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

Good day, and thank you for standing by. Welcome to the Mendus ASH 2022 Conference Call. [Operator Instructions]. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Erik Manting, CEO of Mendus AB. Please go ahead.

Thank you. Welcome, everybody. Thanks for joining the webcast related to the presentation of our ADVANCE 2 Phase 2 data at the ASH conference. We are a listed company. So if you want to read the disclaimer, please go to our website -- related to forward-looking statements. We will have a brief introduction by myself, and then an overview of the data presented at ASH by our Chief Medical Officer, Dr. Jeroen Rovers. As initial background, AML maintenance is about the prevention of tumor recurrence. Relapse rates in AML are extremely high. It's aggressive disease. Even after high-dose chemotherapy, there's a big risk of relapse for patients, and that relapse is often very fast or very soon after the initial treatment. Currently, the only curative option for patients is a hematopoietic stem-cell transplant or a bone marrow transplant. But unfortunately, that is not always available. Actually, for a lot of patients it's not available. Standard of care for transplant-ineligible patients has been for a long time watchful waiting or observation, and recently, that has changed with the addition of oral azacitidine as a maintenance drug in the AML landscape. But that drug, as I will show, still leaves a lot of room for improvement for therapies that are aimed to prevent or delay the recurrence of disease after initial therapy. One of the main contributing factors to relapse in AML is measurable or minimal residual disease. Nowadays, with sensitive methods, MRD can be detected. And as you can see here in this retrospective, large analysis of over 11,000 patients, highly predictive for: first of all, the recurrence of the disease; and secondly, also overall survival. As I indicated, currently, the only approved maintenance drug in AML is oral azacitidine. And what is depicted here is the outcome of the registration trial, the so-called QUAZAR trial, which involves a lot of patients that were either MRD negative or MRD positive. And what you can see on the right-hand side of the graph is those patients that were MRD positive at a particularly poor survival with a median relapse-free survival of less than 3 months. With azacitidine that improved to 7 months, but as you can see, the drop-off in terms of patients being relapse-free is still very steep, meaning that a lot of patients still get ill in a relatively short period of time. So we believe that this still leaves a lot of room for improvement, and where there is a lot of interest is to see if there can be an immunotherapy developed for AML. One of the reasons that is very challenging is that patients are treated with high-dose chemo, and also because AML is a blood-borne disease, it is not given that the immune system will still be active. That is the concept we have explored with DCP-001. And in the graphic representation, this is what DCP-001 has as a therapeutic principle, and also how it relates to the data that we presented at ASH. DCP-001 is, we believe, a very potent vaccine, which is derived from a leukemic cell line that we make highly immunogenic using dendritic cell biology, and the vaccine is administered after patients have achieved complete remission. The aim of the vaccine is to improve immune control and reduce the recurrence related to residual disease. The data we presented at ASH are the results of a multicenter Phase 2 trial in which DSP-001 was studied as a monotherapy in the AML maintenance setting. The data we presented are the data of the completed active study period, combined with longer-term follow-up. And also, we have collected immunomonitoring data by which we wanted to show that the immune system of the patient is actually able to respond to the DSP-001 treatment. That combined, we believe, was a very compelling picture in the data we presented yesterday at the ASH conference in our presentation by the principal investigator, Professor van De Loosdrecht from Vrije University in Amsterdam. Those data will now be summarized by our Chief Medical Officer, Jeroen Rovers.

Thank you, Erik. Yes, it's my pleasure to run through the data, which we presented this year here at ASH. So just for reference, we had 2 moments where we presented today. The first one was on Saturday, which was the immune response data from this Phase 2 trial. And the second one, and that's the one which I will show you now, was the clinical data from the ADVANCE 2 trial. And so we'll go to the next one. So this was a presentation by Professor van De Loosdrecht who is a principal investigator of this study from the Amsterdam University Medical Center. It's entitled to use of allogeneic leukemia derived dendritic cell vaccine in MRD positive AML patients, results in MRD conversion, improved relapse-free survival and vaccine-induced immune responses to tumor antigens. So this study, it was a Phase 2 study. It was a multicenter international study conducted in 5 different countries, and it was a collaborative group called the AML vaccine group, which conducted this study. 20 patients were available for the primary endpoint, which was the changes in [Technical Difficulty], and all these patients were suffering from acute myeloid leukemia. They were treated with chemotherapy as an induction, and they were in a complete remission state called the first complete remission. They were not planned to undergo a bone marrow transplant, which would be the standard of care for these patients. And on top of that, they were identified to have residual disease. So they were MRD positive, which was either defined by flow cytometry or by molecular assay like qPCR. The primary endpoint, as I said, was the effect of the treatment on residual disease. And we looked at the residual disease in the bone marrow up to 32 weeks after the start of the vaccination. The secondary endpoints are, of course, the survival end points such as relapse-free survival and overall survival. But the study also contained a lot of assays to identify potential immune responses or changes in the immune system based on the vaccination schedule given. On the right, we depicted the administration schedule, DCP-001 to patients who were given 4 vaccinations every second week. Then there was a short pause of 2 months before the next vaccinations were given, and these were what you would call booster vaccinations, to re-stimulate the immune system. The flags and the needles indicate the moment in time when we assessed residual disease in the bone marrow. So we are now looking at the MRD responses. This is data which we were already able to present in June earlier this year, so before the summer, because at that time, all the patients have reached the 32 weeks assessment of follow-up period. The patient population, as shown on the right, is a typical acute myeloid leukemia patient population with a median age of 60. We had equal amounts of females and males in this study. And there was a variety of molecular aberrations or mutations, which were driving the acute leukemia of these patients. The median follow-up time for the data which were presented yesterday was already 19.4 months, and that's the date which we will show. The MRD response, like shown on the left, indicated that in 5 patients we saw that the residual disease was totally cleared by the treatment. And in 2 patients, the residual disease was decreased by at least a ten-fold. So altogether, these 7 out of the 20 represent patients who responded to the treatment by looking at the residual disease. We also had an additional 7 patients which continue to be in complete remission. So the disease was still under control, but the residual disease was still there. And there were 6 patients which had relapsed up to that 32 weeks evaluation time point. So this slide, which you see now, represents a graphical representation of how patients are doing in this study. It's what you call a swimmer's plot, and it shows how patients are evolving through the study. On top you see what is happening within this study. So the red arrows indicate when we treated patients with DCP-001. The flags indicate when we measured residual disease in the bone marrow. And the moment of time of evaluation just recently now in November, was when all patients has -- had completed active follow-up in this study up to week 70. And as you can see, a lot of patients had reached that moment in time already. And so, on top of that, we started to follow up patients for the survival, and that's the data which we can now also show. And by looking at the swimmer's plot, you can easily identify that, at this moment in time, out of the 20 patients, 14 were still alive, and of those, 12 were still alive without any relapse. So there was no -- so they were still in complete remission. You also quickly can see what we just showed before, and that's represented by the red stars in the swimmer's lines. That's the moment in time when patients converted or responded on their residual disease. So we had these 5 patients which completely cleared the residual disease. And as you can see, that happens very quickly. So shortly after we started the treatment, after the 4 vaccinations, we were able to identify those patients who converted to become MRD-negative. Before I show you then the survival data, I will show you briefly also the immune response data. We measured immune responses in the peripheral blood. That's either by looking at T cell responses towards specific cancer antigens, in this case, WT-1, PRAME & RHAMM. But we also look at the general immune cell composition to see if there are changes throughout the treatment. On top of that -- and that data will not be shown here today -- we also looked in the skin where we did the injections of DCP-001, what is happening, by looking at the immune infiltrates. So if we look at the T-cell responses, then we were able to observe that, in almost all patients, there was a response to one of the tumor-associated antigens, which we tested, and 17 out of 20 showed what you call a vaccine-induced response. That's shown in the graph underneath. That's a patient, in this case, who converted to become MRD negative. And what you see is different colors of lines which represent the different antigens which we tested for this patient. The red line represents the PRAME antigen. And you can see that there is an increase in the red line shortly after we started the vaccination, and it's indicated with a star. That means the increase was more than twofold over the baseline, which is then indicated to be a vaccine-induced response. It then drops down a little bit, but after the booster vaccinations, you see again an increase, indicated with a star, indicating a vaccine-induced response. A similar pattern is observed for the blue line, which is the antigen WT-1, and if you count these different vaccine-induced responses here, this patient had a total of 5 of these responses. If we then look for the overall population, and that's depicted on the right, we start to see the pattern, which is that, those patients who did not respond well or relapsed to the treatment, had a significantly lower number of these vaccine-induced responses. And you can see on the left-hand side, the red box represents the patients who relapse. They had 1 or less vaccine-induced response on median. The blue box represents the patients who were still in complete remission or who actually converted to become MRD negative. And that's further split out in the graph there on the far right, where the last, say, box represents the MRD responders, which clearly are doing even much better. So this indicates that there is a potential correlation between the number of, say, vaccine-induced responses we observed and the clinical response. If we then look in more depth in the peripheral blood to the overall immune composition, which was done with flow cytometry, we can observe 2 major things. One is that, at baseline, there seems to be a difference already in the immune cell composition between those patients who relapse and those patients who continue to be in remission and do well. The major difference is that the patients who relapsed had a lower level of B cells, a lower level of dendritic cells, and a higher level of a certain type of T cells, the CD8 Central Memory cells. This suggests a slightly different immune profile, which is probably much less responsive to the treatment we try to get. If we then look over time what is happening, we observe that the different immune cell subsets are actually increased. We are able to increase the levels of the immune cells. For instance, the B cells, which is depicted in the graph on the right, but also the dendritic cells and also NK-cells. That is for the overall population, but it's more dominant for those who seem to respond quite well to the treatment. And on the graph, you see that the patients who relapse, they still increase in their B cells, for example, but they start at a much lower level, and they hardly reach the same level of those patients who are doing quite well on treatment. So, what does this come down to? Because that's, I think, the most relevant read out which we were able to show yesterday. That is the survival. And what we show here is relapse-free survival. On the left hand, you see that's for the overall patient population. And in this case, we always try to identify what you would call the median relapse-free survival, which means that the Kaplan-Meier curve, which is shown here, which is the blue line, should cross the 50% level to [ readout ] your median relapse-free survival. As you can see here, it doesn't. I think that's one of the astonishing observations we were able to show, is that, over time, it starts to flatten up. We start to see that the patients who are doing well, continue to do well. And out of what I just indicated, the 14 patients still alive, 12 are still alive without the relapse. On the right-hand side, we have then identified the 2 different subgroups based on the response to the treatment, to those patients who responded and turned into MRD negative, and those who continue to be identified with residual disease. And then you can see that the relapse-free survival is very different between these 2 subgroups. Those patients who respond and have an MRD negative status during this study, they are continuing to do much better, as you can see with the yellow graph on top. So this translates in also an overall survival. And as indicated earlier, the median follow-up for the whole population was already 19.4 months. And you can see again on the left, that's the overall survival curve for the overall population. Here, the curve drops through the 50% level at 30.9 months. So the median overall survival as currently readout is 30.9. But like I said, we are still following up these patients for their survival. So there are still patients who might even continue to do better for a longer time, which will then change the graph. But that's the long-term follow-up, which is still ongoing. If we then split out again, the overall survival, based on the MRD response, you start to see, again, the same pattern, but now it's already statistically significant with a small group of patients we have. So those patients who are converted to MRD negativity, they are continuing to survive, and the ones who are still MRD positive are at risk to relapse and die. So before coming to the conclusion of this study, again, of course, an important parameter is safety. Adding a treatment to already heavily intensive treated patients always comes with the balance of not adding too much [ toxicity ]. In that respect, the data we've seen now in the Phase 2 confirms what we've seen before. We've done over 100 intradermal vaccinations, and so far, the safety profile is extremely favorable. We see responses to the treatment indicated as injection site reactions, so redness, swelling, these kind of effects in the skin. Those are related to the treatment. But further, we don't see any serious adverse events which are deemed to be related to the treatment. This indicates that we can safely apply this in heavily treated patients already, without adding any toxicity. So in conclusion, this study has shown that DCP-001, if we injected intradermally, is very well tolerated and safe. And that confirms the previous observations in the Phase 1 study. We've also now observed that treatment with DCP-001 leads to an effect of residual disease, where we are able to clear residual disease and turn patients to MRD negative, and reduce the residual disease in overall 7 out of the 20 patients. We also observed that T cell responses against tumor associate antigens happen when we inject DCP-001, and that seems to correlate the number of those responses with the clinical response. Additionally, we see that the treatment has an effect in a much broader scale of the immune system, with effects from both natural killer cells, but also B cell populations, improving the potential response of the immune system towards the disease. The survival looks extremely promising. We have the median follow-up of 19.4 months, and not yet reached the relapse-free survival median. For overall survival, the median is read out at 30.9 at the moment. And again, those patients who converted to MRD negativity are doing much better. They have an improved relapse-free survival and overall survival. So we believe that DCP-001 is a very promising immune therapy, which can be used in AML patients specifically to maintain their complete remission. So [ AML maintenance ], [Technical Difficulty] chemotherapy, specifically useful for those patients who have residual disease that are at a very high risk of relapse. With that -- and acknowledging, of course, all the patients, families, but all the investigators who contributed to the study -- I will hand it over to Erik Manting.

Thank you, Jeroen. To wrap the presentation part up -- We are very happy with the data that we presented at ASH. First of all, maintenance therapy is the new treatment paradigm in AML. It's all about the prevention of recurrence and keeping patients in remission longer. Immunotherapy has that potential, but so far, there was very little success. And we believe that the data we presented at ASH showed that it is possible to activate the immune system to trigger anti-tumor responses, resulting in much more durable responses and survival benefit for patients. Currently, the only drug approved in AML maintenance is oral azacitidine, but again, we believe that leaves a lot of room for additional drugs leading to further improvement of survival benefit, and the DCP-001 is an important contribution to that AML maintenance landscape. We also believe that the data that we collected in the ADVANCE 2 trial show that DCP-001 can deliver a relevant survival benefit as a monotherapy. That is a very important starting point because the results we have seen can be attributed to DCP-001 specifically. And secondly, also, it's a great starting point to further broaden our exposure in the AML maintenance landscape and potentially also additional indications such as MDS and CML. So, we believe, we are now entering into a very interesting phase because we have proof of concepts, again, with very relevant survival benefit, but also supported by the underlying disease and immunomonitoring data, and this is a starting point for us to look more broadly into the [ hemato-oncology ] field, and specifically AML maintenance, to further develop DCP-001. With that, I would like to hand it back over to the operator and open the session for Q&A.

[Operator Instructions] We will now take the first question. It comes from the line of Soo Romanoff from Edison Group.

Thank you for the work you're doing here, the maintenance therapy. It's always nice to see the positive results. Could you comment maybe on the differences between the 2 DCP-001 dose groups in ADVANCE 2? In addition, are there any differentiating results between the patients with different molecular aberrations?

No. The short answer is no. We don't see a difference between the 2 different doses. And actually, the difference in the doses is relatively marginal. So it's either 25 million or 50 million cells. And what we see is that it just triggers the immune response. We see that with these patients basically the second day after we do the intradermal injections because they get this redness and swelling, and that confirms that the -- say the immune response started. So yes, we believe that in this case, the 25 million cells per vaccination dose is sufficient to carry forward.

And also maybe whether we believe that the survival figures we saw in MRD positive patients is competitive against azacitidine?

Well, Erik showed you the graphs of the registration study of oral azacitidine. If you look at the MRD positive patient population in that trial, so there are also acute myeloid leukemia patients treated with chemotherapy and they still are MRD positive. Their median relapse-free survival is 7.1 months if treated with oral azacitidine. As we showed -- I mean, we have not formally read out the median relapse-free survival in the Kaplan-Meier, which was shown also yesterday. But you can already see that we have probably at least the median relapse-free survival of 16 months, because the shortest follow-up of the patients still at risk for relapse is 16 months.

I mean, maybe that's something that -- in combination, that would be kind of interesting. The last question I have is, there's some sparsity in -- affecting AML maintenance therapies and the data needed for azacitidine's approval. What data do you think the regulatory -- what data will the regulators require for registering maybe DCP-001? Is the MRD data for ADVANCE 2 sufficient with accelerated approval application?

I think the answer there is no. I think the regulators are following the field. So the field is, I think, leading with more and more, say, emphasis on residual disease as a surrogate marker to see if patients are doing well, not only in clinical trials, but also in clinic. I think if somebody is treated or being monitored for their, say, further development of the acute myeloid leukemia, then, say the occurrence of residual disease is always a sign to potentially start treatment. The regulators acknowledge that, but it's not yet an end point. So the expected end point for regulatory registration would be relapse-free survival or overall survival. But I think the first one is the most applicable for those patients at high risk of relapse and at high risk of dying from this kind of treatment.

We will now take the next question, and it comes from the line of Jacob Mekhael from Van Lanschot Kempen.

I have a few. So now that you have the survival data, what are your development plan? What are your plans on going forward? And what would the future trial look like? And will it only involve MRD positive patients? Or will you aim for a broader patient population here? And perhaps are there any learnings from this trial that you would like to implement in the design of a future trial?

Sure, I'll respond to that, Jacob. I hope I will capture all your questions. Otherwise, remind me if I skip one unintentionally. So starting with what are the next steps. I think what is the most important thing that we've learned from the trial and what we presented yesterday is that, it is possible to design an immunotherapy in AML, and that, we believe, is a real breakthrough. We've had a KOL event. As you know, a couple of weeks ago, there were data presented at ASH. There has been many attempts to design immunotherapies in AML for the obvious reason that we actually now also start to see in the data, which is that, if you are able to activate the immune system of a patient with residual disease leading to improved immune control over the residual disease, you get a much more durable response. And also, of course, immunotherapies have a general better safety profile than, for example, aggressive chemotherapies. So there was a big medical need to find a solution, but also with the data that were presented at ASH with very little to no success. So the fact that we now have shown that it can be done -- and we believe we have shown it convincingly not only on the basis of the survival data, but also the underlying immunomonitoring data -- that is a real breakthrough. That will also mean that we now have a much broader field to play in. That is something we are currently doing. We are also now, on the basis of the data, getting a lot more discussions in the background. Of course, we have already prepared for different study designs by talking to KOLs in the field, to keeping a close eye on what's happening in the ongoing larger trials with standard of care drugs. So, in the background, we have already done quite a lot of preparation work for next trials. But I think you'll also appreciate that now with the data at hand, we will take a bit more time to basically look into all the opportunities that are there. And they are both there in the AML field and they're there in pre-transplant, but also, for example, post-transplant where there's still a lot of MRD and a lot of relapse. But also in additional indications like MDS and CML, we are starting to see now a lot of interest from doctors wanting to work with the product. So this is what we are currently doing, and I think it's a quite straightforward development path whereby you first show, and we hope now have also convincingly shown, that a monotherapy effect can be realized -- and a convincing monotherapy effect, and then as a next step, you look into the full breadth of the landscape to see where you can be most competitively positioned. So that's the exercise we are now going through. And with respect to your question about trial design and lessons learned, I think what we start to see is 2 things, which is, one, MRD is highly predictive of the outcome of disease. That had already been unequivocably shown in that large retrospective analysis we also presented, but also we see it in our own trial. The other side of it is, if you have an immunotherapy that provides for control over the residual disease, you may also see a benefit in those patients, and we are seeing a benefit in those patients that have not converted completely their MRD status. So to cut the long story short, MRD will be a very important predictive factor of the risk of recurrence, but at the same time, relapse-free survival will probably be a much more relevant readout for future trials. Does that answer your question, Jacob?

Yes, it does. And I have just one more follow-up on that. So now that patients have entered into the long-term follow-up, can we expect any more data updates on the trial in the future? And what are the time lines of those?

I think the answer is yes because we are continuing to follow up these patients in what we call a long-term follow-up. So patients on a regular basis will be evaluated again whether there is -- the disease is still under control and whether they're still alive. That's data which we will show once there's, of course, a relevant [Technical Difficulty], we reach the median relapse-free survival. So that is something which is ongoing. You could expect us to notify you on that once it happens. And the timing for that is, of course, unclear, because we don't determine when the relapse occurs. For us, hopefully, that's going to be a long time from now, but time has to [ learn ].

We now have a question from the webcast. Is there any correlation between AML mutational subtype and MRD negativity?

It's a great question. It always comes back. And then we know that the different mutations in AML might have been slightly different, say pattern in response to treatment. In our study, I think the numbers are too small to do a full analysis. So we could not discover with the small numbers we have that there's a specific mutation which responds much better than another. So short answer is no, there isn't. But the remark here is, of course, that is on the basis of a very small subset of patients, because each individual mutation, yes, it's relatively limited. The majority of patients -- and that's -- 10 patients were [ NPM1 ], some with an additional mutation and some without. So -- but if you subdivide that into the smaller subgroups, you're left with too little patients to do a formal analysis.

[Operator Instructions] There are no further questions at this time. I would like to hand it back over to Erik for closing remarks.

Thank you, Sandra. Everybody, again, thank you very much for participating in this webcast. We think it's a very special moment for the company. Also, I think it's a special moment for, let's say, showing proof of concept that immunotherapy is possible in AML. I think if we look into the broader immunotherapy landscape, it still holds a lot of potential, and I hope the data today also will encourage other companies to continue to look for new breakthroughs in immunotherapy. For us, it means an important step for the DCP-001 program. It also means that we will look again in the broader hemato-oncology landscape to see how we can now best move forward making use of the insights that the study has -- have delivered to us. And we very much look forward to keeping everybody informed on our next steps. With that, I would like to close the event. Thank you.

That does conclude our conference for today. Thank you for participating. You may all disconnect.