Syndax Pharmaceuticals Inc (SNDX) 2017 Q1 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Syndax First Quarter 2017 Earnings Conference Call. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will host a question-answer session and our instructions will follow at that time. (Operator Instructions) As a reminder, this conference may be recorded.

It is now my pleasure to hand the conference over to Melissa Forst with Argot Partners. Ma'am, you may begin.

Thank you, operator.

Welcome and thank you to those of you joining us on the line and the webcast this afternoon for a review of Syndax's first quarter financial and operating results. I'm Melissa Forst with Argot Partners, and with me this afternoon to discuss the results and provide an update on the company's progress are Dr. Briggs Morrison, Chief Executive Officer; and Rick Shea, Chief Financial Officer. Also joining us on the call today for the question-and-answer session is Michael Metzger, President and Chief Operating Officer of Syndax.

This call is being accompanied by a slide deck that has been posted on the company's website, so I'd ask you to please turn to our forward-looking statements on slide 2.

Before we begin, I would like to remind you that any statements made during this call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements as a result of various important factors, including those discussed in the Risk Factors section in the company's most recent Annual Report on Form 10-K and other reports filed with the SEC. Any forward-looking statements represent our views as of today, May 8, 2017, only. A replay of this call will be available on the company's website at www.syndax.com following the call.

And with that, please turn to slide 3, and I'm pleased to turn the call over to Dr. Briggs Morrison, Chief Executive Officer of Syndax.

Great. Thank you, Melissa.

As you know, Syndax is a clinical-stage oncology focused company. In the accompanying slides, I'd like to walk you through our clinical pipelines and summarize the encouraging progress we made during the first quarter. Slide 3 summarizes our clinical stage programs, which include two potential best-in-class molecules being tested [technical difficulty] ongoing clinical trials across six different indications.

Slide 4 summarizes the exciting progress we've made on ENCORE 601 since our last call. In the first quarter, we announced that the melanoma cohort of ENCORE 601 comprised of patients who had progressed on prior treatment with a PD-1 antagonist had met the pre-specified efficacy criteria for advancement into the second independent stage of the Phase 2 trial.

(technical difficulty) melanoma patients who failed treatment with a PD-1 antagonist such as KEYTRUDA or OPDIVO do not currently have effective treatment options available to them. We're pleased that enrollment for this cohort has accelerated, and we now anticipate completion of enrollment in the third quarter, one quarter ahead of our prior expectation. Data from the first stage of our Phase 2 trial will be presented at the 2017 ASCO meeting next month, and we look forward to sharing those detailed results with you.

We also recently announced that we've expanded our collaboration with Merck on ENCORE 601 to include a cohort of colorectal patients that represent an important unmet medical need, and I will present further details on this cohort shortly.

Slide 5 details the rationale behind the therapeutic potential of combining entinostat with PD-1 antagonist. Most notably, preclinical data indicate that entinostat can modulate the critical tumor microenvironment by blocking the function of both myeloid-derived suppressor cells, and regulatory T-cells and has been shown to increase the antitumor activities of anti-PD1 antibodies in multiple preclinical models. Through these mechanisms, we believe entinostat can reverse resistance to PD-1 antagonists, and we're starting to generate the first clinical support for this hypothesis in our ENCORE study.

Several posters were presented during the recent annual meeting of the American Association for Cancer Research that highlighted new data and insights into how entinostat alters the cancer cell and the tumor microenvironment to enhance immunotherapeutic approaches.

On slide 6, we show the results of -- just one example of the posters that were presented. This is from a mouse lung cancer model. The far left panel shows the significant antitumor efficacy seen in this model with a combination of entinostat and the PD-1 antibody. The middle panel shows the ability of entinostat to reverse the immunosuppressive function of myeloid-derived suppressor cells taken from mice treated with entinostat and the far right panel shows that entinostat decreases the expression of a number of known immunosuppressive factors that MDSCs use to inhibit in antitumor immune response, including iNOS, arginase-1 and COX-2.

Slide 7 summarizes the two-stage trial design for ENCORE 601. The trial includes two non-small-cell lung cancer cohorts, one cohort of patients who have not previously been treated with a PD-1 antagonist and a second cohort of patients who have progressed on a PD-1 antagonist. During the first quarter, we completed enrollment in these two non-small-cell lung cancer cohorts, and we anticipate being able to make the decision whether to proceed to Stage 2 in either of these two cohorts by the end of the current quarter.

The slide also shows the cohort of patients with advanced melanoma, who progressed on a previous PD-1 antagonist. We are in Stage 2 for this cohort, enrolling an additional 21 patients. We also highlight that recently added cohort of colorectal cancer patients with microsatellite stable tumors. For each of these cohorts, the decision to progress to the second stage of the trial requires a prespecified minimum number of objective responses, as shown in the blue highlighted portion of the slide.

As I mentioned and shown on slide 8, we reopened enrollment in the melanoma cohort, and we'll be sharing more detailed data from the Stage 1 portion of this trial at ASCO on June 3. Looking further out into the year, we anticipate completing enrollment for this cohort in the third quarter, we've scheduled a meeting with the FDA in June to discuss the clinical development of entinostat in melanoma. Given the limited treatment options for the PD-1 refractory population of melanoma patients, we hope to engage the FDA in discussions about potential for an accelerated approval path in this indication for patients who have failed the PD-1 antagonist regiment.

Slide 9 illustrates this clear unmet need for a new treatment option for the roughly 10,000 melanoma patients who fail a PD-1 antagonist, either alone or in combination with CTLA-4 inhibitor. Over the past few years, we've seen a number of new medicines approved for patients with metastatic melanoma, including BRAF inhibitors, MEK inhibitors and of course, PD-1 and CTLA-4 inhibitors and yet there are a significant number of patients whose disease has continued to progress despite these approved therapies.

Before moving on to updates on our other ongoing programs, let me share some additional details regarding the expansion of our collaboration with Merck for ENCORE 601 into patients with microsatellite stable colorectal cancer.

Slide 10 briefly summarizes why we've expanded ENCORE 601 one to include patients with microsatellite stable colorectal cancer. As I've noted, we believe there is a significant unmet need in this patient population. We've now seen clinical responses in patients with melanoma who are refractory to the PD-1 inhibitor and have learned a bit about the characteristics of the tumors of the patients who have respond, which underlies our hypothesis that entinostat may also yield clinical responses in combination with pembrolizumab in microsatellite stable colorectal cancer. We've also learned more about the different immune phenotypes of colorectal cancer, which you can read about in the reference provided on this slide. And in addition, we believe that we can get a rapid clinical read out in this population of patients with a single-arm trial.

Slide 11 shows the typical treatment paradigm for patients with metastatic colorectal cancer. As you can see, the current treatment paradigm relies heavily on chemotherapy. Patients with mutations in a protein called KRAS tend not to respond to EGFR antibodies and often receive to Stivarga or LONSURF as subsequent therapy. Patients who have a normal KRAS protein do respond to EGFR antibodies and can be treated with Vectibix or Erbitux as well as Stivarga and LONSURF. None of these agents are curative and the median five-year survival from the time of diagnosis of metastatic colorectal cancer is still only about 14%. Recently, anti-PD-1 therapy has been tested in patients with metastatic colorectal cancer and unfortunately, patients with the microsatellite stable disease, a subset which represents about 85% of colorectal cancer population, have been minimally responsive to anti-PD-1 monotherapy.

I'd like to now briefly review the remainder of the ENCORE program. Slide 12 shows the trial design of ENCORE 602, our Phase 1b/2 trial, exploring the combination of entinostat with Roche Genentech's anti-PD-L1 antibody TECENTRIQ in women with triple-negative breast cancer. Enrollment in the randomized Phase 2 portion of the trial at the 5 milligram dose of entinostat remains ongoing with a primary endpoint of progression-free survival.

Turning to slide 13, ENCORE 603 is our Phase 1b/2 trial in patients with ovarian cancer, testing entinostat in combination with BAVENCIO, an anti-PD-L1 antibody developed by the Pfizer Merck KGaA alliance. The ENCORE 603 trial design is very similar to ENCORE 602 with a safety running component, followed by a randomized Phase 2 component. We are nearing completion of the dose-finding phase and anticipate beginning the randomized Phase 2 components within the third quarter. As with ENCORE 602, the primary endpoint of the Phase 2 part of the trial is PFS.

Next, I'd like to update you on E2112, our ongoing Phase 3 registration trial of entinostat plus exemestane, an aromatase inhibitor, in patients with advanced hormone receptor positive HER2-negative breast cancer, who progressed following treatment with standard-of-care, as shown on slide 14. This trial is being conducted in collaboration with the Eastern Cooperative Oncology Group, American College of Radiology Imaging Network, otherwise known as ECOG-ACRIN, and the National Cancer Institute under a Special Protocol Assessment with the FDA. The study will enroll 600 patients and as of April of this year, 440 patients have been enrolled. ECOG has advised that completion of enrollment and availability of the progression-free survival analysis is now anticipated in the first half of 2018, a bit later than we had previously communicated.

As we've mentioned previously, the FDA granted entinostat and exemestane combination breakthrough therapy designation for this hormone receptor positive, HER2-negative breast cancer indication based upon positive results from our Phase 2b clinical trial, ENCORE 301. In that clinical trial, treatment with entinostat and exemestane demonstrated approximately an eight-month improvement in overall survival versus exemestane alone. We've designed a Phase 3 trial with two co-primary endpoints, PFS and OS. The terms of the Special Protocol Assessment allow for a potential registration filing on the basis of a positive outcome from either of the PFS or the OS endpoint.

As shown on slide 15, we believe that entinostat has potential as a differentiated second or third-line therapy for the treatment of hormone receptor positive, HER2-negative metastatic breast cancer. E2112 represents the first Phase 3 trial involving a novel mechanism of action in this patient population since the approval of the CDK4/6 targeted agent. We estimate that there could be approximately 34,000 patients eligible for entinostat once they go on to receive hormone therapy following first line treatment.

Slide 16 shows the interaction of SNDX-6352, our potential best-in-class monoclonal antibody therapy with its target the CSF-1 receptor. It functions by blocking the ligand binding domain of the cell surface protein CSF1R, which plays a critical role in regulating proliferation, survival and differentiation of mononuclear phagocytes or tumor-associated macrophages, sometimes referred to as TAM. TAM is our immunosuppressive cells found in the tumor microenvironment that can inhibit the ability of tumor-infiltrating lymphocytes to attack and kill tumor cells. This mode of action could make CSF1R antibodies an attractive therapy for use in combination with checkpoint inhibitors as well as in combination with cell therapy or chemotherapy or radiotherapy.

We believe they may also be synergistic with entinostat, which has been shown to inhibit two other critically immunosuppressive cells in the tumor microenvironment, the MDSCs and Tregs. We believe that the combination of entinostat and SNDX-6352 may therefore provide a more effective mechanism to overcome the intense local immunosuppression known to exist in the tumor microenvironment of some tumors.

SNDX-6352 has a unique profile that we believe position as a potential best-in-class molecule. These properties include its high binding ability, its ability prevent binding of both ligands, both IL-34 and CSF1 binding to the receptor, and its potential synergistic activity with other therapeutic classes.

We've now completed dosing of SNDX-6352 in the first three cohorts of a Phase 1 single ascending dose trial in healthy volunteers, and we anticipate completing that trial and presenting the results in the fourth quarter of this year. We also anticipate starting a multiple ascending dose trial in the third quarter of this year.

Let me pause here and turn the call over to Rick Shea, our Chief Financial Officer, to discuss our financial results and update you on our balance sheet. Rick?

Thank you, Briggs.

Turning to slide 17 for the three months ended March 31, 2017, Syndax reported a net loss of $13.0 million or $0.71 per share compared to $12.9 million or $2.85 per share for the prior year quarter. Our research and development expenses in the first quarter of 2017 increased to $9.6 million from $4.8 million for the first quarter of 2016. The increase was primarily due to increases in clinical trial activities of $3.4 million, employee compensation expense of $0.8 million and legal and consultant expenses of $0.5 million.

Our G&A expenses were $3.9 million during the first quarter of 2017, a decrease from the prior-year period of $4.3 million of G&A expenses. The decrease was primarily due to a decrease in employee compensation of $0.7 million, partly offset by increases in consulting expenses and other costs related to being a public company of $0.3 million. The decrease in employee compensation of $0.7 million was primarily due to decreases in non-cash stock compensation of $0.9 million and in bonus expense of $0.2 million, partly offset by increased salary expense of $0.3 million due to increased headcount.

Total common shares outstanding at March 31, 2017, were 18.25 million. On a fully diluted basis, 21.8 million shares were outstanding.

Additional financial details will be available in our quarterly report on Form 10-Q, which we expect to file this week. Syndax ended the quarter with a cash balance of $92.8 million, which we believe is sufficient to fund development into the middle of 2018, enabling us to reach key corporate milestones.

For the second quarter of 2017, we expect research and development expenses to be in the range of $11 million to $13 million and total operating expenses to fall between $15 million and $17 million. For the full year, we expect R&D expenses to be between $52 million and $57 million and total operating expenses between $68 million and $73 million. We believe that we're in a strong financial position, and we will continue to make appropriate and measured investments in building the Company's pipeline.

Now, I'd like to turn the call back over to Briggs.

Thanks very much, Rick.

Looking forward, we expect several key upcoming milestones summarized in Slide 18, which include announcement of whether either of the two non-small cell lung cancer cohorts in ENCORE 601 have achieved their prespecified efficacy criteria for advancement into the second stage of the trial.

As I noted earlier, we've expanded enrollment in the refractory melanoma cohort of ENCORE 601, and given the rate of enrollment seeing to date we expect this cohort to complete enrollment by the end of the third quarter of this year. We look forward to presenting the results from the first stage of the melanoma cohort of ENCORE 601 at ASCO next month, as well as to our upcoming discussion with FDA to explore the feasibility of a pathway for accelerated approval of entinostat in this setting.

We also expect enrollment to be completed by year-end in ENCORE 602, our Phase 2 combination trial with Entinostat and atezolizumab in triple-negative breast cancer. We expect to complete enrollment in E2112, our Phase 3 registration trial of Entinostat in hormone receptor positive HER2-negative breast cancer and share the PFS analysis in the first half of next year.

Finally, we expect to advance 6352 into a multiple ascending dose trial in the third quarter and anticipate presenting the results from the ongoing single ascending dose trial in the fourth quarter. We look forward to sharing data from these trials at the most appropriate scientific congresses as they become available.

I'd like to end my prepared comments by reiterating our exciting year at Syndax on the progress we're making with our portfolio program as shown again in my last slide and which includes two potential best-in-class molecules being tested in five ongoing trials across six different indications.

Finally, we continue to remain opportunistic with respect to business development opportunities that offer an attractive risk-reward and a strong strategic fit for Syndax, as evidenced by our successful in-licensing of SNDX-6352.

In closing, I'd like to thank all the fantastic employees here at Syndax, our collaborators and perhaps most importantly, the patients, trial sites and investigators involved with our clinical programs.

With that, I'd like to open the call to questions. Operator, can you please open the call to questions?

(Operator Instructions) Bert Hazlett, BTIG.

Congratulation on the progress, especially with the extension of ENCORE 601 in melanoma. My questions are around that program specifically.

What -- could you describe kind of what the intentions of the Type B meeting are and what might represent an accelerated pathway and what that might look like? Could you do something with the existing trial to materially expand that and have that moved into a registration type of a study, I guess is what I'm asking initially?

Hi, Bert. Thanks very much for the meeting -- for the question.

The Type B meeting, we'll want to discuss with the FDA the overall further development of entinostat in melanoma, including the potential accelerated path. And as you know, with the accelerate, even if you were to get an accelerated approval path, what the sort of confirmatory trials would be. So we're trying to discuss the broad overall development strategy.

As I said in my prepared remarks, given that there is a significant unmet medical need, we do have a couple of thoughts that we'd like to discuss with them about an accelerated path. I probably can't say much more about what those options are other than to say that I don't think the single trial that we have ongoing right now would be sufficient. We hypothesize that we need to do something in addition to that.

Okay. And I guess that dovetails into some of the discussions that's going to be presented at ASCO. Could you give a little bit more granularity on what the -- whether specific types of patients might be discussed or whether -- or the types of biomarkers that might be discussed and could that be used to further enrich the trial design as you move forward with FDA -- the discussion with FDA?

Yes, sure. So the ASCO presentation will be the updated data on the 13 patients that were in Stage 1 that we -- the efficacy and safety data from that cohort that we used to make the decision to expand into the Stage 2 of the melanoma cohort. We'll have detailed information on the patient characteristics of those patients as they came into the trial, and we will have some information on biomarker status at baseline. I would hesitate to say that out of the 13 patients, we'll be able to say too much about a subset that could play a role in accelerated pathway, but we can discuss that more once we actually have the data from ASCO.

David Lebowitz, Morgan Stanley.

With respect to the breast cancer trial, would it be reasonable to expect that the overall survival data would be likely to be towards 2019?

That's right, David. I mean, the overall survival data in -- as the trial was put together in model would come roughly 18 to 24 months after the completion of enrollment. So, that's in the 2019 or early 2020 range.

Was there much granularity on what led to the enrollment, I guess, slowing somewhat in recent months?

Not a lot. I mean, I would say that we had very good enrollment throughout last year. The beginning of the year, the enrollment seemed to slow a little bit and then has picked up in the last month. So it's a little bit uncertain exactly how it will play out over the course of the next few months. But in our discussions with ECOG, nothing specific came to light in terms of the variability of the enrollment month-to-month.

Sure. And I guess just jumping over to the combo trials to 601, could you go into a little more detail on the genesis of the decision to add a colorectal cohort?

Sure. As I said in my prepared comments, the -- I think there is a couple of things, because PD-1 antagonist don't really -- in the microsatellite stable population, the sort of general, most common form of colorectal cancer, you don't see very much. We think we can -- if entinostat is adding, we should be able to pick that up in a single-arm trial with -- it should be pretty straightforward. As I said, because the responses we've seen in the melanoma population sort of relates to Bert's question about the characteristics of those populations, which we'll share at ASCO, combined with some of the biology that we see in colorectal cancer, we think it's a reasonable hypothesis that entinostat could actually work in some of these microsatellite stable patients.

Chris Shibutani, Cowen.

Appreciate the updates on the combination entinostat KEYTRUDA study, and it's been especially helpful to have kind of your threshold responses that you were looking for the program to move from Stage 1 to Stage 2.

Can you provide us with some insights in terms of what you think in the totality of the study as you progress through Stage 2, what kind of response rates you might be thinking about once we do get to those total enrollment levels? And also in that regard, when we think about responses, can you comment as well about perhaps the durability of the types of responses we could see?

Sure. So Chris, the Simon two stage design, if we open enrollment in all three of them and end up enrolling the total number of patients that we've described previously, the total number of patients were defined based upon the statistical hypothesis of what the response rates we were looking for. So in the melanoma population, the way the trial has set up, that total of 34 patients gives us sufficient power to detect a response rate of about 25% or the pre-treated patients to 56 patients gives us power to detect a response rate of around 15%; and the 46 patients in the naive is a targeted response rate of 35%. Probably in a subsequent time, we can go through sort of the rationale behind each of those, but they're built off of both, in some cases, what you would expect from a PD-1 alone or what is standard of care and sort of the lower bound of what we need to see to beat the standard of care.

I think your second question about the durability of the responses, in general what we're looking for is responses that have durability of six months, nine months or so; that's really I think the bar that people look for to say that there is something clinically significant going on. So the opening of the trials themselves do not have a bar related to durability, but at the end of the day, we would like to see as high a possible response rate that are durable.

Great, that's helpful. And those target response rates are consistent with what you've had in the previous stack, I just didn't notice it on this one. So, I'm just wondering if there was any change. But the new change is with colorectal cancer. Can you share with us what you think the target response rate could be for that cohort?

Right. So colorectal cancer, you'll notice the Stage 1 and Stage 2 is the same as melanoma. So the target response rate there that we're looking for is about a 25% response rate, which, again, I think in the colorectal -- the microsatellite stable colorectal cancer population would be, I think, a notable advance over the current therapies that are available to those patients.

Tony Butler, Guggenheim.

A couple of questions, if I may. Briggs, when you think about, if we go back to the expansion of 601 in CRC, so the notion is -- I sort of had it before was that you had a fairly high immunogenic response in microsatellite in stable CRC. You also had high permutability in a melanoma patient. So the question is you're looking at lots of mutations and yet you're choosing an area in microsatellite stable colorectal cancer, which likely has fewer mutations, which is unusual, but I'm struck by the (inaudible) article for -- at least that from the Spanish group, which states that you -- there is an assumption that you may get increased expression of T cells chemokines and I'm curious -- or you need to get an increased expression of T cell chemokines. And I'm curious what those might be because they actually end up referencing the same paper which talks about HDAC inhibitors in lung adenocarcinoma. So really, two questions, one about fewer mutations, why? And then the second about what T cell chemokines need to be increased?

So, thanks for your question, Tony.

The question about the mutational load and using that as a predictor of response to PD-1, you're correct that the microsatellite -- the MSA -- MSI-high population has a high mutational load and seems to have a notably positive response to PD-1, but I wouldn't say that the mutational load is a definitive marker of who's going to respond and who's not going to respond. So -- and you are correct that the microsatellite stable population tends to have a lower mutational load than the MSA -- MSI-high.

In some of the pre-clinical work that was done, even in relatively low mutational loads, you still see a beneficial effect of entinostat. And so I think what we're testing more, I think, in the colorectal population is the role of the immunosuppressive cell types, MDSCs and Tregs. And so, as you know, there is a one particular type of -- it's called the inflamed type of colorectal cancer and it's inflamed with essentially immunosuppressive cell that has Tregs, MDSCs, Th17 cells, and so it is inflamed presumably because there are antigens that are recognizable, but have sort of an immunosuppressive phenotype. So we think that's the population -- that particular type is probably the most obvious why entinostat would work.

There are other types as you noted that are sort of cold, they don't -- they're not inflamed and that's the hypothesis that you need to stimulate certain T cell chemokines to -- and there was the paper you reference that (HDAKs) can help do this. I don't remember off the top my head exactly which T cell chemokines that they reference, but so there's different theories on how entinostat could help the different immune phenotypes. And so we're not selecting for each of those; they represent significant cohorts -- significant spontaneous population. So we think by enrolling sort of an unselected population, we can start to take a look at these different immune phenotypes in colorectal cancer and see if in fact entinostat is affecting some of the immunosuppressive factors.

Joel Beatty, Citi.

Hi, this is Shawn calling for Joel, congratulations on the quarter. I was wondering if you could provide a little more color on the potential combo of entinostat and your anti-CSF-1R mono. What type of signal are you expecting from your SAD/MAD trials that (would prompt the combo) trial?

Right. So we're actually doing some preclinical work on that combination now. And hopefully over the -- in the near term, we will be able to give you -- learn ourselves exactly what's happening with that combination. Theoretically, as I outlined, I think there's a possibility of it hitting the TAMs, the MDSCs and the Tregs. So we're testing that first preclinically. I think we haven't said much about the development of 6352 either as monotherapy or which combinations we would do. We do think about doing a combination with entinostat, but I think it's better for us to give you a broader picture of what we're going to do with 6352, which will probably be a little bit later in the year.

Hartaj Singh, Oppenheimer.

I just had a couple. One, I just want to ask on the insights you got from the melanoma cohorts and then gave you sort of insights into colorectal cancer, any thoughts about similar or maybe analogs or insights you got to the lung cancer cohorts, and I know you're waiting for those later this quarter, Briggs, but just any thoughts there on what sort of insights might translate over from the data you're presenting at ASCO in melanoma into lung cancer?

Yes. I would say, yes, Hartaj, there is what we're seeing in melanoma could help us think about a back to that, I think, one of the earlier questions of sub-population of non-small-cell lung cancer. So we're thinking about that.

Got it. Great, Briggs. And then the other question is just on E2112, a question was asked earlier about overall survival. I know you've said that both endpoints are primary endpoints. Can you just sort of walk us through as well as you can or sort of quickly on how -- what sort of our statistical methodology that you'll be utilizing for sort of testing those hypotheses and then how will you walk through these two that are not co-primaries, if I remember correctly, but the primaries and then how you sort of go through the secondaries, et cetera?

Right. Yes, thanks very much for the question. So you are correct, they are not formally co-primaries, because the formal co-primary means you have to hit on both. So, they are two primary endpoints and they're not at this -- very simply, they are not hierarchical statistical testing, it's actually [alpha] is split between PFS and OS. So a certain amount of [alpha] goes to PFS and a certain amount of [alpha] goes to OS, which is why you can win on either.

Got it. And then is it -- I assume that when PFS is completed and you expect to see that in the first half, will you have a chance to look at OS at that point or will you just look at PFS or I guess ECOG will look at PFS and then wait till you get to a certain point to look at OS?

So there is -- the first interim look at OS will occur at the same time as the final PFS analysis. So when the DSMB looks at PFS in the first half of next year, they will also do the first interim look at OS and then OS is reviewed. There are additional interim looks every six months.

Based upon our assumptions in putting the trial together and how these events will read out, we think it's unlikely that OS would be statistically significant at that very first look at the same time as PFS, which is why in answer to an earlier question, we've tend to think of it about 18 to 24 months later. If for some reason the PFS benefit were -- I mean, the OS benefit were greater than hypothesized, of course, you could find that earlier, but based upon the assumptions of the trial, we don't think it will read out at that first interim look.

Got it. We can still file on the PFS assuming its positive?

Exactly.

Mike King, JMP Securities.

A lot of my questions have been asked and answered. So I guess, Briggs, only thing left for me would be to ask you on 6352, what is going to help us understand how the profile differentiates against other CSF1R inhibitors when you show us the data, and do you have any thoughts as to if that -- if the data top-line may come out later this year or is that something we should anticipate next year, maybe just a little bit of color on those topics?

So, the ongoing clinical trial is a single ascending dose trial in normal healthy volunteers and what we'll be able to get from that trial is obviously PK, PD and some safety data. So I think in terms of -- from that trial in terms of the only things that we would be able to potentially inform differentiation really be dose and dose frequency. So as we get a better sense of the PK and PD of the molecule, we'll be able to work with our pharmacometricians to do some modeling of what we think the dose and dose frequency would be and then that would be one thing that we could say potentially by the end of the year. Beyond that, I don't think we can get that much more out of the single ascending dose trial.

Would there be any biomarkers that you could look at that could predict clinical activity?

Well, we have pharmacodynamic biomarkers in the trial. So we're looking at effects on non-classical monocytes and the duration of the effect on non-classical monocytes. So we'll have, I think, a pretty good view of the ability to block CSF1 and IL-34 and what effect that has on downstream pharmacology and how long that lasts. But again, it's normal healthy volunteers, so we won't have information that correlates that to efficacy until we move into the trials in cancer patients.

Okay. But you'll be able to read out that you've got the expected on-target activity?

Exactly.

Okay. And then I guess a bigger-picture strategic question, just as far as your thought process behind the combinations of entinostat with the checkpoints, BAVENCIO in ovarian, dicentric and TNBC, and I know that these other checkpoint modulators have shown activity in those particular tumor types, but I think that most clinicians would agree that these drugs are more alike than dissimilar. So from a Syndax sort of upside or optionality point of view, how does -- how do you guys benefit from continuing with these trials with different checkpoints in disparate tumor types? Thank you.

Yes. So, I think, Mike, your hypothesis that these agents are more similar than different seems to be playing out as clinical data on all of them accumulate.

I think from our point of view, there -- and it goes back to the question about how we would develop the drug, for example, in melanoma, there is a scenario where one could think about combining Entinostat with any PD-1 or PD-L1 that has an indication in the tumor type that you're studying. And so by having safety data with entinostat combined with each of these, that enables us to think about that type of a trial design.

While it's true that I think that from an efficacy point of view, they seem to be more similar than different, from a safety point of view, we just want to make sure that that's true. Remember, they're all slightly different antibodies. So we are generating safety data with three in our ENCORE trials and then there is data being generated with ipi/nivo in a NCI-sponsored trial.

So I think it would be helpful for us to have safety data with all of the agents. So depending on what we do from a development point of view, there could be a possibility to combine entinostat with multiple agents within one trial.

Okay. And is it fair to say that it would also lead to sort of a generalizable effective entinostat that it could work with any checkpoint and any tumor type as long as there has been demonstration of activity with one of those?

I think the philosophy that you're espousing is the one that we're interested in. There's always the regulatory definition of how generalizable is that and that depends, of course, on which ones you've studied. So again, being able based upon safety and to be able to study multiple ones in combination with entinostat, that improves our chances of having a more generalizable label.

Christopher Marai, Nomura.

It's actually (inaudible) for Christopher Marai. And my question is regarding the 601 cohorts. Will any of them provide any biomarker data to help us dish out instant effect on suppressive versus non-suppressive myeloid cells and will any of this data be present at ASCO?

So, to answer your first question is, yes, we've been fortunate working with our investigators to get biopsies in the subset of the patients before they were treated with entinostat and pembro and then after they were on therapy. And so, we are accumulating all of that data now. To be honest, we are still in the phase of analyzing all that, and I don't know exactly what we're going to have ready to present at ASCO versus what we'll have analyzed to be able to present later in the year. But we are collecting quite a bit of information, and we will at a minimum at the ASCO poster be able to describe what all those biomarkers are that we're doing. It's just -- the data is coming in, in real time and we just don't know whether we'll have it all collated and analyzed and ready to present at ASCO or whether we'll have to wait till later in the year.

And should we expect clinical data at the ASCO presentation?

You will definitely see clinical data on the first 13 melanoma patients, yes.

Okay. And I have a second question, kind of follow-up for the question about the combination of CSF-1R with entinostat. So a recent paper in nature highlighted the Class 2 HDAC inhibitor modality to repolarization of TAMs, and what is showed in this paper that co-treatment of anti-CSF-1R abolished this effect. So how -- I mean, taking into consideration that this is preclinical data and the difference between the classes, Class 2 and Class 1, how do you think about this data in relation to entinostat and the ability to combine it with CSF-1R antibody?

Right. So I think if I remember the paper you're referencing, as I think you had said, it was a Class 2 HDAC inhibitor, not a Class 1 HDAC inhibitor, and we've certainly seen in other preclinical experiments, when you look at, for example, Tregs, that a Class 1 inhibitor and in fact and specifically entinostat has effects on Tregs that pan-HDAC inhibitors do not, presumably because the pan-HDAC inhibitors' Class 2 or Class 3 activity is blocking that. So we're running our own experiments, specifically with entinostat and with (inaudible) counterpart of 6352, so we can understand exactly how our selective Class 1 inhibitor does that. It would not be unprecedented that there have been distinctions between a Class 1 HDAC inhibitor and ones that pick Class 2.

Thank you. Ladies and gentlemen, this concludes our question-and-answer session for today. So now, it's my pleasure to hand the conference back over to Briggs Morrison, Chief Executive Officer, for closing comments and remarks.

Thank you very much, operator. Thank you everybody for your participation in the call. Thank you for all the wonderful questions. We look forward to catching up with people at ASCO.

Ladies and gentlemen, thank you for your participation on today's conference. This does conclude the program and you may all disconnect. Everybody, have a wonderful day.