Syndax Pharmaceuticals' (SNDX) CEO Briggs Morrison on Q4 2017 Results - Earnings Call Transcript
Syndax Pharmaceuticals, Inc. (NASDAQ:SNDX) Q4 2017 Earnings Conference Call March 5, 2018 4:30 PM ET
Melissa Forst - Argot Partners
Briggs W. Morrison - CEO
Richard P. Shea - CFO
Peter Ordentlich - CTO
Michael L. Meyers - SVP and CMO
Chris Shibutani - Cowen and Company
Christopher Marai - Nomura
Robert Hazlett - BTIG
Tony Butler - Guggenheim Securities
Joel Beatty - Citi
David Lebowitz - Morgan Stanley
Madhu Kumar - B. Riley FBR
Unidentified Analyst - Oppenheimer
Good day, ladies and gentlemen and welcome to the Syndax Pharmaceuticals Fourth Quarter 2017 Results Conference Call. At this time, all participants are in a listen-only mode. Later we will conduct a question-and-answer session and instructions will follow at that time. [Operator Instructions]. As a reminder, this conference maybe recorded. I would now like to turn the conference over to Ms. Melissa Forst of 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 fourth 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 is Michael Metzger, President and Chief Operating Officer of Syndax. The call is being accompanied by a slide deck that has been posted on the Company's website. So, I would ask that you please turn to our forward-looking statements on Slide 2.
Before we get begin, I would like to remind you that any statements made during this call that is not historical is 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 Quarterly Report on Form 10-Q as well as reports filed with the SEC. Any forward-looking statements represent our views as of today March 5, 2018 only. A replay of this call will be available on the Company's website at syndax.com. And now please to Slide 3 and I am pleased to turn the call over to Dr. Briggs Morrison.
Briggs W. Morrison
Thank you very much Melissa and thank you to everyone joining us on today's call and on the webcast. This afternoon I will share the progress we've made during the fourth quarter as we continued to execute on our corporate strategy in support of our primary mission which is to realize a future in which people with cancer live longer and better than ever before. Slide 3 briefly summarizes our corporate strategy which includes developing three potential best in class molecules entinostat, SNDX-6352, and our Menin-MLLr portfolio which are being tested in five ongoing clinical trials across six different indications. An important component of our corporate strategy is the opportunistic in-licensing for acquisition of products that have both a compelling strategic fit and a potential return on our investment something I will say more about at the end of my prepared remarks.
Slide 4 provides a summary of the investment highlights for Syndax. During this call I will primarily focus on the progress we're making with our lead program entinostat. I will discuss both our Phase III trial for breast cancer which received a breakthrough therapy designation from the FDA as well as our exciting ENCORE clinical trial program which combines entinostat with PD-1 antagonist. Slide 5 provides a summary of the milestones that we communicated on our last call back in November 2017. We have now completed our regulatory consultations concerning a development strategy for entinostat in melanoma and I will update you on the remainder of these milestones throughout the call.
Let me now turn to Slide 6 and give you an update on our Phase III trial of entinostat in hormone receptor positive breast cancer. Slide 6 summarizes the trial design and the endpoints of the trial which also summarized the key upcoming milestone. As we communicated previously in the fourth quarter of last year the ECOG Data Safety and Monitoring Committee completed the final PFS analysis and the first interim OS analysis of this trial. And these analysis are held confidentially by the ECOG-ACRIN study statistician and the data safety monitoring committee. No communication regarding this analysis will be released until the completion of enrollment. The trial is 89% enrolled as of the end of February.
Our colleagues at ECOG-ACRIN maintain a goal of completing enrolment by the end of June and we continue to work with ECOG to bring this important trial to completion. Nonetheless if we were to conservatively predict the timing of completion of enrollment based upon an average of the enrollment rate over the last 12 months we would anticipate enrolment completing sometime in the third quarter of this year. We will continue to update you about the precise timing of the completion of the enrollment of the trial as the final enrollment progresses. Once final enrolment is achieved we will learn of the results of the final PFS analysis and if positive we are poised to file an NDA by the end of this year.
I would also like to remind you that the Data Safety Monitoring Committee will examine updated overall survival every six months. Should any of those interim analyses of overall survival show a statistically significant benefit the trial will end and all data will be released to ECOG and Syndax. We remain confident of the potential outcome of 2112 even that's based upon a strong Phase II data which of course led to the FDA breakthrough therapy designation.
Slide 7 emphasizes the potential for the entinostat exemestane regiment that we are studying in E2112 to be the preferred agent after CDK4,6 therapy for HR+ positive HER2- breast cancer. We know that CDK4 therapy is most notably high brands are being used increasingly as first line agent but there is a clear need for an effective treatment after patients progress. Our current estimate is that between 30% and 50% of patients in E2112 will have received a CDK4,6 inhibitor prior to entering the trial. And thus we will have a highly relevant dataset in this population.
Importantly as shown on Slide 7 we have tested entinostat in three distinct preclinical models of palbociclib resistance and have found no cross resistance with entinostat. That is the median effective dose of entinostat in these model systems and is the same whether or not the cell line is resistant to palbociclib. This preclinical data suggests that the fact that patients have received the CDK4,6 inhibitor prior to entering E2112 should not affect the ability of entinostat to provide a clinical benefit. Together we believe this data uniquely positioned entinostat to be the preferred agent after CDK4,6 first line therapy.
Slide 8 makes the same point and notes that this population of patients is relatively large with an estimated 34,000 patients who go on to receive hormone therapy after failing first line therapy and could therefore potentially be eligible to receive entinostat. And we now turn to Slide 9 which summarizes our exciting ENCORE clinical trial program in which we are testing entinostat in combination with PD-1 pathway antagonist. Either PD-1 antibodies or PD-(L)1 antibodies. We are now exploring entinostat in combination with a PD-1 antagonist in six different tumor types. We have previously talked extensively about our studies in melanoma, non-small cell lung cancer, microsatellite stable colorectal cancer, triple negative breast cancer and ovarian cancer.
In January we announced that in addition to studying triple negative breast cancer Genentech extended its collaboration with us to also study hormone receptor positive breast cancer with a combination atezolizumab and entinostat. It is important to note that we have already presented clinical data establishing that entinostat can reverse resistance to PD-1 antagonist both in melanoma and in non-small cell lung cancer. Our trial in colorectal cancer is open label and we have already seen promising data in that population as well. This broad clinical trial program is supported by an extensive call it science program that is designed to identify biomarkers that could predict which patients will respond to our combination therapy, an effort that is starting to yield exciting preliminary results. We're extremely encouraged by the results we're seeing across this clinical trial program and as we complete our initial clinical trial of each tumor type we will prioritize which indications to advance to registration trials based upon unmet medical need, the competitive landscape, and our ability to generate a return on our investment.
Slide 10 is a summary of where we are with our program in melanoma. We presented the initial cohort of 13 patients at ASCO in 2017 where we saw a 31% response rate. Based upon continued discussions with melanoma physicians it's clear that a response rate of about 20% or greater would be highly clinically relevant especially in patients whose disease has progressed after having received both a PD-1 antagonist and a CTLA-4 antagonist. Given the tremendous enthusiasm for this combination from our investigators we've allowed continued enrolment in this cohort of patients and now are enrolling up to a total of 52 patients. We anticipate presenting a full update of this cohort at ASCO. Even though we have now concluded our regular grade consultations as well as a number of advisory boards with physicians who are expert in the treatment of melanoma we will also be providing details on our registration program sometime in the first half of this year.
Slide 11 is data that we presented at SITC in 2017 that shows the impressive durability of the treatment of entinostat in combination with pembrolizumab. Indeed at this point we now have three of the first 13 patients who have been on therapy for over a year. Slide 12 is a summary of where we are with our program in non-small cell lung cancer. We presented the initial cohort of 31 patients whose disease had progressed on a PD-1 antagonist at 50 in November of 2017. The response rate in that cohort was 10%. Although response rate was on the lower end of our aspirations we have continued to receive strong feedback from physicians participating in the trial. And as I noted earlier we are making exciting progress with our extensive corollary science programs designed to identify biomarkers that could enable us to enrich for responding patients in future clinical trials. We have allowed continued enrolment in this cohort to aid in our biomarker discovery effort, we're now enrolling up to a total of 70 patients and anticipate presenting updated data at ASCO this upcoming June.
Slide 13 highlights that biomarkers are routinely used today to select the most appropriate therapy for patients with non-small cell lung cancer. Outside of oncology [ph] tests for EGFR mutation and out rearrangements are not routine and there are a number of commercially successful therapies that are specifically used for patients with dose genetic lesions. KETRUDA of course is indicated as monotherapy for newly diagnosed lung cancer patients with high PD-(L)1 expression and BMS recently communicated that tumor mutation will burden may be a marker to select newly diagnosed patients who benefit from the combination of OPDIVO and YERVOY. Based upon this established approach to treating non-small cell lung cancer we are focusing our efforts on developing a patient selection strategy that may enable to enrich for a specific population of patients as we progress in our development of entinostat in non-small cell lung cancer.
Slide 14 is a summary of where we are with our program in colorectal cancer. We completed enrolment of the first cohort of patients at the end of the third quarter of last year and are continuing to monitor patients. We anticipate presenting data on this cohort at ASCO and hope to decide whether to expand this cohort by midyear. Based upon continued discussions with physicians who are expert in the treatment of colorectal cancer it's clear to us that a response rate of even 15% would be highly clinically relevant in this population of patients who has failed all standard therapies. Indeed there are no responsers reported in this population of patients treated with APD-1 antagonist at monotherapy and the Stivarga label reports response rate of just 1%.
Slide 15 summarizes some of the recent industry data pretentiousness [ph] in this regard and emphasizes that threshold for approved efficacy is modest in microsatellite stable colorectal cancer. On the left is the recently published data from KEYNOTE-028 with a median PFS with KETRUDA monotherapy was 1.8 months and no responses reported in the PD-(L)1 positive microsatellite stabilization. On the right is data recently presented at ASCO GI of a combination of the TECENTRIQ and Cotellic where response rate of 8% and median PFS of 1.9 months was reported. A combination of TECENTRIQ and Cotellic compared to Stivarga is being studied in a Phase III trial. Again the main point in our view is that the threshold for improved advocacy is modest in microsatellite stable colorectal cancer.
Slide 15 makes the point that microsatellite stable colorectal cancer represents a significant market opportunity for entinostat if we can demonstrate efficacy in the third line setting. And finally on Slide 17 we summarize ENCORE 602 and 603, our Phase II trials in triple negative breast cancer and ovarian cancer. Both of these trials are currently enrolling and anticipate data from ENCORE 602 at the end of this year and from 603 in the first half of next year. Again we're very pleased with the breadth of our ENCORE clinical program and the excitement we are sensing from physicians who are conducting these important clinical trials.
Let me now turn to Slide 13 and SNDX-6352, our potential best in class monoclonal antibody therapy targeting the CSF-1 receptor. To present the Phase I healthy volunteer data at SITC in November of 2017 and the multiple ascending dose study in cancer patients is ongoing. In January of this year we were very pleased to announce our collaboration with AstraZeneca, with a combination of 6352 with Infinity, a Phase Ib combination study is anticipated to start the next quarter. We've now designed a focused clinical development program for this molecule and we will say more about that clinical development program later this year.
Slide 19 summarizes our Menin-MLLr program which I covered extensively on our last call and withstands a broad range of leukemias and potentially other indications as shown on the slide. We remain on track to file an IND in the first half of 2019 and it will be an oral presentation at AACR that's coming up April discussing the exciting pre-clinical data that's been generating with our molecule.
And finally slide 20 summarizes how the transactions that we have completed to acquire both 6352 and the Menin-MLLr programs prove that we have an ability to strategically expand our pipeline. Our management team and board have established relationships that allow us to identify quality assets and the extensive clinical development experience of our team gives us a competitive advantage in closing agreement. We continue to spend significant effort in this area and we consider this capability to be a core strength of our company. And with that I'll turn it over to Rick for the financial update.
Richard P. Shea
Thank you Briggs. Turning to Slide 21, for the two months ended December 31, 2017 Syndax reported a net loss of $19.1 million or $0.80 per share compared to $10.8 million or $0.59 per share for the comparable prior year period. Fourth quarter 2017 research and development expenses increased to $16.6 million from $8.5 million for Q4 2016. R&D expenses for the year ended December 31, 2017 increased to 48.2 million compared to 31.7 million for the prior year. The increases were primarily due to increased trial activities related to our clinical pharmacology studies, increased enrolments in ENCORE 601, 602, and 603, costs related to the 6352 trials as well as CMC activities, increased headcount, legal and consulting expenses, facility costs, and travel costs. Included in R&D expenses in Q4 2017 we expensed a nonrefundable upfront payment of $5 million to Allergan for the Menin assets. And in 2016 we expensed the nonrefundable upfront payment of $5 million related to the UCD license agreement for 6352.
General and administrative expenses totaled $4.1 million during the fourth quarter of 2017 and $15.9 million for the year compared to $3 million and $13.3 million for the respective prior year periods. The increase in G&A expenses was primarily due to increases in headcount, pre-commercialization work, professional fees, and costs related to being a public company. And these increases were partly offset by decreases in legal expenses. As of December 31, 2017 there were 24.4 million common shares outstanding on a fully diluted basis using the treasury stock method we had 26.9 million shares outstanding. Additional financial details will be available in our annual report on Form 10-K which we intend to file this week. Syndax ended the fourth quarter of 2017 with a cash balance of $133.2 million which we believe is sufficient to fund development into 2019 enabling us to reach key development milestones.
Looking ahead our 2018 revenue which consists of the amortization of payments from KHK will be $0.4 million per quarter. We expect R&D expenses to be $18 million to $22 million for the first quarter and $67 million to $76 million for the full year 2018. And total operating expenses are expected to be $22 million to $26 million for Q1 and $86 million to $96 million for 2018. Now I'd like to turn the call back over to Briggs.
Briggs W. Morrison
Thanks very much Rick. Looking ahead we anticipate several key upcoming milestones which are summarized on Slide 22. We will be communicating our registration strategy for entinostat in melanoma in the next quarter along with data presentations from the melanoma non-small cell lung cancer and colorectal cancer population to ENCORE 601. We anticipate to be able to make a decision regarding the expansion of the colorectal cohorts by midyear. As I indicated earlier the timing of the completion enrolment of our Phase III trial of entinostat in hormone receptor positive breast cancer has some uncertainty which we have illustrated at sometime between the second and third quarter of this year. Top line results from ENCORE 602 remain on track for the end of this year and with regards to SNDX-6352 we look forward to sharing both the data from our multiple ascending dose trial and our focused clinical development strategy. It will certainly be a busy year for us here at Syndax.
As always I would like to thank the team here at Syndax, our collaborators, and most importantly the patients, trial sites, and investigators involved in our clinical programs. With that I'd like to open the call for questions.
[Operator Instructions]. And the first question will come from the line of Chris Shibutani with Cowen. Your line is now open.
Yes hi, thanks very much for the update and just making sure that we fully understood the factors that contributed to this shift in timeline for the breast cancer study with entinostat moving into Q2, Q3. So is it fair to say that this is primarily related to the ECOG group and the pace for their enrolment, are there any other factors that have shifted this timeline at all? Thanks.
Briggs W. Morrison
Hi Chris, first congratulations on your kids performances, really very inspiring. Yeah, no it is really just we're getting into the end of the enrollment and there's a month to month variation in that and we just wanted to clarify for people that again as I said if you draw a straight line around the average enrolments comes out a bit later than the end of June. You talked of course they are still trying to do everything they can to finish the enrolment by the end of June.
Great, and thank you for your comment. If I could shift quickly over to CSF1R opportunity, I noticed you used the phrase potential best in class and obviously there's several ongoing, can you talk about how you're thinking about potentially positioning this given that there are sort of several simultaneous trials going on with different indications, can you talk about where you think perhaps the best opportunity is, obviously we've all seen some competitor data in pancreatic etcetera, if you can help us how to think about that that would be great?
Briggs W. Morrison
Sure, as I said in my prepared comments because I think what we'd like to do is through maybe the middle of the year give you a full update on the clinical development strategy. As you have correctly noted there is a fair amount of competition here and so we want to be a little careful about what we talk about until we're sort of well underway. So we have a lot of efforts ongoing to set up some trials in areas where we think we can differentiate from what some of the others are doing and we look forward to sharing that plan with you probably the middle of the year.
Great and then lastly I think you used the word encouraging when you characterized some of the early signs and data that you're seeing in the CRC opportunity. Any chance I could bully you into perhaps elaborating on that? Thank you.
Briggs W. Morrison
So, what I would say is as you well know the ASCO abstract deadline has passed so we have submitted abstracts for CRC for non-small cell lung cancer and for melanoma. And so that I don’t think comes out until middle of May or so I think before the meeting. But when those abstracts come out I just wanted to highlight that you'll see some data in the colorectal cohort that we find promising.
Great, thank you very much for the questions.
Thank you and the next question will come from the line of Christopher Marai with Nomura. Your line is now open.
Good afternoon, thanks for taking the questions and congrats on the progress this year. First wanted to touch upon the last question just on the CSF1R data and maybe the focus that you may have bringing that forward in the clinic, recent data and not your pre-clinical data suggests that this drug may be helpful beyond the IO space. How should we think about your positioning, would you look at this development pathways more of an IO specific focus or potentially outside that for instance combinations with chemo, etcetera? And maybe could you frame that in light of your recent cooperation AZ? Thank you.
Briggs W. Morrison
Sure, so I think Chris yeah you're absolutely right. If you review the literature for this target you'll find evidence for using it in combination with PD-1, in combination with chemotherapy, in combination with radiation therapy, in combination with cell therapy, in combination with hormonal therapy so there's lots of opportunities we believe. That's why I think the opportunity set is a little broader perhaps than people have talked about and that's what we'd like to talk more about at -- in the middle of the year. Clearly the combination with PD-1 or PD-(L)1 is on our list because we have an agreement with AZ to do combination work with durvalumab. So that is one of the things that we're interested in but I think your question sort of backs up our view of we should take a broader view of the potential of this molecule and adjust the combinations with PD-1.
Great, and then just a follow up with respect to that colorectal biomarker studies that you have been doing for really the IO combos, I was wondering if you could further elaborate on some of the biomarkers that you are looking at and some that may appear most promising in your view? Thank you.
Briggs W. Morrison
Sure, so still on the slide we are looking at things that probably wouldn't surprise anybody. PD-(L)1 expression tumor mutation will burden various immune cells some both in the tumor and in the peripheral blood as well as nanostream assays of the tumor specimen. So I think we're really quite fortunate that our Chief Scientific Officer, Peter Ordentlich has set up a really comprehensive approach. And as I said in my comments I think as we look at that it's still early days but as we look at some of that biomarker data coming in and look at it relative to the clinical activity we're seeing some encouraging data there that I think makes us feel optimistic that we'll be able to find a way to segment patients which is why I spend all the time talking about segmentation in lung cancer. So, obviously what we do today and we think if we can similarly find segments in population it would give us an efficient path forward in that disease.
Great, thank you.
Thank you and the next question will come from the line of Robert Hazlett with BTIG, your line is now open.
Thanks, I realize you're going to be discussing some of the melanoma registration strategy a little later in the year Briggs but could you just give us a little bit of an understanding of what the pushes and pulls with regard to that strategy may be?
Briggs W. Morrison
Sure, so I think Bert you know Michael Meyers and his team have done a wonderful job speaking to regulators not just in the U.S. but in Europe as well. So I think we have a very good view of what regulators around the world would expect from either an accelerated approval or full approval strategy. His team has also done a terrific job talking to melanoma physicians again from around the world not just in the United States. So we have a pretty good sense of what melanoma physicians are looking for. I think the -- what's involved in the melanoma space I think perhaps compared to when we started the trial and sort of what's evolved overtime is really the issue of the combination of PD-1 CTLA-4. So there are patients today who get treated with PD-1 monotherapy, there are patients who get treated with PD-1 CTLA-4 combination therapy either in combination from day one or in sequence. And those two populations are probably distinct from both the clinical and regulatory point of view. So the patients who have failed both of PD-1 and CTLA-4 probably represents a patient population that was the highest unmet medical need. Patients who have failed a PD-1 monotherapy have not yet received a CTLA-4 or still has an option of receiving a CTLA-4. So, we are sort of looking at those different if you will patient journeys and understanding the regulatory view of those patient journeys and how therapy is evolving. So that sort of factors into the way that we think about our final registration program.
Okay, thank you. Just kind of a blocking and tackling question, it is -- the ECOG-ACRIN group going to announce it themselves in terms of the results or is it yours to announce? In terms of the PFS-1, the PFS data?
Briggs W. Morrison
Yeah, it will come from us. The Data Safety Monitoring Board will communicate to ECOG and to us. And again our clinical team will sort of review what they communicate to us but the communication on whether the PFS data was potentially significant positive or whether we just continue the trial that will come that.
Okay, thank you and just one last one you looked at another number of abstraction including the oral presentation at AACR, you highlighted the Menin program previously, is there any other abstract or there are other abstracts of particular importance at AACR that we should be focused on?
Briggs W. Morrison
Yeah, I'll leave that maybe Peter Ordentlich can take that question, Peter.
Yes, sure hi. I think there are some interesting abstracts and you know our focus in the past has been on the mildly compartment active -- that will have data at AACR on factor of intent status on the T cell compartment that is the collaboration with Samir Khleif so that will be interesting to see. And then you -- I have noted the collaboration with [indiscernible] and the combination [indiscernible] and the HER2-14 and this was follow up to the original data that was shown with high dose IL-2 so those are just studies done in a couple of different tumor models looking at effects on various immune end points and tumor efficacy.
Okay, well thank you.
Thank you and the next question will come from the line of Tony Butler with Guggenheim Securities. Your line is now open.
Thanks very much Briggs. Three questions if I may, it is all around 2112. And apologies if I had missed this previously, was there a futility analysis when the last interim was done, point one? I will just go ahead and announce all three of these if I may. Second is, what to assume for the moment that the trial is positive, do you have -- or have you thought of other plans with the entinostat monotherapy in breast cancer or other tumors with -- maybe to our CC for example or you think there maybe some utility, again monotherapy? And then the third question relates to the notion of you showed some other -- there were some interesting data on CDK4,6 inhibitor and not showing an adherence. So the question is I will refer you to 50% patients who have been on palbo for example, are those patients still on palbo when they get entinostat, are they also allowed to switch perhaps to another CDK4,6 inhibitor, regardless of that is there combo and during the drug how are they -- I assume they are going to still take their entinostat is that the case? Thanks.
Briggs W. Morrison
Hi, Tony thanks very much for all your questions. So first let me just take them in order. The question on the futility analysis there is -- the protocol calls for a futility analysis and overall survival only if the PFS analysis is negative. So we don't know whether futility analysis was done on overall survival or not because we don't know the result of the PFS analysis. But the protocol does allow for futility analysis and in all subsequent OS analysis there is also the protocol will allow us for futility analysis as well.
Your second question about what if 2112 is positive, what we would do next in terms of monotherapy, it's a good question. In the case of 2112 of course the rationale for the combination is that essentially what entinostat in simple terms when I think about it is essentially restoring actual insensitivity and so therefore you want the antiestrogen in aromatase inhibitor that's how you get activity. There was some monotherapy work done with entinostat early in its development, more in hematologic malignancies. We haven’t given that much thought to doing monotherapy trials either in breast cancer or other tumors at this point. But that of course is part of the life cycle management.
And your last question about the CDK4,6 is if a patient came into 2112 they would not remain on their CDK4,6 inhibitor, they would be a patient who has received CDK4,6 probably with an aromatase inhibitor progressed and then they commenced the trial and get randomized to your exemestane and monotherapy or your exemestane plus entinostat. So, that's not to say that again to your question about life cycle management, somewhere down the road when we do a trial where we combine entinostat legacy CDK4,6 that’s certainly something that would be of interest but the way 2112 is designed they do not take the CD4 -- they did not stay on their CDK4,6 inhibitor.
Thanks very much Briggs.
Thanks and the next question will come from the line of Joel Beatty with Citi. Your line is now open.
Hi, thanks. The first question is on Phase III 2112 trial and the dynamics between the PFS and the OS endpoints. Could you share how the powering is split between those two analyses? And then also I know we're still waiting for the trial to finish enrolment to find out about the PFS results but I believe there's also been OS analyses and if that was positive would the trial have been staffed early or conversely if the futility analysis was non-OS would the trial have stopped early or can we read into how OS is performing?
Briggs W. Morrison
Thanks Joel for your questions. So first on the separation of PFS and OS. As you may know the trial has essentially two independent end points and so alpha suspended [ph] split between the two. So for PFS 0.002 of the alpha is the sign to PFS, and 0.048 of the alpha is a sign to OS. Now your question about the OS analysis, so at the time that the protocol calls for, at the time that the final PFS analysis is done the first interim analysis of OS would also be done. And there's a very, very small amount of that spend to do that interim analysis.
If the trial had been positive on OS at that point that would have been communicated to us. So if at any of the interim OS analyses the trial is positive, the trial ends and that's communicated. So what we can say is based upon that interim OS analysis the trial was not positive on OS at that first interim. To be honest that's not all that surprising because the level of significance and treatment effects you would have needed to see we estimate probably no more than 10% of the OS events have occurred so you would have actually seen a fairly large OS benefit for it to be declared positive on that first interim. So we don't read very much into that. But again as I pointed out in my prepared remarks there are additional OS analysis every six months so there are roughly May and November of each year. So by the end of this year we will have two additional interim analysis of overall survival.
Thanks for that and then one other question on the melanoma IO combo study, I know we're waiting to hear about the trial design but now that you've finished the communications with FDA are you doing anything to help prepare to start a Phase III trial before the final [indiscernible]?
Briggs W. Morrison
Yeah, thanks for the question Joel. Yes indeed we are. There our Chief Medical Officer and the Clinical Operations Group is actually working quite diligently to get the program up and running. We haven't yet sort of communicated to you what exactly that program is but that's not deterring them from taking a lot of work on the collaboration.
Great, thank you very much.
Thank you and the next question will come from the line of David Lebowitz with Morgan Stanley. Your line is now open.
Thank you very much for taking my questions. With the expansion of the melanoma and refractory non-small cell lung cancer cohort how did you decide on the new population sizes?
Briggs W. Morrison
Yeah, hi David, thanks very much for the questions. So the -- as I indicated in my comments the investigators in both trials are quite excited about what they're seeing clinically and so our team adjusted essentially the power of calculation to give us more precision around the point estimates and that's what led to the specific numbers. But to be honest it was really in large part driven by the investigators that want us to be able to see lot more patients.
Okay, thank you very much for taking my question.
Thank you and the next question will come from a line of Madhu Kumar with B. Riley FBR, your line is now open.
Good afternoon, thanks for taking my questions. My first question relates to the cyclicality of patient requirement in the 2112 trial. Is there any reason to think that say fourth quarter recruitment rates seem to be slower than other quarters or as you mentioned is the straight line of recruitment kind of the best way to think about the pace of recruitment in the breast cancer trial?
Briggs W. Morrison
Yeah, I'll let Michael Meyers, our Chief Medical Officer answer that question, he is probably closest to the data.
Michael L. Meyers
So, I don't think there's any evidence that recruitment is that cyclical, certainly not quarter-by-quarter. What is obvious is that on a month-to-month basis there are variations which do not appear to play out from a year-to-year and have been rather unpredictable.
Okay, great, thanks. And now thinking about the melanoma trial, looking at the Phase II as you have enough patience to be able to distinguish the effects of entinostat with pembro [ph] in combination -- and paged to our post PD-1 loan versus post PD-1 and CTLA-4?
Briggs W. Morrison
Yeah, I think -- thanks very much for the question. I don't think with any -- and certainly we did not power the trial to be able to make that distinction. So we can certainly look at those from sort of a point estimate point of view. But I wouldn't say we have a large enough sample of patients to make that distinction. Obviously since we've increased the sample size, again mostly driven by investigator interest we'll have some information on that but I wouldn't say that it would be -- we haven’t power for that question.
And from a kind of operational expenses perspective, when you give the ranges for 2018 OPEX, what kind of trials does that encompass. I mean you are at 2112 you've got the Phase II in melanoma, the Phase II in non-small cell, the Phase II in microsatellite stable colon, is that kind of the base case of trial that you would have running through 2018 or does it assume for example registrational study in melanoma?
Briggs W. Morrison
Yeah, Rick you want to take that one.
Richard P. Shea
Yes, I will. Yeah, right now it does not include the full impact of a registration study in melanoma. So, at the time we announced that study we will be updating that guidance on operating expenses. Now since that trial would be starting in the second half of the year the impact would be more felt in 2019 and less so in 2018.
Alright, thanks for taking my question guys.
Thank you and the next question comes from the line of Hartaj Singh with Oppeheimer. Your line is now open.
Hi guys, this is Emma on for Hartaj. So you said that Menin MLLr program is on track for an IND selling in the first half of 2019, could you just expand at that on where you are now in the -- work and what exactly we can expect to see at AACR and then just what the remaining guiding factors are for getting that IND submitted and entering the clinic?
Briggs W. Morrison
Right, so AACR is -- it would be a presentation on of course the rationale for the development of the molecules and pre-clinical efficacy models. Some of the standard model that people use as well as pre-ex models. In terms of where we are with the work, it's sort of standard preclinical work up at this time of scaling up the molecules, getting through -- getting the GLP talk studies done and putting the IND together.
Thank you and we are showing no further questions at this time. I would now like to turn the conference back over to Dr. Briggs Morrison, CEO for closing remarks.
Briggs W. Morrison
Thank you very much everybody for joining us on the call. We look forward to updating you on our exciting program as the year progresses. Have a good evening.
Ladies and gentleman, thank you for participating in today's conference. This does conclude your program. You may all disconnect. Everyone have a great day.
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