA Seq. You had metronomegene sequencing. And obviously, you need the capacity to be able to interpret those results. So we went back and selected peripheral T cell lymphoma as our case study. And the reason why we did that is there's a number of reasons. One of them peripheral T cell lymphoma, they are novel disease, they are amenable to biopsies, so you're going to have tissue. But also there was a historical record of activity of Tipifarnib. Some of you were able to meet Tom Wixey today. He's a professor at Mayo Clinic. And he conducted a trial that was published in 2011 in which he treated relapsedrefractory lymphoma patients with Tipifarnib. And there were like 3 stratifications in or 3 cohorts in that trial. There were patients that were in dominant lymphomas, B lymphomas, aggressive B lymphomas. And there was a third group of T cells and Hodgkin lymphoma patients. And he saw actually a 31% response rate in that subset. And then the drug was tolerated. There were some hematological events that they were manageable. So we decided to reproduce that study. And if you have a 30% response rate, it means that at least 1 out of 3 patients, if the original data was right, 1 out of 3 patients at least they will respond. So once you have positive or negative and having the technologies that we have these days, then you can conduct an screening. So what is in the responders that is not in the responders and vice versa, okay? So it's a good model. We had the means. We should be able to identify why patients that do why tumors that do not carry ERAS mutations response to a farnesim transference inhibitor. It's also very appropriate to conduct trials in peripheral T cell lymphoma because there's a high unmet medical need. And a number of views have asked today what is the treatment of T cell lymphoma. So these patients normally are treated with a combination of chemo therapy agents and you try to drive them to an autologous stem cell transplant because transplantation give an opportunity to long term benefit, but many patients do not get there. And consider whether they are treated either with chemotherapy or second cell like agents such as belinostat, romidexin or pralatrexate. What are the response rates there? It's around 25%, 27%. Patients progress within 1.6% to 4 months half of the patients have died within a year. So it's a dramatic diagnosis and a high unmet medical need. So our study KOTIP-two was designed to again reproduce the activity that Doctor. Wissink saw initially and investigate the mechanism of action of Tipifarnib. The primary objective was response rate based on the standard criteria and it was designed as a monotherapy with tipifarnib given at 900 BIV on days 1 to 7 and 15 to 21 of the 20 day cycle. So this is the regimen that we're using initially in solid tumors in head and neck. We call it the alternative weeks regimen. We later had to dose reduce to 600 milligrams because this patient population, it was kind of more sensitive to or presented more adverse events with Tipifania, the 900 milligram dose. So the regimen was modified to 600. We were very cautious. We conducted in 2 stages, an assignment design enrolling 11 patients waiting to see responses. We see responses. We are at a second stage. This is a refractory population. We didn't know how many prior lines at the end. The initial study was a 5th line study. So basically, they have progress from the chemo, they have progressed from the 2nd line chemo, they have progressed from other agents and then they came into the study. And as I mentioned before, there was a major translational component, sequence every tumor, investigate gene expression in every tumor. The results of that study were presented last year at ASH. And we identified 3 responses out of 18 patients that give you around 17%. There were additional 4 patients with a stable disease. Those are actually very good stable diseases, if I can say that way, over you need 50% to call it a response. 3 of them, they were 38% to 45%, so very close to actual responses. The stable disease, 3 of them were durable beyond 6 months. So that gives you around 39% clinical benefit with a progression free survival of 2.4 months with 4 prior treatments. So what it's telling you is that tipifamily have activity. However, when you compare with the standard of care, well, it's kind of like similar to the standard of care that I showed you a minute ago of belinostat or prolytics. So it's active, but not much more active than what is currently available, okay? However, one of the as I said, one of the objectives for the study is to can we screen and identify what subset of patients respond and what are the markers associated with that response. And we conducted a number of screenings and we discovered that those patients with tumors that have high expression of a chemokine called CXCL12 experienced clinical benefit in terms of PRs with stable diseases. So those were actually we couldn't get tumors from 1 patient. So 2 of the PRs and the stable diseases all of them those tumors have high levels of CXCR12. We also did a number of analysis and then we realized that a couple of those tumors that have a histology called AITL, angiemunoblastic T Cell Lymphoma. Those express high levels of CXCL12 that actually is not surprising. The CXCL12 is secreted by the stroma, by the vascular endothelial cell. The angioimmunoblastic is called angiopic because it's highly vascularized. So it has vessels, it has vascular endothelial cells. No surprising you have higher CXCL12. We did also sequencing of the we did a net generation sequencing and we discovered that there's a variation in the 3 prime nuclei in the regulatory portion of the CXCL12 gene that one of those variants was associated with higher levels of expression of CXCL12. So that gave us 2 tools to prospectively verify the hypothesis. So we enroll the patients, we see responses, we look retrospectively and we see the association with CXCL12. Now you want to confirm your hypothesis prospectively. Now ideally, you already have a clear validated test that will allow you to select the patient, but those things don't happen overnight. So the fastest way to enrich for high CXCL12 expression is to select with patients with AITL histology. And it's something that do not require any work at our site. The hospitals, the clinical sites already do the diagnosis of AIPL. So the initial step was continue the trial and roll a cohort of AIPL patients as a method to enrich for tumors with higher CXCL12 expression. The gene sequencing also provided this variant. Now the variant is present in the gene, so it's a piece of DNA. So that is amenable to sequence and using PCSAs. So these are normally very robust, they say. You can do a buccal swab, is present in the stroma, so it's germinal to the patient. And you can give a yes or no answer. This variant is present or is not present. And we know that it's not perfect. It's not synonymous of high levels of expression, but it's another method to enrich. So we set up a second cohort that will enroll for what we call CXCL12 positive. In reality, it's those that have the AA sequence in that polymorphism of the gene. In addition, we actually modified the regimen to 300 milligrams BID in both of these cohorts, because the expectation that the drug will be more tolerated with the 300 milligrams 3 weeks on 1 week on. Also now that you start understanding the mechanism, this is different from the SRA. Here is the production of CXCL12, not by the tumor, but by the stroma. So you want to maintain certain levels for as long as you can. So you want to maintain that CXCL12 low for as long as you can, okay? We also conducted a number of ancillary study to understand better the mechanism. So we know there was an association with high CaCl2 and activity. And you can say, well, maybe high CXCL12 is just good prognosis. Anything that you give to the patient, the patient is going to do better. So we wanted to investigate the expression of CXCL12 in a tumor bank of patients treated with a standard of care and see how high CXCL12 related to the prognosis of the patients, a good prognosis or bad prognosis. And then we want to understand better the molecular mechanism. So what happens when stroma cells are treated with tipifarnib? Do the does the expression of CXCL12 change? So a number of experiments were conducted actually in the CD1 mouse model that is a model of culture or actually bone marrow stroma. So the status is that obviously we were able to initiate the AITL cohort very soon because the diagnosis was ready at the sites. So that cohort have completely enrolled. Is the cohort that we have presented today. We also presented some of the translational work as well as the preclinical studies. The CXCL12 positive cohort, the one that is using the SNP have already enrolled some of the patients, but need to continue enrolling and we will be presenting additional data at the medical meeting next year. Okay? So what is the current patient disposition? And we are reflecting here the whole trial. So the whole trial now have 39 patients, 19 of them they are AITL, 20 half and half twenty they are non AITL. These are fairly advanced patients. So we are now overall on a 4th line setting, number of regimens from 1 to 7. And again, this is a salvage setting. So you most of the patients eventually progress. So progressive disease is the main reason for discontinuation in the trial. Now an important slide is that, is the drug active? And the answer is yes. So we remember we saw a 17% initially in the overall study in this new cohort of AITL patients per protocol. So per protocol mean that the patient enrolled received the drug and got an scan. So we have 10 of those patients, 2 complete responses, very rare in a 4th line setting to see a complete response, 2 partial responses to stable diseases. By intent to treat, you have to consider another 6 patients. 2 of them they are pending to read and then we lost 4 patients most of them for reasons not related to the treatment, the reasons related to the disease under study. These are fairly advanced patients. That gives you a 40% response rate in the cohort. If you consider every single AITL patients, the ones that we enroll in the new cohort plus 3 additional patients that were enrolled previously, that gives you 13 per protocol gives you 46% response rate and 62% clinical benefit. Good results for patients that have failed 3 prior therapies. And certainly when you consider that 2 of those responses are complete responses. The toxicity is not dissimilar to what we have seen with Tipifarnib in the past. We have been reported mostly hematological events. These have well managed by hematologists. You can see that the AATL cohort look a little bit better. This by the way, this is all grades. If you consider severe toxicity will be more or less half of those numbers. And the AATL cohort look a little bit better than the PTCL NOS, the initial part of the study. And perhaps that is a reflection of moving from the remember the initial 900 milligram dose to 300 milligrams BIV 3 weeks on 1 week off. So that will be one of the reasons to continue with what we call the 3 week regimen. This is the waterfall plot. You can see in dark blue the 2 complete responses. I got the questions of why those couple of patients have a significant tumor site reduction, but they are progressive disease. And it's because when you choose the target lesions, the ones you're going to measure, you can see a reduction. Those are mostly not lesions, but maybe the patients may have a new lesion in the liver. If you have a new lesion by definition of the response criteria, you have to call it a progressive disease independently that you have seen reduction in tumor size. Now one of the main objectives was to identify the mechanism of action and to verify that our initial hypothesis of Tipifarnib as an inhibitor of the CXCL12 pathway. So last year, we reported Stage 1 and Stage 2. And we mentioned that these 2 experiments are done independently. You enroll an initial cohort. You verify expression of CXCL12. You can see that those tumors that express the highest levels, you see a PR to stable diseases, you get a second group of patients, You do the experiment again. Those with a higher level, you have EPIA and a stable disease. Now you try to enrich by using the CXCL12 SNP or by enrolling patients based on AITL histology, you can see already that you are enriching in response rate. So those patients with a higher level of CCL12 will have complete responses with so you see 2 CRs and 2 of the PRs. There's even one patient that although the best response is progressive disease already saw a 16% reduction in tumor size. When you put the 24 patients of which we have samples available, there's a clear cutoff around 0.25. That is the ratio in order to normalize, but sometimes you get more RNA in one tumor versus the other one. We normally do the relationship between the ligand to the receptor. So the 0.25 for the cutoff of CXCL12, CXCL4 ratio over that 50% of the patients are responding, 90% clinical benefits. So 9 out of 10 they're going to have a partial response or they're going to have disease stabilization in a 4th line setting. So that level of activity is very rarely seen in relard refractory lymphoma. In the closest, it will be the brentussimabbedotin when you select for the CD30 positivity. Recall that the current standard of care have a response rate around 25, so half of that. We obviously need to do more. We need to follow these patients, give you a duration of response, a progression free survival. But it's already looking very good. It's already suggesting that if you select for the marker, you potentially can displace the standard of care in that setting. If you do some diagnostic work, determine that the CXCL12 diagnostic potentially may have 90% sensitivity, 93% specificity that is acceptable as a companion diagnostic parameters. So this is the waterfall plot of the patients that have high CXCL12. I put a list of anecdotes about these patients. So we start with patient number 1 that AITL. So that is a 46 years old, white male. He had 2 prior chemo regimen, go to transplant, progress and now has lesions in the neck in the right cat cilia, iliac and periportal area. So really flow it progression enter the trial within 2 cycles complete response. So complete disappearance of all the lesions. That is important because if you can drive a relapsed refractory patient to a complete response that is an opportunity to move the patient to a transplant. That is the highest probability for a patient to have long term benefit in terms to GS, drive it to a complete response and move them to a transplant. This patient left the study actually was transplanted and we hope that that translate to long term clinical benefit. With our second complete response is another AICL number 2, 67 years old, 3 prior regimens, also prior transplant, multiple lymph lesions complete response and cycle 4 the trial the patient is still ongoing in the trial and obviously transplant is transplantation is potentially one of the options. With also major responses in non AIPL patients that have high CXCL prevalence. So that's the example of case number 3. Elderly gentlemen 75 GSO, 2 prior regiments, excuse me, complete disappearance of extranodal lesions. There's still some lymph node present and not measurable. So we can call it only a partial response, but the lesions that were measurable in the patient have completely disappeared. So I'm not going to go through all of them. Maybe of interest is that one of the patients was progressing from romidexin. Another of the patients have a very strong stable disease with bertuzumab then progress then receive tipifarnib translate to a response. So major complete responses and major responses in highly refractory patients and at least one of those responses has translated to a transplantation. I mentioned before, so you can see the activities have been reported in AITL with prolapsedexate 8% response rate with Ramidase, 30% response rate. But in those times, it's a little bit higher, 46%, although in a small subset of the pivotal and again the closest 54% with the brentuximabidotin in the CD30 positive subset. Mentioned the question of, well, is the patient that have high CXCL12 going to do well with everything? The answer is no. They actually they do worse. So we in a collaboration with an investigator, we test the CXCL12 levels. We use here the same cutoff the CXCL12 to CXCL4. We used to with titifarnib. And in orange is the survival from diagnosis of the patient that have high CXCL12. And you can see that the 40 months median survival from diagnosis have now decreased to 22 months. So that's a hazard ratio of 1.8. If you keep increasing the cuts or higher ClC12, the patients are doing worse and worse. Some patients that are in the upper 30 aisle may have a survival of around 4 months. One of the patients I forgot to mention, the patient that had the highest CXCL12 levels in the study. In direct counts of CXCL12 around 15,000 counts that patient had been for 2 years on the study. It was one of the initial patients, one of the patients that drove us to think that there was something on CXCL12. Again, 2 years with Tipifarnib with 15,000 counts, patients treated with the standard of care with 15,000 counts have a median survival of 1 month. So very clearly, CXCL12 drive poor prognosis with a standard of care treatment. The other important question is what is the size of the subset? So again, using the same cut that we use for Tipifarnib 0.25, give you about half of AITL. AITL is about 30% of PTCL and about 1 third of the non AITL cases. So that in total gives you 40% of the population. Okay? So 40% of the population will have poor prognosis based on high CXCL12 levels. And those high CXCL12 levels are predictive of clinical benefit from Tipifarnib in terms of responses of prolonged disease stabilization. Now how Tipifarnib work? So from data that is available in the literature, work that have been done previously with this chemokine, we know that it is essential for the homing and growth of tumor T cells in lymphoid organisms. And this is data that come from actually a knockout model. So in red, you can see the results from animals in which CXCL12 production was knockout in the vascular endothelial cells. So the tumor completely disappeared from the lymph node, from the spleen and from the bone marrow. So the chemokine is required for the T cell tumor to grow in lymphoid organs. What Tipifarnibas? Tipifarnib down regulates the expression of CXCL12. So this is the CD1 model that I mentioned before. We don't know yet which one is the farnesylated protein that is necessary for this effect. It could be several of them. But what is important is CXCL12 is necessary for the growth and the homing of the T cell in the lymphoid organ. Tipifarnib down regulates the expression of CXCL12. What this is telling you is that Tipifarnib is a CXCL12 inhibitor. That is the mechanism of action in PTCL. We are doing other things like measuring CXCL12 in patients and this is data that potentially we will present next year. So in conclusion from the ASH presentation, CXCL12 is an stroma. There are chemokine. It is relevant for the growth of lymphoma. Lymphoma actually expressed CXCL12 had 2 resettles, CXCL12 and CXCL7. Lymphoma expressed high levels of one of them, CXCL12. We know that high expression CXCL12 is about expressing about 40% of PTCL, and that is a negative prognostic factor for the standard of care. When we treat these patients with tipifarnib in the case of AITL, we observed a 46 response rate, 62% clinical benefit that translate to positivity of the cohort and proof of concept of Tipifarnib in the indication. And high CXCL12 pressure by itself can identify this responding population in the AITL and the non AITL population. The regimen was well tolerated. The hematological events have been previously described. They are manageable. Again, the mechanism of Tipifarnib is the down regulation of the expression of CXCL12. That will explain how the inhibition of T cell homing and growth of these tumor T cells in Foype organs. It also help us understand some of the toxicity, bone marrow stress CXCL12 that is important for the growth of myeloid cells. So that will explain the neutropenia and the thrombocytopenia on the bad side. On the good side, it also explain all the responses that have been seen in myeloid tumors. So AML growth in the bone marrow that growth and that localization is CXCL12 dependent. Tipifani also down regulates CXCL12 in the bone marrow that will explain the responses in AML. So based on these results, we can characterize Tipifarnib as a CXCL12 inhibitor. And to my knowledge, this is the 1st CXCL12 pathway inhibitor that had reported proof of concept in an oncology indication. Just to remind you that we have patent protections for these findings. We have a patent of tipifarnib acting in CXCL12 expressing cancers. And we already obtained the patent protection for use of 3P farnib in annual immunoblastic T cell lymphoma. So where do we go from here? What are the next steps? We certainly want to understand these populations. And once you start realizing the potential of CXCL12 inhibitors, then you have to prioritize what do you do first. In the case of PTCL, it's very clear. I mean, we still have another cohort to enroll. We need to have additional follow-up of the current AATL patients. Before you ask me what is the progression free survival, so we are following up. And we're also working with collaborators to determine what other lymphomas will be relevant for treatment with potential targets of treatment with Tipifarnib because they are known to express high level of CXCL12. So again, CXCL12 is actually produced by the stroma, by the lymph node. There's going to be growth there of lymphomas. Some of them there will be T cell lymphomas. Some of them will be B cell lymphomas. Which are the right B cell lymphomas to investigate? This is one of the our current objective. The ultimate goal is to expand the development of Tipifarnib as a CXCL12 inhibitor as broadly as possible in lymphoma. So in order to understand what could be those patient populations, you're going to stop for a minute and understand the relevance of CXCL12 inhibition as a cancer targeted therapy. As I mentioned, CXCL12 is produced by the stroma, but also by some immune cells, vascular endothelial cells, so that's the connection with angiogenic tumors. The 2 recesses CXCR4 and CXCR7, most of the hematological indications CXCR4 is important, but the indication like breast cancer in which the second recess of CXCR7 will be important. And again, the main producer is the stroma. The tumor cell had the 2 receptors CXCL4, CXCL7. So the CXCL12 and this receptor mediated interaction between the stroma and the tumor cells. What are the potential role of CXCL12 inhibition? Well, the most clear one is in addition of growth and homing of lymphoid and myeloid tumors to the bone marrow and to the lymph nodes. That's the direct case that we had just discussed. So the important application and is in many cases when the primary tumor is treated by surgery there's a recurrence. So think for example a primary breast cancer is treated where is the recurrence most of the cases not to the breast, the recurrence is to the bone marrow or to the bone. That mechanism is known to be CXCL12 dependent. And the other case the final case is in relationship to immunomodulation. It attracts CXCL12, attract T cells, attract myeloid cells, but in some cases those cells have a negative effect on immune response. It's attraction of regulatory T cells, attraction of negative effect from neutrophils. So there's a number of samples of combination of CXCL12 inhibitors and PD-one or PD L1 inhibitors, mostly data that is currently available will be in tumor modules. So 3 different mechanism by which effective CXCL12 inhibitor could be important in the treatment of cancer. Now being specific, we have already a number of cases that now will make sense with this hypothesis and the actual evidence of activity of Tipifarnib. If we have activity in PTCL, we will have activity in CTCL. Most agents are active in PTCL peripheral T cell lymphoma will be active in cutaneous T cell lymphoma such as the case of mycosis fungoides. In our case, we don't need to have doubts about it because 2 weeks in the OLE study actually enroll a few patients with mycosis fungoides. Out of the 4, he saw 2 partial responses. So there is definitely some level of activity in cutaneous T cell lymphoma. We had the expectation that those responders potentially will be high CXCL12 stressors. This I'm just showing you one of the cases. This is a patient that had been treated with multiple skin directed therapies. It has been treated with Enterferon. Enterferon fell. It is treated with Rituxim, CHOP 7 cycles eventually fell have major lesions. Those lesions continue on remission 1 year after treatment with Tibifarnib. Mointer in diffuse larvae cell lymphoma. At least a third of diffuse larvae cell lymphoma express high levels of CXCL12. That is what allowed the B cell lymphoma cells to be located in the lymph node. High CXCL12 expression in this B cell aggressive B cell lymphoma is already known to be a negative prognosis factor for the outcome of the disease. And Doctor. Wixit, when he ranked his relapsedrefractory lymphoma studies, already saw about 20% of the population responded to Tipifarnib, another opportunity to investigate the connection between CXCL12 expression and tipifarnif activity in this case on an aggressive B cell lymphoma. So those were the non Hodgkin P's and B's, the associativity in Hodgkin lymphoma. 19 patients enrolled, 2 complete responses, 2 partial responses for a total of 20% response rate. Again, this is overall. Our objective now is to be able to select. Bringing a case of patient treated with ABVD, so that will be the standard of care, another chemo rating, radiation, eyes, transplant, failed the transplant, received emtuzumabbedotin progress from Axitrix, receive tipifarnib and is in remission 6.5 years. That is what I call activity in a setting. It will be important to investigate was the connection between expression of CXCL12 activity and resistance to the standard of care. So that will be lymphomas, non Hodgkin TB and Hodgkin. But as I said, there's also potential for selection of patients in myeloid tumors. This is actually data that we presented last year. We retrospectively look at the Janssen Phase 2 study, CTLA-twenty, we can reproduce the phenomenon of homing. Those patients that have high CXCL12, they have few circulating blast, they have high proportional mirror blast. So what is happening? If the tumor AML express CXCL4, when the bone marrow express CXCL12, where is the tumor? The tumor is in the bone marrow. Those patients that have high CXCL12 those patients stay a median of 654 days on a study. What is really unlikely in a setting of elderly unfit AML with monotherapy. So we have the connection between the homing, the high levels of CXCL12. And you can tell me now, but you really don't have a control here. Well, I don't have a control, but Janssen and collaborators actually conducted a Phase 3 where they compare Tipifarnib monotherapy to best supported care. We don't have genetic data, but we have homing data. We can go back to the old report and determine. We know high CXCL12 is associated with blast in the marrow, few blast circulating. Let's look for the patients that have high proportion of blast in the marrow versus field circulating. You select those patients, you see a doubling of the survival with TP family versus best supportive care from 100 days to 200 days has a ratio of 0.6. So potential for activity in frontline elderly AML by selecting the patient population with expression of CXCL12. So that will be an example of myeloid tumor. And but CXCL12 is already known to play a major role in solid tumors. So these are a number of meta analysis that have been conducted. High CXCL12 expression consistently is associated with reduced survival in pancreatic, esophageal and Lantumus. Now in the case of pancreatic, we're a little bit fortunate because Janssen actually conducted a pancreatic study, a pancreatic study that was negative. So if this hypothesis is true, we should be able to identify a subset of pancreatic cancer that will receive clinical benefit from Tifafenib. But we don't have genetic we don't have samples that we can test for CXCL12. But we know that expression of CXCL12 is associated with a particular phenomenon. It's those lesions that express high CXCL12 suppress pain. So pain in pancreatic is a hallmark of pancreatic patients. The patient tell you is a hallmark of pancreatic cancer. The patient tell you it hurts here and point with a finger. It has been reported that when CXCL12 is high, those lesions have lower abdominal pain. Since this is collected in every pancreatic study, we can go back to the report of the Janssen Phase 3, look at the subset that have no reported pain and determine was there clinical benefit from Tipifarnib. So I'm not going to show it today because it just got accepted as an abstract for ASCO GI. It will be presented in January and at that time we'll be happy to give you an update. But it's potential further evidence of activity of tipifarnib in this case in a solid tumor driven by CXCL12 expression. So my closing remarks. So we have presented the data at ACH. The potential application of tipifarnib now as a CXCL12 inhibitor in lymphoma, in myeloid tumors, potentially in solid tumors. We believe that the data that we have presented attach further support our hypothesis that Tipifarnib is a CXCL12 inhibitor. That give us a path to extend the application of Tipifarnib beyond T cell tumor to other lymphomas to myeloid indications to solid tumors. We plan to continue these efforts to identify these patient subset and to bring Tipifarnib to those patients in need. And with that, I will acknowledge the initial work that was conducted by Tom Wicksick, his collaborators at Mayo Clinic, the O2 investigators, the study teams, our patients and their families. And that's all. Thank you. Thank you very much, Antonio. At this point, we're going to take any questions. Does anybody in the room have any questions? Yes, Jonathan, let's start with you, Jonathan. And if everyone would please state your name and affiliation before you ask your question. Thank you. Jonathan Chang from Leerink. Thanks for taking my questions and congrats on the data. First question, I know you guys already touched on this, but can you help us contextualize how we should be interpreting the data presented at ASH? What kind of benchmarks should we be using for these late line PTCL patients, I guess, specifically for AITL and CXCL12? So the numbers that we show 25%, that is second line. The activity, the complete responses that we are showing you is 4th line. So you will expect in the 4th line the activity to be much lower than 20%. So I don't want to call it transformative because that is almost a regulatory term, but it's significant. And I think any investigator will tell you that it's significant to see responses, complete responses, patients going to transplant. There have been so in my career have seen a phenomenon like that only one time that was in Axitix in Hodgkin lymphoma when you could move a patient in a refractory setting to a complete response and a transplant. And second question, how are you guys thinking about next steps, I guess, both in PTCL and beyond? You mentioned all the other potential indications where CXCL12 could play a role. What would you guys need to see from the ongoing PTCL study and maybe even from the MDS and CMML studies? Well, from my part, you obviously you want a duration of response while progression free survival is more or less the same term. If you recall, if we look at the data from the last year, a very small data set 40% response rate 6 months medium production free survival. That will be on the production phase 3 fold the standard of care in a more advanced setting. So if you are able to have the progression free survival that is higher than the standard of care that shouldn't be that difficult because you are in between 1.6 and 3.5. That is an indication that you can potentially displace other therapies in that subset. So next step is determine the time to endpoint, your progression free survival. Is your progression free survival better than the standard of care for that patient population. Yes. Jonathan, just to add to Antonio's comments, from our perspective, we have more data and data of the same quality as the data that we had in HRAS mutant head and neck cancer when we went to the agency and had an end of Phase 2 meeting to set up the AIM HN registration directed study. We're there with AITL. To Antonio's point, we want to continue to enroll. We want to get more information on duration of response PFS for AITL. We need to continue to enroll the what we're calling the CXCL12 high PTCL. And we need to do work with collaborators to understand the CXCL12 expression in other tumor types. And then I think at that point, already you can begin to see paths as to how you would move the compound forward. Question is how big do you want that trial to be, right? What's the result in patient population? Do you want to go in a smaller population where you have a very outsized clinical activity? Or do you want to go a bit broader? I don't think we have an answer to that yet. We're very encouraged by the data that we have and we're going to be intensely mining the lymphoma data. To your point, we are expecting an additional update on this study as well as some of our other studies next year. So we'll provide an update there as well. And then Antonio left you with a teaser for the pancreatic study. We're already and have actually been for some time trying to understand how you can take this what we think is very clear proof of concept that Tipifarnib is a CXCL12 inhibitor and now go back to the solid tumor context. And this is in the realm of very high class problems where you have multiple opportunities. It's becoming increasingly clear to us though that tipifarnib is a franchise in a molecule. There's a franchise in HRAS mutant solid tumors. There's going to be a franchise we think in CXCL12 driven heme malignancies. There may be a franchise. It's early days, but there may be a franchise in CXCL12 mediated solid tumors. And we'll work through that in due course and give an update next year. Other questions? Yes, go ahead. Tyler Van Buren from Piper Jaffray. Thanks for taking the questions and a very interesting presentation. It's relatively early, but in the data we've seen so far, maybe some of the patients that started on therapy in the beginning. Is there anything you could say or any anecdotes about duration of response in progression free survival and how it's tracking relative to the initial data that you saw? You mentioned the 6.3 median progression free survival? Yes. 1 of the initial AITL, actually that patient had the highest CXCL12 levels, 15,000 counts in the retrospective center of care that is a median survival of 1 month. That patient have been already 2 years on titifarnib and is ongoing. So it's an anecdote, it's not a proof, But very high levels that translate to dismal prognosis with the standard of care have been seen with the patients that have been already 2 years on the study. So that strongly suggests that this is a main mechanism for the activity of Tipifarnib in this class. Okay. And I know the CXCL12 positive SNP patient population is that trial is still ongoing. But is there any reason scientifically, I guess, believe that it should we see better or worse data in that subset of patients relative to AIT? So, Saket, the only question is a scientific question and is that what is the role of that SME in the 3 prime UTR? And this is an important scientific question, but on a development standpoint, we have many choices. I mean, we can do ISC or CXCL12. That's probably in the long term what is going to work the best. The way that this disease who treat peripheral T cell lymphoma, Those that can diagnose peripheral T cell lymphoma, who diagnose peripheral T cell lymphoma, who can have a T cell lymphoma pathologist on staff. So those are the Dana Farber, the Mayo Clinic. So how they do it? These are very difficult tumors to diagnose. They just use a panel of antibodies. So what you want in the future is that one of those I imagine that CD30 now is in the panel. What you want in the future is that CXCL12 is introduced in the panel. The moment they are CXCL12 positive, they are potential candidates for treatment with Tifanin. Again, we are not there yet, but that potentially can be it's not that complicated, San IFC has said. For now, we can continue with the tool that we have that is the SNIP because it's very robust. We're working on NanoString probes. Obviously, ISC is an important consideration for the use of for the identification of the population once the agent is approved. And then on the just the safety profile and the ability to potentially move into earlier lines of therapy over time? What are your thoughts on that and the ability to combine it with other treatments in earlier lines? So the pancreatic study for example is a combination with gencitabine. So one of the advantage of having a licensed compound that has 70 trials is that you have combination data with a multitude of agents. You will have to be careful with certain things. If you have some renal tox, you obviously need to see what happened with the cisplatin or carboplatin. But FOXA combined Tipifani with a large array of compounds. Some of the doses may have to be decreased in the case of gencitabine around 200 milligrams or is tolerated. But sunset is may not need very high dose. For example, think about and this is just an example. If you go to an adjuvant breast cancer setting and you want to have a patient 2 years to block a recurrence, you don't want to you don't have to reduce a tumor. The tumor is not there. You're just blocking the possibility of a recurrence. A lower dose like 200 milligrams that have very little toxicity may be sufficient. So different setting is going to have different needs. As an upfront therapy, if it's very effective in the subset, you may take other agents out. That's something that had been with Axitri for example. So what Andres said different settings may require different ways to use Tipifarnib, but we can take advantage of the large prior experience of the Janssen program. Chris Shibutani from Cowen. Question on dose, question about patient selection and then thirdly on strategy. On the dose, I noticed that there was one patient who had, I guess, a weekly regimen as opposed to 3 weeks in a row. Talk a little bit about that. And then also just the progression of the history. You have context for a lot of the work that Janssen had done. You started at the 900, stepped back to 600, 300. What are the guiding factors that you're using to thread that needle of dose that you're going to choose to move forward with as well as the schedule? In retrospect, when you understand the mechanism, then you have you comprehend better what is the most appropriate regimen. So when we didn't know much before we identified CXCL12, we used the same regimen that we have in the solid tumor. You wanted to so what happened in the Eskuemos SRAS mutant? You want to give a high dose and drive the tumor to a collapse. The tumor is very dependent on fezfras. You get as much inhibition as you can, 900 milligrams daily for a week and then you give a break to the patient. But what we have seen, I mean, we have a patient that were on response within 1 week on a 1 week treatment on a partial response. But this is not the case. Here is not the tumor carrying a mutation. Here is the stroma in polycystic fibrosis. So now that we understand the mechanism, it makes sense to have a regimen that for as long as you can maintain low levels of the chemokine. So that's the reason why we are using the 300 milligrams. To complement that, we are looking to plasma levels of CXCL12 in the patients. That data is not ready yet, but we will present it at one of the next year updates. Then on patient selection, there is that one outlier where you're using the ratio of CXCL12 to CXCR4 as opposed to the absolute value of the CX CL12. Can you talk about that versus the ratio and All you got now. So it could be that was a laboratory error. It could be maybe that patient carry an SFRAS mutation. Not that we will know. But there could be other reasons. Maybe say mutation in the pharmaceuticals or no. They are always outliers. There could be other mechanism response. But certainly they are not the main mechanism of response. And then in terms of like how you're thinking about the strategy you're developing, the additional indications that you're expanding to be far enough into, can you talk to whether or not the implications that may have in terms of the intellectual property opportunity to extend the franchise if you think further out commercially? Yes. So obviously you have to take into account many considerations. So something that we always take into account is not just the unmet medical need, but also the commercial value and how fast we can move the agent to the registration. If you want to target larger populations, you try to go to April line in combination. But having done this for a number of years, you realize that that goes through a Phase 1, Phase 2, Phase 3 larger trials. By using these markers in the case of ESFRAS, we have been able to move quickly to in this case in the case of a registrational trial with 59 patients. So we can prioritize indication based on the unmet medical need, the commercial value, find what is the faster way to get a registration and from there to expand the light. So that could be one phenomenon. In other cases, companies prefer to once they have got the initial registration to take a larger risk, then you may consider maybe you want to take a higher risk and run a Phase 3 in an easier line. So what I'd rather say, there are different possibilities once you balance what is the risk associated versus the commercial value. Anything that we do is sufficiently protected. So we are constantly filing patents. We are constantly doing the research to identify what are the responding populations. Everything that we have described today have been put in place. Trevor, do you want to put your J. D. Hat on and add on to the commentary? Yes. I mean, I think Antonio said it correctly in that particularly in that closing comments. Our scientific strategy and activities, our clinical development and our intellectual property are all walking together in lockstep. So we're trying to be very thoughtful, trying to look through in my initial slides I showed you that sort of inverted Nike swoosh of the development. We're thinking in terms of label expansion, lifecycle management. The advantage that we have is there were a number of companies that worked on farnesyltransferase inhibitors without success. And so when we're able to identify biomarkers, office has looked favorably on our applications and we have now 4 issued patents in the U. S. For tipifarnib, a number of other applications pending both domestically and worldwide. So we're bullish, we're thoughtful, we're a little bit coy about our strategy as we have to be. But we've tried as much as possible to lay out decade long plans for HRAS and CXCL12 that will drive the development as Antonio mentioned into much larger indications. These are attractive. They're very doable. You can do them quickly with relatively low capital and low risk, but we'd like to be able to do more. We're the as far as I know the only company driving on HRAS. We're I think the only company in oncology working on a CXCL12 inhibitor. We've I think got great data. That's a great place to be. We just have to stay very, very focused on our strategy. And that leads to my last question for me. The beauty of the precision medicine strategy that you're taking is looking precisely for the right patient, for the right drug, etcetera, broadly speaking. But then when we think about how the pace of clinical development will happen when you're particularly going to get into that pivotal trial level, what rate limiting factors will contribute to kind of getting across the finish line in that final aspect, finding these patients that you pinpoint and identify can be challenging. And so particularly with this indication and this data set that you're showing, can you help us with what rate limiting factors there might be when you get to that point of expanding the clinical trial efforts? Thank you. Yes. So it's a good question. So this is arguably this is a different challenge from HRAS. HRAS is a numbers game. 5% of head and neck, you're doing next generation sequencing in a disease indication where genetic screening is not standard of care. So that has been the challenge that we've had to address and ultimately will overcome. As Antonio mentioned here, physicians are already primed to think about subsets. We have although a number of the HDACs are in unselected populations, we have ADCETRIS ahead of us in a CD30 positive population. And that set a very nice example for how to think about a franchise extension across indications. And we have to do the heavy lifting. I think to your point, we have to identify is it a different cutoff in each disease or is it how much how quickly can you go and how many things can you parallel process. The big here is, as Antonio I think very elegantly laid out, the road map is clear. We know exactly what to do with sufficient resources. I think there's a lot of value to be created here for patients. Any other questions? Yes. Robert, in the back, there's a question. Wonderful work. And my name is Ming Tong from the NIH I now joined the pharmaceutical industry and also the investment group from the China funding. One quick question is that the system looked to me very promising and I love new modality. I trained as MD in Boston. So we have a lot of activity going on. My number 1 first question is that when I look into the big picture, you are more on the upstream on the surface on the CXC motif access system, in your case you pick the pancreatic cancer, how do you compare to people say a little bit more down there the using the STACK 3, the JAK 2, STACK 3 Also involved in the same network system and how do you compare thinking about internal the clinical and molecular actions that kind of things? I think it's a combination of the 2. So in the case of pancreatic cancer, you will have to understand what is the pathology and what are the drivers. And in the idea for example of locally advanced disease is not that different from the homing. So you can define the population. But there's going to be some downstream mutations for a support. Not to give you too much today or we're going to be presenting in January, but there is a balance between what the path is and what elements here may or may not circumvent the driver. So if you have an understanding of the subset of the population, what medically who those patients are. You know that the driver is CXCL12 and what you should avoid downstream that you have a high probability of success in a trial. I agree almost all the company when they have a wonderful pipeline, they shift Zoom NAND, make it enlarge on that part of the system or the access within a big system biology picture and say if I have $30,000,000 to spend to develop one agent, So do you think that your wonderful program would come up to be monotherapy for the pancreatic cancer? Or are you thinking about a combination using the 6CL12 antagonist plus something else or just by itself? Yes, that's actually it's an easy question to answer. So pancreatic cancer have already been described that the expression of the receptor CXCR4 is actually gencitabine inducible. So that will explain why you see activity of the gensitabine tipifanib combination. So gensitabine in DUCXCL4 that made the tumor CXCL12 dependent. Tipifenib down regulates CXCL12. So in that particular case, I think the combination is clear. Medically, there's a number of things that you have to take into account. There's a good chance that it could be even a first line setting independently of FOLFIRINOX and independent of Abraxane for a number of reasons that we are not ready to discuss today. But there's a possibility of displacement of other therapies based on the patient characteristics. Great. So with that, I mean, we've been going here for a while. I'm going to thank all of you for coming tonight. Just to remind you, as Antonio indicated, we'll have data at ASCO GI, sort of the next installment of this story in pancreatic cancer. We are expecting updates on our squamous cell carcinoma Phase 2 next year as well as updates on our hematologic malignancy trials with Tipifarnib also next year, as well as hopefully data on our ERK inhibitor, the Phase I data on ERK inhibitor next year. So a lot of exciting things going on. We'll be around for a little while to help answer any additional questions. And I want to thank all of you here in the room for your time and your attention and your questions. Thanks all very much. Good night.