Study Update

Jun 14, 2019

Good day, ladies and gentlemen, and welcome to the Kura Oncology Data Review Conference Call. At this time, all participants are in a listen only mode. Later, we will conduct a question and answer session and instructions will be given at that time. As a reminder, this conference may be recorded. I would now like to turn the conference over to Doctor. Troy Wilson, President and CEO of Kura Oncology. You may begin. Thank you, operator, and welcome everyone to our data review. I'm Troy Wilson, Kura Oncology's President and CEO, and I'm here with Antonio Gilberto, our Head of Development and Chief Medical Officer as well as Mark Grasso, our Chief Financial and Chief Business Officer. We're going to be referring to certain slides that are available on our website at kouaroncology.com in the corporate presentation section. And in addition, the actual oral presentation that Doctor. Foss will be presenting tomorrow as well as the poster presentation are available in the Scientific Publication section of our website, should you choose to refer to them. If we can go to the next slide, Slide number 2, we're going to be making certain forward looking statements today, and I would refer you to our website and to the SEC's website for more information about Kura Oncology, our programs and the risks and uncertainties associated with the investment in the company. So on Slide number 3, the agenda for today's call. We're going to start with just some introductory comments and a little bit of background information on our efforts relating to the CXCL12 program and our clinical trial in T cell lymphoma. At that point, Antonio is going to walk you through the slides, a subset of the slides that will be presented tomorrow and highlight the data from our positive Phase 2 trial of tipifarnib in PTCL. I will spend a couple of minutes talking about what those results mean and the opportunities to expand to additional CXCL12 driven indications. And then we'll close with a brief recap on upcoming milestones you might expect and a question and answer session. So turning to Slide number 4, key themes. Kura Oncology is a precision medicine company and our as all of you know, our focus is on advancing a pipeline of targeted therapies. These targeted therapies are an essential category for new drug development in oncology. And the reason are that they provide enhanced clinical benefit in selected patient populations. And with that enhanced clinical benefit, we have the potential either to displace existing therapies or become part of the standard of care in populations of high unmet need. The rationale, we have an effort underway at Kura to understand what we call exceptional responders. These are patients who even in a context of high clinical benefit, these are patients that seem to do extraordinarily well. The way that we do that is we leverage technologies, particularly comprehensive tumor profiling that allows us to identify biomarkers for clinical activity and also to understand mechanisms of both sensitivity and resistance to our drug candidates. And as Antonio is going to talk to you, that's been an important part of what we've been able to do in this CXCL12 pathways in T cell lymphoma. If we're successful, ultimately a precision medicine based approach should allow us to undertake accelerated development and registrational strategies. We should be able to expand the potential label from the initial population to other biomarker guided populations and of course extend treatment to other earlier lines of therapy either by displacement of the standard of care or combination with other agents. Turning to Slide number 5, we just wanted to recap for you a timeline related to the identification and validation of CXCL12 and it's from top to bottom, it's most recent to the original reference. So at the bottom, we have the Witsik reference in blood in 2011. That was an unselected patient population in BNT cell lymphomas and was really the inspiration for our effort to try to understand the biomarkers associated with clinical activity. As we move toward the top, we've presented a number of either oral presentations or posters where we continue to make the case for the tipifarnib being a CXCL12 pathway inhibitor relating either to AML, to pancreatic cancer, to diffuse large B cell lymphoma. And this effort is culminating now in this, the presentations here at EHA, where for the first time we now have prospective validation of tipifarnib and the CXCL12 hypothesis in both the AITL cohort and the CXCL12 3 prime untranslated region SNP cohort. As you'll see, we've been successful in identifying and validating robust markers of sensitivity, including certain genetic markers. And we've also identified patient subsets that we can characterize as having exceptional activity that may be particularly amenable to accelerated strategies. The final slide before I turn it over to Antonio, it's Slide number 6. And again, this is just to help provide context. In the upper left corner of Slide 6 is the original WITC study. It was an investigator sponsored study of tipifarnib in relapsed refractory lymphomas. It was the observation that tipifarnib was able to drive objective responses in both B and T cell lymphomas that led us to the work that we're describing today. As many of you know, we undertook initially a Phase 2 study of tipifarnib in an unselected population through sequencing and molecular characterization. We identified the CXCL12 biomarker and then we sought to validate the CXCL12 hypothesis prospectively in 2 different cohorts, an expansion cohort that was enrolling patients with angioimmunoblastic T cell lymphoma or AITL and a cohort that is enrolling patients that are wild type or reference SNP in the CXCL12 gene that can include both AITL and non AITL patients such as PTCL NOS, we call that expansion cohort 2. So as Antonio is walking you through the data, we're going to draw, you're going to see both the data for the expansion cohorts as well as the overall trial. With that, we'll turn to Slide number 7, which is the cover page for the EHAU presentation and I'll turn it over to Antonio to walk you through the slides. Yes. Thank you, Troy, and thank you all for your interest on Kura and the Tipifarnib program. So as Troy mentioned, we are going to summarize some of the slides that will be presented tomorrow regarding the update of our Phase 2 of Tipifan in the large refractory peripheral T cell lymphoma. The full presentation by the way is available at our website. The presentation will be given by Doctor. Francine Fost. Doctor. Fost is a Professor of Medicine at the Yale Cancer Center and a well established key opinion leader in peripheral T cell lymphoma. Presentation will take place at 16:45 at hall S5 for those that have the opportunity to attend in person. So let's move to slide number 8. This is an introduction of the tipifarnia CXCL as an inhibitor of the CXCL12, CXCL4 pathway. Many of you are familiar with these data, those that have been following the data from the company. But just we just want to remind you of a couple of points. If you look at the images in the right side of the slide, on the top, you may recall that we provided previous data indicating that the CXCL12 is a negative prognostic factor for pancreatic cell lymphoma. So you can see in the couple of measures how the orange curve, so those are the patients that express high levels of CXCL12. Those patients have the reduced survival respect to the rest of the population. And in the lower image is a sacrotum showing how CXCL12 down regulate the secretion sorry, how tipiparnib down regulate the secretion of CXCL12. We in addition to the oral presentation, tomorrow we will have also a poster in the AML section showing how some alterations in the 3 prime NUTI, some variants regulate the expression of schizophrenia. We have shown some data previously. We have now additional data in diffuse large pixel lymphoma that reproduced the previous findings in peripheral pixel lymphoma. And this is relevant because now we can use that tool, the sequencing or the PCR or the 3 prime nuclear of the gene to distinguish between which patients are going to have high levels of CXCL12 or low levels of CXCL12. So moving to slide number 9. So there's going to be 3 major findings that will be presented tomorrow. So one of them is a proof of concept in the reference or if you prefer wild type CXCL12 3 UTR cohort. The second one is an update on the AITL cohort. We presented at HASH that this cohort this AITL cohort have also reached proof of concept. So we will show additional patients, additional responses, including complete responses plus time on a study. And finally, the 3rd major item is that we have put the characterize the mechanisms of sensitivity and resistance to titiparne in peripheral T cell lymphoma. And in particular, we have identified certain mutations that characterize patient population with extraordinary activity of tipifarnib. So let's go to the first one, proof of concept of tipifarnib in the wild type CXCL12 3UTI cohort. You can see that we are reporting 42% response rate. This cohort includes not only NOS patients, but also AITL patients with 33% and 67% response rates respectively, very high levels of clinical benefit from 67% to 100%. So fairly high activity, a second proof of concept and further corroborating that by using these tools, we can enrich for the activity of Tipifarnib in peripheral T cell lymphoma. If you go to slide number 10, this is just to reiterate the point. The initial patients that carry the variance in the 3 prime UTR shown in the slide in the red box. Basically, we did not see responses. There's no clinical benefit versus those that have the NOS histology. You can see 20% response rate. This is of interest in a 4th line setting. These are very sick patients and also close to 90% clinical benefit. So they have good disease stabilization, many of them very close to a partial response. As an example, we are bringing you on Slide 11. They say that an image is worth 1,000 words. So if you can see the PET scan on the left side of the slide, you can see that this is a very, very advanced patient, the disease all over the body, all over lymph nodes. And by the end of cycle 2, most of the disease have disappeared. There's a little bit of disease in the right knee and is then considered a partial response, but a very remarkable response for a patient that is with fairly advanced and high tumor burden. Now moving to the ITIL cohort in Slide 12, we have enrolled additional patients. We can see now 3 complete responses, 2 partial responses. When we consider all the ATL patients that were enrolled in the study, so in the initial stage onetwo in the AITL cohort and those AITLs that were enrolled as part of the CXCL12CUTR cohort, we were able to see 5 complete responses, 4 partial responses for a total response rate of 53%. We have been now being able to follow-up the patient for an additional 6 months. On Slide 13, you can see that for those that experience clinical benefits in terms of a stable disease, PR, OCR, we have 5 to 6 months at median time of the study. Some of the patients with complete responses, so these are patients that may have one line of therapy, 2nd line of therapy, a transplant. They have progressed from the transplant and now with 3 mgotibifarnib, they can experience a second complete response that now allow allogeneic transplant. So and that actually may translate to long term clinical benefit in this very advanced population. Slide 14, we confirmed the data that we had shown previously. Patients with the highest patient of CXCL12, those are the ones that have the highest clinical benefit from tipifarnib. That is consistent, I can see in the waterfall plot, patients with AITL have high level of pressure of CXCL12. Those are the patients that experienced many of the PRs and COMFIC responses. Now that said, you will notice in the graph that CXCL12 by itself does not explain all the responses, does not explain all the progressions. So we consider that there must be other factors that influence the sensitivity of PPFR. In order to address that question, we did additional molecular screenings to identify what could be those co factors, are there any mutations that could be quickly characterized and identified as sensitive population. To make a long story short, in slide 15, we indicate that those AITL patients that carry mutations in one of the key receptor key CDL2 are extremely sensitive to TCL5. So you may recall that we had shown that the CXCL12 expression, CXCL12, CXCL4, those drive sensitivity of tipifarnib. We had shown previously that CXCL2 particularly in myeloid indication may drive resistance to Tepiphany. Here we see that CXCL5 that is a ligand of CXCL2 actually may drive resistant to tipifarnib in peripheral T cell lymphoma. AITL is an indication that express both liver CXCL12 and CXCL5. But interestingly, in the patients that carry this KIR mutation, KIR receptors of the innate immunity, the DLs actually have anti inflammatory properties. So these patients carrying the mutation in Q3, DL2 express very low levels of the resistant factor, very low levels of CXCL5. So as a consequence, having high CXCL12, low CXCL5 translate to a very sensitive population. You can see in the panels in the right, out of 16 patients with AITL that were sequenced, A carrying the mutant Q3 DL2, 4 of them experienced complete responses at the 50% CR rate, 2 additional partial responses, 75% response rate, 100% clinical benefit. What I would call extraordinary activity in a fairly advanced relapsedrefractory population. There is still some activity in the AITLKIR3 DL2 wildtype. You still can see 2 partial responses. By the way, one of them appeared to be now converting to a complete response to a 25% response rate. So there's still some activity in the rest of the AITL, but remarkable activity in the key EL-three DL2 mutant population. Support of that hypothesis, when we test for the allele frequency, so how much mutant is pressing in those patients, those that have high allele frequency of the mutation respond the quality of response is higher. The patients with complete responses have very high allele frequency of KIR3DL2 mutation. Furthermore, when we compare the outcome of the patient with tipifarnib to the prior line of therapy, patients treated with a standard of care, chemo combinations, immune therapy, they do better with Tipifanib in subsequent line of therapy than with a previous standard of care therapy. So again indications that this could be an unmet medical need that can be addressed by TP5. Slide 16, you can summarize the mechanism. If you go to the middle panels, typically down regulates CXCL12 secondretion, but does not affect the secretion of CXCL5. AITL expressed high level of CXCL12. Those AITLs with mutations have low levels of CXCL5, low level of the terraceptor CXCL1, CXCL2. So as a consequence of increased sensitivity mediated by CXCL12, low resistance mediated by CXCL5. You have this very high activity 50% CRA, 75% OA, 100% clinical benefit. So to summarize, in conclusion, we have now reached 2 proof of concepts on pre specified hypotheses of selection of patients based on high CXCL12. This reiterate that titifarnib is the first CXCL12 inhibitor that had reached proof of concept now twice in the clinic. Tipifarnib is highly active in AITL patients and those with NASS that have wild type CXCL12 UTR about 50% response rating AITL patients with PTCL NASH, again, fairly advanced patients, 20% OA, but also significant levels of clinical benefit. But using sequencing, the genotype of KIR3 DL2 and CXCL12 provide very robust tools that we can use in the clinic for the selection and the stratification of patients. I mentioned the mechanisms before, The patients that carry the AITL patients that carry the mutation appear to be about half of the AITL population. This population of AITL patients is approximately now 30% of PTCL based on the additional molecular tools that allow the characterization of these patients. Patients carrying the CXCL12 reference or wild type genotype is about 70% of the population. So this translates to different opportunity or potential opportunity for registration of tipifarnib. So you have the larger populations, 70% of the patients carrying the wild type CXCL12 genotype. You have also the AITL population by itself, 30% of the patients 40% to 50% response rate, very good response rate for a 3rd, 4th line population. And then you had that subset of patients with a key mutation having 50% CRA, 75% or extraordinary activity in the subset. So this may translate to different potential registration for dbfirmid that we are currently discussing with the key opinion leaders in the field and obviously we'll need further discussion with regulatory agencies. Just to mention that there is no changes in the safety profile. The safety profile is identical to the one that we had reported in prior occasions and that is well managed by the investigators. With that, we'll pass the call to Troy. Thanks, Antonio. And for those of you who may have dialed in late to the call, we are referring to a set of slides that are available on our website. This is a subset of the slides that will be presented in an oral presentation tomorrow at EHA. In addition, a copy of the AML poster that Antonio mentioned is also available on our website. So now referring to Slide number 18 of our EHA overview. The point that we want to make here is we started in T cell lymphoma because that was the easiest place to identify the biomarkers of activity and validate them in terms of enrichment of clinical benefit. But one of the things that has us quite encouraged is, as Antonio mentioned, we see the potential to extend to other disease indications, including diffuse large B cell lymphoma, acute myeloid leukemia, pancreatic cancer, CTCL and others. And as Antonio discussed, we continue to develop a set of tools, including genetic markers that we think will allow us to very rationally extend the development and extend what we're doing in T cell lymphoma to these other diseases. So shown on Slide 18, you can see the percentage of what we call the CXCL12 high population for each of the diseases going clockwise, the lymphoma the T cell lymphomas, diffuse large B cell lymphoma, pancreatic and AML. Collectively, that's quite a significant population. And with each result, we have greater and greater confidence that Tipifarnib is a CXCL12 pathway inhibitor and should be able to drive meaningful clinical benefit in these populations. So turning to Slide 19, the key takeaways from the data that we're presenting that will be presented tomorrow. As Antonio mentioned, we're encouraged because we've now a second time achieved a pre specified proof of concept, the first time in the AITL cohort now in the wild type CXCL12, 3 prime UTR cohort, As in the AITL and related lymphomas are as much as a third of PTCL and that's due to the development of new diagnostic technologies. We are developing genotyping tools including care mutants, CXCL12 variations and mutations that we think will allow us to select or stratify for patients in the clinic. And as Antonio mentioned, we see a level of extraordinary activity in AITL patients who carry the cure 3DL2 mutants. Collectively, we see multiple pathways to registration in both AITL and non AITL PTCL. And we look forward to talking to our clinical investigators, key opinion leaders and of course seeking regulatory feedback to determine the next steps for this program. Finally, as I mentioned, we do see a significant potential now to be able to move to other indications, including DLBCL, AML and pancreatic cancer. So with that, I'll turn to Slide number 20 and just remind you that we do have a presentation and another poster that will be presented next week at the International Congress on Malignant Lymphoma in Lugano. That will largely be a reprise of what we're talking about today. But we will go into more detail on the cure mutants and the as Antonio mentioned, the allele frequencies. The next data update that we're anticipating is in the Phase 2 trial in head and neck squamous cell carcinoma, our ongoing trial RUN HN. We intend to give a data update on that in the second half of the year. And of course, we're planning to provide data from our ongoing Phase 2 study in chronic myelomonocytic leukemia. That's a study where we're stratifying patients for high or low CXCR4. And we are hopeful that that trial will represent the first proof of concept in a myeloid indication and further extend our confidence in the CXCL12 hypothesis. So with that, that concludes our prepared remarks. And operator, at this point, we'd be happy to take any questions. Thank Our first question comes from John Barrett of SVB Leerink. Your line is now open. Hi, guys. Thanks for taking my call. The first question I have is, where could the tipifarnib be positioned within the heterogeneous PTCL patient population and the competitive landscape? Yes, let me address that one. So one of the things that we could do is to pursue different settings. For example, if we are reaching 75% response rate and converting patients to potentially eligible to transplant that is affecting that is you are getting to levels of effectiveness that are similar to the frontline. So I personally have not seen that level of activity in lymphoma since the years that our World Cup's ADCETRIS. So that could be a very similar situation that you could get an approval potentially in the second line and then you can consider how the elements of the first line could be modifying around the combination. That's just to give you an example. You could potentially also pursue a histology and say, I'm going to pursue AITL because we are seeing 40% to 50% response rate. We see certain standard of care that are in 20% to 30%. And I consider, first of all, looking at the mutation retrospectively. So that give us within the same trial different opportunities, extraordinary activity and an extension to the rest of the population that commercially could be attractive, could fit better on the standard of care. And then finally, you can pursue a much larger population, but that potentially could require bigger trial, potentially randomization or maybe a more advanced setting, like second cell line setting in which you select patients based on the wild type free UTR and then you compare to whatever is available in that second cell line setting. So those different trials have different sizes, different costs, different timing. And that's currently what we are discussing internally with key opinion leaders about what will be the best strategy for the compound and for the company. Great. That's helpful. I have two quick questions on duration of response. I noticed for the AITL cohort, the median DOR was 5.5 months, but that included those patients who went on to transplant treatment. Does the inclusion of those patients sort of reduce the total duration of response? Would it have been longer if those patients didn't go on to transplant? Of course, I know they want to go on to transplant, but just trying to understand how that's calculated? Yes. So we did the most conservative assessment, so those patients are not sensory. So those patients were considered as treatment failure. That is not the fact, obviously moving to a patient to transplant is not a failure, but it was the most conservative assessment. The Atezumab by the way it will be TTF or time on a study rather than duration or response. It's still early because you can see 4 of the patients they are still on therapy. So the median is likely to be higher. We will follow-up those patients. We'll try to provide an update by the end of the year. Got you. That makes sense. And then one more. With relation to time on treatment for the CXCL12 like overall population, is there any trends that you can talk to for the patients who have above 0.25 level of CXCL12 ratio versus those who are below? I mean, obviously, the one below those come up very quickly. For the I mean, models those patients normally go to progression or at least study because of other reasons. For the so we have seen very durable disease stabilization in the NOS population. You have to give us a little bit of time for the you may have seen some of these patients in the Stage onetwo, so those we have reported. But you need to give us a little bit of time for the report of the either progression free survival or time on a study or the CXCL2 cohort. Kind of like similar situation that when we reported the proof of concept of AITL in December, we need at least another 6 months of follow-up. So I would say probably similar situation for the CXCL12 wild type 3 UTI cohort would probably need to report that data by the end of the year. Great. Thanks for taking my questions and congrats on the data. Yes. Thanks, John. Thank you. And our next question comes from Joel Beatty of Citi. Your line is now open. Hi, congrats on the data. I guess first question is on some of these other settings like DL, BCL, AML and pancreatic that there's potential to expand into. Can you discuss your plans for and how quickly those can be studied? So I think we have now a complexity of riches. So we have reported that we can identify retrospectively the CRs in AML. There's by the way, there are certain variants in the 3 prime UTR in AML. We have now further characterized diffuse large D cell lymphoma. We have limited data, but now we will be showing in the poster tomorrow that in addition to the natural variance, those patients that have low CXCL12 have multiple mutations in the 3 prime UTR. So now you can establish the relationship mutations, low expressions, progression versus reference UTR high level of expression response. So that's limited data, but it's very encouraging. And we have already made a commitment for pancreatic, obviously of interest not only because of the data, but the potential commercial value and providing benefit for that patient population. So we will be we have already committed ourselves to conduct a proof of concept starting pancreatic. And obviously we are looking for those opportunities in AML and diffuse lab that's B cell lymphoma. Yes. I think, Joel, just to add to that, we do have some additional work to do in DLBCL to make sure that we characterize the population. It's similar to what we did in T cell lymphoma, where we took banked patient samples. We analyzed the frequency either mutation or variation, the CXCL12 expression levels and so forth. You'd like to do the same thing in DLBCL. And in all likelihood, I think as a first step, we would want to do some sort of proof of concept. But what I hope that we keep emphasizing here is, now we have a clear path. We have mutations and variations that seem to consistently predict clinical benefit. And it's easy to get lost in the complexity of these sort of different subtypes of PTCL. But the reality is, no matter how you cut the data, we're getting positive results. I think we're optimistic that if we design the experiment correctly, we can translate that to DLBCL and AML. As Antonio mentioned, we have a high degree of confidence we can predict the CRs in AML. We are at a point where there's more to do than we can do. And that's a high class problem, but it's still a problem. It's definitely a strategic problem that we're discussing internally about how do we think about prioritizing these different opportunities, how do we think about label expansion. But given that we're the only compound we know of that has clinical proof of concept in modulating the CXCL12 pathway, I think we can continue to now gather momentum to work this out. And we'll continue to provide updates on our strategy and would look probably toward the end of the year when we can say a little bit more about how all the pieces fit together. Got it. That makes sense. And maybe another question on the regulatory feedback that you plan to seek. Could you just maybe discuss at a high level the key topics that you are hoping to discuss with the regulators? I think what will be of interest is to can and this actually had not been done before in peripheral T cell lymphoma. So the Romidexin, pralatrexate, those compounds were approved with single arm trials that have about 120, 103 patients. But molecular approaches had not been done before. And our intent will be to potentially reproduce what we did in Estrace mutant, let us know. Can we conduct a trial with 50, 60 patients, kind of like similar to the kind of like CD30 ALCL of Tipifarnib sorry of axetrixino and find a quick registration. Argium for unmet medical needs, extraordinary circumstances in Europe. Can you do a minimal entity that gives you a fast approval in T cell lymphoma and then an expansion of the label either horizontally or vertically through combinations? The other option I think that is fairly attractive is can we go directly for the AITL population. I mean that now AITL used to be small, but now that the technologies keep advancing, there is less known otherwise specified and more AITL, more follicular healthy cell related. Can we just go for AITL with a 40% to a retrospective category that can help with reimbursement in difficult markets like for the U. K. For NICE negotiations etcetera. So there are different options, but all of them will follow a model of market driven unmet medical need conditional accelerated approval that is consistent with the precision medicine objective for the company. Yes, Joel, just to add to that, I mean, we started that slide with the key themes of the company and talking about the power of a precision medicine based approach. And one of the powers is, if you can demonstrate outsized clinical activity, you have the potential to displace everything else from your population because you're the most active agent. I think we're confident that's going to be the case in HRAS mutant head and neck. We'd like to position it similarly in this in the T cell lymphoma population. And once you're coming from a position of strength, because you're the most active agent, then it becomes very difficult for anyone else to displace you and it gives you the option then to continue to expand the label. We make a lot of references to ADCETRIS because I think that's a good lesson about it's a different marker and it's different biology, but it's thematically the same thing. The initial registrations were in the relapsed refractory population in ALCL and Hodgkin's CD30 positive Hodgkin's, but now they're in the frontline in Hodgkin's, the frontline in PTCL and the patient population and the revenues keep going up. And as ADCETRISX is projected to hit $1,000,000,000 a year in sales. Tipifarnib should follow a similar trajectory. There's a very substantial patient population, but we do have to be mindful of what we as a small company can do. And we can do these 50, 60 patient registrational studies all day and then lay the track such that you can come right behind it with larger studies that allow you to go to earlier lines of therapy or more expansive populations. So I think we're quite encouraged by the amount of opportunity and flexibility that we have. Great. Thank you. Thank you. And our next question comes from Chris Shibutani of Cowen. Your line is now open. Thanks very much. Congratulations on the data update. Can you just speak to what the practical experience has been through this stage of the trial in which we anticipate it could be whether it would improve in terms of finding patients, the biomarker sort of the pragmatic aspects of establishing and ascertaining what the patient status is. Your strategy has typically involved a degree of precision and just as it translates through your clinical trial experience and you think of how that could improve, helpful to get some color on that? Thank you. Yes. One would think that these rare population, you may see our Astra have 43 patients in February. We are reporting now 50 at this oral presentation and we continue to enroll more. So I think the message is that the centers that treat peripheral T cell lymphoma, they are highly specialized centers. They are a well need community. The KOLs, they all know each other. The moment that you come with an agent that is highly active in a particular setting, everybody starts sending new patients. So when we are starting to think about AITL, We have the same considerations that you mentioned, the realities that we have enrolled AITL. We enrolled the cohort so fast that the initial intention was to dedicate the 2nd cohort, the one with the wild type 3rd year just to the nose. But the AITL patients were doing so well and they were coming so many of them that we finished putting any AITL that will have this wild type 3 UTR in the second cohort. Now that those cohorts are mostly those cohorts are full, basically we need to extend a little bit the cohort to keep assessing patients and consider amending the protocol. So we continue the engagement with the site and providing benefit for that population. Yes, Chris, just to add to that, I mean, we're in a Antonio said it a couple of times, we're in a 4th line setting here. So these patients, you're expecting response rates in the single digits and time on therapy of maybe a month or less. And we're seeing pretty impressive activity, both in terms of response rate or clinical benefit and time on therapy. There really hasn't been any challenges with patient enrollment. As Antonio mentioned, sometimes the trials enroll so fast, you can't actually make changes to them, which you'd like to do. The other thing I'll add is, hopefully it's clear, we are building a tool set that is useful not only for T cell lymphoma, but for other diseases as well. And that includes histology. So the easiest assay is histology, but also mRNA expression profiling, genetic assays and potentially ultimately in the commercial setting immunohistochemistry. And we'll make sure to tie all of those together, but the genetic assays you can do with NGS testing and that's why we have this push toward genetic approaches because they're robust, they're binary, they're very, very easy to use. And I think that should serve us well. So Fred, flipping an important point. So as you can imagine, those folks that work in these type of panels, NDS panels, obviously, they are always interested in having genes in the panels associated to high activity of an agent. So we didn't have any issues with SRAS genes like KIL-three DL2, they are not currently in the panel, but I can tell you that they are not timid of putting an additional gene in the panel that could translate for separate companies be able to provide a diagnosis or enrollment of a patient or a patient receiving a new treatment. So we already had those conversations. And I'm trying to indicate, I mean, these are fairly robust assay. So we don't see any issues for these markers to be introduced in the NGS panels. Great. Thank you. That's helpful perspective and good luck with the additional indications. Thank you. Thanks, Chris. Thank you. And our next question comes from Tyler Van Buren of Piper Jaffray. Your line is now open. Hey, thanks guys. Good morning and congrats on the positive data update. Just there's been a fair amount of discussion already about the different patient populations and registrational strategy. And you've obviously got PTCL, AITL, CXCL12 and now KIR. And I think Troy described it best when he said you could get lost in the complexity of the subsets of PTCL. So can you in advance of obviously defining the exact registration strategy, can you just give us a little bit more clarity in terms of what cohorts of patients you think are most interesting and closer to starting a registrational trial with? Is it fair to say that AITL the AITL patient population potentially looks more interesting in terms of the response rates. Obviously, when you look at patients with cure mutations, it gets way higher, but then you're also reducing the number of patients that the drug would be labeled for. So how do you balance that as well? Yes, it's a good question. And it's as Antonio mentioned, Tyler, it's really a very topical topic within the company. With AITL, Antonio kind of already sketched it out, but I'll let me say it again. You could imagine, for example, a design where you enroll all AITL patients and then you retrospectively study them for the presence or absence of a cure mutation. Given that we have a 40 plus percent response rate in 4th line AITL, that sort of design should give you should be possible for an accelerated registrational strategy and it will give you 2 tiers of patients, the all AITL population and that the Cure mutant population. The 3 prime particularly when you consider that the clinical benefit rate in the 4th line setting is greater than 80%, almost 90%. As Antonio mentioned though, there you might need to do a randomization. And our preference would be single arm response driven trials initially because we think they're that's a little bit more within our wheelhouse. But we certainly wouldn't shy away from doing a randomization we needed to. But that's sort of the way to think about it. And if we were a larger company, a larger company would just do both of those trials simultaneously. For us, it's simply a matter of Antonio has a saying, he tells me, Troy, everything can be a priority. It just can't all be a priority at the same time. So we have to kind of run through that exercise just as you mentioned. And in a world also, I'll add one more thing. We do increasingly operate in a world where people are looking at the cost of drugs and the clinical benefit. And certainly, if you can drive response rates of 40%, CR rates of 50%, you're definitely within a realm of being able to command premium pricing. And that's something we'll have to think about. But all of those elements will come in together. And I don't want to put a time limit on when we'll make a decision. I think we need to talk more internally and we need to talk with the KOLs and the regulatory authorities. Yes. Just to explain a little bit on the same. So potentially you could enroll patients based on the 3 brand new TR that's relatively fast as a book swap and then you get. So it's been molecularly driven. It is the largest population, could be up to 70% of PTCL. That's Remus. You could then stratify histology on the mutations if you want. But there's a possibility that that could be a randomized trial that would require 200 patients. So again, a possibility, larger market, but you will have to wait more time. What Troy mentioned is kind of and then the other extreme is what you're saying. You can go just for the mutations and maybe you run a 50% sorry, a 50 patient trial that is going to report 50% to 75% response rate and that can translate to an approval very quickly. The sample that we are giving you is something intermediate. We can pursue AITL that if at least 1 third, it had very good response rate. So that still can go to a single study without the randomization. We are it look like AITL are coming from all over the place now to ask for treatment with Tipifarnib. We could do retrospectively the care that will help in certain markets. So one of the criticism we get sometimes is some of these agents are they are not approved in Europe and our answer is they don't show 50% response rate. So if you are on the 50% to 75% response rate, you can have arguments to get approvals in reimbursement in very difficult markets like, for example, like the U. K. You can negotiate where you get reimbursement in AITL only or AITL with the mutation. So I think the 2 important aspect is that we do have activity and we have good tools and we can run different trials to and we are balancing time versus cost and obviously commercial value. But this is something that we can hatch in the coming months and provide you guys with an update. Sure. Okay. Yes, that's incredibly helpful. And so with respect to PTCL NAS, is it fair to say that, I guess, you guys would potentially have to do a randomized clinical trial. So you guys will continue to collect more data or what's your thoughts on that moving forward? So I think it's so that will be a 10,000,000,000, not necessarily percent of the population. They actually the investigators, they are quite enthusiastic because many of those disease stabilization, they may have kind of like 45% tumor side reductions that are 50. So you don't call it a PR, but it still is a very durable PR. What's happening is that it may require a 2 to 1 randomization and I just look at it a little bit here. So very good disease stabilization many of them up to 90% clinical benefit, but because it's not a partial response You may have to do some kind of time to employ a progression free survival, for example, and that require a randomized, the minimal trial will be a 2 to 1. Again, good opportunity. And Troy indicated, this was the last company we will be running those trials that we mentioned in parallel. Okay. Very helpful. And just final question, Briefly DLBCL, given its size and number of patients, is potentially very exciting indication. Can you guys speak towards any plans to do a trial in DLBCL? I think it's premature, Tyler, to talk about doing a trial. I think we want to do more non clinical work to give us confidence and help inform what a trial would look like. So as I mentioned, it was very helpful to do so the big breakthrough here is we now have not only CXCL12, but as Antonio mentioned, variations or mutations in the gene. So now you know what you're looking for. Now you can go to banked patient samples as a proxy for what a trial might look like. And that will help us to inform what a proof of concept study would look like. So it's not something we're going to start imminently, but it be given the size of the population and the unmet need, we are definitely doing non clinical work in that direction. And that tumor work is already ongoing. So will show tomorrow 3 patients and the description of the mutations in the 3 prime nuclei, but analysis of a large number of tumor backspace may have been already received. Yes. I mean ideally, Tyler, when we run that study, I mean we could run a study today in unselected DLBCL. But we know that would that's probably not the optimal study. So we need we still need to develop the tools to be able to run a study in an enriched population. And as Antonio mentioned, the non clinical work is underway, and it's high on our list of priorities. Thanks for taking the questions. Our pleasure. Thank you. Thank you. And our next question comes from Jay Olson of Oppenheimer. Your line is now open. Hey, guys. Congratulations on the progress and thanks for taking the questions. My first question is that, since it seems like you may have a potentially accelerated path to registration for tipifarnib in AITL and wild type CXCL12. I was wondering if you envision tipifarnib use in this population primarily as a monotherapy or if you eventually expect it to be used in combination therapy and if so, what sort of combinations you might be considering? I think at the end of the day, you will want it to use in combination in the frontline. That is the ultimate objective. The standard development paradigm is that you take relapsedrefractory patients and you get your first registration. And it's also important not just because of the characterization on the efficacy and the safety of the agent, but also allow either it's not a randomized comparison based on that outcome, you can decide what other agents may be modified in the front line. So what I'm trying to say, if we were to run now a combination in the front line, it kind of like CHOP, kind of like the standard regimens, we will have to kind of like dose escalate tipifarnib. So you kind of like dose reduce tipifarnib to maintain the other agents. A different situation that have been, again, with other agents, again, the sample of Axitrix is that if you show that your agent is the most active agent in that setting, then you will consider the full dose of your agent as monotherapy and reducing other agents that, let's say, chemotherapy agents that they are not as efficacious as monotherapy. So that appeared to me as a totally better strategy for Tipifarnib and for the patients. So that's most likely the most likely paradigm of monotherapy registration and then expanding horizontally in other populations and vertically in combinations with the standard chemotherapy for frontline. Great. That's very helpful. Thank you for that. And then, I know it's not the focus of today's call, but I was wondering if there's any update you could please give us on the development of tipifarnib for ATRAS mutant indications? Yes. Jay, thanks for the question. So, we currently have ongoing the ongoing Phase II trial, which is enrolling 2 cohorts, the head and neck squamous cell carcinoma cohort and the other squamous cell carcinoma cohort. The last time we provided an update on that trial was ESMO 2018. We've continued to enroll patients in both cohorts. And the particular focus in the head and neck cohort is around the patients that have the higher variant allele frequency. So we're looking forward to giving an update on that trial later this year. That's important because we're using the same enrollment criteria in the pivotal, which is also ongoing. That's the AIM HN study. And our intent there is to increase the response rate to the point where, I mean, Antonio, when I say colloquially, you'd like to be in a range where every other patient is responding. We do have some other studies ongoing. There's an investigational study in lung squamous ongoing in Spain. There's no update yet on that trial. But I do think we'll be in a position to give an update on the head and neck squamous and the other squamous later this year, hopefully at ESMO, again, provided that the abstract is accepted. And of course, the pivotal is on track. We continue opening sites and we're expecting to reach our targets by the end of the year. Great. Thanks again for taking the questions. Great. Pleasure. Thank you. And ladies and gentlemen, this does conclude our question and answer session. I would now like to turn the call back over to Doctor. Troy Wilson for closing remarks. Thank you, operator. Thanks everyone for attending our call today. We're very excited with these results. For those of you that will be here in Amsterdam, we'd welcome an opportunity to see you either at Doctor. Foss' oral presentation or We appreciate your participation in this call and we wish you all a good day. We appreciate your participation in this call and we wish you all a good day. Thank you.