Good afternoon, ladies and gentlemen, and welcome to the Syndax Third Quarter 2019 Financial 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. And as a reminder, this conference call may be recorded. Would now like to turn the conference over to your host today, Ms.
Melissa Forse with Argo Partners.
Thank you, operator. Welcome, and thank you to those of you joining us on the line in the webcast this afternoon for a review of Syndax's Q3 2019 financial and operational results. I'm Melissa Forrest with Argo Partners, and with me this afternoon to discuss the results and provide an update on the company's progress are Doctor. 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 and Doctor.
Michael Myers, Chief Medical Officer. This call is being accompanied by a slide deck that has been posted on the company's website. So I would 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 not historical is considered to be forward looking 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.
This includes being discussed in the Risk Factors section in the company's most recent quarterly report on Form 10Q as well as other reports filed with the SEC. Any forward looking statements represent the company's views as of today, November 7, 2019, only. A replay of this call will be available on the company's website following the call. And with that, I am pleased to turn the call over to Doctor. Briggs Morrison, Chief Executive Officer of Syndax.
Thank you, Melissa, and thank you to everyone for joining us on today's call and webcast. Slide 3 provides a high level summary of our current corporate priorities as we strive to realize a future in which people with cancer live longer and better than ever before. We recently announced 2 significant updates for our lead program. First, the ECOG Data Safety and Monitoring Board has communicated to us that E2112 has passed its last interim analysis and will proceed to its final analysis at 410 events. This brings us closer to a potential near term FDA filing, approval and launch in hormone receptor positive metastatic breast cancer.
The second important event is that we have begun dosing patients in our Phase 1 AUGMENT-one hundred and one trial of our highly selective rationally designed menin inhibitor SNDX-five thousand six hundred and thirteen. As a result of this accomplishment, we are now entering a new and exciting chapter in the evolution of Syndax. The SNDX-five 5,613 program takes us into the treatment of genetically defined acute leukemias and importantly broadens our portfolio. Both programs have the potential to become important new medicines. We expect to know much more about the future prospects of both entinostat and SNDX-five thousand six hundred and thirteen over the next 6 to 12 months.
So let's review these opportunities in some greater detail. Slide 4 summarizes the design of the Phase 3 trial of entinostat in hormone receptor positive HER2 negative breast cancer. The trial randomized 608 patients to exemestane plus placebo versus exemestane plus entinostat and the focus of this trial is now clearly on the final overall survival analysis. The final analysis will be conducted once there are 4 10 events. Based upon our modeling, we believe that the final readout of E2112 based on the full 410 events will occur sometime in the Q2 of next year.
Positive outcome would allow us to file for regulatory approval in the U. S. Based upon the terms of our breakthrough therapy designation in hormone receptor positive metastatic breast cancer and our special protocol assessment with the FDA. Our team is prepared to submit a regulatory filing should the trial be positive within about 6 months of receiving the data from ECOG, which would set us up to launch entinostat in 2021. As we have now successfully passed 5 futility analyses and are poised for the final readout of the trial, I'd like to take a moment to remind everyone of the assumptions that were used in the design of the E2112 study.
The trial has 80% power to detect a hazard ratio of 0.75 and the maximum hazard ratio that would yield a statistically significant positive trial is 0.82. Based upon the design assumptions, if E2112 reached a hazard ratio of 0.82 that would indicate that patients receiving the combination had about a 5 month improvement in median overall survival from about 22 months median
over survival in the control arm to about 27
months median overall survival in the combination arm. Our market research indicates that this magnitude of benefit in overall survival is perceived by prescribing physicians to be important and clinically meaningful. We remain confident in the potential for E2112 to be a positive trial. Slide 5 emphasizes the potential for the atinostat exemestane regimen to be the preferred agent after a first line aromatase inhibitor, which is typically given either as single agent or in combination with a CDK4six inhibitor. Our current estimate is that between a third and half of the patients in A2112 will have received a CDK4six inhibitor prior to entering our trial.
Thus, we should have a highly relevant data set in the post CDK4six patient population. In our opinion, the rapid adoption of CDK4six inhibitor such as Ibrance in the first line setting underscores the desire of physicians and patients to improve the outcomes associated with anti estrogen therapies. In the setting of a positive E2112 result, we would expect entinostat to achieve similar widespread use. This population of patients is substantial with an estimated 34,000 patients each year who go on to receive hormone therapy after failing first line therapy and who could therefore be eligible to receive the entinostat regimen. Importantly, we will be prepared to launch entinostat in the U.
S. On our own and we are actively building out our internal commercial team to ensure we are well positioned for the potential launch of entinostat in 2021. Let me now turn to SNDX-five thousand six hundred and thirteen, our genetically targeted agent. Yesterday, we announced the exciting news that the first patient has been dosed in the AUGMENT-one hundred and one trial. I'll review that trial shortly, but first we'd like to provide a brief overview of SNDX-five thousand six hundred and thirteen.
Slide 6 summarizes the biology that underlies the development of SNDX-five thousand six hundred and thirteen. Mixed lineage leukemias are driven by a fusion protein known as MLLr. This fusion protein is half derived from MLL1 and half derived from a variety of fusion protein partners. For the fans of Greek mythology, you can think of the fusion protein as a centaur, mythological creature that is half human and half horse. The MLL half of the fusion protein binds to menin, a scaffolding protein involved in activating transcription, while the other half is responsible for recruiting a cancer producing transcription program.
This interaction between menin and the MLL1 half of the fusion protein has been defined at the molecular level and as illustrated on Slide 7, SNDX-five thousand six hundred and thirteen has been rationally designed to block this interaction. FNDX-five thousand six hundred and thirteen is a potent and specific orally available small molecule. Slide 8 is an illustration of how the fusion protein causes cancer and how SNDX-five thousand six hundred and thirteen should work. In the left panel, we see the MLL1 portion of the fusion protein bound to menin and fusion partner half of the protein attracting a multi protein complex to DNA. This results in activation of a family of genes that cause cancer.
In the panel on the right, you can see that SNDX-five thousand six hundred and thirteen binds to menin displacing the fusion protein and its accompanying multi protein complex. The genes that were activated are turned off and the cancer cell differentiates and dies. We've presented extensive preclinical data showing that this mechanism has potent and sustained anticancer effects in numerous in vivo models of both MLLr leukemias and NPM1 mutant leukemias. On Slide 9, we summarize the 1st in human trial in what we call the accelerated understanding of menin inhibition or AUGMENT program. The first in human clinical trial is combined Phase 1, Phase 2 trial.
The Phase 1 portion is a dose escalation trial designed to identify the maximum tolerated dose and a recommended Phase 2 dose of SNDX-five thousand six hundred and thirteen. Patients with relapsed or refractory acute leukemia will be enrolled and will take SNDX-five thousand six hundred and thirteen daily by mouth until they experience either progressive disease or unacceptable toxicity. The first 28 days of dosing will serve as the period in which safety is evaluated for determining dose escalation. Patients are not required to have specific genetic abnormalities in order to enroll in the Phase 1 portion of the study. The first cohorts follow an accelerated dose titration with only 1 patient required per cohort.
Upon entering a pre specified label upon encountering a pre specified label of toxicity, the trial will convert to a standard 3 plus 3 design. We will carefully assess pharmacokinetics, safety and efficacy. It is anticipated that upwards of 30 patients may be enrolled in the Phase 1 portion with the precise number dependent on the number of cohorts that need to be explored and the toxicities that are encountered. We announced this week that enrollment in the AUGMENT-one hundred and one trial has commenced with our 1st patient in the 1st single patient cohort. I want to emphasize that the PK analysis is a key component of the Phase 1 trial.
Our preclinical data indicates that the menin MLLr interaction needs to be continuously inhibited in order to achieve optimal efficacy. And so we will be carefully examining the drug exposures in patients to assess whether we are indeed achieving adequate target coverage. We look forward to seeing these initial PK data in the first dose cohorts as those data will significantly inform the likelihood and timing of single agent efficacy in the MLLr rearranged and NPM 1 mutant leukemic population. Given that patients are not required to have specific genetic abnormalities in order to enroll in the Phase 1 portion of the trial, we believe that PK data from the Phase 1 portion could be more informative than the efficacy assessments with efficacy being an exploratory objective. Furthermore, we believe that safely achieving adequate target coverage in the Phase 1 trial could bode well for establishing efficacy in the Phase 2 portion.
Once a recommended Phase 2 dose is established, the Phase 2 trial will proceed to enroll 3 distinct expansion cohorts, each of which consists of a specific genetically defined relapse or refractory acute leukemia. The 3 cohorts are adults with MLLr acute lymphoid leukemia, ALL adults with MLLr acute myeloid leukemia, AML and adults with NPM1 mutant AML. The Phase 2 portion will further characterize the safety of SNDX-five thousand six hundred and thirteen and will provide an initial estimate of the complete response rate as the primary measure of therapeutic benefit. We know that a lot of people, patients, physicians and investors are eager to see initial data from the first AUGMENT trial. Given that we are just getting the trial up and running, it's not possible to provide specific guidance as to when we will present data.
As of now, we expect to report initial clinical data from the trial in 2020. We should be able to give you a better sense of the data timing as the trial progresses. In addition, we are eager to advance this molecule into the pediatric population. It is a key component of our overall strategy and we will have more to say about the details of the pediatric timing and approach on a future call. We know pediatric leukemias with MLLr rearrangements a significant unmet medical need and we're eager to work with the pediatric oncology community to bring SNDX-five thousand six hundred and thirteen to their patients.
Based upon preclinical data and the underlying biology of the pathway, we are expecting evidence of single agent activity. As a result, there could be a rapid and straightforward clinical development path for 5,613 perhaps similar to the path taken for agents addressing patients with FLT3 or IDH mutations. As we continue to learn more about the potential of SNDX-five thousand six hundred and thirteen in acute leukemia, we see this molecule becoming an additional and important value driver for Syndax. Let me now turn to Slide 10 and SNDX-six thousand three hundred and fifty two, our potential best in class monoclonal antibody therapy targeting the CSF1 receptor. We are conducting a trial testing 6,352 as monotherapy in chronic graft versus host disease.
Chronic graft versus host disease is a frequent complication of hematopoietic stem cell transplantation, wherein the donor derived immune cells contribute to the initiation and development of fibrosis and manifestation of many of the advanced disease symptoms. In preclinical models, blockade of CSF1, CSF1R axis with an antibody can result in the depletion of donor macrophages, thereby preventing and reducing chronic graft versus host disease. We believe that chronic graft versus host disease represents an important opportunity. I mentioned on our last call that when our IND was cleared for the study, FDA required that we'd limit enrollment to patients we'd enrollment has been a bit slower than anticipated. We've now worked with the FDA to modify the enrollment criteria and we are now in a position to enroll a broader set of patients.
We hope to provide an update on this program in the second half of next year. Finally, Slide 11 summarizes transactions that led to the acquisition of the Menin MLR program and the SNDX-six thousand three hundred and fifty two program. We believe that we will be able to continue to expand our pipeline through the acquisition or in licensing of quality differentiated assets. We believe that we have the necessary clinical development expertise to bring these compounds through valuable inflection points and expect to remain among preferred partners such transactions. I will now turn the call over to Rick, who will review our financial results.
Thank you, Briggs. Results of our operations for the Q3 of 2019 and the comparison to the prior year periods are included in our press release, so I won't repeat them in these remarks. Additional financial details are available in our quarterly report on Form 10 Q, which we have filed today. Turning to Slide 12, we ended the Q3 of 2019 with $72,200,000 in cash and 31,600,000 shares and prefunded warrants outstanding. The net change in cash for Q3 was a decrease of $8,300,000 The net loss for the quarter of $12,800,000 was offset by non cash items of $1,600,000 and a net favorable balance sheet change of just under $3,000,000 Looking ahead, I'd like to provide updated financial guidance for both Q4 and for full year 2019.
For the Q4 of 2019, we expect R and D expenses to be $11,000,000 to $12,000,000 and total operating expenses to be $15,000,000 to $16,000,000 including approximately $1,500,000 of non cash stock compensation expense. For the full year 2019, we expect R and D expenses of $45,000,000 to $46,000,000 and total operating expenses of $60,000,000 to $62,000,000 Operating expenses for 2019 are expected to include non cash stock compensation expense of $6,000,000 and our interest income is approximately $2,000,000 So our net cash burn for 2019 is expected to be $52,000,000 to $54,000,000 Cash at year end 2019 is expected to be approximately $57,000,000 and this current cash will allow us to operate the company to achieve key milestones for our prioritized programs, specifically OS results for the E2112 study results anticipated in Q2 of 2020 and early proof of concept for our targeted menin inhibitor SNDX 5613. I'll now turn the call back over to Briggs.
Thanks very much, Rick. I'd like to close our call with a clear summary of our company priorities and important near term milestones. We believe that a positive OS result in E2112 would be transformative for Syndax and create significant shareholder value and we anticipate a final readout in the Q2 of 2020. We also believe that SNDX-five thousand six hundred and thirteen, our menin MLLr inhibitor is well poised for near term proof of concept data. We believe that safely achieving adequate target coverage in the Phase 1 trial could de risk this program with single agent activity in patients with either MLLr or NPM1 mutant leukemia, providing clinical proof of concept and enabling early regulatory clarity and planning for next steps.
For 6,352, we are expecting initial efficacy data in chronic GVHD in the second half of next year. Finally, we are optimistic that we will continue to identify and bring in novel molecules to deepen our portfolio. We have a proven track record of delivering on this pillar of our strategy and I believe this remains the core strength of our company. As always, I would like to thank the team here at Syndax, our collaborators and most importantly, the patients, trial sites and investigators involved with our clinical programs. With that, I'd like to open the call for questions.
Thank you. And your first question comes from the line of Chris Shibutani of Cowen. Chris, your line is now open.
Great. Thank you very much. Briggs and team, appreciate all the update on the programs. A lot to look forward to certainly in the next 12 months. If I could just ask for a little bit more, background to help us understand what we can expect from the AUGMENT trial.
It sounds as if in terms of patient selection standpoint, you're not going to be requiring any specific genetic profile. Therefore, what should we contemplate might be the mix of patients in that study? And then can you also help us with giving us a sense for at what time point you'll be looking to measure efficacy, particularly in the Phase 1 study? And in particular, also, you have the CR, which I believe is kind of a gold standard from a regulatory standpoint. I think in leukemia, there's a lot of discussion about different aspects of complete response rate, CRI, CRH, and as well now minimal residual disease.
So can you help us understand any additional parameters that you think would be helpful to help us understand the efficacy profile?
Great. Thanks so much, Chris, for your question. So, the first point on the mix of patients. So, you're correct that we do not require that there be either MLLr or NPMO mutations in the Phase 1 portion. Having said that, I think as we've talked with investigators to get the trial up and running, they're particularly interested in the enrolling those types of patients.
So we would not be surprised to see the even the Phase 1 portion enriched for patients who have either MLR or NPM1. I can't tell you exactly what that mix will be, but we would not be surprised to see a pretty good enrichment. The time point at which you measure efficacy, so again, I think if we think about the analogs of IDH inhibitors and FLT3 inhibitors, oral agents for targeted mutations in leukemia, the time to response can be anywhere from a month to 6 months. So we'll be monitoring that on an ongoing basis, as the patients continue to get treated. You're correct that the gold standard in leukemia is complete response.
There are other intermediate, I guess we would call them CRI is basically complete response with incomplete bone marrow recovery. CRH is essentially you have half normal amounts of platelets and neutrophils, but CR, just straight flat CR tends to be the endpoint, at least as we've talked with leukemia docs, that is the best predictor of eventually showing overall survival. So in the Phase 2 portion, we do have CR or CRH. CRH seems to be by many people a good marker of efficacy. But and then your last question about MRD.
So, as you know, there's a lot of work going on with MRD and what is from a regulatory point of view and from a clinical point of view, validated assays to assess MRD both in ALL and AML. We're continuing to monitor that. Thus far, I don't think from a regulatory point of view, it's been acceptable to simply take patients and make them MRD positive to negative. They really want to see, pathologic CRs from patients who have frank leukemia, but that's an evolving area of the science and we'll sort of see how it progresses.
Great. And then one last aspect with the Phase 1, you mentioned potentially 30 patients is what you might be aiming for ultimately then taking it into Phase 2 and 3 subgroups of subtypes of leukemia. Should we expect that you will be able to maybe with some intention try to get a relatively balanced number of the different types of leukemia from the Phase 1 or is that the way you're going to be designing or executing the trial?
So I think the Phase 1 is really focused on safety and rapid execution of enrolling patients and assessing safety. So we're not trying to guide physicians or investigators as to enriching one versus the other and trying to slow down one arm or increase another arm. It's really just try to get through quickly so we can get to recommended Phase 2 dose and then do detailed assessment of each genetic lesion in Phase 2. So Phase 1 is, as I said earlier, I think it will be enriched for MLLr and NPM1 not be 100%. And but I can't really give you a breakdown of those 3 different arms in Phase II, how much of each of those we'll see in Phase I.
Okay, great. Thank you very much for the clarification.
Thank you.
Next question comes from the line of David Lebowitz of Morgan Stanley. David, your line is now
With the final analysis from E-two twelve coming up, assuming that a positive analysis would come through, what type of preparations would you have to put into play, I guess, given where your organization stands now to be able to prepare for I mean the submission sounds like it's far along, but to prepare now for a potential launch downstream?
Yes. So you're right that the regulatory submission piece we're really in good shape for and I'll let Michael Metzger comment on the commercial preparation.
Thanks, David. So, yes, I think there's always quite a bit of work to do before you're able to launch a drug. And I think, we're planning to launch this product in the U. S. On our own.
And so we'll be prepared to do that. And we're taking necessary steps now to put necessary infrastructure, specifically internal commercial team together that could be in position to launch that drug. And so we're preparing to do that now. In terms of how we actually ultimately launch the drug, ex U. S.
We'll look to partner most likely, and we'll be prepared in the U. S. To do it on our own.
Thank you for that. And as far as SNDX-six thousand three hundred and fifty two, does GVHD manifest itself similarly in adult and adolescent populations?
To my knowledge, yes. Remember GVHD can affect multiple different organ systems. But to my knowledge, there's nothing unique about how it presents in adolescents versus adults.
Thanks for taking my questions.
Thanks, David.
And your next question comes from the line of Christopher Marai of Nomura Instinet. Christopher, your line is now open.
This is Jackson Harvey on for Christopher Marai. Thank you for taking my questions. The first one is for entinostat. If the trial comes up negative, will you be able to do any subset analysis to identify a subpopulation that might be a good responder? The next question is about the menin inhibitor.
Do you plan on presenting any preclinical data in the first half of twenty twenty? Thank you. Right. Thanks, Jackson for your questions. So the first one, if the trial is negative, one can always go back and look at subsets.
It's generally not possible to rescue a negative trial by saying that you saw efficacy in a subset of patients. That is always perceived to be hypothesis generating and could be the ground for another trial if you wanted to do another trial. I think our own as we sit here today, I think if the trial were negative unless there was something very, very compelling in one of those post hoc subset analysis, I don't think we would have a strong case to go to a regulatory agency nor would we necessarily have a strong case to do another trial. So I think if it's negative, it's negative. Your second question about presenting preclinical data, I don't think we have plans just now.
A lot of preclinical data, as I said on the mechanism has already been put into the public domain with a tool compound that we call 469. We're looking for opportunities to present preclinical data on the development candidate itself, but I don't know that we have a defined timeframe of when that will be available.
Your next question comes from the line of Bert Hazlett of BTIG. Bert, your line is now open.
Thanks. Yes, I have two questions. First on 2,112 and that program, could you just remind us what the status is with the rest of world in terms of regulatory activity? It's clear what might happen in the U. S, but have you had any discussions OUS?
Did you have a second question, Bert, or just that one?
The second question was with regard to Menin and that the AUGMENT program. Would you expect there to be different response rates in the subgroups? Thanks.
Yes. Okay. So first let me take the rest of world regulatory activity. We have had regulatory consultation in Europe with regard to 2,112 pretty early on I think after the end after the Phase 2 study. We have not gone back to have additional conversations.
I think our clinical and regulatory team believes that a positive OS trial would be something that the European regulatory agencies would be willing to take a look at, but we'd have to go have that a more contemporaneous conversation about that question. So that's sort of where that stands. And as Michael has pointed out, we would be looking for a partner ex U. S. And so we would obviously if we were able to find a partner rely a little bit on their regulatory insight on that question as well.
In terms of menin, the response rate in different subgroups, what we've seen preclinically is both in MLLr AML and ALL samples and NPM1 samples, we see really quite significant activity. So there's nothing from the preclinical data that would suggest that the response rates would be different by subgroup, but that's something we'll have to figure that's why we have split out the 3 subgroups in the Phase 2 portion of the trial is to answer that question in the clinic. Okay. Thank
you. Your last question comes from the line of Madhu Kumar of R. W. Baird. Madhu, your line is now open.
Hey, guys. This is Jennifer on for Madhu. Thanks for taking the question. So I know that you guys discussed the AUGMENT-one hundred and one trial and sort of had it being a little bit of a proof of concept. But I'm wondering if you can give us a little bit more detail and sort of maybe let us know how many doses in that trial, you would expect to see a signal?
And then sort of on the back of that, if you expect to see just primarily PK data or if you think there might be an initial therapeutic response? And then I have one more financial question after that.
Right. So I think that your question is really about how many dose escalations do you think we have to go through to get to our recommended Phase 2 dose. Obviously, we don't know that as it is in here today, we have to do the experiment. In general, if you look at these Phase 1 dose escalations, it's often 4 or 5 dose escalations before you get to your therapeutic dose. We're hopeful that we're on the lower end of that.
Based upon the projections we've done for PK, we think we will get even at the first dose compared to PK that we think we need for efficacy. We think we're in, again on the lower end of the number of dose escalations we would need. Whether or not we see an efficacy signal again really depends on the types of patients that are enrolled. If we are fortunate enough to get some of the MLLRs and NPM1s, then there's a potential we'll be able to pick up an efficacy signal as we get to adequate exposures. If there are patients who don't have either of those mutations and it would be from the work we've done so far, we think it would be unlikely to pick up an efficacy signal.
And then if you want to ask your financial question.
Great. Thank you. That was really helpful.
So roughly how do you divide cash burn between entinostat, 5613
and 6353 52?
As of right now, we don't have a significant cash burn relating to entinostat, it's just the 20 12 study, the number of patients that still remain on that study. And 5,613, that program is just in Phase 1. So and same thing with the 6,352. In both of those earlier stage programs actually we've had more significant CMC expenses over the past 6 months or so as we produce material for the clinical studies and get the process squared away on those programs. So I would say our cash burn is spread across the programs.
There's no one program that is bearing the brunt of the cash burn.
All right, great. Thanks so much guys.
And we have a follow-up question from the line of Bert Hazlett.
Bert, your line is open.
Thank you for taking the follow-up. I was just on the CMC comments. Are there assuming success with E2112, is there anything in particular that is a gating item either from the CMC or manufacturing specifically that might present challenges in terms of a timeline assuming success in the trial?
Yes, Bert, I'll let Michael Metzger take that question.
Yes, Bert, it's I think safe to say that it's nothing to do with CMC's gate or rate limiting in terms of filing. I think that was your question. We feel very confident with what the process and what we have. So we're in good shape.
Okay. Thank you.
There are no further questions at this time. Presenters, you may continue.
So this is Briggs. Thanks everybody for again joining in on the call. We look forward to seeing you at upcoming meetings. Thanks again for your time.
Thank you so much
to our presenters and to everyone who participated. This concludes today's conference call. You may now disconnect and have a great day.