Good day, and thank you for standing by. Welcome to the December corporate event conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star 11 on your telephone, and you will then hear an automated message advising your hand is raised. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Nancy Simonian, Chief Executive Officer. Please go ahead. Thank you, operator. This is Nancy Simonian, the CEO of Syros. Hello, everyone, thank you for joining us today. Earlier this morning, we issued a press release with highlights of data from the safety leading portion of SELECT-AML-1, our phase 2 clinical trial evaluating the triplet combination of tamibarotene, azacitidine, and venetoclax in newly diagnosed unfit AML patients with RARα, overexpression. You can access the press release as well as the slides that we'll be reviewing today by going to the investors section of our website at www.syros.com. Next slide. We will be making forward-looking statements and a full description of our risk factors can be found on our website. Turning to slide 3. On today's call, I will be making a few opening remarks, followed by Dr. David Roth, our Chief Medical Officer, who will review the data from the safety leading portion of the SELECT-AML-1 clinical trial, which are being presented in a poster session at the ASH annual meeting today. We are thrilled to have Dr. Daniel Pollyea, Professor of Medicine, Clinical Director of the Leukemia Services, and Robert H. Allen Chair in Hematology Research at the University of Colorado, join us today. Dr. Daniel Pollyea specializes in the care and treatment of people living with leukemia. He has been involved in the development of new therapeutics for both MDS and AML. He is also an investigator in our SELECT-AML-1 trial. Today, Dr. Daniel Pollyea will discuss the unmet need and evolving treatment landscape in AML, as well as his perspectives on our data and the opportunity for tamibarotene. Following Dr. Daniel Pollyea's remarks, we'll open the call for Q&A. Now turning to slide 4. There are several key points to take away from today's event. First, we hope you'll share our excitement around the safety lead-in data from SELECT-AML-1. While early, we are encouraged by these initial results. The triplet regimen of full-dose tamibarotene, venetoclax, and azacitidine led to a high CR/CRI rate of 83% with a rapid onset of action. Importantly, treatment with the triplet regimen did not result in new toxicities compared to tami-aza or ven-aza alone. These data provide additional evidence that tamibarotene can augment the existing standard of care to deliver improved outcomes for newly diagnosed unfit AML patients with RARα, overexpression. We are now moving into the randomized portion of the SELECT-AML-1 trial, with initial data expected in the 2023/2024 timeframe. We also hope today's event will help illuminate the significant unmet need that still remains for unfit AML patients in the frontline setting. Despite the approval of venetoclax with azacitidine, approximately one-third of patients do not respond and nearly all relapse. Resistance to ven-aza has been associated with a monocytic form of AML, which is also associated with RARA overexpression, the very genomic alteration tamibarotene is designed to address. We believe this creates a tremendous opportunity for tamibarotene and underscores our commitment to advancing this program as quickly as possible for patients living with AML and higher risk MDS. I'd like to begin with a brief introduction to Syros. Slide 6. Our vision has always been to deliver better medicines and, as a result, better outcomes to patients with diseases that have eluded other approaches. We are well on our way to achieving this goal. Today, Syros is a late-stage company developing new standards of care for frontline treatment of three hematologic malignancies, MDS, AML, and APL. There is significant unmet need in each of these diseases, with patients and physicians looking for new, convenient, and well-tolerated options that enhance clinical outcomes and maintain quality of life. Together, we believe MDS, AML, and APL represent a multibillion-dollar market, which we can address through our own commercial efforts. Importantly, we are positioned to execute on this opportunity. We are well-funded with capital to fund our operations into 2025. As we'll discuss today, we expect to initiate the randomized portion of our SELECT-AML-1 trial in the first quarter of 2023, with initial data in the 2023/2024 timeframe. We also remain on track to report data from the pivotal phase 3 SELECT-MDS-1 trial in late 2023 or early 2024, which, if positive, will enable our first NDA submission in 2024. We expect to initiate our phase 3 trial of SY-2101 for APL in the second half of 2023. Turning to slide 7. Turning now to tamibarotene, the focus of today's event. Over the past few years, we carefully and methodically evaluated tamibarotene for the treatment of hematologic malignancies, amassing a body of evidence supporting its development as a novel oral biologically targeted therapy for the treatment of MDS and AML patients with RARα overexpression. This began at ASH 2017, when we shared data showing monotherapy activity in patients with relapsed refractory AML and higher risk MDS with RARα overexpression, including improvements in blood counts and reductions in leukemic blasts. In relapsed or refractory higher risk MDS, 60% of patients had hematologic improvement, including a patient with a durable marrow complete remission. At ASH in 2020, we presented our first combination data from a phase 2 trial evaluating the doublet of tamibarotene with azacitidine in newly diagnosed unfit AML patients. In patients with RARα overexpression, we observed a 61% CR/CRI rate and rapid time to clinical response. In patients with low blast count AML, which is similar to higher risk MDS, we saw a 67% CR rate. This important data was just published yesterday in the journal Blood Advances. Now today, we're announcing a third set of data, the safety lead-in portion of the SELECT-AML-1 trial. The triplet combination of tamibarotene, venetoclax, and azacitidine delivered an 83% CR/CRI rate, also with a rapid onset of action. Importantly, we were able to combine tamibarotene at full doses with existing standards of care, as tamibarotene does not have overlapping toxicities with other agents used in the treatment of AML and MDS. We are incredibly encouraged by the consistency of these results, which suggest that we have honed in on the right combination regimens to use in the right patient populations and substantially de-risk our later-stage development efforts. Overall, these data form the basis of our decision to advance the combination of tamibarotene and azacitidine into a pivotal phase 3 trial in higher risk MDS and move into the randomized portion of our phase 2 trial in newly diagnosed unfit AML. Slide 8. There is a significant market opportunity for tamibarotene. We are focused on large targeted populations and frontline settings in both AML and higher risk MDS. We are incredibly motivated by the opportunity to impact the lives of so many patients and families and look forward to sharing additional details on our early launch preparations as we move towards our first pivotal data read out. With that, I'd like to turn the call over to David to review the SELECT-AML-1 results in greater detail. David? Thank you, Nancy. Moving to slide 9. I'll be covering the safety lead-in data from the SELECT-AML-1 study. This data is being presented today at a poster session at the ASH conference in New Orleans. It's poster 1444. For those of you who are here, I hope you can visit this in person. Moving to slide 10. Let me begin with some points about tamibarotene. Tamibarotene is a potent and highly selective synthetic retinoid. Its properties include very tight sub-nanomolar binding to RARα, selectivity for RARα over beta and gamma, and a favorable metabolism such that it's not cleared by CYP26A, which allows for continuous daily administration. Using our novel blood-based biomarker assay, we identified a subset of non-APL AML and MDS patients characterized by RARA overexpression, which we believe accounts for approximately 30% of newly diagnosed unfit AML and approximately 50% of the higher risk MDS population. The reason this is clinically important is because it defines a new patient subset with an actionable target for treatment with tamibarotene, which can lead to the expression of RAR Alpha target genes in the context of RARA overexpression with restoration of normal myeloid maturation, which potentially can benefit by its anti-leukemic effects in patients. While several other targeted agents exist, such as IDH1, IDH2, and FLT3 inhibitors, the combination of venetoclax and azacitidine has become a standard of care for newly diagnosed unfit AML patients and unquestionably has made a significant positive impact. About a third of patients don't respond to upfront treatment with ven-aza, and a majority of those with initial responses will ultimately relapse. We believe this leaves substantial room for a novel agent like tamibarotene, particularly if it's able to address an identifiable patient population for whom existing options may not work in the frontline setting, or if it delays relapse in those who initially respond to available therapy. Slide 11. With the increased use of venetoclax and azacitidine in the upfront treatments of patients with unfit AML, we've started to understand more about patients who respond, as well as those who are resistant to frontline venetoclax treatment. Mounting data suggests that a monocytic phenotype in particular may be associated with venetoclax resistance. Either primary resistance, which can be associated without ever responding, or acquired resistance, which occurs after an initial response at the time of relapse. This is particularly relevant for our efforts because, as we've previously reported, there's a relationship between the features of cells that overexpress the RARA gene and monocytes. That's not to say that the RARA overexpressing AML cells are themselves always monocytes, but rather they have monocytic features based on molecular gene expression patterns. As Nancy mentioned earlier, our phase 2 data was published yesterday in Blood Advances. We're really excited about that, it's available online if you wanna look it over. This paper describes the important relationship of RARA overexpression status to the monocytic expression score, a gene expression signature that we used as a probe to identify the presence of monocytic features in the AML patients who were enrolled and treated in our prior phase 2 tamibarotene study. We demonstrated there that the majority, 80% of the RARα-positive patients demonstrated this monocytic phenotype defined by a high MES score. They also had lower BCL-2 expression and higher MCL-1 expression, which are two other gene expression changes that have also been identified in patients with resistance to venetoclax. The majority of patients from our earlier phase two study who achieved a CR demonstrated this monocytic gene expression pattern of high MES, low BCL-2, and high MCL-1 that may be associated with clinical venetoclax resistance. Together, these data suggest that the RARα biomarker could select out those patients who may be more likely to respond to tamibarotene while also predicting which patients are less likely to respond to the combination of ven-aza alone. Together, this is the basis for the SELECT-AML-1 trial. Okay, moving on to slide 12. Turning now to the SELECT-AML-1 study design. SELECT-AML-1 is enrolling newly diagnosed AML patients positive for RARα overexpression who are ineligible for standard intensive induction therapy. They're also referred to as unfit AML patients. The part 1 safety lead-in, highlighted on the top left of the slide, was designed to characterize the safety, tolerability, and pharmacokinetics of the tamibarotene, Venetoclax, and Aza triplet regimen as a prelude to part 2, where we plan to randomize approximately 80 patients, 1 to 1, to either the triplet of Venetoclax plus azacitidine or Venetoclax plus azacitidine alone, with an objective of providing randomized data comparing the clinical activity, safety, and tolerability between these two arms, triplet versus doublet. tamibarotene is being dosed, as in our other trials, twice a day by mouth on days 8-28 of each 28-day treatment cycle. Azacitidine and venetoclax are dosed as indicated in their respective labels at the approved doses. Aza is given on days one to seven or the first week of a treatment cycle, and venetoclax is given daily throughout the treatment cycle without interruption, except for toxicity. Slide 13. Here you can see the demographics of the patients who were enrolled in the safety lead-in. As of the data cutoff of October thirteenth of this year, eight patients had enrolled. Six were response evaluable. Patients were defined as response evaluable if they completed one cycle of therapy or had progressed or died prior to their cycle one assessment, as well as having available data. There are two patients without data entered into the clinical trial database for the analysis who were not not response evaluable, so that leaves us with a total of six evaluable patients. The important takeaways from this slide include the median age of patients at 61 and the high median baseline AML blast count, which was 63%, ranging up to 100% blast at study entry. We also analyzed locally reported cytogenetics and AML-associated mutations, which demonstrated that 2 patients each had adverse risk, intermediate risk, and favorable risk. There was no evidence for underlying bias of favorable or poor risk impacting the clinical activity that was observed. Lastly, the monocytic expression score, or what we call the MES profiling, was available for 5 patients. The majority, 4 of the 5 or 80%, had high MES, which would predict for venetoclax resistance. This is important for 2 reasons. First, the high rate of MES positivity is the same as that which we demonstrated in our prior phase 2 study testing tamibarotene plus Aza. Second, this further suggests that most patients may be expected to have a suboptimal response to venetoclax based on the presence of the monocytic features. We should keep that in mind as we interpret the early clinical outcomes from the safety lead-in. Let's move to slide 14. Of the 6 response evaluable patients, 5 patients or 83% achieved a composite CR/CRI with a median time to response of 33 days. These are early data, the clinical activity indicators, composite complete remission rate, and time to response are encouraging. With our data set being limited in number, it's difficult to estimate durability of response or overall survival at this time. Of note, 4 of the 5 patients achieving a CR/CRI had a high MES score that we believe is associated with venetoclax resistance. This makes these early response data particularly encouraging. Moving to slide 15. Displayed here is the adverse event summary for the six patients with available data. The median duration of therapy at the time of the analysis was 76.5 days, with a median follow-up of 107 days. As shown in the figure on the right, hematologic adverse events demonstrated evidence of myelosuppression, which appears to be comparable to what was reported for venetoclax plus azacitidine in unfit AML patients in the VIALE-A study. As shown in the figure on the left, the majority of the non-hematologic adverse events were low grade, and the AEs were also reversible in nature. Serious adverse events, or SAEs, were reported in all six patients, with the most frequent including febrile neutropenia and pneumonia, which is consistent with those that might be expected in patients with AML, including those treated with ven plus aza or with other AML therapies. Moving to slide 16. In conclusion, we're very encouraged by the early results from the SELECT-AML-1 safety read. We observed a high CR/CRI rate with a rapid onset of response. There were no new safety signals generated by the addition of tamibarotene to venetoclax and aza, each used at full dose per their respective labels. Together, these data support initiating the randomized portion of the trial. Moving to slide 17. As a reminder on this slide, approximately 80 patients positive for RARA overexpression will be randomized 1 to 1 in the second part of the study to receive either the triplet combination of tamibarotene, Venetoclax, and aza or ven-aza alone. We're evaluating a primary endpoint of composite CR, defined as the rate of CR + CRI. As noted earlier, tamibarotene is orally administered on days 8 to 28. Azacitidine is administered on days 1 to 7, and venetoclax on days 1 to 28 of each 28-day treatment cycle, each at the approved label doses. Recently, ELN published a new diagnosis and management guideline for adult AML patients, and this includes venetoclax dosing modifications as an acknowledgment of the ongoing need to minimize the risk of myelosuppression and complications of myelosuppression that are common with venetoclax treatment and which we also observed in our study patients. As we initiate the randomized portion of the study, we've decided to incorporate this into both arms of our SELECT-AML-1 trial to align our protocol-recommended venetoclax dose modifications with the new ELN guidance and the emerging clinical practice for the use of venetoclax, with an aim to enhance tolerability and safe use of venetoclax in the context of our triplet with tamibarotene. Importantly, this was well-received by the study investigators. We look forward to initiating the randomized portion early next year and to reporting data in the 2023/2024 timeframe. In my final slide, on slide 18, as a reminder, we're also evaluating tamibarotene in combination with azacitidine alone in the ongoing SELECT-MDS-1 trial, which is exploring the safety and efficacy of the doublet in newly diagnosed higher-risk MDS patients with RARα overexpression. We continue to expect data from this study in the fourth quarter of 2023 or first quarter of 2024, which if positive, could enable a potential NDA filing in 2024. I'd now like to turn the call over to Dr. Dan Pollyea who will share his perspective on the unmet need in newly diagnosed AML and the opportunity for tamibarotene. Dr. Dan Pollyea? Thanks. Excuse me. Thank you so much. really happy to be here with you to speak on, you know, my thoughts on the landscape here going forward. Pretty exciting times, for sure, for the field. Just slide 20. By way of background, acute myeloid leukemia is the most common acute leukemia in adults, about 20,000 cases a year in the United States. It is a disease of older patients. The median age is 68. That has brought forward a lot of discrepancy and discordant sort of results that, you know, over the last several decades, because the only relevant or acceptable treatment for newly diagnosed patients up until just a few years ago was intensive induction chemotherapy. There were variations of this all over the world and even within the United States, but that was basically the standard of care. You know, that was a very toxic regimen, is a very toxic regimen. It excludes many, if not most, older patients for whom this is the, you know, normal population for this disease. You have this disconnect between the standard of care treatment and the population of patients who have this disease, and that really made for a very poor outcome. It also made for very important decisions as to who was fit for this intensive induction chemotherapy. Lots of ink has been spilled on this topic. Lots of experts have debated it, what it means to be fit, and how you, how you are supposed to evaluate this. That was very problematic because it was never felt to be an acceptable metric for that decision. You know, you heard about the advance of venetoclax, and that really was a major breakthrough because it brought an effective therapy for a population who previously had not had an effective therapy, and that population happened to be the majority of patients who have this disease. We were very quickly ushered into this new era in which we had an effective tool to combat this, and it really happened very quickly. Next slide 21. You know, with respect to the venetoclax, you know, you can see here the difference. Actually, Keith Pratz, who's gonna be updating this for longer term purposes a little later today at the ASH meeting. The azacitidine plus venetoclax, you know, was certainly superior to what was sort of the de facto standard of care at the time, the azacitidine alone. That was not, you know, an approved therapy for that purpose. That's why I say de facto. There was no approved therapy for this population. There was a clinically and statistically meaningful improvement with those metrics. It's widely been adopted as the standard of care. It's, you know, very increasingly being used even outside of the typical label of, you know, the just the strictly elderly or unfit. The fitness discussions that I referenced before that were never resolved have become largely irrelevant because, you know, the important question of the day is not is a patient fit for an intensive chemotherapy regimen, but rather which of these options that we now have is the best treatment. All of this is great and news, and it's been a very sudden and enjoyable transition. Those of us who have been using the venetoclax regimen for the last several years now know that it's not a panacea. There is a massive effort on right now amongst like-minded people that we need to improve this further. We cannot be done or satisfied with what we have. That brings me to slide 22. With respect to venetoclax resistance, we know that 30% of patients don't respond at all. They are refractory. We also know that almost all responders will ultimately relapse. This has been challenging because initially, because all we've ever done is treat this disease with intensive chemotherapy, we look to the traditional risk factors to see if those, and assuming those would be applicable in the setting of a new treatment, not surprisingly, the factors that predict outcomes for patients with intensive chemotherapy are not the factors that predict outcomes with venetoclax-based therapies. The field is just now starting to appreciate this. Again, ASH later today, Hartmut Döhner is gonna be doing a pre-presentation on this specific topic. I'm the senior author of it, you know, it's really fascinating writing the new rules for response prediction to venetoclax, but that's been a major effort by our group and others recently. How do you predict venetoclax resistance if you can't do it with the old, with the old rules that are applicable in the setting of intensive chemotherapy? Slide 23. This is what I think has been our major contribution to the field. This was a couple years ago in Cancer Discovery, we reported that you can predict venetoclax resistance being refractory to venetoclax using a sort of discarded classification system, the French-American-British, or FAB classification system. This was the dominant classification system for AML, probably from the 70s into the late 80s. It was based on morphologic assessments of the disease and astute hematopathologists who noticed that the leukemia cells had different characteristics, appearances under a microscope, and those could be classified basically in seven or eight groups. That this had nothing to do with cytogenetics, nothing to do with gene mutations. Of course, that was all, this was all pre-predated all of that. When cytogenetics and gene mutations became available, people quickly reclassified AML based on those factors and discarded AML based on differentiation stage or, the way the cells look under a microscope. What we stumbled upon was this observation that if you, if you do classify AML patients in that way, you could really reliably predict a population of patients who do not do well to venetoclax-azacitidine, and those are the patients who have monocytic disease biology. Here, we've listed that as the AML-FAB M5 category. You can see that 2/3 of AML-FAB M5 patients were refractory to venetoclax and cytarabine. If you take out all the M5 patients, you can see response rates are north of 90%. To us, this was a big change in how we evaluated this and we have been readily incorporating more stage of differentiation into our disease assessments as a result of this observation. Slide 24, just to show you that we're not the lone wolf on this, multiple other groups have made this observation in different ways. You know, whether it's been in vitro signs of drug sensitivity by the Finnish group on the left, and multiple other papers from, you know, very well-established groups, including Jeff Tyner's group up at OHSU, have made this observation. We think it's pretty well established that this is a subgroup of patients that doesn't do well with venetoclax regimens. Slide 25, what does that mean? If you just look at the old VIALE-A survival curve for venetoclax and cytarabine, I think there are a couple of populations that are relevant here. In blue, you can see those patients who I believe are, well, not I believe, who are clearly refractory to this regimen and quickly bring the survival curve down. You can also see in red a group of long-term responders. The majority of patients, they respond, but then they relapse. I think we need to think about each of these different categories differently. They're all very important, but they warrant different treatment approaches. Slide 26, those patients who are going to be in a long-term remission, we have to do our best to identify who those patients are early on and leave them alone, and in fact, maybe even minimize their therapy. Slide 27, we need to really be able to focus on what factors make patients relapse, and once they're in a remission, don't allow them to relapse. While that's a logical, sort of policy for any malignancy, it's particularly acute for our field because we have no effective salvage regimens, particularly for a patient population who from the beginning was deemed ineligible for intensive chemotherapy. You know, sure, we have FLT3 inhibitors, and we have IDH inhibitors, but those only apply to a subset of patients. I will, you know, be honest with you, from my own feeling and most of my colleagues at this point, you know, those have really underperformed. Those aren't the sort of disease-modifying therapies that allow long-term remissions that we would've hoped. We have no good salvage therapies right now. Our only hope is to prevent relapse, or that's our best hope. You know, there's all kinds of ways to consider doing that, intervening when there's a rising MRD, adding triple combinations, to venetoclax backbones. All of those things are really important and we need to be thinking about them. You know, for slide 28, what do we do about this group of patients who doesn't even respond in the first place to venetoclax-based regimens? They have the worst outcomes. You know, just like patients who relapse, patients who are refractory, we can't salvage them. We have no good salvage therapy. In this case, this represents the most acute situation in which we need to do better because we don't even get a temporary period of a response or a remission from them. My take on this, and this is maybe not, you know, with, in, you know, consistent with everyone in the field, but it's not indiscriminate triple combinations. That's not the way to go, in my opinion. You know, you're going to be over-treating many, to get at the crucial population of patients who need to be treated. What you need to do is understand who are these people unlikely to respond and recognize who they are early and intervene on them, independently. That's why I think there's convergence with us and Tammy Behrent's team. At least my vision, our group's data, and Tammy Behrent team. Because of the data you already heard, that, about a third of non-APL AML patients overexpress RARA, and we were very intrigued by this publication, that there seems to be this overlap between the patient population we identified as resistant to venetoclax-based regimens, those with monocytic disease biology, and those who overexpress RARA. What a great opportunity from our perspective to try to get in on this clinical trial where these folks are, you know, specifically looking at this population and only intervening on them. And, you know, venetoclax and cytarabine backbone with a therapy that could overcome the resistance that we're seeing, perhaps with the from the monocytic disease biology that overlaps with the RARA overexpression. That was slide 29. Sorry if I didn't say that. So just sort of like summing things up, slide 30, you know, the conventional wisdom is that AML drug development is gonna be like multiple myeloma, and that everyone's gonna get everything early. I don't know that that's the way that it's going to go. I think what I'd much prefer at least is that we take an approach like you've seen outlined in this clinical trial. We make, you know, intelligent decisions based on each individual's disease biology and intervene when we think it's going to be most likely to have an impact. You know, taking ideally oral, well-tolerated therapies and adding them to this backbone in those select situations is the way to go. You know, doing this in a randomized fashion is, of course, the preferred approach. That's a little bit on why we're involved in this project and why I'm enthusiastic and also a little bit about my thoughts on the field in general. Thank you. Thank you, Dr. Pollyea. If you turn to slide 32, before turning the call over to Q&A, I wanna take a moment to recap today's discussion. Up through these presentations, I hope you've gained a better understanding of the tremendous value we see in tamibarotene. First, on the new data presented at ASH, we are increasingly confident that tamibarotene can alter the treatment landscape for patients with RARA overexpression. Importantly, the results shared today add to a growing body of evidence demonstrating consistent data across multiple trials and reinforce our clinical development strategy, both in AML, where we intend to initiate the randomized portion of SELECT-AML-1 in the first quarter of 2023, and in higher-risk MDS, where we are continuing to enroll patients in SELECT-MDS-1 with data expected in late 2023 or early 2024. As Dr. Pollack alluded to, there is a high need for a biologically targeted agent like tamibarotene that is convenient and well-tolerated with a novel mechanism of action that can be used in combination in the frontline setting to address the significant unmet need that remains in higher risk MDS and AML. We look forward to providing additional updates as we initiate the randomized portion of our phase 2 trial in the very near term and to report clinical data in both MDS and AML in 2023 and 2024. With that, I will turn the call over to the operator for questions. As a reminder, to ask a question, you will need to press star one one on your telephone. Please stand by while we compile the Q&A roster. Our first question comes from Eva Privitera with TD Cowen. Your line is now open. Hi, congratulations on the data. Thank you for taking our questions. A couple for Dr. Pollack. What do you estimate the response are for ven-aza in these frontline unfit patients who have the monocytic phenotype that you discussed? Yeah. In our experience, it's about a third of patients who have monocytic disease biology respond to ven-aza alone. And that's, you know, that's we haven't, you know, the best resource there is that Cancer Discovery paper. That's sort of my expectations when I'm seeing patients with that biology. Thank you. That's helpful. Are there any other characteristics associated with these monocytic phenotype patients, like blast counts or other mutations? Yeah. There's quite a bit known about sort of what co-occurs with monocytic biology. You know, I think there is not a monolith. I think some of them, you know, obviously have different characteristics. There's a group that co-occurs with NPM1, and those might do better. There's a group that co-occurs with KMT2A gene rearrangements. Those are usually younger AML patients. We don't see that often in the older population, those are typically bad actors, at least with respect to venetoclax-based regimens. Then anything that, you know, any monocytic disease with a complex karyotype or certainly a TP53, you know, those do poorly with everything we have. I'm, you know. There's also very frequent RAS mutations that co-occur with monocytic biology. That's well known to be common and may have at least partially explain some of the resistance. On that one, I'm not even sure what the, what's the chicken and the egg. They seem to be so closely related. Oh, thank you. That was very helpful. My last one is just on the SELECT AML trial. Can you remind us of the powering assumptions for the randomized portion of the trial? David? Sure. The randomized trial is set up with 80 patients, randomized 1 to 1 across the two arms. That's 40 per arm. It's a randomized phase 2 and has about 80% power to detect a difference in the CR CRI rates across the two arms. Perfect. Thank you. Thanks, Eva. Please stand by for our next question. Our next question comes from Ted Tenthoff with Piper Sandler. Your line is now open. Great. Thank you very much, to everyone for the presentation today. Dr. Pollyea, I enjoyed what you were saying about kind of your vision for the future. Just to hear this specifically, but if these data hold up, would your intention or expectation be that tamibarotene would be appropriate for all RARA-positive patients? Then for the company, what with this data and what can be done to kind of accelerate that enrollment so that we can maybe get the data in the fourth quarter rather than first quarter of 2024? Thanks. Dan? I mean, you know, the beauty of this is that, you know, this is a randomized study, and they have done it in a very smart way, in my opinion. I mean, they, you know, they're only looking at the monocytic patients. I mean, if they show improvement in outcomes in this, in a, in this study with this population, I mean, I think that that would be something we'd be enthusiastic to use for all the RARA-positive patients. David, do you wanna take the next question? Sure. Yeah. You know, like, the initial focus of this study has been a safety lead in a relatively small number of patients. The trial it was opened at a few centers, and we've taken advantage of the time during that to open up sites elsewhere across the United States, actually in France as well, and we're really well-positioned to enroll the 80 patients with a rate of enrollment that, you know, reflects the larger enrollment objective of the trial compared to the first part. I think we're in good shape in that respect. Great. Excellent. Thank you, and great progress here. Thanks, Ted. As a reminder, to ask a question, please press star 1 on your telephone. Our next question comes from Mark Breidenbach with Oppenheimer. Your line is now open. Hey, guys. Thanks for hosting this call and thanks for taking our questions. I apologize for any background noise. It's a bit noisy here at ASH. Just a couple from me, probably all aimed at Dr. Pollack. First of all, I'm wondering if we should be at all surprised that the study population here in terms of FAB classification doesn't really seem to jive with the monocytic expression score. I'm not seeing a lot of M4, M5 patients. Is that at all surprising given that their monocytic expression score is so high? I also wanted to get your comments on a data set we saw from an MD Anderson group a couple years ago, where they tested venetoclax plus the cytarabine, so a different HMA, in M4, M5 AML, they still saw quite respectable response rates. If you're aware of that data set, I'd love to get your comments on that. Thank you. I'm happy to talk about that. Yeah, I'm aware. Yeah. It also... I mean, I don't believe that has been published in a manuscript form. You know, when we very specifically, our finding is, this is an M5 phenomenon, we get a little loose with our talk about what monocytic means these days. You know, technically, per the FAB, monocytic is M5. Myelomonocytic is M4. As we showed in that figure, M4s do quite well with ven-aza. This is specifically, when I say monocytic, I'm really meaning an M5 phenomenon. I've asked those folks, MD Anderson, and also there's a German group who had kind of a similar observation, to tell me what happens when they look at their ven-aza data with just the M5, and I have not heard back what, you know, if they have a similar observation. You know, that's our finding on it. You know, the biology seems pretty clear. And the, you know, the other groups that I've cited around the world that have kind of come to this conclusion as well makes me feel better about this observation. Yeah. I could also add just a little bit about that. It was a poster at ASH, I think in 2020. you know, yeah, if you look closely at their analysis, you know, there was a, it looked like there was a significant enrichment in the NPM1 mutation, which is a favorable risk mutation in the patients they classified as monocytic, and there was also an enrichment in the P53 in those who they said were not. It's very possible, you know, one, you know, the monocytic did, you know, the NPM overwhelmed the monocytic phenotype impact, and the TP53 brought down the control arm, so to speak, so they equalized. The bottom line is, you know, there's multiple things going on in AML. It's a heterogeneous disease, lots of mutations in the backdrop. You know, it's important to look at these covariates to see if there's influencers in the outcomes. You know, I can't be more specific than that. It's not our data set, so it's hard to interrogate it more deeply. You know, we're confident in the information. Interestingly, we, you know, we did our own work following on, you know, Dan and his group's publication in Cancer Discovery, looking at RAR α expression in populations through publications and then aligning them with these monocytic expression features initially anchored on the M5 phenotype through the TCGA database and then more broadly. We demonstrated strong correlations, using real-world data, as well as, you know, supplemented by, you know, drugs, high-throughput drug screening assays and in vitro experiments. You know, we're in the camp that this is important enough to test in the clinic. We're really excited that we're gonna develop the first prospective randomized test of this very important hypothesis. Okay. Should we kind of be worried that there are no confirmed M5 patients in this? No. Initial complete. No, I wouldn't be worried about that. First of all, half the patients didn't have a result, so it's not like they're not there, they're just not known or reported. The other point is that of the 5 who we could get MES scores on, 4 of the 5 were MES positive. Through a different probe, a molecular probe, which perhaps is more precise than the one that involves just visual inspection of the cells under a microscope, which I used to be quite facile at when I was a hematologist in practice years back. You know, I think we're, you know, we're convinced we have this represented in our patients now. Okay. One quick follow-up. Just I know it's early days to talk about durability, response durability, but what remind us what the typical range is for a venetoclax doublet in newly diagnosed AML and, you know, are we at least kind of following at the lower end of that range that you would expect for venetoclax alone? Thanks. Sure. I, yeah, I can take that. You know, it could be upwards of a year or more, like once you go into a response to, you know, retain that response. You know, I think you're right to say it's early. I mean, our primary endpoint was really focused on, actually in the trial is on safety, just for the safety lead-in. We were able to garner some, you know, early clinical activity data based on the CR CRI rate, as well as the time to CR and CRI. We're really encouraged by this 83% value. It's just too early to speak to the duration of response or the overall survival at this point. You know, we're committed to obviously getting this randomized trial underway as soon as possible and reporting out data on that in the 2023/2024 timeframe. You know, we'll certainly provide an update on a whole slew of activity parameters, including response duration, survival, all the usual things, probably around that time. Okay, thank you. At this time, I show no further questions. I would now like to turn the conference back to Nancy Simonian for closing remarks. Great. Well, thank you again for taking the time to join us today, and please feel free to reach out directly with any further questions. This concludes today's conference call. Thank you for participating. You may now disconnect.