This call is being recorded on Tuesday, June 25th, 2024. I would now like to turn the conference over to David Roth, Chief Medical Officer, Syros Pharmaceuticals. Please go ahead.
Thank you very much. Welcome everybody, to our medical expert webinar event. We're here today to describe the opportunity for tamibarotene to transform the care of newly diagnosed higher-risk myelodysplastic syndrome with RARA gene overexpression. I just wanted to make sure everyone knows I'm David Roth, and I'm the Chief Medical Officer of Syros Pharmaceuticals. This next slide, on slide two, overviews our forward-looking statements, and you can review that in greater detail after the webinar. Today we have a very exciting agenda. We will begin with me providing an overview of tamibarotene, well, an introduction of higher-risk MDS, as well as the SELECT-MDS-1 phase III trial that we have ongoing.
I'll be followed by three distinguished medical experts in the field who are going to provide the following content for you. Our main objectives are to make sure that everyone understands what it is we're doing and what the backdrop is, so one can understand our approaches and how to interpret the data as they evolve. We'll start with Dr. Amy DeZern. Dr. DeZern is Professor of Oncology and Medicine at the Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, and she'll provide a disease overview and current approach to patient management. Dr. DeZern will be followed by Amer Zeidan. Dr. Zeidan is Chief of Hematologic Malignancies at the Yale Cancer Center and Smilow Cancer Hospital, and Associate Professor of Medicine, Hematology at the Yale School of Medicine.
And Dr. Zeidan will overview an understanding of patient outcomes in higher-risk MDS trials, including the importance of complete response. Our third medical expert is Dr. David Sallman. Dr. Sallman is Head of the Myeloid Section and Associate Member of the Department of Malignant Hematology at the Moffitt Cancer Center and Research Institute in Tampa. He will overview current therapies for MDS, the emerging treatment landscape, and ongoing areas of unmet need. We'll conclude with closing comments by Conley Chee , our CEO at Syros, who will overview the commercial opportunity and provide some closing remarks. So here's what we hope you'll take away from today's event. Three important objectives we have, and we want you to appreciate why we believe the combination of tamibarotene and azacitidine offers a potentially transformative approach for the treatment of higher-risk MDS.
We also want you to understand why we're confident that the SELECT-MDS-1 trial is designed to support regulatory approval and also to drive uptake amongst treating physicians. And lastly, we want to share with you why we believe there is a significant unmet need in higher-risk MDS for a new therapeutic option that may be addressed by tamibarotene, and which has the potential to improve upon the existing standard of care. So let's begin with my section of the presentation, and I'm going to go over tamibarotene and higher-risk MDS and the SELECT-MDS-1 trial. Again, I'm David Roth, the Chief Medical Officer. I'm a hematologist by training, and I've been at Syros since 2015. To start with, Syros is advancing our vision to deliver on the value of tamibarotene.
Now, at this time, we're advancing tamibarotene as a potential new standard of care for higher-risk MDS and AML patients with RARA gene overexpression. Preparing for product launch and commercialization, and importantly, we have a cash runway to fund our planned operations into the third quarter of 2025. Since the beginning, we've had a vision to evolve into a commercial company, delivering new standards of care for the frontline treatment of hematologic malignancies. And as you'll see, we're well on our way to achieving our vision. I'm going to start on slide seven, and I think it's really important, especially for those who are joining us today, who may have less familiarity with our program, to help you understand how this all began, and why tamibarotene is a novel, targeted mechanism of action that provides competitive differentiation.
At the time we began, our company was founded on the scientific principles that we can identify areas of the non-coding region of the human genome that were important in driving the abnormal expression of genes that were important in causing diseases. We used a method of identifying super enhancers, which are these very large, expansive regions of the non-coding region of the genome that drive high-level expression of genes that they control. We were able to identify super enhancers, specifically in the patient tissues, patients who had certain diseases. We looked, for instance, at patients with AML and with MDS, and we found that there was a super enhancer driving very high-level expression of the gene that encodes RAR alpha.
It wasn't anticipated at the time w e were very excited when we made this discovery because we knew that the biology of retinoids, including RAR alpha, were very much involved in leukemogenesis. Here we found that the RAR alpha gene was overexpressed in sizable percentages of patients. As we now know today, about 50% of patients with higher-risk MDS have RAR alpha overexpression, and about 30% of patients with AML have elevated expression of the RARA gene. So how does that all work? Well, look at this cartoon on the left of the slide, and you'll see in the upper left corner what represents the normal situation. You have RAR alpha. It's a nuclear hormone transcription factor. It sits on the gene upstream of the genes that it regulates, and these are highly involved in myeloid maturation and differentiation.
When this nuclear hormone transcription factor is bound by its ligand, in this case, retinoic acid, shown in green, it assumes certain shapes or conformations, and it's able to cause the expression or activation of those myeloid maturation genes. And what we end up having is what's referred to as healthy, differentiated myeloid cells. In the context of a super-enhancer, we have very elevated expression of the RARA gene, and we see that there is unliganded or unbound transcription factor. So you can see in the middle cartoon, RAR alpha is not always complex by its natural ligand, retinoic acid. And in that situation, myeloid maturation does not proceed, and we have increased circulating undifferentiated cells that are overexpressing the RARA gene with increased proliferation, and this is an underpinning of AML and MDS.
So here comes tamibarotene, and what we identified is that tamibarotene, a selective and potent RAR alpha agonist, can bind all of the unbound RAR alpha and restore that normal ratio of liganded RAR alpha, so that we can then recapitulate normal myeloid maturation and provide more differentiated myeloid cells in that situation. So this is how we're using pharmacologic doses of tamibarotene, shown in purple, to restore normal and normalize the biology of the retinoid pathway. And we believe that tamibarotene provides competitive differentiation with respect to how it works because it's biologically targeted, which we think is very important. We can actually identify patients who may benefit. We have demonstrated high complete response rates by using tamibarotene in patients who overexpress the RARA gene.
These responses occur quickly, and very importantly, the safety profile appears favorable as it's emerging in the various studies that we've done over time. We believe that the toxicity profile supports ongoing development and ease of use. It's readily combinable, largely because of non-overlapping mechanisms with other drugs that it may work with, and because of its favorable tolerability profile. And very importantly, in particular, for the patient populations we're focused on, we don't see additive myelosuppression when combined with drugs like hypomethylating agents or BCL-2 inhibitors. We've not seen increased myelosuppression, which really is an important feature for adding this into the backbone of other existing regimens that are in use.
Slide eight gives an overview of some of the highlights of our data over the years, and we've developed a growing body of clinical evidence for tamibarotene in higher-risk MDS and in AML patients with RARA overexpression that have supported our development strategy even as of today. Back in 2017, we reported on our single-agent experience with tamibarotene, and in those data sets, we were able to show that single-agent tamibarotene in relapsed/refractory higher-risk MDS patients demonstrated hematologic responses with increased blood counts in all three cell lineages: the red cells, the white cells, and the platelets. We even had a patient who had a durable complete remission in the marrow, a marrow CR that lasted over half a year at the time of that report came out.
In 2020, we reported data from our phase II trial that evaluated the combination of tamibarotene and azacitidine in newly diagnosed unfit AML patients. We showed that in RARA overexpresser patients, we had a very high CR/CRi rate. It was about 61%. We looked at the low blast count segment of the AML patients enrolled, and there we saw an even higher CR rate. It was about 67%. Importantly, the majority of the patients who were treated, who had RARA overexpression, developed transfusion independence. By that we mean they were dependent on the blood bank for getting platelets or red cells before they came into the study. Upon treatment with tamibarotene, their need for blood transfusions resolved because their blood counts improved.
The drug worked quickly with a median time to response of 1-1.2 months. The response lasted nearly a year, about 10.8 months in this analysis, and the overall survival for those with responses was about a year and a half. In 2023, at the end of last year, we shared data from our very first pre-specified analysis of our ongoing phase II trial that was advancing tamibarotene in the combination of venetoclax and AZA. So the middle study in 2020 was looking at the combination of tamibarotene plus AZA. Here we added it to VEN and AZA, which had emerged as the new standard of care in the frontline treatment of unfit AML patients.
So we added Tami to that combination, and we actually are conducting a randomized trial where patients either get Tami plus VEN plus AZA or VEN plus AZA. These are all newly diagnosed unfit AML patients, and they're all RARA-positive for overexpression. In the treatment arm, we showed a 100% CR, CRi rate. 78% of the patients had CRs, and in the control arm, we saw a 70% CR, CRi rate, and 30% of the patients had CRs. The median time to response was about three weeks or 21 days for the Tami-VEN-AZA arm. Again, quick responses, and the overall safety profile was very favorable. This slide, on slide nine, overviews the safety that we've demonstrated over many years, and it supports the use of Tami in combination with AZA in MDS and with VEN-AZA in AML.
Just so you know, tamibarotene has been well characterized in over 1,000 patients with acute promyelocytic leukemia as a single agent. It's been shown here in our studies as a single agent in AML and MDS patients, and as a doublet in patients with azacitidine in patients with AML, to have a generally well-tolerated safety profile. More recently, the study I most recently mentioned, the triplet with tamibarotene and venetoclax in AML patients. We've administered the drug using daily dosing as a single agent and in combination with AZA. It's been well-tolerated with no evidence of increased toxicity. Rates of myelosuppression have been comparable to single-agent AZA, and in the triplet, myelosuppression has been comparable to that of VEN and AZA. The majority of the non-hematologic adverse events have been low grade and reversible.
The next slide just illustrates some of the more recent safety data of the combination with VEN and AZA. In our initial randomized data readout, the heme safety profile showed no additive myelosuppression when combining Tami with VEN and AZA. Shown in the graphic, we focused on the heme toxicities of febrile neutropenia, neutropenia, thrombocytopenia, leukopenia, and anemia. Tami VEN-AZA is shown in the dark blue bars and VEN-AZA in the light blue bars, and you can see there's no increase in myelosuppression compared to the VEN-AZA treatment assessments. Interestingly, in several of the evaluations, it appeared that the trends looked even more favorable toward the triplet.
While at first that may be somewhat perplexing, because it's more typical that you increase toxicity when you add a drug into an existing treatment regimen, if you think about the mechanism of promoting myeloid differentiation, it's very possible that tamibarotene can expand the myeloid compartment and promote the release of differentiating myeloid cells from the marrow, which in some respects may offset some of the toxicities that are known to exist for venetoclax and azacitidine. So we're looking forward to providing an update of another pre-specified analysis of this ongoing trial in the third quarter of this year, and we're very eager to see whether or not these safety data continue to hold up.
One last slide before going into the trial design was just to illustrate a point that I think you're going to see in at least one or two of our medical experts' presentations. And that has to do with the fact that higher-risk MDS is closely related to AML. You know, there have been publications recently where MDS with excess blasts and AML have been put forward essentially as a continuum rather than as distinct diseases, in part, perhaps promoting more streamlined efforts at drug development. And we do know that MDS evolves from precursor states with abnormal cells.
Typically, the evolution of the disease or the natural history can be described as someone progressing through lower risk MDS, and as their blast counts increase or they acquire additional mutations, they then evolve into higher risk MDS. And then they go through a stage where they may have low blast count AML, which may be one and the same with higher risk MDS, and then frank AML. What we do know is that more than half of higher risk MDS patients will ultimately clinically progress from higher risk MDS to AML. And we also believe there's a relationship based on shared underlying biology with common molecular abnormalities.
This is, in part, been acknowledged by the continuous evolution of disease classification criteria over time, and you'll hear about this as well in some of the presentations from our medical experts. When I was a hematologist in training, AML was classified as having over 30% blasts in the marrow, and this had then been revised to include the upper segment of the higher risk MDS subtypes, who had lower blast counts in the 20%-30% range. So now AML is defined as having a blast count of 20% or more, and there are even newer proposals to include a new category called MDS-AML, a disease category that would be defined as having 10%-19% blasts.
As I mentioned in one of my earlier slides, we've seen higher CR rates, 6%-7%, in our phase II study, looking at the AML patients who had low blast count AML with RARA overexpression. And we believe that our clinical data have reinforced the potential for tamibarotene, in combination with AZA, to deliver a clinically meaningful benefit in populations with high risk MDS with RARA overexpression. Our trial design, the trial is named the SELECT-MDS-1 trial, and it's an ongoing trial. It's a phase III study in newly diagnosed higher risk MDS patients with RARA overexpression. And the study is designed as a randomized trial, 2-to-1 randomization. Patients who enter the study are either randomized to tamibarotene plus azacitidine or placebo plus azacitidine.
The primary endpoint, which is based on the initial 190 enrolled patients, is the complete response rate, and the study continues to enroll to achieve its key secondary endpoint of overall survival, which is targeting approximately 550 patients. Some of you may know that we received Fast Track designation by the Food and Drug Administration for the development of tamibarotene in combination with AZA in higher-risk MDS patients with RARA overexpression. We believe the study is robustly designed, double-blind, placebo-controlled. I mentioned the 2-to-1 randomization. It's a global study. We have over 120 sites recruiting in 13 countries. We've received FDA feedback supporting that we focus our population on patients with RARA overexpression, so those without RARA expression are not eligible.
The complete response rate serve as a primary endpoint for the approval, either full or accelerated, with supporting data on the durability of the remission, and we were also advised that AZA is an appropriate comparator. Some of you may know, if you follow our news feeds closely, that we passed a futility analysis based on an analysis of 50% of the enrolled patients to support the primary endpoint of CR rate. This was conducted by an independent data monitoring committee.
Our primary endpoint is over 90% power to detect the difference between the experimental and control arms with a one-sided alpha of 0.025, and we've included overall survival as the key secondary, so this allows for a single study to efficiently serve as a confirmatory trial if needed, for full approval, should we get accelerated approval, at the initial pass. Our key milestones. We initially achieved our last patient enrolled for the pivotal CR data readout in the first quarter, and this enables us to predict that we will have the pivotal data for this trial, by the middle of the fourth quarter of this year.
So it's very exciting times, and that's why we feel it's very important for us at this time in our progress, to now bring together three medical experts to make sure that everyone who's following the Syros story clearly understands the disease, how we assess the disease in a study like ours, and how the drug will be incorporated into the future treatment landscape based on what else is available and how we're approaching patient management. So with that, I'm gonna turn the presentation over to Dr. DeZern, and I will leave it to her. And by the way, at the end of all of the presentations, there'll be an opportunity to ask questions.
For those who don't get to ask a question in real-time by voice, you can also enter a question into the chat box, and we'll do our best to address as many as we can. But we're not gonna interrupt the presenters. So, Dr. DeZern?
Thank you so much. Yes, thank you, Dr. Roth , and good morning or good afternoon to everyone listening in, wherever you are. My name is Amy DeZern, and I'm a high-volume MDS clinician and clinical trialist who's a professor here in Baltimore at Johns Hopkins, and I really, really enjoy taking care of patients who suffer with MDS. MDS is actually the most common myeloid neoplasm in the world. You can see there on the left of your screen the overall incidence and then what it is in the United States. The median age at presentation is a bit more experienced in years, around 70, with more than three-quarters of the patients diagnosed over age 60. And as with many cancers, you can see the incidence increases by decade of life.
I think it's sometimes interesting to use the SEER database to think about how this relates to other hematologic malignancies in terms of incidence, as well as select solid tumor malignancies. You can see in the red rectangle on the right that MDS actually is common relative to many of the malignancies that you might think about in other settings. This truly is a disease that we need to improve upon. Dr. Roth gave you a similar overview of the spectrum of myeloid diseases. As we have newer technology and better ways to make diagnoses, we increasingly do diagnose these states earlier, but we are not currently in an era where standardly in the myeloid world, we treat precursor states.
But as MDS progresses through lower risk disease and higher risk disease, all the way on the way to AML, we really know that these diseases are biologically very similar. It's a continuum. And you heard Dr. Roth mention how when he trained, it was a threshold of 30%, sort of as I trained, we're still in the 20% range, and I think the next generation is going to think the threshold is 10%. And that really speaks to the biology of the disease and how we can really confidently extrapolate data from an AML population to a high-risk MDS population so that we can improve the outcomes for all. And that's because MDS is truly an umbrella term biologically.
With this newer testing capacity, and as we learn more and more through the data, we're understanding that MDS is this umbrella term, and there are conditions which we are not speaking about today that are indolent, and they have years of chronicity. Then what we're focusing on today are the more aggressive, high-risk myelodysplastic syndrome entities that approach the same outcomes as AML. The way we make a diagnosis in the clinic is somewhat complex, perhaps more straightforward, but prognostically, what many patients in the clinic want to understand, as you are not surprised, is their prognosis. What we use for their prognosis on clinical trials and in the standard of care setting in 2024 is predominantly the Revised International Prognostic Scoring System, and this is what gets us to high-risk disease.
You take a patient's clinical factors, these are data available from a diagnostic bone marrow to look at their metaphase karyotype and changes there, put that in a risk category. Then you look at their clinical cytopenias, how deep they may or may not be, and then you assign points that get you a risk stratification. And you can see here that we have very low and low, which, again, we're not really speaking about these lower-risk entities today, and then we have intermediate, high, and very high-risk disease, and these are those who get points greater than 3.5 on the Revised International Prognostic Scoring System.
In the current era, where all information is usually available to a patient at the same time as it is available to their clinician, commercial bone marrow biopsy reports from diagnosis often print this score out for the patient, so they come to see us knowing this. In addition to that clinical information that you use to calculate the International Prognostic Scoring System-Revised, we have next-generation sequencing. We call these acquired or somatic mutations that have a great deal of value with risk stratification. Unfortunately, we know that the biology of certain of these mutations is less favorable, and these are the mutations that we commonly see in higher-risk myelodysplastic syndromes and AML, TP53, ASXL1 frameshift, EZH2, and so on and so forth.
The quantity of mutations, more than 2 or 3, is also less favorable, and certain co-mutational patterns we're learning predict a specific adverse biology for some patients. Which leads us to another way in 2024 that we're learning to prognosticate risk of MDS for our patients, and that's the International Prognostic Scoring System-Molecular. You may remember I focused on karyotype and cytopenia for the IPSS-Revised. Now, this is the IPSS-Molecular, which incorporates not only those clinical parameters, but now we use the next-generation sequencing. And again, you get very low, low, moderate-low, which we're less focused on today, or moderate-high, high, or very high-risk disease. And again, patients understand this information and often want to discuss it quite a bit at the time of diagnosis. Using this next-generation sequencing and the IPSS-Molecular is really helpful.
As someone who has practiced in the era where this has become standard of care, it's very exciting, it's very useful. Understanding the biology helps me take better care of patients from a conceptual perspective. But I'm candid that in 2024, it does not guide our therapeutic choice in all patients. And so the concept of having a biomarker-driven therapy is really quite appealing. We hear on commercials and in other diseases that it's all about targeted therapy, but as a clinician, something that is driven by a biomarker is really helpful. We have this molecular information, and we know that certain mutations, like TET2 or DNMT3A in retrospective data, may predict a positive response to our standard hypomethylating agent therapy. The lack of other unfavorable mutations may also suggest a patient will do better.
We've long known that a TP53 mutation is quite adverse, and we're still just really trying to understand how we can use this biologic information and ultimately make the right choice for patients. The reality is we have very few truly targeted therapies in the MDS space. We do have an IDH1 inhibitor, and in the AML space, we have IDH2 inhibitors and FLT3 inhibitors. But we still have great opportunity for a biologically targeted therapy, perhaps like tamibarotene. So when I see a patient in the clinic, they come with their report, they come with their IPSS-R score. We usually do at least get or already have their next-generation sequencing.
But also, this is about the human being, and I need to look at the patient and think about how we're going to do this and work with them and their family within their goals to make the best therapeutic path ahead. Fitness is currently a very big part of it. As I mentioned in the beginning, and you probably know, this is a disease of people who are in their seventies. Are they really fit? They're a marathon runner in their seventies, or they have a number of other comorbidities and might be less fit, and we need to think about what to do. In the high-risk MDS, and certainly AML setting, there's the concept of the potential path to cure, which is bone marrow transplantation or stem cell transplantations. The same thing, different verbiage. Are they a candidate for that or not?
It was alluded to earlier about some of the tamibarotene data that allowed transfusion independence, but I need to know if they are already receiving red cells or platelets from their local blood bank when they come to meet us. That's very important. And then we have patient factors versus disease biology, making sure we really have a well-characterized disease with all the genetic information I mentioned, and then thinking about someone who might want a clinical trial or perhaps someone that's not as interested in it. And all of this is incorporated to a very engaged consultation for a patient with MDS. But what is uniform in all patients who come to see a clinician like me or Dr. Sallman or Dr. Zeidan or others, is that the goals are pretty constant for someone suffering with high-risk MDS.
We need to decrease those blasts, the young leukemia cells that are the space-occupying tumor in the bone marrow. We need to stabilize that marrow function, so hopefully, they're not getting as many red cells or platelets. We also need to make sure their neutrophil count, which are the good infection-fighting white cells, is at a level where they can protect themselves from infection from their own body and their outside world. Tri-lineage improvement is more of the same, where we improve those three main cell counts: white cells, red cells, and platelets. Certainly, lowering the risk to a high count proliferative AML has a lot of merit, and you find that this bullet point is what patients and their families are quite keen to focus on. Then we have to move towards definitive therapy and maximize the benefit.
Expectation management throughout all of this is absolutely critical at the bedside. But the truth is, I have to be honest with my patients, that we are not doing as well as I would like for most of us who care for these high-risk MDS patients. We must do better. The current issues that have limited our improvement and outcomes for these patients is that our standard of care hypomethylating agents aren't great, and once a patient has progressed through that therapy, they just don't do as well. We've talked about how there's unfavorable disease biology, and we've been limited with our translational colleagues, as some of the animal models are not as successful as recapitulating what we might see in a human being, and we just don't have enough therapies to improve normal hematopoiesis.
We're so keen for more options in our therapeutic arsenal for our patients. This is a treatment paradigm that you would see in the vast majority of MDS talks from here on out and have for the past decade or so. We talk about the patient's goals. We think about whether or not they're a candidate for bone marrow transplantation. We use standard of care, maybe a clinical trial, and there's not a lot of drugs in the purple on this, and we have to think about how to do better. It's rare that we treat somebody with induction chemotherapy, and we don't always get to transplant. This is a realistic set of percentages of how these patients do in each facet of this. We talk about their goals.
If we're optimistic, they're going to go down the right side to transplant and think about these options. But if they don't necessarily get there or it's not successful, they end up over here, and we just have to keep trying what we have, which needs to be more. What about this potential path to cure? It's a very common question early on from patients and their families, and we have to balance the risk of this intervention, which is not a guaranteed cure, it's a potential path to cure, and how eligible or the candidacy for this is a moving target. We think about using transplant from the beginning, but we balance it with the prognostic scoring system, whether or not their MDS came from having treatment for another solid tumor, if they've already progressed through standard of care, and so on and so forth.
And so you can imagine, some of these suggest how someone is going to do without a transplant, and some suggest how it's going to do with a transplant. But the reality is, the majority of MDS patients do not go to bone marrow transplant. So we really need to improve at the upfront time point where we pick the best treatment upfront from the beginning that is tolerable, durable, and of course, efficacious. So that means something maybe that they take partly as a pill, it can be given as an outpatient, and the toxicity is quite manageable. And using single-agent HMAs, as I keep alluding to, or hypomethylating agents, has not gotten us where we want to be, and I think you'll hear some more of this data later. So what is the ideal therapy?
What do we hope with our patients when we're having these conversations at diagnosis? We want to do better than HMA monotherapy. We want durability, and that means it works in the here and now, but also it might be a tolerable bridge to bone marrow transplantation. If these are people that are not going to transplant, we still want what I call the cruise paradigm, which is keeping them out of the clinic, except on the days that they're treated, so that the rest of the time, they don't have to think about their disease. The side effects need to minimally affect their quality of life and have a predictive capacity, a priori of working. You'd be surprised how much patients resonate with something that they might be likely to respond to because there's a biomarker for prediction a priori.
It's very powerful for their hope and the way they approach things. So I think we can learn a lot, and I feel very optimistic about the AML data I've seen from tamibarotene in combination with azacitidine, and I think it is truly extrapolatable to MDS, and that's why I have a lot of hope for the SELECT trial. If we look at phase II AML data of tamibarotene in combination with azacitidine, these patients are newly diagnosed, the same high-risk MDS population I'm speaking about. These are patients who have the biomarker positivity for RARA overexpression a priori, and those that had the positivity and high-risk disease, similar to what I've alluded to, still have the possibility of doing quite well. They have high complete response rates with a rapid time to response.
So these are all the ideal features that we were talking about with how we want our patients to do, having bone marrow stabilization and tri-lineage improvement. Dr. Zeidan will get into how the counts recover and how this gets us to a CR. A time to initial response that is really favorable of just a little over a cycle or 1.2 months. And because these rates were seen in low blast count AML patients, it's back to that continuum of these are very biologically similar to high-risk MDS patients. And so I think this is very positive in the, no pun intended, rah, rah, positive patients, and something we're looking forward to understanding in the MDS patients. And if you look at the responders, this also gets to that durability that we're talking about.
You know that someone who can stay on a clinical trial with a high-grade myeloid malignancy for over a year, 20 months, things like this, these are people that are tolerating it well and are very optimistic about how they're doing clinically. So why would we choose a clinical trial in the current era over things that aren't a trial? Azacitidine and venetoclax, despite its discussions as being a low-intensity paradigm, certainly is not easy, and this is also not free. It is also not approved for MDS in the current era. Vyxeos is also not approved purely for high-risk MDS, and so these off-label costs and what not have a lot of toxicity.
The cytopenias can be quite deep, and we have to think about drug-drug interactions, and that we don't have the ability to predict a response to justify this therapy upfront, at least at this point in time. As an academician, I have equipoise about a clinical trial, and it's been very fun to have these conversations with patients to offer an opportunity to more, as you saw the design with the SELECT trial . Practically, from the community, something that's oral, it's combined with a drug that they know how to use, like azacitidine, is also very promising. Hopefully in my little time here, I've shown you that MDS is very common, so it's a lot of people to help when that's what we want to do. We're really evolving rapidly from a diagnostic perspective. These biomarkers and targets are key as we think through prognosis.
Our field is incredibly hungry for novel therapeutics because in the higher risk disease space, we need to start treatment efficiently, we need to improve response rates. If I can have predictive capacity upfront for response, it's a really improved conversation with the patient as we talk through something that I hope is tolerable for them and has durability to get them to their goals. We're all looking forward to the future of a new drug with a novel mechanism of action. Now I'll turn it over to my colleagues to talk about some of the other important features of MDS diagnosis and management.
Thank you very much, Dr. DeZern. That was very helpful. And now we're going to turn the presentation over to Dr. Zeidan, who will explain how we assess drugs in clinical trials. Zeidan?
Many thanks, and, it's a pleasure to be with you here today. So my name is Amer Zeidan. I'm an Associate Professor of Medicine at Yale University and, Chief of the Hematologic Malignancy Division. This talk clearly represents my own opinion and not the, my employer. These are my disclosures, including consulting for Syros. So what I will be talking about in the next 10 or 15 minutes or so is the endpoint aspect of approval for MDS, and in particular, high-risk disease. This is an important subject because it has seen significant, back and forth, and I have to say, I think there has been some misconceptions about the value of some of the endpoints that are used, because of the results of some of the recent trials.
I think it's very important to make sure we all understand what counts from a patient perspective as a clinically meaningful endpoint. Generally, when we think about any trial for any cancer, really, the main goal is for patients to live longer or better, or ideally both. Clearly, to have an endpoint, it has to be either a hard endpoint, like an outcome where no one would disagree on what on the value of that, versus an intermediate surrogate endpoint that predicts a long-term survival or carries a clinically meaningful impact on the patient by itself, such as having transfusion independence, such as having a blood count improvement, reduced infection, etc.
So, for this to happen, the endpoint has to be clearly defined, it has to be practical, it has to be measurable with reasonable reproducibility between different observers, meaning that if the investigator looks at the data, if another, independent committee looks at the data, if the regulators, such as FDA, looks at the data, they all come up with the same results in terms of, the rates of, responses. So I think all of these are important when you think about, clinical trial endpoints. Now, the problem in MDS is that, MDS, as you have heard from Dr. DeZern, is, very complex and biologically very heterogeneous. So you have patients, who clinically behave in more indolent fashions. Those are what we call lower-risk MDS patients who can live for many years, some of them more than 10 years.
There are patients who have higher risk disease, the ones who have excess blast, more than 5% blast, or high risk cytogenetic or molecular features. And those patients, as you have just heard, act more like acute myeloid leukemia, with a survival of less than a year without treatment. Trying to come up with response criteria that accommodates this entire spectrum, I think has been challenging, and that leads to some of the misconceptions about what is actually needed to kind of approve drugs in the space of MDS. I think the most important point here to make is that the clinical endpoints vary between what we call lower risk and high risk disease.
The issue that Dr. David mentioned about, like, the moving blast count and the increased blurring of the boundaries between AML and high-risk MDS, where the 20% used to be the mark. Now we have this new category on the new classification, the ICC of MDS/AML, when you have 10%-19% of blast. And that has brought up the question, and indeed, some trials have been doing that. Like, do you use AML response criteria for those patients? Do you use MDS response criteria for these patients? And this is an active discussion that's, I think, becoming more important as these new classifications have been published.
I think a very good example, I suspect some of you have tuned into the very excellent ODAC discussion on the imetelstat data when the drug went in front of the FDA for potential approval based on the IMerge study. So this is a drug that was being studied for lower risk MDS, and I think as I mentioned earlier, I think improvement of blood counts is really the most important aspect in lower risk MDS management because those patients generally have low blast count, and generally, they have a survival that is not easy to improve with the current treatments. While high-risk MDS patients behave more like AML and cytoreduction is important as well as count improvement.
Indeed, I think as an example of what have been an issue with some of how this is viewed is the FDA took issue, I think, with not having CR and PR being achieved with the imetelstat. And I think CR, complete response and partial response, actually are important endpoints for higher risk MDS, not necessarily for lower risk MDS. So I think it's very important, again, to make that distinction between lower risk and high risk MDS. The problem, of course, is how do you define high risk MDS? And this has been a moving target. There are different definitions. I'm showing you here three or four s orry, I'm not sure what's the slides keep jumping around.
But here you can see what's happening with some of the response criteria, or sorry, with the classification tools in terms of what defines high risk versus lower risk disease. And you can see different tools have used different parameters, but most of them will use a blast count being more than 5%, along with adverse cytogenetics, and most recently, based on the molecular IPSS that uses molecular features to define high risk disease. But what this has led to is that the same group of patients could be classified into higher risk in some trials, but not in other trials, based on which tool is being used. And this is an example from the recent sabatolimab trials in high-risk MDS that were presented over the last couple of years.
You can see here the shift in the risk stratification between the IPSS, IPSS-R, and IPSS-M. So I think this is an important issue when you consider clinical trials to have uniformity, and using a clear definition, which is the case here in SELECT-MDS-1. So I think, when we talk about response criteria, there has been an evolution of these response criteria trying to address some of the limitations that we were just discussing. The most recent revision was in 2023, but most of the current phase III trials, including SELECT-MDS-1, have been using the IWG 2006.
This is what has been generally kind of accepted by the regulators so far, in terms of like looking at drugs, in terms of looking in particular about complete response and partial response. I think part of the reasoning why the criteria were revised in the year 2020, 2023, is removing some criteria from the 2006 that were not clinically meaningful in the sense of not being shown to correlate with patient outcomes in a very clear fashion. For example, mCR, which means that you reduce the blast count, but not necessarily with getting improvement in the blood counts. This is important because, as you heard, most of the patients with MDS will not go to transplant, they will stay on chronic therapy.
So being transfusion dependent and neutropenic and having recurrent infections and complications of anemia and thrombocytopenia can be quite significant in terms of adverse outcomes, even if you reduce the blast count. So we actually have a number of studies that showed that durable, complete response is the endpoint that really correlate with therapeutic benefit in terms of association with the long-term outcome of overall survival. And this is a meta-analysis that we did as part of the revision of the International Working Group criteria. Several groups have actually conducted similar analysis, and every single one of them have shown that complete remission is the endpoint that has the best association with long-term outcomes, including overall survival, as you can see very clearly in this very large meta-analysis that we have published.
But marrow CR, as I mentioned to you earlier, if or if it's not associated with hematologic improvement, it actually has generally been not shown to be associated with improved outcomes. The only value of this marrow CR could be as a bridge to transplant, but most patients with MDS, due to their age, due to the comorbidities, most of them are in their early to late seventies, and many of them will not go to transplant. So for that reason, I think most people agree, based on the available data, that marrow CR improvement is not a great endpoint. And why is that important?
Because many people get scared out of the MDS field when they see phase I, phase II trials showing you a response rate, overall response rate, which includes marrow CR of 70%-80%, but then the phase III is negative, and they say, "Well, the problem is the drug." I would say the problem is the response criteria, because marrow CR, as I mentioned, if no hematologic improvement, it probably doesn't mean much. While here you can see that things in the middle, so if you are not complete response, but you have better than marrow CR, you have some reduction in the blast, but you have improvement in the blood counts.
This is an example of analysis that looked at a large data set that showed that what we call CRh, complete response with partial count recovery, which means that the platelet count and the neutrophil count improved above 50,000 and 500, which means less chance of infection, less chance for bleeding, does actually associate with overall response, probably as good as CR. So it's clear that you don't have necessarily to achieve the full threshold of CR to actually derive a benefit, but if you already have a large number of patients achieving CR, it's very likely that this will translate into long-term outcomes, not to mention the already present outcomes of reducing infection, bleeding, and improving the quality of life of patients.
So the main changes that were included in the 2023 criteria were along those lines of eliminating marrow CR, eliminating stable disease, but also we included some clear definitions regarding time to event endpoints, such as event-free survival and progression-free survival. And importantly, we also reduced the threshold of the hemoglobin in the CR from 11 to 10. This was one reason why many trials could not achieve a full CR definition, like only 15 to 20. We have a good example of that with the CPX trial. But once the hemoglobin threshold is lowered from 11 to 10, and hemoglobin of 10, generally, most patients will feel well, they are transfusion dependent, and I think this is a very good hemoglobin level to use in terms of complete remission definition.
Indeed, we and others have looked at these complete response criteria according to the 2023 criteria and have looked at some of the near CR responses, such as CR unilineage and bilineage, where one or two lineages improve in addition to the blast reduction, and we saw that they are quite good. So I think the bottom line from these slides is that if you have a high rate of CR with a combination that is significantly better and significantly different than the CR with HMA monotherapy, and that CR was durable, this is very likely to translate into an overall survival benefit.
I think it should not be mixed with the fact that you see over CR responses in phase II trials for some drugs that are 40%-50%, and once you go to the phase III, the phase III is negative. In the phase III for the same drugs, and Dr. Sallman is gonna show you that, you are 40, 50% in a phase II with limited number of patients. But once you go to the phase III, most of those negative phase III trials, the CR rate was only 20%.
So the problem was not that the CR is not a good endpoint, the problem was the CR did not hold up when you are in a much bigger scale, in a large phase III trial with hundreds of patients, compared to a limited phase II trial with only, you know, 20 or 30 patients. So, this is an example of the response criteria between 2006 and 2023. As I mentioned with this drug that Dr. DeZern mentioned, Vyxeos, this is our prospective French trial that showed that using the 2023 criteria, with lowering the hemoglobin from 11 to 10, actually significantly increasing the CR rate.
And I think this is, again, something that is important to think about in the context of the SELECT-MDS-1 trial, that if you hit your CR, it's very i f you had a significantly different, improvement or significant, statistically significant improvement in CR with the combination of a monotherapy that's durable, that likely will translate into a long-term, benefit, including OS benefit.
But also, even if you don't hit that CR, but you hit a lot of near CRs, where, you achieve blast reduction, but you achieve very good count recovery and hemoglobins that are closer to the 10, I think potentially that also could, lead to improvement in survival. But of course, this remains to be seen, but I think everybody agrees that CR by itself, if it's durable and if it's statistically higher, it's very likely that this would translate into overall survival benefit. So in conclusion, MDS is a highly complex and biologically, heterogeneous disease. There has to be clear distinction between lower risk and higher risk.
And aside from hypomethylating agents, there's very limited therapies for high-risk MDS patients. Dr. DeZern mentioned the IDH1 inhibitor that's approved, ivosidenib, but this IDH1 mutation is only 3% of patients, very rare. So clearly, there are significant opportunities for drug development and approval, and I think we have good surrogates for overall survival with the durable complete response that we currently have. And I think that makes a lot of sense to consider this as an endpoint to justify accelerated approval, pending confirmation with OS as a secondary endpoint. And I think the 2023 revision of the criteria will also kind of make these criteria more patient-centric by focusing on blood count improvement that are reasonable, not necessarily reaching a hemoglobin of 11, but at the same time, getting rid of marrow CR without any count improvement.
I think this hopefully will accelerate moving drugs that are clinically meaningful in terms of their benefit from early-phase to late-phase trials. This is my last slide, and thank you so much. I'm happy to take questions at the end of the presentations after Dr. Sallman concludes.
Thank you very much, Dr. Zeidan. That was very helpful in explaining the complexities of how we assess patients during studies. I'm gonna turn this back over now to Dr. Sallman, and we appreciate the time you've taken to share that information with us. Dr. Sallman?
Yeah, perfect. Thanks for the introduction, David. And, you know, I think, Amy and Amer, you know, really gave some beautiful presentations. I think a little bit of duplication, so I'm really just gonna try to frame some high points and really move us on into the discussion session as well. So kind of charged with, kind of where are we at with the sort of current era of therapy, particularly thinking about a lot of the setbacks that we've all been faced with, with recent clinical trials. I think you, you've heard a lot about the sort of molecular architecture of these patients. I think, you know, really the path going forward, and I think this is relatively probably a uniform consensus, is that p53 mutant disease really should be considered its own entity.
Many trials now are excluding or potentially going exclusively for p53 mutant. But this has, I think, both ended potentially early drugs that could have had activity and potentially given maybe overpromise to some agents, you know, based on what the makeup of that group is. I think the key takeaway, and people will argue about how do you call this, and actually, there'll be an article in Blood published, you know, I would say, within this next month. But this kind of summarizes the key data, that essentially p53 mutant with increased blasts, and this is actually just 5% or greater, so different than the ICC definition. This is the orange and the red curves on the top left, which you can see are completely superimposable, or patients that have multi-hit disease.
You can see really there's a strong degree of overlap. As soon as you really have 5% blast or greater, there's really a high predominance of multi-hit disease. So basically, p53 excess blast, complex karyotype, two p53 mutations, or mutation with some sort of altered chromosome 17 is essentially one disease. And I think, you know, we will be managing these patients distinctly, and trials going forward will be thinking about this disease. The reason why it matters is, I think, as everybody aware, the outcomes in this patient group are truly dismal. You could argue this is, you know, the worst disease that exists, potentially, in all of oncology. And especially if you, if you kind of uniform this with the definition of above, particularly in AML patients, where maybe the i t's, it's always been a little bit cleaner.
You have a median overall survival of around six months. That's not improved with any therapy, including, you know, extended course decitabine, addition of venetoclax. This shows actually kind of the randomized five-day versus 10-day, led by the MD Anderson group. And again, really many argue that there is no standard of care, and clinical trial is essentially, it, the, the main option. I think when we get to at the end, again, the question is: How does RARA overexpression impact this disease? I think, you know, as David presented earlier, it has been agnostic to molecular subtype, so definitely intriguing in look, you know, looking at outcomes in this patient group.
But I do think if we had a new approved doublet, although this is a subset, right, there's no question that we would be looking to something that is not the standard, given how poor the outcomes are in this, in this group. And again, we'll get into a little bit more in the p53 later on. Again, you saw this by Amy already. It's just to summarize that we essentially have one therapy, HMA therapy, and although patients can be considered to go to directed transplant, that actually very rarely occurs, I would say, particularly in the United States. And then upon failure, there's really no, you know, salvage options, at least approved.
I think one thing to think about, and this is impacting, you know, current trials, and we'll see the ultimate impact in the SELECT trial as well, is that, you know, earlier transplantation strategies or in general, more incorporation of transplant into the overall paradigm. I think, you know, you heard from Amy, in general, anywhere between 10%-20% of cohorts, you know, are ultimately going to transplant. But I think as you get better responses, particularly better hematopoietic responses, patients' performance statuses are improving, you're getting better quality of response, and this may lead to ultimately more patients to transplant, which of course, is our only curative option. Just to kind of show this in some detail, and this publication is now available, on JCO. This is led by Della Porta.
I think all of us on the call were involved with this well. But essentially shows that, you know, even if you molecularly upstage patients, you know, this may, you know, really be the main trigger to think about earlier transplant. And although the approvals would be based on, you know, IPSS-R, you know, based on, on how the SELECT trial was, was designed, again, we'll be thinking about, hey, you have a, quote, unquote, "lower clinically risk, but molecularly higher risk." We're thinking about transplant. You know, would we think about, you know, azacitidine in that setting, potentially expanding from the label? I think those things would definitely be a strong consideration. So this is our only positive, you know, curve that we need to show. This is in the history of high-risk MDS, this is it.
This is the AZA-001 study, which everybody is very aware of on this call. And then, you know, Amer, he's actually done a lot of work, as well as several others, looking at real-world outcomes, probably in the modern era, and we can talk about this in the discussion session. You know, we're, we're probably dealing anywhere between an 18-month to 20-month, you know, OS, as far as control arm, probably somewhat contingent on what the molecular makeup of the, control arm is, with around, you know, a 15%-20% CR against some heterogeneity, from that perspective. And I think you really nicely heard by both Amy and Amer before, right? We've had, you know, amazing, updates in classification. At the same time, we have these updates in prognosis, but we still have, you know, the one therapy.
Of course, you know, we try to move this along, incorporate it in studies. But is some of this increased heterogeneity in the studies, particularly as we go from early to phase III, leading to a little bit, you know, of the downfall, I think, is an open question. And thus, trying to make the group somewhat more, you know, homogeneous, which potentially can be done with evaluating RARA overexpression, I think is relevant. Of course, we just had 2 studies, which I'll talk about just in a little bit of detail in a moment, that have at least press released and now been formally presented at EHA. Again, with the main studies being this study and the VERONA study from that perspective.
So again, just background, you know, again, for p53, you know, this was a trial that we helped lead. There were parallel phase II trials in the US and the GFM that showed really high CR rates, above 40%, leading to this trial. Now, this was an open-label trial, which was probably one of the negative aspects. You know, what was the loss in the control arm from patient population? Relatively smaller study. Did have a higher CR rate, but again, did not reach statistical significance. This has still not been formally evaluated. But it's just to also bring up the point that p53 specific trials can be run. This trial actually accrued quite rapidly, even with mainly enrollment during the kind of earlier COVID era as well.
Moving on to pevonedistat or the PANTHER trial, I think, you know, maybe the negative things to take away from this study, of course, there was no difference in the primary endpoint. You could see the curves are completely superimposable. Although if you look at, you know, OS and EFS in sort of the high-risk MDS patient population, you do get some of the separation, not statistically significant. And again, making increased heterogeneity, including CMML patients, including oligoblastic AML, despite, you know, some overlap based on the underlying molecular architecture, is probably not helping and, and potentially, you know, hurting, you know, studies from that perspective. I think in that regards, like, even trials that are considering adding CMML, I think the FDA is getting more and more against that just 'cause CMML-specific trials need to be run. So this just shows magrolimab.
You know, I presented the ENHANCE data at ASH, and actually, the ENHANCE 3 data was presented by Josh Zeidner, and ENHANCE 2 is in press release form. I think, as everybody is aware, you know, all of these trials were ultimately negative and essentially kind of magrolimab being discontinued. Again, this just summarizes the data. Again, this is a table that was in the abstract. Of course, the presentation is now public. And I think the challenge is that the, you know, magrolimab toxicity, I think, was definitely underappreciated. I think at small expert centers, there was really no issue, no early mortality, no patients being discontinued.
As this rolled into phase III, this actually became a huge number, you know, over doubling of patients off early in the investigational arm. And then I think the major other thing, you know, again, if you have increased cytopenias, that is very challenging with multiple continents, you know, greater than 100 centers worth of studies. And so if your agent combines much more well, particularly from a cytopenia perspective, I think we see this both with sabatolimab, which I'll talk about in a moment, and of course, with Tami, which has been very clean from a cytopenia perspective, that at least will allow to see that full synergistic benefit. The other challenge, and again, you know, will this have any impact or not in SELECT? I don't know.
But again, there was a huge imbalance on patients going to stem cell transplant, both actually based on, you know, were they or were they not transplant eligible from the get-go, but also, you know, ultimately, a doubling of patients went to transplant. In the control arm, again, that may speak to response, efficacy, safety as well, but that is a challenge. And the reason why it matters is, again, in the earlier experience, you know, we had about 40% of patients go to stem cell transplant, which is actually what the control arm did in the phase III study. And you can see, particularly in that group, you know, we had over 70% long-term survival. I think these subsets, based on transplant status, again, those will come out in the formal publication and future presentations as well.
So sabatolimab was also presented. Again, this is phase III. Again, this with the ENHANCE trial represent the two largest MDS trials ever conducted, both over 500 patients, primary endpoint solely of overall survival. And again, Amer just presented these data at EHA as well. And, you know, notably, there was a survival difference. You know, there's this kinda 3-4-month delta. Granted, there's been t here's absolutely no differences in response rate, and I think that's always been a challenge from the, you know, some of the thoughts around the sabatolimab program. I think some thoughts, whether or not you'd maybe get this late separation, which was not necessarily observed here. But question is, you know, if this was an 800-900-patient trial, would this been a positive phase III? I think that's a question in all of our minds.
But again, this trial was, this agent was very well-tolerated, and only 10% of patients went to transplant in both cohorts. So why these differences in trials that relatively were similar, you can actually argue higher risk in the ENHANCE trial, I think is an interesting question. And then lastly, kind of moving on to venetoclax. These are the updated phase I data. Actually, this is now over 100 patients, study presented by Jacqueline Garcia. And again, a lot of discussions that we've had today and around this presentation, you know, what's the response rate? It does—you know, if you look at sort of MCR plus HI or CR or maybe composite CR responses, you're probably pushing 60 to two-thirds of patients, so clearly higher.
These trials, in general, have excluded therapy-related, so significantly less p53s than some of these other programs have had from this perspective. Although the median overall survival is 26 months, is it better? Is it not? Again, you know, what are the percentage of patients that went to transplant? HMA venetoclax is still gonna be here regardless of VERONA reading out. You know, these are our data, smaller cohort and frontline, although the, we will update these at ASH. And in general, our data look relatively identical to what Jacqueline presented. And, and including subgroups like ASXL1 mutation that perform poorly to HMA therapy, at least as far as a CR rate, seeing quite intriguing response rates. And then back to p53, yes, response rates are no different, but survival is still poor.
I think HMA venetoclax does have activity in the salvage setting, particularly patients to transplant. And then if you, thus, if you have multiple doublets, considering side effects, other things that you heard Amy talk about as well, I think that it, that does have some relevance, you know, as well as far as what's being chosen. So again, this is the phase III VERONA trial. Again, essentially, we're going to be seeing overall survival. I think what is intriguing, probably the investors on the call, you know, are aware. I think ClinicalTrials.gov just got updated about a week ago, and now it's, you know, the date is reportedly September 2025.
Again, this has continued to be increased farther out, which is, I think, questions about control arm, transplant, others, but now it may be, you know, a full number, you know, 15 more months before we learn. Of course, this is an estimation. Again, that was on ClinicalTrials.gov. So we have the phase III SELECT-MDS-1 trial. Again, we're aware, so I'm not going to rehash. And again, I think as Amer has, you know, also pointed out, right, no phase III trial has ever improved complete remission rates.
There's very, very robust data showing that, especially if you achieve true CR by the older IWG or particularly or potentially CR, CRh, CR, CRi, which I think would be a key secondary analysis to look at even in this first presentation, that that has a very strong correlation with overall survival and we would be quite, you know, optimistic that that would translate should this response rate occur. So again, you know, just a couple of take-home points on this slide. The next, you know, Verona, you know, is positive. You know, there's still challenges with venetoclax. It's still the biggest call that all of us get. You know, real world, a lot of patients are on it, far less based on these side effects. I think there's discussions, you know, do we treat differently transplant-eligible versus ineligible populations?
Very clearly, and didn't have enough time to go into an MDS, but p53 has had no improvement of outcomes with venetoclax, so survival is completely unchanged, and true complete remission rates are likely unchanged both in MDS and AML. You know, I think, you know, obviously the field has dramatically moved to triplets in the AML setting, and although I'm, I think you would get some pessimistic people, I do think that it, it, let's say both trials were positive. I, I do think, you know, a triplet, and especially based on their very exciting, you know, early data in AML with the overlap would be important. You know, what's nice is that venetoclax is only 14 days and thus potentially even easier to combine in a high-risk MDS setting with, with tamibarotene.
We've actually proposed sort of a study to ideally open, you know, as this, as the SELECT trial reads out. And again, I think some of the sequences, you know, may matter based on kind of the overall, you know, picture of the patient and what the goals are. And again, I think what have we learned, you know, really just in conclusion, I think the heterogeneity of these trials has been a major issue, and thus really focusing on a more homogeneous population, such as RARA overexpressing high-risk MDS, I think is critical. Cytopenia toxicities have probably been the biggest challenge moving some of these agents from earlier studies to later studies.
That really seems to be a completely non-issue, so I don't think we're gonna see many early discontinuations, and thus, you know, ideally, the CR rate and the synergy holds up from that perspective. We've heard a lot of talking about it, that looking not just at CR, but composite CR. Now, that will not support the accelerated approval, but I think it will really speak to the quality of the responses. And I think if you see both CR and sort of a composite CR, CRh, CR, CRi being statistically higher, that will really speak to kind of a slam dunk that the OS would ultimately be positive from that. And again, p53 is gonna be its own entity going forward. We need to learn more about what Tami's activity and outcomes in that subset are.
With that, thank you for listening and look forward to the discussion with my colleagues.
Thank you. Ladies and gentlemen, over the phone, if you'd like to ask a question, please press Star one. If you'd like to withdraw your question, please press Star two. Again, to ask a question over the phone, please press Star one. One moment, please, for your first question. Your first question comes from Phil Nadeau from TD Cowen. Oh, sorry.
Hi.
I apologize. I will return the call over to the presenters.
Yeah, sorry. So it's David again. David, thank you very much, Dr. Sallman , for a great presentation and summarizing a lot of work over many years to advance therapies for the patients with high-risk MDS. I just wanted to give our CEO, Conley Chee , an opportunity to provide some closing remarks, and then we will turn it over to the operator for questions. Conley, thank you for your great-
Great. Thanks, David, and thanks for facilitating what I thought were some really interesting presentations today. A huge thank you to our medical experts for joining us today to share with us their expertise and give us some insights into this really devastating disease, and one that's been notoriously challenging to treat and in desperate need of novel therapies. On that note, let me just share a few thoughts around our tamibarotene program and our plans going forward. As David mentioned in the onset, we remain highly encouraged by the consistent data that we've seen with tamibarotene across multiple clinical trials in both MDS and in AML. 2024 is setting up to be a tremendously transformative year for our company. This program leading the way in delivering two meaningful near-term catalysts, the first being the pre-specified data of 40 or more patients in our SELECT-AML-1 trial.
And following that, in Q3, I should say, and following that, our pivotal phase III data from our SELECT-MDS-1 trial, with our top-line data to be shared with you in mid-Q4. And that data will support the potential of tamibarotene to really establish itself as the standard of care in higher-risk MDS, particularly when you think about the patient population, as Dr. DeZern has described, in terms of the fact that many of them are elderly, many of them are being treated in the community. And so to offer a therapy that is easy to administer in terms of an oral therapy and one that has very manageable side effects, I think will deliver great benefit to this subset of patients. In terms of the market opportunity, perhaps I can offer a couple thoughts.
First is around the epidemiology, and so each year, 18,500 or so patients are diagnosed with higher-risk MDS, half of which are in the US and approximately half of which are in the EU. Within this patient population, there's roughly 50% RARA overexpression. On the unfit AML side, approximately 25,000 patients are diagnosed each year, again, roughly half of which are in the US and half in the EU. In this patient population, there's roughly 30% RARA overexpressers. And so, as you can see, a fairly sizable patient pool that could benefit from tamibarotene treatment. And just as a reminder, we're developing tamibarotene in the frontline setting, so you could expect that the duration of treatment would be relatively longer than other settings, such as relapse refractory.
So as you can see, a potentially attractive commercial opportunity, certainly in the U.S., and so we continue our plans to seek approval in the U.S. based on our pivotal-based off of our pivotal data, and we plan to launch ourselves and commercialize this product in the U.S. And there's a few reasons for that. One is that we have a tremendously experienced leadership team in place that has launched products in the U.S., both in terms of oncology and hematology, so deep experience. Second is that there's a well-defined and fairly finite group of physicians that treat higher-risk MDS, and so we will be able to cover this market quite effectively with a targeted, specialized sales force. And with that, build quite an efficient infrastructure to support the business.
The teams are already putting in place a highly detailed commercialization plan to ensure success, and we've engaged in pre-launch activities in terms of engaging with our medical community to assure that there's awareness of RARA overexpression. Finally, of course, we'll need to have a commercialized test that can help identify these patients, and we are continuing to partner with QIAGEN to develop a commercialized diagnostic, which will be readily available across the U.S. So just in closing, Syros, again, is well-positioned heading into the second half of the year with multiple significant value-driving milestones. So again, we look forward to sharing with you the upcoming pivotal data from our SELECT-MDS-1 trial by mid-Q4, and additional data from our SELECT-AML-1 trial in the third quarter of this year.
We certainly remain committed to our pursuit of developing and providing meaningful treatments for patients in need of better care. With that, let me turn it over to David for Q&A.
Thank you very much, Conley, for those closing remarks. And again, thank you to our three medical experts for really expert presentations. I found them very interesting and illuminating and always learning something important. So again, thank you. We greatly appreciate it. Now I'm going to turn the call over to the operator, who can field some questions from some of the analysts who may be on the call. And for others who may want to type a question into the chat, we'll do our best to address any of those questions if time permits. Operator?
Thank you. For people over the phone, if you'd like to ask a question, please press star one. If you'd like to withdraw your question, please press star two. One moment, please, for your first question. Your first question comes from Phil Nadeau-
Our experts can go on, on video if they want.
Your first question comes from Phil Nadeau from TD Cowen. Please go ahead.
Hi, this is Alex on for Phil. Thanks for taking my questions. So first, just wanted to get your thoughts on how the VERONA data in 2025 could potentially alter the MDS treatment landscape? And more specifically, if the venetoclax combo is ultimately approved, showing superior OS data, what would Tami's opportunity look like here? For instance, would you maybe focus on going after that less fit transplant-ineligible population? Or would you maybe think about launching a study evaluating the Tami venetoclax triplet in MDS like you did in AML? And then I also have one for the docs as well.
I'm just curious if they would be comfortable adopting tamibarotene as a new standard of care based off of solid CR data alone, or would they really need to wait for the OS data to get a more nuanced view of tamibarotene's clinical profile and how it compares to venetoclax? And if CR alone is fine, what kind of durability would you maybe like to see there? Thanks.
Okay, thank you very much for that question. I think since you're asking about the impact of the outcome of the VERONA trial and how that would play with the future of tamibarotene and AZA in MDS, I'm gonna turn that over to some of our medical experts and get some of their opinions. Perhaps, Dr. Sallman, you can take that lead in answering that, and we can turn it to some others as well.
Yeah, I'm sure all of us on the call have opinions. You know, again, in the US, I, there's not gonna be that dramatic of a change, right? So, you know, venetoclax is significantly used, particularly again, for P53 wild type patients, and the outcomes can be good. Granted, there are a lot of challenges from the toxicity perspective. There's no question, you know, if we have tamibarotene approved and even before VERONA reads out, that triplet is going to be a key study to be done right away. And again, the combinability of it has looked quite favorable from that perspective.
I think your one question about, you know, what do we have to see? I mean, I think all of us just want to see a positive phase III trial and, you know, an approval and a, and a P value of point zero four nine. Obviously, it has to correlate with an increased durability, you know, of CR, you know, at the same time as y ou know, if we have it, we're gonna use it. Now, I think there's always gonna be a lot that shapes out afterwards in subsets of patients. But again, I think the tolerability of the combination as well, and I think it would get utilized, you know, quite, you know, quite, you know, quite, you know, rapidly.
Again, probably the only thing used maybe in p53, but I think in the other subsets, I think you'll get some opinions on transplant eligibility or, or not, but I think it would have a significant uptake, quite quickly. But I, I look forward to other discussions from Amer and Amy.
Amer, do you wanna take a stab at that?
Yeah.
With-
I think I share, yeah, I think I share the same thoughts. Maybe starting with the second question is, what would be the uptick if, if the CR rate is, is positive, pending the survival, kind of, read out from the tamibarotene trial? I mean, in my opinion, this would become the standard of care. Again, depending on whether VERONA is positive or not. But if you have a CR positive by, you know, a statistically significant margin, and that's, in my opinion, for two reasons. One of them is that CR, as I mentioned during my talk, is clinically meaningful by itself, not only as a proxy for an OS. CR means that you're not needing transfusions, you have low chance of infection, you are generally not coming to the office for transfusions frequently. Our clinical impression that it correlates with quality of life.
So durable CR that is proven in a large, statistically stable sample size, like a phase III trial, you know, I think that would be, in my opinion, should be more than sufficient to adopt this. Of course, we would like to see the OS impact. As I mentioned, my, my general sense is that that would correlate, but, sometimes there could be issues related to imbalance between the arms and who goes to transplant and who goes not to transplant things like that. But I think CR by itself should be sufficient. Now, venetoclax, I share the opinion of David, that, venetoclax is going to continue to be used in the U.S. regardless of, VERONA.
Of course, the degree of using it is gonna depend on VERONA, but I think many people are using venetoclax now as a bridge to transplant in younger, fitter patients who have excess blast. I think what is not clear with venetoclax, and what many of us are looking for VERONA for answers, is the ones who are not going to transplant, the ones who are gonna be on chronic therapy. And of course, the myelosuppression is something that can be managed, but, you know, can cause some headaches for some patients. So having an option that is not suppressive, that can be used long term, I think, could potentially be attractive. So I can see many ways in which both drugs coexist if both of them have positive trials.
You know, from a physician perspective, of course, this is what I would always hope for, is we really need a drug approved on top of HMA, ideally more than one drug. But I think this actually opens the door for additional combinations, for triplet studies. It's gonna be a very good thing for the field. And I would actually add one thing, because this keeps coming up in my opinion, when we have these investor calls, is that there are a lot of patients with MDS who are not being treated at all. So I don't only think about how much high-risk MDS patients who are getting HMA are gonna get HMA plus X, or who are getting HMA plus VEN will move to HMA plus X.
Our real-life studies show that around 50% of patients who have high-risk MDS do not even get HMA, and that's largely because in real-life studies, HMA by themselves do not have great outcomes, as we just discussed. The CR rate is only 15%-20%. So I think there is a large untapped pool of patients that potentially will be open for, and their physicians would be likely more convinced to start treating those patients with HMA combinations because they perceive the CR rate to be much better, quality of life, et cetera. So I, I think the opportunity is much bigger than just moving between HMA-VEN or HMA alone. I think that's important to remember.
Thank you very much. Dr. DeZern, I know you've had some video trouble, but we believe you're still on, and if you wanna contribute some of your thoughts about, you know, upcoming readouts for venetoclax, as well as the tamibarotene studies and how they would work in the treatment landscape, how you might make clinical decisions around what therapy you might offer a patient, that could be very helpful to the audience.
Absolutely, and I'll certainly highlight some really nice points that both David and Amer made. The first, which needs to be repeated, I feel, is there's absolutely space for both combinations. We need more for these patients, period. This gets back to what I alluded to, of the very nuanced but highly important conversations at the bedside, assessing the situation up front and how we think about what the goals are for these patients. I think if we're thinking in doublets alone, we go back to the biomarker predictive capacity a priority for tamibarotene, and that is very helpful. We also have a little bit of guidance in the venetoclax space, perhaps with some IDH mutations and things like that as well, and so that would be a branch point. The fitness of the patient, I think, is important and what their other medications are.
Venetoclax has quite a lot of drug-drug interactions and is very myelosuppressive, and so it really is a fairly intense, quote, "non-intense therapy" for some patients, and it might be more appropriate that tamibarotene fits the goals for patients in a different setting. Then to the definitive therapy or maximized benefit as to where the patient is going, I think there's different roles there as well. Both have the option to bridge a patient to transplant, and some of it may depend on speed and tolerability to get there. Then lastly, as Dr. Sallman had mentioned, the triplet combination is really exciting because I think this goes back to the biology, and it p atients want to hear they're going to get better, but it's helpful for us to tell them why. And what your presentation talked about, Dr. Roth, is that tamibarotene is a differentiation agent.
We know how well that therapy works in other myeloid malignancies, and that in combination with BCL-2 inhibition, so let's decrease the blast, let's improve the marrow function, when the toxicities are not necessarily overlapping, is a really exciting triplet combination as well. So I think this is just tons of fruitful opportunity for the myeloid space that I find really exciting as a clinician.
Thank you very much. I think we have time for one more question.
Thanks, very helpful.
Operator, are there any further questions?
There are no further question over the phone line at this time.
Maybe I can just ask one last quick question. Or maybe I'll give this to Dr. Sallman. Do you anticipate any challenges incorporating RARA testing into the patient flow when you see patients in the clinic and, in the post-approval setting, how do you, how do you envision that, working with other, other diagnostic tests that are current, currently administered to these patients?
Yeah, I don't really see any challenge. I think, you know, especially in the community, everybody sort of adapts post-approval. I think what's nice is, you know, this is a peripheral blood test, so it's, you know, it's not like, "Oh, I forgot to check it on the bone marrow," which would create definitely a major logistical, you know, challenge, especially in the community where it can take a little longer, and even getting results back and things like that. You know, the point was, like, IDH mutations weren't really tested for very often until IDH inhibitors, so I think it's the same thing.
I think clearly there are important major educational, you know, directives that your company's gonna be, you know, focused on, you know, as this trial is positive and before approval just to get that. But I think as far as incorporating it, with it being a peripheral blood test, I don't really see any major challenges, and the turnaround is quickly, right? This is much quicker than that any at least community group will have from a next-gen sequencing, where they're still often taking two weeks plus, right? The turnaround on this is much faster. So it actually may make it easier for them in some regard. Yeah, I think in academics, less impact, like we'll of course have no issue, but we have turnaround times.
But in the community where NGS turns around quite slowly, this actually could be, you know, advantageous. Of course, maybe slight issues with, you know, you know, failures and having to resend the test, et cetera, but no, no major issues.
Well, that's very helpful. Well, it's just after the hour for ending the Webex, and we really appreciate everyone who joined in. I hope that everyone has had a chance to learn something. I know I did, and we appreciate the contributions of our medical experts who volunteered their time to help teach. We all like teaching. And so thank you again, everybody. And for those who come up with questions after we close, please be in contact with us. Karen, who's on the call, would be more than happy to receive any inbound questions through email, and we'll do our best to address them. Again, thank you very much.
Thanks.
Ladies and gentlemen, this concludes your conference call for today. You may now disconnect. Thank you.