Faron Pharmaceuticals Oy (FARN) Earnings Call Transcript

Good day, everyone, and welcome to the Faron R&D Day. My name is Juha Alkane. I am the CEO and one of the founding members of Faron Pharmaceuticals. For those new to the story, Faron is a leading biotech in the fight against higher-risk myelodysplastic syndrome. Higher-risk MDS is one of the true unmet needs still in oncology, also known as the pancreatic cancer of hematology. We are listed both in London and Helsinki, so standard corporate disclaimer as we will be making forward-looking statements. It is our pleasure today to bring a comprehensive agenda on our activities and thinking. The first part will concentrate on our lead program in higher-risk MDS and slight update to the schedule. We will start with Professor Xidan due to his tight conference schedule. The second part concentrates more broadly on the pipeline, the market opportunity and the company vision. Also a bit on housekeeping. We will have a larger Q&A session at the very end, but that is for the Faron management. if you have specific questions for an external expert like Professor Zaidan please type in your message, and we will have a short Q&A after every external speaker so that we can let them go on their daily duties. So again, specific Q&A specifically for some expert otherwise, large Q&A at the end. That's all from me for now, your host, and I will give the floor to our esteemed Chairman, Mr. Dumas.

Thank you, John, and welcome, everyone, also on my behalf. Thank you for joining these events. So we have a great program today that Johan just shared. And I hope it addresses the request from many of you who have asked for a more thorough information about our science and our R&D plans at for. I'm personally especially excited about our lead opportunity. So pexmerilumab in high-risk MDS. As early in my career, I held executive roles at some of the leading global biopharma companies, Amgen, Celgene and SDN. And these are all companies that tied Volt with developing and commercializing cancer therapies and also hematological cancers like AML and MDS. And over the 35 years that I've been in the industry, we have seen a lot of progress, a lot of progress in many cancer indications, also hematological cancers. But there are some where the progress has been truly limited and high-risk MDS is one such indication. The last significant improvement was probably the introduction of hypomethylating agents, like azacitidine. And I was lucky to be part of launching that product internationally while I was at Celg. And that was already 17, 18 years ago. So it is definitely timed out for the next breakthrough in this indication. And we hope that we will be able to build on the current standard therapy and further improve the outcomes for patients with adding exam. We can move on to the next slide, please. So 2026 has been you could call it, a clarity building year for Faron. So we have now a clear focused plan, and the team is focused on executing this plan. So with longer follow-up of our PExMaPstudy, we have continued to see excellent results with begin both first-line and relapsed refractory high-risk MDS. And that has given us conviction and also to the clinical experts across the world to move back Marilia now to the next phase of clinical development. There were also some external events late last year that impacted our plans. So namely fails of other product candidates in this indication. And rather than repeat what was not working in terms of study design, we took these insights and modified our development plans accordingly. So we are now focused on starting a randomized double-blind Phase IIb trial as the next step. So this will be a comparison of bexmarilumab plus azacitidine to placebo and asacyntatib, and it will be in first-line high-risk and gears. And we will hear more about this study and the plan in the minute. To be able to execute this plan, we raised EUR 40 million through rights offering earlier this year. And now we have the funding to get this randomized trial to get to the readout of this randomized trial. And obviously, this will be a major value inflection point for the company. So we have a clear plan. We have the funding needed for the next milestone. We have a great team at Faron, so we have strengthened the team recently and very importantly, we have the support of the experts in the world's top research centers. And let's not forget, in addition to MDS, we have our program in solid tumors, and we will be hearing more of this as well. And as we recently announced, we already have the first patients in these combination studies initiated. So an exciting year, and we have an exciting program ahead of us today. So let's now move on to our first expert presentation. And presentation will be by Professor Andrea from Yelkoromextine and he's broadly recognized as the leading global expert in MDS. And he will share more details on the planned big study and the evolving NDDS treatment landscape. So over to you, Professor Zeg.

Yes. Thank you so much, Tom, and it's a pleasure to be here with you today. A couple of disclaimers on my own that this represents my own opinions and not my employers, and I have consulted for on but also I'm a little bit under the weather. So I apologize for my voice and there's a big thunderstorm behind me. So if you hear tender, that's what it is. So can we go to the next slide? So what I'm going to do today is I'm going to talk about MD as a disease and the challenges in terms of drug development and then talk about the evolving treatment landscape, in particular, some of the most recent S3 trials and their failures and how we have been working in the field in general, but I've been working closely with the foreign team to design the trial in a way that we have learned a lot from the previous trials, so that we can optimize the chance of success in the big Sara and hopefully, in the sequent Phase III trial. Next, please. Next, so and as many of you have probably been following these calls know the disease by now, but MDS is cancer. It's a formal or block cancer. It's associated with bad motor failure and therefore, symptoms of anemia and neutropenia and thrombocytopenia, leading to infections, bleeding and life-threatening complications. And while patients with MDS, many of them will not progress to AML, they still often will die from complications related to the bone motor failure but still one that the patients will progress to acute myeloid leukemia and the survival with are MDS really has been quite limited, as I'm going to show you in the next slide. Next, please. Next -- so you just heard from Tom, like really the standard of care for MDS has not changed significantly over the last 20 years in any substantial fashion. Bone marrow transplant continues to be the only potential way to get a cure; However, with the median age of MDS patients being there early to mid-70s and with many patients having comorbidities related to edge, most patients with MDS are not candidates for transplant. And real-life analysis actually have suggested that just the 5% to 10% of patients undergo transplant. Therefore, the main stay of treatment has been hypomethylating agents with azacitidine and decitabine for a long time. In the U.S., both of those drugs are approved, plus an oral version of the citing called cities already. while in many countries around the world, only azacitidine has been approved because it has been the only drug to show a survival improvement in our randomized is III trial. Now in the relapsed refractory setting, really, there are no approved drugs outside of an IDH1 inhibitor that's approved in the U.S. based on a single arm Phase I data, but that really applies to less than 5% of patients with MDS who have this particular mutation. So for the vast majority of patients, really, there are no treatment options. We know that intensive chemotherapy can be used in younger patients who have excess plans, but this is generally is used as a bridge to transplant and not as a definitive treatment by itself. And while hypomethylating agents have helped patients, there is a number of problems. First of all, less than half of the patients will achieve a response. So half of them will not have a response. And when you look -- when you talk about complete response, it happens in 20% or less of patients. So 80% will not achieve a complete response. And even those who respond typically or relapse dually within 1 to 1.5 years. And the median survival with hypomethylating agents is limited to around 18 to 20 months, as I'm going to show you on some of the real-life studies. But importantly, many patients with MDS, even if they respond, they will eventually progress. So everybody will progress after some time on HMA. And once they progress the median survival is less than 6 months. And we don't have a reliable way of kind of predicting responders to hypomethylating agents. So this really left a kind of an unmet need for almost everybody with MDS, including patients who receive hypomethylating agents with a goal to increase the rate of complete response but also to deepen the response improve the quality so that it's more durable and ideally reducing transfusion burden and improving survival as the main goals of treatment. Next, please. So this paradigm for the treatment has not really changed over the last 20 years. As you can see, it's a much simpler paradigm compared to other diseases like myeloma or AML or CLL here, if the patient is a transplant candidate, the recommendations go to transplant. But again, this is only 5% to 10% of patients. Sometimes we use bringing therapy. There's controversies on this. We can discuss that later. But for the vast majority of patients who are not transplant candidates, the standard of care has been hypomethylating agent monotherapy, although a number of drugs looked at competitions, and we are going to show you some of the data. But unfortunately, all of them have failed. And in the relapse of factory setting, as I mentioned, only IDH1 inhibitor ivoside has been approved for only 5% of patients who have IDH1 mutations. Next, please. So while the randomized is 001 study showed a median survival of 24 months, which was significantly longer than the with conventional care regimens in real-life analysis has been very difficult to replicate those 24 months with azacitidine. Here, you can see 3 different sets of real life analysis that we have done, including kind of pulling data from a number of frontline high-risk MDS studies. And what you can see is that the median survival range is somewhere between 12 months in older patients, all the way to 19 months for patients who were included in clinical trials. So even worse than what was seen in the randomized clinical trial and clearly showing the need for improved therapies -- next please. Now bexmarilimab, you'll be hearing a lot during this kind of session about bixmanilumab, but the activity with combination with azacitidine I think has really demonstrating very promising responses. And in this slide, you can see a nutshell of all the kind of -- or the top kind of line data from the study that looked at patients. We studied 21 patients in the frontline setting and the response rate using the traditional 2006 criteria was 45%. And using the IWG 2023, which emphasizes count recovery, the CR rate is -- many of those patients, 57% who were transfusion dependent became transfusion independent, which is an important clinical benefit for patients. and 67% of patients achieved MRD negativity using local assays. The median duration of response for CR patients was 16 months. And most of the patients achieved some plus reduction. As you can see, and this latest data cut from EHA 2026. Next, please. In the relapsed refractory setting, we studied also 33 patients and Again, this is a setting where, as you may remember, is a very difficult setting, no approved drugs for most patients. Median survival is around 4 to 6 months. So when we give idea -- it did seem that bixmarilumab was resensitizing patients to ESA. So we saw complete responses and partial responses and 12% of those patients. The overall response rate was -- some of those patients were able to be bridged to transplant, which again is the only way to try to cure these patients. But importantly, the median survival was around 14.5 months in the relapsed/refractory setting, which again, in direct comparison small study, but this looks much better than the expected 6 months after came failure. And I think this -- given that these patients who are already refractory to -- I think this provides very good proof of concept about the additional activity of bexmarilumab when it's combined with AMA,both in the frontline, but also in the relapse/refractory setting. Next, please. The safety profile of the drug. And remember MDS patients, as I mentioned at the beginning, they are older patients, most of them are in their 70s. They have a number of morbidities. So they are flying patients. They often don't tolerate a lot of additional myelosuppression or combination drugs that kind of induce significant toxicities. Here with bixmarilimab, we saw a very good safety profile. The hematologic adverse events were largely what you see with azacitidine by itself, although, of course, in a single-arm study, it's always difficult to kind of attribute 100%. But overall, given the solid tumor data did not suggest myelosuppression with bexmarilumab. And historically, when you compare this data to azacitidine by itself. It does not seem the hematologic toxicities are increased with the combination. But importantly, bixbarilmab has low rise of infusion reactions and no patients died from the drug so far in the clinical trials and the incidence of infusion-related reactions and immune-related adverse events have generally been low and the drug is well tolerated. Next, please. Here, you can see a kind of a comparison to the historical Saeta, as I mentioned. So it does not seem the rise of thrombocytopenia and neutropenia loss. Actually, it does look a little bit better. But of course, this is in direct comparison with historical control. But I think this gives reassurance that -- it's unlikely that adding BixmarIlmab tesa is leading to us in hematologic toxicity. Next, please. Now of course, these were all single agent -- also single-arm trials, both in the frontline and the relapsed refractory setting. So we need to go into a randomized setting and we have spent a significant chunk of the last 1.5 years kind of working with Faron but also with the regulators to kind of develop a randomized trial program, but also learn from the multiple failures that we have seen in combining azacitidine with other drugs, you can see here a listing of -- some of these trials with other drugs, including venetoclax, sabatolimab, magrolimab, pevonedistat APR-246 and semi-pro and you can see that they have used different endpoints, but the shared feature is that none of them have reached their primary endpoints. Next please. So what are the last ones? I think one lesson is of our estimation of the treatment effect. This is something that we have seen people kind of are too optimistic based on the initial small data in terms of the effect size. And I think when you power your randomized trial to a very large treatment effect difference which is not replicated on the ground that will lead to missing the primary endpoint. Also, there was not a lot of understanding of the subgroup analysis and the best dose and kind of selection for patients. All of these have suffered across a number of trials. -- overall survival, I think can be sometimes tricky in these early phase trials because they are different baseline disease characteristics. And this means that what you try to power for can be challenging depending on how many patients go to transplant and the different operational and statistical assumptions. There has been some trial or results variability by region and differences in the supportive care, for example, the use of antibiotic prophylaxis as well as the kind of robust assessment of responses, which sometimes can be tricky. So it really needs the sponsor involvement in making sure those responses reflecting accurate results. And finally, I think trying to improve the kind of the design of the trial to account for variability that might occur, for example, allowing adaptive design to reestimate the sample size based on evolving data as we will talk later. So we implemented all of these lessons kind of in the design of the fees around the Mars Phase II, which is a dose finding -- so it will involve bixmarimab at 2 different doses, 1 milligram and 3-milligram per kilogram combined with azacitidine versus azacitidine with placebo. And this will allow both to establish contribution of components, but also it would allow us to select the best dose to move forward. The effect size that was assumed in this trial was realistic. So a small effect, the difference will allow the trial to move forward in terms of dose selection. The trial will stratify by things that are important to patient outcomes and that have been causing some problems when they are imbalance in other studies, such as TP53 and glass percentage and IPS. And I think this study also, again, will provide a lot of understanding about the differences in the dose activity. as well as PD dose intensity and hopefully, biomarker predictors and subgroup analysis to inform the selection of patients for the randomized Phase II trial -- next piece. So with that all in mind, we meet with the regulators, and I think we discussed the different options and the program moved towards the BICRA trial, which is a randomized Phase II trial, you can see here, which will, as you just heard, already enrolled the patient and is activating in a number of centers, including my central -- and here, 90 patients will be randomized 30 patients per arm 2 doses OpEx versus placebo, all of them combined with actin and that will inform the design of the subsequent confirmatory trial. Next, please. Of course, this trial will use a complete response plus CR equivalent as a primary endpoint, and we'll also introduce kind of will introduce data -- or sorry, we'll introduce analysis focusing on the dose selection, but also other analysis looking at inventory survival and safety analysis next piece. This will be a global study, many sites, as you can see, 35 sites across U.S., Europe and U.K. which will allow very hopefully rapid accrual so that the results can result in late 2027. And you can see here some of the size from the U.S. that will open the trial next. And this is more details about kind of the trial. I would mention that most of the sites that opened the lab, the Phase I trial are proceeding with the Phase II, I think, reflecting kind of the confidence of the investigators and the drug and the good experience, but also, I think, helping with the logistics and since many of those indicators, including myself, have worked with an in the past and the other sites were selected to 4 sites, which have good experience with MDS to optimize the conduct of the study. Next, please. So in summary, I think there's a significant high unmet need in all patients with MDS, high-risk MDS, including the frontline as well as the refractory lapse setting. James and transplant continue to be standard of care, but transplant, most patients will not undergo it and actually means you have limitations I think the big map study of bixmarilumab have shown a very nice safety and efficacy data, including Europe in 45% of patients. And we saw good survival data in the relapse refractory setting as well as good data and TB53. And therefore, I think we are ready to validate that in a randomized placebo-controlled study of 2 doses of brexmarelumab compared to esoplacebo to understand the contribution of component but also to understand the dose selection to inform the subsequent Kral, and we have used the learnings from previous Phase II and Phase III randomized studies to design the BIG CERA trial in OA that will optimize the chance of success, including discussions with the FDA about the use of the endpoints, which will be complete CR here plus CR equivalent and the durability of the CR and stratifying the patients for important factors such as IPS SM risk plus percentage and TP53 status. And I believe this is the last slide. Happy to take any questions.

I have received the message that we have some questions from the audience, and we'll be hearing them. So...

Thank you, John, and thank you for the excellent presentation. There is multiple questions, but we know that you are -- you have limited time today. So let's kick off. There is a lot of discussion about safe -- how important is the safety in this setting and in this patient population when combining with ASA?

Yes. This is very important because we have seen 2 things. One is that most of those patients are in their 70s and they are frail and have comorbidities -- so it's very easy for them to get a drug that is combined with -- as that causes myelosuppression and that can cause significant problems. We've seen some of that with venetoclax. We've seen some of that with and that really can derail the trial. So having a drug that is easy to combine and that can be administered on chronic long-term basis without causing high rates of discontinuation is very important. So I think this is critical in any drug design for high-rises.

Thank you. Based on the results seen so far, especially on the last line, -- do think that we can establish a contribution of each agent from these results seen so far.

I think so. I mean it's always difficult to kind of make a very solid conclusions from Phase I studies with a relatively limited number of patients. But I think all what we have seen in terms of the efficacy and the safety from the trial, but also in terms of my own kind of personal experience with the drug looked very promising. I think we are very well positioned to do the Phase III trial -- the Phase II randomized trial which, as I mentioned, is designed in a way to optimize the success of the trial. So we don't end up in a situation where you have a drug that to ease, but because the trial is not very well designed at least to problems. So I think here, the trial is really designed to show the full benefit of the drug.

And what makes you confident about PEG or what gets you excited? Is it TP53 safety profile? Or what makes you confident about pegs?

I think all of it. I think the CR rate, the durability in the front line setting, the early activity we see in TB53, the safety profile. But also importantly, we are seeing some evidence of pharmacodynamic changes like some immune activation suggesting the mechanism of action of the drug, some early signals that you could predict responders using T cell subgroup or subset analysis, but also the survival in the relapse refractory setting of 14 months when only 20% of them went to transplant, is quite good. So I'm really hopeful and look forward to kind of seeing these results replicated in the randomized study.

And then for the last question, based on your experience and the recent activities in the field, do you think that Bexis the one who can succeed or make it as a positive?

Yes. I mean I'm someone who's like optimistic by nature, and I certainly -- I think all what we have seen so far with the drug is very positive. -- ideally from patient perspectives, we want not only one drug multiple drugs. So I'm hoping there will be a number of drugs kind of succeeding and helping our patients. But for bixnarilumab, in particular, I think the data really looks as good as you can within a single-arm Phase I study. And of course, the confirmation will be through our randomized studies, which we are going to do. So I think we will find our answers, hopefully, by the end of next year.

Thank you, and over to you, Jo.

Thank you, Professor in we will let you go have a wonderful and productive day. And as you mentioned, we are here to seek the truth, and that's what we're going for. Thank you. And next, actually, a great segue after that is I'm going to invite our Chief Scientific Officer, Dr. Maya Holman to the stage because she receives all these samples from the ongoing trials, analyzes them and see what's going on in these patients. It's something that Professor Zedan also alluded to that what we're seeing happening in these patients really validates the clinical activity of this drug. But over to you.

Thank you, John. Hi, everyone, and welcome also on my behalf. So as Johan mentioned, I will be talking about what we know about bexmermab in MDS -- but first, I want to just briefly go to the basics of cancer and how it grows -- and for cancer to grow, it needs to gain several functions that are called the hallmarks of cancer, which include enabling repeative immortality genomic instability and mutation, so they acquire mutation so that they can achieve these goals. They have deregulated metabolic functions. They have tumor-promoting information within the tumor microenvironment. They need to induce angiogenesis to grow bigger than 1 cubic millimeter. And so you can see all of these functions on the left-hand side of your screen, but it's what is interesting and the current state now is that the pharmaceutical companies are trying to target these hallmarks by different drugs. So they are developing drugs to each of the hallmark separately. But I now want to introduce you something that we are trying to do. And it's on the middle of the graph, you can see the immunosuppressive myeloid cell. So what is known about these cells is that they can support Nine out of the 10 hallmarks that I'm representing here now. So there are very powerful cells in supporting tumor angiogenesis metastases and information that promotes even more genomic instability. So what can we do utilizing these cells to promote antitumor immunity and tumor destruction. So we propose that we can reprogram these myeloid cells to actually activate antitumor immune responses and therefore, reduced tumor growth and impair metastases events that are normally seen and eventually kill tumor patients. So there, you can see on the right-hand side, -- if we can then reprogram these macrophages to a pro-inflammatory antitumor myeloid cell, we can succumb all of these 9 hallmarks except for the enabling recreative mortality that the cancer cells have themselves. But that, of course, if you reduce all of the other hallmarks you can really gain super powerful effects on the tumor growth itself. So going back to now our target and knowing what our target does based on preclinical and translational research that we have gained during the years what normally the macrophage, this is now representing a macrophage that is expressing Clever 1, which is the target Bacman 2. Clevers callings situated LDL and oxidized repeats on the cell surface to take them inside the cell and induce the lipid necro receptor singling pathways that promote tolerogenic macrophage subsets. So basically, I can easily say so that whatever the macrophage is eating, it's hiding it from the immune system. And this can be seen as an increased secretion of IL-10 and regulatory T cell formation. What is also interesting within these macrophages is, which is shown on the left-hand side corner, that these -- when macrophages eat different endogenous substances, it takes them very rapidly into fageysosomes. So they acidify integrate everything that they're eating and kind of hiding it. Now when we target these macrophages with bexmerumab, it binds to clever inhibiting the scavenging of, for example, these oxidized lipids and they are not taken inside the cell that then impairs the induction of these torogenic macrophages. While during this spectrum can impair the certification of the lysosomes coming to the promotion of Antigen presentation via this impaired endosomal acidification, so that it kind of has time to present the antigen, the immune system. It also activates NFCP signaling, producing TNF 512 and CCL 3, 4 and 5 -- can that are important molecules to supporting antitumor immune responses, for example, T cell activation towards cancer cells. And there, you can see that, that leads to an expansion of activated effector T cells. So why this is important in MDS? Because I want to highlight now that MDS is not only a cone of malignant cells. Also, these are myeloid cells that are -- have gained malignancies, but one needs to always remember that malingland cells are within their tumor microenvironment. And now we're discussing the bone marrow tumor microenvironment where you have suppressive myeloid compartment that is supporting the tumor growth, and that is suppressing the effective T cell response that you would normally have against the tumor. What you also get, of course, is that if you have this clonal expansion, you get this functional hematopoisis that causes all the side effects or the effects that Amar was just presenting which are the anemia, neutropenia and thrombocytopenia that is really severe and people get bleeding infections and so forth. So to understand this in the concept, I will go through what we know about clever and how it can support these activities for a better outcome for the patient. So I want to briefly tell you about Clever 1 and what we know about clever in myelodysplasting syndromes. So basically covers a scavenger receptor expressed also by low chemic myeloid cells in addition to the normal monocyte macrophage subsets. You can see on the right-hand side, a Hemat, where each dot represents one patient sample. And the more red that patient sample is the higher the expression of Clever is in this samples. So you can clearly see that you get a lot of red, AMO is super red, MDS is also. So they are very good indications for targeting clever one. So Clever is involved in the receptor-mediated endocytosis was just explaining, but it also regulates locate trafficking, inhibit T cell activation and promote some growth, which is demonstrated by different publications during the years. What is also known that high clever expression in cancer associated with poor prognosis and contributes to treatment resistance. So it's a very important factor regulating tumor growth and metastases. So now going back to HR MDS and what we think is our very good approach why Beckman works so well is that it kind of has a dual mode of action because clever is expressed on the monocyte myeloid compartment, but also on the blast cells. So by becremab, you can target both of these arms that then, in one hand, induces immune activation by presenting the antigens to T cells and therefore, affecting adaptive immune activation and clearing of glass cells. On the other hand, on number two, best remember, by binding to Cover 1 on the blast cells, it can impair their metabolic parameters and sensitize cells to azacitidine, for example. And so how it's now shown, this is data from the bone marrow of the bema patients that were treated with combination of pectumumab plus azacitidine in the Phase I CROGI study. And now on the left-hand side, you can see HLA-DR expression on monocyte and blast populations that was measured from the patient bone marrow. HLA-DR is an antigen-presenting molecule that activates CD4 T cells. And here, you can see that on the monocytes, [indiscernible] is increasing the HLA-DR expression on the responding patients. which is very interesting that you can activate the immune system and get a response of the combination therapy. What is also happening interestingly is that the absolute numbers of CD8 T cells increase in the bone marrow and the CD8 T cells are the killer T cells that kill the tumor cells very effectively. So by increasing these numbers, you can actually affect how the blast cells are getting killed. And on the right-hand side, you can see that during the treatment cycles, this observation of the absolute numbers of T cells is increasing significantly when you increase the doses OpEx ramp-up. But going back to now the metabolic changes that we see in the blast cells. So what we see is in the clinical trial is that there are some indications that bexmarmab would help azacitidine treatment. So what we have done in the lab is that we have analyzed for example, first, how does Clever One interact with other molecules in the cell. So this is in the A figure here, you can see the whole interaction map of the clever proteins or the proteins that are interacting with Clever 1 inside the cell. So you can see it's quite a big interaction map. Now when we treat these cells with bexmermab, you can see that there are no longer that many proteins that are interacting with Clever 1. And if we now look what functions then this impaired interactome has on the cell you can see that these cells are stressed. So they are increasing their mitochondrial RNA granules to produce mitochondrial respiration. And this can be seen in the D part where you can see impaired oxidative capacity. So the mitochondria cannot produce energy via oxidative phosphorylation. So this then translates to the viability arm in the E part where you can see that sale that is normally is cited in resistant becomes sensitive to azacitidine if you add back to these cells. So this is basically telling us that became is priming the mitochondria to standard of care treatment so that they can more reliably gain impaired viability after standard of care treatment. So I want to also highlight, as Amar said that ex map was a combination trial. So it's very difficult to say what is Bexaumab adding on to assign treatment. So when we look at this figure here, we have measured target engagement of bexmermab on soluble Clever 1 in Anelisa assay. So meaning that we can see how much of our drug is binding to clever one. And this figure is now showing that the patients who get a complete response for the combination treatment have actually a higher target engagement of bexmerumab on CLEVER1. And this kind of states to me that our drug is actually doing something because the complete response is associated with increased target engagement. which is very hopeful, and we want to, of course, study this further in the BICE trial. Then there was this interesting figure or data that Amar showed is on the left-hand side showing that -- there are some indications that actually the side effects in neutropenia, thrombocytopenia and EMEA would be reduced in the combination compared to Astin alone. This is interesting because when we go and see the bone marrow samples of the Besma patients that were treated with the combination. So you can see here 2 Ooma plots in the right-hand side of this screen, this Ooma plot is showing single cell RNS data from 5 patients that got a response for the combination. And each dot is 1 cell. And the more closer the cells are together, the more similar they are in this map. So we can annotate these cells. And you can see that we have unlocated them as monocytes, granulocyte midodprogeniturs and blast cells. And this left-hand side, OMAP is at entering the trial. So it took a bone marrow sample of the patients before they got the combination therapy. Now when we look at the same map or the map, you can see after 3 cycles of treatment, you get a robust reduction of sales on the monocyte lineage, and these markers are telling us that these cells are very immunosuppressive and not good to have in the tumor microenvironment. So we can reduce these cells a lot by the combination. But what is also interesting is that you can see on the really right-hand corner, an increase in eosinophil basophil mass precursors, error precursors and the mega precursors. So they are increasing by the treatment. So this was after 3 cycles. So if we want to -- so we went back to the lab and actually asked the question can beam promote hematopoiesis by itself. Just to look at this effect from the percenter populations is not coming from the combination, but it's actually coming from Bexemab alone. So we performed this colony-forming assay. So you can see here on the lower hand or on the left-hand side, you can see this colon is that we are counting from this colony-forming assay, so you have a small, medium, large and mixed colonies. And you can see here that adding bexmarmab into these colonies compared to isotype control, we can see a significant increase in the colony formation of mega carriers colonies and different mixed colonies. And that indicates to us that became is affecting these hematopoietic protein cells metabolically soda can induce their proliferation by itself. So I want to conclude of the exciting scientific findings that we have found from the lab and from the patient samples. -- that exam, combined with society induces very broad hematopoietic anemia reprogramming in the bone marrow as it activates progenitor population, enhances lineage commitment and niche normalization. It increases complementary epigenetic and metabolic pathways in blast cells. And these findings support the therapeutic potential with this combination in migrate malignancies, which we are again, then doing now in the Beer trial to actually really see the difference in placebo controlled controls to define how Bema is really working. So that was my last slide, and I'm happy to take questions if there are any.

Thank you. Thank you. So I'm going to take this opportunity myself if you may, because I've gotten to learn that you're a macrophage expert and macrophages seems so feeling fascinating sense, but why do you love macrophage? Why are they so fascinating for you?

For me, the first time I actually became fascinated by them was that I understood that the tumor can consist half of the mass of macrophages. So I was -- it was Interesting to me what were they doing there? And then I learned that keep our calling them the Swiss Army knife of the immune system. And that's fascinating that they can do anything they have the possibility to become everything and perform many, many tasks. So that's why they're so fascinating to me.

It sounds like a tricky sale to target, it's a Swiss Army knife. So why is clever such an important target on macrophage is an?

So of course, there are many scavenger sectors, many checkpoints on macrophages, but what we have learned from the lab is that Clever has a really nonredundant function on macrophage immunosuppressive vet -- and that's why we believe that targeting lever, we can gain many multiple functions within the macrophage that supports antitumor immune responses.

Okay. Well, that's an important thing because what I've learned also from the field is that since there's been failures in macrophage targeting, people are talking, should we use 2 macrophage targets or even free macrophage targets? What do you feel about that?

Well, of course, it might benefit if you target macrophages in different angles. Let's say, one is inducing picocytosis, and we are inducing antigen presentation. This, of course, might be good approach. But I also want to emphasize that I think we should also consider other cell types like macrophage T cell activators so that we get both components activated. So I think we still need to learn a lot, but I'm very I think Clover is a very good target due to the fact that I said that it's regulating many of the functions that are needed for the antitumor?

Lever alone could be enough at refit?

Yes, yes.

Okay. Well, we'll get to the bottom of that. -- thank you, my query audience. May will be back for the management Q&A.

Next, I want to take this opportunity to share the stage with an important partner for us. And it's blood cash United and their therapy accelerator program, the TAP program. Not that many may be aware of the good work and important work blood cancer United does. So we wanted to give them the chance to put the word out on what do they do and how have they been working with us to take the BEx program forward. So with these words, I give the floor to Dr. Blaine Robinson, VP of the TAP program. Over to you, Blayne.

Thanks so much,. Good to see you. Thank you so much for the opportunity to join Inferen's R&D Day today. It's a wonderful pleasure. As Juha mentioned, I'm the Vice President of our Therapy Acceleration Program or TAP for short. -- a blood cancer United's venture philanthropy initiative. And I've worked with this organization for more than 15 years, all as part of the TAP team. Before that, before coming to Blue Cancer United, I worked as a pediatric leukemia laboratory in the Children's Hospital of Philadelphia. So my connection to blood cancer really goes back more than 20 years. So I'll first start today with our mission and the research programs behind a Blood Cancer United and then use MDS as a model to show how our mission can inform some of our commitments. I'll introduce our TAPS investment and collaboration model before turning to the patient need and the history of our partnership with fairness, as you alluded to. My purpose today is not really to position 1 company over another, but really to show how a mission-driven organization like ours decides where to accelerate development. So before I speak about TAP and MDS, first, I'd like to tell you a little bit about our nonprofit and why we're here at an R&D day. Next slide, please. So many of you may know us by our former name, the Leukemia Lymphoma Society or LLS. We recently rebranded about a year ago as blood cans United really to better reflect the full breadth of our patients, families all the different blood cancer diseases and the communities that we serve. Our name has changed, but really, our mission has not. Our vision still remains a world without blood cancer, and our mission remains to cure blood cancer and improve the quality of life for all patients and their families. We do 3 things at the Blood Cancer United organization. We pioneer life-saving research worldwide. We help empower patients, caregivers and providers with free information and support services and we help amplify the voices of patients seeking access to quality, affordable care. For this audience today, research is the reason I'm here, but the other 2 pillars are really what make our perspective on any development program different from any other foundations or investors. Next slide, please. So our organization, blood cancer United, formerly Leukemia Society of America and then leukemia-lymphoma Society was founded more than 75 years ago. really on the goal of finding a care for leukemia. But today, we've become the world's largest nonprofit health organization dedicated to blood cancer, funding research worldwide, providing education patient services and having leading policy efficacy efforts, especially in the United States. We have helped fund the vast majority of breakthroughs in blood cancer research over that period. Next slide, please. So this show really -- this slide really shows like 7 decades of what research and investment has helped produce. We've seen dramatic improvements in 5-year relative survivals in many of the major classifications of blood cancers from the 60s to today and then especially accelerated by the explosion of new therapies over the past 20 years, really exciting time to be in this blood cancer space in drug development. For example, myeloma, only 12% of patients survive 5 years in the 60s to over 60% today. very similar to leukemia and patients with non-Hodgkin's lymphoma have even better outcomes over almost 90% of patients are surviving 5 years. Recently, interestingly, our organization led a specific analysis, and it was published in Blood Advances, just this past month. And we've sort of done analysis that puts this progress in more human terms than just these numbers. And what we've come to conclude was that -- over these years, advances in blood cancer treatment have helped save nearly 26 million years of life. And that's really what our organization is about saving, saving life years. That's decades of science translated into something every patient and family can understand more time together. So these are obviously all of the field numbers, not ours alone. So it takes our organization along with all the other organizations and companies in the world, but it really reflects the breakthroughs that have changed what's possible for patients. Really, there's 2 well-known examples to help make this progress a little more tangible. For example, a drug called Gleevec, changed the outlook on chronic myeloleukemia by once turning a really fatal disease into 1 that many patients can manage for many years with our targeted therapy -- in addition, rituximab is another good example of really reshaped B-cell lymphomas and other CD20 positive diseases, helping more patients achieve durable remissions. And really, that track record is why nonprofit like us belongs in a conversation about drug development. And it's also a reminder that still there's a lot more work to do. Next slide, please. So shown here is kind of a snapshot of lots of different numbers and our contributions to research. A couple I wanted to point out. So as I mentioned, we're the largest nonprofit funder of blood cancer research. We funded more than $2 billion since our founding. However, all our different programs. Just today, we have over 330 active projects, spanning 43 different blood cancers. Obviously, immunotherapy is very key. We have 90 different projects in immunotherapy alone. We have several different programs focused on bringing trials into the community settings, and we have 17 active tab partnerships, so I'll speak about a little later. Annually, we received more than 600 grant applications a year and review them through a multistep peer review process with blood cancer experts. So this is really the portfolio behind the MDS work that I'll come to a bit later. Next slide, please. So shown here, this is how our research programs really map onto the development path, starting from just an idea through basic research, preclinical drug discovery, and ultimately, clinical research and all the way up towards FDA approvals, we have career development programs that these are awards that support the most promising emerging scientists in blood cancers. We have some discovery grants that fund the earliest science. And then we have a couple of grand programs, translation research and specialized centers of research. These help discoveries move a little bit closer to clinical application. And then we have a couple of programs focused on trials, academic clinical trials programs and impact program support trials and access to community centers. Specifically today, our Therapy Acceleration program. This is where we invest and work directly with biotech companies such as Ferran and these are typically on clinical stage assets. And our organization also has several master clinical trials one's called PAML. They are celebrating their 100th year actually and a pedal trial, which is focused on pediatric leukemias -- these are master trials where we're actually the sponsor of the trial. We hold the IND. We run the trials with CROs and have dedicated sites committed to these diseases, especially in AML and for pediatric clinical development, respectively. We also run several special initiatives where there's a high unmet medical need. These include CMML, hairy cell leukemia, mantle cell lymphoma, and follicular lymphoma. And these are typically co-funded or supported by a clinic donor or another disease foundation we working in collaboration with -- so for scale, our academic grant programs runs approximately $40 million to $50 million a year. And over the history of our organization, we have supported more than 4,000 projects in more than 80 institutions worldwide. So let me show you what that looks like at this current time in 1 specific disease, MDS. Next slide, please. So this is what our MDS commitment actually looks like across the whole organization in biomedical research. We have 28 active MDS relevant awards for TAP, where we focus with companies and invest, we have investments in 4 programs across 3 companies, one of them is far and another with Oro and Cross Alongside these, we have 3 specialized centers of research. These are large multi-institutional grants, $5 million commitments that includes multiple principal investigators whether they're working towards 1 overarching goal. And obviously, these ones are focused in an area in MMDS. We have 14 career development awards in the MDS space along the 3 discoveries to academic clinical trials, and these are really specifically funding investigator-initiated trials for using companies drugs or drugs that have been developed by the academic institution running investigator-initiated trials. -- and to impact access programs in the MDS space. So -- obviously, there's lots of different examples of what these programs are studying, but a few examples include RNA splicing, epigenetics, especially important MDS TP mutant disease. -- clinical metoplesis and other metabolic vulnerabilities. So the message here really is what we cover everything from the bench to the bedside even to patient access -- and really no single company or foundation can really cover that span like we do. And this is what we bring to a partnership with any of our collaborators. One thing I did want to point out just recently announced, we do have a collaboration with the Evans foundation. They focus on MDS. They have a program called Evans MDS, and they have obviously a commitment to do more collaborative MDS research. So we just announced that the Evans Foundation in Blood Cancer United are going to be supporting a new score graft to bring together interdisciplinary teams together from around the world to focus on MDS translational research, try to bring more discoveries to the clinic. This application window is now open and we hope to fund a new MDS focused score brand next year. So now as I sort of transition to more about the Therapy Acceleration Program. This is the part of the organization that works directly with the company. So let me now turn to that model and how it operates. Next slide, please. So I know there's a lot here on the slide, but I'll walk you through it. So TAP is our venture philanthropy program, and we've been supporting companies developing novel blood cancer therapy since 2007. So we are approaching our 20th year next year. to the different sections. So first, I want to bring your attention to the circular bulls eye on the right. This is a snapshot of all the biotech companies TAB has ever supported. There's over 50 of them there. Some of them might be on the slide, more than once as they might have different assets in blood cancers. They either show the current stage of development or where the program ultimately ended. The outer ring represents preclinical stage companies as we move towards the center, you see Phase I, Phase II and Phase III and ultimately, FDA-approved therapies, of which several have been completed with TAP-supported therapies. The blue boxes highlight recent or incremental investments over the last couple of years, and we have a couple of other partners that are actually still in active development in blood cancers. So the main goal here is our mission. We invest to accelerate therapies to help cure blood cancers and improve patient outcomes. As I mentioned, in the center of the bull's eye or 6 approved therapies that have either been FDA approved or included in the NCCN guidelines. These included in diseases: AML, lymphoma, rare blood cancers called BPDCN and T-cell lymphomas. One of our most recent examples of an approval for Tata contribution with ziptimenab. It's one of the new class of therapies called MEN inhibitors. It was approved last November. So when TAP makes an investment, we invest as part of a syndicate with other like-minded investors, we take an equity position in the company. So the model is really designed to both impact mission for accelerating development for therapies and also a possible financial return. We've invested more than $120 million to date in over these 50 companies, and there's more than 30 active clinical trials running across the portfolio with tap supported therapies. -- strategic transactions, financings and financial returns do matter because these returns that had to come back to us and we cycled into the mission and helped fuel the next generation of TAP investments. So over the years, we've been doing this for quite some time. We built up sort of a pattern recognition to distinguish companies that best fit our thesis for investments and have the potential to impact patient care, which is our primary driver. The next slide sort of shows this thesis and what we look for before deciding to partner with and invest in a company. Next slide, please. these criteria are what we look for in a company during due diligence and the same ones we have applied to Faron, First and always first, we really look for the unmet medical need, what are the existing emerging patient populations where patients have very few good options. Is there a real gap in the current and emerging treatment landscape -- we look for innovative science, things that are first-in-class. We have others or other companies in pharma well covering a development target or particular diseases, we may be less likely to invest there, we can use our dollars to invest in a space where there's really that unmet need and the lacking of the standard of care. We look for, is there a plausible path forward either through a first in human study or even through registration-enabling studies, making sure that the plan -- the company has an alignment with the FDA, how we can assist with them and make sure they have the best chance for success. And in additionally, beyond the science, we look into the company. We will make sure that the company has got the proper intellectual property. The management team is in place. They have expertise -- they want to work well with us, and they have the ability to finance and execute the development plan. And so an important framing point, when we look at these opportunities, -- we're just looking for ones that fit criteria. We have a due diligence process shown here. We typically look at over 100 inquiries a year. So we're not really ranking ones. We're looking for all the different companies that fit. If we have the dollars to make an investment, we will. So we're looking for -- through a mission lens first, not looking for the best winners, looking to see which companies can have the best impact for patients. So we have a very strict due diligence process. We have a number of staff members with expertise that do our initial due diligence. Ultimately, we do work with some KOLs to provide additional feedback -- and we do have an oversight committee called the Top Committee, where any of the opportunities we want to make an investment with, they oversee our program, and I have to get the go ahead if were to proceed with an investment. A lot of these national Board members have investing finance and scientific expertise. Some of them have been Fortworth CEOs. Some are investors and other VC groups. So they have expertise and also help us due diligence on these investment opportunities. but very, very rigorous. We've been told sometimes we do much more rigorous due diligence on the scientific and management than other investors. So a lot of companies that they make it through our due diligence process and become a partner they really look at us as for a seal of approval and can be used as a catalyst for additional financing. And really, we only make several investments a year, typically bring on 1 to 2 new partners, and we're also reinvesting or a follow-on investing with some of our current portfolio partners. So as I showed, this funnel shows a broad set of inquiries down to small investments. We look through investment inquiries to year round, -- and once a company selected for investment, that's part of their syndicated financing. That's really where our true partnership begins. And I'll speak about that more in a little bit. Next slide. So this is our current portfolio of companies that we've invested in across the blood cancers. It really illustrates sort of the breadth of the different partnerships -- we certainly have a concentration in myeloid diseases, particularly AML, MDS, which obviously have a lot of high unmet medical need, boxed in red or a current MDS portfolio for TAP, which includes Faron or on and the 2 robot programs. What I want you to see is not just different company logos, but it's really a living pipeline. We're always hoping when we joined a company investment, whether it's preclinical or in Phase I or Phase II, we want to see them sort of moving toward the right into pivotal trials and ultimately for an approval. There's a whole host of different modalities, stages of development. So really agnostic to those. We have cell in immune therapies, targeted small molecules antibodies and other different approaches all selected because they sort of address difficult blood cancer settings where better options are needed for patients. So really, the concentration is not accidental. It really follows sort of leading with unmet need. So this sort of gives you the portfolio view. But the next slide I'm going to show you just looking at our commitment through different type of lens and how many dollars we've invested in a particular disease areas. Next slide, please. So putting the portfolio into context where we have committed our resources across all the different blood cancers. This chart shows our historical commitment over time, as I mentioned, is over $120 million looking at 5-year survival for a lot of the large buckets of blood cancers and their annual incidents, which is the size of the bubble. It shows how unmet need really aligns where we put our substantial commitments in diseases where survival is the poorest shown here, those the areas are AML, MDS and aggressive non-Hodgkin's lymphoma. So this is just provided for context. It's not really a formula. We're not saying we can only best in these areas, but this is how it's played out over time where we've made all our historical investments. So really focusing on MDS. We've invested nearly $20 million in MDS alone and several different companies, including Faron, and really behind those commitments are patients that have very limited options. And let me now reframe the unmet needed MDS before we can get to talking about our Fern partnership. Next slide. earlier on today's program, resident covered the clinical science of MDS at much greater depth from the perspective of physicians who actually treat these patients. My role here is a little bit different. -- just want to explain from our perspective, why high-risk MDS is the kind of unmet need, it's urgent and it's patient-centric that drives us our commitment to making a stepson investment decisions in these blood cancers. High-risk MDS is a disease of older adults. Many are too frail for intensive therapies or transplant -- the standard of cares are HMAs, which produce overall response rates, roughly 40%, 50%, but only 10% to 16% can have received complete once and many of those are transient. The harder number is really what happens after you fail the initial therapy once HMA stop working, there's really no approved therapy and overall survival is only several months. So for most patients after they fail A2A, the next conversation is supportive care, and not really what's the next therapy they can go after. And underneath survival statistics is really patients' daily lives. -- patients have the deal of cytopenias, transfusions, infections, -- going back to the clinic multiple times a truly quality of life in addition to being a survival story, -- and also, there's some adverse molecular subgroups MDS, right? We've talked about before, TP53-Ulter disease. These patients far worse to wall. So having therapies that can address these patients is critical. So that's really the gap we're looking to address when we evaluate it fair -- before I walk through the partnership timeline, let me first sort of explain how the program fit our mission and development lands. So this slide sort of shows -- highlights 5 reasons why Ferren's program fit our mission lands First, on the need, as I mentioned, that's the first thing we look for substantial in both frontline and higher-risk failure MDS. Second, there's great science. There's bexarilumab targets CLEVER, a novel target. -- unique biology. There's a distinct mechanism especially including with an HMA-based resident in combination. Third, there's clinical data. There's clinical signals from the BEAT trial, including some response observations in TP53 ultra disease. And as we'll go through the partnership a little bit, this has informed us to make several different funding reviews, and we continue to be encouraged by the development and have made 3 investments in Faron so far. Fourth, development path now includes a randomized follow-up study, really to test these early signals. This is always critical as you're moving forward to determine if it has a chance to make -- get towards approvals to see if there's meaningful patient benefit -- and five, we're looking for companies. We see a role for our organization to help companies through disease insight are providing our patient perspective, getting expert inputs from some of our KOLs and help with development networks. So these are sort of the 5 areas that we thought are fair and fit and happy to go through the partnership in a second with. And really, so just to be clear, still be and Rima remains investigational. -- randomized studies need to be conducted to establish additional patient benefits. So really, let's now go through the partnership to describe to show everyone how it's developed through the time through several different reviews in our stage investment process. So next, I'd like to have you join me for the next couple of slides.

Thanks for having me, Blaine. I have to be here with you and discuss the partnership. So next slide, please. So we thought it would be also good for the audience to really understand how we've been working together and how our partnership has evolved. So it actually all began in '22 when we were wrapping up our first-in-human trial with vaccine solid tumors. And the most important learning out of the first in human was that those patients benefited who had Clebe1-positive macrophages in the tumor microenvironment. So we screen a lot of databases and we learned that AML and MDS, basically everybody is lever 1 positive, and that is an area we need to move into, but we didn't -- we had limited experience in the heme space. So that's when we reached out for the first time, 2 blood cancer United and started the dialogue.

Yes. Exactly. It's interesting that's when we made our first investment in June of '22. -- actually look back this morning and I found that we actually first connected a JPMorgan conference in January of '21. During COVID, -- so we've actually worked and engage with Faron over 18 months, looking at a strategy, the data, connecting the experts -- and ultimately, given all that preclinical data and rationale like Yiho mentioned, especially moving into AML and MDS, we made an initial $500,000 investment through took far through the entire stage diligence process. This is one of our few investments we made coming out of COVID with dollars were limited. And that investment help support expansion. The existing MATS trial going into AML now in high-risk MDS and help support clinical protocol development.

Yes. And ultimately, that initial investment then that resulted in the Bema protocol and then early on already in dose escalation, In Phase I dose escalation, we saw very strong signals and blast reductions in relapse refractory patients where usually you don't see anything happen, and we were seeing this. And again, we sat together hey, we need to move on to the Phase II part, and we needed further investment, so it comes up to 23 then.

Yes, exactly. I mean those -- I mean when we made the initial investment in June, obviously, we were collaborating together. We were following the data -- and I have to say from being in the organization for quite some time, making a subsequent investment, we've done several times, but doing within 7 months later, I mean that sort of goes to show that the company was able to execute all those early signs are really promising. So we took through our state due diligence process again, and we took the company Farand had to present in terra committee and get approval. And we ultimately, yes, we agreed to do a larger investment this time another $3 million to help support part of the Bexbag study and also to start enabling expansion into the U.S. sites where we think TAP will be helpful given our network and experience.

Yes, it was very essential that way we were able to expand to the U.S., get more sites things going for the Phase II part and execute on the Phase II part. And ultimately, the Phase II then confirm those early signals seen in Phase I, which then led to a successful end of Phase II meeting with the FDA in the fall of 25.

Exactly. And we were following all along and very excited to hear the engagement with the FDA and coming up with plans to move forward. And based on that meeting, we again brought our -- sometimes we bring portfolio companies to the tap Committee to give them updates on how things are going, thinking things are going really well. They're engaging. They're developing a plan to move forward. we were discussing the registration study. So both our TAP team and the committee expressed continued support for another investment in the near future. And we would continue to follow the data and development plans. We knew the company was preparing to present some data at ASH. So we're looking forward to getting those updates and hearing more about their plan. And then after those checkpoints happened, we said DASH data came out. The company came up with a financing plan. The revise the plan. So we brought the opportunity back to the committee. The committee was supportive again, and we made a third investment of EUR 3 million as part of Ferren's financing in that period to finance the randomized Bexeratrial.

Exactly. So this is how I see that what we're looking at in this slide and in this 4-year period, Faron emerged as the leading company in high-risk MDS? Or how would you blame summarize this? Yes, I mean to say, I mean it's really been a wonderful partnership as the years have progressed, it really reflects sort of the continuity over these different columns showing here. Four years of collaboration, successive reviews of encouraging data of the development plan moving forward, execution -- this has led to different investments. And really, every milestone along the way has given us the opportunity to evaluate the science, how is the Farenteam executing the plan. what's the path forward? And it's never just really about a single check. It's really about the relationship with the company and it deepened as the data mature.

Yes. So we thought also it will be then beneficial that we will talk a little about. So what actually in practice does this mean? So how do you work not just with pharmacist it's not just about fires the amazing work that's being done in blades. So how do you work with companies actually in practice? And again, it's with us, but also with other companies. so, could you explain?

Exactly. This is a really important piece. So we're just not giving dollars and checks out and just waiting to see what happens. We want to work and find companies that want to collaborate with us, and we really think that our organization brings a more partnership and a value-add beyond just the dollars. It's really about the continuing collaboration with whomever the biotech partner is. This is where our value proposition really becomes a little bit more concrete for every partnership, we form a research advisory committee. And so we form it between our TAP team and the company team, in this case, obviously, Faron, it's done when we make our first vestment. It's a really structure that's put in place that we can have recurring dialogue all throughout the year, typically quarterly, both virtually and in person as possible at some of the scientific meetings really to touch base to make sure we're assisting the company, however we can. Every company is a little bit different. Some need more expertise on the science side, KOL connections, Others might even more business development side.

Absolutely. And I think 1 of the key things that really differences or sets Parkins United tap apart from anything else that I've seen is actually your engagement and network to leading U.S. KOLs and sites, so you can really tap into the best minds of the field and then companies can benefit from that for you. So I think that's the real key how you differentiate and your uniqueness.

Exactly. I mean we -- like as I mentioned, we engaged KOLs in several different ways. We utilize some during our review process as we do with every company some of the KOLs may be more experts in the target area or the particular disease or development plan. But once we've become partners with companies we can help convene the right voices, clinical voices around trial design endpoints, selecting patients and those types of things. We've organized events at ASH, bringing in KOLs to meet with companies. We've made specific introductions to companies saying, "Hey, this -- and hearing from us is an easier connection from a company just trying to reach out to some expert they want to connect with, right? If it comes from us today, hey, we know this company -- they're doing really great things. They had some presentation at ASH, maybe you weren't able to see it. When you think about it and all the times, the KO like hey, this looks really great, put me in contact with the company and maybe they become a site, maybe they come an adviser. -- or maybe just someone they can sort of bounce some ideas off of. So it's really been a wonderful collaborative aspect that we bring to all of our partnerships. And not only like KOLs, we have other resources within our organization like Black Cancer United. We have a clinical trial support center, for example, where nurse navigators, we have almost 20 of them, they speak directly with patients and caregivers. They're always looking for what trial are they eligible for? Are there slots open and access, how do they get access to these sites? Are there any barriers to enrollment -- we always encourage our tap partner companies to speak with the nurses, give them the most updated information about the trials. -- what's going on. So obviously, the trial, the trial support center is their job to put more patients on clinical trials than people can get because we all know these are more beneficial than just going on the standard of care in many of those cases. So it's really the patient-facing perspective that we can bring for companies helping them refine their clinical development plans, enrollment strategies. And obviously, moving forward with companies that are getting closer to the finish line, discussing the registration strategy has become really a great discussion point between us and the tap partners.

Absolutely. So maybe just to sum up what I see here, and again, it's one of the specialties of Black cash United and Tabs there's this very operational side. We're working together even on a site KOL level, meeting frequently on an operational level. But then there's, again, the tap committee that makes ultimately investment decisions. And through a continuous operational partnership, we've then repeatedly gone back tap committee, keeping them up to date and the evidence as it's building up of the under development plan as it builds up, which has ultimately led to this, I would say, amazing and very flourishing partnership.

Yes, exactly. I mean we make the investment right. Our role really is to help collaborate advises and convene whatever the companies need and the company, fair in this case, they own the program. They make their decisions. We're just the advisers. We're not taking board seats and those types of things. That's how we do this all sort of our collaborator research advisory committee model. trying to make those connections. And even as beyond them, we've done connections with companies sort of on the business side, introducing it to the other investors. Our organization works for -- works with many of the large pharma companies. We can make introductions and those types of things. So -- we kind of bring out a full engine to all these partnerships to try to obviously bring the science forward and impact patient lives as best we can.

Wonderful. So a true partnership, if I may add. And it's true sense?

Exact SP1 Yes, exactly. That's what we would like to talk about. Our tap partners. We always say top partners. It's a partnership. If there's a company that wants to take our money but don't really want to work with us, this is not really works for our model, right? We really want to be very collaborative and true partners with it. So yes, it's -- we're contributing just alongside our investment, which are so unique angle was how a venture philanthropy should work and how we operate.

Thanks a lot, Clay. Let's move on to the next and last slide, and you can wrap it up. Again, amazing work. We want to raise awareness of this work that Blood Cancer United is doing over to you plan to wrap it up.

Thank you Yes. First, thank you for the opportunity today. So just a couple of take-on points from today. Blood cancer United, our organization really exists for patients to secure blood cancers, improve the quality of life for patients and their families. Our venture philanthropy program, TAP, can help accelerate mission-aligned innovation, providing capital plus expertise and collaboration in a patient-centric perspective. Third, high-risk MDS remains a major unmet need. There's new therapies needed for patients that they need more tolerable therapies, more effective therapies and to be tested in rigorous studies and fourth Ferron is a current tap partner that this program aligns with the MDS unmet need, has unique biology and unique mechanistic rationale and it's got the clinical data so far that's very encouraging. And a promising clinical development path moving forward. So it fits all the check boxes. So if you really take 1 thing away, our R&DS really commitment runs from -- starting from the bench from sum from early science to bedside and patient access and fair and fits a lot boxes and really sits inside of all that. Shown here today, we really wanted to acknowledge some of our supporters. We've been doing -- looking for supporters to help financially provide dollars to TAP for -- to make additional investments to grow our program. So I want to acknowledge a recent partnership with Royalty Pharma and a couple of foundations, the Butler Family Foundation and also blood cancer U.K. They're all our supporters now. They're helping to expand our reach and impact, fueling our growth and trying to -- for our TAP program to become a self-sustaining venture forlandopy. So really, the goal is simple to move promising science to patients who are in need better therapies. So thank you very much for the opportunity to present today.

Thank you, Blaine. Awesome work. Just checking any questions from the audience to plan. Or shall we let Blaine go?

Yes. And there is a few questions for Blaine. There's sort of discussion that how do you see the data as overall -- how would you describe the data how promising is the data which we have seen so far.

So I'm not going to speak about the data today. I mean obviously, I think from my perspective, the TAP program has made several investments in the company. So I think that's sure suggests that we are encouraged by the data and looking forward to the registration study starting.

Thank you. And there is the second question about tails that do you support broad range of programs hoping to find one that will make the change? Or are you very selective doing with these investments and you need a high level of conviction.

So I think if I understand the question right. I mean when we make investments, I think we're very selective in programs. They have to check off a lot of the boxes, as I sort of discussed before. We're really looking for high conviction programs and for us to make a subsequent investment in the company. So we're not like another investor, which is keep pouring dollars into a company just to maintain our shares and our levels on the cap table. We only make investments in the companies where we feel like there's a forward momentum in blood cancers to justify an additional investment.

Thank you. That was the last question. Over to you, John. Okay. Thank you, Plan. We're up on time. So wishing you a wonderful day. And then I think we're up to the break. We will now to, again, align our time table with another external expert coming soon. We will now have a 20-minute break, so continuing 16, 45 finish time, 15:45 Central European time. Thank you, and see you soon. [Break]

Welcome back, everybody. I hope you had a good break, a fresh cup of coffee. Now next is what else is happening in Faron and here to tell us all about it is our Chief Medical Officer, Petri Bono, on pipeline review and ongoing other trials. Over to you, Petri.

Thank you, Juha, and good afternoon, everyone, and good morning to you. Really delighted to tell about our pipeline review, and let's start with first slide. So we have done very good progress recently. And this is the current pipeline, and you can see the second trial is Besma, where we already a year ago stopped enrollment of new patients. good to remember that although the enrollment is closed, so the study data continues to mature. We released in July NewsOdata to the market. And in an upcoming major hematological meeting, we will then present the newest data in more detail. Then Amiran presented the design of the Beira trial that is in the treatment naive higher-risk MDS patient population and we are on track. We have earlier told to the market that we -- the study will start enrolling places in Q4 this year, and we are on track with that. And very excitingly, there we have blades and begs that are not anymore just in planning, both up and running both have received or regulatory approvals. And actually, we have released the market also that first patients have already been enrolled to both Bexar and Blaze. In Bear it's metastatic soft tissue sarcoma, and we will hear today more in detail about it by the study principal investigator, doctor, Sesa Serrano from Barcelona. And then I will update the blade situation and blade design is a trial where we try to overcome secondary resistance to PD-1 inhibitors in metastatic melanoma and non-small cell lung cancer patients. And really, what I'm so proud to tell you actually that today, we received the information that the first cohort in Bexar that's fully enrolled. And the second cohort has been open for enrollment and in the blade we have already 2 patients that have been -- have started on their treatment, 1 in London in RoMarston Hospital and the other 1 in -- at the Christie Hospital in Manchester. So both trials in solid tumor, these investigator-initiated trials, they are also progressing very nicely. And as mentioned, so Blaze and Bexar, they are not just anymore first patient in, but up and running. And of course, when they have had so good and strong start, so it means that we can expect to have results from GREs trial at H2 27 next year from the first part of the trial or first stage -- and then we have also another 2 IIT trials that are progressing also the preparations. The other one is the Nordic AML trial BEAM trial that is led by Dr. Mika Contra from the Helsinki University Hospital, together with Karolinska Institute. So it's bexmarulumab plus azacytidine in MRD-positive AML patients after transplant. And trial is currently at the submission stage. And then the other trial that is an investigator-initiated trial run in California, the City of Hope contract as it Cancer Center that's in relapsed and resistant MDS patients combining bags for the first time with an oral agent in this time, it's in is a combination of decitabine plus cedazuridine -- and these are progressing. We are finalizing the full protocol with the City of Hope trial and then the other one beam to be submitted extremely soon. Then a couple of words, what's the rationale actually behind these IITs and go a little bit more into that. So let's start what we have learned from Matin trial. And as a reminder, so Matin was a single agent a treatment for patients with advanced metastatic solid tumors. At that time, when Mathis was started, I was working still at the Helsinki University Hospital Conference Cancer Center and had the privilege to be the global PI of the Matin trial. -- altogether, 216 patients were enrolled to the trial from various large European cancer centers, and we got a lot of learnings from the trial First of all, good to remember, patients were really late-stage patients. They had received a median number of previous treatment lines of 3 before entering the trial. So it wasn't a frontline metastatic trial at all. And why this is important, when we're talking about novel immuno-oncology agent. So you need also to have good immune system so that if the -- so that immune system shouldn't be too exhausted to get the benefit from I-O treatment and so in that way, Martins wasn't the optimal setting. But this is always how it goes with first-in-human trials, it late-stage cancer patients are enrolled. So what we were able to show actually in these Matin patients that we were inducing macrophage activation that was leading to treatment benefit in solid tumor patients. And this is really important. The clinical benefit we observed that with some cohorts in 25 to 35 percentage of the patients including liver, gastric melanoma patients that were benefiting from the treatment. We also learned that targeting level one with BEC is extremely well tolerated. The rate of immunological adverse events were extremely low. And also the rate of any treatment emergent adverse event was not either high and treatment-related adverse events, so we only had in less than 10% great tree or higher treatment-related adverse event. Then we were able to show that it's realistic to get a disease control in late-stage cancer patients with single-agent bexmarumab treatment. And very importantly, we were able to show that low baseline immune activation is associated with bexmurilmab treatment benefit. And why this is important, those patients who have low baseline immune activator status are typically patients who don't respond to PD-1 inhibitors. And also, we were able to show in the translational studies that BEx converts intratumoral macro phases to support adaptive immune responses. Also, based on the translational results, we were able to show that we have a good biomarker candidate that is the intratumoral clever positivity by immunohistochemical staining. When we talk about checkpoint inhibitors within solid tumor patient treatments, it's important to remember that although there's been a lot of puzzle for the last 10 years, how they have transformed the treatment of cancer. So actually, just 20% of the patients do respond to checkpoint inhibitors. On the right side of the slide, this is from a Landsec review, you can see that the reasons for that, the mechanisms of resistance, so there are several mechanisms. And actually, many of these are related to the macrophage function. And then on the left side, we can see that how many -- how many patients actually respond to checkpoint inhibitors and you can see that, for example, Hodgkin's lymphoma, melanoma they have like 50% or more of patients who do get benefit from PD-1 inhibitors. But on the lower side of the left side figure, you can see that these big tumor types like liver cancer, colorectal cancer, hormone receptor positive breast cancer actually, it's less -- it's less than 15% who get benefit for PD-1. So from the patient's perspective, there's really a lot of need for further improvement of the treatments. And what do we know about clever 1 mRNA expression and its association with survival of patients from large databases. On the left side, you can see Kaplan-Meier survival curve that shows that clever 1 or the mRNA coding for that stub one. So the expression level, so it's associated among all cancer patients with worse prognosis. So the high clever on patients shown in red, so their couple curves are clearly inferior to the blue ones who are clever low. And on the second panel from left, you can see separated therapy IO treated patients, and the difference is even higher there. So that the ones who are lever on high, so they are actually the ones with the worst prognosis. And then on the right side, we have also done a split between the I-O treatment between PD-1 inhibition and between Clay for blocking and the same result holds through there. And then I would like to spend a little time with this slide that is taken from a very elegant Chinese paper that was published last year in the Journal of immunotherapy of cancer. And this is one of the good reasons why we want to study in solid tumor clinical trials, the combination of BEC for example, with PD-1 inhibitors. Maya has shown earlier mouse work, mouse tumor work also supporting that but this is an external validation from gastric cancer patients and gastric cancer data showing that Clever 1 expression is actually related to clinical resistance to nivolumab -- it's related to CD8 T cell functioning and also related to tumor cell killing. On the left side, the patient numbers in that paper were still fairly small, but patients were treated with the combination of 5FU plus oxaliplatin plus nivolumab, gastric cancer patients. And not all patients do get a response and when the tumor-associated macrophage infiltration was analyzed, so the responders versus the nonresponders, nonresponders in orange. So they had not higher clever 1 positive rates than the responders indicating that Level 1 expression is really related to the treatment resistance to a PD-1 inhibitor. In the middle graph, what they did, they actually isolated tumor cells from gastric cancer tumors and put them on our petro dish and then treated those cells either with control antibody, nivolumab PD-1 antibody or -- with anti clever antibody or the combination. And as you can see in purple, the combination. So they do a block it. So it produces the strongest interferon gamma response in this tumor infiltrating, CD8-positive T cells. And this is a really good rationale to go to clinic treat patients with the combo. of interest. So a single agent antiCLEVER1 antibody was at least as efficient as nivolumab, if even a little bit better. And the same direction or trend can be seen on the right panel also -- this was not measuring T cell reprogramming the right panelists measuring, apoptosis, so tumor cell killing and how that is enhanced, best in clever 1 positive tumor microenvironment, high tumors with the combination. And in summary, this elegant Chinese work this makes a really good rationale to move forward also with the patients. So then where are we actually and how do the IITs look like Blade, Blaze is melanoma nonsmall cell lung cancer study in second-line treatment after the patients have failed their frontline checkpoint inhibitor or PD1 inhibitor therapy. -- and it's testing whether additional bags can overcome the secondary resistance of these patients. in order to patients to be enrolled to the trial, they need to have received PD-1 inhibitor get a response to that -- and then before entering, they need to have received the latest PD-1 treatment within 3 months. And this is a Phase I, Phase II investigator-initiated study where the Part 1 will include approximately 10 to 12 patients and the Part 2 will then include 25 melanoma patients and 25 non-small cell lung cancer patients. And the primary objective is safety an overall response rate in this trial. And with rechallenge with the PD-1 inhibitor, for example, in melanoma, you don't expect more than 5% response rate there. So in the -- within the first 10 patients, even onEUR response would mean a green light to proceed to the Phase II part of the trial. Then Bexar, this 1 I will do very shortly since Cesar will go through. Just want to highlight that by purpose, this is in frontline patients. and in frontline because the immune system of a patient is optimal to be treated with [indiscernible] and this trial is a combined Phase Ib/II trial. And the first Phase Ib trial will include up to 46 patients with PFS and safety as primary endpoints. And then the City of Hope trial, which is extending BEC's evidence to an oral hypomethylating agent backbone. So the rationale, of course, from [indiscernible], we know that combining bags with azacitadine. So it has really encouraging efficacy -- but at the same time, we know that oral use of HMAs will be increasing. And with BEx, of course, we will need evidence that its activity can be translated from IV subcutaneous ASA also to oral agents such as decitabine sedatsurisidin or Inco as a brand name. And this trial has 34 patients that are planned. It's an open label Phase II investigator-initiated trial that will be run in the network of city of hold. They have satellites elsewhere also in Europe. -- elsewhere in U.S. in a couple of major cities. And the primary objective of this trial is to measure over rate at 12 months and also overall response rate. And as we know, when patients fail HMA in front line. So basically, you don't get any responses or it's, again, less than 5% of the responses and the overall survival rate at 12 months. So we talked typically about 25%, and the plan is to increase that from 25% to 50%. And then Beam. So Beam is a setting that we have a low disease burden that will allow be-driven immune and hematological effects to be detected before an over disease relapse. So that patients have to transplant AML patients when they become MRD positive with sensitive measures, so they will receive azacitidine plus be in an open-label Phase II investigator initiative trial, plant trial size is 24 patients, and the primary objective is MRD negativity at 24 weeks. And this was my last slide about the pipeline and the activities related with these trials, really proud what kind of progress we've been doing for the last couple of months with these ones. And by purpose, didn't touch too much today. The Bega trial since that will be presented by the next percent doctor era who is a group leader of the sarcoma translation research program at the Prestige Valero Hospital in Barcelona. Sears also ESMO faculty member also this year at ESMO in 2 weeks, leading sessions there as a moderator. -- and has been long involved with both translational and clinical research of sarcoma treatment and certainly represent a true key opinion leader within Europe in this disease type. So without further introduction, so Cesar, please. stage is yours.

So thanks so much, Petri, for your very nice introduction, and hi, everyone. Over the next few minutes, my idea is yes to transmit you why it's important to target clever 1 in patients with sarcoma and why? I think this is low-hanging fruit. So maybe you hear before, but ever 1 is a type of a protein that is mainly basically uniquely expressed in sales of meloid lineage. And in physiological conditions, Creval has multiple functions that help the body. But the problem comes when there is a context of a tumor type where it actually promotes tumor growth mostly through altering ecocide trafficking and inhibiting T cell activation, basically stating an immune suppressive microenvironment, which is you may know already that it is pro-tumorigenic -- what is known already quite well is that high-level expression in cancer is associated with proved prognosis and also it contributes to more resistance. This is based on clinical studies, making association between expression of clever 1 protein, a stab gene that is the same of clever and patients' outcomes. Next, please?. So the fundamental for working on STEP 1 gene inhibition or clever protein inhibition in sarcoma is actually very rational. So what we did at some point was to study across all the tumors that have been profiled under the is to check for the expression of STAP 1 gene that is responsible for clever protein expression. And we observed that among solid tumors. -- basically, sarcomas is the second together with Mesothelioma the 21st and with a big range of exploration of STAP 1 gene. We've established a very nice and interesting rationale for again stop 1 in sarcomas. It also comes under another observation for many papers published in the recent years. Basically, the main immune infill trade that we have in sarcomas are macrophages that promotes tumor microenvironment that is immune suppressive. So it's quite well connected. It's immunosuppressive microenvironment in sarcomas with a predominant predominance of macrophages together with this high STAP1gen expression. Next. There are multiple sarcoma subtypes, you'll see in a minute, but these that you can see here are basically the most come-type representing up to 80% of all sarcomas. So we could observe in the same study, preliminary study of RNA expression of STAP that there are differences in this STAP 1 expression across the different sarcoma subtypes. And basically, the 3 in our right are those that express more quantity of STAT1 G. And basically, these 3 subtypes are the most common sarcoma subtypes that are typically treated by chemotherapy in our daily routine clinic. So this findings are actually foundational for what is going to come in the trial design that I will speak about to you nominate. Next, please? So what are sarcomas? Arcoma tumors of Mesena origin. There are nearly 70 sarcoma subtypes, 150 tumors of Mesena origin -- and the big problem that we have with these patients is that the main treatment is for localizes is surgery, perhaps rather therapy to. And then when this is metastatic that, of course, in more than half of the patients we've been treating these patients since for the past 3 decades, basically doornatracyclin is the most typical common 1 that everyone has now. The program with doxorovisinis first, the activity is relatively modest with our overall response rate of 10% to 15%, median progress on free survival of around 6 to 8 months. And the very last 2 clinical trials challenging doors in a single agent that you can see those in the table up in the right. Basically, just they were negative for the endpoints which transmit us first that they weren't the right combinations, but it's feasible to do in the sarcoma community trials challenging the doors first-line combination. They are a big area of sarcoma subtypes that can be treated with different type of somewhat specific drugs for -- against those subtypes, but we don't truly have a biomarker that can direct or this different TKIs or agents that you can see in the table bottom right linking those with subtypes. So we have big troubles in treating these patients, and we haven't improved outcomes of sarcoma patients again for the past 2, 3 decades. Next? So here, this is the mindset, why targeting clever 1 in sarcoma is such a long hanging fruit. First, because of the rationale about craver 1 that you heard before is the solid tumor with the highest expression with some specific sarcoma subtypes that we know that they express more step 1 gene expression and that they are actually the most common come subtypes. And or that in the second part is that these patients have poor outcomes with drugs that are the same for decades and that they have a very, very modest activity. Next, so while combining the chemotherapy with WEX, where there have been a few clinical trials to 3D clinical trials combining chemotherapy with the checkpoint inhibitors that have shown very limited efficacy in so sarcoma, basically because, as you've seen before, the microenvironment is already quite immune suppressive for PD-1 inhibitors, smolotherapy or in combination to help to do any type of effect. And also, we know that chemotherapy can price tumors for immune responses and abrogates already Crave express and you'll see that in a minute. So -- so there is a strong biological rationale that combining cytotoxic chemotherapies with immune therapies. -- may offer a maximization of the therapeutic response and improve patients of COGS in the short term. Next -- so some data that I wanted to share with you regarding some of these affirmations I just made it. So first is that clever on blockage in combination chemotherapy, can has a broad potential and sarcoma is ORKAMBI 1 of the main paradigms -- so we know that there have been many reports already that chemotherapy and many types of chemotherapy. -- can actually increase the infiltration of STEP express in macrophages with actually leads to a more tumor immune-suppressive tumor microenvironment. And then there is also some other clinical data, as you can see in the upper part, first, that Histon expression after niajuvant chemotherapy in ovarian cancer decreases patients' outcomes. And in the lower part, you can see the Songshan cohort from Shanghai and China, which finds that actually ever on a clever, high expression in the tumor microenvironment, infiltration is associated with procreates of the stage of the disease in gastric cancer. Next. We also have some data from in vivo studies performed in different types of mice. But basically, here what you can see is the feasibility first of combining chemotherapy, in this case, FFO with be -- and second, we can see actually the analysis of how the addition of be to the chemotherapy improves the tumor microenvironment, the infiltrate making it less immune suppressive and it can be -- it was assessed in the left, you can see by prostate in the black and then in the right with in this knockout mice. So we have this proof of how first this of course in patients, the increase of more immune-primin mediated by macrophages expressing Kleber and second, that the combination of chemotherapy plus pets is feasible and then it's real wires the tumor micro environment. Next, -- so altogether, the evidence in sarcomas about Craver One expression, the knowledge about chemotherapy inducing clever 1 and this immunity trade based on 1 express macrophages. And then the -- the clinical need actually that we have in sarcoma and the visibility to do these trials read out to this Phase I being Phase II trial that we have currently active in Spain. So here, what we are conveying in the combination of first-line doxorobisin, so doxorubicin with BEC. So we have first, and this is what we have ongoing now, the dose escalation, which is followed by a dose expansion -- and then if this is positive by the end points that we've said, we will follow by a Phase II randomized clinical trial. Basically in the dose escalation that now we just opened the second cohort of the escalation -- so we said Doxorubicin 75. This is the standard dose. Why? Because you seen before by Petri and others, the tolerability of bags is wonderful, actually. So it makes it easy to combine and we establish the dose as the standard 1 with increasing levels of mix. So on the dose escalation is over Next, and then followed by back after Doxorubicin is finished. And end points are basically the typical ones about MTD, tolerability and has about efficacy. For the Phase II, of course, it will be PFS that is such a very common endpoint and additive for sarcoma trials. -- next. So this is the clinical trial. So we are almost in the -- we are actually in the finishing line of June 20 -- in definition line of 2026, sorry. And we already included 3 patients in the trial in the first dose level. We clean it up and now we are starting the second dose level, already 3-year slots has been able. People investigators have applied already to flats. So we are recruiting very rapidly and we aim to have initial results around April, May of the next year, very rapid results, but this is actually what we want to move on this trial that we aim also to squeeze this time, but probably by the beginning of 2029, we will have the full data set that will be moved towards the phase trial. So the time lines have been committed. The investigators here, we are very excited because this is such an operation behind this clinical and also we think that we may have finally a compound that can challenge in 3 decades. Doros in a single agent standard of care in Circo, -- so thanks so much, and happy to take any questions.

Thank you, Cesar. -- fantastic progress. First cohort already full. -- time to take some questions. Do we have any questions online?