Faron Pharmaceuticals Oy (FARN) Earnings Call Transcript & Summary

Good afternoon, I'm Markku Jalkanen, Faron's CEO. Welcome to this key opinion leader event on hematological malignancies. Could I get the next slide, please? As you know, we really have been focusing on the new type of the treatment for the acute myeloid leukemia, and that's the focus. And next slide, I will just introduce our speakers. We will have very exciting 2 experts with us today, Dr. Naval Daver, Houston Cancer Center of MD Anderson; and then Mika Kontro from Helsinki. Mika is also the PEI of BEXMAB map, a study which has been ongoing for more than a year now, and he will share also the results from that study. While we are presenting, you are entitled to make questions, you can just type your question to the Q&A box and our people will then evaluate them, and we will come to the questions at the end of the event. So next slide, please. This is a call for a disclaimer because we may be doing some forthcoming towards what will be happening next and this is our disclaimer for those activities. But let's then focus on the mode of action of bexmarilimab. We have been studying for years the immune suppressive elements, which prevent the immune activation against tumors and cancer cells. And we have learned that there is a molecule called CLEVER-1 that maintains an immune suppressive phenotype. These macrophages are really meant to remove all the great materials from the environment and not to present that to our immune system. The reason really why the tumor wants to do is to hide them against the immune system. The call is to not so missing now. And having that around, they also support the regulatory cells to build in the immunosuppressive environment. When you expose the CLEVER-1 to the bexmarilimab, you block the function. And now this macrophages will get a completely different phenotype, they become immune activators. And obviously, this is what we want to happen in the patients, who have cancer cells growing in them. And this is the major mode of action, which we have now shown in order to take place in the solid tumors, but we are more excited about the malignancies, which are born from the bone marrow. Next slide, please. So the rationale here is that you have one single antibody that can activate the immune system. And when that takes place, it will then help the immune system to fight against the cancer and can support the current treatments. Some of the leukemia cells, who have a myeloid background, they do express this cell on their surfaces. So now you could have a situation where not only to activate the immunity, but we also block the function on these cancerous cells. And then it's very interesting to understand what the outcome will be. We know that the immune activation can take place in vivo settings, as we have shown and studied more than 200 million patients. And all that we know that it's a very safe treatment in those. And obviously, that is something that we will be discussing also today. So the next slide is just telling that the concept of turning cold tumor into hot tumor is really something that we need in the current cancer treatments in order to really boost the immune system, which is often a really decline by the tumor cells and the mediators they can generate in the people. Looking next slide, the presence of CLEVER-1 on the hematological malignancies. On the right-hand side, you can see all those red and dots. They indicate a different hematological cell types. And you can see that the CLEVER-1 as seen is called Stabilin-1 is very abundant on the surface of these cells. So obviously, now we have a situation that we have a dual mode of action to activate the immunity, but also then to regulate the CLEVER-1 function on the surfaces of those cells. And on the left-hand side, you can see some information what is ordered in the literature. If we have a high expression of CLEVER-1 on the surface of these cells, the patient usually saw poor response to the current therapies, and the outcome is worse if we have our expression of CLEVER-1. We also have seen data that you can sensitize the current standard of treatment using a bexmarilimab. In other words, you can also induce sensitivity that actually could then make the treatment more powerful in combination therapies. And obviously, that is the purpose of the BEXMAB study. So the next slide is just summarizing that we do have a dualistic mode of action, we activate the monocytes in the circulation, to activate the immune system, and at the same time, we block the CLEVER-1 function on the surface of these acute myeloid cells. We know that this blocking a CLEVER-1 on the surface of the myeloid cells is really declining, the oxidative phosphorylation capacity of these cells. And if that then results in the reduction of the ATP, it's normally really reducing the viability. And obviously, that is the purpose of these treatments when we go into the patients. So, next slide is really to introduce now Dr. Naval Daver. The need for the improved treatments is very evident, because this myeloid leukemia are really the ones that we really need to have helped. And obviously, Naval, please tell us how serious condition is leukemia patients need to go over when they have the disease?

Yes. Thank you very much and a pleasure to give a brief overview of the acute myeloid leukemia space and the ongoing current prognosis and future research directions. I'm at the Department of Leukemia, the MD Anderson Cancer Center in Houston, Texas, and I focused on clinical trials, especially with novel therapies, both immune-based therapies as well as targeted treatments in acute myeloid leukemia and excited to collaborate and work with Mika and the team here on this target. Next slide, please. So this is kind of just showing the overview of where we have been and where we're moving with acute myeloid leukemia. There is no doubt that there has been a lot of progress, especially in the last 6 years or so, we've had a number of drugs approved, 9 actually, now 10 drugs approved. These are mainly in targeted therapies, IDH inhibitors, FLT3 inhibitors. One of the major players that has made a big difference, especially for older unfit AML is a drug called venetoclax in combination with azacitidine or low-dose cytarabine issuing great activity and also maintenance therapy has now been approved oral azacitidine. So this is very encouraging and good. But when you look at the bottom, you see that at the end of the day, the long-term survival, what we consider 5-year survival, which is when we start talking about cures in acute myeloid leukemia patients, is still 30% or less. Now we do think it will probably go up a little bit. But even the most recent database from 2022, the 5-year survival for all comers was about 33%. So we're definitely still way below 80%, 90% cure rates like we are achieving in acute lymphoblastic leukemia or in multiple myeloma. And I think there's a lot of work to be done and especially maybe immunotherapies could be important here. Next slide, please. So just kind of further highlighting that when you look at the survival of AML by age and treatment era over time, what we can see is that there has been improvement, especially in the younger AML. When you go back to about 50 years ago, even in younger AML, less than 20% had long-term cure survival. Today, that number is closer to about 50%, 55%. And with the incorporation of FLT3 inhibitors, IDH inhibitors, potentially venetoclax in the frontline setting, CD33 antibody gemtuzumab, and choosing the patients based on the molecular or cytogenetic abnormality that responds to particular therapy, there is great progress happening in younger. But in older AML, or what we call older or not fit or not suitable for intensive induction, we unfortunately are still not having a big shift. We were about 5% to 10%. Now we're probably close to 20% to 25% in long-term survival. But I think there's a huge scope for improvement beyond that 20% to 25% in the near future. And even with the advent of HMA venetoclax, we still are not getting much better than 30%, 35% long-term survival. So I think both the older unfit AML and then, of course, the relapsed refractory AML, as well as MDS transformed to AML are probably the 3 biggest unmet need population still in this field. Next slide, please. So just to highlight because I work with a lot of investigators across both U.S. and across the world. And a lot of companies and a lot of people say, well, now with HMA venetoclax, it's very difficult to develop new drugs. Or I don't think that the FDA is going to be excited for approval. And I think this is completely incorrect. We actually in MD Anderson led the Phase Ib and the Phase III studies of AZA and venetoclax, Dr. DiNardo and our group that led to approval. And no doubt, we think it's a fantastic drug and it's really improved the outcome for older unfit AML. But I think it's actually the beginning of the research for order unfit AML, not the end. So when you look at the long-term survival in these patients, we had data presented at ASH by Dr. Pratz, who was one of the coinvestigators on the BLA Phase III study of Aza and venetoclax. And what he showed was that the 3-year survival with HMA venetoclax in older, unfit patients was 24%. This was definitely better than the 3-year survival with azacitidine alone, which was 8%. So you can look at it as glass half full, 23%, 24% is 3x 8%. That is great. But also, if you can look at it with glass half empty that a decade from now, we don't want to be a 24% survival for older, unfit. We would like to get to 50%, 60%, 70% and higher. Also, the thing here that was also highlighted at the last ASH meeting a few months ago is that all patients do not have uniform benefit from AZA and venetoclax. We have started to identify what we would call the difficult patients or bad ACTR mutations. And these include TP53, where you can see the median survival is only 6 months. This is actually not really even better than AZA alone. So this is one group venetoclax has minimum to no benefit and then even other groups such as the FLT3, RAS mutation, MLL rearrangement, adverse cytogenetics, yes, they're getting 11, 12 months, maybe a little better than AZA, but not really ideal for what we want for our patients. And then there are some that do, do quite well. These include the patients with IDH1, IDH2 and PM1. And so the point here is that we now can start identifying and selecting where we need new drugs to be developed most, whether these are on top of AZA-VEN or with AZA alone. And this data will help us as we move forward with new studies. Next slide, please. So this is kind of the current landscape of AML treatment is a review we published a couple of years ago. And what we do clearly highlight and what is seen in clinical practice in the U.S. and also now in Europe, as many of these drugs have become available in the last couple of years in Europe and other regions, is that we are using molecular stratification for patients, especially for younger where we definitely check for the mutation, core binding factor, IDH and select appropriate therapy. But even in the older patients more and more, there's a selection for FLT3 IDL-based combination treatments and most importantly, TP53, which we will probably discuss and hear about more later from Dr. Kontro and the team, is an important group where we still have a huge unmet need and whether the patient is young or old, fit or unfit physically, we believe for TP53. There is no good standard intensive chemo does not work. HMA does not work. HMA VEN does not work, and we need new regimens. And this could be also a very good opportunity and an area for development of immunotherapies that focus on macrophages, such as the BEXMAB. Next slide, please. So just kind of further highlighting this was a review we just published on TP53 kind of putting together all the recent 2 decades of clinical trials and efforts. And unfortunately, it still remains quite a depressing field. The response rates are 30% to 35% and the survival remains below 7, 8 months. There are some leads with CD47 antibodies, which also actually work in a very similar way to remove the inhibition to macrophages and increasing the innate immune macrophage attack against leukemia. And so again, here, I think bexmarilimab could potentiate or could bring a new avenue for activating macrophages. And that seems to be so far after toolings of work, the pathway that is actually having activity and response in TP53. So we will hopefully hear more about this in the next talk. Next slide, please. So again, just highlighting the importance of immune system, there's a huge movement and focus on to immunotherapies and AML, which kind of makes sense. If you look at all of the major breakthroughs in lymphoid diseases in the last 3 to 4 years, these are predominantly immunotherapies, CAR T cells, blinatumomab in ALL, CAR-Ts in lymphoma and now bispecifics and CAR-Ts in myeloma and these have really revolutionized the disease by eradicating minimal residual disease and achieving durable long-term cures, even in advanced relapsed and older patients. So there is a huge effort, and we have been working, leading these efforts in the U.S. to develop immunotherapies especially for acute myeloid leukemia. I think we're still in the early days as compared to ALL lymphoma, but there are some promising targets that have emerged, especially focusing on the innate immune system, again, the macrophages and the NK cells, which we think are going to be better, because the T cells in AML often carry the mutations seen in the permanent hematopoietic stem progenitor cell. And we have actually done studies and published that the T cells are often dysfunctional or very suppressed function in the AML microenvironment as compared to the macrophages and NKs that seem to maintain activity. So I think this makes a lot of sense to approach the innate immune activation for AML. Next slide, please. And again, just kind of highlighting that the innate immune system is a very critical part, the central part that works in concert with the adaptive immune system. So for solid tumors, just activating the T cell adaptive immune system, may be sufficient, but in heme malignancy, especially in myeloid disease with the T cells themselves may be poorly functional, we believe that we could directly activate the innate immune component, the macrophages, NK cells, which actually have a very powerful ability to do cytopathic cell damage. And so we're actually going more and more towards that approach. Next slide. Just kind of highlighting here what we think are the good immune targets. So as I said, for the ones in clinic currently in the U.S., the macrophage activating ones are the ones that are most exciting. And I think here, bexmarilimab either the combination of AZA, AZA-VEN or even in the future in combination of AZA-CD47, if this space matures, could be very, very exciting, especially for TP53 adverse , very high-risk groups where we think a complete immune approach with the hypomethylating agent is going to be the eventual path in the next 3 to 5 years that we will look at. And then NK cells very early, but also could be an interesting combination or sequential approach to think about. Next slide. Just highlighting the many different CD47 drugs, which could be good, I think, combination partners here or the CLEVER-1 antibody to kind of like supercharge the macrophages and they have different properties. All of these are in advanced clinical trials. So I think we're very excited, especially about magrolimab, for example, which is now in 3 Phase IIIs. And based on the data published so far, we think has a good chance of being approved and then could be a great backbone in addition to AZA-VEN to be used with the CLEVER-1 or other innovative macrophage-activating approaches. Next slide, please. So I think just kind of in the summary that yes, we have a lot of new treatments, but we are still very, very far away from the goal. Yes, there are certain groups, FLT3, IDH1, IDH2 mutated, NPM1 mutated, core binding factor. These to make up about 30%, 40% of all new AML where we can have 75% to 80% cure rates. But for the majority, 60%, 65% of the AML and especially for the older, unfit, we are still in need of new agents, whether they're added to AZA-VEN or AZA-magrolimab in the future or to intensive chemo, I think that is fine, but we still need to move the bar in those patient populations, increased response rate while maintaining safety. And I think this will be something to really look at with the BEXMAB drug. If we don't see cumulative myelosuppression, thrombocytopenia, neutropenia, other new or unexpected toxicity, then of course, that makes the drug a very good potential combination partner to add to AZA-venetoclax or the AZA-magrolimab, and I'm looking forward to hearing that data. Next slide, please. Okay. Thank you very much.

Thank you. Thank you very much. Now really exciting, and I think it's easy to understand what the need to realize for these patients, because it's really an increasing number, but we can see when people are aging all the time. Thank you very much. And now I introduce Mika Kontro, who is really the PI of the BEXMAB study and has been really closely looking at the data, building up from those patients. And I'll let Mika to introduce what the current situation and what kind of data we have at the moment. Please, Mika.

Thanks so much, Markku, and thanks, Naval, again for a great presentation. Yes, as Markku mentioned, I will be giving you an update from the BEXMAB trial, which is Phase I, Phase II study, evaluating bexmarilimab with standard of care in myeloid malignancies. Next slide, please. BEXMAB trial is basically all-comers trials. So basically, trial includes newly diagnosed MDS, MDS failing previous HMA therapy or relapsed resistant AML patients. And these patients, whose standard of care currently is azacitidine are receiving the combination of azacitidine and bexmarilimab. As Naval pointed out, the current standard of care for those patients that have none of it AML, meaning that they are not eligible for conventional chemotherapy, these are commonly receiving azacitidine plus venetoclax. And in this trial, they're receiving triplet in combination with bexmarilimab. And for the first part of the trial, we are evaluating the optimal doses for both these cohorts that will then be taking into Phase II part of the trial dose expansion cohort. We currently have 4 active sites in Finland and 1 in the U.S. Actually, these all sites are already recruiting patients. And we are really, really excited to see that MD Anderson, Yale and UNC will be opening during this spring and early summer. The U.S. sites will be recruiting initially patients for doublet cohort. There is an amendment ongoing to open the triplet cohort also in U.S. Next slide, please. Here's the data, what we currently have on treatment-related toxicities. We started from 1 milligram per kilogram with the doublet, then entered 3 milligrams per kilogram and currently are recruiting patients for 6-milligram per kilogram. We have evaluated now 1 milligram and 3-milligram per kilo cohort 5+5 trial participants. And this far, we haven't observed any dose-limiting toxicities. There hasn't been any infusion reactions and no serious adverse events that would be related directly to bexmarilimab. We also have evaluated the triplet, the first dose of the triplet cohort 1 milligram per kilogram in combination with azacitidine and venetoclax. And for that patient cohort, we also haven't detected any DLTs or SAEs that would be related to bexmarilimab. Next slide, please. Here is just the swimmer's plot for those patients receiving doublet from 1 milligram to 3-milligram and 6-milligram. I want to underline a few things here. First of all, we have quite many patients that are still active in trial, receiving therapy. These are marked as arrows. We actually have quite many patients with relapsed resistant AML. And, of course, we want to also include more patients with MDS. With relapsed-resistant AML patients, we actually have very good treatment responses. We have very stable SD or stable disease responses, but we also do have achieved CRI responses as well as blast reductions. Next slide, please. This is just to give you the flavor that what we are aiming with bexmarilimab-azacitidine, or bexmarilimab-azacitidine/venetoclax combination. The first rows shows that what is kind of the current response rate for patients in each patient cohort. And as Naval was alluding to the overall survival of this patient actually is very dismal. This is presented on the second line. The aim with BEXMAB trial is outlined on the third row. And finally, we have the response rate in those patients that are evaluable on the last line. Of course, this is extremely early data, but it's very good to see that where we are heading at. And then it's actually quite promising that we see responses across all patient cohorts. We had responses, good responses, CR responses in MDS with HMA failure, MDS partial responses, I actually will be discussing this patient a bit later and also responses in very difficult to treat relapsed resistant AML. And for the triplet cohort, the data will be read out in July and will be presented later. Next slide, please. I will next briefly discuss about 3 interesting patient cases. I will be starting from our first patient, a 52-year-old man who was diagnosed with AML already in 2009. Then he was diagnosed with secondary MDS in 2018. He received allotransplant, but unfortunately, as often the patients relapsed and progressed to AML in June '22. He had RUNX1 and BCOR mutations. The previous therapies are outlined here, but I just want to mention that patient had received azacitidine prior, he was included in the BEXMAB trial, and he was recruited due to the fact that actually the disease progressed while the patient was receiving azacitidine. So we started the study therapy in doublet cohort, 1 milligram per kilogram almost a year ago. And now the patient is in cycle 9. Actually, during the third cycle, the patient developed fever, there was actually no signs of infection. And quite interestingly, at the same point, we observed that the peripheral blood blast count started to decrease from 20% to actually to 0. So the blasts were diminished or gone totally from the peripheral blood. And here on the right-hand side, you just see the bone marrow samples. So the upper figure panels. So the blast count after the 2 cycles -- so these kind of brown cells are the blast cells. And basically, as you can see, the whole bone marrow is almost full of the blast cells. But after the therapy response was achieved in the new bone marrow biopsy, we actually observed that there -- of course, there wasn't any blast cells. But quite interestingly, the bone marrow was infiltrated with these blue cells and these are lymphocytes. So these are B cells, T cells, both CD4, CD8 cells. So failing the immune response that we actually observed in the bone marrow. And the patient is currently still on trial receiving study therapy and he's in very good clinical condition. Next slide, please. I will then shift gears to patient with MDS, who had previously received HMA. This patient is 59-year-old woman, who was diagnosed with very high risk MDS. And as Naval pointed out, TP53 mutated diseases are the most difficult to treat. The patient received previously, Vyxeos, which is liposomal formulation of daunorubicin and cytarabine and also azacitidine. The patient was resistant to both these therapies. The patient was included in the BEXMAB trial in September and he received a doublet with 1 milligram per kilogram and actually received 4 cycles of therapy. And on the right-hand side, you can see the bone marrow blast count decreasing from 22% to 7%. And actually, in this partial remission, we were capable of reaching the patient to allotransplant. And of course, it's always when the patient is on trial, and this is the first patient undergoing allotransplant, it's always somewhat of a concern. But for this patient, the allotransplant was very uneventful. There hasn't been no surprising toxicities or unaccepted toxicities and no graft-versus-host disease and the currently the patient actually is doing quite well. Next slide, please. And this is actually the last patient case that I will be discussing about. This patient is a 61-year-old male diagnosed with intermediate risk AML in 2020 with the DDX mutation and deletion 20Q. Received conventional chemotherapy, but wasn't allotransplanted due to comorbidities. And actually, the patient then received maintenance therapy with perioral azacitidine. And during that therapy, the disease progressed and the patient relapsed. We entered the patient to the trial with 3 milligrams per kilogram cohort. And actually, quite interestingly, during cycle 2, the patient actually developed pulmonary infiltrates. The PCR was positive for aspergillosis, and also the patient was diagnosed to have organizing pneumonia, which is kind of an immunological process perhaps due to the aspergillosis, but perhaps bexmarilimab might play a role here. We started antibiotics and corticosteroids and actually, we were very pleased to see that after this therapy start and when the blood count started to increase after pancytopenia, the patient actually had normal comps and had entered to remission, as you can see from the right-hand panel. So the blast count decreased from 30% to under 5%, and the patient currently is in remission, doesn't need any transfusion and general condition actually is quite good. So with that, I hope that with these 3 exciting patient case and the data reported earlier, you get some flavor of what we currently are working on and are really excited to see the next steps of the trial.

Thank you, Mika, very much. It's very exciting to see that detailed information on these patients. And obviously, we are really encouraged really to continue and happy to also say that the size that I -- extremely we're recruiting at the moment. And I think we can really move fast. But let's come to that one. Also, once we listen our CMO, Marie-Louise Fjallskog, thinking what will happen next. Marie-Louise, please.

Thank you so much. So first of all, I would like to thank Naval and Mika for fantastic presentations, and let's go to the next slide. So what is -- what are the next steps for BEXMAB? So as you understand, we are in the Phase I part of the study, so we're doing the dose escalation. And as Mika said, this is sort of like an all-comer study. So we are including different indications and looking at the safety for the doublet and the triplet. However, when we moved into the Phase II part of the study, when we are really looking at the efficacy, we need to have different development plans for each of the different indications. So far, the indications that have been enrolling the most is the relapsed refractory AML. So I'm just going to share that development plan with you right now. We're hoping that we will be able to decide on the 2 doses to move forward with in the Phase II part by Q3. So per the new guidance from FDA Project Optimus, it is not sufficient to move forward with 1 dose in Phase II. We need to have 2 doses, at least. So we are randomizing between 2 different doses to see which of these 2 doses is the best for the patients. We look at safety, we look at efficacy, we look at PK and PD. So after we have done that, we will be able to determine the RP2D, the recommended Phase II dose. Meanwhile, we are eager to submit an application to FDA regarding orphan drug designation for AML, and that will happen within the next weeks. We also want to apply for fast track designation. And then, like everyone, wants to have breakthrough designation. It's a little bit early for breakthrough designation, because you need to have treated at least 20 to 30 patients, and you need to have good response rates, which we have, but we don't have sufficient number of patients. So that is what is happening very soon for relapsed/refractory AML. So with that, I would like to go to the next slide. Well we have already heard the clinical data presented by Mika. I just want to summarize a little bit. So we have safety data from more than 200 patients being treated with single in the [indiscernible] study, and the drug was very well tolerated. I'm very happy to see that even with the doublet and the triplet, it looks well tolerated. As Mika pointed out, early days, we haven't treated so many patients, but so far, so good. Regarding efficacy, we are in the dose escalation, and the primary objective here is to look at the safety. However, it is very interesting to see that we do see some very interesting and encouraging efficacy signals. So to summarize in the doublet, we have 2 complete remissions with incomplete blood count recovery in patients with relapsed/refractory AML. And what I think is important to point out here is that both of these patients had azacitidine as the immediate prior therapy to study treatment and they progressed. They are azacitidine refractory. In doublets, it's always very difficult to know which component is doing what. But in this case, it's highly unlikely that azacitidine again would like to completely sand for all of this response. BEX is doing something. So that is fantastic, I think. The second patient -- or the third patient, I could say, is the partial remission, and Mika described this patient very well. So these patients had received 2 therapies and did not respond to anything the last therapy with azacitidine did not respond. Now with the combination, the patient got a nice partial remission and has undergone allo transplantation. And this could potentially be curative. Then in the frontline setting, we also have 2 very interesting responses in high or very high risk MDS. So we have one patient in CR and another patient that is early in treatment, but we already see a recovery of the platelets. So we are extremely excited about the data. So although early, we are looking forward to the next coming months to see what more can we see. So with that, I would like to hand over to the Q&A session with Julia and Dan.

Thank you, Marie-Louise. And thank you again, Naval and Mika for fantastic presentations. We are now ready to open up for Q&A session. [Operator Instructions] Our first question of 2 patients have remained on the study for 9 and 10 months. How long is it common survival length of these diseases?

Mika, maybe you could take this one or...

Yes, I can take it. Can I actually have my slide where we have the exact information on the patient responses.

That's the table, yes. The table, yes.

The next one, please. So as mentioned, there is on AML patient with relapsed resistant disease receiving azacitidine. And as you can see, the current kind of response rates for this patient population, approximately 14% to overall survival median approximately 6 to 9 months. And that this patient has now been on trial longer than that. But of course, as mentioned, we are looking at small patient numbers. But also this response is highly promising. Regarding the MDS patient, I think that most of us who are treating patients with MDS are considering that responses are between 9 to 12 months. This 24 months was actually from the registrational study and hasn't been repeated since. So I think that the both responses are actually, as mentioned, quite promising. Thanks very much for putting up this slide.

Thank you. The next question goes to either Mika or Naval. If you compare BEXMAB results so far to the $1 billion BEX compared to magrolimab results, what would you be able to say?

Yes, I'm happy to take that. I mean, I think these are very different populations. So as you may have seen, the magrolimab studies are all focused on frontline, at this time AZA-magrolimab, AZA-venetoclax, magrolimab. And especially enriched for TP53. The data Mika showed here is predominantly more in prior HMA-exposed MDS or relapsed AML. And actually, there, we did look at magrolimab, they're both a single agent and with HMA. And we actually saw a very, very limited, almost no activity really. I think the single agent experience is going to be published by [ Dr. Parish ] from U.K. who did that study almost 3, 4 years ago. So I would actually say that you're seeing single-agent activity here, especially true CRs with good count recovery. Even if it's not a high response rate, we will see where the study how thin go is still a very encouraging sign. And I don't really think of these drugs as competitors. I think that these actually will be -- in time, we hope complementary drugs, different ways to enhance macrophage, innate immune activity against the leukemia and similar to venetoclax as well. I think the combination of AZA and venetoclax with bexmarilimab or AZA-magrolimab with bexmarilimab, I think, are what we would be excited about in the future. Mika,any comments?

Yes, here's a view on it. I think it's -- these are complementary compounds. And as mentioned, it will be highly interesting to see responses for a combination of trials. Thank you.

We have a couple of questions on the enrollment. I'm going to combine them in one. How has your patient enrollment been? And how many sites do you have for the current ongoing Phase I/II study? And there was also a question on the U.S. sites. How is that enrollment looking?

I think I will take that. So I think the enrollment is going really, really well. In fact, when we have dose selection meetings, we already have a list of patients waiting for the next cohort, so we're super excited. And we have 4 very active sites in Finland that are doing a great job, and we just have the first U.S. site opened very recently. And we have 2 patients enrolled there. Naval is coming on board very soon, hopefully, in May. So that is looking really good.

Great. To switch up to the solid tumor status. How much is the data coming from the BEXMAB trial influencing the future trial design in solid tumor studies?

Marie-Louise, you want to answer or should I?

Well, you can start it, Markku, and I can add to it.

Yes. Well, what has been really important for us is the original MATINS trial, because that has given us understanding on the dosing levels and the frequency. And as you can see, we hit really well the right dosing level with these AML patients from the very beginning. So that was really the significant value of what we did with the MATINS trial. Now we have also shown that was released last -- yesterday actually, saw that we can really convert the intratumoral M2 macrophages into M1 activators. So it really shows up that the bexmarilimab when given to the patients can penetrate to a number of waysides, including the tumors. And that's obviously very critical for us when we are treating the AML patients, because obviously, these cells go around and if we want to get -- to really catch them to blast all over the places. So it looks really promising.

Yes. What I can add to that is that because of the safety data in the MATINS study, we were able to run really quickly into the hematologic cancer studies and study designs. So they feed into each other. Like safety data is really important to get combination data in BEXMAB in hematological malignancies will help us in the development and moving forward in the solid tumors. Also the translational data and a better understanding of the combinations and so on. So they're helping each other. So whatever data we get is good for the future development.

And as a follow-up from the strategic point of view, are you more excited about hematological or solid tumor opportunity?

Well, as a CEO, maybe I like the fact that AML would be really much faster to the market than the solid cancer. And obviously, as you may understand that if we can help the solid tumor where the intraparenchymal [ levels ] allow, and then they become more sensitive for the PD-1 blockade, that opportunity among us, because we really need to increase the PD-1 blockade. But the AML is clearly so that the condition for the patients that we want to help them as soon as possible, and it obviously provides us also a faster way to the market. So both are very exciting, and we do everything really to speed up these recruitment opportunities.

Thank you, Markku. Next question, how much help has the LLS organization being in assisting in the BEXMAB trial?

Marie-Louise, maybe you can take this, because you have been more so close with them.

So I mean -- so we have gotten very good advice and guidance from LLS. They have helped us to reach out to investigators and to work very closely with different sites, et cetera. We have also gotten very good input into our study design and so on. So I think it has been extremely helpful for us to build our network and also to get guidance from their vast experience in the development of hematological malignancies.

And I'm also happy to say that they have invested in Faron. So Leukemia & Lymphoma Society will do those when they see that technical data is filling up. And at the end of the day, it will help those hematological malignancies also have cured one day, very, very fruitful kind of a collaboration with them.

Great. I've got 2 questions coming specifically for the BEXMAB trial design. How long does the protocol allow to continue treatment with BEX?

So of course, all the patients that are -- sorry, Mika, go ahead, you're the PI.

Yes. So basically, there is no limitation in the protocol. So basically, patients may receive steady therapy as long as they benefit from it.

Great. And we have a question on the stable disease patients. Why did some of the stable disease patients leave the study earlier?

Of course, there are several reasons. First of all, there are a few patients that entered another clinical trial. Of course, as Naval pointed out, these diseases are extremely difficult and can be extremely aggressive. So certainly, many of these patients have diseased from their disease. So basically, these are the 2 main reasons that patients have been come off study.

Another study-specific question, would it be possible that treatment with BEX is curative without stem cell transportation?

We all hope that.

Yes. I mean just most treatments we're doing in AML, even AZA-venetoclax or AZA-magrolimab or FLT3 inhibitors that are all very exciting and active. Especially in the relapse setting, the reality is that the duration of these -- none of these agents that are all very well established and approved is going to be long without transplant. And the FDA is actually totally fine with that. as long as the agent is able to be safe, get a good remission, and allow the patient in a good condition to go to transplant. That actually is considered to be an effective and safe drug. And many of the drugs we have approved, gilteritinib for example, IDH1 and 2 inhibitors hopefully in the near future, Quizartinib. In fact, the duration of response does often include the transplant if they go to transplant in remission. So I don't think that this is an issue. In the frontline setting, yes we hope if the data is really good, maybe there will be some patients using minimal residual disease and molecular clearance that we may consider not having to go to transplant. But for now, transplant is an integral and accepted part of treatment.

Great. We have the next question, what are your understanding about the possibility to combine BEX and CD47 drugs?

Yes. I mean I can start with that and then if Mika has any additional comments. But it's kind of similar to what we said these are complementary. So -- we think that the more activation you can get on the innate immune and the magrolimab plus the bexmarilimab having synergistic activity, the better we can have antitumor effects. Because even if you look at AZA-magrolimab, right, in TP53 mutated, yes, the response rate is good about 50%. But the true CR is only about 35% and the duration of response is better than AZA or AZA-VEN, which are 4 or 5 months, but it's still only about 8, 9 months. So there's definitely room for improvement. And yes, I think this would be one of the number one priority combinations I would like to look at. Let's say, AZA-magrolimab does well, gets approved in the near future, then I think this would be immediately the next combo that kind of me and others would want to do.

Yes, exactly. We are exploring more and more triplets, but still kind of combination of therapies with immunotherapies, we actually haven't had very many trials doing that. So that's certainly something very exciting to be done in the future.

Great. We have a question on the registration path forward. How much more data would it require in the trial for it to become feasible to apply for the emergency use authorization or other priority status to speed up authorization?

You start, I can come later.

I just -- I mean from a U.S. FDA perspective, I mean, I think they have been very open to early discussions and submissions. If we see kind of consistent responses in a high-risk population, which would mean post HMA, MDS or relapsed AML. So I think approval is a big word, but I think at least for breakthrough designation or combined oncology development, I would say once you have 8, 10 responses very early on, one could start these discussions. But Marie, I'll turn it to you.

Yes. So most of the patients, or actually all of the patients that we have treated in the BEXMAB study so far of the relapsed/refractory AML patients are HMA refractory. So that gives us even a better chance of potentially getting some sort of accelerated approval, because there is really no standard of care there after azacitidine. So as Naval said, I think breakthrough designation and discussions with FDA could really be fruitful here, and we're very hopeful and enthusiastic about the coming path.

And we have what looks like the last question so far, and we did touch on that before, but I think it's a great summary for both Naval and Mika. What excites you about bexmarilimab??

Yes. I mean, I can start. We have not yet had the opportunity to start enrolling patients. But as was mentioned, we hope to very soon, maybe even in May, things are moving ahead with the regulatory and approvals within MD Anderson. I think to me, the safety is looking very, very good. That is something we also did see with CD47 working on the same cell type. So I do think that unlike T cell activation, which does cause a lot of immune -- IRIS, immune-related AEs, especially the leukemia. We had a number of toxicities more than what was reported in solid tumors. So I do like that with macrophage activation, this has not been a problem. And it sounds like from Mika's data with BEXMAB CLEVER-1, that will be very well tolerated as well. The second thing, obviously, is we are always looking for something. There's nothing currently in the landscape at all for relapse or post HMA, MDS as we call it, or for relapsed AML if they don't have a targetable mutation. Yes, if you have a FLT3, IDH1 or 2 MLL, NPM1, now with the menin inhibitors, those 40%, 45% subset, we can have effective salvages. But for the remaining 50%, 55% relapsed AML and for all of relapse MDS, I would be excited to build on this initial signal and response data. Mika?

Thanks so much, Naval. Perhaps building according on what Naval said, but treating with these patients and working with them, it's actually quite good to see that as Naval mentioned, the patient tolerated treatment well. The patients do not have to spend time in hospital. Of course, there are, every now and then, infections that need to be taken care of. But otherwise, then that the quality of life of the patient has been quite good. So those certainly excite me as an AML and MDS doctor. And what, of course, what was brought up already earlier that we do see responses in patient population that already has exposed to HMA. And still, we do see the treatment responses. So I think that there are actually quite many encouraging things and really, really looking forward for expanding to other sites and exploring these other dose levels as well.

Thank you. And this concludes the Q&A part of the call. Thank you, everyone, for participating. Great questions and answers. And I'm going to pass the microphone back to Markku for the closing remarks.

Thank you, Julia. I also want to thank all the speakers. Really excellent. And I think the knowledge we need to build around this bexmarilimab is really important from both the solid tumors, but also from these hematological malignancies. And there are some indication that there could be some other hematological malignances, which actually could be targeted with CLEVER treatment as well, but later on. So we are so excited really to move on, and I'm really happy that the clinicians are with us really doing excellent recruitment whenever that is provided to them. And once we get to the expansion phase, we obviously want to have all the sites open in U.S. as well and maybe even add more to those. And then looking forward, really all the interactions with the regulators, because if you want to have an accelerated pathway, you need to really discuss with them what is the best thing really to do that. So with this really, thanks again for excellent talks. Thanks for the audience making excellent questions, and we keep you informed as the new data comes up. This will close this session. Thank you very much.