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Constellation Pharmaceuticals (CNST)
Q3 2020 Earnings Call
Oct 29, 2020, 8:00 a.m. ET
Contents:
- Prepared Remarks
- Questions and Answers
- Call Participants
Prepared Remarks:
Operator
Ladies and gentlemen, thank you for standing by. And welcome to the Constellation Pharmaceuticals Third Quarter 2020 Earnings Conference Call. [Operator Instructions]
I would now like to hand the conference to your speaker today, Kia Khaleghpour, Vice President of Investor Relations and Communications. Please go ahead, ma'am.
Kia Khalaghpour, Ph.D. -- Vice President, Investor Relations and Communications
Constellation's Third Quarter 2020 Financial Results and Operational Performance. Participating in our call this morning are Jigar Raythatha, Constellation's Chief Executive Officer; Dr. Jeff Humphrey, our Chief Medical Officer; Dr. Patrick Trojer, our Chief Scientific Officer; and Emma Reeve, our Chief Financial Officer. Please turn to Slide two. Before we begin, I want to point out that our presentation today will include forward-looking statements, which are subject to certain risks and uncertainties.
Actual results may differ materially due to various important factors, including those described in the Risk Factors section as well as discussion of potential risks uncertainties and other important factors in the company's most recent filings with the Securities and Exchange Commission, including the company's quarterly report on Form 10-Q for the quarter ended September 30, 2020, which we filed earlier this morning.
And now I will turn the call over to Jigar.
Jigar Raythatha -- President and Chief Executive Officer
Thank you, Kia, and good morning, everyone. Please turn to Slide three. Let's begin with an overview of Constellation. We are building a fully integrated pharmaceutical company. Our roots are in discovery and with the advancements that we've made with our preclinical and clinical programs, all of which are home grown, we now have a pipeline that we believe is sustainable. The next step for the company is to launch and commercialize our own therapeutics. As for how this translates into what we are doing right now, we aimed with CPI-0610 to transform the standard of care in myelofibrosis with a potential disease-modifying therapy. We're also working hard to deliver a potential best-in-class EZH2 inhibitor therapy to expand the addressable patient population with therapeutics against that target.
And we are also continuing to invest in novel and impactful hematology and oncology therapies with our discovery platform. All of this is made possible by the strong team that we have built, and we are continuing to grow it to take Constellation to the next level. Turning to Slide four, please. Today, you'll hear updates about CPI-0610 and CPI-0209 from our management team. Our Chief Medical Officer, Jeff Humphrey, will recap what you've seen so far from CPI-0610 in the MANIFEST study as well as what we're gearing up to present at the upcoming ASH medical meeting in a couple of weeks. In addition, Jeff will review with you the details behind the Phase III study that we will soon initiate. Patrick Trojer, our Chief Scientific Officer, will tell you about our plans for CPI 209, which we believe to be a best-in-class N PH2 inhibitor. He will share with you some of the science behind the compound and how that translates into differentiated development opportunity.
Beyond this, we have a robust preclinical pipeline, which we will talk more about in the upcoming months. Turn to Slide five, please. On this slide, I'd like to remind you that we believe CPI-0610 has the potential to be a disease modifying therapy. We've all been very focused on CPI-0610 impact on spleen volume reduction and symptom improvement, and we're very pleased with the profile that we've seen on those measures. But we're also excited about presenting translational data at the ASH Medical Meeting to highlight the improvements that we are observing in red blood cell biology, anemia and bone marrow fibrosis. We believe that the four measures shown here taken together point to the potential for disease modification.
And with that, I'd like to turn the call over to Jeff.
Jeffrey Humphrey, M.D. -- Chief Medical Officer
Thanks, Jigar. Let me review data we have presented to date on CPI-0610. Please turn to Slide six. MANIFEST is our Phase II trial of CPI-0610 in patients with myelofibrosis. In Arm three, CPI-0610 is given in combination with ruxolitinib in patients with JAK inhibitor naive first-line disease. In Arms one and two, CPI-0610 is given as monotherapy or as add-on to ruxolitinib in patients with second-line disease. I'm pleased to say that Arm three is completed accrual at approximately 80 subjects.
Please turn to Slide seven. This slide shows key preliminary data from Arm three that motivated us to start a Phase III trial. In Arm three, JAK inhibitor naive patients receiving 610 plus ruxolitinib experienced consistently high spleen volume response rates over time. The 24-week SVR 35 rate was 67% and 63% in the first 15 and 30 evaluable first line patients, respectively. These rates of spleen volume response compare favorably to historical rates of 30% to 40% in prior randomized trials of ruxolitinib. Please turn to Slide eight. Here is a summary of the safety profile reported in Arm three and the on-target toxicity of both CPI-0610 and ruxolitinib is thrombocytopenia. As you can see here, the rates of Grade three are higher, are relatively low and we believe that the combination is generally well tolerated.
Please turn to Slide nine. Preliminary data for 610 monotherapy and combination therapy in second-line myelofibrosis were also promising. In Cohort one B, second-line patients receiving CPI-0610 as a single agent demonstrated an SVR 35 response rate of 24%, a rate significantly higher than other agents in the second-line setting. In addition, transfusion-dependent patients in Cohorts 1a and 2a achieved 21% and 34% rates of conversion to transfusion independence, respectively. We believe that the data for CPI-0610, which include reductions of spleen volume, improvements in total symptom scores, conversions to transfusion independence and changes in bone marrow fibrosis at 24 weeks, are preliminary signals of a potential disease-modifying effect of CPI-0610.
Please turn to Slide 10. We will be updating our data from MANIFEST ASH 2020. And please note that the abstracts to be published in November will not contain new clinical data, the new data will be presented at the ASH meeting itself in December. New 24-week data for Arm three and Arm two will be discussed in separate oral presentations on December five by Dr. John Mascarenas and Search for stope, respectively. We will also present three posters on December six and seven. One poster will discuss new 24-week data in Arm one. A second poster will discuss translational data, including 24-week changes in bone neuro fibrosis and cellularity from patients enrolled in MANIFEST and a trials in progress poster will discuss the design of MANIFEST two. The new data will also be reviewed at an investor event with discussion by key clinicians on December 7.
Please turn to Slide 11. Our experience with 610 continues to grow. The data is set at ASH for CPI-0610 ruxolitinib in first-line myelofibrosis will include 24-week data for approximately 50 to 60 patients. The data set at ASH for 610 monotherapy or is add on to Rux in second-line myelofibrosis will include 24-week data for approximately 90 to 100 patients. Please turn to Slide 12. The the data in first-line myelofibrosis support our decision to conduct a pivotal Phase III trial MANIFEST two.
As a reminder, the trial is a blinded, randomized pivotal study in JAK inhibitor naive patients with primary or secondary myelofibrosis who have advanced disease with splenomegaly and symptoms requiring therapy. Approximately 310 patients will be randomized 1:1 to CPI-0610 plus ruxolitinib versus placebo plus ruxolitinib. We've begun site initiation activities and remain on track to dose our first patient in the fourth quarter. We continue to be focused on executing this important clinical trial.
And now I'll hand the call over to my colleague, Patrick, to discuss CPI-0209. Patrick?
Patrick Trojer, Ph.D. -- Chief Scientific Officer
Thank you, Jeff. Please turn to Slide 13. As CPI-0610 has emerged from our internal discovery efforts, I would like to turn your attention now to another product candidate that stems from Constellation's oncology research platform. The EZH2 inhibitor CPI-0209. We continue to be excited about progress of this program in the clinic. You will recall that EZH2 is a histone that transferase. Its role is to trimethylate H3 and live in 27 and thereby to suppress the expression of specific letern. We believe that CPI-0209 has the potential to be a best-in-class EZH2 inhibitor. We designed CPI-0209 to improve on first generation EZH2 inhibitors in a number of ways, including increased potency, long residence time and maintaining exposure levels by not inducing its own metabolist.
With that type of profile, we can now pursue a very broad application of EZH2 inhibition. Doubling down on contexts where EZH2 inhibitors already have shown clinical activity and where EZH2 is an oncogenic driver or where EZH2 cooperates with established oncogenic driver pathway such as in the case of prostate cancer. We are also excited to explore whether CPI-0209 can exploit potential synthetic legal relationships. We sensitize to chemotherapeutic agents in the context of acquired pro resistance and reprogram the tumor microenvironment and tumor cells to promote to mount. Please turn to Slide 14. This slide presents data that corroborates the three key properties of CPI-0209 that supported best-in-class potential: increased potency, longer residence time and lack of induced metabolism. The table on the left illustrates the superior biochemical potency of CPI-0209 compared to other clinical stage EZH2 inhibitors. The middle panel demonstrates one of the key properties.
For which we designed CPI-0209, which is to achieve 24/7 target coverage because we think that's an important component for driving efficacy. And as you can see here, after CPI-0209 binds to EZH2, it doesn't come off for extended periods of time, where its first generation EZH2 inhibitors come off in a matter of hours. On the right, you can see the exposure profile of CPI-0209 with orally administered to mice after single B1 and maintenance of CPI-0209 exposure at steady state after 12 days of once-daily dosing D12. This is consistent with the observation that the compound does not induce its own metabolist group over the course of treatment. With this profile, we believe CPI-O209 may extract the full therapeutic potential of EZH2 biology.
Please turn to Slide 15. This slide highlights some of the context that we're interested in for the initial development of CPI-0209. The cartoon on the left illustrates molecular context where genomic aberrations create a functional dependence on EZH2. Such as gain of function mutations in EZH2 itself as observed in certain subsets of platform or Atofina patients in for such as observed in several solid tumor indications. We continue to be interested in the exploration of prostate cancer as an indication for CPI-0209, where we have repeatedly seen functional cooperation of EZH2 inhibitors with AR or androgen receptor targeted agents.
In addition, we are interested in acquired drug resistance. Preclinical data delist rated that EZH2 suppresses the expression of the 11 gene. And SHL at 11 reactivation, please emphasize this tumors to chemotherapeutic agents. So by combining CPI-0209 with chemotherapeutic agents, one could potentially reverse or prevent acquired drug resistance.
Turning to Slide 16, please. Now that we have seen the breadth of the opportunity in various contexts of cancer genetics, let me give you examples of CPI-0209 performance in some of those contexts. On this slide, we show data that CPI-0209 demonstrates superior efficacy in preclinical mouse models on a once daily dosing schedule. In two in vivo studies, CPI-0209 achieved tumor regression in one of the both hematologic cancers with EZH to gain a function mutation shown on the lay and solid tumors with Area one a loss of function mutation on the right. It's comprehensive EDH to target engagement achieved by its potency, loan residence time and other favorable properties may allow us to harness deeper responsive and to expand to patient populations, not adequately addressed by first generation EZH2 inhibitor.
We are currently an safing CPI-0209 in a Phase I dose escalation study in an or commerce patient population. We have completed multiple dose cohorts and seen a dose-dependent increase in exposure and no evidence of induction of compound metabolist. We have also seen those dependent increases in target engagement as measured by assessment of multiple pharmacodynamic markets. We continue to dose escalate to determine a recommended Phase II dose. And while we are in the tail end of the year, it's still possible that we will reach the Phase II dose later this year. We are excited to test several of our biomarker hypothesis in Phase II.
And now I invite Emma to take the floor.
Emma Reeve -- Chief Financial Officer
Thanks, Patrick. Please turn to Slide 17, and let's review our financial results for the quarter. We had a net loss attributable to common stockholders of $33.8 million in the third quarter, which was in line with our expectations. The net loss per share was $0.71 in the third quarter compared with $0.82 per share in the third quarter of 2019. The R&D expenses increased by $9.2 million year-over-year, mainly due to work related to CPI-0610. Personnel costs also increased compared with the prior year quarter as we continue to build out our organization. Without financing in June, our cash, cash equivalents and marketable securities were $489.4 million as of September 30, which we expect will fund our operations into mid-2023.
We plan to use these resources to complete both MANIFEST and MANIFEST two, our Phase II and Phase III clinical trials for CPI-0610, respectively, and to substantially build the commercial organization needed to launch the compound. In addition, our cash will allow us to complete the Phase I/II clinical trial for CPI-0209 as well as to support our discovery platform. To conclude, we're very pleased with the progress we are making. We look forward to presenting new dates of the CPI-0610 at the upcoming ASH meeting. And to start dosing patients in MANIFEST two. For the CPI-0209 program, we're making progress toward determining the recommended Phase II dose and initiating that part of the study. We look forward to giving you further updates along the way on our program.
So with that, I'll turn things back over to the operator. Operator, would you please now open the line for questions.
Questions and Answers:
Operator
Thank you. [Operator Instructions] Our first question comes from Anupam Rama with JPMorgan. Your line is now open.
Anupam Rama -- JPMorgan -- Analyst
Thanks so much for taking the question. Just two really quick ones. So what are the final gating factors to getting MANIFEST to up and running and enrolling patients later this quarter? And a second question, did see anything in the release today or in the slides on 610 in additional indications like ET? Maybe just an update there on time lines.
Jigar Raythatha -- President and Chief Executive Officer
Maybe I'll just quickly touch on the second question first, and then I'll turn it over to Jeff to answer your first question on timing. We are -- we announced earlier that we are aiming to start a POC study in essential thrombocythemia that work is on track. We're going through the protocol writing, site selection, all the work that kind of operations happen to start enrolling patients. And so we do anticipate being able to do that shortly. And there may be other indications that it likely with some of the myeloid biology that we've uncovered with CPI-0610 that will also begin to kick off in the next six to 12 months. And so that's all kind of in progress and on track. And Jeff, do you want to comment on kind of where things stand with the benefits to initiation?
Jeffrey Humphrey, M.D. -- Chief Medical Officer
Yes. Thanks, Jager. As you know, we've listed on clinicaltrials.gov now the trial design. And we're in final preparations at the site. We're very much on track for a second half start. And we're very focused on a rapid start and execution of MANIFEST two.
Anupam Rama -- JPMorgan -- Analyst
Thanks so much for taking my questions.
Operator
Thank you. Our next question comes from Brian Abrahams with RBC Capital Markets. Your line is now open.
Brian Abrahams -- RBC Capital Markets -- Analyst
Thanks for taking my questions and congrats on all the progress. A few questions from me, if I could. First off, I know there's going to be a lot of focus on the clinical data at ASH, but you mentioned there's going to be a poster on translational data for 610. What should we be looking for there? What -- how should we think about the bar? And how important is that data going to be do you think for -- for earlier stage usage of the drug, if it ultimately becomes available?
Jigar Raythatha -- President and Chief Executive Officer
Yes. So I'll start with that and then maybe, Patrick has anything to add, you can add to that. Brain, the way I would look at the translational data at ASH, it's kind of the first of kind of growing set of disclosures that we'll have over the course of the next several scientific meetings that start to really tie together the clinical effects that we're seeing with the mechanism of action that we believe is at play with CPI-0610. And again, it comes back to the myeloid biology and potential impact on red blood cell biology. And so I think the way to think about the the ASH disclosure is kind of -- it's starting to kind of peel back beyond in a bit more. We talked about bone marrow fibrosis to date, but we can start to dig into patient samples and look a little bit more closely at the biology to tie the mechanism together. Patrick, would you want to add anything more on kind of the how that compares to kind of what we might do in the future?
Patrick Trojer, Ph.D. -- Chief Scientific Officer
Well, I think we said it, we want to connect the mechanism of action to the clinical benefit that we have seen. So as for the ASH disclosure, I think we'll be able to report on white set of locally pathology reviewed phone myelofibrosis data across the MANIFEST patients, a subset of these will be centrally reviewed by them. And we will also report, as Jigar said, on a subset of patients for some of the myeloid changes that we have seen in the bone marrow of the patients treated with CPI-0610.
Jigar Raythatha -- President and Chief Executive Officer
And then, Brian, just to add to kind of the second part of your question there in terms of how important that will be. Again, I think this is the beginning of a growing dataset. But ultimately, we think it will be very important because as we mentioned in the call, spleen and symptoms, it's required for regulatory approval. But ultimately, you think what's really special about CPI-0610 is the potential to modify the course of the disease. And it's data like these that will start to allow us to be to redemonstrate that.
Brian Abrahams -- RBC Capital Markets -- Analyst
Got it. And then speaking of symptoms, just curious your latest views on potential powering of MANIFEST two with respect to the symptom score and designing an interim to enable resizing there? And I'm also curious if recent precedent from other MF drugs changes your view as to whether or not you need to hit statistical significance on that endpoint.
Jigar Raythatha -- President and Chief Executive Officer
Are you referring to
Brian Abrahams -- RBC Capital Markets -- Analyst
Yes.
Jigar Raythatha -- President and Chief Executive Officer
Yes. Just to take that, I mean, definitely, I think, an interesting and positive development in the regulatory landscape, and we'll be watching it carefully as it unfolds. And so it's something to keep an eye on. But I think our kind of path that we laid out as a base case has been and always will be, always has been and will continue to be the Phase III design of the outline. And of course, we'll continue to explore anything else that we think is possible. And nothing has really changed on the -- how we're approaching the trial design with regard to powering. We think we've done a pretty good job here with the assumptions from the data that we've generated as well as historical data sets to power the study pretty robustly. And we've given ourselves added flexibility to refi the needed. I don't have any more details today on kind of the details of how we would make that decision. That's for an earlier date.
Brian Abrahams -- RBC Capital Markets -- Analyst
Got it. And one more quick one, if I could just squeeze it in. On the geno toxicity, I know that's something that's seen with other epigenetic modulators like HVAC. I'm just sort of curious if any additional work around that or changes to inform consent might it all impact the timing of the MANIFEST to start or have any significance for future label?
Jigar Raythatha -- President and Chief Executive Officer
Yes. So you may noted in the queue, we're going through various kind of nonclinical work. Nothing that we think impacts any any of the time lines that are on critical path, and there's certainly more work to do to a underdosing that, but I think it was pretty pretty normal course. And I know if Patrick, would you want to comment any more on that?
Patrick Trojer, Ph.D. -- Chief Scientific Officer
Yes. We haven't completed the genotox package yet. I agree with you. I think there's nothing at this point that makes us feel like that we deviate from the time lines.
Brian Abrahams -- RBC Capital Markets -- Analyst
Thanks again.
Operator
Thank you. And our next question comes from Mike Ulz with Baird. Your line is now open.
Mike Ulz -- Baird -- Analyst
Hey guys, thanks for taking the question. I just had a quick follow-up on the MANIFEST two study. So it seems like you guys are fairly on track to start that soon. So I'm just curious if maybe you can share your thoughts around enrollment time lines. Now that you've had experience with MANIFEST?
Jigar Raythatha -- President and Chief Executive Officer
Jeff, do you want to take this one?
Jeffrey Humphrey, M.D. -- Chief Medical Officer
Yes, sure. Thanks, Jager. Mike, we accrued MANIFEST well. We -- as you know, there was slowdown during cohort during which we learned a lot. We anticipate that MANIFEST two will accrue well. Right now, we're not currently disclosing expected time lines for full accrual.
Mike Ulz -- Baird -- Analyst
Great, thank you.
Operator
Thank you. Our next question comes from Biren Amin with Jefferies. Your line is now open.
Biren Amin -- Jefferies -- Analyst
Yeah, hi guys thanks for taking my questions. Maybe just to start on MANIFEST two. Can you talk about whether there's still an adaptive design feature in the trial? And what drivers would lead to enrolling additional patients from the target of 310, do you expect to enroll? And then I guess, what's the overlap in clinical sites for MANIFEST two compared to the Phase II study?
Jigar Raythatha -- President and Chief Executive Officer
Thanks for your question. So first of all, I think we've done a really robust job at powering the study. However, as to the question that was raised earlier, we've given ourselves flexibility to increase the size, if you think that we'll want to do that based on the fact that we are making our power assumptions for TSS on a a single-arm study. So it's really just to give us the flexibility on that if it's needed. We feel like we've done a pretty good job with the assumptions that we've made so there's no additional kind of information that we have at this point in terms of when and how that decision would be made done.
Biren Amin -- Jefferies -- Analyst
Okay. And then maybe on the second line study. Can you maybe talk about, I guess, what you expect your past to be there? Do you feel that the data at ASH, I think you'll have an additional five to 15 patients in second-line at 24 weeks. Do you feel that, that would be sufficient to inform you for next steps forward in that indication?
Jigar Raythatha -- President and Chief Executive Officer
Yes. So we're really excited about the entire litigative package that we've been presenting around 610 in first-line and second line. We've taken a careful look at what we think is the right kind of regulatory commercial path forward. And at the end of the day, we concluded that the right kind of study to do for us to be -- to focus our registration work in the naive patient. Our expectation is that the label that we could achieve would be a broad label that would cover first and set line patients similar to the label that ruxolitinib and fedratinib pad. And so we'll continue to enroll patients in those second line cohorts to drive publications and ultimately, hopefully, drive reimbursement. But we currently are not planning to do a another registration study in the second-line setting. Having said that, we're really excited about some of the results that we've been seeing in that context.
Biren Amin -- Jefferies -- Analyst
Great, thank you.
Operator
Thank you. Our next question comes from Srikripa Devarakonda with Truist Securities. Your line is now open.
Srikripa Devarakonda -- Truist Securities -- Analyst
Hey, guys. Thank you so much for taking my question. You mentioned in your filings that there were some instances of incomplete data collection in MANIFEST, considering the ongoing pandemic. Can you talk to us about what sort of cadre, a place to ensure that your data collection would be complete and MANIFEST, what sort of package that you talk to the sites and what sort of pointers you're giving to the sites to ensure that you have complete data collection? And also another question barring any delays associated with COVID, given that inside and maybe some other competitors that are also initiating pivotal trials, looking at other rux combos is there any expectations that there could be competition and delays in enrollment for MANIFEST two?
Jigar Raythatha -- President and Chief Executive Officer
Srikripa, thanks for your question. I first, I just maybe take your second question first. We believe that the previous guidance we provided on timing, there's nothing new from our perspective on that. We -- it is a patient population that we have a lot of experience with, sites and investigators that we have a lot of experience with. We had 50-plus sites in our MANIFEST study, and we'll end up more than doubling that in the Phase III. And I think you have the most robust data set out there in the first-line setting that should should really position us well competitively for accrual, among other agents. And so we feel really excited about the ability to do that. So we think -- I think we said in the past, a couple of years start to finish for the Phase III from first patient into data, and that deal continues to feel about like. So can you repeat the first part of your question again?
Srikripa Devarakonda -- Truist Securities -- Analyst
So in your filings, you mentioned that there were some instances of incomplete data collection in MANIFEST. So I was wondering what sort of guardrails you have to play to that doesn't happen in Pivotal.
Jigar Raythatha -- President and Chief Executive Officer
Yes. Yes. So it's nothing new, by the way. This is all kind of in the spring when they were -- when we were kind of in the heat of shutdowns around COVID. There were a couple of patients who not -- it wasn't something that was -- they weren't space to patients, but there were a couple of patients here and there that may have missed the scans. And so we were able to put together guidance for how to make sure that, that data gets collected and reported.
And so -- and that was some good practice with that, and we'll be able to use that if there is not another coded related kind of shutdowns in the future. There's already -- there's been a good deal of flexibility on the number of weeks prior to and after the actual date of, for instance, 24 weeks for it to impute to that time point. There's also flexibility on the location of where the data can be collected. So there's -- we work through that nicely in MANIFEST, and we'll be able to use those same procedures and benefits too.
Srikripa Devarakonda -- Truist Securities -- Analyst
That's very helpful, thank you so much.
Operator
Thank you. Our next question comes from Kenneth Atkins with Cowen and Company. Your line is now open.
Kenneth Atkins -- Cowen and Company -- Analyst
Hi guys, thanks for taking my questions. For MANIFEST two, do you plan to provide updates in terms of how enrollment is progressing? And in terms of the interim analysis, could the resizing at that point allow for lowering the target number of patients? Or are you only able to expand the study at that point?
Jigar Raythatha -- President and Chief Executive Officer
So Kenneth, I think it's best -- I mean, we're not at this point ready to talk about any kind of an interim. We're still kind of making final kind of decisions on what to do there. And so maybe we can save that for a later discussion.
Kenneth Atkins -- Cowen and Company -- Analyst
So Kenneth, I think it's best -- I mean, we're not at this point ready to talk about any kind of an interim. We're still kind of making final kind of decisions on what to do there. And so maybe we can save that for a later discussion.
Jigar Raythatha -- President and Chief Executive Officer
Yes. Nothing changed about the molecule itself. I mean, I mean EZH2 has always been biologically very exciting in liquid tumors like lymphoma. And as our company profile in hematology rose, I think it's natural for us to consider other opportunities to take advantage of the infrastructure that we have and we'll continue to build. And there's a nice fit there with EZH2 biology.
Operator
Makes sense. Thanks. Thank you. Our next question comes from Guyn Kim with BMO Capital Markets. Your line is now open.
Guyn Kim -- BMO Capital Markets -- Analyst
Good morning, thanks for taking my questions. First, on your expansion into ET, could you speak more to that opportunity and what the addressable patient population looks like in terms of those who are on standard of care or failed it.
Jigar Raythatha -- President and Chief Executive Officer
Thanks for your question. I'll start, and then I'll turn it over to Jeff. Maybe I'll just start by saying that we're going to be learning from this study. I think that base -- there's no approved therapy today for EP. I think the previous studies have inclusion criteria have not really focused on what we think are the right set of patients. And so we're -- part of what we we're trying to do here is to is to really identify who are those patients? And what the endpoint would be. But maybe, Jeff, you could talk a bit more about that. And I can add more about the opportunity then.
Jeffrey Humphrey, M.D. -- Chief Medical Officer
Yes. Thanks, Jigar. So 610 has a reduction of platelets as one of its effects. And certainly within essential thrombocythemia patients present with very high platelet counts. We're looking for a population that is hydroxyurea refractory. We high platelet counts and symptoms. And the consequences of this disease include symptoms such as headache and thrombosis, bleeding events and our trial would be done to look for a signal of efficacy, including complete hematologic response and response and symptoms, would be looking at things like the MPN SAF?
Jigar Raythatha -- President and Chief Executive Officer
Yes. And we're still doing some work on the commercial side to understand the overall opportunity, but we think it could be pretty significant.
Guyn Kim -- BMO Capital Markets -- Analyst
Great. And another question on -- if you had any updated thoughts on your ex U.S. strategy, what your plans are for an EU study? And what factors you're considering in a decision on whether to partner in Europe?
Jigar Raythatha -- President and Chief Executive Officer
Yes. Yes. So I think from a regulatory perspective, we believe the study we've designed is the correct study to address approvals globally. And we'll execute on it to drive to that. So from a partnering perspective, we don't need the assistance from kind of a global player to help us execute on the study and to get drive to global approvals. Now commercially, I think it's a different question. We have not yet, as a company, made the decision to build a commercial infrastructure outside the U.S., I think it's quite reasonable to assume that at some point that we would seek a partner to help us do that, but we have not yet made that decision.
Guyn Kim -- BMO Capital Markets -- Analyst
Great, thanks for taking my question.
Operator
Thank you. Our next question comes from Ren Benjamin with JMP Securities. Your line is now open.
Ren Benjamin -- JMP Securities -- Analyst
Hey, good morning guys. Thanks for taking the questions and congrats on the progress.
Jigar Raythatha -- President and Chief Executive Officer
Good morning.
Ren Benjamin -- JMP Securities -- Analyst
I guess just -- just maybe two for me. Can you talk a little bit about what might impact response rates over time? Is it is it a mix of kind of heterogeneous patients? Or is it maybe patients over time, not adequately being controlled? And I guess I'm trying to get a sense how 52-week data might look? And how much of that we might see at ASH? And maybe as a second question, in MANIFEST two, we noticed that the trial includes post ET and PV patients. And so I'm kind of interested to know your thoughts on how these patients differ from primary MF patients? And what's your experience been for those patients been treated with the combination?
Jigar Raythatha -- President and Chief Executive Officer
Yes. So kind of the durability of the response. I mean, I think now we've got a subset of the patients who have been on therapy long enough that we can start to look at that. I think just kind of qualitatively from what we've been hearing. We feel pretty pleased about the effects that we're seeing from a durability perspective. And then including also from the durability that we've seen from our second-line patients and some of those patients have been on for over three years. That -- and this is a very thick kind of refractory patient population setting.
So I think it's fair to say that we can start to examine some of that data at the upcoming ASH update. I think we're -- as I mentioned, at least qualitatively, so far, pretty pleased. And as we start to get more and more experience, we can start to quantify that. With regard to post ET and post PV and primary. I think we've treated patients of all types, similar to previous MF studies that have therapies. I think we haven't seen anything jump out as kind of a major difference in how those patients are responding. Again, the response rates overall have been pretty high. So not a clear separation in that signal from post CT, post PV and primary MF.
Ren Benjamin -- JMP Securities -- Analyst
Great, thanks for taking the questions.
Jigar Raythatha -- President and Chief Executive Officer
Yeah.
Operator
[Operator Instructions] Our next question comes from Jay Olson with Oppenheimer. Your line is now open.
Jay Olson -- Oppenheimer -- Analyst
Hey, thanks for taking the questions. I had a few on 209. Can you share any comments on the safety and tolerability profile that you're seeing in the dose escalation study? And then also, I think you mentioned the potential for synthetic lethality. Could you maybe provide some additional color on that hypothesis? And then I was wondering what combination with 209 that you're most excited about? And finally, will 209 be developed as a monotherapy? Or is this a drug that will only be used in combination?
Jigar Raythatha -- President and Chief Executive Officer
So I'll start but also listen to Patrick to help. So from a safety perspective, you can into the details, but I think kind of implied and Patrick's kind of update there was that we are continuing to escalate and looking to then of the RPTWOD and kind of thinking about the Maxim tolerated dose is a key component of that. So I think we're doing pretty well from a safety perspective and this mechanism. I think you've demonstrated with our previous experience 1205 can be very well tolerated. And then the synthetic locality kind of context, I think, is very fascinating there tends to -- seems to be kind of a tug of war on gene expression. Maybe, Patrick, do you want to kind of get -- talk about that a little bit as well as some of the other questions about combinations and potential for monotherapy activity?
Patrick Trojer, Ph.D. -- Chief Scientific Officer
Sure. Yes. Thanks, Jay, for the questions. So as Jigar said, we're really happy about the safety profile and the performance of CPI-0209 to date. We have seen nice dose-dependent increases in exposure, increasing levels of PD assessed by multiple pharmacodynamic markets. Since the study was really designed as an all commerce study to primarily determine safety and MTD, we can't really comment on the particular biomarker hypothesis that we have designed for the expansion cohorts in Phase II.
We get they're still in the midst of the study with further dose escalating, and we hope that once we get into the expansion cohorts, we can start answering some of the questions that we built around this area on a hypothesis as well as some of the other molecularly guided hypothesis that we have that we have shown an interest in. As for the question regarding the combination, so our -- we haven't completely finalized our expansion plans yet, but we have planned to open monotherapy cohorts as well as have a combination development plan. So at this point, we would think that are opportunities for CPI-0209 as monotherapy but also in combination.
Jay Olson -- Oppenheimer -- Analyst
Great, thank you for taking the questions.
Operator
Thank you. I'm not showing any further questions at this time. I would now like to turn the call back over to Jigar Raythatha for closing remarks.
Jigar Raythatha -- President and Chief Executive Officer
Well, thank you very much. I wanted to thank everyone for taking the time to listen to our call, ask a question. I think you've got a very exciting couple of months ahead of us as we head into ASH, with plenty of new data and progress on our execution toward bringing 610 to fruition for patients as well as progressing our pipeline. So thanks again, everyone, and look forward to talking to you all soon.
Operator
[Operator Closing Remarks]
Duration: 46 minutes
Call participants:
Kia Khalaghpour, Ph.D. -- Vice President, Investor Relations and Communications
Jigar Raythatha -- President and Chief Executive Officer
Jeffrey Humphrey, M.D. -- Chief Medical Officer
Patrick Trojer, Ph.D. -- Chief Scientific Officer
Emma Reeve -- Chief Financial Officer
Anupam Rama -- JPMorgan -- Analyst
Brian Abrahams -- RBC Capital Markets -- Analyst
Mike Ulz -- Baird -- Analyst
Biren Amin -- Jefferies -- Analyst
Srikripa Devarakonda -- Truist Securities -- Analyst
Kenneth Atkins -- Cowen and Company -- Analyst
Guyn Kim -- BMO Capital Markets -- Analyst
Ren Benjamin -- JMP Securities -- Analyst
Jay Olson -- Oppenheimer -- Analyst
