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

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

Thank you, Tara, and welcome, everybody. Today, I'm joined by our Chief Medical Officer, Jeroen Rovers; and by Professor Dr. Aart van de Loosdrecht from Amsterdam University Medical Center, who is also the Principal Investigator of the ADVANCE II Phase II trial and who will assist us in presenting the data that we earlier this week presented at the American Society of Hematology Meeting in San Diego. If we look a little bit tired, it's because we just came back from San Diego, but we're more than happy to share with you the exciting data we presented at ASH. We are a public company, so please be aware that we will be making forward-looking statements. Mendus is about pioneering cancer maintenance therapy. Cancer recurrence or relapse is the major cause of cancer-related deaths. And we are addressing that by trying to prevent or delay tumor recurrence with products that are based on our unique expertise in dendritic cell biology. Our lead product, vididencel, is designed to boost immunity against residual disease in acute myeloid leukemia, and we have reported positive data out of a monotherapy trial in AML in patients with measurable residual disease. And that is also the basis for us to expand and continue the development of vididencel in AML. Today, we will obviously present you the latest update, which we also presented earlier this week at ASH. As further progress we realized this year, we closed an alliance with the Australasian Leukemia & Lymphoma Group, ALLG, to [ perform ] a next trial with vididencel in combination with standard of care with oral azacitidine, and we have put in place a manufacturing alliance that will allow us to scale up the manufacturing of vididencel for pivotal stage development and in the end commercial launch. We have an additional trial ongoing in ovarian cancer, which is also disease characterized by a high rate of tumor recurrence, and we have additional programs based on intratumoral priming and the preclinical NK cell program. About Acute Myeloid Leukemia, AML is a highly aggressive blood-borne tumor that can actually only be reduced after it's been diagnosed with high-intensity chemotherapy. After that initial chemotherapy, there is still a very high chance of the disease recurring. And the only way to deliver a curative approach today is a bone marrow or hematopoietic stem cell transplant. For all those patients not being able to undergo a transplant because of age or health or [indiscernible] not being available, there was not a real treatment to stabilize those patients. And particularly patients with measurable residual disease, which is a remaining amount of cells, disease cells that can be picked up by sensitive molecular methods like flow-based cytometry or PCR, the chances of relapse are very high. In fact, disease relapse remains a major barrier to long-term survival in acute myeloid leukemia. Maintenance therapy is something that could address that major challenge. One very important element of maintenance therapy is that it has to be safe. Patients have already undergone very harsh treatment to reduce the disease into a state of complete remission. But again, if there's residual cancer cells that will lead to relapse, they will have to be treated. But you cannot treat such patients for a long period of time with toxic treatments basically that harm the patient's health and quality of life. Immunotherapy, which boosts the patient's own immune system could deliver a very promising alternative. However, so far have been that the development of immunotherapies in AML has been unsuccessful. And this is where we are developing vididencel, which is designed as an active immunotherapy, so an immunotherapy that's designed to boost the patient's own immune system to improve the immunity against residual cancer cells and thereby prolonging disease-free and overall survival. Why do we believe vididencel has a competitive product profile? Vididencel is based on the concept of reprogramming leukemic cells, so originally cancer cells to express dendritic phenotype. Dendritic cells are orchestrators of the immune system. They are very good in stimulating other immune cells, whereas cancer cells are not. But by combining the cancer cell biology with the dendritic cell biology, we can design a product that is very effective in triggering the immune system against cancer cells. A big difference that we believe we can make as a company is to capture this concept in a way that it can be manufactured. So we have developed a proprietary cell line in a proprietary manufacturing process that allows us to produce a product based on leukemia derived dendritic cells in a scalable way. Also very important because the product is cell line based, we can manufacture it in advance and store it as a frozen product so that the product is immediately available for patients when they need it. And unlike other cell therapies is not dependent on, for example, first [indiscernible] patient material. Also, the product is administered by intradermal injection, which means an injection into the skin where there are a lot of immune cells, and we'll see some examples further down the presentation of what that means, but the skin is a very good place for vaccination, and it's also a very safe side of administration. What we have demonstrated in the past is that vididencel, our lead product based on these leukemia derived dendritic cells is able to stimulate very strong immune responses in vitro and in vivo, so in-patient material. And it is a well documented mode of action that involves the patient antigen-presenting cells to stimulate the immune system against residual cancer cells. The product-related side effects are limited to injection site reactions. So as soon as we inject the product into the skin, it triggers a strong local immune response, which results in redness and swelling but that's a transient phenomenon and is currently the only product-related side effect we have observed with the products. And finally, we have built up an extensive regulatory dossier, including orphan drug designations in the U.S. and in Europe and recently Fast Track designation in the U.S. So all in all, we believe vididencel has a competitive product profile because of its nature, which is to induce strong and also durable new responses combined with a good safety profile, and we have, as a company, translated that into a manufactural product with an extensive regulatory dossier. So with that background introduction, I would like to hand it over to our Chief Medical Officer, Jeroen Rovers, to summarize what we have presented at ASH.

Yes. Good afternoon, and thank you, Erik, for the introduction. So at the American Society of Hematology Annual Meeting, which was just held this week in San Diego in the U.S. that we were able to present 3 different abstracts, so 3 different parts of the ADVANCE II study. First of all, on the Sunday, during the poster presentation, we were able to present 2 abstracts. One was 2957 and that's an abstract we dealt with the assessments and analysis we did on the peripheral immune responses. So we represented the data there from flow [indiscernible] analysis of the different subsets of the immune cells and looked at the changes with the treatment with vididencel induced. All these posters, by the way, will be available on our website for people to look at the details, and we will not describe the details of these specific posters during this session. The second poster, which was presented was abstract number 2942, that was a part of the study where we looked at the immune responses triggered by vididencel treatment locally in the skin. So when we inject the product, there is a reaction of the immune system in the skin, which is basically the trigger of the whole cascade of the immune response we intend to induce in these patients. That is data, which was generated by the Haukeland University Hospital in Bergen, Norway. And that in-depth analysis of the local interactions between the different immune cells, which take a role in the response to the injection of vididencel. And so I urge you for more details to look at the website and look at these posters. And on the Monday morning, there was an oral presentation by Professor Dr. Aart van de Loosdrecht, which - who is present during this call and we will go through that data, which was presented there, which dealt with the clinical update of the ADVANCE II study. Next slide. And it's a pleasure that Aart van de Loosdrecht is be able to join us and like Erik said, we just returned from San Diego and sometimes either tired or suffering from small viruses, but luckily, he's able to run you through. Professor van de Loosdrecht is a Professor in Hematology at the University Medical Center in Amsterdam. He's a staff member of the Department of Hematology there and he's a Project Leader for preclinical and translational immunotherapy programs, both in myeloid leukemia [indiscernible] AML but also in myelodysplastic syndromes. And he's a Chair for the working group for myelodysplastic syndromes [indiscernible] cytometry where a lot of work goes into the implementation of flowcytometry assessments in MDS, and he is also the Chair of the Sharing Committee of the International Working Group for the prognosis of MDS. We're happy that he has been the leading physician to start and lead this trial, which we kind of presented data now, the ADVANCE II study. And he's been working on vididencel for a long time. So he's the expert, I would say, and it's my pleasure to hand it over to Aart van to run you through the presentation he gave on a Monday in San Diego. So Aart van, be my guest.

Thank you, Jeroen, for the kind introduction. And I'm also very happy to go through the slides we presented just Monday at the ASH meeting, as I said. So I go through the data to show you the induction of the cellular and humoral immune responses that is associated with the durable remissions in patients with AML, but measurable residual disease positive showing that by these maintenance treatment with leukemia dendritic cell vaccine, vididencel, we had major [indiscernible] remissions as well as in immune response. Next slide. As already introduced by Erik, it's not a problem at the moment to have complete remissions in patients with acute myeloid leukemia. Over 90% of the patients reached by conventional therapy, a situation of complete remission. However, the major problem is that there will be a relapse. So therefore, we need new therapies, which are relatively safe and may not have many impact of quality of life to delay the disease progression or even prevent disease progression. And as already was introduced is that immunotherapy, which can boost the immune system might be most effective in a state of minimal or measurable residual disease, and therefore vididencel has been developed, which is then depicted in the lower part of the slides. Next slide. So about the product already Jeroen alluded about in the right panel, he showed the basic leukemic cells based on the leukemic cell line. And these leukemic cells could be driven to mature dendritic cell [indiscernible] phenotype. That means that by the leukemia derived dendritic cell, all major so-called tumor-associated antigens can be expressed in these cells, which can then be presented actively to the immune system. And the major prevalence of the major issue is that it is an allogeneic cell product, and it is directly available off the shelf and can be easily given intradermally by injections. And we previously showed Phase I data, which has been updated recently and showing that by applying intradermal injection of vididencel it is safe. And also, we found some interesting efficacy signals already in the Phase I study. Next slide. Going back to the potential mode of action, we could show recently that vididencel, given here in green, can be easily taken up by the so-called antigen-presenting cells in blue. And within -- after taking up, this product can be degraded into parts, which are highly immunogenetic and can be presented to the immune system. And in the right panel, we could show that the product itself, vididencel can be better [ uptake ] by the antigen [indiscernible] than the [ allogeneic ] leukemic cells as a baseline. So leukemic cells driven to a mature dendritic cell phenotype can even be better [indiscernible] by surrounding so-called monocytic derived dendritic cells, and thereby maybe efficiently presented to the immune system. Next slide. So coming to the Phase II study, it is a multicenter international open-label study in which we treated 20 patients with acute myeloid leukemia in complete remission, that means by conventional cytoreductive therapy, the patients do not show any blasts -- the leukemic blast. However, these patients are still measurable residual disease positive. That means MRD- positive. And MRD positivity is a surrogate marker for a high risk of relapse. So therefore, we use the primary endpoint to change MRD levels either to fully convert it to zero or have at least a [ 1 log ] decrease in MRD assessment in MRD level. And secondary endpoints are, as always, relapse-free survival, overall survival and very important in this presentation today, immunological responses next to [indiscernible]. And if you look to the right panel, you see the scheme. We used the vaccine, the vididencel every other week, 4 times. And at week 14 and 18, we use the so-called Boost injection. And during the phases before at week 14, just before the boost after the boost and at the time [ point ] of end of treatment, they used extensive MRD assessments as well as extensive deep immunophenotyping to show whether or not we can introduce an active immune response in these AML patients. Next slide. These are the baseline characteristics, we have 20 patients median age 60 years. The days from complete remission to start the vaccination is approximately 250 days. All patients were in CR by definition, by conventional induction chemotherapy, most of the time containing of cytarabine with or without or most with anthracycline in all patients. According to risk classifications, most of the patients are favorable and intermediate -- and in the bottom of the left part, you can see the known appearances which define the European Leukemia Net Risk Classification. In the right part, we show the use of the MRD assessments, and we use the flowcytometry in 4 patients on a very well-defined standardized platform according to European LeukemiaNet Guidelines as well as more [indiscernible] assays to detect measurable residual disease, for instance, by QPCR regarding the NPM1 mutation. And next, we showed that in 5 out of 20 patients, we could show a fully conversion of measurable residual disease to a negative stage. In addition, 2 patients showed at least a [ 1 log ] reduction in the MRD level. 7 patients remained stable in the MRD and additional 6 patients progressed, relapsed after complete remission. So the next slide, first show the survival date. In the left panel, we showed a total group of relapse free survival, and you can appreciate that the median relapse free survival is 30 months and the relapse free survival at 2 years at 24 months is 56%. If we now dissect the patients into whether or not they show a MRD response, you can appreciate that those patients who showed a MRD response do much better, although not significantly, it is at least a trend. But if you then translate that to the overall survival in the next slide -- the left part is a total overall survival of the group. The median overall survival has not been reached yet. The estimated 2-year survival is 75% and the 2 years estimated overall survival is 65%. But again, in patients who do have a MRD response upon vididencel application, you see that all patients are still alive. In contrast to those patients who did not show AMD response, they do more [indiscernible] and it is highly significantly regarding to the overall survival. Next slide showed you what we actually see. And as a major part of the study, are we able to induce an efficient immune response to so-called vaccine-induced responses. And what we are doing actually here is that we look into the patients, whether or not we can introduce a immune response by assessing so-called [indiscernible] gamma release of T cells upon stimulation with the so-called tumor associated antigens, [indiscernible]. And you could observe in 85% of the patients at least such a vaccine-induced response. But moreover, in the left part of the slide, the number of vaccine-induced responses is highly significantly correlated with remaining of a complete remission in the blue bar as compared to those who were elapsed. Going to the right lower table, the vaccine-induced responses is also correlated to measurable residual disease response. If you look to the right part of the table, in the patients showing over 3 -- at least 3 vaccine induced responses that were 7 patients, 5 of those 7 showed an MRD response, which was complete in 4 of those 5. And if you have a lower vaccine induced response of only one or 2, you can appreciate that 2 patients showed an MRD response and one complete and if you have at all no vaccine induced responses -- of no vaccine induced responses you did not see any MRD response. But most importantly is that the number of vaccine induced responses is also related to the overall survival which is on the right upper panel of the slide. Here you can appreciate that if you have at least 3 or more vaccine induced responses in blue, all those patients are still alive in contrast to a lower number of vaccine induced responses, the middle yellow line and actually all patients died if they do not show any vaccine -- vaccine induced responses, meaning that we could have a correlation between T cell responses and overall survival. Next slide. In addition we looked in the patients to the immune response in a skin at the site of the intradermal injection of vididencel. Almost all patients showed local site [indiscernible], redness, swelling of the skin and by routine immunohistochemistry we could identify the T cells and macrophages only at the site of the intradermal injection of vididencel. And by a very interesting new technology, so called imaging mass cytometry on the right panel and we start at the lower panel to show that in color the T cells CD4 cells are depicted in blue, CD8 cells are depicted in red and several dendritic cell subsets are in the bottom yellow and light blue. And if we now merge those colors together in the upper part of the right panel, we can appreciate for instance the dotted arrow that the CD8 positive cells are in close interactions with the [indiscernible] dendritic cell subsets, indicating that at the site of the intradermal injection there is an immune cell composition that may show interaction and that could be functional and thereby indicating the assumed mode of action that upon vaccination immune cells come together and try to establish an efficient immune response. So finally, in the next slide we showed by extensive so-called deep immune phenotyping of the cellular composition of the peripheral blood that as compared to baseline that during the vaccination process there is an increase as compared to baseline in so called B cells, we could find an increase in dendritic cells and we could find a decrease in the so called inhibitory CD8 positive [indiscernible] positive cells, saying that we indeed have a direction of the immune response towards an antitumor activity. Finally, the number of circulating dendritic cells in the peripheral blood is related to overall survival depicted in the 2 right graphs and mainly in patients showing MRD conversion as indicated in the blue dots, we had the highest number of dendritic cell subsets. So circulating dendritic cells correlate with overall survival and are more pronounced in those who converted to MRD negativity or at least an MRD response. So coming up then with the summary slides in the final slides we could conclude that vididencel in AML patients in complete remission, however with a measurable residual disease, showed a long term overall survival [indiscernible] survival with a median overall survival not yet reached, and that a conversion or at least an MRD response strongly predicts survival. More importantly also is that we could really show the induction of a so called vaccine induced immune response to what's known but also to unknown. But we can measure these ones to tumor associated antigens is also correlated to survival. And that at the site of the injection we could find by the new imaging cytometry technology a very close interaction to dendritic cells and the T cells. Finally, an increase in circulating dendritic cells after vaccination is also correlated as long as survival and the number is also correlated to those who really showed an MRD response. In other words, vididencel looks like a promising immunotherapy as an AML maintenance treatment schedule. And Erik alluded already about that, that we will further investigate whether or not we can make the immune reactions more stronger by adding for instance HMA to this vaccine program. So I would like to thank in the last slides all those who contribute to the study, the patients, but also Professor [indiscernible] from my center who did the standardized platforms of MRD assessments according to the ELN working groups in Europe as well as abroad, as well as the support of Jeroen Rovers and [indiscernible] for collecting the data, analyzing data and presenting that in this way. Thank you for the attention. Give the words back to Jeroen or Erik.

Yes, if we go to the next slide, Erik. Yes, thank you Aart van for running us through the presentation which you gave in San Diego and outlining the results for the ADVANCE II study. Before we go into say concluding and questions and answers, we briefly also want to indicate where Mendus is planning to go further with the development of vididencel. And on the slide you see now in front of you, we're actually showing some data for the orally formulated azacitidine, which is since 2020 the only product registered for maintenance treatment of patients who suffer from acute myeloid leukemia and who have been able to get into complete remission after chemotherapy treatment. And the data -- so the graph you see are actually from the registration study, the QUAZAR AML-001 study. And what we put in the box on the right hand side is the survival curves from that study. And on the bottom you see the relapse-free survival, in this case specifically for the MRD positive patient population. And in blue is the placebo trial. So those were patients who were incomplete remission after chemotherapy treatment and who did not get any further treatment except for the placebo. And you can see that the median relapse-free survival for that population was actually less than 3 months. So specifically 2.7 months. The red graph represents the relapse-free survival for the patients treated with the oral formulated azacitidine, which shifts the median to 7.1 months. But I think it's relevant to still notice that after 2 years, 2 to 3 years, roughly, both populations have gone down to a mere, say, relapse-free survival between 10% and 20%. And the same holds for overall survival on the top, where the median overall survival for patients not treated. So the placebo group was 10.4 months and the patients treated with oral azacitidine was 14.6. And again, at, say, 36 months, you see that their overall survival was roughly between 20% and 30%. So this study led to the approval and the registration of azacitidine. But I think it's fair to say that there's still room for improvement for providing patients with a more durable, say, survival and response. If we go to the next slide; so in our labs, the preclinical studies we've done was actually to investigate, can we combine vididencel with those products, in this case, specifically with azacitidine? And the answer is yes, we can. On the left hand side, you see some of the results generated using a mouse model where we treated patients, where we treated mice, in this case with vididencel. So that's indicated to be the vaccination, the green bar, or we treated them with a combination of azacitidine and venetoclax, which is one of the standard combinations for patients suffering from acute myeloid leukemia. But if we combine the 2 and that's the red line in the graph, so we use vididencel in combination with azacitidine, then you see that the results are even better. And there's also a clear rationale. Azacitidine is reported to lead to an upregulation of cancer antigens expressed in tumor cells. And these [indiscernible] agents also lead to a reduction in myeloid derived suppressor cells and increased T cell receptor repertoires. So these things together indicate that the combination of azacitidine with an immunotherapy such as vididencel might provide a synergistic effect. And that's the preclinical say, support for the rationale to combine vididencel with azacitidine. If we go to the next slide, and the steps we are taking to do that is the recently announced collaboration with the Australasian Leukaemia & Lymphoma Group, ALLG for short, and specifically Professor Dr. Andrew Wei, who is the lead investigator for that study. This is going to be a randomized Phase II trial where we will assess the safety and efficacy of vididencel as an add-on to the registered treatment of oral azacitidine. The brand name is ONUREG and specifically in AML maintenance. And the study design is shown on the right hand side of this slide. And it will focus on those patients like what we already recruited in the ADVANCE II study who suffered from acute myeloid leukemia and who were brought into complete remission using intensive chemotherapy. These patients were not planned or should not be planned to undergo a bone marrow transplant, and then they will be treated on a randomized way to either receive oral azacitidine or oral azacitidine in combination with vididencel, and that's shown on the right hand side of that part. This study is a 2 stage study where the first stage will randomize 40 patients in total and it will focus on the safety of that combination and the second stage will then include an additional 100 patients, which will then focus on the efficacy of that combination looking at leukemia event free survival as an endpoint for that study. We're very happy that this study has been submitted and is shortly to be approved by all the regulators in Australia and can commence and that we are able to collaborate with an experienced group of researchers in Australia to make this happen. So maybe I can hand over to you, Erik, for the final remarks.

Yes, thank you, Jeroen. To conclude, as explained, we believe vididencel has a very competitive product profile for AML maintenance therapy and that is based on its excellent safety profile, but of course, very promisingly durability of clinical responses which is based on the induction of immune responses in the patient's own immune system which improve the immune control over residual disease. The data presented at ASH demonstrate long term survival benefits and confirmed the data which we first reported last year, where we saw at the end of the active study phase that 14 out of 20 patients were still alive and then after the follow up, also of this year's long-term follow up, are still alive. That was basically the best possible outcome we could hope for at this point with median relapse-free survival currently standing at 2.5 years. Also, very importantly, what came together is all the analysis we did on the immune-monitoring side of things, where we analyzed patient samples for immune responses and which came together in the presentation just presented by Dr. van de Loosdrecht on how the immune responses also can be visualized and correlate with MRD responses and survival benefits. These positive data out of the monotherapy ADVANCE II trial support the expansion of clinical testing of vididencel in AML and to prepare for a registration study that will, in the end, allow us to bring the product to market. It's a very important step. We have closed the collaboration with the Australasian Leukaemia & Lymphoma Group, which will allow us to develop vididencel in combination with azacitidine, and for which we have put everything in place for the study to start and announce that recently. And then we will look for a potential indication expansion in the broader AML maintenance setting. There's more patient populations requiring maintenance therapy in AML. And with the current data we have for vididencel as a monotherapy and with the safety profile, we believe that we can potentially broaden the clinical development of the program. We look forward to the Q&A. And of course after that I'll make some concluding remarks to close the session. But first, handing it over to Tara and Corey at LifeSci to manage the Q&A.

Great. Thanks, Erik. [Operator Instructions] So our first question comes from Soo Romanoff at Edison.

And it's obviously a very complex topic, so this discussion is actually very helpful. The data that was presented at ASH is very encouraging, and it seems that the 3 vaccine induced responses have a very high correlation to that survival, overall survival. I mean, can you comment to why that is and if that's going to obviously play a role in your discussions with the regulatory authorities?

Yes, I think to keep it simple, Soo, the latter would be a stretch. But to explain a little bit what we've done, we had to select a few antigens. For technical reasons you cannot measure all immune responses against all antigens or all potential antigens that could be relevant, but you can always pick a few. So we picked a few antigens of which we knew were quite dominant, typically in, let's say, immune responses against AML. So it's a snapshot, right? And in that snapshot, we see that some patients respond better than others. And that's not only for the T cell responses. It's actually also the broader picture which was presented by Dr. van de Loosdrecht, which also shows that other compartments of the immune system actually play a role in controlling the residual disease. So you do see a correlation between the status of the immune system of patients and the clinical outcome, but it's not so clearly defined that we can on forehand say that this patient will be eligible for this treatment and this patient cannot be eligible for this treatment, and also given the very good risk benefit profile. So we're treating patients with a safe product that would not be desirable. Jeroen, do you want to add anything to that more general statement?

No. Well, I think the remark from a regulatory perspective, I think, yes, that's for the data we showed, something which cannot be used. I mean, this is not an endpoint on which a regulator will support data submitted, for instance. I think it's, of course, a clear indication, as what Erik indicated, that there is a correlation between the number of, say, immune responses triggered by vididencel and survival. And that's something which we, of course, will continue to monitor throughout further studies with vididencel.

For the positive data that we've seen, we've seen it in the maintenance setting. Are there some applications for -- as an induction therapy? And then I guess in parallel to that, I think there was like a recent FDA approval for both AML induction and maintenance. So maybe that gives you a little bit more of what I'm asking here.

You want to answer that, Jeroen? Yes, and I think the short answer is no. Induction is something which, as indicated also by Professor van de Loosdrecht, is dealt with relatively efficiently so far by the treatments we have. And these are all highly cytotoxic treatments, which are, of course, capable of inducing an immediate effect. And what we are, of course, doing with vididencel is we're creating an active immune response. So we need time for the host, in this case, the patient's immune system, to respond. And that's why the whole treatment schedule is 4 vaccinations every 2 weeks. So biweekly, that's scheduled, and then we boost it again with the booster vaccinations. So vididencel will not be able to, say, be cytotoxic in an induction phase, but it's meant, and it's basically designed to come in after reducing the bulk of the disease and then really provide the immune system with a chance to get control over residual disease. And I think that's where it's positioned, bringing it frontline to say, induction, in my view, will not work. But maybe, Aart van, is there some remark from your view on the general field, which you can add?

I think I fully agree with what you said, is that by induction chemotherapy classical, we can rid of the burden. And I think that's important because immunotherapy in general is a slower mechanism. As you know from a classical allogeneic transplant procedure we only go to a transplant with the patients in which is the kinetics of the disease is in that way very slow, so that the immune system has time to evolve into an efficient immune reactivity. So this product is not able, I think, to be efficient in the induction phase of the disease. Adding to what Erik was saying about the vaccine induced responses, we should note that this is a very specific immune response and thereby you can translate that to the expansion of T cell specific immunity. And all the other immune cells are basically the support to make T cell specificity happen, and [ these cells ] can then attack the measurable residual disease. So I would agree the approach should be in a maintenance strategy and not in an induction strategy.

Maybe you have many more questions, but maybe we can do it so that we ask other people if they have questions too, and we stick to 2 and then you can come back if you have more questions. Is that okay for you?

Yes, that'd be great.

So our next question comes from Chien Lee at Pareto.

Congrats with the data. So maybe the first question for Professor van de Loosdrecht. So in your view, how comparable is the data with the registrational trial of oral aza that you showed earlier, which include more than 200 MRD positive patient? In terms of the patient baseline characteristic, do you see any potential deviation?

The question you raise is whether or not the population we have done is comparable to the data of the Onureg study. That's your question? Okay. Actually the data in the way comparable that they show that they were used in patients with complete remission. However, we have some selection, as always, in a smaller subsets of patients, stressing that we have a larger amount of relatively intermediate and good risk patients. So therefore the overall survival and leukemia free survival data sets are not really comparable. However, in the context of MRD, it shows in both studies that in the presence of measurable residual disease after complete remission, they do worse. I think that is the comparison you have. Is that what you would ask?

Yes, that explained quite clearly. And the second question [indiscernible] Mendus is, for the upcoming combo trial that you are planned for, could you provide just a bit about the timeline and when do you plan to start the study? And if I understand correctly, the decision of stepping up to pivotal trial would be the readout at 18 to 24 months. Is it correct?

Maybe I can start with the last part of the question, Chen, then hand it over to Jeroen for the more specific questions related to the CADENCE trial. What we mean with stepping up the pivotal stage development is for us, the very positive data we got out of the ADVANCE II trial is a signal to start preparing for pivotal stage trial. And that means we are doing everything that we can currently do to make sure the product is ready for a registration trial. And that includes all preparations for a global registration trial. It means setting up the large scale manufacturing to facilitate such a trial, in the end, commercial launch and the potential broadening towards additional AML maintenance indications. So it's not a direct translation of the ALLG trial to a registration trial. The ALLG trial will deliver additional data in combination with azacitidine, further helping us guide the design of, in the end, the pivotal stage trial design. So handing it over to Jeroen, maybe for more specific comments on timelines of the CADENCE trial.

Yes, and like what we communicated. So we've put everything in place for the trial and collaboration to get started and the protocol has been submitted to the Ethics Committee and we expect that we have an outcome for that before the end of the year, which means that early into 2024, patients will be enrolled into that study. The expectation is that it will take 12 to 15 months to enroll all the patients. But the readout of safety will of course, already start with the first patients treated, and that will be a close monitoring of safety for batches of, say, 5 to 10 patients each. After each time, we will see if there's no incremental toxicity of adding vididencel to in this case, oral azacitidine. So the intermediate readout after [indiscernible] patients is going to be in 2025. And like what Erik said, that by that time, we've also defined how to move forward in a pivotal, say, stage design. I hope that provides you with the insight we can give now, but we will report of course, in due course, how the study will emerge.

So our next question comes from Antti Siltanen at Inderes.

Some of my questions were already answered, but I wanted to ask about immune or the adverse event. So as I understood it, the adverse events you saw in this trial were very mild and related to injection site. So I would maybe expect that in this type of immuno treatment, you would see some kind of systemic, more aggressive adverse events. So what are your thoughts on this?

Jeroen, you want to answer that?

Yes, I'll get started and I will give Aart van also a chance to provide a bit on his clinical view. What happens to the patient he treated, for instance. But it's an interesting question and basically remark that you might expect more. And that really comes down to say, classically, of course, the treatment we use for cancer in general, that we typically look for as much toxicity as possible, or what is bearable in the idea that that is also directly related to also a better effect. I think with immunotherapy that is really something which is less of an issue. It's not that we in an immunotherapy setting are looking for a maximum tolerated dose. No, we really have to look for a dose which provides a sufficient immune response to have a control over the disease. What we see emerging from the studies we're doing with vididencel is that, yes, what is directly related to vididencel is the injection. So once, say, the product is injected into the skin, we see within 2 to 3 days that patients develop warmth, swelling, redness at the site of the reaction. And that's also what was shown by Professor van de Loosdrecht, a local immune response so an inflammatory reaction which takes place in the skin. And that's actually the mechanism of action. That's what we want. I mean, we want that to happen in a patient because that will provide the immune response which we need for systemic control. Other, say, more severe or long lasting effects of this treatment, we've not seen so far. But maybe, Aart van, you can provide a little bit of color on, say, what you saw when you treated patients with vididencel.

In the Phase I study I treated all the patients myself, actually I did also all the intradermal injections myself. And the only -- what we have seen only was local skin reactions, from less [ warm ] and swelling to some pain locally towards [indiscernible] activities. And that's also in the Phase II quite similar. We did not show any other adverse events that might have any impact of the quality of life of the patients. And therefore, I think this kind of a maintenance strategy in those spaces who already have received a lot of immunotherapy who get the stage of complete remission is, I think, very, very interesting. And what Jeroen was saying is that we only would like to induce immune reactivity. And that process should be started in the skin. The vaccine will thereby uptaken by the local skin antigen presenting cells, and then the machinery is going to work. And that is what we see, and that is exactly also related to the safety profile.

Yes. And maybe just a last remark there, Antti, a vaccine is something different than a chemical drug, right, which is why you can't really look into, let's say, dose escalation, that kind of phenomena. What we have looked into carefully is how we administer the product. And in the Phase I, we had 4 biweekly vaccinations. In the Phase II, we decided to add 2 booster vaccinations. And actually, in some of the patients, we saw that MRD that was sometimes resurfacing after the initial treatment was brought down again with the booster. So that's more where we, let's say, can play around with the vaccination scheme as compared to the classical dose escalation.

And it may also be -- if I comment on that also, Erik, is that the optimal scheme is also a longer maintenance in the future if we have more signals that, for instance, not only an induction of the immune response is important than a boost, but mainly there are still some ways to further explore that we need additional boost later on in the treatment program.

So our next question comes from Christian Binder at Redeye.

Christian, it's difficult to hear you.

Christian, your audio isn't coming through.

Can you hear me better now?

Yes, perfect.

All right. Perfect. So first question regarding the key eligibility criteria for the CADENCE trial. Now you're recruiting both MRD positive and negative patients versus only MRD-positive in ADVANCE II. Can you elaborate a little bit more on the strategic reasoning for including both MRD positive and negative patients?

Yes. So the registration for oral azacitidine, which is under standard of care for AML maintenance, is regardless of the MRD status. So that product was approved regardless whether somebody is an MRD-negative or MRD-positive status. So we felt that we have to stay close to, say, the label, which is used for oral azacitidine. And it gives us a chance to also explore the benefit of the treatment in the MRD-negative patient population, which we expect is also there, of course. And so also to be clear, I mean, the thing is that what we see in the ADVANCE II study is that even if somebody continues to be MRD positive, they still remain for a long time in complete remission. So being MRD positive doesn't mean you're going to relapse for sure. The other way around also doesn't hold. So patients who are MRD negative might still need additional treatments because they can still relapse. So I think the use of this as it is prescribed for oral azacitidine and adding vididencel on top of it should provide us with a good view initially, of course, of the safety and then also, say, the later efficacy of that combination specifically.

All right. Got it. And then one more regarding the interim readout of the first 40 patients. So are you also going to report exploratory efficacy? And do you believe that kind of survival data, for example, do you think they will also be ready or at least there could be a visible effect in about 18, 24 months? Or do you think those data, especially since you also include MRD-negative patients, will probably need a little bit more time to mature?

Well, it depends a bit which parameter we will look at. But if you look at MRD for instance, then yes, of course, that will be something which we will be able to read out for the first 40 patients as well. If you look at the, say, overall efficacy endpoint, so the leukemia event-free survival, then you would have to probably need a larger number of patients to get a sufficient evaluation. But yes, in the interim, we will definitely look at some of the efficacy parameters. And again, the study is designed in such a way that it allows us to move very quickly. So there's no specific hold plans between, say, the first 40 patients and enrolling the rest. So it's like a [ seamless ] adaptive design. But with the, say, interim and looking also forward, we, of course, look at efficacy parameters to guide us if the next phase is going to be a good adventure for this combination yes or no.

Thanks. I think, Corey, with respect to time, if there's one more urgent question, we can take it, but otherwise, we'll have to wrap it up.

I think we do have one written question, which I'd like to read and answer because it's directed towards Professor van de Loosdrecht and asking about how you're treating your AML patients right now that are in remission. And is -- are they all candidates for Onureg, the fairly recently approved oral azacitidine? And what types of patients might you not put on that drug? How do you make decisions as to which of the patients that are in remission get Onureg and which don't?

Yes. This is a very nice question. Actually, patients who are eligible for a transplant will go to a transplant. However, the patients with AML are at median almost 65 or even upwards to 70 years. And therefore, by comorbidity MIH, a lot of patients with AML, the majority cannot go to a transplant. And therefore, we need after induction chemotherapy, to maintain the maintenance programs because we cannot consolidate after complete remission. So the place of azacitidine in those patients is rather high. And Onureg as an oral formulation is thereby of great interest because of its safety profile, but also that it is quite easy to take. And in contrast to that, we have also the subcu azacitidine, which is much cheaper at the time now. However, in future, in the near future, Onureg by oral formulation will be more used than a subcutaneous formulation of azacitidine. So by answering this question, any patient in complete remission and beyond the specific age has the right at the time being for a maintenance program. Is that clear?

It's very clear to me, and hopefully that person that asked [indiscernible]. Now in the -- we have a couple of other written questions, but we don't have time to get to those right now. So why don't we wrap things up. On behalf of LifeSci, thanks to everyone for listening. And thanks to our KOL guest for a very informative presentation, and I'll turn it back to Erik for some closing remarks.

Yes. Fantastic. Thanks for keeping it tight, Corey, and thanks, everybody, for being part of this call and we're more than happy to also answer questions, of course, afterwards. For now, this is what we could do. We're obviously very excited with the strong ending of the year and also thanks to Aart van de Loosdrecht for presenting the data that we have presented at ASH so quickly after we have presented them at the conference for everybody to watch now in the form of this webcast. I would like to thank all of our academic collaborators. This was obviously a trial in which a lot of academic hospitals were involved throughout Europe. We are very grateful to the patients that participated. It's obviously up to, let's say, the patient to decide whether or not to enter into a trial and we are extremely happy with the outcome so far now that the 14 patients that were seen to respond and were alive at the end of the active study phase are still alive. That's in the end what we do it for. So in that sense, for us, it was a very rewarding end of the year. Again, thanks to all our collaborators, particularly also now allowing us to expand our global network. We already have built up a network throughout Europe. Based on the ADVANCE II trial, we opened the IND in the U.S., but now with the ALLG collaboration, we also have the possibility to expand our network in that region. And we are very encouraged by the data to move forward the clinical program. So with that, I wish everybody a good end of the year and looking forward to keeping [ you all ] up-to-date of our progress.