Heidelberg Pharma AG (HPHA) Earnings Call Transcript & Summary

Welcome, everybody, to today's R&D Day of Heidelberg Pharma. It's my pleasure to welcome you here today and to present our technology to develop novel ADC drugs for targeted and highly effective cancer treatment. Please see our safe harbor statement about our forward-looking statements. My name is Andreas Pahl. I'm the Chief Executive Officer of Heidelberg Pharma since February 1 of this year. Before the CEO, I served as the Chief Scientific Officer for many years, Heidelberg Pharma in developing the technology and the clinical assets of Heidelberg Pharma. With me, Andras Strassz, our Chief Medical Officer, who joined a couple of years ago, Heidelberg Pharma after doing clinical development in a few other companies and gaining the experience in the oncology space for early clinical development. In addition to our company presenters, we have 2 external presenters where you find the bios on the next slide. Rakesh Dixit is a worldwide renowned expert in this ADC space. He is working for several companies, especially for Medimmune, AstraZeneca, where he did a lot of ADC drug development. And since a couple of years, he is an independent consultant consulting many companies in this space of ADC drug development. He will give an overview about the nonclinical data of HDP-101, which will be the focus of today's presentation. He will be followed by Jonathan Kaufman, who is an associate professor of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, USA. He's one investigators of our HDP-101 clinical trial, and he has been on from the first cohort on and treated several patients by himself. So he has first-hand on experience of HDP-101 treated patients. In his presentation, he will give a major update about the HDP-101 trial, especially about the last, the fifth cohort we have seen already objective responses and partial remissions in these patients, which makes us very excited about our HDP-101. On the next slide, please let me introduce first our company. So the mission is to build a world-class ADC pipeline with the use of differentiated ADC technologies. We spent quite some years to develop our platform technologies, but the development is finished and we're now in the plug and play mode. So we can identify new targets with new antibodies, put this in our platform and we're able to develop from a new target to IND and ADC development candidate in 3 years. Protected our platform with several IP families and especially in the field of Amanitin and its mode of action. We believe we have strong monopoly which keeps other players in field away and to the best of our knowledge the only company in the world developing Amanitin as a new payload for antibody drug conjugates. We also established the supply chain for the GMP manufacturing of Amanitin and Amanitin based ADCs. We completed 5 GMP batches already. In addition, we have strong partners Huadong medicine is a China based company which fall thinks sink on China plus territories which take our drugs and develops and market these drugs for each territories. Takeda has obtained license for our technologies, so they use it for their own targets and antibodies and to develop with our technology and new ADCs. The latest addition to the partnerships few weeks ago that we signed a deal with HealthCare Royalty from Telix Pharma where we were able to sell royalty stream partially to that company which gives us further financing of the company. Meanwhile a clinical stage company [ lead program ] which will be the focus of today HDP-101 in multiple myeloma, it's an adult escalation trial and we've seen the first objective responses and partial remissions in patients and this will be the focus of the clinical presentation of the day. Later this year we will file CTA for our next candidate HDP-102 and we expect first patient in this year and 2 additional clinical trial applications on preparation for next year. We have a highly experienced leadership team, roughly 105 employees really having the expertise for the platform, the technology in our house, the cash runway is now until mid '25, but we expect from the royalty further milestone payment by the end of the year of USD 75 million, which gives further financing of our clinical pipeline. On the next slide, please, as a reminder, the patient is the focus of all our efforts. And one of the biggest challenges on oncology is resistance. One out of 2 human beings will be diagnosed with cancer in their lifetime. And more of 90% of these cancer patients will die by cancer because of drug resistance. So that's the one of the biggest unmet medical needs in the space of cancer. And on the next slide, you just see an example of a journey of cancer patients. So that's a melanoma patients you see on Part A before the treatment of the melanoma growing under the skin of this patient, and with today's standard of care, you can really treat this patient very well. So like on Part B, it looks like this patient is cured after a few weeks. But what happens, and this is the common observation, tumor cells get resistant to standard of care, the tumor relapses. And on Part C, you see the regrowth of the tumor. And that patient died a few weeks later on. So we desperately need new drugs with new mode of action to overcome the resistance of cancer cells. And that's the mission of our company, we want to create value through the development of best-in-class agencies, so we are already focusing our expertise in the ADC space. We are scouting, partnering and doing in-licensing for targets and antibodies. And then we combine this with our toolbox of proprietary payloads and generate new antibody drug candidates. And with our research and development expertise, we then further develop these ADCs into clinical candidates in early clinical development. And then we look for partnering, co-development or retain territorial rights for potential commercialization. So that's the business model of Heidelberg Pharma. On the next slide, you see the focus of today's presentation because our lead programs are based on a new payload, which was called Amanitin, which is a main representative of a unique less of natural toxins. It basically comes from the poisonous green death cap mushroom, it's bicyclic octapeptide. This has some exceptional biophysical properties like stability and hydrophilicity, which makes it very different here, as you see with the red bar on all the other payloads. So this gives rise to unique properties with regard to the [ CMC ] of this payload. What is also very unique about the Amanitin is its mechanism of action. It's a specific inhibitor of the RNA polymerase II. And what you see on the right part of that slide, that almost all fundamental processes of cellular metabolism has been exploited for cancer therapy. But only one specific part of this one, namely the eukaryotic transcription is never being used for cancer therapy and Amanitin is the only compound known in the world to be an inhibitor of the RNA polymerase II. So this was the core idea to exploit and harness this compound for cancer therapy. And we use the ADC technology to make that compound amenable and applicable to cancer therapy. One very specific feature what we believe is very important, very differentiating, it has a cell cycle independent mechanism. So we can even kill dormant tumor cells, which is in contrast to the other payloads. Furthermore, the intracellular concentration of the RNA Polymerase II is very low. So we have a one-on-one binding, and we need to deliver a rather small amount of toxin molecule to the tumor cell in order to achieve [indiscernible]. Last but not least, for the supply chain, we made Amanitin synthetically accessible. As mentioned, we have the GMP manufacture growing and we protected these processes by IP. On the next slide, you see a brief comparison how RNA polymerase inhibitor Amanitin fits into the landscape of payloads. You see the well-known tubulin inhibitors like Maytansines and Auristatines, you see DNA damaging agents and the new one, the topoisomerase inhibitors. And you see the differentiation of the Amanitin. So we are a medium potency agent, which is the trend in the space that these ultrahigh-potent payloads, usually suffer from toxicities. We have a hydrophilic payload. We can overcome resistance. We have never found any tumor cell which was resistant to the Amanitin through its mode of action. We are active on nondividing cells. We have a biomarker, which is also the only payload in this space where we have a platform-wide biomarker to be exploited for clinical development. And as already mentioned, we have target and modification exclusivity for the Amanitin. So there are no copycat versions of the Amanitin known, and its mechanism of cytotoxicity is radically different from conventional chemotherapy in contrast to all others, has never been used as a small molecule in cancer therapy. So every patient will be naive to the Amanitin when delivered to the patient. On the next slide, you see the development of our platform. So the result, what I call the plug-and-play mode. So we optimize, and I call it the honestly ADC technology to make Amanitin applicable to cancer therapy. On the right, we're just drafting the regions from the antibody, which recognize the target on our standard backbone. The standard backbone in blue was optimized for the Amanitin, we screen for the best positions for a site-specific communication. We optimized the drug to antibody ratio, and we found that the 2.0 is sufficient specifically conjugated to an engineered system of the antibody. Furthermore, we do Fc silencing, we truly believe that the potency of our payload is sufficient to cure the tumor cells, and we want to avoid unspecific interations with non-tumor cells via the Fc receptor. So that's the reason why we do Fc silencing on our antibody drug conjugates. And then in red, you see the Amanitin as a warhead with a differentiated mode of action, the 3 hallmarks we cured tumor cells, we overcome resistance and we have a predictive biomarker. And with the synthetic Amanitin derivatives we found by our synthetic process, we have improved properties over the natural count. On the next slide, you will see a summary why we believe that we can further differentiate from the current cancer therapies which has limitations. As what I have shown you in the beginning, in the pictures of the patient, the standard therapy is good in debugging the tumor, but we have some cells, most people call them cancer stem cells, CSC, which survive which getting dormant and to survive and become resistant to the standard therapy. And in the long term, these cells leads to the regrowth of the tumor and to the minimal survival increase of the patients. Our payload is different. We not only debulk the tumor, but we also care this cancer stem cells because our payload is able to eliminate nondividing cells and cancer stem cells. So we truly believe that the long-term responses improve with the application of ATACs into cancer therapy, again, with the mechanism of cytotoxicity, which is radically different to conventional chemotherapy. On the next slide, you see a summary of preclinical features of our ATACs where we believe that this can turn a potential clinical benefits. The efficacy against dormant tumor cells can probably lead to longer progression-free survivals in this patient. We have seen efficacy in very low target expressing tumor cells, which we believe can lead to deeper responses and higher response rates. The mode of action is radically new to all patients we can overcome the resistance. In particular, for the HDP-101, which is important, we haven't seen ocular toxicity for the Amanitin, where we have a superior safety profile, and Jonathan will point later to this feature of our HDP-101 drug, which we have now approved already in the patients in the dose escalation trial. And last but not least, not mentioned here with the 17p deletion, we have a biomarker where we can stratify patients and which leads to an accelerated approval and breakthrough designation. On this slide, you see our growing pipeline of proprietary and partner programs. Pursuing the success of HDP-101 and multiple myeloma, we already started the development of follow-up program. HDP-102 is a program which targets CD37 and non-Hodgkin's lymphoma, and we are planning to submit the clinical trial application later this year and even have the first patient for that program later this year for non-Hodgkin's lymphoma. This program will be followed by HDP-103, which is targeting PSMA in prostate cancer, another program using the Amanitin as a payload, and we are highly confident that we can make a difference to these prostate cancer patients. The next program 104, has been down-prioritized now. We are focusing now on the program HDP-201 targeting GCC. And this will be the first program based on our new payload platform which is based on the TOPO 1 inhibitor, where we identified a new link over the new soluble for topoisomerase 1 inhibitor, and we are very excited to run this program for colorectal cancer targeting in GCC. HDP-103 and HDP-101 will be submitted for clinical trial application later in 2025. In addition, Takeda is also very excited about technology. They're pursuing actively the first own ATAC program on a proprietary target, and they are very far in the progress of IND-enabling studies in the clinical development. On the last slide, you see the summary of our upcoming catalyst to become a leading global ADC player. Really believe that these multiple inflection points coming of these 4 different clinical development programs have a huge potential to increase the company valuation significantly. As mentioned, we expect the approval of the clinical trial application for 102 soon and having the first patient in by the end of this year. In addition, we expect also to recommend Phase II growth of HDP-101 by the end of this year, which will be followed by the extension cohorts and the expansion part of that trial for the HDP-101 program. Next year, then we will have the clinical trial application for 103 and 201. And through the upcoming years, also, we will see then the recommend Phase II doses for the programs 102 and 103. Our partners are very active. They are [indiscernible] actively starting the clinical development of HDP-101 in China and, let's say, enrolling patients as soon as we have reached the recommend phase II dose for the HDP-101. And as mentioned, Takeda conducts IND-enabling studies. And by this, I would like to conclude my introductory presentation. Already I thanked everybody for the attendance. And I'm handing over to Rakesh, who is giving [indiscernible] about the HDP-101 program.

Thank you Andreas for a very kind introduction. My name is Rakesh Dixit, I'm an adviser and consultant for Heidelberg Pharma. And today, I'm going to present some important points about this ATAC molecule, HDP-101. It is a BCMA-targeting ATAC, and I'm going to present some of key points on the pharmacology and safety of this molecule. So we can go to the next slide, which basically describes about the differentiated profile of HDP-101. So what makes it unique, given BCMA therapeutic area is very crowded. But this molecule stands out quite well in many ways. Because of its potent payload, which is a very potent inhibitor of RNA polymerase II. You can see on the left-hand side, very left. You can see it's highly [ efficacies ] even in the tumor cells that have very low expression of BCMA, which is very unique because not many therapies work in the low BCMA-expressing multi-myeloma cells. And it's because of the potency of the payload, we can kill the very low expressing BCMA tumor cells. And on the dash line, you can see that it doesn't harm the healthy sales, which is very unique. In the middle, you can see that its actually much more efficacy with the current ADC, which has been approved. And then it was withdrawn by the company because safety issues on ocular toxicity. And then likelihood it might come back. But in any case, the HDP-101 is way a lot more potent than the current BCMA, MMAF, ADC, which uses a microtubular inhibitor, again, showing that the potency of the RNA polymerase II inhibitor extremely good, and that's why we are seeing a very good tumor piling activity. On the far right, you can see the right-hand side that in the multiple myeloma tumor cells, where the current therapy like elotuzumab and [ pomalidomide ] combination was daratumumab where you see resistance against this multi-myeloma cells BCMA. The HDP-101 is extremely active. So you can see from this slide, you can say it's very active in low BCMA expressing cells much more efficacies than the current approved BCMA ADC and a third also resistant tumor cells. So I can go to the next slide. Here, it's important to also understand the pharmacokinetics of the HDP-101 in both monkeys and humans in cancer patients. And you can clearly see that a lot of similarities in the pharmacokinetics profile between animal studies and in the human studies. On the right-hand side, you can see that despite the differences in doses, you're seeing a pretty similar exposure, suggesting that the kinetics is at least on the qualitative level, as was quantitative, there's a lot of similarities in the exposure profile, including the half-life, Cmax and the AUC. And another important thing to note that it is linear in doses, which is also a very important thing. Despite the half life of 12 days, which in my opinion, is not easy to achieve with any ADC molecule. They're seeing a very good half life of the molecule. Despite that, we don't see an accumulation of drug and the most important thing to note is that there is no free Amanitine or minimal Amanitine circulating in the system regulation. Next slide. And this slide actually talks about the pivotal GLP toxicology study that we ran for IND filing. And you can clearly see in this slide that the adverse of the profile we are seeing for this drug is actually related to the prepay load, which basically intercellular release of the payload. And you see because Amanitin is well known to cause liver kidney dysfunction. That's what we're seeing. But unlike the MMF ADCs, we don't see any ocular changes. We're not seeing any toxicity. We're not seeing any effects on cardiac system. The toxicity profile is based almost reflective of the payload, which is Amanitine. You see transient thrombocytopenia, which you'll expect from the MoA of the molecule, but is transient, is reversible so that on the right-hand side, you can see as soon as we dose, you do see depletion in the platelets. And then during that time, it's a transient, so it comes back. And then again, you give the next dose, it comes down again and comes back again suggesting that there is no direct killing of the platelets by HDP-101 because those in vitro studies have been done directly with the ADC, and we don't see direct killing of the platelets. And also, we don't see any major effects on the bone marrow [indiscernible] that are making the platelets. So that's really important because thrombocytopenia is fairly common in multiple myeloma patients, and that's something we had to pay a lot of attention to. We do see some changes in the carting times, but you expect when you have RNA polymerase II inhibitor that affects the protein synthesis that some of the clotting factors, and this could be also affected at fairly high doses. Next slide. And here, you can see also that in terms of the liver enzymes elevation, we are still remaining below the threshold for a very high increase in ALT and AST. These are 2 important liver enzymes that reflect the liver function test. And you can clearly see that we are well below those numbers. And the same kind of profile we also see in cancer patients that the biomarkers of liver function tests like ALT and AST increases, are somewhat identical between monkeys and humans and actually, we can easily monitor the liver toxicity by looking at the rise of the ALT and AST. Next slide. And here is a very quick on the mechanism of Amanitin ADC action. So I mean, we all know that alpha Amanitine, which is present in certain mushrooms. When you ingest it, it goes through absorption through GI track, small intestine. And then it makes it to liver. And in the liver, Amanitine binds to a transporter called OATP1B3. And the transporter is responsible for intake of this inside the hepatocytes where universally target RNA polymerase II, and that results in liver toxicity. Some of that Amanitin can also get reabsorbed back through intrahepatic circulation and that can also be responsible for liver tox. And also because it's a peptide molecule that can also with a similar mechanism can also produce some toxicity as well. Next slide. And so just to comment on 3 important mechanisms of liver toxicity caused by the ATACs or Amanitine-based ADCs. So in the first instance, that the intact ADC does not mind to the OATP1B3. So that is not direct entrance of the intact ADC. However, once the ADC makes into liver through some nonspecific mechanism, which could be through FcGamma receptors, macropinocytosis [indiscernible] receptors, multiple mechanisms could be involved. And once it's taken there and then the Amanitine is released by lysosomal proteases, then you start seeing that free Amanitin that can bind to the OATP1B3 transporters, and that's how it gets inside the liver pericytes. And then where it can affect the RNA polymerase II [indiscernible] protein synthesis inhibition and apoptosis and causing oxidative stress, and that is responsible for the death of the liver cells. So clearly, you can see it's not the free Amanitine, which is very minimal in circulation is actually the Amanitine release inside the cell that is responsible for liver tox. And that's really important to understand that the ADC itself does not have any binding to OATP1B3 is a free Amanitin payload. That's what especially that one is really intracellular. And also, the free Amanitin is a polar molecule, and that cannot be entered into cell that easily can of polarity. And the one last slide is this is an important slide, where we did an extensive PK/PD modeling using the nonhuman primate toxicology data as well as several mouse models where we look at the efficacy dose, plasma levels, and then we also look at the drug levels in one case and then try to model it. What is clear from this data that the human equivalent dose as where we have seen the tolerability problems in monkey studies is about 0.75 mg per kg that equivalent dose for human is about 0.25 mg per kg as you see in the black line. And you can see that if you look at the dose response modeling, you can clearly see that we will be able to maintain fairly good concentrations of drug, ADC concentration well above the tumor inhibition concentration, at least, I will say, 100 microgram per kg dose and above. Our goal is not to move it up to 250 microgram per kg dose, which was shown to be toxic in monkey's equivalent dose. So I think you can see that we are seeing activity in clinical trials at substantially lower doses and which is also a good news that we are still below the threshold of toxic doses. So I think it's all good news for this molecule and this is providing good therapeutic index to continue moving forward. So this is where I'm going to end my presentation.

My name is Jonathan Kaufman from Emory University in Atlanta, Georgia. And on behalf of Heidelberg Pharma, I'd like to present a study update on HDP-101, a first-in-human study of a novel BCMA-targeted antibody drug conjugate. In this slide, you will see the overview of the study as a whole. And again, as noted in previous presentations, HDP-101 is an antibody drug conjugate targeting BCMA. We'll initially do a Phase I study to establish the safe dose using a novel dose escalation adaptive study design with 15 to 25 patients approximately. And then once we establish the right dose and schedule, we will have a recommended Phase II dose. And then in that recommended Phase II dose, there will be 30 patients stratified by the amount of deletion 17p. Patients who have essentially no deletion 17p, less than 10% of the myeloma cells with 17p, those patients with a moderate amount of 17p deletion 10% to 59% and then at a minimum of 10 patients who have the greater than 60% 17p deletion. In terms of the study scheme there is a screening period with relapsed/refractory patients with myeloma patients have no or limited therapeutic options. We'll then go to the screening period in enrollment followed by the cycle 1 with the DLT observation period in that 21 days, and again, HDP-101 is administered intravenously every 21 days. And then cycle 2 and beyond, given every 3 weeks, we'll have ongoing tumor and toxicity assessment. Treatment will end upon adverse reactions or investigator/patient decision. And then finally, there will be a follow-up period for subsequent treatments and survival. And we had 18 patients so far, 7 females and 11 males. They were enrolled in 5 different cohorts at 20, 30, 60, 80 and the most recent cohort of 100 micrograms per kilogram. The median age was 70 years old, which is typical of a relapsed/refractory myeloma patient population. They were heavily pretreated and had multidrug resistance in a medium prior lines of 6.5 prior lines of therapy with a range of 2 to 15. And next slide is an overview of the efficacy data, and you'll see this with the swimmer spot, to orient you to the slide, the bars in red are those patients who have PD. The bars in blue are those patients with stable disease. And you'll see in the top here, all 3 in the 100-microgram per kilogram cohort, 3 IMWG responders at a PR and highlighting in the green box is this one individual who had both prior BCMA and GPRC5D exposure previously. And these patients achieved a PR and nearly a VGPR, a deepening of the response with a 90% reduction in the amount of myeloma in the patient. This slide highlights the most common adverse event to HDP-101. And you'll see in these beginning cohorts, there's very little systemic toxicity. There is what was noted as adverse events with hematologic toxicity, but in these very early cohorts, most of these AEs are likely to do to disease. When we get to the dose where we had responses, it's what you'll note is that all of the 6 patients did develop thrombocytopenia, and 2/3 of the patients develop grade 3 or 4 thrombocytopenia, and I will highlight this in the next few slides. The other thing we saw is in one subject, again, I'll highlight in the next slide, had increased AST and ALT and required a dose reduction. What is really critical about this AE table is not what we see, but it's what we don't see. We don't see any ocular toxicity and ocular toxicity has really hampered other BCMA targeted antibody-drug conjugates in this space. So there's no ocular toxicity, no renal toxicity, no infusion-related reactions. Overall myelosuppression is minimal, if any, what we see in thrombocytopenia, which I'll talk about in a moment. And while we saw transient increase in ALT and AST, we saw no liver dysfunction. There were no DLTs in cohorts 1 through 4. And in cohort 5, that we saw 3 DLTs related to transient thrombocytopenia. After cohort 5 based on the DLT rules, we have switched to a dose optimization strategy, and I will show you that strategy in a few slides. In this slide, you'll see the one patient who developed transient AST and ALT evaluation. This was Cohort 5, again, the 100 micrograms per kilogram dose cycle 1. The patient had Grade 3 AST and ALT. Subsequently, there was a dose reduction and no further increase in ALT and AST, again this was transient resolved within a week and the bilirubin remained normal and there was no downstream liver dysfunction. In this slide we'll focus on the platelet levels in Cohort 5. And what y you'll see here is that there was a rapid and transient thrombocytopenia and again 3 of the patients met criteria for DLT in this scenario importantly outside of the one patient just cohort how a dose reduction for the AST and ALT. There was no dose reductions in the other 5 patients and you'll see here there was not ongoing thrombocytopenia. So it was really only after that first dose and it was transient. We saw no other signs of myelosuppression and we found no evidence of direct toxic effect on platelets or the mega carrier sites. And so in order to overcome this transient significant thrombocytopenia we have developed a dose optimization strategies after a detail safety analysis. And you see now that we have 3 optimization schedules Arm-A, which is dosing every 3 weeks with pre-medications. We have Arm-B with using weekly dosing, and then we have Arm-C where the first cycle is associated with a split dose and then every 3 weeks. And our hope is that we can maintain the dose intensity at that 100 micrograms per kilogram eventually while minimizing the thrombocytopenia. And I'd like to finally comment about where I think where this falls in the current myeloma space. Firstly, we know that BCMA is a well-validated target in myeloma. The current approved BCMA targeted medications are CAR-T cells and bispecifics which are not appropriate for all patients. And we're really missing an antibody drug conjugate that can be given to all patients. And that is given on a once every 3-week basis. And we're really missing a drug for our deletion 17 patients. And so what we see here is a proof of principle that this medication does have efficacy in the relapsed/refractory patient population. As a proof of principle, we saw efficacy in a patient with prior BCMA and GPRC5D exposure. And very importantly, and again, I'll reiterate what other antibody drug conjugates have suffered from is ocular toxicity. And we have not seen any ocular toxicity to date. And with that, I believe that this drug is right for further development, and I remain very helpful.

With this, I would like to hand the call back to George for any web questions. Over to you, George.

Apologies. Hello. My name is George Badescu. I'm Chief Business Officer at Heidelberg Pharma, and I'm going to read out questions we received through the web interface. There were a number of questions on this topic, so I try to group them together. The first question is related to Magenta Therapeutics who have encountered issues in the clinic. Have you seen any similar toxicities in the HDP-101 trial? Andreas, if you want to start answering the question.

Thank you so much George. So my name is András Strassz. I'm the Chief Medical Officer of Heidelberg Pharma. And as I can tell you that on the tested doses so far, we haven't encountered anything similar to the Magenta cases. And as a matter of fact, we overcome the dose where Magenta already had a patient passed away on this unlikely or unfortunate lung issues. And after that case is we implemented extra safety features in our study by having checked the patient previously in entering the study and on study and despite this really thorough check, we have not seen any cases which could be related to our drug as of today. And we concluded based on our assessment that those cases were really most likely due to the target and not related to the technology itself.

The second question is related to the future of the trial. Do you intend to dose higher? How many more cohorts do you intend to recruit. Andras, if you can take this question.

Yes. Thank you. Definitely, we would like to escalate the dose furthermore. So we will open up this study. Actually the study is currently open for recruitment for this dose optimization cohorts. And if any of our strategies or if all of them are addressing the issues, we will definitely escalate the dose. But as we encountered quite a number of patients responding to the drug on the 100 micrograms per kilogram, where we have strong reason to believe that our sweet spot, our recommended Phase II dose is not far from these dose cohorts.

So that really only addresses the efficacy part of blenrep. So the question is how do you compare blenrep the other well known ADC targeting BCMA. Is blenrep a competitor and I would handover this question to Jonathan.

I think on some of those I tried to have mentioned this when I reviewed the data. Comparing blenrep and [ HDP-101 ] they are both antibody drug conjugates that target BCMA. The toxicity is what has really limited blenrep's ability to be used widely and the challenge is behind using blenrep. And primarily that toxicity is ocular toxicity. And it was the ocular toxicity and failure to meet their primary endpoint on their phase III study that led to the removal of blenrep from the conditional approval both the United States as well as in Europe. And we've seen the preliminary data that they now have a positive phase III study. So that really only addresses the efficacy part of blenrep and there's no real fix for the toxicity part of blenrep. And so the ocular toxicity will remain. The challenges of giving the drug will remain. And as a proof of principle, we know that it's an effective drug. We saw in this most recent cohort efficacy with HDP-101 as an antibody drug conjugate BCMA. And we have not seen any ocular toxicity, and we don't anticipate any ocular toxicity. And I think between that, and the fact that there is predicted efficacy in the deletion 17p patient population represent differentiators between blenrep and 101.

Maybe I can add some features from the Amanitin on the mode of action to remind everybody the management is able to kill nondividing cells, and we know the myeloma are nondividing cells. So we have seen this in our data. This is far outcompeting the payload blenreps using. And we also have the potential to address very low expressing target antigen cells. So I believe the preclinical profile is supporting what Jonathan has said, that we are very well positioned versus the blenrep.

Thank you very much. The next question, can you give an update on the 6 cohorts? We are able to recruit patients. In general, given the promising data of the fifth cohort, is it now easier to recruit patients? Andras I think this one is for you.

Yes. Thank you so much, definitely easier to recruit more patients. So I already can share, but maybe Jonathan could add to that later that we feel the enthusiasm from our investigators and we already had no issues enrolling patients in the last couple of cohorts, so cohort #3 and #4 were and enrolling really fast. And we do participate the same after all the approvals are in place. So we already opened up this cohort for enrollment. But of course, as you know, we have to have the approvals in each and every country and almost for each every site individually. But I think the enrollment will have no issues. Maybe Jonathan?

Yes. I think there's a real excitement about the efficacy signal that came out in the last cohort. And so this is going to be a study that where in the first handful of cohorts, it's a more narrow population of patients that would accept, but now that we see that efficacy signal, I think accrual and there's been a real good team of investigators put together, we'll go rapidly through this cohort.

And a follow-on question from that is asking for an update on the patients that continued treatment on the fifth cohort. Can you give an update on the disease status?

Yes. Yes, definitely. Thanks much. So we have still 2 ongoing patients from this last cohort, which means quite remarkable, because they started treatment before Christmas last year. And they are still ongoing. One of them are in a really, as Jonathan already mentioned, in a really deep response almost achieved VGPR, so which means that 90% of the m-protein, which produced by the myeloma is gone from this patient and the trend is still declining so we really hope that in the next couple of quarters as these patients will even deepen the response.

The next question is what is the current state of knowledge regarding the development of resistance to Amanitin and what strategies does Heidelberg Pharma pursue to monitor and manage potential resistance to HDP-101 in the clinic. Andreas?

Yes. Maybe I can take this question. Amanitin is a very new payload. It has never been used in oncology. So every patient will be naive to Amanitin, even not as a small molecule, it was ever used and we have never come across any tumor cell response versus to Amanitin. We have seen this in, let's say, in translational data. So we believe there is no [indiscernible] system to the Amanitin. And of course, we will monitor the patients. We are not saying that we cure the cancer for the rest of the life. But we are very confident that we can break resistance that we give the patients a good duration of response and of course, we are monitoring if patients develop resistance, we will, let's say, do some translational studies in order to understand what possible mechanisms of resistance may develop against the Amanitin.

Thank you very much. And the next group of questions relates to the deletion 17p status of patients. Can you say which of the 6 patients that showed progression have TP53 deletion trait?

The Phase I study part for the dose escalation part is open for 17p deletion patients but not exclusive for 17p related patients. So we enroll all kinds of patients. And as of today none of our enrolled patients showed definitive 17p deletion, so we tested all of them but none of them has definitive 17p deletion, but we will address this question in the Phase II portion of the study. Because in the Phase II portion as you know we will stratify this patient on the 17p status and we will enroll at least 10 patients in that portion of the study who have definitely which means more than 60% of the myelomas showing 17p deletion in their bone marrow sample. So as of today we don't have any data on that, but hopefully it will be the Phase II portion we can answer this question.

Thank you very much. Can you give an update on the preparation of a Phase I study for HDP-101 in China?

Yes. As you know, we have the partner Huadong medicine, but we don't initiate a study in China before recommended Phase II dose. So our current plan is to include them into the Phase II portion of the study.

I'll pick the next question. Again, there are several questions on this topic. This question is as you regularly participate in industry conferences after the publication of the data on the fifth cohort on HDP-101, what kind of market feedback have you received? Have you noticed a pickup in interest of the scientific community related to the ATAC technology and HDP-101? Perhaps Andreas, you can start answering this question.

Yes, sure. We protect as announced, post at AACR, it was a very crowded post, so Andras presenting and 3.5 hours for the whole time, he was overwhelmed by people looking at the poster, talking to the poster. I believe also the investigators see more, let's say, interest in the program. As we are progressing, as Jonathan put on the table, with the responses we see now, we see a huge interest in our technology and also the HDP-101 program. And of course, also, we will continue business discussion. Obviously, that's a huge interest also for the asset from possible partners in that space.

There are a number of questions related to whether we are concerned about liver tox. Andreas, please go ahead.

Maybe Rakesh and Jonathan can comment on this one. So we did quite a good job, let's say, in the preclinical studies. We understand this very well. So we are not concerned. I believe the clinical data. let's say, see responses without significant liver tox, so I'm not concerned, but I'm happy to hear the comments of the external people from Rakesh and Jonathan, about that.

So let me comment on that. I think what we have seen, at least from the animal studies. The liver toxicity is a function of dose. So you don't achieve very high doses it's unlikely you are going to see the extreme liver toxicity you see with the Amanitin poisoning. So that's the biggest hope for me. The second thing as I tried to explain in my mechanism of action slide that Amanitin free Amanitin is enabled to cross the membrane. So it's not liver toxic by itself. In order for the liver tox to happen, the entire molecule ADC has to get in into liver. And that's again, dose-related. And when it gets into liver, then the payload gets removed and then biased to the transporter on the hepatocytes and that cause toxicity. So clearly, it's a dose-related process. And since we are still well below the doses where we have seen the high degree of liver toxicity in monkeys, I think I'm extremely hopeful that we won't reach to that dose level or see that kind of extreme DLT of these sever toxicities. Jonathan, do you want to comment on something?

Yes, I agree. I mean I think the patient who had the transient increase ALT and AST was my patient. And very clearly, this elevation of ALT was transient. It was not associated with liver toxicity. And there were confounding variables during the administration of the medication. And so there really is no evidence that I've seen looking at having looked at all the data of liver toxicity.

Also, I would like to comment on the resistance. I think there was a question. So I wanted to add what Andreas said. I think one thing we know that how tumors develop resistance, they typically develop a resistance against the payload. And payload resistance is quite often is through the, what I call, the PDP transporters. And since Amanitin does not bind transporter, so that means you have a less chance of seeing that kind of resistance process. And that's also a positive thing compared to let's see other statin like molecule, MME or other payloads, which are a very good substrate for PGP transporters. So I think that gives me hope that we will not see the payload based resistance, of course. And also even if we lose the BCMA target. And since we have shown the data that even the drug can work in a very low BCMA expression, BCMA cell that also gives me hope that you will have a much better chance of not seeing the resistance either due to target loss or due to payload logistics.

We are coming close to the top of the hour. So we're going to take one more question despite receiving many questions still. One question is, have you tested HDP-101 in cells from BCMA-treated patients either with bispecifics or CAR-T? Andras do you want to take this question, I suppose.

Yes, actually, because you asked this question on maybe preclinically, but we have a clinical evidence because one of our patients and eventually, that patient who had the deepest response in our study received prior treatment with the GPRC5 targeting bispecifics and with the BCMA targeting CAT-T and that this patient failed both treatments or progressed on this treatment. So there is a clear evidence that our drug is effective post-BCMA targeting and post GPRC5 targeting drugs on top of everything as because most of our patients received all other treatment modalities that you can imagine for myeloma patients.

Thank you very much. We will stop here. However, thank you very much for all your questions. There are a number of questions that we were not able to answer. Please get in touch with us separately and we'll be very happy to answer the questions. And now I'm going to hand over to Andreas for some closing remarks.

Yes. Thanks George. Thanks, everybody. Our external collaborators presenting, giving answers. The people of Heidelberg Pharma contributing not only to this R&D day, but to other work and the programs we have right here. Thanks, everybody outside for questions and attending. We are very excited. I hope we could excite you as well as we are about the potential of our technology and our first program, the HDP-101. I believe everybody agrees, ADCs are our frontier modality in oncology, they are proven. And we are a strong believer and I believe the data shows that the payload is the most important piece of the ADC because this makes a difference what payload you are delivering to the cell. And everybody is now looking at the world what is coming after the TOPO1 payload class, the next new payload. And we are the most clinically advanced new payload in that space and we believe with today's, let's say, first glimpse of the data we can demonstrate it works clinically. We have a therapeutic window. And we are able also like what Andras mentioned, with that patient, we can break out systems. And as a last reminder, we have a radical new amount of action, never seen, never used in any patient, so no cancer service resistant to Amanitin. So we have all the potential to really, let's say, bring a new class of payload to the patients. We are working on new programs. So we are very excited, stay tuned watch Heidelberg Pharma.