Mendus AB (publ) (IMMU) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Mendus KOL event. [Operator Instructions] As a reminder, this call is being recorded and a replay as made available on the Mendus website following the conclusion of the event. I'd now like to turn the call over to Dr. Erik Manting, Chief Executive Officer of Mendus. Please go ahead, Erik.

Thank you, Tara. Dear participants, thank you for joining today's KOL event about AML maintenance therapy. The event will feature 2 leading clinical experts, Professor Dr. Uwe Platzbecker from the Leipzig University Hospital; and Dr. Amer Zeidan, who is an associate professor at Yale School of Medicine for a discussion on the current treatment landscape in AML and, particularly, the emergence of maintenance therapy. A live question-and-answer session will follow the main session, and our moderator today will be Tara Sobierajski and John Fraunces from LifeSci Advisors. My name is Erik Manting, and I'm CEO at Mendus, a clinical-stage, public biopharmaceutical company listed on the NASDAQ Stock Exchange in Stockholm, Sweden. Also present today from the company is our Chief Medical Officer, Dr. Jeroen Rovers. I would like to take this opportunity to speak a few words about Mendus' lead program, DCP-001, which is currently studied in a Phase II trial as a potential novel AML maintenance therapy. If we move to the next slide, please. As a general background to our approach, cancer immunotherapy has seen a revolution since the discovery of immune checkpoint inhibitors, which clearly demonstrated that the immune system can be reactivated and contribute to cancer treatment, even leading to cure in previously untreatable tumors. The challenge today is to find more applications for immunotherapy in cancer treatment, and we believe that AML maintenance is one of those opportunities. Tumor recurrence is by far the leading cause of cancer-related deaths. And this is due to the presence of residual disease after initial treatment. In AML, it has been clearly demonstrated that measurable residual disease, or MRD, is associated with fast recurrence and as a result, strongly reduced overall survival. DCP-001 is a proprietary immunotherapy developed by Mendus. It is based on leukemic-derived dendritic cells. Mendus has developed a proprietary leukemic cell line, which allows for scalable manufacturing. During manufacturing, the leukemic cells are reprogrammed to express dendritic cell biological markers. This renders the cancer cells highly immunogenic and suitable as the basis for vaccination. DCP-001 is an off-the-shelf product, which is administered via simple intradermal injection and has demonstrated an excellent safety profile in multiple clinical trials. As depicted in the slide, DCP-001 is designed to improve immune control over residual disease, leading to relevant survival benefit for AML patients in complete remission. We also believe that strong safety profile so far in the clinic will contribute to its positioning as a maintenance therapy. The discussion today will set the stage for the results of the ongoing ADVANCE II Phase II trial with DCP-001 in AML patients who are in a complete remission but with MRD. The data will be presented in an oral presentation at the next annual American Society of Hematology Annual Meeting, or ASH 2022, on December 12, by the principal investigator of the ADVANCE II trial, Professor Dr. Arjan van de Loosdrecht. So please keep an eye out for the next big communication moment. With that, I would like to hand it back to Tara to introduce our first KOL session of today.

Thank you, Erik. It is now my pleasure to introduce our first speaker today, Dr. Uwe Platzbecker, from Leipzig University Hospital, who will be discussing the emergence of AML maintenance therapy. Please go ahead, Dr. Platzbecker.

Hello, everybody, and thanks for having me at this meeting. The topic of my presentation is the emergence of AML maintenance therapy, which I think is, at the moment, one of the major topics studied within clinical trials for AML patients and I think is probably the future of AML therapy for those patients achieving a complete remission. First slide, please. Next slide. So this is the current WHO classification of AML, and it's actually -- I didn't want to go through this in a very meticulous way. I just want to show you that the classification of AML has become very complex. And it's more and more a reflection of the heterogeneity but also of the biology of the disease. So I think the understanding of AML is a complex disease driven by mutation specific in the hematopoietic stem regenerator cells, I think, has allowed us to stratify certain therapies. But at the end of the day, treatment is still very homogeneous and is basically not a reflection of the heterogeneity as shown here on this slide. Next, please. So in a very simple fashion, this is the way we treat AML at this stage. Disease-specific therapy, more or less disease-specific therapy is aimed to induce a complete remission. And the, let's say, classical concept at this stage then is to offer a transplant, allogeneic stem cell transplantation to those patients below the age of 70, 75 who achieved a remission in order to maintain the remission. So this concept, of course, in the classical way was not considered to have any maintenance or any therapy after the approach or after achieving a complete remission, except for offering a transplant as a potential curative consolidation therapy. Next, please. This is just from the NCCN practical guidelines. It's a very busy slide. But what I would like to show you is that we dichotomize patients based on their ability to tolerate classical chemo or who do not tolerate classical chemo. So on the left side -- left upper side, you see chemo-fit patients where induction chemotherapy is followed by a post-remission therapy, so-called consolidation. And then patients who are not considered for allogeneic stem cell transplantation should be offered AML maintenance with Onureg, which is approved for this indication. The other subgroup of patients, the so-called chemo-unfit patients, mostly those above the age of 60, 65, 70, it's a moving target at the moment, are not candidates for the allogeneic stem cell transplantation and are offered a nonintensive or less intensive therapy. On the right side, you see the backbone of therapy, remission induction by anthracycline in combination with cytarabine, so-called 7+3, and then consolidation is applied with high-dose chemotherapy containing, again, cytarabine. Next slide. This is the recent FDA approvals in AML and just highlighting that the oral azacitidine, which was approved in 2020, is the treatment of choice currently as a maintenance therapy for patients achieving a remission by intensive chemotherapy and who are not eligible or not considered at this stage for allogeneic stem cell transplantation. Next, please. Again, at the very beginning of patients who can tolerate intensive chemotherapy, we dichotomize patients based on the presence of certain mutations. So you see AML with FLT3 or non-FLT3 mutations are treated the same way with regards to chemotherapy. So it's induction followed by consolidation, with the exception that midostaurin, a broad kinase inhibitor, also inhibiting FLT3 is given in FLT3-mutated patients during induction and also as a maintenance therapy. All other patients, non-FLT3-mutated patients, basically 70%, 75% of these patients of the overall AML population are given the chemo backbone followed by oral azacitidine. Next, please. For the unfit population, there are several options based on approval. But I think the majority of patients are currently treated with the azacitidine or decitabine backbone in combination with venetoclax. We have also recent advance for a small subgroup of patients with IDH1 mutation where azacitidine and ivosidenib can be considered or should be considered as a first-line therapy. But I think azacitidine and venetoclax are -- I think, is the major backbone. And again, this therapy is a therapy which is given as long as the patient responds. So sometimes patients are treated for many years if they don't lose the response. Next, please. So the concept of that a complete remission can be achieved in roughly 60% to 70% of fit AML patients with the intensive chemotherapy backbone has, of course, brought several opportunities after remission induction. And one opportunity to maintain a remission, of course, is allogeneic stem cell transplantation. But I would just introduce to you in the next couple of minutes, not only maintenance but also the concept of preemptive therapy triggered by minimal residual disease. Next, please. The risk of relapse of these patients achieving a remission, roughly 65% to 70% of the patients, is determined by the biology of the disease. And again, coming back to the first slide where you saw the heterogeneity of the WHO classification. This is a reflection of the biology. So the genetics, determining the risk of relapse, but also what is still left in the bone marrow when the patient achieved a complete remission, and this is so-called MRD or minimal or measurable residual disease. Next please. So the way we stratify patients after they achieved a remission is based on genetics. And you see this is the ELN classification. There was a recent also update, but I think the overall message is still the same. So you see that patients with an intermediate or adverse risk should be offered an allotransplantation because that's the optimal therapy to reduce the risk of relapse and therefore, the majority of patients having a donor are offered allogeneic stem cell transportation. Only patients with a favorable carrier type, so patients, for instance, with a single mutated NPM1 mutation can be potentially cured also by intensive chemotherapy followed by maintenance. Next, please. This is just the concept of MRD. This is the first guideline published in 2018. There has been a recent update with regards to technique. So the preferred marker for MRD detection is on the molecular level. If that's not available, multicolor flow cytometry is recommended. Next, please. Just highlighting the impact of MRD in patients achieving a remission, which is valid in every clinical setting but also in patients basically undergoing allogeneic stem cell transplantation even there MRD matters. But this is just MRD detection in AML patients prior to transplantation all patients being in complete remission. And you see the relapse-free survival for patients being MRD positive versus MRD negative. So this has become a very important certification factor also in the clinical routine. Next, please. Just highlighting why MRD becomes so important because what we can offer the patients -- the fit patients with regards to transplantation can offer a cure, but we also have to consider the risk of relapse after transplantation, have to balance it against other opportunities like maintenance therapies, for instance. And as you can see here, the ELN intermediate or adverse patients, you see the risk of relapse even after transplantation is determined by MRD at the time of allogeneic stem cell transportation. Next, please. So there is, as I said before, growing relevance of MRD in the clinical practice. Just on the left side, you see patients achieving MRD negativity with conventional therapy versus MRD positivity. So this leaves a large bunch of patients also available for maintenance or interceptor therapies in order to modulate or to lower the burden of MRD. And by doing so, to positively impact disease-free or relapse-free survival after transplant or after conventional chemotherapy. Next, please. So MRD assessment in AML is used to provide, of course, a quantitative methodology to establish a deeper remission status. It can refine post-remission relapse risk assessment. It can identify impending relapse and may also though open a window of opportunities or a window of interventions and therefore, is also a surrogate endpoint to accelerate drug testing and approval. And as I said before, there are 2 methods, multicolor flow cytometry or molecular methods, and they are used depending on the specific AML subtype. Next, please. Again, highlighting what is currently done in the clinic. So we have an AML diagnosis. Then the patient is categorized according to fitness or non-fitness. The left side, you see the fit patients induction 7+3 consolidation and consolidation is either the oral azacitidine, which is a maintenance therapy and approved or allogeneic stem cell transplantation. Whereas on the other side, chemo-unfit patients, AZA-VEN, decitabine-VEN or maybe IDH1 plus azacitidine inhibitor are continued lifelong or until disease progression. Next, please. So again, I would like to highlight in the next couple of minutes, the concept of maintenance and what is available so far with regards to data. Next, please. This is actually the first drug approved in the European Union for maintenance therapy, so-called Ceplene and combination, including IL-2. It's a little bit cumbersome administration, subcutaneous every second day. But the data available, I think, showed a strong signal that maintenance therapy with this compound actually improves not only leukemia-free survival, but also seems to improve also overall survival. The drug actually, although it has been approved. It was not used very much in the clinic due to several reasons. I think the mode of administration, for instance, and also the paucity of strong data apart from this trial, I think, prevented the widespread use of Ceplene in patients with AML as a maintenance therapy. Next, please. There are also other, of course, clinical studies available to show the impact of maintenance. For instance, this trial used azacitidine as a subcutaneous injection in patients with AML and high-risk MDS achieving a complete remission. And you see here that the disease-free survival was significantly improved by this intervention. The overall survival was not also mainly because patients received a salvage therapy upon relapse and also including azacitidine. But again, this study highlights the fact that maintenance treatment is advantageous in AML patients. Next, please. I think this trial is the backbone for the approval of Onureg azacitidine was given for 14 days and was randomized versus placebo in patients age 55 to 65 years who basically underwent intensive chemotherapy and achieved the remission and were not considered for allogeneic stem cell transplantation. Next, please. And as you see here that the study actually met the endpoint with improvement of relapse, but also overall survival. And this is just a subgroup analysis for patients who achieved a complete remission, all of those patients achieved complete remission, but were MRD negative or MRD positive. It is on the right side at the beginning of the maintenance therapy. And you see that Onureg actually improved the relapse-free survival, but the extent it did improve the survival was dependent on the presence of MRD. So even in the setting of maintenance treatment, MRD is a key factor for success and also drives the disease evolution and progression during the course of the disease. Next, please. So this is -- these are actually available data now for maintenance after allogeneic stem cell transplantation. There have been some Phase II trials, non-randomized but also randomized trials who changed the landscape and also changed our clinical practice, for instance, with sorafenib, a multi-kinase inhibitor, which I think is now commonly used, although not being approved in FLT3-ITD mutated patients with AML after allogeneic stem cell transplantation. Next, please. This is a recent publication of a trial with azacitidine as a maintenance treatment after allogeneic stem cell transplantation, which actually was not successful or did not meet the primary endpoint due to several, I think, reasons. Also recruitment was an issue in this trial. But what this trial, I think, showed is that the overall feasibility also of maintenance treatment with azacitidine after allogeneic stem cell transplantation. Next, please. This is just, again, the incidence of relapse and of transplant-related mortality, which was actually the same in both arms, either observation or azacitidine. Next. Another concept to basically interfere with the reappearance of MRD is the preemptive concept, which basically means that you don't give a flat maintenance to allcomers, but you wait for the emergence of MRD and treat preemptively in order to prevent relapse. Next, please. Just here again, showing the concept on the left side, AML patient diagnosis. You achieve a CR, patient is basically also free of MRD undetectable and then MRD evolves. And next, please. At this stage when MRD comes up, you preemptively treat in order to prevent the emergence and rise of MRD and also prevent the overt hematological relapse. Next, please. This study actually we did where we treated patients with AML after allogeneic stem cell transplantation based on MRD with azacitidine. And what we could show is actually that patients responding to azacitidine at the time of MRD occurrence had improved relapse, but also overall survival compared to patients nonresponse. This was a Phase II trial, which also showed the feasibility of MRD-triggered approaches after stem cell transplantation. Next, please. And this slide also taken from this study is about to show that the blue curve, these are the patients who were constantly monitored for MRD every 4 to 8 weeks and who remained MRD-negative without any intervention. And therefore, the study is also -- and the data are also a proof for that MRD is a valid surrogate for the biology, but also for the outcome of patients with acute mild leukemia. Next, please. So to summarize, I think in the majority of AML patients, especially fit patients, we can achieve a complete remission. The challenge is to maintain the complete remission. And the way we do it, we conventionally do it is with allogeneic stem cell transplantation or nowadays also with maintenance treatments. There's an emerging role of MRD, which can dichotomize patients into MRD negative versus positive patients and which makes also monitoring of disease recurrence by MRD, a very attractive strategy also to stratify patients. I think the 2 concepts at the moment are an MRD-triggered therapy versus a flat maintenance which, of course, requires also a stratification of patients based on their biology and their risk of relapse. And I think the future is bright. I think that the tools we have in our hands will allow a personalized treatment for every single AML patient in the future. With that, I would like to thank you and hand over to Tara.

Great. Thank you, Dr. Platzbecker. I would now like to introduce Dr. Amer Zeidan, associate professor at Yale School of Medicine, who will be discussing AML maintenance and immunotherapy. Please go ahead, Dr. Zeidan.

Yes. Thanks, Tara, and nice to be with you today. Apologies about joining late, I'm actually on the in-patient service. And there will be a little bit of overlap with Dr. Platzbecker talk on the AML maintenance side. So I actually will be focusing more on the immunotherapy aspects of -- especially on the maintenance strategy setting. If we can go to the next slide. And these are my disclosures. I have consulted for Mendus. Next slide. So these are the areas I will cover. Basically, I think, an area that I think is important to kind of always emphasize, in my opinion, is that the significant unmet clinical need in acute myeloid leukemia. And then we'll cover the maintenance MRD just, I think, very main highlights because Uwe covered this quite a bit. And then the bulk of the talk will be on the immunotherapy evolving use in acute myeloid leukemia. Next, please. So you can see here, this is SEER data. This is the largest registry for cancer in the U.S. You can clearly see here that only 25% of patients with AML are alive basically cured at 5 years, which is a functional definition of cure. Most patients will die of their disease. And that is actually significantly affected by age. You can see above the age of 60, the percentage of 5-year survival becomes very low to the point where it's almost negligible above the age of 70. So especially in older patients, we certainly need new therapies. Next, please. Next slide. I don't know, Tara, can you hear me? I don't know, the slide is not advancing to me. I don't know if it's from my computer or...

No, we also don't see it move, Amer. So I think we're...

Okay. Now it moves. Okay, perfect. So this is another slide showing similar data release that you can see over time since the 1970s until 2015. You can see to the left that the overall survival has improved gradually over time. But to the right, you can see that most of this benefit has happened in younger patients where the survival continues to go up in the Kaplan-Meier. But when you look at the right lower area, the survival really in all the patients continues to be quite dismal with a median survival of only 4 months in patients who are older than the age of 65 in the U.S. Next, please. And I think there are multiple reasons for this. One of them is that, this is real-life data that we generated from SEER Medicare, that there's a significant risk of dying from chemotherapy. And this is actually, in my opinion, much more than shown in clinical trials, like many clinical trials will tell you induction has like 1% to 2% or less than 5% induction death rate. But in this analysis, you can see that the induction death is closer to 10% in younger patients, and it could reach up to 25% in older patients. So intensive chemo, while can cure some patients, certainly is very toxic. Next, please. And the development of hypomethylating agents has certainly helped patients improved quality of life, led to some objective responses. But you can see, again, in real-life analysis, the median overall survival that you get with HMA alone is really 8 to 9 months with no significant difference between the azacitidine and decitabine, so very minuscule improvement with those agents by themselves in older patients. Next, please. And what that has led essentially in the U.S. for a long time and this data up to the year in 2015, so it might have changed more recently with new drugs. Many older patients in the U.S. are not even getting treatment altogether. They just get transfusion support, antibiotics, but many of them, especially in smaller areas, you can see the blue part of the curve, the number of patients who are not getting active treatment has been dropping over the years. But as soon as the year 2013, more than 40% of patients are not being treated. So I think there's a big opportunity to treat and help these patients. Nex, please. And of course, things have started to change as Dr. Platzbecker showed you. I think one of the biggest developments have been in older patients, especially the introduction of venetoclax. You can see here the VIALE-A and the VIALE-C, the pivotal trials where the overall survival was improved, clearly, a very important development. But again, in big picture, even in VIALE-A, you moved the overall survival from 9.5 months to 14.7 months, so 15 months. So still most patients are either not responding or they respond, they relapse very quickly. And there is, I think, a lot of need to build up on the venetoclax-based treatment, especially for older patients. Next, please. And even for patients who are younger or patients who undergo bone more transplant, while we think of transplant as the only way to cure many patients with AML, the reality of things is that even patients who go in for remission and undergo transplant, the most common reason for death is relapsed. So even after transplant, you really need some strategies where you can keep the patient in remission. And I think this is an area that is significantly under capped. And currently, there is actually no approval -- no approved therapies as a maintenance strategy after bone morrow transplant. Next, please. And other reasons, I think while we have not done so well for many years in acute myeloid leukemia is that we treated all patients the same way either 7+3 or hypomethylating agents, but we realize that AML has a lot of biologic heterogeneity. And those patients behave differently and their therapies should be really adapted accordingly. And that's starting to change now. I think the treatment of AML is becoming more complicated. I think Uwe showed you a very nice diagram of how things are evolving. Next please. And also our understanding of what remission means. This is a quote from one of my previous mentors at Johns Hopkins. We always talk about complete remission in acute myeloid leukemia, but there is really nothing complete about complete remission because most of those patients still relapse. And while we talk about minimal residual disease, it has been suggested should be called measurable residual disease because, again, there is nothing minimal about it. Most of those patients will still relapse. And I think that there is increased recognition that how we define endpoints is evolving, and we should focus more and more in defining MRD-negative CR really as the real way to define like true response to a treatment and for those who are positive to convert them to negativity. MRD testing, as you have heard from Uwe, is not perfect. Certainly, there are patients who are MRD-negative who still relapse and there are patients who are MRD positive who do not relapse, but I think that's probably largely to the different subsets of how we -- or the different ways in which we measure MRD. So we need some improvement in measurement from MRD, but I think the direction over the next 10 to 15 years is more focus MRD targeting. And I think the regulatory agencies are also going in that direction. But clearly, we need more prospective data and better standardization of the approaches, which actually is being done these days. Next, please. Those I'm not going to discuss in detail again because Uwe showed you this data from the approval of the oral azacitidine, the only approved maintenance treatment really currently post-chemotherapy in all their patients. And the reason why I wanted to show you this figure again is that even among patients who are MRD negative, it seems that they get helped by oral azacitidine. And I think the way I take this is that our assays are not perfect, but that everybody with AML, in my view, should be treated with maintenance -- some kind of maintenance strategy because even if they are MRD negative, many of them still relapse. The question, of course, is finding therapies that are not toxic that can be used for a long time, that can be effective and reduce the relapse risk. And this is what a lot of the field is currently focusing on. Next, please. And even among the aza-ven treated patients, and I'm showing you this because for a long time, MRD data has been mostly among intensively treated patients, those who received intensive chemotherapy. But now we also realize that even among patients with aza-ven, for example, or lower intensity treatments, MRD positivity continues to be an important predictor of relapse and very prognostic. And I think one of the important development routes is building on aza-ven is trying to increase MRD negative CR and I think potentially that will translate into less relapses and longer survival of those patients. Next please. So here, I'm going to spend the next 10 minutes talking about some of the immune development in terms of immune therapies for acute myeloid leukemia. This is clearly a very complex area. I think it would require like at least an hour just assessing all the details. So I'm going to focus mostly on some of the major highlights and some of the direction of the field. So I think immune dysregulation has been clearly a big component in the pathogenesis and progression in acute myeloid leukemia. We know that those patients have dysfunctional microenvironment, dysfunction in the effector T cells, increase in the expression of inhibitory molecules, immune checkpoint pathways as well as the regulatory T cells and dysfunctional NK cells. And this has been shown again and again to be associated with worse outcomes and higher relapse rate in patients with acute myeloid leukemia. So certainly, it provides a lot of rationale to intervene on the immune component. And bone marrow transplant is the most effective way. It's really an immunotherapy. So I think there is a lot of rationale to target the immune system. Next, please. And there has been different ways. This is like just a general summary of like the different ways in which you can target the immune system. I'm showing you here basically 2 big areas. One of them is cellular therapies, and that could include T cell therapies, chimeric antigen receptor cells and NK cell therapy approaches, but also antibodies. And I'm going to discuss some of those in more detail in the next few slides. Next, please. So targeting AML with antibodies. So there are 3 ways in which antibodies generally can be used to target AML. One of them is to use them as a vehicle to deliver either chemotherapy or radiation really. And those are antibodies drug conjugates. The only one that's currently approved in AML is gemtuzumab ozogomycin, which delivers calicheamicin to CD33-positive cells. The others are all investigational. Iomab is undergoing a Phase III trial. This is a CD45 radioimmunoconjugate. And then you have other antigen CD33 and CD123 targeted antibodies. And then you have the bispecific T-cell engagers, which are -- have been quite a success in b cell acute lymphoblastic leukemia with blinatumomab approval but they have been tested in AML, and you can see some of those antibodies that have been most advanced in clinical trial testing in -- to activate the T cells against a specific leukemia cells. I'm going to discuss later in the talk why I think many of those agents have had problems or have not been taken to approval based on the results. Next, please. CAR-T cell therapy is the other type of targeting using, what I call, living therapy because one of the biggest advantages in CAR-T cell therapy is that doses could hang around and they could lead to a prolonged and sustained remissions. Again, for the sake of time, not going to go through a lot of details of how these are made and manufactured and the different generations of CAR-T cell therapy development. Next, please. But I think the main highlights, and this is showing you some examples of those slides. But the main highlights, I think is that using an external T cell that can overcome this host immune tolerance that is present in the microenvironment of many patients, and it can lead to direct plus cell killing that is independent of the MHC complex. The main challenges that we have seen across immunotherapy for AML really, in general, is the lack of universal leukemia-specific antigens. We don't have those holy grails, like the antigen that you can knock out only in leukemia cells or you don't have the dispensable antigens. For example, in B cell acute lymphoblastic leukemia, you can get rid of all the B cells using the CD19 targeting. And you can live almost completely normal with IVIG replacement, but you cannot do that in the myeloid compartment because you have prolonged myelodysplasia and recurrent infections, neurotoxicity and cytokine release syndrome and manufacturing challenges also have plagued this area. So it really has stalled compared to lymphoid malignancy development and even multiple myeloma potentially. Next, please. Vaccine strategy is another, I think, area that has received a lot of attention historically in AML. And there generally has been 2 ways of using anticancer vaccines, peptide vaccines or dendritic cell vaccines. And the most commonly targeted antigens have been the Wilms tumor and the PRAME. Next, please. And these are some of the trials that have looked at those antigens. I think the main issue that many of those trials have suffered from, again, is the lack of universal antigen that you can target that is leukemia specific, but not present in normal cells. But I think the bigger issue in my opinion, is that many of those patients, as I mentioned, their own immune system is very dysfunctional, and it's not easy for them to respond to external antigens. And I think one of the best areas to try to improve on this is how you can make sure you stimulate either internally or externally, how you can need to lasting responses to these vaccines. Next, please. Immune checkpoint blockade in myeloid malignancies is an area that I actually have done most of my kind of work in myeloid malignancies. And there are a number of those antigens that have been targeted in solid tumors and also in myeloid malignancies. Next slide, we can go to -- actually can show you some of the early data that we have used, for example, using ipilimumab, which is approved in melanoma. We used it in refractory MDS. We have not seen success with ipilimumab as a monotherapy. And we generally have not seen a lot of success with what I would call the kind of the traditional immune checkpoint inhibitors against PD-1, PD-L1, CTLA-4, which has been difficult to kind of fully understand compared to what you see in some of the immune sensitive solid tumors, such as renal cell or melanoma. Next, please. And for example, in the study that I just showed you, when we use ipilimumab, we did see increased frequency in ICOS and some evidence of immune stimulation, but that did not translate into responses in most patients. Next, please. However, other studies, for example, the study from the MD Anderson, this suggests that adding nivolumab, for example, another PD-1 inhibitor to azacitidine, did seem to increase the response rate. However, this was a single-arm study without a control arm. And I think this is one of the issues that plagued the development, in my opinion, in many immunotherapy trials for AML and MDS is that you don't have control arms to fully understand not only the clinical activity but also at the biology level, what's actually happening when you add an immune therapy intervention. Next, please. So we actually conducted the first randomized clinical trial of an immune checkpoint inhibitor, both in AML and MDS. This is the durvalumab, the anti-PD-L1, which is an approved immune checkpoint inhibitor in multiple solid tumors and have improved survival in some of them. This was added to AZA in a randomized trial. I'm showing you only the AML part here since this is a focus of the talk today. Next, please. And here, you can see you don't need a p-value to tell that those survival curves completely overlap, the progression-free survival and overall survival. And there was no difference in responses as well with the addition of AZA -- durva and AZA. And this study actually, one of the areas that I've been kind of, when I were sponsor, I've been pushing on is that when you develop these immune checkpoint inhibitors, in my opinion, you should really focus on things like MRD-negative CR because -- quick like responses might not fully capture what you are getting from an immune checkpoint inhibition. But also in this study, the follow-up was short. And what we know from solid tumors is that not everybody response. You could have a tail at the end of the curve. So you really need to have longer follow-up in those patients to understand the full effect of whatever immune intervention you are using. So trying to look at things just by overall response rate and minimize follow-up like what happened in this study can be counterproductive. Next please. And actually, for the sake of time, I'm going to skip through like some of those slides, some of those details about the study, and I'm happy to take it in questions about why we think this drug did not work. But the bottom line, we did not see significant immune activation with adding durvalumab to azacitidine. Next please. And we did not see any specific subsets of patients that responded. For example, TP53, you might be aware is a subset that has significant unmet need, and there's a lot of efforts to develop drugs in this space. But we also did not see specific response with adding durvalumab there. Next, please. We actually have developed other trials in this setting, for example, adding entinostat with pembrolizumab based on the idea that entinostat can knock down the myeloid-derived suppressor cells, which have been shown to affect response to immune therapy. And this is a trial that we have conducted in collaboration with Leukemia & Lymphoma Society and CTEP still ongoing. Next, please. Another area where I think there has been a lot of interest, and I've been advocating our pharma kind of collaborators to focus on is adding immune interventions to AZA-VEN because for a long time, there was concerned that venetoclax can kill the T cells and can antagonize an immune intervention you are doing. But what actually has been demonstrated in this nice paper from Cancer Discovery is that venetoclax seems to enhance activity of immunotherapies such as anti-PD-1 and murine tumor models. Next, please. And based on this, we actually have -- we have developed 2 studies that we are conducting within the cooperative group mechanism here in the U.S. using the CTEP mechanism, one randomized study in which AZA and VEN are being combined with pembro. And you can see here that the primary end point is MRD-negative CR. As I mentioned, I think MRD-negative CR is -- could be the area where you can get the most out of immune intervention. It might not increase your overall or CR rate, but it might deepen the response in some of the responding patients, and that might correlate with long-term responses. Next, please. And this is a sister study combined with intensive chemotherapy. So this is 7+3 with pembro or 7+3 alone. Next, please. And as I mentioned, I think one of the problems with MRD assessment is probably the issues of standardization and the issue related to the depth of what you are measuring. So in those studies, we are collaborating with Jerry Radich to do central MRT assessment. And he's using actually also duplex sequencing, which is a very sensitive way, error-corrected way of measuring MRD beyond what you get typically with next-gen sequencing. So here, you can go up to 1 million level of sensitivity. And again, I think this is the model that I think those studies should be done in central assessment of MRD at using very sensitive assays. Next, please. I'm going to skip through these slides for the sake of time, but sabatolimab is an anti-TIM-3 novel immune checkpoint inhibitor. This is the similar AML study that was presented in EHA. Just for the dose-escalation part, you can see the results in the next slide. Only the first 18 patients on this study were presented in EHA, just the dose escalation. This study now has fully accrued. It has close to 90 patients, and I think it will give good information. And you can go to the next slide. You can go to the next one actually. The other one that, I think, is driving a lot of excitement is the field is targeting CD47, that don't eat me pathway basically where it activates the macrophages against MDS and leukemia cells. And it seems that there could be a specific signal within TP53. You can see in the next slide, if we can go to that the rate of MRD rate of responses is high, and many of those patients have cleared their MRD. So half of those CRs are achieving MRD negative CR. Again, the caveat here is that this is a single-arm study without a control arm and with limited short and small number of patients. But certainly, this drug is generating a lot of excitement. And there are three different randomized studies that are ongoing in AML and MDS with this drug macro. Next, please. So this is my last slide. I mean it's a busy slide, but I think it summarizes many of the points that I mentioned earlier is that I think immunotherapy in AML offers a great opportunity, but there are many challenges with it. I think the biggest opportunity is that those drugs generally are easier to take than many of the chemotherapies. I think maintenance approaches, in particular, require you to give something that ideally, it's not given every day. It's an injection every 3, 4 weeks, that is easy to tolerate, and many older patients can take it. But at the same time, I think how we went -- [ part ] development has been challenging because those are rare tumors. We know that in solid oncology tumors, they test like a very large number of patients, like 500, 700 patients so that they can pick up using biomarker-directed strategies, which are the patients who are more likely to respond. And this is very difficult to do in rare tumors such as MDS and AML, and that resulted in many single-arm trials with mixed patient populations, relapsed, frontline combination monotherapy, very difficult to get like specific conclusions from. And I think the management of the immune-related adverse events is a little bit tricky in AML. Again, I'm happy to talk about this in the Q&A. But I think the biggest challenge has been really defining these holy grail oral antigens that are only present in the tumor cells universally and without harming the myeloid compartment, and I think the development strategy, in my opinion, should focus on early line intervention because we know that T cell fitness decreases significantly with subsequent therapies. And in settings where you have minimal antigen burden, I don't think these drugs will work as monotherapies or in patients who have a lot of disease. And it should be also biomarker-driven selection of patients because the same way you think about FLT3 or IDH2 positive patients in AML, I think this is how we have to think about immunotherapy. It's not going to well for everybody. We have to figure out how we can pick up the patients who are more likely to respond then. Sorry, I think I went over time, but I wanted to show as much data as possible. Happy to take any questions. Thank you.

[Operator Instructions] So our first question comes from Jacob Mekhael from Kempen.

I had a few. So I think the first one is, why do you think immune checkpoint inhibition has not worked so far in AML? Is it just on the trial designs have not worked so well? Or is there an underlying biological reason for that? And then my second question is, how do you think the AML maintenance space will develop in the next 5 years or so? And what are the factors that will determine the success of certain treatments over others? And just one final one on -- just on your personal opinion, what you think the best promising immunotherapy strategies in your view?

Yes. Maybe I can take the first question, and Uwe can talk about the maintenance part. And Uwe clearly has done a lot of immunotherapy work as well, so he can probably also add to the first question in response. So I think I kind of covered some of the main, I think, aspects that I think have led so far to kind of lack of response. I think the biggest problem, in my opinion, is the design of the studies. I do think that because we have rare patient populations, it's not easy to enroll those huge number of patients so that you can pick up the subpopulations that more likely to respond. I think at the biology level, it's not likely that all of these pathways will work. So I think also identifying the right pathways that PD-L1, PD-L2, is it, for example, some of the newer ones, the TIGIT, the Lag-3, all of these are going to be important to kind of evaluate. Clearly, the magrolimab and the TIM3 are also other exciting ones. And there are some challenges, I think, that are somewhat unique to my leukemia development. For example, management of immune-related adverse events, it's not easy for us to biopsy our patient. The patient has come with, for example, with a pneumonia, which is very common in AML, many times as fungal pneumonia. We cannot do a biopsy and then someone says, oh, this is pneumonitis and it counts as a toxicity on the drug when it's potentially fungal and not really pneumonia. We are also cautious about giving steroids, for example, in those patients because of those risks. So I think that can make some of those drugs, in my opinion, appear more toxic than they are in reality. So I think it's a mix of things, patient selection, not having biomarker-driven strategies, experience of leukemia doctors in handling those types of therapies. Our solid tumor colleagues do much more of this as standard of care. But clearly, in our world, we don't use in standard of care. So some degree of experience is needed and better understanding of the biology is -- all of these are important, but I'm also interested to see what Uwe thinks.

Yes. I think adding to that, I would I would like to state that there are 2 areas, I would say, of research at the moment in 2 directions. Number one is to better define patients require relapse. I mean, there is a considerable amount of patients, especially after stem cell transplantation, who may be overtreated just by a flat maintenance. I mean it's the same like what we -- maybe not the same but comparable to breast cancer adjuvant therapy for everybody. And now we know that maybe with novel techniques also in solid cancer, you may omit maintenance or adjuvant treatment in some patients with solid cancer. I think the same is true here for AML that to better define the subgroup of patients who are at a high risk of relapse will also better define trial design with valid endpoints because, I mean, maintenance is a treatment indefinite therapy and sometimes relapse occurs, I think, quite late. But I think we need to define the patient population at a very high risk 1 or 2 years after completion of therapy, who may benefit from such a treatment. Number two is we have an approved maintenance therapy, which is Onureg, oral azacitidine, at the moment. And I think this is -- I mean it's still azacitidine. It's not a magic bullet. And it's -- there is -- so far, even for patients getting subcutaneous azacitidine, there is no biomarker available for response for patients getting azacitidine treatment. And the same is actually true also for the oral formulation. So I think -- but still we need to start from there because this is what we have in our hands. And there are -- currently, there are trials with the addition, for instance, of venetoclax as a maintenance therapy, adding AZA plus venetoclax as a maintenance therapy, not only after conventional chemotherapy but also after stem cell transplantation and other studies, which I think take advantage of this backbone. But I think Onureg is not the answer to everything. And as you have seen, in the slides before, it is a maintenance and a successful maintenance for a subset of patients, but the majority of the patients basically still do relapse. It just delays the time to relapse. So -- but coming from there, I think we need to improve this or maybe substitute Onureg or azacitidine with more specific agents for a -- maybe also still to be defined subset of patients who may benefit from other interventions. I think this is the current landscape in maintenance therapy in AML.

Our next question comes from Christian Binder from Redeye.

To start with, could you maybe discuss a little bit more? Looking at different immunotherapies in hematological diseases, you have, for example, stem cell transplant or CAR-T cells where you add something external? Or in the case of CAR-T cells, you remove the cells and you stimulate them, or you have other treatments like different antibodies, checkpoint inhibitors, et cetera, where you stimulate the patient's immune system. But you kind of touched on the problem with immune dysregulation, immune suppression, et cetera. So can you discuss a little bit more which kind of treatment you think is more promising?

Yes. I think this is, again, a good question. I think it's very difficult at this point to kind of provide the specific answer. I do think the biggest issue is removing the inhibition within the microenvironment of the specific patients. So I think the easiest way to do that potentially is to get external sales like CAR-T cells, for example, or could be NK cells or some other external like cells that are already active. However, the problem, as I mentioned, I think these treatments have been associated with significant toxicities, especially in the prolonged myeloid aplasia. So using them basically in myeloid malignancies, in my opinion, currently, it's going to be either as a brit transplant, which is clearly not ideal, or if you want to use them without transplant, I think you have to have a way in which you can kill these like inserting suicide genes or some other way. And the manufacturing difficulties and all of that is going to make it very difficult to use these like on a wide scale. I think the easier way and I think that's something that could help the population -- and a bigger impact would be ways that are -- that does not involve CAR-T cells because I think those could be relatively easier to give in the community. And I think figuring out how to activate the immune system internally for different patients, so it could end up being a combination of some of those strategies. For example, a bite cell with an immune inhibitor or some other way to stimulate the immune system so they have a patient who respond to a different strategy. Eventually, the answer to all these questions, I think, are doing more clinical trials and better understanding not only of the biology, but the different subsets. I mean I think the biggest probably -- one of the biggest problems, as I mentioned, is treating all these patients the same way when there are different subsets of patients.

All right. Got it. And then another question when it comes to MRD measurement. You talked a little bit about current methods are not particularly sensitive or not sensitive enough. There's at least an indication that even the patients that are supposedly MRD-negative apparently still harbor some residual disease. So do you think the ultimate solution will be to develop sufficiently sensitive methods? Or do you think the more pragmatic solution will be just for everyone with maintenance?

Maybe Uwe, do you want to take this?

Yes. I think for the moment, maybe the latter is what we would prefer, the latter, meaning a flat maintenance to everybody because I think even after cancer transplantation, roughly 30% to 40% of the patients do relapse. And if you have a tolerable maintenance therapy in your hand, which is applicable and tolerable for a long time after transplant, for instance, or even after non-transplant, I would favor your suggested way of treating everybody in the absence of clear biomarkers of MRD for every patient. I think this is quite clear. On the other side, you may say that maybe -- I mean, the MRD assessment at the time of start of therapy may be one part of the solution, but it could be also that disease biology and markers at the time of diagnosis and the subsequent treatment may also help you to guide and to make a decision on which patient population actually is at risk of relapse and may require a subsequent maintenance therapy. But as long as this is still unanswered and cannot be personalized for every patient, I think you are right that a flat maintenance with an agent or with a drug which is tolerable, and can be given for a long time, I think, is the treatment of choice for the moment.

Okay. Then one last one. You already talked about -- a little bit about potential combination therapies with checkpoint inhibitors. So I wonder whether you could just elaborate a little bit more on the potential prospect of combining a cancer vaccine in AML with checkpoint inhibitors, whether you could have any statistic effects there generally about the feasibility, so to speak?

Yes. I mean, I think this is one of the areas that I think should be explored further because I think one of the biggest problems with the vaccine has been like the lack of list good responses in some patients. So I do think that immune thin inhibition might be a good way. However, again, I think rather than blindly combining this kind of together, I think there has to be more kind of rational approach about how do you do it and what's sitting, what subsets of patients. But I do think combining different immunotherapy intervention is probably one of the ways in which it can help more in myeloid malignancies.

This concludes the verbal portion of our Q&A session. I'll now turn it over to John Fraunces from LifeSci Advisors to read the remainder of the question.

Thanks very much, Tara. The next 2 questions come from Arvid Necander of Carnegie. And the first is directed to Dr. Platzbecker. What do you argue should be the primary end point in a pivotal trial in AML maintenance? And what do you view as a clinically relevant improvement?

Yes. I think that's a very important question. And I definitely think that the endpoint should contain relapse. it could be, of course, a combined endpoint. But I think event-free survival with a major part being the relapse, I think, is what we would call clinically relevant. Of course, the patient selection in such a trial is very important. I would design a trial with a given therapy, I would select the patient population with a very high risk of relapse in a given time period. You have seen before in our presentation that there's a diversity of the time to relapse with a wide range also based on the biology and on the depth of remission and also the presence of MRD. So I think event-free survival with a highly selected cohort of patients, especially if you have a very targeted therapy, which is maybe highly selective for a certain gene or a search in a certain biological pathway, I think, could be the design of choice.

Okay. The second question is -- and this is directed to Dr. Zeidan. Are there any other clinical-stage therapies that you believe could have practice-changing potential in the persistent MRD setting?

I think there is like a lot of drugs that are currently being tested in AML, clearly, the immune interventions that are most advanced currently, which are in Phase III testing are mostly in the MDS space currently are the TIM-3 inhibitor, sabatolimab, and CD47 targeting agent, magrolimab. And magrolimab also has a randomized to randomized Phase III trials in TP53 mutated AML and one with a triplet, AZA, VEN, magro. In terms of other Phase III trials that are ongoing with immune intervenions, one of them is Iomab trial using that CD45 immunotoxin. But aside from that, as far as I know, most of the others are still in Phase I and Phase II. So clearly, if any Phase III trial is -- most of it would be the kind of the closest to changing practice, but others, I think, have some long way to go.

Okay. This next question is really directed or both or KOLs. And first, they begin by thinking for the great presentation. So obviously, very well-received. But the question is, they would like to hear from the KOLs their thoughts on the use of Mylotarg and its benefit/risk in clinical settings.

Amer, you want? Should I?

Yes. I'm happy to start. I think I suspect this is a physician since it's a clinical question. I think gemtuzumab is clearly that has -- and the way we use it here for us or let me backtrack. So there are three approvals in the U.S. It's combining it with about 7 plus 3 for patients who have core-binding factor leukemia, adding it or using it as a single agent in refractory relapsed setting, and I would say that this use as a single agent does not work very well in my opinion. So I rarely use it as a single agent in refractory relapsed setting most of my use of it or as a single agent in frontline older patients where it has an approval, but we always use AZA-VEN in that setting. So the only use, I generally do it is as part of induction with 7 plus 3. And you usually use it in patients who are core-binding factor leukemia positive because this is where is the biggest survival advantage has been seen. I think if you do it in the right setting, it's generally well-tolerated. We don't see toxicity. Many of those patients don't go to transplant because they are core-binding factor leukemia. So we don't see a lot of VOD or other problems. But certainly, you could see liver issues or other things. But generally, it's a very -- in my hands, very well-tolerated drug. The cost is, I think, is the biggest issue in it.

I fully agree. I would just add that at least in Europe, I think we would also give it to concomitantly to induction chemotherapy or intensive chemotherapy to patients with NPM1 mutations, not harboring flat mutation, where also the benefit of adding Mylotarg to conventional chemotherapy has been shown. But again, it's -- I mean it is considered to be immunotherapy, but it's rather a chemotherapy, which is basically brought to the cell of interest and is, I think, one of the first steps start immunotherapy, but I think rather a drug which is only valid for a highly selected cohort of patients. And I think further developments are needed. Also, the CD33 as an antigen is not targeting early progenitor cells. So it is a drug which targets the majority of leukemic cells, but may not be curative as a single agent.

Okay. This next question is for Professor Platzbecker. I've shown there appears to be a clear and higher risk of relapses in patients with MRD before and after a bone marrow transplant. So will there be a need to reduce or eliminate residual disease before going into a transplant procedure? And if so, what kind of treatment modalities would be useful for this?

Yes. I think this is the paradigm currently also for transplant physicians because all the retrospective data show that the presence of MRD prior to translates into poor outcome after transplant. On the other side, the conclusion that simply eradicating MRD prior to transplant may improve outcome after transplantation may be only half of the coin because the presence of MRD prior to transplantation is a reflection of the disease biology. And so I think if you are not able to eliminate MRD with the current means, with the current therapies, I think it means that there is some residual stem and progenitor cell, which is left still in the bone marrow and which even if it's measurable, I think it means sometimes that you can cure the patient because with the application of bone marrow transplantation afterwards chemotherapy. Also the immune effect, so-called grafters leukemia effect, is able to do that. So in general, I would agree, but I think this requires really targeted therapies, which are a reflection of the biology of the disease. And I think these kind of therapies are currently in development.

Okay. And final question directed to Dr. Zeidan. With oral azacitidine currently showing an improvement for AML maintenance post chemotherapy, do you feel there are needs -- there is a need for additional products in this space?

Yes. I think for sure, I think the biggest area is really in the post-transplant setting in my opinion, because we still go to transplant for many of our patients who can go for it and many of them, as we discussed the relapse. The problem with oral azacitidine in my opinion is it's a very not space. It's very -- it's not easy for us to find those patients because it has to be someone who has got an intensive chemotherapy, who's all but who cannot go to transplant because some complication or some other reason happened during their induction or consolidation. So those patients are not that easy to kind of find it at least in my practice. I don't know if it's different in other in other settings. But I think both transplant is a very important area. And also, I think maintenance strategies after, for example, AZA-VEN or other lower entity strategies, how can we -- for example, deescalate the treatment, can we continue the VEN alone? Can we switch to oral AZA with VEN after? Because one of the problems that come with, for example, with AZA-VEN is that for patients who are responding very well is that they don't want to come every week -- sorry, every month for 7 days to get injections. And so I think going for oral therapies in this space or something that does not require you to come repeatedly, maybe like once every 3, 4 weeks in addition to [indiscernible] or just by itself, I think, would be logistically very good developments.

Thank you for that perspective, Dr. Zeidan. That's all the time we have, and I'm going to turn closing remarks back over for Erik Manting. Erik?

First many thanks to Dr. Platzbecker, Dr. Zeidan for making precious time to be part of this KOL event. Thanks to LifeSci, thanks to all the participants for what I believe was a very high-quality event. When we entered into AML with an immunotherapy approach, we realized that we are entering a very tough field. And I think also today, it became clear that it's not an easy task to find effective not addressing AML and more particular AML maintenance. We know one thing for sure, which is that if we stop trying, we will never succeed. And I think that was a key message that was conveyed by the both of you. So we are very grateful to doctors like yourself and other doctors we work with to patients that are committed to the field and to continue to find new ways to address the high medical need of AML maintenance. We very much look forward to ASH to our own data, to data by others and hopefully, we'll continue to find new ways and to find new impulses for the field and hopefully also to see the both of you there in person. Thanks so much.