Welcome, everybody. Thank you for joining our session. This is about today. We would like to share you with some new, really exciting details about HDP-101 clinical development, which is a new ADC with a novel payload. What I will do today is that I will give you a couple of sentences as an introduction. After that, we will have some guests here, guest speakers, two of them, who will present our clinical data. Finally, of course, there will be some room for questions as well. This is just our safe harbor, of course, which we have to show at every time. We are not really familiar with our HDP-101 compound. Heidelberg Pharma is really an innovative drug company who develops HDP-101 as one of our leading technologies, which combines new novel ADCs. I am happy to share that we have really positive clinical data achieved. One of our patients achieved a complete remission, and we have multiple responses with a terrible safety profile. What is this ADC about? Of course, ADC is not a new technology, but what is new is really the payload. The payload really matters the most in the ADC technology. This novel payload is exclusive to Heidelberg Pharma. We are developing it. Our first compound is HDP-101. This payload also has an interesting biomarker feature, which could be utilized later on because, for a reason, this drug could be super effective with cancer which harbors the 17p deletion, which, as you might know, is one of the most difficult to treat cancer types. How does it really look like? I think our colleagues will talk about this as well later on. Really, the payload is coming from nature. Nature provided us this payload in the form of a mushroom toxin. This was included into an antibody-drug conjugate. Really, the novelty is in the target of this payload. The target of this payload is RNA polymerase II, which has not been targeted before in cancer. Why is it important? Because it is a cell cycle independent target, which means that this drug is capable to kill dormant and non-dividing tumor cells. Because it is a new mode of action, currently, there is no known resistance against this mode of action. All of the cancer patients will be naturally naive to this new payload. The target, actually, the drug targets the BCMA-positive cells, which are exclusive on plasma cells. Therefore, it's a really precise tool to eliminate cancer cells. With our technology, we have a site-specific conjugation, which means that with that, we silence the FC portion. There is no additional effect on the target. I think our colleagues will discuss this further. With this small introduction, I will introduce you to our guest speakers. The first speaker will be Professor Martin Raab from Heidelberg University. Both of our speakers actually are principal investigators and have direct experience with the drug, which they will share with you. After Professor Raab's presentation, we will have Jonathan Kaufman from Atlanta Emory University, who will talk about, again, the experience in the study. With that, I finish, and I will come back after Professor Raab's and Jonathan Kaufman's presentation. Welcome to the webinar on the new amanitin-based ADC. I'm happy to share the data of our ongoing phase I trial with you today. Our ADC is equipped with an amanitin payload. What is amanitin? It's alpha-amanitin, well known as a poison from the Amanita phalloides mushroom. It has a completely novel mechanism of action. It is an inhibitor of RNA polymerase II and very efficiently kills dividing as well as dormant non-dividing tumor cells and has no known resistance mechanisms as of now. We use a fully synthetic process of synthetic amanitin derivatives attached to an antibody targeting BCMA. Each antibody is equipped with two molecules of alpha-amanitin and has a reduced FC gamma receptor binding affinity for improved therapeutic index. In our preclinical data, we were able to show that HDP-101, the alpha-amanitin conjugated antibody against BCMA, kills efficiently non-dividing tumor cells, as you can see on the left graph in the green curves compared to the same antibody conjugated with MMAF, which, as we all know, is killing cycling cells compared to HDP-101. In the middle panel, you see also that it very efficiently in vitro kills primary myeloma cells from patients with resistance mechanisms and resistant disease to known drugs like daratumumab or pomalidomide. On the right side, you see also that while the upper curve shows stromal cells that do not express BCMA, you see that several patients with different levels of expression of BCMA are all efficiently killed in vitro or ex vivo. Let's move on to the ongoing phase I clinical trial with HDP-101. This is a phase I trial with dose escalation. It is a Q3 weekly, so every three weeks intravenous dosing and a BLRM design for dose escalation. The objectives are, of course, DLT and cycle one response rates, as well as safety, tolerability, and PFS and overall survival, the secondary endpoints. The final goal, of course, is the RP2D identification to move on to dose expansion in phase II. In the middle, you see the scheduled dose escalation steps. Key eligibility criteria were a triple-class exposed patient cohort with, of course, immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibody exposure. They had to be refractory or at least intolerant to any established standard of care therapy that provided meaningful clinical benefit for the patient. Here you see the swimmers' plot of the so far evaluated cohorts, Cohort 1- Cohort 5, before I show you later the most updated new cohorts. What you see here is that while in the first four cohorts, there were some stable diseases, also some durable stable diseases, you see with Cohort 5, the 100 microgram per kilogram, we see quite some responses in green, the partial response, and one patient that actually received or achieved a complete response now way over a year out. Let's look at this very interesting patient a little bit further in more detail. It is a 70-year-old female with stage II IgG kappa myeloma that was diagnosed already in 2002. As of now, the patient had nine prior lines of therapy when she was screened for this study. The last three lines of therapies are depicted here. The seventh line was a BCMA CAR T cell therapy in 2018, followed by a GPRC5D bispecific antibody in 2020. The immediate prior last line of therapy was IBRDX in 2022. She was started on HDP-101 in October 2023 and received or achieved a PR already after cycle two. After 225 days, there was no detectable M protein left. A confirmed stringent complete response was achieved after a little bit less than one year. She tolerated the treatment very well overall, very mild adverse events. No keratopathy, no liver damage or lung toxicities, no ocular or renal signs of toxicity at all, and only one transient grade 3 thrombocytopenia in cycle one. Talking about thrombocytopenia, this was a sign in Cohort 5, so in the 100 mg per kg cohort, where we saw that almost all patients starting at this dose had a drop in platelet counts at around day five, as you can see here. Very early on, but also a very rapid recovery as of day eight to 15 to almost baseline limits or levels or about above baseline levels. That led us to adjust the regimen and test several optimization strategies in the following Cohort 6 to overcome this transient thrombocytopenia that occurs within the first one or two weeks in cycle one. Those adjustments to the schedules in cycle one, for example, are depicted here on the lower right part, where you see that Cohort 6 was split in three arms. One where we continued with the Q3 weekly dosing in RMA, but added a pre-medication prior to the first dose. In RMB, we split the dose to weekly dosing instead of every three weeks. In RMC, we only split the first dose into day one and eight and then continued with the next cycle as a three-weekly dosing. To take it safely, we reduced a slightly dose reduced for this cohort to 19 mg per kg and then went on with Cohort 7 with 112.5 mg per kg and continued with two arms with a split dosing for weekly dosing and a split dosing in cycle one only, day one and eight, and then continue with three weeks dosing, as you can see here. As of now, the currently recruiting cohort is Cohort 8 with 140 mg per kg. There we continued with the split dosing with weekly dosing as well as the split dosing in cycle one only and then continue with the three-weekly dosing. Why is that? Why did we choose this strategy? We saw on the right side with Cohort 7, so the 112 mg per kg, we saw that both strategies, the weekly dosing as well as the dosing that had a split dose in cycle one only, could mitigate almost completely these thrombocytopenic events in the first two weeks, as you can see as a comparison on the left side with Cohort 5, where this was not implemented at that time. Very importantly to say is that we do not see any impact on liver function with these new strategies compared on the right side with Cohort 7. While Cohort 5 on the left side, we saw a slight increase in liver enzymes, as you can see here with AST at day five, but only one that was a little bit higher grade, all others were low grade. Now the swimmers' plot on the ongoing cohorts with Cohort 5 that you have seen before with this one patient achieving SCR, in Cohort 6 with a slightly lower dose and those alternating schedules, you see that there are still some patients actually achieving partial response at least. With this newest cohort now, with a short follow-up, of course, Cohort 7, we also see three patients having at least a durable stable disease and actually two of them having partial response. Also, in an overview of the waterfall plots here in terms of dose-dependent efficacy with relative changes from baseline in the M protein, you also see here that starting with Cohort 6 and Cohort 5, so 90 and 100 mg per kg, we see patients responding. This continues now with Cohort 7 in about half of the patients where we see actually a decline, a decrease from baseline in the M protein level, so responding patient. In terms of safety, we do not see any major issue otherwise than now the mitigated thrombocytopenia, as you can see here. There were no signs of ocular or renal toxicity, no infusion reactions, no really severe myelosuppression or other issues that led to a grade three or grade four AE event in this patient cohort with single-digit numbers, if at all, as you can see here on this table. Talking about all those outcomes in patients, what kind of patients did we enroll so far in this study group? You see it was 34 patients, a median age of 68.5, and most importantly, probably the number of prior treatments. You see here on the right side, it's a median number of prior treatments of seven, so really, really heavily pretreated patients. They had to be triple-class exposed and refractory to the immediate last line of therapy. Some patients here, as you can see, 5% and 12%, even had a BCMA bispecific and/or a CAR T cell exposure prior to enrollment. Summarizing these data, you can see from this HDP-101 phase I, phase II a trial that we see multiple responses starting with 19 mcg/kg and continuing now with the 140 mcg/kg cohort that is currently enrolling. We saw three out of six patients responding in Cohort 5 and seven out of 22 patients in those three cohorts in a relevant dose range. At the 100 mg per kg, we had one patient who achieved a stringent complete remission and continues maintaining this remission now for 19 months on treatment. As I said, the Cohort 8, 140 mg per kg, is now enrolling as we speak. In terms of safety and tolerability, treatment was generally really, really well tolerated. There are no signs of ocular or renal toxicities, no real myelosuppression or liver damage could be noted. Clinically, we saw an asymptomatic thrombocytopenia in this one dosing cohort and with a Q3 dosing schedule, but this has now been mitigated with a split dose in the first cycle and then continue with a three-weekly dosing in the following cycles. So far, 34 patients have been treated. They were all heavily pretreated. HDP-101 as a monotherapy really shows a favorable safety profile, shows clearly and confirmed efficacy as disease stabilization, but also including stringent complete responses in patients with prior treatment of CAR T cell and GPRC5D bispecific antibody. With this, I thank you for your attention. I'm looking forward to the discussion. Hi, my name is Jonathan Kaufman. I'm a professor in the Department of Hematology and Medical Oncology at the Winship Cancer Institute of Emory University in Atlanta, Georgia, United States. Today, I'll be presenting pioneering new treatment options in relapsed or refractory multiple myeloma with a new alpha-amanitin-based antibody-drug conjugate. These are my disclosures n ote that I have research support for a clinical trial with Heidelberg Pharma. While myeloma is a disease that we're very good at treating, we still are not able to cure myeloma. Hence, myeloma is a disease that we continue to need new therapeutic options for. Myeloma is cancer of clonal plasma cells. The job in life of a normal plasma cell is to make antibodies to help fight and prevent infections. Myeloma manifests itself clinically as high calcium, renal dysfunction, anemia, lytic bone disease, increased risk of infections, fatigue, and others. Worldwide incidence of myeloma is about 180,000 individuals with a mortality of 120,000. Myeloma is typically a disease of older individuals with the average age of diagnosis somewhere between 65 - years- old and 70- years- old. We have significant improvements with new therapeutics in terms of progression-free survival and overall survival, but still no cure. The backbone of therapy currently is a combination of immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies, and newer therapies with immune therapies. Several years ago, we've identified a new target for myeloma, BCMA or B-cell maturation antigen. B-cell maturation antigen represents an excellent target because in a large part, BCMA is only on plasma cells and myeloma cells. It also gives us somewhat of a clue of what the expected toxicities of BCMA targeted therapy would be, considering not only do we target myeloma, but in targeting normal plasma cells, there is a decrease in antibody production and hence an increased risk of infections. In terms of classes of drugs that target BCMA, there are currently three classes of drugs. One is an antibody-drug conjugate, antibody-drug conjugate, where the BCMA targeted antibody binds to the BCMA positive cells and then delivers the cytotoxic payload or the chemotherapy directly to the cell of interest. Again, ADC binds to BCMA on the myeloma cell. It's subsequently internalized. After internalization, there's linker hydrolysis that occurs inside the lysosome and the endosomes. The chemotherapy is released, and subsequently, there's cell death of the target cell. Because these are monoclonal antibodies, it does have the potential for also immunologic cell death, including ADCC and ADCP. CAR T cells that target BCMA are re-engineered CAR T cells that express a chimeric antigen receptor for BCMA. They're then grown ex vivo and then re-infused into the patient for expansion in vivo after lymphodepleting chemotherapy to, for lack of a better term, make room for the new CAR T cells. Finally, there's bispecific antibodies. As the name mentions, these antibodies target two things. One is the antigen of interest, BCMA, and two is the T cell. The T cell becomes activated. It creates an immunologic synapse, and that induces cell death of the myeloma cell. There are significant amounts of monitoring that is important in CAR T cell therapy and bispecific antibody therapy. The antibody drug conjugate that was previously approved and then taken off the market had a fair amount of ocular toxicity, keratopathy to be specific. From a positive standpoint, antibody drug conjugates are off the shelf, and it's an outpatient use with infrequent dosing, typically after one or two cycles, every three to potentially even four-week dosing. With the prior antibody drug conjugate, because of the ocular toxicity, it required a significant amount of monitoring by an eye care professional before the treatment and before dosing. CAR T cell requires the most amount of care and coordination. There's the collection of mononuclear cells that are then sent for cell manufacturing, which can take four to eight weeks. These are typically hospitalized patients that will need to be in a hospital. Again, I had mentioned there's lymphodepleting chemotherapy with a combination of cyclophosphamide and Cytoxan and requires, again, most of these are done in specialized centers, typically centers that do stem cell transplant. There's monitoring for post-CAR T cell toxicities like cytokine release syndrome, which manifests as little as fevers, but could be as bad as hypotension and hypoxia and in rare cases, death. Neurologic toxicity can happen early, and it can be as simple as a challenge with word finding or change in writing to as severe as coma, seizures, and even deaths have been reported. There then subsequently needs to be a lifelong monitoring for second primary malignancies. Bispecifics, also off the shelf, very little time. Again, typically delivered in specialized centers because of the monitoring that you're required for, again, CRS and neurologic toxicities. The majority of patients are treated in community centers. What we've noted is that there's a significant fraction of individuals who don't get subsequent lines of therapy. In this study, they showed 38,000 individuals had frontline therapy, but a significant drop at second, third, and fourth line therapy. At fourth line therapy, really only a quarter of individuals get fourth line therapy. What ADCs offers is a more convenient dosing regimen and potentially improves safety, driving value over bispecifics and CAR T cells. If you look, there's outpatient administration without the need for ramp-up dosing. It's off the shelf. From a mechanism of action perspective, it does not require functional T cells to be effective, a manageable safety profile, and importantly, because of the safety profile, able to combine with other therapies. BCMA-directed therapies are being studied in all settings of myeloma, from precursor conditions like smoldering myeloma to newly diagnosed myeloma to potentially replacing autologous transplant as consolidation with CAR T cells, and then early relapse as well as late relapse. There are also multiple combination studies of combination bispecifics, using bispecific before CAR T cell, using bispecific after CAR T cell. There is a lot of very active research in this field. From a value proposition in myeloma, the unique features of HDP-101 is it's effective against dormant tumor cells, effective in ultra-low BCMA-expressing tumor cells, novel mechanism of actions to which all patients will be naive, favorable safety profile, and use in combination, stronger and longer-lasting tumor responses, deeper responses, higher response rate, overcoming resistance, possible long-term in combination with improved therapies, long treatments and combinations, and even potential with entering earlier lines of therapy based on the belantamab mafodotin recent data with DREAMM-7 and DREAMM-8. I would like to thank you for your attention. Thank you so much, Professor Raab, and Professor Kaufman, for this excellent presentation. Now I will have some conclusions for this, and after that, we will take questions together with my colleagues. I really would like to highlight the excellent safety profile of this drug. Overall, we had really mild adverse events with this drug. We have not seen any signs of ocular toxicity, which is typically associated with belantamab treatment. We have not seen any renal toxicity, which always puts difficulties with the multiple myeloma patients. Myelosuppression on top of the thrombocytopenia, which we saw, and we have not seen real myelosuppression. There is no lymphopenia or anemia associated with this treatment. As of today, none of the patients showed liver damage in our study. We only really see transient liver function test elevations, but no definitive liver damage. The transient thrombocytopenia was associated only with every three-week dosing. When we changed the dosing with the split-up dose and we split the first dose, this was actually mitigated from Cohort 6. After Cohort 6, we have not really seen issues with thrombocytopenia either. We really have a mild, favorable safety profile. We also have, of course, I have to admit, this is just a few patients we have treated for a longer period, but those few patients have not showed any kind of cumulative toxicity, which was associated for several multiple cycles. We even have a patient which was treated more than 20 months, since more than 20 months, and not showing any cumulative toxicity so far. If those who are familiar with our technology, they know that there was a case with a really similar compound containing also amanitin, which was associated with lung toxicity, but we actually have not seen, although we really thoroughly checked for each and every patient for this, we have not seen any similar toxicities in our studies. That was clearly just related to this Magenta 117 compound and not associated in general with amanitin-based ADCs. On top of that, we have excellent, really good preliminary efficacy, which was actually unparalleled, and we didn't really expect to see such good efficacy in the phase I study. We've seen a stringent complete remission, and above 90 micrograms per kilogram, we see patients with continuous partial responses at least, and we have quite a few ongoing patients reported. What will come next? Obviously, we would like to have the recommended phase II dose as soon as possible, but this is actually a data-driven decision with our colleagues, which means that we predict that we might reach it by the end of this year, the recommended phase II dose. After that, we definitely turn to the study, to the phase II portion, and we confirm the efficacy and the safety signals that we have currently. As of today, we haven't seen DLTs in Cohort 7, so the last cohort we completed, and therefore we enroll patients in Cohort 8, which is 140 micrograms per kilogram. The escalation continues. We haven't reached the maximum tolerable dose yet. We would like to extend this study into China, and also we would like to have the clinical development continued as a monotherapy and combination therapy as well. I will talk about this strategy on this slide. This is our future outlook, that what is planned for this study. One of the real, I would say, a kind of obvious space we would like to go is the post-BCMA field. Those patients who are relapsed refractory multiple myeloma patients and received at least one prior BCMA treated BCMA treatment for their disease, and these patients can be treated. We have evidence already gathered in our phase I study that these patients can be treated in our study with our drug as well. Of course, this is an ever-growing patient population, and this is what we would like to tackle with the monotherapy of HDP-101. The other strategy that we will pursue is that we would like to try this drug together with other drugs, maybe with combination with an immunomodulator drug and dexamethasone, which would be a quite favorable combination for relapsed refractory patients. This is similar to the DREAMM-8 trial. This could be also an approval in earlier lines of treatment for relapsed refractory multiple myeloma. Of course, exploiting the del(17p) benefit that I showed you previously could have that we could go into a high-risk population for relapsed refractory multiple myeloma or in newly diagnosed high-risk population. Of course, these require combinations and other tests, but this will be a little bit later because our primary focus is really the monotherapy followed by the combination treatment for that. What does it mean in the timeline-wise? Our colleagues put also not just the timelines, but also the addressable market next to the timelines for these two major scenarios or three major scenarios that we have. The post-BCMA setting will be the fastest, and we really hope that this also comes along with an accelerated approval or conditional approval, if you name it in Europe, until 2030. This conditional approval or accelerated approval needs to be converted, and we plan to convert to full approval with the Lenalidomide board for the earlier lines of treatment with the combination. This strategy is many companies use similar strategies, and these can be done later after 2030. This will address two quite considerably large markets in the multiple myeloma field despite the alternatives that we have currently in this field. Of course, we would like to have the high-risk patients as well addressed sooner or later. Most likely, these will start a little bit shifted from these two primary goals, but this also addresses a really difficult patient population, which we would like to treat with our drug. Of course, HDP-101 is not our only drug. This is our flagship drug, and this is our first asset in the clinic, but we have other really interesting compounds. We have a CD37-directed amanitin-based drug treating non-Hodgkin lymphoma and various similar diseases. Also, we have a PSMA-directed drug, which we might be able to treat a difficult patient population, but it is a huge patient population, the prostate cancer field. We also have a really interesting drug targeting GCC in gastrointestinal cancer, which includes colorectal cancer, gastric cancer, or pancreatic cancer potentially. These are all in preparation. Currently, the HDP-101 is in phase I dose escalation. The HDP-102, we already have a couple of the first patients treated in non-Hodgkin lymphoma, and we have the preparation for the prostate cancer and the GCC-directed drugs on the horizon as well. In terms of timelines, as I already briefly mentioned, the phase I study we would like to have, but of course, this is a moving target. This is a data-driven target. The recommended phase II dose is close to the end of this year, and then we will start the phase II portion of the study immediately. This is allowed by our protocol design. We would like to launch as soon as possible the registration-directed monotherapy pivotal trial as soon as we can. Of course, which is not in the graph, as I showed you, in between, we would like to see or start the preparations for the combination treatment as well, parallel to this one. The HDP-102 is already ongoing, and we would like to complete in the next one and a half years the dose escalation for this compound. We plan to start the HDP-103 study by the end of this year. With this underscore, I mean submit to the HUD-30s, and the first patients should be expected the first quarter of the next year for the prostate cancer program. With that, I conclude my presentation and would like to invite our two colleagues to the question and answer session. I also would like to encourage anyone who is online and watching live this session to put your questions in the chat or in the format. We also received quite a few questions upfront. Until you put your question into the chat box or into the formular, I will already have one question, which we get a lot, this question. I will ask both of you, Mark and Jonathan, because I think you can give your perspective on both ends of the Atlantic that how do you see that? This is a question that comes quite often, that we know that there are quite a few new drugs that have been approved for multiple myeloma recently, CAR T cells, bispecifics, new targets, new interesting drugs with superb effect. How do you see that? Where can we position this drug? Where can you position this drug in your practice, particularly considering the U.S. environment and the European environment? Maybe Jonathan, you could start in the U.S. environment. Yeah, thanks so much for asking. Every day in clinic, I pine for the day of having readily available a BCMA antibody drug conjugate. I think what the DREAMM-7 and DREAMM-8 taught us about antibody drug conjugates is that you can use it earlier in combination with really good outcomes that, quite frankly, are as good as other more intensive BCMA therapies. I take the combination of the DREAMM-7, DREAMM-8 data and the data that we see with HDP-101 where there's no ocular toxicity, and I really see a perfect space for that right now. That is to understand the registrational strategy of going to the post-BCMA space, but I really like the idea of much earlier in course of disease in combination. Thank you, Jonathan. Marc? Yeah, I can only echo that. Maybe I add that in addition to having something that is really, really, I have hardly ever seen a drug that is as well tolerated as this one in our patients so far, is the fact that it actually targets resting, so dormant cells. I think especially in earlier lines of therapy, there is a huge potential to help eradicating the clone that is giving us all the trouble. In combination therapy, as always in myeloma, we aim for combinations with by far the highest efficacy. I think this makes a lot of sense. Thank you, both of you. There was another question which I received preliminary, and this was regarding the expression and expression downregulation of BCMA. This question, I would like to direct to Professor Raab because I think you also did some pre-clinical work together with us identifying low expressor cells. What is your view on the expression, and particularly when we talk about HDP-101 treatment? Yeah, we did quite some pre-clinical work a few years ago and published that. What we can say is that really very few molecules are sufficient on the surface of the myeloma cells to be addressed by HDP-101 and efficiently killed. That is one big advantage for the post-BCMA space, as we have several data published from colleagues around the world that after BCMA addressing targets or addressing agents, the BCMA can be downregulated to some extent. Actually, the issue that it is like biallelic deletion, BCMA loss on myeloma cells is relatively rare. It might be like 10%, maybe 15%. That does not happen very frequently. What also has been observed is mutations, so BCMA mutations that might lead to a loss of binding. However, this is compared to the other widely used immunotherapy target, the GPRC5D, is also relatively rare. I think there is a good chance that we still can address post-BCMA myeloma cells in respective patients. We can also, I mean, there are tools basically that we can test before, expression and mutation status, to maybe prevent unnecessary exposure. Thank you, Marc. We got a question about, let me—I'm sorry, I'm trying to find it because we received quite a few questions recently. Before we go to that, I will check these online questions. There was another question around the bystander effect because we do know that this drug doesn't have a direct bystander effect because the payload is inert to the environment. Do you think that this could be a limiting factor for this drug? Maybe I put this question to Jonathan, or could it be an advantage or disadvantage for this drug? Yeah, I mean, I view it more as an advantage in that I think that there's a reason we're not seeing myelosuppression, and the thrombocytopenia is not from depletion of megakaryocytes. I view this as a positive. Again, just the comment right now requiring a small number of BCMA molecules on the cell surface in order to still see activity, I sort of don't think that's necessary at all. My guess is that it's one of the reasons why there's so little toxicity. Thank you, Jonathan. There was one question we received that, and this is the question's congratulations to Heidelberg Pharma and to the investigators for remarkable progresses on the ADC platform. Do you have any exposure PK data in patients? Any evidence of immunogenicity? If you don't mind, I will take this question because of the details. Yes, we have excellent PK data. We shared some of this PK data in our last presentation during the ASH meeting. Currently, our PK is well within the boundaries of the expectations. As of today, none of the patients has showed clear evidence of immunogenicity, which means that we haven't identified any patient with anti-drug antibodies in their bodies. Of course, we're continuously checking this inside all of our patient samples. I have a little technical issue there. There was one question which was submitted prior to the meeting, which I want to direct to Professor Raab. This is the question that what is the uniqueness of the amanitin and targeting RNA polymerase II in your view compared to other payloads? Yeah, I mean, it is actually, as you said, Andras, and I think I also touched upon briefly, it is inhibiting RNA polymerase II. It basically shuts down all RNA processing in the cells. That is why, of course, you cannot give it like a free drug systemically, as we all know from the mushroom poison. It is very, very effective in, so to say, disturbing all cell function of the cells that take the drug up. That is why it is the perfect payload for ADCs to be delivered specifically to the target. Again, as I said, and you said as well, Andras, it absolutely does not depend on proliferation or cell cycle, whatever. It's completely cell cycle independent, which you showed also in our paper very clearly, directly comparing it with an MMAF payload. The other thing is that the locus, so where the—I think I have a connection issue. Where the RNA polymerase II is coded is very close to where the TP53 is coded. We know that if TP53 is deleted in myeloma cells, then almost always the locus of the RNA polymerase II is also deleted, which lowers the expression of the enzyme, which again, at least in vitro so far, makes the cells actually more responsive to the payload. We have still, of course, to prove that in the patient number, but there is certainly a potential—there is certainly a potential that del(17p) patients, which is absolutely high risk in myeloma, are better or more susceptible to response towards this drug compared to other drugs. Thank you, Marc. Very well said. We received another question, which is more likely for the non-clinical. I will take this question, which means thanks for the presentation. Are pre-clinical data available for killing of non-BCMA presenting cells? What is the toxicity profile of the free payload? The ADC, the intact ADC itself is inert and not able to kill non-BCMA presenting cells. Of course, there could be an a specific uptake on a really high concentration of the ADCs, which we hopefully in the clinic, we are not near to this concentration. As of today, we haven't seen any such effect. The free payload is actually not able to penetrate normal tissue cells. Only one type of cells are able to pick up the free payload, which are the liver cells through the OATP1B3. As of today, what we—and this is also what we presented, I think, in the last couple of presentations—we were not able to measure the free payload in the circulation because it is such a low concentration. However, we could measure the free payload. We know where it goes. It goes to the urine, and this is where we can recover the free payload. After the cycling, the free payload is really washed away quickly from the circulation and goes where we want it to go, and this is the excretion. We also got a couple of questions around. I'm really happy to see that people are already wanting to know details about the combination therapy of this drug and asked if we have any data. As of today, obviously, we don't have any clinical data on the combination. This is what you have to wait a little bit because we have to run the clinical combination studies for that. I will put the question to Jonathan on top of what we showed, like this imid + dexamethasone combination. What else you would like to see as a clinician on the combination repertoire for HDP-101? Yeah, I think that you really can use because when you're looking at combinations, you're not looking at something specific in mind that you need to increase the—you want to increase the immune system or overcome T cell dysfunction. You really can make this accommodation drug with any active myeloma drug that is hitting a different target. It is primarily because, A, we know the target is effective. The target is an appropriate target. B, the significant lack of toxicity, you are not going to have problems with overlapping toxicity. I really like the idea of combining with starting with pomalidomide. No reason we cannot think about in the future state combining with cell mods, things like iberdomide and mizigdomide. Again, because we do not have non-overlapping toxicity. I like the idea of combining with a proteasome inhibitor. I like the idea of using this as part of a quad. There's no—again, looking at the really impressive triplet versus triplet data that we saw in the DREAMM study that you take similar efficacy, maybe better, and you eliminate the ocular toxicity, you have a drug that you can combine with anything. Sorry, mate. Yep. We did in vitro combination studies, of course, but it's in vitro. But it was very synergistic with as simple as dexamethasone, right? And we combine all drugs with dexamethasone in myeloma. That could be also quite an easy and cost-effective starting point. Good. Thank you. We also received a couple of questions before regarding lots of people are interested in our long-treated showcase patient that we all love, this patient. Mainly the questions are around, can we give any update? This is what I have to say that what we just released at the EHA meeting a couple of days ago, a few days ago, we unfortunately cannot give any more update because this is treatment still ongoing. That is the case. The treatment is still ongoing. The patient is doing well. We do not have any other news. The patient is already 20 months in therapy. We will give an update actually in the upcoming IMS meeting because hopefully if the abstract is accepted, we just submitted an abstract together with our colleagues to the IMS meeting in Toronto. Wish us luck that the abstract is accepted. We can give you an update, obviously, not just on these ongoing patients, because as we mentioned, we have also ongoing patients from Cohort 7 and from Cohort 6. Hopefully we can give you an update from those patients as well and maybe some data on the Cohort 8 patient as we progress into the clinical study. I will just go through again the list of questions if we have something new that we should—I think we answered most of the questions. Yeah, we had one question. I know this was answered. Yeah, Benjamin Prudhomme, we answered this question already. There was one question regarding benchmarking our drug. One of our—and this is, I think, a difficult question. I asked our colleagues what is the benchmark as efficacy and safety benchmark in the relapsed/refractory multiple myeloma post-BCMA treatment. I think it's a difficult question to answer because I don't know if we have any kind of clinical data currently out there for this particular patient population. Jonathan, do you have any idea on that? I think, again, ultimately, I view this as a combination drug. If you're looking at single-agent activity, I mean, if you're in a post-BCMA space and you're above 30% and your duration of response is 10, 11, 12 months, I mean, that's a—I have said this before to you. That's a drug. Exactly. Exactly. That's what I was tending. Marc, can you confirm that from your perspective? Oh, yeah, absolutely. I mean, if you think about Belantamab mafodotin as not post-BCMA, of course, at that point, really. It was like 25% response rate, and it was approved. That was, as I said, not post-BCMA, right? From what we see so far, small patient numbers need to be confirmed. The larger numbers, no question. What you see so far, that can be confirmed in phase II. I mean, there's no doubt that this is going to go a long way. Yeah. Thank you, both. We also received a question about our strategy, and this mainly reflects what I said about potential accelerated approval. Of course, this is a potential. This is dependent, will be dependent on the clinical data. People are already asking us about breakthrough therapy designation and acceleration, potential acceleration, and what is the trigger and what is the response rate. I think it's really too early to address these questions. Really, I think we need to do first things first. We need to complete the dose escalation. We need to find the therapeutic dose for the recommended phase II. I think we are really close to that because the data which we just presented are really superb, which means that we have a dose level when we continuously—or multiple dose levels, to be honest—where we continuously see responses, and the adverse event profile is really favorable to our patients. We need to do our homework. We need to do the phase II portion of the study. We need to talk to the respective health authorities, discussing the case, and propose some next step. I think this is the point when we really can decide if we apply for a breakthrough designation or if we apply. First things first, let's generate the clinical data and then talk about the potential next step. I think this drug really has a good potential. I think with that, our time is also up. Any last words, Jonathan or Marc, to the audience? We're investigators here, and we are excited about the ongoing investigation of this medication. I think it's going to be really important in our field. Thank you. Marc? Yeah, I can only confirm that. I mean, the trial is enrolling relatively quickly, I think, for a phase I with a BCMA targeting agent. I think that speaks on its own. Yeah. Thank you, both of you. I especially thank you for your support, not just with the webinar, which is also outstanding, but also your continued support to this development. Thank you for the audience for your contribution for today. Excellent questions. Thank you so much. Stay tuned for our next update.