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 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 Oncology. 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 first 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. 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 Gualberto is going to talk to you about tonight. 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.
Without further ado, let me just introduce just a few members of the leadership team here with me. Antonio Gualberto is our Head of Development and Chief Medical Officer. He's going to take you through the slides and most of the presentation.
Marc Grasso, our Chief Financial Officer and Chief Business Officer, and James Farnham, 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 Gualberto, but I just want to help you sort of frame the slides that are to come.
Recall that we out-licensed this drug from Janssen in 2014, really around a hypothesis that we could drive anti-tumor 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 two additional clinical proof of concepts, one 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.
We've moved the compound now just in a few short years to a first registration-directed trial in HRAS-mutant head and neck. Then the question is, what's next? How do you think about the development of tipifarnib in both hematologic tumors and solid tumors? 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. That's really going to be the focus of tonight's discussion, these 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.
I'm going to let Antonio Gualberto walk you through these slides, then we'll pause at the end and take as many questions as there are interests. With that, let me introduce Antonio Gualberto, our Head of Development and Chief Medical Officer.
Thank you, Troy Wilson. Thank you for the opportunity to discuss tipifarnib with you. I'm going to start with the data that was presented at ASH today, then all the potential opportunities that the association of CXCL12 expression with tipifarnib 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-1990s, every single major company will have a farnesyltransferase inhibition program.
By 2005, 2006, all those programs have disappeared. One of the potential reasons for that failure is that the actual mechanism of action was not completely known. With that, I mean that obviously, farnesyltransferase inhibitors inhibit the farnesyltransferase. That's well-known. But for a clinician like me, what is important is how inhibition of farnesylation translate to clinical activity.
That question was never answered. Now, since we in-licensed tipifarnib, we were able to determine that the HRAS mutation in head and neck provided evidence of selection of patients. Provided evidence that the HRAS mutation drives a portion of squamous head and neck, and by inhibiting farnesylation of HRAS, we can see clinical activity.
But the issue is that in many tumors in which there is anecdotal evidence of activity from prior studies, tumors like breast cancer, acute myeloid leukemia, T-cell lymphoma, pancreatic cancer. You can go back, some of these old programs, they are fairly large programs. In the case of tipifarnib, Janssen and collaborator conducted more than 70 trials. You can see multiple cases of activity, but you cannot explain it. You cannot explain it because HRAS mutation is really uncommon. HRAS mutation is not present in those tumors.
The big question is, what are the determinants 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 lung patient that received tipifarnib for 13 years, or a Hodgkin lymphoma patient that received tipifarnib for six and a half years. What was the determinant of activity?
That's actually not an easy question, as many people had tried before, and there have been multiple hypotheses, and unfortunately, none of them translated to proof of concept in the clinic. In order to address that question, you need a disease model. You need technologies that now they are available. You have RNA-seq, you have next-generation sequencing, and obviously, you need a capacity to be able to interpret those results. We went back and selected peripheral T-cell lymphoma as our case study.
The reason why we did that is, there's a number of reasons. One of them, peripheral T-cell lymphoma, they are nodal disease, they are amenable to biopsies, you're going to have tissue. Also, there was a historical record of activity of tipifarnib. Some of you were able to meet Thomas Witzig today. He's a professor at Mayo Clinic, and he conducted a trial that was published in 2011, in which he treated relapsed refractory lymphoma patients with tipifarnib.
There were three stratifications in, or three cohorts in that trial. There were patients that were indolent lymphomas, B lymphomas, aggressive B lymphomas, and there was a third group of T cells and Hodgkin lymphoma patients. He saw actually a 31% response rate in that subset. The drug was tolerated. There were some hematological events that were manageable. We decided to reproduce that study.
If you have a 30% response rate, it means that for at least one out of three patients, if the original data was right, one out of three patients at least, they will respond. Once you have positive or negative and having the technologies that we have these days, you can conduct a screening. What is in the responders that is not in the responders, and vice versa. Okay? It's a good model. We had the means.
We should be able to identify why tumors that do not carry HRAS mutations respond to a farnesyltransferase inhibitor. It's also very appropriate to conduct trials in peripheral T-cell lymphoma because there's a high medical need. A number of you have asked today what is the treatment of T-cell lymphoma?
These patients normally are treated with a combination of chemotherapy agents, you try to drive them to an autologous stem cell transplant because transplantation gives an opportunity to long-term benefit. Many patients do not get there. Consequently, they are treated either with chemotherapy or second-line agents such as belinostat, romidepsin, or pralatrexate.
What are the response rates there? It's around 25%, 27%. Patients progress within 1.6 to four months. Half of the patients have died within a year. It's a dramatic diagnosis and a higher medical need. Our study, KO-TIP-002, was designed to, again, reproduce the activity that Dr. Thomas Witzig saw initially and investigate the mechanism of action of tipifarnib. The primary objective was response rate based on the standard criteria.
It was designed as a monotherapy with tipifarnib given at 900 BID on days one to secen and 15 to 21 of the 20-day cycle. 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 mg because this patient population, it was more sensitive to or presented more adverse events with tipifarnib than 900 mg dose, the regimen was modified to 600 mg. We were very cautious.
We conducted this in two stages, an assignment design, enrolling 11 patients, waiting to see responses. If we see responses, we have a second stage. This is a refractory population. We didn't know how many prior lines at the end. The initial study was a fifth-line study.
Basically, they have progressed from the chemo, they have progressed from second-line chemo, they have progressed from other agents, they came into the study. 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. We identify three responses out of 18 patients.
That give you around 17%. There were additional four patients with stable disease. Those were actually very good stable diseases, if I can say that way. You need 50% to call it a response. Three of them, they were 38%-45%, very close to actual responses. The stable disease, three of them were durable, beyond six months. That gives you around 39% clinical benefit with a progression-free survival of 2.4 months with four prior treatments.
What it's telling you is that tipifarnib have activity. However, when you compare with the standard of care, well, it's kind of similar to the standard of care that I showed you a minute ago of belinostat or pralatrexate. Is active, but not much more active than what is currently available. Okay?
However, one of the, as I said, one of the objective for the study is to, can we screen and identify what subset of patients respond and what are the markers associated with that response? We conducted a number of screenings, and we discovered that those patients with tumors that have high expression of a chemokine called CXCL12, experience clinical benefit in terms of PRs with stable diseases.
Those, well, actually, we couldn't get tumors from one patient, two of the PRs and the stable diseases, all of them, those tumors have high levels of CXCL12. We also did a number of analysis, we realized that a couple of those tumors that have a histology called AITL, angioimmunoblastic 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 angio because it's highly vascularized. It have vessels, it have vascular endothelial cells. No surprising you have higher CXCL12. We did also a next-generation sequencing, and we discovered that there's a variation in the three prime UTR, in the regulatory portion of the CXCL12 gene, that one of those variants was associated with higher levels of expression of CXCL12.
That gave us two tools to prospectively verify the hypothesis. We enroll the patients, we see responses, we look retrospectively, and we see the association with CXCL12. You want to confirm your hypothesis prospectively. Ideally, you already have a clear validated test that will allow you to select the patient, but those things don't happen overnight.
The fastest way to enrich for high CXCL12 expression is to select with patients with AITL histology. It's something that do not require any work at our site. The hospitals, the clinical sites already do the diagnosis of AITL. The initial step was continue the trial, enroll a cohort of AITL patients as a method to enrich for tumors with higher CXCL12 expression. The gene sequencing also provided this variant. The variant is present in the gene, so it's a piece of DNA.
That is amenable to sequence and using PCR assays. These are normally very robust assays. 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. We know that it's not perfect. It's not synonymous of high level of expression, but it's another method to enrich.
We set up a second cohort that will enroll for what we call CXCL12+ . 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 mg BID in both of these cohorts because the expectation that the drug will be more tolerated with the 300 mg, three weeks on, one week off.
That you start understanding the mechanism, this is different from the HRAS. Here is the production of CXCL12, not by the tumor, but by the stroma. You want to maintain certain levels for as long as you can. You want to maintain that CXCL12 low for as long as you can. Okay? We also conducted a number of ancillary studies to understand better the mechanism.
We know there was an association with high CXCL12, an 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. We wanted to investigate the expression of CXCL12 in a tumor bank of patients treated with the standard of care and see how high CXCL12 related to the prognosis of the patients, a good prognosis or bad prognosis.
We want to understand better the molecular mechanism. What happens when stroma cells are treated with tipifarnib? Does the expression of CXCL12 change? A number of experiments were conducted actually in the CD1 mouse model, that is a model of culture or actually bone marrow stroma. The status is that obviously we were able to initiate the AITL cohort very soon because the diagnosis was ready at the site.
That cohort had completely enrolled, is the cohort that we have presented today. We also present some of the translational work as well as the preclinical studies. The CXCL12+ 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 in a medical meeting next year. Okay? What is the current patient disposition?
We are reflecting here the whole trial. The whole trial now have 39 patients. 19 of them, they are AITL. 20, half and half, they are non-AITL. These are fairly advanced patients. We are now overall on a fourth line setting, number regimen from one to seven. Again, this is a salvage setting, so most of the patients eventually progress. Progressive disease is the main reason for discontinuation in the trial. An important slide is that, is the drug active?
The answer is yes. Remember, we saw a 17% initially in the overall study in this new cohort of AITL patients per protocol. Per protocol mean that the patient enrolled, received the drug, and got a scan. We have 10 of those patients, two complete responses. Very rare in a fourth line setting to see a complete response.
Two partial responses, two stable diseases. Intent to treat, you have to consider another six patients. Two of them, they are pending to read. Then we lost four patients, most of them for reasons not related to the treatment. They are reasons related to the disease. Excuse me. Disease under study. These are fairly advanced patients. That gives you a 40% response rate in the cohort.
If you consider every single AITL patient, the ones that we enroll in the new cohort, plus three additional patients that were enrolled previously, that gives you 13 per protocol, gives you a 46% response rate and 62% clinical benefit. Good results for patients that have failed three prior therapies, and certainly when you consider that two of those responses are complete responses.
The toxicity is not dissimilar to what we have seen with tipifarnib in the past, what have been reported, mostly hematological events. These have well managed by hematologists. You can see that the AITL cohort look a little bit better. By the way, this is all grades. If you consider severe toxicity, that will be more or less half of those numbers.
The AITL cohort look 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 mg dose to 300 mg BID, three weeks on, one week off. That would be one of the reasons to continue with what we call the three-week regimen. This is the waterfall plot. You can see in dark blue the two complete responses.
We got the questions of why those couple of patients have a significant tumor size reduction, but they are progressive disease. It's because when you choose the target lesions, the ones you're going to measure, you can see a reduction. Those are mostly nodal lesions. Maybe the patients may have excuse me, 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.
One of the main objective was to identify the mechanism of action and to verify that our initial hypothesis of tipifarnib as an inhibitor of the CXCL12 pathway. Last year, we reported stage one and stage two , and we mentioned that these two 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 the second group of patients, you do the experiment again. Those with a higher level, you have PR and a stable disease. 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.
Those patients with a higher level of CXCL12 will have complete responses. You see two PRs and two other 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, sometimes you get more RNA in one tumor versus the other one. We normally do the relationship between the ligand to the receptor. The 0.25 for the cutoff for CXCL12, CXCR4 ratio. Over that, 50% of the patients are responding, 90% clinical benefit. Nine out of 10, they're going to have a partial response, or they're going to have disease stabilization in a fourth-line setting. That level of activity is very rarely seen, in relapsed/refractory lymphoma.
I think the closest it will be the brentuximab vedotin when you select for the CD30 positivity. Recall that the current standard of care have a response rate around 25, 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, you determine that the CXCL12 diagnostic potentially may have 90% sensitivity, 93% specificity, that is acceptable as a companion diagnostic parameters. This is the waterfall plot of the patients that have high CXCL12.
I put a little, some anecdotes about these patients. If we start with patient number one, that AITL. That is a 46-years-old white male. He had two prior chemo regimen, go to transplant, progress, and now have lesions in the neck, in the right axilla, iliac, and periportal area. A really florid progression. Enter the trial within two cycles, complete response. 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 years. Drive it to a complete response and move them to a transplant. This patient left the study, actually was transplanted, and we hope that translates to long-term clinical benefit.
We saw a second complete response is another AITL number two, 67 years old, three prior regimen, also prior transplant, multiple lymph node lesions, complete response on cycle four. The patient is still ongoing in the trial, and obviously transplantation is potentially one of the options. With also major responses in non-AITL patients that have high CXCL12 levels. That's the example of case number three. Elderly gentleman, 75 years old, two prior regimens. Excuse me.
Complete disappearance of the sternal lesions. There's still some lymph node present, although not measurable, we can call it only a partial response. But the lesions that were measurable in the patient have completely disappeared. I'm not going to go through all of them. Maybe of interest is that one of the patients was progressing from romidepsin.
Another of the patients had a very responsive, stable disease with brentuximab vedotin, then progressed, then received tipifarnib, translate to a response. Major complete responses and major responses in highly refractory patients, and at least one of those responses had translated to a transplantation. I mentioned before, you can see the activities have been reported in AITL with pralatrexate, 8% response rate, with romidepsin 30% response rate.
Lenalidomide is a little bit higher, 46%, although in a small subset of the pivotal, and again, the closest 54% with the brentuximab vedotin without in the CD30+ subset. Mentioned the question of, well, if the patient that have high CXCL12 going to do well with everything? The answer is no. They actually do worse. In a collaboration with an investigator, we test the CXCL12 levels.
We use here the same cutoff, the CXCL12 to CXCR4, we used with tipifarnib. And in orange is the survival from diagnosis of the patients that have high CXCL12. You can see that the 40 months median survival from diagnosis have now decreased to 22 months. That's a hazard ratio of 1.8. If you keep increasing the cut, so higher CXCL12, the patients are doing worse and worse.
Some patients that are in the upper tertile may have a survival of around four months. One of the patients, I forgot to mention, the patient that had the highest CXCL12 levels in the study. In direct count, CXCL12, around 15,000 counts. That patient had been for two years on the study, was one of the initial patients, one of the patients that drove us to think that there was something on CXCL12.
Again, two years with tipifarnib, with 15,000 counts. Patients treated with the standard of care with 15,000 counts have a median survival of one month. Very clearly, CXCL12 drive poor prognosis with the standard of care treatment. The other important question is what is the size of the subset? Again, using the same cut that we used for tipifarnib, 0.25, give you about half of AITL.
AITL is about 30% of PTCL and about one-third of the non-AITL cases. That in total gives you 40% of the population. Okay. 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 or prolonged disease stabilization.
Now, how tipifarnib work. From data that is available in the literature, work that had been done previously with this chemokine, we know that it is essential for the homing and growth of tumor T cells in lymphoid organisms. This is data that come from actually a knockout model. In red, you can see the results from animals in which CXCL12 production was knocked out in the vascular endothelial cells. The tumor completely disappear from the lymph node, from the spleen, and from the bone marrow.
The chemokine is required for the T cell tumor to grow in lymphoid organs. What tipifarnib does, tipifarnib down-regulates the expression of CXCL12. 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. 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, this is data that potentially we will present next year. In conclusion, from the ASH presentation, CXCL12 is by the stroma. There are chemokine. It is relevant for the growth of lymphoma.
CXCL12 have two receptors, CXCR4 and CXCR7. Lymphoma express high levels of one of them, CXCR4. We know that high expression CXCL12 is expressing about 40% of PTCL, that is a negative prognostic factor for the standard of care. When we treat these patients with tipifarnib, in the case of AITL, we observe a 46 response rate, 62% clinical benefit. That translate to positivity of the cohort and proof of concept of tipifarnib in the indication.
High CXCL12 expression 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 downregulation of the expression of CXCL12. That will explain how the inhibition of T cell homing and growth of these tumor T cells in lymphoid organs.
It also help us understand some of the toxicity. Bone marrow express CXCL12 that is important for the growth of myeloid cells. That will explain excuse me, 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. AML growth in the bone marrow, that growth and that localization is CXCL12-dependent. tipifarnib also downregulates CXCL12 in the bone marrow.
That will explain the responses in AML. Based on these results, we can characterize tipifarnib as a CXCL12 inhibitor, to my knowledge, this is the first 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, we already obtained the patent protection for use of tipifarnib in angioimmunoblastic T-cell lymphoma. Where do we go from here? What are the next steps? We certainly want to understand these populations. Once you start realizing the potential of the CXCL12 inhibitors, you have to prioritize what do you do first. In the case of PTCL, is very clear, we still have another cohort to enroll.
We need to have additional follow-up of the current AITL patients before you ask me what is the progression-free survival. We are following up. We also working with collaborators to determine what other lymphomas will be relevant for potential targets of treatment with tipifarnib because they are known to express high level of CXCL12. Again, CXCL12 is actually produced by the stroma, by the lymph node.
There's going to be growth there of lymphomas. Some of them will be T-cell lymphomas, some of them will be B-cell lymphomas, which are the right B-cell lymphoma to investigate. This is one of our current objectives. The ultimate goal is to expand the development of tipifarnib as a CXCL12 inhibitor as broadly as possible in lymphoma. In order to understand what could be those patient populations, we'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 two receptors, CXCR4 and CXCR7, most of the hematological indications CXCR4 is important, but the indication like breast cancer in which the second receptor CXCR7 will be important. Again, the main producer is the stroma.
The tumor cell have the two receptor CXCR4, CXCR7. The CXCL12 and this receptor mediate the interaction between the stroma and the tumor cell. What are the potential role of CXCL12 inhibition? The most clear one is inhibition 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.
The third important application is in many cases when the primary tumor is treated by surgery, there's a recurrence. Think, for example, if 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. The other case, the final case, is in relationship to immunomodulation. It attracts CXCL12, attract T cells, attract myeloid cells.
In some cases, those cells have a negative effect on immune response. It's attraction of regulatory T cells, attraction of negative effectors from neutrophils. There's a number of examples of combination of CXCL12 inhibitors and PD-1 or PD-L1 inhibitors, mostly data that is currently available in tumor models. Three different mechanisms 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 the case of mycosis fungoides.
In our case, we don't need to have doubts about it, because Thomas Witzig in the early study, actually enrolled a few patients, four patients with mycosis fungoides. Out of the four, he saw two partial responses. There is definitely some level of activity in cutaneous T-cell lymphoma. We have the expectation that those responders potentially will be high CXCL12 expressers. I'm just showing you one of the cases.
This is a patient that had been treated with multiple skin-directed therapies. He had been treated with interferon. Interferon failed. He was treated with Rituxan, CHOP, seven cycles, eventually failed, had major lesions. Those lesions continue in remission one year after treatment with tipifarnib. More interesting, diffuse large B-cell lymphoma. At least a third of diffuse large B-cell lymphoma express high levels of CXCL12. That is what allow the B-cell lymphoma cells to be located in the lymph nodes.
High CXCL12 expression in this aggressive B-cell lymphoma is already known to be a negative prognosis factor for the outcome of the disease. Dr. Thomas Witzig, when he ran his relapse refractory lymphoma studies, already saw about 20% of the population responded to tipifarnib. Another opportunity to investigate the connection between CXCL12 expression and tipifarnib activity, in this case, on an aggressive B-cell lymphoma.
Those were the non-Hodgkin, Ts and Bs. There's also activity in Hodgkin lymphoma. 19 patients enrolled, two complete responses, two 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, that will be the standard of care. Another chemo regimen, radiation, ICE, transplant, failed the transplant, received brentuximab vedotin, progressed, strong axitrix, received tipifarnib, and is in remission 6.5 years.
That is what I call activity in a setting. It will be important to investigate, was there a connection between expression of CXCL12 activity and resistance to the standard of care? That will be lymphomas, non-Hodgkin TV, and Hodgkin. 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 II study, CITA 20. We can reproduce the phenomenon of homing. Those patients that have high CXCL12, they have few circulating blasts. They have high proportion of marrow blasts. What is happening? If the tumor AML express CXCR4, 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. We have the connection between the homing, the high levels of CXCL12. You can tell me now, "You really don't have a control here." Well, I don't have a control, but Janssen and collaborators actually conducted a phase III where they compare tipifarnib monotherapy to best supportive care.
We don't have genetic data, but we have homing data. We can go back to the old reports and determine. We know high CXCL12 is associated with blasts in the marrow, few blasts circulating. Let's look for the patients that have high proportion of blast in the marrow versus few circulating.
You select those patients, you see a doubling of the survival with tipifarnib versus best supportive care from 100 days to 200 days, hazard ratio of 0.6. Potential for activity in frontline elderly AML by selecting the patient population with expression of CXCL12. That will be an example of myeloid tumor. CXCL12 is already known to play a major role in solid tumors.
These are a number of meta-analysis that have been conducted. High CXCL12 expression consistently is associated with reduced survival in pancreatic, esophageal, and lung tumors. 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. If this hypothesis is true, we should be able to identify a subset of pancreatic cancer that will receive clinical benefit from tipifarnib.
We don't have samples that we can test for CXCL12. We know that expression of CXCL12 is associated with a particular phenomenon, those lesions that express high CXCL12 suppress pain. Pain in pancreatic is a hallmark of pancreatic patient. The patient tell you it's a hallmark of pancreatic cancer. The patient tell you, "It hurts here," and point with a finger.
It had 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 reports of the Janssen phase III, look at the subset that have no reported pain, and determine was there a clinical benefit from tipifarnib. 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. It's potential further evidence of activity of tipifarnib, in this case, in a solid tumor driven by CXCL12 expression. My closing remarks, we have presented the data at ASH, the potential application of tipifarnib now as a CXCL12 inhibitor in lymphoma, in myeloid tumors, potential in solid tumors. We believe that the data that we have presented at ASH further support our hypothesis that tipifarnib is a CXCL12 inhibitor.
That give us a path to extend the application of tipifarnib beyond T-cell tumors to other lymphomas, to myeloid indications, to solid tumors. We plan to continue these efforts to identify these patient subsets and to bring tipifarnib to those patients in need. With that, I will acknowledge the initial work that was conducted by Thomas Witzig, his collaborators at Mayo Clinic, the auto investigators, the study teams, our patients, and their families. That's all. Thank you.
Thank you very much, Antonio Gualberto. At this point, we're going to take any questions. Does anybody in the room have any questions? Yeah, Jonathan Chang. Let's start with you, Jonathan. 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, can you help us contextualize how we should be interpreting the data presented at ASH? What kind of benchmark should we be using for these late-line PTCL patients? I guess specifically for AITL and CXCL12.
The numbers that we show, 25%, that is second line. The activity, the complete responses that we are showing you is fourth line. You will expect in the fourth line, the activity to be much lower than 20%. I don't want to call it transformative because that is almost a regulatory term, but it's significant. I think any investigator will tell you that it's significant to see responses, complete responses, patients going to transplant. In my career, I have seen a phenomenon like that only one time. That was in ADCETRIS in Hodgkin lymphoma, when you could move a patient in a refractory setting to a complete response and a transplant.
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?
From my part, obviously you want a durational response or progression-free survival is more or less the same term. If you recall, if we look at the data from the last year, very small data set, 40% response rate, six months median progression-free survival, that will be on the progression-free survival threefold the standard of care in a more advanced setting.
If you are able to have a 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. 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?
Jonathan Chang, 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 II meeting to set up the AIM-HN registration-directed study. We're there with AITL. To Antonio Gualberto'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 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. I think at that point, already you can begin to see paths as to how you would move the compound forward. The 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. We'll provide an update there as well. 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.
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. We'll work through that in due course and give an update next year. Other questions? Go ahead.
Tyler Van Buren from Piper Sandler Companies. 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 and 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.
Yeah. One of the initial AITLs, actually, that patient had the highest CXCL12 levels. 15,000 counts in the retrospective standard of care. That is a median survival of one month. That patient have been already two years on tipifarnib and it's ongoing. It's an anecdote. It's not a proof. Very high levels that translate to dismal prognosis with the standard of care are being seen with the patient that have been already two years on the study. That strongly suggests that this is a main mechanism for the activity of tipifarnib in this class.
Okay. I know the CXCL12+ SNP patient population, that trial is still ongoing, is there any reason scientifically, I guess, believe that we should see better or worse data in that subset of patients r elative to AITL
I'll take it. The only question is a scientific question, it's that what is the role of that SNP in the three prime UTR? This is an important scientific question, on a development standpoint, we have many choices. We can do IHC of CXCL12. That's probably in the long term what is going to work the best. 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? Those are the Dana-Farber, the Mayo Clinic. How they do it, these are very difficult tumors to diagnose. They just use a panel of antibodies. What you want in the future is that. 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 see a CXCL12+ , they are potential candidates for treatment with tipifarnib. Again, we are not there yet, but that potentially can be, it's not that complicated as an IFCSA. For now, we can continue with the tool that we have, that is the SNP, because it's very robust. We're working on NanoString probes, obviously IHC is an important consideration for the identification of the population once the agent is approved.
Okay. On 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?
The pancreatic study, for example, is a combination with gemcitabine. 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 happen with the cisplatin, with carboplatin.
Folks have combined tipifarnib with a large array of compounds. Some of the doses may have to be decreased. In the case of gemcitabine, it's around 200 mg, or it's tolerated. But some settings 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 two years to block a recurrence, you don't have to reduce the tumor. The tumor is not there.
You are just blocking the possibility of a recurrence. A lower dose, like 200 mg, that have very little toxicity may be sufficient. Different setting is going to have different needs. As an up-front therapy, if it's very effective in the subset, you may take other agents out. That's something that happened with axcitabine, for example. What I'm trying to say, 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?
Thank you. Chris Shibutani from Cowen. Question on dose, question about patient selection, thirdly, on strategy. On the dose, I noticed that there was one patient who had, I guess, a weekly regimen as opposed to three weeks in a row. Talk a little bit about that, then also just the progression or the history. You have context for a lot of the work that Janssen had done. You started at the 900 mg step back to 600 mg, 300 mg. 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, once you understand the mechanism, then you comprehend better what is the most appropriate regimen. When we didn't know much, before we identified CXCL12, we used the same regimen that we have in the solid tumor. What happened in the squamous HRAS mutant, you want to give a high dose and drive the tumor to a collapse.
If the tumor is very dependent on HRAS, you get as much inhibition as you can. 900 mg daily for a week, and then you give a break to the patient. What we have seen, we have a patient that went in response within one week. On a one-week treatment on a partial response. This is not the case. Here is not the tumor carrying a mutation. Here is the stroma producing CXCL12.
Now that we understand the mechanism, it makes sense to have a regimen that for as long as you can maintain low levels for the chemokine. That's the reason why we are using the 300 mg. 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.
On patient selection, there was that one outlier where you're using the ratio of the CXCL12 to CXCR4 as opposed to the absolute value of the CXCL12. Can you talk about that versus the ratio?
Only God knows. It could be there was a laboratory error. It could be maybe that patient carry an HRAS mutation. That we will know, but there could be other reasons. Maybe it's a mutation in the front next little. There are always outliers, and there could be other mechanism response, but certainly they are not the main mechanism of response. Yeah.
Then in terms of how you're thinking about the strategy you're developing, the additional indications that you're expanding tipifarnib 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 we think further out commercially?
Yeah. Obviously you have to take into account many considerations. 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 a registration. If you want to target larger populations, you try to go to earlier line in combination.
Having done this for a number of years, you realize that that goes through a phase I, phase II, phase III, larger trials. By using these markers in the case of HRAS, we have been able to move quickly to, in the case of HRAS, a registrational trial with 59 patients. We can prioritize the 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 label. That could be one phenomenon.
In other cases, companies prefer to, once they have got the initial registration, to take a larger risk. You may consider maybe you want to take a higher risk and run a phase III in an easier line. What I'm trying to say, there are different possibilities once you balance what is the risk associated versus the commercial value. Anything that we do is sufficiently protected. 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 patent-protected.
Troy Wilson, do you want to put your JD hat on and add on to the commentary?
Yeah, I think Antonio Gualberto's said it correctly, particularly in that closing comment. Our scientific strategy and activities, our clinical development, and our intellectual property are all walking together in lockstep. 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, life cycle management.
The advantage that we have is there were a number of companies that worked on farnesyltransferase inhibitors without success. When we're able to identify biomarkers, we're able to couple those with doses and schedules to drive outsized clinical activity. Thus far, the patent office has looked favorably on our applications, and we have now four issued patents in the U.S. for tipifarnib, a number of other applications pending, both domestically and worldwide.
We're bullish, we're thoughtful, we're a little bit coy about our strategy as we have to be. 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, 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 focused on our strategy.
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, et cetera, broadly speaking. When we think about how the pace of clinical development will happen, when you're particularly going to getting to 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. 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. It's a good question. This is arguably, this is a different challenge from HRAS. HRAS is a numbers game. It's 5% of head and neck. You're doing next-generation sequencing in a disease indication where genetic screening is not standard of care. That has been the challenge that we've had to address and ultimately will overcome.
As Antonio Gualberto mentioned here, physicians are already primed to think about subsets. Although a number of the HDACs are in unselected populations, we have ADCETRIS ahead of us in a CD30+ population, and that set a very nice example for how to think about a franchise extension across indications. We have to do the heavy lifting. I think to your point, we have to identify, is it a different cutoff in each disease? How quickly can you go, and how many things can you parallel process?
The big aha here is, as Antonio Gualberto, I think, very elegantly laid out, the roadmap 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? Ming Tong, in the back, there's a question.
Wonderful work. My name is Ming Tong. I from the NIH. I now join 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 train as MD in Boston. We have a lot of activity going on. My number one first question is that, when I look into the big picture, you're more on the upstream, on the surface, on the CXC motif axis system.
In your case, you pick the pancreatic cancer. How do you compare to people, say, do a little bit more downstairs, using the STAT3, the JAK2, STAT3? Also involved in the same network system. How do you compare thinking about in terms of the clinical and molecular actions, that kind of things?
I guess I said, I think it's a combination of the two. In the case of pancreatic cancer, you will have to understand what is the pathology and what are the drivers and the idea, for example, of a locally advanced disease is not that different from the homing. You can define the population. There's going to be some downstream mutations. For example, not to give you too much today or we're going to be presenting in January.
There is a balance between what's the path is and what elements here may or may not circumvent the driver. If you have an understanding of the subset of the population, medically who those patients are, you know that the driver is CXCL12 and what you should avoid downstream, then 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 lens, make it enlarge on that part of the system or the axis within a big system biology picture. Say, if I have $30 million to spend to develop one agent, do you think that your wonderful program would come up to be monotherapy for the pancreatic cancer? Are you thinking about a combination using the CXCL12 antagonist plus something else or just by itself?
Yeah. That's actually an easy question to answer. Pancreatic cancer have already been described that the expression of the receptor CXCR4 is actually gemcitabine inducible. That will explain why you see activity of the gemcitabine, tipifarnib combination. Gemcitabine induce CXCR4 that made the tumor CXCL12 dependent, tipifarnib down regulates CXCL12.
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. There's a possibility of displacement of other therapies based on the patient characteristics.
Great. With that, 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 Gualberto 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 II 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 our ERK inhibitor next year.
A lot of exciting things going on. We'll be around for a little while to help answer any additional questions and 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.