SELLAS Life Sciences Group, Inc. Aktie

Good morning, and welcome to the SELLAS Life Sciences R&D Day. As a reminder, this call is being recorded, and a replay will be made available on the SELLAS website following the conclusion of the event. I'd now like to turn the call over to your host, Dr. Angelos Stergiou, President and Chief Executive Officer at SELLAS Life Sciences. Please go ahead, Angelos.

Good morning, and welcome to SELLAS' R&D Day. Thank you all for joining us today. I would like to remind you that during the conference call today, we will make projections and forward-looking statements regarding future events. Any statements that are not historical facts are forward-looking statements. We encourage you to review the company's SEC filings, which identify the specific risk factors that may cause actual results or events to differ materially from those described in these forward-looking statements. Now a little bit about the agenda. Before we begin, I'd like to quickly walk you through today's agenda. I'll start with some opening remarks to set the stage for our discussion. Then Dr. Omer Jamy will provide important context on the AML treatment landscape, including current standards of care in areas of unmet need and how GPS and SLS009 fit within it.

From there, Dr. Panagiotis Tsirigotis and Dr. Dragan Cicic, will discuss the mechanism of action and differentiation of GPS, along with the Phase III REGAL trial and will walk us through the clinical and commercial overview of the study. We'll then turn to our second program, SLS009, beginning with Dr. Philip M. Ryan, who will outline the scientific rationale for SLS009 in high-risk and venetoclax refractory AML. Dr. Cicic will then present recent efficacy and safety data from the Phase II trial and share insights from recent FDA discussions, and Dr. Sharif Khan will offer his clinical perspective based on real-world experience treating AML patients. Finally, we'll wrap up with a Q&A session of questions we have received from our analysts and investors, and then we'll have final closing remarks.

We're hosting this R&D event to give our scientific and clinical community as well as our shareholders and partners a deeper look into the innovation that drives SELLAS. Today is about more than data. It's about the science, the strategy and the vision that define our work and the long-term value we're building. As I've stated many times before, the work we do at SELLAS is not for the faint of heart. Our commitment to patients and stakeholders requires courage, resilience and an unshakable belief in the transformative potential of GPS and SLS009 to change lives.

Together, we're developing treatments that hold the promise to change the treatment paradigm to be disruptive in the future for patients battling cancer, a responsibility that humbles and drives me as well as everyone here at SELLAS every single day. I'm grateful for the SELLAS' team's extraordinary efforts getting to this pivotal time for the company. And I can assure you that this group is dedicated and committed to seeing GPS and SLS009 make a difference in patients' lives. Over the past years, we continued to present positive clinical and key regulatory news across our programs. I strongly encourage you to focus on the long-term potential and the exciting milestones that lie ahead. We appreciate the support of our institutional investors and the fact that a meaningful portion of our shareholder base is retail who understand the great potential of our clinical assets and pursuit to add to those physicians' portfolio of treatments in their battle against devastating disease.

At SELLAS, we believe that the rigorous high-quality science is the foundation of meaningful therapies and ultimately of lasting value for patients and shareholders alike. The strength of our pipeline and the consistency of our results reflect the discipline and our focus on delivering both patient impact and sustainable growth. To that end, we have significantly strengthened our balance sheet this week with the additional $31 million in gross proceeds from outstanding warrant exercises, which not only allows us to see through key clinical data for GPS and SLS009 but also allows us, particularly in such a volatile market to keep and accelerate the momentum and deliver on our clinical programs.

When I founded SELLAS, it was driven by a simple conviction that science when pursued with focus and integrity can truly transform patients' lives. We set out to build an oncology company that blends breakthrough innovation with rigorous execution and strong capital allocation discipline. Our first major step was the development of GPS, a novel WT1 targeted immunotherapy designed to address a range of cancers through a differentiated mechanism. Over the years, GPS has consistently delivered positive and encouraging clinical results, reinforcing our scientific foundation and our commitment to patients in need. Building on that success, we advanced into the next frontier of targeted or precision oncology with SLS009, our highly selective CDK9 inhibitor.

The preclinical and early clinical data have been compelling, showing significant activity across aggressive leukemias and beyond. This diversification and the complementary nature of both assets from frontline treatment with SLS009 to maintenance with GPS in AML positions SELLAS as an emerging leader in targeted cancer therapeutics. Today, we are a late-stage oncology company with a clear mission to bring forward innovative therapies that extend and improve patients' lives while driving sustainable long-term value for our shareholders. We have achieved this through focus, discipline and steadfast belief in our science and our team. The journey hasn't always been easy, but it has always been purposeful. And as we look ahead, we do so with the same determination that got us here to deliver on the promise of innovation and to make a lasting difference in the fight against cancer.

To help us explore the significance of our programs and their potential in the evolving oncology landscape, we're joined by an exceptional group of key opinion leaders as well as our Chief Development Officer, true experts in the fields. It's my pleasure now to introduce them. Dr. Omer Jamy is an Associate Professor of Medicine at the University of Alabama, UAB in the Division of Hematology and Oncology and an Associate Scientist in Experimental Therapeutics at the O'Neal Comprehensive Cancer Center. He serves as a principal investigator of the Phase III REGAL study at UAB and is also a principal investigator in our SLS009 program. Dr. Panagiotis Tsirigotis has been a Professor of Hematology at the National and Kapodistrian University of Athens School of Medicine in Greece and Scientific Director of the Transplantation Program of the Hematology Unit since 2010. He's an investigator in the Phase III REGAL study.

His clinical work focuses on AML with particular emphasis on cellular therapies and application of immunotherapy methods to prevent leukemia relapses. Dr. Tsirigotis serves as the President of the Acute Leukemia Working Group of the Hellenic Society of Hematology and Vice President of the Hellenic Transplant Organization. Dr. Philip M. Ryan is an Assistant Professor of Medicine at Harvard Medical School and a physician at the Massachusetts General Hospital, where he is part of the Cancer Center, Leukemia, Cellular Immunotherapy and Hematology Oncology departments. He specializes in treating adults with acute and chronic leukemias, myelodysplasia and myeloproliferative neoplasms and leads multiple clinical trials exploring novel treatment approaches. Dr. M. Ryan has conducted research with SLS009 and is an expert in cyclin-dependent kinases. Dr. M Ryan also serves on our Scientific Advisory Board.

Dr. Sharif Khan is a hematologist at Bon Secours Health System in Greenville, South Carolina. He's a highly rated specialist in indications such as AML, myeloproliferative neoplasms, multiple myeloma, non-Hodgkin's lymphoma and bone marrow transplantation. In addition to his clinical care, Dr. Khan is a researcher for cutting-edge breakthrough therapies and started the CAR T-cell program at Bon Secure Health System. He serves as an investigator in both the REGAL trial of GPS and the SLS009 clinical program.

Before I turn it over to our KOLs, let me start with our pipeline. We have 2 highly differentiated clinical stage assets, each addressing significant unmet needs and each with first or best-in-class potential. First, galinpepimut-S or GPS, our late WT1 targeted immunotherapy continues to demonstrate meaningful clinical benefit across multiple hard-to-treat cancers. GPS has shown consistent positive trends in overall survival, durable immune responses and a favorable safety profile across a broad range of indications, including AML, mesothelioma, ovarian cancer and multiple myeloma. Our most advanced program is the Phase III REGAL trial in acute myeloid leukemia, a global randomized study evaluating GPS in patients who have achieved remission but remain at high risk of relapse. The rationale is strong. The data to date are compelling and the unmet need remains clear.

We expect our 80th event by year-end. But as you are aware, this is an event-driven study, and we are blinded to study outcomes. Survival times in REGAL indeed appear unexpectedly long and due to significantly longer-than-expected survival, the timing of the final analysis is difficult to predict with any certainty, and the 80th event may occur at a different time than currently expected. Should that event occur later than anticipated from a mathematical standpoint and the fact that we administer GPS to patients even 3 years out, every passing month may increase the probability of a successful study due to a potential GPS effect as we have seen in our previous CR1 and CR2 studies, far surpassing median overall survival versus standard of care. When the 80th event materializes, we will inform the public, which represents the most important near-term catalyst for SELLAS.

A subsequent positive outcome could position GPS as the first-in-class maintenance therapy in AML and unlock significant commercial potential. Furthermore, there's been significant interest in evaluating GPS in combination with bone marrow transplant in AML, an area that Dr. Tsirigotis will likely discuss further in his remarks. Turning to SLS009, also known as tambiciclib, our highly selective CDK9 inhibitor. This is a next-generation targeted therapy with a broad applicability across hematologic malignancies and the potential for activity in solid tumors as well. Our trials have generated compelling clinical data showing strong response rates as well as overall survival benefit in relapsed/refractory AML patients and these results position SLS009 as a potential first and best-in-class CDK9 inhibitor, clearly differentiating it from earlier, less selective agents in the space.

Following discussions with the FDA, we will advance SLS009 into the frontline setting in both newly diagnosed AML patients and those who have not seen an effect with venetoclax and azacitidine alone after 2 cycles. Furthermore, we are conducting transcriptomic, genomic and proteomics analyses, among others, with esteemed academic institutions and utilizing an AI model to further predict patients that will most likely benefit from our SLS009 treatment and gearing our clinical development efforts accordingly.

As far as I'm aware, we're the leading company in this space with this level of data, and Dragan will address this in more detail later. Clinically, we expect to advance our SLS009 program in the frontline setting, both newly diagnosed as well as early refractory patients by the first quarter of 2026 and expect initial data later that year, which will help define the registrational development path and potentially lead towards accelerated approval. And with that, I would now like to turn it over to Dr. Omer Jamy, who will provide additional perspective on the AML treatment landscape and discuss how both GPS and SLS009 fit within it. Dr. Jamy?

Thank you, Angelos, and good morning, everyone. It's my pleasure to be here. So my name is Omer Jamy. I'm an Associate Professor at UAB. I focus mainly on leukemias and allogeneic stem cell transplantation. And today, I'll be talking a little bit about AML and a couple of agents with SELLAS Life Sciences that I've had the opportunity to work with over the past several years. So this first slide will focus on the diagnosis progression and standard of care treatment for acute myeloid leukemia. We've had -- we made significant progress in understanding the pathogenesis and biology of acute myeloid leukemia over the past 10 to 20 years. And that has fortunately led to the approval of several drugs for the treatment of AML, whether it be in the frontline setting, in the maintenance setting or in the relapsed/refractory setting. But despite the approval of several drugs, the outcomes of patients with AML still remain modest, and there's a lot of room for improvement.

And therefore, we continue to figure out how further to improve outcomes for our patients. So I'm just going to walk you briefly through the journey of a patient with AML when they're first diagnosed. So when you have a patient with a newly diagnosed AML, you can treat them with either intensive chemotherapy for a fixed duration, which is a traditional chemotherapy with the addition of targeted agents if there are any specific mutations available or you can treat them with a hypomethylating agent or venetoclax broadly termed as less intensive chemotherapy, which is usually continuous in nature. And then you can add another agent to this combination in the setting of a clinical trial if there are any targetable mutations present. What makes you choose one regimen over the other is dependent on several factors, mainly patient-dependent factors such as age, comorbidities, performance status and then disease factors such as what particular molecular and chromosomal abnormalities are present that may indicate that there's a higher chance of responding to one type of therapy compared to another kind of therapy.

With all the advances we've made, approximately 2/3 of the patient in the upfront setting are able to achieve complete remission. And this is speaking for all comers, whether they're treated with fixed duration chemotherapy or continuous chemotherapy. And then after they achieve remission, if they have favorable risk disease where you think you can treat them without needing a transplant and first remission and there's potential for cure, some of those patients undergo observation. And then those that may benefit from a stem cell transplant first remission undergo transplantation. But as we all know, that many patients whose disease may be eligible for transplant are unable to proceed to transplant for various reasons. Again, those could be patient factors, those could be socioeconomic factors, disease-related factors, donor availability.

So in those patients, you apply a maintenance strategy, whether that's with a hypomethylating agent alone or a hypomethylating agent plus venetoclax or a targeted agent in the setting of a clinical trial. And with maintenance, the survival of these patients is approximately 18 to 24 months. So we still see that there's a lot of room for improvement in this setting. On the other hand, when you treat these patients with frontline therapy, if you focus on the extreme right and left of the -- on the top and they don't respond to therapy, survival is really poor for these patients, unfortunately. So if you -- if they were treated with intensive chemotherapy and were unable to achieve remission, you're looking at a survival of approximately 6 to 8 months, whereas if they were treated with a hypomethylating agent plus venetoclax combination and were unable to achieve remission, that survival post venetoclax, which several groups have published, including our own, is around 2 to 3 months, so very short.

So when you have patients who either are refractory to their frontline therapy or unfortunately have relapsed after achieving first remission, you treat them in second-line therapy, either on a clinical trial or if there's no trial available, you basically treat them with a combination of drugs approved in the frontline setting, which they may not have seen before or they may have seen before, but you may use them in a different combination. So it's basically coming down to, again, either fixed duration intensive chemotherapy plus/minus targeted agents or continuous therapy or less intensive chemotherapy with hypomethylating agent and venetoclax plus/minus targeted agents. So every time the leukemia comes back, it is a little smarter than before. It's a little stubborn. So it's a little difficult to get it into remission again. So if you look at the proportion of patients that achieve a second remission, it is less than the proportion that will achieve a remission if they were newly diagnosed.

So you would think around 30% to 50% of patients go on to achieve CR2, whereas the rest of them, unfortunately, are not able to achieve remission after having relapsed disease or being refractory to frontline therapy. And so -- but for those who achieve CR2, if your patient is eligible, nearly all of these patients deserve a consultation for stem cell transplantation and should proceed to stem cell transplantation if they are eligible. But as we know that, again, there are barriers to transplantation. So for the vast majority of these patients, you need to have some sort of maintenance strategy for which currently, there is no FDA-approved agent. So physicians like myself would use either a hypomethylating agent plus/minus venetoclax combination or a targeted agent to try to maintain that second remission, which we know without transplant is very difficult to maintain.

And studies have shown in the past that the survival of these patients who achieved CR2 and are unable to proceed to transplant is approximately 8 months. So this slide basically highlights a couple of areas of unmet need. Number one, what to do for patients in second remission who are unable to go to a transplant. And number two, what to do with patients who unfortunately are refractory to venetoclax-based therapy. So I have been working with 2 agents with the SELLAS Life Science Company, one being GPS, which is a vaccine against Wilms Tumor 1 as a maintenance strategy for patients in second remission who are unable to go to transplant. And some of the earlier phase data for GPS looks very promising. So when it was studied in patients who are in first remission where, as I showed on the slide above or at the top portion of this slide, the standard of care median survival is around 18 to 24 months. Survival with GPS was -- median survival was upwards of 60 months or 5 years in that study.

And then when they looked at the same agent in earlier phase studies in second line or beyond where the standard of care survival is approximately 8 months, they demonstrated a 21-month overall survival in that population. So significantly higher than what is currently published as the standard metrics. The other agent that I've been working with is the CDK9 inhibitor or SLS009, where we treated patients who were refractory to or did not respond to venetoclax, where as we previously discussed, the median overall survival for these patients is 2 to 3 months. And on this trial, which was a Phase I, Phase II study, we showed that the survival for these patients with the addition of SLS009 as a means to overcome resistance to venetoclax improved survival to almost 8 to 9 months. So again, highlighting the important results and the advancements with these 2 agents in areas where we really need agents to help improve outcomes for some of our patients.

So moving on, a lot of us use azacitidine or any other hypomethylating agent plus venetoclax to treat patients with relapsed or refractory AML. But we still see that there is a lot of room for improvement even in that setting. So this is the AVALON study results that I'm presenting over here, which actually looked at real-world evidence of the efficacy of venetoclax plus hypomethylating agents in patients with relapsed acute myeloid leukemia. So with the combination you see over here, approximately 1/3 of the patients were able to achieve a composite complete remission. So 1/3 as compared to, as we discussed on the previous slides, upfront, 2/3 achieve remission, second line, maybe half of them achieve remission. Real-world data is usually less than what you actually see in clinical trials. Out of these patients -- out of the patients achieved remission, slightly more than 50% were able to proceed to transplant, but the rest were not, again, due to various reasons.

And if you look at the duration of response in the study, it's 8.3 months, but it does appear to include patients who got a transplant as well. So for patients who are unable to proceed to transplant, it is likely to be lower than that. And when we discuss survival for this population, again, replicating previous results for patients who relapsed on azacitidine and venetoclax, the median overall survival was 2.4 months. But what is even more surprising is that even if patients had a transplant, the median overall survival was 10.7 months, just giving you a sense of how aggressive some of these -- some of the -- how aggressive these diseases are and difficult to treat, especially if they've relapsed. So the median -- if you look at this data, what you can take home from this is that maybe the median overall survival of patients in CR2 who did not proceed to transplant is around 6 to 8 months.

And again, if you compare this to the earlier data with GPS in earlier line studies where patients in CR2 who did not undergo a transplant, the median overall survival was 21 months. And having used GPS in the REGAL trial, it is an agent which does not come with any myelosuppression, which is associated with most of the chemotherapy agents that we use to treat AML, and it is a very tolerable profile. And importantly to note is that patients in the REGAL trial could not have had a transplant prior to enrollment. So all of the patients enrolled on the CR2 did not have a prior allogeneic stem cell transplantation. So what are some of the areas of unmet medical needs in acute myeloid leukemia?

So after going through the previous 2 slides, it's -- we believe that a lot of patients need to go to stem cell transplantation, but unfortunately, the vast majority cannot. We think that transplant is potentially curable for a lot of AML patients. And the reason I say potentially is because there is still a significant risk of relapse after transplant that could depend on what is the disease state before transplant, what is the intensity of the conditioning you use for transplant.

So although our intention is always to cure with transplant, cure is never guaranteed with transplant. And in addition to relapse, you have other complications of transplant contributing to non-relapsed mortality such as graft-versus-host disease and infectious complications. Therefore, not all of your patients who need a transplant will be able to go to transplant. And those who do maybe more or nearly 50% of them will relapse, unfortunately, even after transplant. So for patients who are unable to go to transplant, their treatment usually consists of either intensive chemotherapy or less intensive chemotherapy and less intensive chemotherapy is usually hypomethylating agent and venetoclax combination, which is the current standard of care. And as we've seen before, if you were responding to venetoclax and stop responding or you are refractory to venetoclax, your median overall survival is only 2.5 months.

And this is where SLS009, the CDK9 inhibitor has shown to extend survival for these patients 2 to 4 times after they have -- by 2 to 4x after they've not responded to venetoclax based on the clinical trial that I'm participating in, and we wait for more data over there as well. But this is a very exciting finding because it actually gives us a sense of trying to overcome resistance to venetoclax and improve outcomes for most of these patients and maybe even potentially bridge them to a transplant. So what about patients who are on this therapy and are responding and are doing well, meaning who are on hypomethylating agent and venetoclax and they are in remission, but they cannot go to transplant, what does their trajectory look like? So for most of us who are very used to giving this agent in clinical practice, we realize that with time, if you keep on giving this regimen every month, every 6 weeks, you will encounter cumulative toxicities.

And one of the main side effects of giving this combination indefinitely is that you cause bone marrow toxicity or leading to myelosuppression and low blood counts, which eventually leads to -- which sometimes leads to temporary reductions or dose reductions, temporary introductions or even sometimes permanent discontinuation of the agent because your patient is not able to tolerate this regimen because of very low counts. And this is even more important for people who are in second remission or beyond because they've already got a bone marrow, which has seen so much chemotherapy before. So their bone marrow microenvironment is sort of compromised. So we would expect them to have more side effects when it comes to myelosuppression and cytopenia. So we don't know how long will they tolerate this regimen for.

And a lot of studies these days and including standard of care practice is to reduce the dose of venetoclax or alter its schedule either by giving it for less days or reducing its dose in most of our patients. And then we do know that although we get responses with this agent, those responses are not very durable and most of the patients will eventually relapse. So this hypomethylating agent and venetoclax combination is unfortunately not meant to be curative in nature. And we need areas to improve upon these outcomes further. So to summarize, the couple of areas of unmet needs, which we've discussed over here are what to do for patients who have achieved a remission, but are unable to proceed to transplant, as we've already discussed. In the front line, the median survival for these patients is 18 to 24 months. In second remission and beyond, it is 8 months. We've already seen GPS data from earlier phase studies where the frontline data, the median survival is more than 60 months.

And in the second-line setting, the median survival is 21 months, significantly higher than what has already been published. So again, really looking forward to the results of the REGAL trial. Of course, we don't know the survival status between both the arms, but we hope that the previous trials will be replicated. The longer duration obviously implies that the patients are living longer, which would be in keeping with previously confirmed GPS outcomes. And with that, I'd like to end my presentation. Thank you.

Thank you very much, Dr. Jamy, for the insightful overview. And it's really my pleasure now to turn it over to our Chief Development Officer, Dr. Dragan Cicic, as well as Dr. Panagiotis Tsirigotis to provide an overview of the REGAL study.

Thank you, Angelos. And now we'll start with Dr. Tsirigotis discussing the science behind GPS in the context of his long experience with similar agents with attempts to extend survival in patients in remission in his clinical and scientific practice. So I will hand it over to Dr. Tsirigotis now.

So thank you very much for this kind invitation. For me, it's an honor to be here and working with the excellent project. I know this vaccine, first time I was aware of this vaccine was 25 years ago when I was a trainee in Israel, in Hadassah Medical Center. Of course, at those times, the peptides that we use for vaccination were 1 or 2 peptides. So it was not -- it was restricted only to certain patients with certain HLA alleles. But from that times, I remember and I was really enthusiastic because I saw patients that they have a decrease in the blast cells in the bone marrow and in peripheral blood. So when I met Angelos, I was really enthusiastic to participate in this trial. Now why WT1? WT1 is, to my opinion, is an ideal target for immunotherapy for many reasons that I'm going to explain to you briefly.

First of all, WT1 is not expressed under normal circumstances or normal hematopoietic stem cells. It is only expressed at a tiny amount in certain subpopulations like myeloid progenitors. However, WT1 is overexpressed in almost all AML, more than 95% of patients with myeloid leukemia, they express, they overexpress WT1, and this is not related to any mutation. It is also overexpressed in many other hematological malignancies and also in solid tumors. And the story here is that when the WT1 is overexpressed, it becomes highly immunogenic. And the immune system can elicit an immune response, which is directed against the leukemic cells. So WT1 under these circumstances, it's considered as a tumor-associated antigen that is cancer selected, cancer specific. And that's way we target this, then we can avoid and we can avoid killing of the normal stem cells. And this is really important.

Now something that is also very important is that WT1 is proteolyzed by the proteasome and creates a number of peptides with multiple epitopes. And therefore, it creates multiple antigenic targets. And we know that the more the antigenic targets, the less the possibility of immune escape, and this is really important. And another, of course, important thing is that it can activate not only CD8 cells, but also CD4 cells. For all these reasons, GPS was designed as a vaccine that can elicit strong immune responses against WT1. Now because WT1, the overexpression of WT1 remains constant through all phases of acute myeloid leukemia. Therefore, GPS is really a very important drug to be used not only in those patients who are in CR1, but also for patients who are in CR2 and also for patients in the post-transplant setting. And this is something that is really important because we all know that the major limitation of allogeneic stem cell transplantation for high-risk acute myeloid leukemia patients is the high relapse rate.

So we need maintenance treatment for prevention of relapse in the post-transplant setting for this patient. And so far, I have to say that all previous trials that tested various combination of drugs for maintenance, they failed. And I'm going to say a few things about -- you know that aza plus ven tested as maintenance post-transplant. And this trial closed prematurely because of lack of efficacy in the experimental arm. And moreover, it was a lot of toxicity and there were also deaths because of severe myelosuppression in the transplanted patients that they received this kind of drugs. And the same also is true for MORPHO trial, as you know, that gilteritinib failed to show a survival advantage in patients who received it as maintenance in the post-transplant setting.

So I think that -- and I strongly believe and my plan is to have a trial test the efficacy of GPS as a maintenance in the post transplant setting because I strongly believe that it will make a huge difference in this setting. Now let's see a few things about the mechanism of action, which is really simple. And never forget that great things are always simple. So what is GPS? GPS is a mixture of peptides from WT1 and you simply inject them subcutaneously in combination with Montanide, which is an immune adjuvant used in all the kind of vaccines. And also at the same place of peptide injection, we inject GM-CSF, which is a cytokine.

And the reason we do this is that because GM-CSF activates immune cells and recreates many immune effectors in this area in close vicinity to the peptides like monocytes and most importantly, antigen presenting cells like dendritic cells. So dendritic cells phagocytose these peptides and then they move to the regional lymph nodes when they present these peptides to T cells. Now antigen-specific T cells for these peptides are activated, become -- they undergo a phase of expansion and finally differentiate to immune effectors like cytotoxic T lymphocytes.

These immune effectors there travel through over the body. And when they meet the cells that they -- the leukemic cells that they have, I mean, the peptides or the cell surface in the context of HLA, then they recognize them and with -- by using T cell receptor, they attack them and kill them. One important thing here is that these immune effectors, they do not attack normal cells simply because normal cells do not overexpress WT1 peptides. And this is very important because that makes GPS an extremely safe drug. And this is something that we -- this is not only a theory. This is practice because we see this in the clinical practice. None of the patients have any problem with GPS. GPS is not a myelotoxic agent. We have to be -- this is something very, very important because most of the drugs we use as maintenance, they induce myelotoxicity and this cause many problems. GPS is not myelotoxic because GPS does not have any effect on the normal cells. And this is very important. The only thing you have is just irritation in the place of injection.

Now I would like to stress several points. I would like to stress these points because these are the reasons that makes GPS the most promising vaccine so far. So GPS, it consists of a mixture of many different peptides that are derived from the WT1 protein. And this is very, very, very important for 2 reasons. First, these peptides can be bound to many different HLA alleles. So you don't -- GPS is not an HLA restricted drug. You do not need to check the patient before this administration for -- you don't need any HLA typing as we do -- we used to doing this in the past. In the past, when we have only 1 or 2 peptides and these peptides, they were specific -- HLA specific, then we had to test patients for HLA. And only a few patients were eligible for these peptides. Now the GPS is a universal drug. You do not need to test HLA that is really, really important. The other thing is that the multiplicity of epitopes results into many different allogeneic targets. And this is very important because the more the allogeneic targets, the less the possibility of immune escape. This is a basic rule in immunotherapy.

Another important thing that I want to make it clear is that the peptides in GPS are not like the old peptides. There are heteroclytic peptides and heteroclytic peptides are products of artificial intelligence when you can -- by changing a little bit, the amino acid sequence of these peptides, you can make it more immunogenic. So these peptides are capable of elicit strong immune reaction against these peptides and this makes them very effective and also you can prevent the mechanism of tolerance, which is observed with the use of other peptides. Finally, another one important thing is that these peptides are not -- do not activate only CD8 cytotoxic cells, but they also activate CD4 cells. And this is very important because antigen-specific CD4 cells are required because they give help for better cytotoxicity, but also they maintain the effect of the CD8 cells. So for all these reasons, I think that GPS is currently the most promising vaccine that we have.

Now this is the REGAL trial. The REGAL trial was a prospective -- is a prospective randomized trial, included patients in CR2 or less CR. The patients were not eligible to have intensive chemotherapy and they were not eligible to have a transplant, which is, as we all know, and Dr. Jamy said before that if you are in a state of CR2, the only way to have a prolonged survival is to undergo allogeneic stem transplantation, but these patients were ineligible. 120 patients enrolled in this trial and the patients were randomized to receive either the GPS vaccine or the best available treatment. The only available treatment that we have for patients who are in CR2 is to give the maintenance with the single agent hypomethylating agent. We can give them EMA in combination with venetoclax or we can see we observe them. Now patients who receive GPS, they receive GPS every 2 weeks for the first 10 weeks, and then they receive it once monthly for 1 year.

Now as you said -- as you listened before, it seems because we don't have the 80 events so far. So it is clear now that the median overall survival for the whole group of patients that are enrolled in the REGAL study, it will be more than 2.5 years. So this is really, really important. And you will allow me to say that I'm totally convinced that this is not due to the best available treatment because we know Professor Omer Jamy said before that if you use ven/aza in the setting of CR2 as maintenance, then I mean, the median overall survival is just a few months. So I'm pretty convinced that this prolongation of overall survival is due to GPS. And because we treat patients and we see these patients, that's why we request our request to SELLAS was to allow us to continue treatment with GPS because as a physician, if I see that my patient is getting benefit from a drug, then I'm really reluctant to discontinue this drug.

So now the maintenance phase is extended, thanks to SELLAS, not only for more 3 years, but even more. And this is really, really important. Now we know from previous trial that the vaccine is effective, okay? We know this. And published so far, we have 2 Phase II trials. The first one was GPS was administered in patients of all ages in CR1. These patients were not eligible for allogeneic stem cell transplantation. And the results from this trial were really impressive because the median overall survival has not been reached yet. And it is estimated that will be -- the median overall survival will be something like more than 6 years.

Now if we see the historical control for those patients who are not eligible for allogeneic stem cell transplantation in CR1 and for all ages, then the median overall survival is approximately 8 to 20 months. So this is really very convincing data that GPS actually works. And the second study is in patients with a median age of 74 years old that they were in CR2. And again, as you can appreciate from the slide in the right side that the median overall survival again was significantly prolonged as compared with the control group.

And finally, I want to say a few things about the immune responses, okay? We can move to the next. So this is a slide that's very important to my opinion because as you can see, in the Phase II study, when GPS was administered as maintenance of the second remission, then patients, a group of patients was tested to see if these patients after GPS, they had a response to WT1. And you can do this with 1 technique like immunophenotype or many other tests. But what we observed is that 64%, almost 2/3 of patients, they actually had an immune response after GPS administration. And the important thing is in this trial is that the patients who actually have an immune response to GPS are those patients who actually have a significant prolongation in disease-free and overall survival as compared to those who didn't managed to mount an immune response to WT1. So this is a proof of the concept that this vaccine acts through the immune activation and by creating immune effectors that they destroy the leukemic stem cells.

And finally, the REGAL study in a sub cohort of patients that also tested for the presence of immune response against WT1. Surprisingly, we observed that 80% of the patients, they manage to have an immune response against WT1. So with this, I like -- I think that I conclude, and I strongly believe that GPS is a really promising agent that my plan is actually to persuade the people here to make a trial in the post transplant setting when I think that it will be really, really effective. And I have to say that I'm really enthusiastic about this drug. Thank you so much. Thank you so much.

Thank you, Dr. Tsirigotis. I will now move to a bit more mundane and technical aspects of the trial. I'm Dragan Cicic. I'm heading Clinical Development at SELLAS. And I will give you a summary of the data as they -- I mean, not the data because we don't know the efficacy results as a company as the trial is blinded. But we do know that we have completed enrollment last April -- early April. So when I say last April, I mean, in 2024. 126 patients were randomized 1:1 into the study arm and the control arm. And the trial was multinational. We conducted a trial in 3 regions, U.S., Europe and Asia. 11 countries participated with the highest enrollment in the U.S. and the U.S. and Europe accounted for approximately 75% of the patients enrolled, which makes the patient population representative of the U.S. patient population, and it meets and exceeds FDA guidelines on pivotal trials, patient demographics. Importantly, the last patient was randomized about 19 months ago.

And we have heard in previous presentations that expected survival in this patient population treated with currently available care is around 8 months or so. So we are encouraged by what suggests to be longer-than-expected survival in our trial. But obviously, we have to wait for the results that will become available, as Angelos said, once that the sufficient number of events has been reached, which gets us to survival of these patients again and the number of events because survival is the key metric of the REGAL trial. It is the primary endpoint in the trial. So just as a brief reminder, we are comparing survival of patients in the study arm, meaning patients receiving only GPS as monotherapy against the survival in control arm meaning patients receiving best available therapy defined as physicians' choice of venetoclax combinations with hypomethylating agents or hypomethylating agents alone or low-dose cytarabine, which are all available treatments. So there are no other treatments that are available today. None of these treatments have been ruled in these settings.

So therefore, we cannot call it standard of care, but this is conventional care, meaning the only ways in which these patients are treated today. Now what -- when we said physicians' choice, what dictates physicians choice is, as previous presenters have said, a lot of toxicity with the available treatment, right? So because of the toxicity, they have to make a decision on what patient indeed can tolerate in these settings. So the control arm is truly a real-world experience, right? It's not artificial in any way, shape or form. Now when we say that survival is the primary endpoint, I just want to clarify here as we got some questions in the past where people would ask about median survival. And I just want to say that median survival is one endpoint, right? But the actual endpoint for this trial is hazard ratio.

So the difference is that although these are closely related measurements and usually commonly we express this when we discuss it as median survival, and that's how it's -- that's what physicians and patients remember. But actually, median survival is not used as the primary endpoint because median survival is although correlated different because it's a snapshot of one time point in the patient treatment. So basically, you are reporting that patient who's in the middle of the survival curve has lived for, for example, 10 months. And then you say the patient who's in the middle of the survival curve of the comparator has lived for, say, 11 months. So then you would say it's 10 months versus 11 months. But that's not in itself approvable endpoint. The approvable endpoint is hazard ratio because it tracks patients over time and compares their probability of survival at all time points. So hazard ratio is reported as a proportion between the arms. For example, if you say hazard ratio 0.636, that means that overall, over time, patients in one arm had probability of dying of 63.6% compared to the other arm.

So in other words, almost 40% lower, right? So that's really what we are going to be looking for, and that's why we need 80 events so as to be able to tell over time to make an ironclad conclusion of which trial benefit -- which arm or which treatment benefits patients more and how much more. So again, this can be shorthanded in a way by correlating it to median overall survival. So if median overall survival, for example, is 8 months for control arm and 12.6 months for study arm, then this would imply that the hazard ratio is going to be met. But again, this is just a way to explain this more intuitively. Now in the initial assumption, we expected and Angelos spoke about that as well in his introduction. We expected that final analysis that 80 events and therefore, final analysis would occur approximately 12 months after the last subject is randomized. So we thought it may occur then sometimes in the second quarter this year or at the latest in the fourth quarter. But now we know that 80 events have actually not occurred 12 months later and have not occurred even 19 months after enrollment completion.

So -- but as my predecessor and other presenters have said, what's really important here that this is a very encouraging -- potentially a very encouraging sign because we are seeing longer-than-expected survival, which is, again, we cannot say that this is because of GPS at this point until we actually see the data, but this is an encouraging sign. Now I'm going to switch to just addressing briefly the market size. And AML is a rare disease, rare enough to qualify as orphan disease, but it's actually not that rare. It's actually the most common leukemia, the most common type of leukemia, and I would say by far the most common. So there are around 77,000 patients in U.S., European Union, Europe, 5 biggest markets, Japan and China, who are diagnosed with AML each year. Out of those patients, and these are the markets for drugs, right? These are the largest markets for drugs. Now in the U.S., there's almost 22,000 actually closer to 22,000, we have 21,000. But at this time, it's getting more like 22,000. So the incidence is increasing.

And almost all of these patients, as my colleagues have said, 97% of these patients express WT1, right? And vast majority of patients get treated because in the absence of treatment, AML is invariably little. So there are no patients who can survive AML without treatment. As we have learned, unfortunately, most of the patients cannot survive it even with treatment. And complete remissions are actually in the largest 4 markets are actually closer to 50%, 55% because United States has probably the highest rate of success in treating. But nevertheless, in the absence of transplant, all the patients -- almost all patients will relapse. And now their probability of getting into the second transplant -- sorry, into the second remission is now much lower as we've heard. So altogether, in the end, there is about 15% of patients who end up in CR2.

And these are the patients that GPS is focused on. Now in the front line, we -- in the first line where we are developing tambiciclib, we estimate that approximately 1/2 of the patients would benefit from tambiciclib. And of course, all patients in CR1, we believe, would benefit from GPS. So that's really, in a nutshell, the technical aspect of the trial and the market size. And with that, I...

Thank you, Dragan, and thank you, Dr. Tsirigotis, for this detailed and exciting discussion really of our REGAL study and the potential GPS holds to alter the GPS treatment paradigm. And I think Dr. Tsirigotis, I think you made a very strong case to support you with the post-transplant work with GPS. Thank you.

At this point, I would like to switch our discussion to our SLS009 program and invite Dr. M. Ryan and Khan and Dragan to provide an overview and thoughts around SLS009 and our differentiated asset versus other CDK9 inhibitors in development and treatment of really the hardest-to-treat AML subgroups, including those with TP53 mutations. We'll talk about our biomarker strategy and upcoming trial design and how it all really comes together finally to hopefully benefit patients in dire need of effective and safe treatments in AML. So with that, I'll turn it over to Dr. M. Ryan, please.

Thank you, and greetings from Mass General in Boston. And I will try to dig deeper into the rationale of why we're excited about SLS009 for the treatment of AML. As you've heard, the outlook for these patients is really not good, but the azacitidine venetoclax combination has become much more popular over the last year or 2. In fact, more and more younger patients are receiving this combination rather than intensive chemotherapy. But as you can see, even though the combination is better than azacitidine alone, the median survival here in this older population is 14 months and few patients actually are being cured, we know the outlook for these patients is largely driven by the mutation analysis. Not all mutations are bad mutations, but there is quite an assortment, as you can see here, of mutations that's being looked at.

And in Europe, by Donor and the Mayo Clinic and others are starting to develop a classification of high-risk patients that really have a very poor prognosis. As you can see here, PKD3 mutations, RAS mutations, KMT2A rearrangements are very poor prognostic indicators. KMT2A is a new classification for MLL rearrangements. And as you may recall, the menin inhibitors are very popular right now, and they act in that pathway. So anyway, in these high-risk groups, the remission rates are poor. They're like 20% and the overall survival is only 2 to 7 months, unlike the others. So we're excited to work with this group and try to make some progress in this unmet need. So why target CDK9 with SLS? Well, there are good reasons to target CDK9. It is required in RNA polymerase activity and hence, protein synthesis.

And a lot of leukemias are generally dependent on high levels of metabolism that is protein synthesis to stay alive. More specifically, these leukemias are dependent on short half-life molecules like MCL1 and MYC. I'm sure you've heard of MYC before. and MCL1 over the years has been a favorite target in acute leukemia and few have been able to target MCL1 for various reasons. By targeting protein synthesis, you don't have to target it directly. It has a short half-life and you just have to stop protein synthesis and it goes away very quickly. We have been doing some testing in the laboratory, and we can show, as others have shown that with just a 6- to 8-hour exposure at very low concentrations, 20 to 50 nanomolar, it kills practically all leukemia cell lines very handily. So why combine it with azacitidine and venetoclax? Well, there actually are good reasons to do that. They're somewhat synergistic. I'll go over that in a minute.

We are targeting mainly older patients, which is the vast majority of leukemia patients. Already, the standard of care is azacitidine and venetoclax. So it's very simple to design a trial where we just add SLS to what people would be using anyway. And in our lab, we show synergy in the early studies, Phase I, Phase II, it looks like it can be synergistic with azacitidine, venetoclax. And I'll now go over some of the details of why scientifically this makes sense. So there have been other CDK9 inhibitors in clinical trial already. You may recall Flavopiridol has been in clinical trial for quite some time. They have been fairly toxic, and it's mainly because when you look at the assortment of kinases that are inhibited, they are not very specific and therefore, more toxic. SLS is very specific for CDK9, and therefore, it is much better tolerated than the other CDK9 inhibitors that have been tested.

And if you look at the picture to the left, I'll just briefly tell you exactly how this works. So RNA polymerase is depicted in green and it's going along DNA making messenger RNA. However, generally in most cells, RNA polymerase is halted very quickly, waiting for PTEFB, which is in blue, to allow it to proceed further to make messenger RNA and protein synthesis. And as you can see there, CDK9 is a controlling protein for PTEFB. And until it gets involved, the negative elongation factor in red NEFP holds RNA polymerase in check. Now when CDK9 is activated, NEM is ejected from RNA polymerase and messenger RNA is now synthesized as expected. And listed there are some CDK9 inhibitors that prevent this process. So on a molecular level, that is what is going on. So when cells are exposed to SLS or any other CDK9 inhibitor, protein synthesis stops abruptly, perhaps for 8 to 12 hours.

The short half-life molecules disappear like MCL1. And under many circumstances, that's enough to trigger apoptosis and cell death. Now venetoclax does not interact with those proteins. Venetoclax interacts with BCL-2, which in conjunction with MCL1 keeps cells alive and affords the resistance to chemotherapy treatment. So when you attack cells with azacitidine along with venetoclax and SLS, you pretty much initiate cell death and then block the resistance mechanisms, the main 2 resistance mechanisms through BCL-2 and MCL1. I'm just going to touch on briefly special cases as listed below. Again, you may have heard of menin inhibitors, which are very popular right now and menin triggers the MLL-KMT2A pathway, which leads to upregulation of HOXA9 and leukemia. And the menin inhibitors appear to be quite active and have a future. It may be that SLS is very similar to the menin inhibitors in the way it works, and I'll show you that in a minute. SLS has also been effective in a high-risk population with the ASXL1 mutation. Many patients have that, and it's a high-risk resistant population of leukemia.

However, SLS seems to be quite active in that population. We've seen that in the early clinical trials, and I'll show you why in a minute. Finally, the p53 mutation patients are highly resistant to conventional chemotherapy. It's a huge unmet need, and it may be that SLS has an answer for that population as well. So here is a diagram for the menin-MLL-KMT2A-HOXA9 pathway. And as you can see, that purple circle there is menin and that triggers this pathway to leukemia and the menin inhibitors act at that level. But if you look down the road here, you see P-TEFb in orange that's controlled by CDK9. Well, if you inhibit P-TEFb, that pathway is shut down just like the menin inhibitors will shut it down. And to see that is kind of exciting because it's a big unmet need in the KMT2A mutated patients. Over here, initially, we were kind of curious as why the high-risk ASX-01 patients seem to respond nicely to SLS. And as you can see here, full-length ASX01 in the orange box does not bind to BRD4. And so this pathway is not triggered with wild-type ASXL1.

However, when you mutate ASXL1, it binds BRD4, triggers, guess what, P-TEFb and RNA polymerase and it stimulates protein synthesis. And if you inhibit CDK9, this pathway is halted. And finally, what about the biggest problem we have is PKD3 mutation and null cells. Well, in this diagram, BAX and BAK are your executioners causing apoptosis or cell death, and they are controlled held in check mainly by MCL-1 and BCL-2, BCL-XL is a minor player here. And if they are held in check, the cells do not die. But if standard chemotherapy comes along, triggers p53, suddenly, it causes release of BAX and BAK through MCL1 and BCL-2. And if you don't have p53 or it's mutated, conventional chemotherapy has nothing to work on. And so MCL-1 and BCL-2 continue to hold on to BAX and BAK and you don't get the cell kill that you expect, you get resistance.

Now if you have venetoclax interacting with BCL-2 and you have SLS causing MCL1 to disappear because it has a short half-life, suddenly BAX and BAK are released and you get the cell kill you were hoping for even in the absence of p53 or mutated p53. And we've seen some responses in patients with the p53 mutation already. And that is truly exciting as that is explained. I'm going to stop here. In conclusion, we're excited about adding SLS to the now very popular azacitidine venetoclax regimen, and we will see in a randomized setting, just how good this is. I'm excited, and I think it may be a positive experiment. Thank you.

Thank you very much, Dr. Amrein. Really appreciate you. So I think with that, we'll turn it over to Dragan to discuss the trial design, the upcoming trial design, discussions with FDA and some of the -- what I feel not only really exciting biomarker work, but really, I think as I mentioned in my earlier statements, as far as we know, we're really the lead company having done transcriptomic genomics and proteomics work and to utilize that data then into really our trials. So Dragan with that?

Thank you. So let me start by providing the results of our Phase II trial. That's the basis for the next trial that I will also address. So it looks very complicated, the design of the trial, but it's actually not that complicated. I think that what we need to say here is that all the patients who were enrolled in this trial were relapsed after or refractory to venetoclax-based therapies.

So the design of the trial because at this point, this trial is a single-arm trial, right? So we wanted to have a control built into the trial, into a single-arm trial. And the way to build the control in is to have patients who we know failed venetoclax-based regimens.

So then by definition, their response rate is 0 to aza/ven alone to venetoclax-based regimens. So again, all the patients were relapsed and refractory to aza/ven and importantly, we did not provide any exclusion criteria, which would limit the number of previous exposures.

So we had patients who were actually really at the end of their line who were beyond the graphic on the slide that we've -- that I've discussed earlier in terms of the market size. So they were on the far right of that slide. So now patients who did not benefit from this, from aza/ven, right?

So here's what we had. We had these patients. You can see here their characteristics. Per the FDA request, the patients were -- the trial was designed to follow the guideline of Project Optimus, meaning that we explored 3 dosing regimens to come up with the regimen that has the best combination of safety and efficacy, right?

So 58 patients treated across all cohorts and you can see the number of patients per cohort. You can also see that vast majority of patients, 51 out of 58 were AML myelodysplasia -- with myelodysplasia related changes. Now the reason for that was that we designed the trial so that vast majority of patients would be AML-MR. And the reason for that is, as Phil -- sorry, as Dr. Amrein discussed in his presentation that they have certain genetic changes, certain biomarkers that indicated per Dr. Amrein and other scientists work that they would be particularly susceptible to the treatment with our drug.

So another area of focus was patients with myelomonocytic AML or myelo monoblastic. So patients classified as M4 or M5 patients in the FAB, French-American-British classification of AML. So we had a decent number of patients of that type, again, by design, right, because as Dr. Amrein focused on role of MCL1, it is believed that based on the data, right, that MCL1 plays a much larger role in these particular subtypes of AML.

So median number of prior therapies was 2. As you can see in some cohorts, it was even 3. So these patients were refractory not only to venetoclax-based combinations, they were refractory also to chemotherapy and they were also refractory to other experimental drugs, new drugs like CAR-T and so on, right?

So very -- patients truly at the end of their line. Now I'll start first with the safety data. So right after that, I'm just going to give you a review of this. So what's important here is you have really different safety profiles, as Dr. Amrein said, other CDK9 inhibitors because of their propensity to bind to other kinases have volume side effects.

So now here, we wanted to check in the Phase I trial, we have shown very little toxicity as a single agent. Now we wanted to check whether adding this to aza/ven regimen will result in more toxicity. And as you can see here, first of all, there were no dose-limiting toxicities at any dose level, right?

So when you look at all these cohorts, right, very little toxicity. Then you can also see if you look at the far right, just to make it very easy to follow. If you look at what really matters here is all dose levels, so far right columns, and you can see side effects of any grade and side effects of grade 3 and higher, which are considered more important side effects, right?

Now those that can limit the use of the drug. So you can see here, it's really -- so what we are giving here is not a selection of side effects, representative selection. This is truly all the side effects that occurred with at least 5% frequency. So you can see the list is very short. And you can also see that there are very few hematologic toxicities.

So my colleagues before were KOLs were talking about the importance of myelosuppression. You can see that myelosuppression of high grade is occurred in between 5% and 6% of the patients as an additive effect of our drug, right? And then you can see that there were some gastrointestinal disorders, but they were all low grade and easily treatable and self-limited.

So we had really, really good indications of safety here. Now again, that's very important because it allows us for any drug, it's important that the safety is not limiting its use, and we are in a position where we can say here that it is not limiting its use. Now even though there's very little toxicity, it appears, another important thing is obviously efficacy, and if you look at efficacy at the dose level, optimal dose level that we are using now and moving forward, you can see that response rates, now bear in mind, again, these are response rates that are in addition to whatever has been achieved before with aza/ven.

And you can see that response rates and survival far exceed what would be expected and what our original goal was. So really in AML-MR patients, 44% altogether in AML-MM patients, and M4 and M5 patients, 50%. And importantly, now the number of patients with TP53 mutations was not very high. But importantly, it's 57% response rate, so -- which confirms what Dr. Amrein was hoping to see because of the mechanism of action.

Now -- we are -- we have discussed -- Dr. Amrein discussed some of these biomarkers and c-Myc, MCL1 and then also other biomarkers, ASXL1, other AML myelodysplasia-related mutations and transcriptomic markers, proteomic markers that measure the translation of genes into proteins and then interactions of proteins.

We have done a lot of work in this field, and we are continuing. So let me just give you a brief illustration. So we already know that Myc and MCL1 are directly affected by SLS009 CDK9 inhibition, right? We -- that was explained by Dr. Amrein. Now we also know that MCL1 is a protein that confers resistance to venetoclax and that overexpression of MCL1 is found with high frequency in myelomonocytic types of leukemia, M4 and M5. So that's why we had particular interest in that. So leukemia cells that overexpress MCL1, but have low expression of BCL2, which is the target of venetoclax, right? should be particularly sensitive to SLS009.

You may want to go to the next slide. I think...

We need to prove this in clinical trials. Yes. So this is an example of what we've done so far. We are continuing this work. So just briefly, if you look at the red oval, these are leukemia cells. And you see that they are very cold to BCL-2, very low levels of BCL-2, but very high levels of MCL1.

Now what actually happened with this patient. You can see here that leukemia cells, leukemic monocytes and leukemic blasts here before the treatment, after treatment with venetoclax, but before treatment with our drug and then after treatment with our drug. So we can connect here, tie together clinical features, biological features, mechanism of action and predictive values, and that's a big focus of our work.

Now based on that, all of that, we've designed this new trial with input from the FDA, which agreed that safety and efficacy data are sufficient to justify a first-line study and recommended that we move the development into front line because we now know based on these biomarkers that Dr. Amrein and I discussed, we actually can identify patients who are unlikely to benefit from venetoclax-based standard of care before they even get treated, and the FDA also put specific emphasis on MCL1, which they want us to -- and we are doing that, as you've seen, explore further as the biomarker.

Now the proposed trial, the trial that the FDA proposed is going to be conducted in two groups, right, two settings. The first setting will be patients with AML-MR biomarkers and/or M4, M5 biomarkers and/or Mayo-based biomarkers. So then these patients will be randomized 1:1 to receive venetoclax and azacitidine alone, which is the current standard of care. These are all newly diagnosed patients or received aza/ven plus our drug, and then we have a very direct comparison prospective trial.

In the setting two, which we designated as group 5, we are going to enroll patients who started already on azacitidine and venetoclax, went through two cycles, but did not benefit from azacitidine/venetoclax. Now standard of care is 4 cycles. So -- but if the patient did not benefit in the first two cycles, then the probability of response is very, very low, and they also develop features that we believe will make these patients particularly amenable to our drug.

So we have two options, two possibilities that we are exploring, and we do not -- we have an ability to develop our drug in one setting or the other setting or both, right? So that's really where we are. We are now getting ready to commence this trial in the next quarter.

With that Dr. Khan.

Yes. Hello. Good morning. Thank you for inviting me to this symposium. My name is Sharif Khan. I did my fellowship in hematology and stem cell transplantation. I'm a community hematologist. By definition, that means you work in a small town with a medium-sized hospital or a large hospital. My previous position was at the Geisinger Health System. I was there for 11 years, and I've been here at Bon Secours over 9 years.

My area of practice includes acute myeloid leukemia, acute lymphoid leukemia, CML, CLL, MDS, Hodgkin lymphomas, T-cell lymphomas, B-cell lymphomas, autologous transplant, allo transplants, CAR T-cells and BiTE therapy, and I also participate in clinical trials. And I also treat a number of benign hematology patients with ITP and iron deficiency and sickle cell. So it's kind of an old school job, we do everything.

And when I -- before opening a clinical trial at my center, I have three criteria. Number one, based on the information available, is this likely to benefit my patients? Number two, are the logistics such that it would be acceptable to the patients that can we get? And number three, do we have these kinds of patients in clinic so that we can enroll in a meaningful manner? Those are the three criteria. That's why I participated in the REGAL study, and I was also part of the Phase I in GFH009 and then the Phase II on SLS009 and enrolled patients in multiple cohorts.

So I'd like to -- I'll keep this simple, and I will put the results that Dragan shared with us into more of a clinical context and summarize things. So in clinical practice and in the studies that we've seen, when patients fail venetoclax-based therapies, whether it's first line or second line, their prognosis is terrible. Most of them don't live more than a couple of months.

In the VIALE-A study, which led to the approval of venetoclax, the patients who were nonresponders who did not respond, their median survival was only a couple of months, and that was in the first line. And in second-line patients, patients who are treated with venetoclax combinations, their median overall survival is about just over 2 months. Overall response rate is low at 30%. And it's really, really dependent on the mutations.

If you have unfavorable mutations like ASXL1 and the RAS mutations and TP53, you're not really going to respond. It will be barely in the low single digits. And if you have the favorable mutations like IDH1, IDH2 and NPM1s, about half the patients responded. And if we have patients who stopped responding to venetoclax-based combinations and were treated with something else, the overall response rate was only about 15% and median overall survival is just over 2 months.

That was also heavily dependent on mutations because if you had the bad mutations like the RAS mutations, ASXL1, TP53, nobody lived a year and median overall survival was just over 2 months. And if you didn't have the bad mutations, then 42% made it to 1 year with median overall survival just over 4 months. And patients who didn't respond to venetoclax-based combinations or relapsed after initial therapy, whether it was first line or second line and were treated with another agent, their overall response rate was in the single digits, about just over 5% and half of them didn't make it beyond 2 months.

So -- and for first-line refractory patients, the median overall survival is about just over 2 months. And for second-line refractory patients who are refractory to venetoclax-based therapy, it's under 2 months. So it's actually dismal. And none of these patients were obviously continued on HMA-Ven once they progressed unlike in our SLS study. They were treated with other treatments. And in our study, we compared the data from our real-world reported numbers to what we saw.

Could we see the next slide, please? Yes. So over here, if you look at the AML-MRC patients, myelodysplastic-related changes that had mutations like ASXL1, EZH2 and SF3B, SLS009 did really well. Almost half the patients responded, whereas traditionally, if you treated them with something else, response rates are in the single digits.

And if you looked at the criteria, the Mayo criteria patients with the RAS mutations and TP53 mutations, nobody responded to currently available therapies. Whereas in the SLS cohort, it was about just over half the patients. So Dragan has already described the myelomonocytic population and its dependence on MCL1, and we have excellent biomarkers now that can, number one, predict the patients who will do very poorly on available therapies and those same biomarkers seem to predict a pretty decent response to SLS.

Could we -- is there that other slide we were going to check or no, okay, can we go back one? So one of the things we know is that patients who are -- whom we treated in our study had a response rate. If they received previously two or more therapies, their response rate was like 30%, 40%. And if they received one previous therapy, it was 60%, right? And Dr. Wang has also presented some data in ASCO last year that said that the same regimen can produce much better responses in patients who were treated earlier.

So in the future study, which the FDA wants, we're going to be treating in that one arm, patients who have received 0 prior therapies. So two prior therapies with -- for these patients who don't respond, it's 30%. One prior therapy, it's 60%. So we expect that with 0 prior therapies, it will be a number much above 60%, and the survival on this -- what we've seen historically for these patients is about two months. So -- and the survival, what we've seen in some of these cohorts is about 5 or 6 months or more, 8 months sometimes.

So that's the background on which the new study is going to be started, and my expectations are heightened by the FDA's request to move into the front line because when we look at all the data from the past, we should be able to hopefully -- and it's not unreasonable to believe that, that our numbers should be better because all we're expected to beat is a response rate that's in the single digits and a survival of two months, and we've already shown numbers in the Phase II that are multiples of that. So that's why I'm really excited and looking forward to the new frontline therapy trial. Thank you.

Thank you, Dr. Khan. It was very interesting to get the clinical context and how all of this fits in, which obviously, as you know, very well, gets us really excited. And again, I just want to thank Dr. Amrein, Dr. Khan and of course, Dragan for this very informative overview.

I think as you heard from our experts, we're indeed on the cusp of potentially bringing transformative drugs to patients in need. And I would just like to add a few remarks and summarize some key points that you heard. Regarding GPS in the REGAL study and beyond, I'm really pleased to report that we have not observed, as you heard, any intolerable toxicities in our patient population. Although toxicities are commonly observed with therapies used in the control arm, physicians are allowed to modify the treatment regimen in any way they deem necessary. This includes the option for observation, which for the purpose of the trial is considered a valid treatment option.

Due to regulatory reasons, as the study sponsor, we lack specific information on the outcomes of study participating patients, including data on how many of them relapsed, but have not passed away yet. As I mentioned at the beginning of the event, although we do not know survival outcomes per treatment arm from a mathematical standpoint, every passing month may increase the probability of a successful study due to a potential GPS effect as we have seen in our previous CR1 and CR2 studies far surpassing median overall survival versus standard of care.

Again, when the 80th event materializes, we will inform the public which represents the most important near-term catalyst for SELLAS. The determination of the relevant survival outcomes, including the final analysis, belongs to the independent data monitoring committee, the IDMC. And during the next IDMC meeting, when scheduled, the IDMC will analyze the accumulated data and assess the safety and efficacy of the treatment. So statistical significance, as Dragan alluded to, in our REGAL trial will be achieved by an estimated hazard ratio for overall survival of 0.636, corresponding to an overall survival of 12.6 months versus 8 months for GPS versus BAT, respectively. The IDMC must not disclose event rates and clinical data to us. So we will not know in advance when the ADF death has been reached. But again, once it happens, we will inform the public.

As for SLS009, I think the results to date, as you have seen, have been extremely encouraging and they represent an important advancement, I would say, for SLS009. As a reminder, our upcoming trial and with the input by the FDA, and we were actually pleasantly surprised because we have had really constructive discussions with the agency and met with them within a short period of time numerous times. So we're very pleased with the FDA interaction and their support and constructive feedback. We will administer SLS009 in the frontline setting, as we discussed earlier as well as in patients who did not respond to venetoclax and azacitidine after 2 cycles.

So the goal of the next study in addition to safety, one is going to be to assess the efficacy of SLS009 as an add-on therapy measured by at least 50% increase in complete response rate compared to control arm percentage, and increased overall survival by at least 50% compared to control arm. And finally, to confirm the predictive properties of biomarkers identified in the previous trial and to compare and confirm with our transcriptomics, genomics and proteomics work that we're really very proud of.

Switching briefly to finance and our currently -- and our recently completed $31 million financing this week. We're extremely pleased to have significantly strengthened our financial position with that transaction of $31 million in gross proceeds as well as the close to $24 million gross proceeds we brought in last month. Really, this funding will enable us to reach our important upcoming milestones, notably the final analysis for our Phase III REGAL study, continue to build out our corporate infrastructure for GPS, our upcoming SLS009 trial and pertinent study data in 2026 and potential expansion of this study while further pursuing regulatory and business development and licensing efforts.

We're really extremely excited about the potential to use that data towards an accelerated approval path and/or quickly move into a registrational study with our CDK9 inhibitor based on the predictive biomarkers we have identified in addition to other solid cancer indications that these biomarkers express. So this financing gives us additional firepower, if you will, to execute on our objectives. So this journey ahead is filled with promise, and we're just really excited about the evolution of our company.

I think with that, maybe it's time to switch into the Q&A session. John Fraunces, if you want to.

Sure. Thank you, Dr. Stergiou. I appreciate that. As you can imagine, we received many questions from the audience. So we are going to group the questions by clinical program, starting with GPS, and we'll move to the SLS009 program. And at the end, we should have time to answer SELLAS corporate-related questions.

So the first question is for Dr. Cicic. Can you talk about the enrollment strategy -- excuse me, how the enrollment strategy has evolved since the Phase III REGAL trial began in 2020. For example, One of the recent protocol changes allows patients who remain in remission after 52 weeks to receive treatment every 2 months during the second year and after 2 years, every 3 months. Can you help us understand the rationale behind these changes? Does this mean there are GPS patients who have remained on therapy for a much longer period than originally expected 10 to 15 months? I believe you have to unmute Dr. Cicic.

Sorry, apologies. Okay. Well, first, let me state that protocol amendments are a common practice throughout clinical trials. And indeed, we had protocol amendments. -- we do not have insight into how patients are surviving per arm, which, as I mentioned before. But we can say in response to the question that trial has obviously been lasting longer than expected and more patients are alive than we initially projected.

Okay. Our next question is for Dr. Tsirigotis. Regarding the 80 events we are expecting, it seems that the longer it takes, the better the outcomes are for patients. Do you share this interpretation?

Yes, of course. I think that it's pretty clear that we are going to have prolongation in overall survival for the whole cohort of patients enrolled in REGAL as compared with historical controls. And again, I would like to stress the point that, to my opinion, as a physician because I work with patients. So if you see what is the outcome of those patients in CR2 who are receiving ven-aza, you will -- you can see from the data that the median overall survival is a few months. So I'm convinced. I can say I'm totally convinced. Of course, we have to see and wait for the final results. But I strongly believe that this prolongation in overall survival is due to the GPS effect as maintenance treatment.

Okay. Thank you. The next several questions are directed to Dr. Stergiou. And the first of these relates to several aspects on GPS manufacturing. Can you explain the preparation of your GPS manufacturing capabilities, its CMC work, where is GPS manufactured? And how complex is the manufacturing process? And is that process -- is the production outsourced?

Yes, I'll try to keep it simple. So the drug substance or the peptides of GPS, those are manufactured at polypeptide. If I recall correctly, it's in Southern California, which is an extensive experience and expertise in peptide manufacturing really for the global market. Now that's a drug substance. And then we have the final product, which is called the drug product, and that's manufactured at PCI Lab Services, LSNE in New Hampshire, which really has experience with manufacturing sterile lyophilized products.

So the peptides are manufactured using for easy use here, a standard chemical process, widely used to make other small peptide drugs. And the final product, again, is a sterile lyophilized powder for injection, which is a commonly used dosage form.

Okay. The next question, again, for Dr. Stergiou. GPS has received orphan drug designation from the FDA and EMEA as well as Fast Track and rare pediatric disease designation from the FDA. Do you expect a reduced review period for the GPS BLA?

Yes. I think -- so given GPS regulatory status and other FDA procedural guidelines, we would absolutely expect a priority review designation. However, we cannot comment on what the FDA's actual review period would ultimately be.

Okay. And back to one more question on manufacturing, it seems. In your presentation, you note that certain peptides in GPS are engineered and artificially mutated. Can you explain the difference between these 2 types and what that means?

Yes. I think Dr. Tsirigotis put it very nicely into context in his presentation. But sort of when the early discovery work happened and at Dr. Scheinberg's team at Memorial Sloan Kettering Cancer Center, which is where we licensed the asset from, they screened the entire WT1 amino acid sequence for literally thousands of binders and then selected the best ones of hundreds with the methods of in silico prediction of peptide MHC Class I binding that really helped to provide optimal target for CD8 T cells. And then systematically, they modified them to see if they could be further improved. And similar methods were used for the selection of CD4 T cell activating peptides. So longer peptides allowed for reactivity, if you will, with more epitopes, multivalency and presentation to both CD8 and CD4 cells.

Now as you know, we have a [indiscernible] of 4 peptides. Two of the peptides within the GPS mixture are native. So it means that they contain the exact same amino acid sequences as the fragments of the WT1 protein they originated from. The remaining 2 peptides where we utilize the heteroclitic technology are by design modified by an amino acid mutation. And in that sense, the heteroclitic WT1 peptide, it carries a mutation and is presented to the native CD8 cell through the host antigen presenting cells, Dr. Tsirigotis said the macrophages dendritic cells or monocytes. And the CD8 cell gets activated and becomes a cytotoxic T cell, which now is able to recognize not only the mutated version of the WT1 peptide against which the host was immunized and does not get expressed naturally, but also to the corresponding native WT1 fragment. And the native fragment gets expressed and gets presented on the membrane of cancer cells in MHC Class I context.

So the similar events again occur on CD4 cells after cross-presentation of the WT1 heteroclitic fragment and eventual activation of the CD4 cells into effector and memory cells. So the heteroclitic technology really mitigates, among others, against the emergence of tolerance. And that allows us treatment over a long period of time to the administration of booster inoculations as mutated peptides are classified as nonself antigens.

That's a really great detailed answer. It's a good segue for our next question, which is directed to Dr. Tsirigotis. AML can lead to the depletion of both dendritic cells and macrophages. Is this a potential issue for AML patients in CR2 who could benefit from GPS therapy but may not have enough of these cells for sufficient antigen presentation, excuse me, to CD4+ helper and CD8+ CRL cells. Do you measure for a certain level of APCs before administering GPS?

Okay. Thank you very much for this question. First of all, I have to say that this is not completely true. From the time that we have a full-blown leukemia, of course, there is a decrease in the production of new dendritic cells, which are the most efficient in presentation. But they already -- those cells that already are in the tissue, they long live. They are long-lived cells. So this is not true. I mean from the time you have full blown leukemia, you don't mean that you don't have any dendritic cells.

Now to move a little bit, we treat patients in complete remission. So the block, this block in production of dendritic cells doesn't exist anymore. And finally, as I show you in my presentation before, 80% of the patients who received GPS, they managed to elicit a strong immune response against WT1. So this is the proof of the principle that GPS is effective. And so this, again, it's an indirect way to understand that dendritic cells are there. This is my response to your question.

Okay. Thank you. The next set of questions relate to the SLS009 program. And the first question is to Dr. Cicic. Is there another example of an AML clinical program where the FDA recommended advancing the drug candidate into the frontline setting based upon clinical data from relapsed/refractory patients, similar to your Phase II study for SL009?

Yes, there is -- so I would here reference quizartinib. The development went -- so it's a pretreated inhibitor, and we are now talking about AML directly, right? So quizartinib, they had a trial that was called QuANTUM-R in relapsed and refractory patients. And based on the results of the trial, the FDA actually asked them to move into another first-line trial, QuANTUM-First and the drug was approved as the frontline drug in QuANTUM-First -- based on the QuANTUM-First results.

Okay. Also for Dr. Cicic, do you consider 009 a next-generation CDK9 inhibitor primarily because of its higher potency and selectivity? Or are there other attributes that distinguish this molecule from past CDK9 drug candidates?

Well, yes, I'll be very brief here because I can't get into a lot of detail here. But in principle, right, what dictates this drug's potency and selectivity is biodistribution, which in turn dictates pharmacokinetics and pharmacodynamics and then the attributes that determine that are charge, lipophilicity and functional groups. which then determines how the protein binding and so protein binding lots of these data are not like public and they're proprietary. But yes, so I would just say charge lipophilicity functional groups and then protein binding and all that comes out of it.

Thank you. Okay. Next question is for both Dr. Khan and Dr. Jamy. With twice weekly IV dosing for SLS009, will this be seen as a logistical barrier limiting adoption, especially in community oncology practices that manage AML patients?

Omer, you go first?

Thank you. So even in -- when we have our patients getting hypomethylating agents and venetoclax, we expect them to get labs checked either at their treating center or locally 2 times or 3 times a week. So I think if they're already going for that to getting the drug twice weekly should not cause any additional logistical burdens to the system.

So if patients enroll in this trial, they'll be taking oral venetoclax they'll be on Vidaza, azacitidine. They're coming to clinic 7 days anyway in that first week were on treatment. So they're just going to spend an extra hour for 2 of those 7 days, getting the SLS009. So it really -- it's not going to really mean that much in terms of visits. And patients that are diagnosed with acute leukemias, they're different from with some other cancers. When you have that conversation with them, it's a sobering experience, right, because you tell them if you don't get treatment, you're not going to live more than a few weeks or a month or 2. So they're very motivated to trying to put this leukemia behind them.

Understood. Okay. The next and final set of questions will focus on SELLAS corporate-related topics, all for Dr. Stergiou. How should we think about R&D spend on an annualized basis moving forward, assuming the new 009 study is initiated in the first quarter of 2026?

Yes. As you know well, we don't give guidance. But suffice it to say, we have the strongest cash position in our history as a public company. And this firepower really allows us to reach several value-driving inflection points through this year and next.

Okay. Assuming success in the Phase III REGAL study, can you discuss your commercialization plans, a potential European partnership or -- and perhaps going it alone in the United States?

I think as you can appreciate, we think through all scenarios and the best value propositions really for patients and ultimately, our shareholders. Our commercial strategy is to be prepared, and we have to be ready to launch and market our product candidates ourselves until someone knocks us off our tracks. And we continue to prepare the organization at this pre-commercial stage for the necessary infrastructure for a successful launch globally. At the same time, the team has been engaging with potential partners. And I'll come back to what I said earlier, and we'll evaluate all potential scenarios that delivers the best value proposition for patients and ultimately for our shareholders.

Given the recent capital raise, next question you may have already answered it, but I'll ask it. Given that you're advancing 2 late-stage programs, how will you prioritize capital allocation between the 2, they both approach registrational stages around the same time?

Yes. Our capital allocation strategy remains to be as cost effective as possible while driving our assets further through the clinical development process. So at this point, REGAL is approaching the finish line and our spend has been reduced as the study has been fully enrolled for about 18, 19 months now. While we anticipate initiating a new frontline study of SLS009, as you heard, that study is not as capital intensive as the REGAL study, and we expect our current financial position to deliver us meaningful data from the study.

So we remain prudent in our spend. For example, and please remember, we have only 14 full-time employees, all of us, every single one in our company wears 3, 4, 5 hats. And we don't expect additional headcount, and we've not had any additional headcount for the last 18 months.

Okay. Understood. Final question. What makes SELLAS stand out from other small-cap biotechnology companies working in AML? Why should investors believe SELLAS can win in such a competitive space?

I think that's an excellent question. I would say it's definitely our assets and our experienced team. While AML may appear to be a crowded space, there's nothing approved in the maintenance setting in AML. And if GPS demonstrates what we all hope a clinically meaningful and statistically significant survival benefit with a favorable safety profile that we know we have, we have the potential to change the treatment landscape for these patients with a targeted immunotherapy. In both of our assets, GPS and SLS009 have the potential, and I've said this many times, and I'm so proud of saying it again, to be the first-in-class and the best-in-class. The former is a WT1 targeted immunotherapy and the latter, as you know, is a CDK9 inhibitor.

So we welcome the new therapies that are getting to patients that are getting patients into remission and potentially expanding our addressable patient population for GPS, venetoclax resistance as well as the refractory setting is a large unmet need for AML patients. If we can reverse that resistance, as we have seen in our studies in frontline or early refractory AML patients with SLS009, we would become a staple in the treatment landscape. You heard from Dr. Tsirigotis also the potential of GPS in post-transplant.

So our investigational products are truly differentiated within the AML space, and we look forward to really expanding our footprint from early on to the maintenance setting. And I think that would be my answer to that question. It's definitely our assets, and it's definitely our amazing team that we have here.

Okay. Great. Well, that concludes the Q&A session. Dr. Stergiou, I'll just turn it back over to you for final closing comments.

Yes. I think in conclusion, we have placed great emphasis on bringing about the next stage of value creation on behalf of SELLAS shareholders. On behalf of the entire SELLAS team, we want to express our gratitude for your continued support and confidence in our company, a matter that I and we collectively do not take lightly.

I also want to thank our employees who are most integral in our mission and for whom our clinical programs would not be possible without their diligent and tireless work. And my sincerest appreciation goes out to all our physicians, and I really so greatly appreciate our KOLs participating on this call today, our nurses, the study teams and most importantly, our participating patients and their families. It's very emotional for me many times because we get a lot of feedback from patients. And it's just great to see, and it's all we want is to see smiling faces and families that really appreciate all their support for their -- and contributions in advancing our programs. It would not be possible without them, and they're just really the cornerstone where we are today.

So really collective let us stand firm, steady and resolute knowing that we work -- that our work that we do today will really reverberate far beyond the walls of SELLAS. We're not just developing treatments. I said before, we're creating hope for those who need it the most. And together, we aim to transform lives.

So thank you once again to everyone, and we look forward to sharing further updates with you. Thank you.