Good morning. My name is Breaker, and I will be your conference operator today. At this time, I would like to welcome everyone to the Blueprint Medicines conference call. The powerful mast cell, a promising target for treating allergic and inflammatory diseases. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, please press star followed by the number two. Please plan to limit yourself to one question. Thank you. Cassie Saitow, you may begin your conference. Those of you who have followed the Blueprint story are familiar with the development and launch of AYVAKIT in SM. It is the first and only medicine to directly target the root cause of the disease, the KIT D816V mutation. AYVAKIT was groundbreaking in demonstrating a broad spectrum of clinical benefit and is now firmly on the path of long-term growth. We anticipate that AYVAKIT will achieve more than $2 billion in global peak revenues. Our goal on the call today, the first in a series of educational webinars, is to share insight into how we are investing in our pipeline to drive long-term growth. As you'll see in today's discussion, the insights and knowledge that we have gained through the last decade of work in the mast cell space have provided a foundation for us to pursue a wide range of large opportunities in allergies and immunology. Following Dr. Fouad Namouni's introduction today, you will hear a conversation between Doctors Becker Hewes and Mariana Castells, a renowned expert in mast cell biology, on the power of mast cells and how targeting them has therapeutic potential across multiple diseases. Dr. Percy Carter will then discuss our research strategy and the profile of BLU-808, our wild-type KIT inhibitor, including preclinical data recently presented at the AAAAI annual meeting. Before we begin, I'd like to remind you that some of the statements made during the call today are forward-looking statements as outlined on slide three, and are subject to a number of risks and uncertainties. You are cautioned not to place any undue reliance on these forward-looking statements, and Blueprint disclaims any obligation to update such statements. Now, I will turn the call over to Fouad. Fouad? Thank you, Cassie, and good morning, everyone, and welcome to the powerful mast cell webinar. At the time of Blueprint's founding, our vision was that we could use our expertise to make highly selective Kinase inhibitors make highly selective kinase inhibitors and make medicines for highly sought-after targets. This led to multiple medicines either in development now or approved, most importantly, AYVAKIT. Blueprint has a long track record of leadership in mast cell biology, as proven by the success of AYVAKIT. One key thing about the success of AYVAKIT is not well known is how much it depended on our ability to master mast cell biology and build a deep understanding of not just the aberrant activity of mutated KIT in systemic mastocytosis, but also its wild-type KIT's role in the physiologic functions of mast cells. At Blueprint Medicines, we have built what we believe are one of the most advanced mast cell drug discovery capabilities in the industry. With our expertise in highly selective small molecules, developing a wild-type KIT inhibitor is the obvious next step that we are taking. Now, as we can see, our vision for scientific leadership in mast cell disease is built on four key pillars. First is to leverage a deep understanding of the mast cell biology to modulate its activity. Second, is to select the best targets and modalities for monotherapy and combination strategies to achieve first and best-in-class positions. Third, to establish a strong preclinical and early clinical proof of concept or POC to de-risk development. And lastly, is to pursue a pipeline in opportunity in major mast cell-associated disorders where there is a medical need. So why are we focused on mast cell-driven diseases, building a franchise in allergy and inflammation? Well, we have built a foundation of success in systemic mastocytosis, a disease, as we all know, driven by a mutated KIT. And it is because of this success that we know mast cells are a major central effector, and KIT is master control switch for these cells. We know there is a significant medical need in large patient populations where multiple blockbuster medicines can play in the same indication. This is different than precision medicine oncology markets. We also know that targeting mast cells directly is a novel mechanism with high potential across numerous indications using monotherapy and combination approaches. We believe that focusing on mast cells as the key target in allergy and inflammation will build a robust franchise in these diseases. Mast cells can be key driver in the inflammatory response to most allergic disorders. Being able to prevent their activation and degranulation may have a major impact on the way we treat several allergic disorders. Example given, chronic urticaria, type 2 asthma, atopic dermatitis, eosinophilic esophagitis, food allergy, and many others. A different aspect from precision oncology market dynamics is the large patient populations with medical needs, where multiple blockbuster medicines can play in the same indication. As the mast cell leader, Blueprint Medicines is writing a new chapter in the treatment of mast cell-associated [NMI] diseases. Scientists have been trying to crack the code of allergy and inflammation for the past 100 years. Yet most therapeutic approaches have been focused on individual mast cell mediators, stimulators, or activators. We are targeting the cell itself, the central effector. We are pioneering an area of science with broad applicability, and wild-type inhibition with an oral agent like BLU-808 is a robust first tool in our vision for a broader toolkit. This space may seem crowded, but when we look at addressing mediators versus the mast cell itself, there is a lot of wide space for innovation, including new agents like 808 in monotherapy and combination strategies. I'm really excited about the potential of our R&D strategy, and I look forward to sharing more in the future. With this, I will turn the mic, the mic over to Dr. Becker Hewes. Thanks, Fouad. So I'm joined today by Dr. Mariana Castells, and she requires no introduction, but I will remind people that Dr. Castells is a professor at Harvard Medical School. She's also the director of the Mastocytosis Center there, and she actually just got back from Chile, where she's helping locals set up a center of excellence for mastocytosis and mast cell disorders there. Really illustrating her reach in the mast cell allergy community, as well as the importance worldwide addressing mast cell-related disorders. And Dr. Castells is not only a pioneer in the mast cell arena, but she was an investigator on the pioneer trial of Avapritinib in systemic mastocytosis. So before I dive into the conversation with Dr. Castells, I wanted to reflect a little bit on what—on how I see this inflection point in medicine from the 20 years that I've spent in the industry. So I was lucky enough to be part of the Herceptin development program, where I saw the impact of really targeted tyrosine kinase inhibitors on a devastating disease, and heard stories about patients going in to a hospital not expecting to come out, and then leaving with their family the next week. I've been part of the ribociclib development program, where the treatment of breast cancer, metastatic breast cancer, the hormone receptor-positive, changed in almost an afternoon with the introduction of CDK4/6 inhibitors. And nowadays, that compound is the standard of care in patients with metastatic breast cancer. Then I was also part of immuno-oncology when I was at Novartis, and really watching the evolution of therapy for devastating diseases like lung cancer and melanoma that had no treatment in the relapsed refractory setting. Now to see immunotherapy, which interestingly addresses T-cells, which are very central to the immune system, also very powerful cells, and that's completely changed the way that we treat lung cancer, melanoma, and a number of other disorders. And I believe we're at a similar inflection point now. Mast cells are making a reemergence, and a lot of this is because of the understanding of the biology of mast cells, but it's also because we now have tools. We have small molecules and antibodies that help us address mast cells. The biology surrounding the mast cell has really changed the course of a number of different diseases that we're having. So you can see that the mast cell, part of it's just an allergic cell, but it's really sits at the center of so many different processes in the immune system. You've got the innate immunity, which is the part of the immune system that is ready to go all the time, and that is what the mast cells participate in. They're ready to go when an allergen enters the body. But you also have the adaptive immune system, where mast cells influence T-cells and influence B-cells, and we'll see some of those data today. But this is really a central part of the immune system, and addressing mast cell biology can help us address a number of different diseases. Now, mast cells are the first line of defense against pathogens and allergies. We'll talk about how they execute that function today with Dr. Castells. They are enriched normally in tissues that interface with the external environment, like the GI tract, and the skin, and the lungs. They also are present in the heart, and when they are overactive, they can cause a number of different pathologic processes in the body. Mast cells degranulate, and they release not only short-acting mediators, that Dr. Castells will talk about a bit more, but also cytokines and chemokines that impact the rest of the immune. The downstream impact of either activation or, more importantly, overactivation of mast cells can really alter the adaptive immune system. Dr. Orfao in Spain has done a lot of work, and we'll take a look a little bit at today, to show how the T- cell repertoire is actually changing when you have chronic mast cell activation. And all of this overactivation can really cause disruption across the immune system. We'll talk about the impact of that and the potential to address mast cells as the linchpin to ameliorate some of these. So, Dr. Castells Let's, you know, when I first came into your office, you showed me pictures of mast cells, and your first message to me was, "All mast cells are not created the same, and they don't behave the same." Talked about different tissues, different gene types. Maybe take us through a little bit of that biology, dive a little bit more deeply into the details. Yes, and I'm delighted to be here today because I'm following in the footsteps of my mentor, Frank Austen, who actually defined the field of mast cell biology. He actually defined in his, like, 50-plus years of his own career, we think maybe it is coming from mast cells, and that changed the landscape of asthma. Well, I'm coming from like deep research into the mast cell biology, and what I can tell you is that mast cells were thought to be a unique cell when George described that in the early 1980s. Right now, we have here in front of us a single cell RNA description of how many mast cells in the human body can be. You can see that there are at least six descriptions of mast cells that possess different proteins, different RNA, and different classes of DNA. In the different tissues in the right side, you see that the definition of those tissues, the bladder, the intestine, the lungs, have very different compositions. Six different mast cells, and each tissue has a different composition of the mast cells. So the mast cells, again, we define them in six classes. In the future, there will be more. As we refine our single cell RNA, we will be able to unfold more mast cells in the different tissues. Addressing what those mast cells can do in the different tissues, something that we can have, you know, more conversation. Because there are two things that mast cells can do in the tissues. They can have cell-cell interactions with the surrounding environment and with the cells in those tissues, and they can also have local and long-distance mediators release that can actually prolong their action. So, you've described mast cells as very social, and it looks like they're geographically distributed in quite a variety of ways. Maybe just talk a little bit about kind of the distinction between the local effect of a mast cell versus the more distant effect. Yes, and I want to say that maybe we can look at this slide and say that we have here mast cells that are described as being round cells that have a nucleus, and then little dots that are the granules. And those granules possess all what we call the biomarkers or the mediators of biology. Through those mediators, we now have this conversation about releasing histamine, a powerful vasodilator, proteases, which are tryptase, chymase, carboxypeptidase. The membrane of the mast cell also has arachidonic acid, which will release prostaglandins and leukotrienes upon activation. And then there is long-term and long-distance effects, such as the release of cytokines and chemokines. If you look at the variety of cells that mast cells can influence, we have here that it can influence a lot of, you know, systemic symptoms, which could be fatigue and others. But it has a neurological impact, musculoskeletal impact, respiratory, digestive, cardiovascular, and cutaneous. And I can say that there's no organ system that has been uncovered that does not contain mast cells. Potentially, the kidney has fewer, but the rest of the organs, they all have tremendous amount of mast cell located at very strategic positions and capable of reacting with the local cells, but also releasing those powerful mediators that have a tremendous impact, even locally and systemically. So as I look at this, the variety of systemic effects that these mast cells can have, I imagine your clinic is quite varied. You must see patients with a lot of different gene types, different types of diseases. Is that- Right. So we started by looking at the kind of bread-and-butter impact of mast cells in the respiratory system, so allergic rhinitis, asthma, all those kind of diseases. But then we look also at urticaria with the mast cell in the skin. We look at gastrointestinal diseases also that have a tremendous impact. Even inflammatory bowel disease and other inflammatory bowel diseases that we are unfolding have been addressed by mast cell blockers, for example. And then we have, you know, other. In addition to all the respiratory, we have systemic impact, anaphylaxis, food allergies. So all of those diseases are those that we are addressing. But there are novel diseases that we are just seeing. For example, neurological diseases are now thought to be, you know, an association between the impact of the adrenal and mast cells. So as we are speaking, we are unfolding many more diseases than we even initially thought would be having a space of the mast cell. So on addition to being able to see a lot of different types of patients, it sounds like you need to understand a lot of different types of biology. Can you maybe talk a little bit about how mast cells contribute to inflammation here for that? Yes. So mast cells initiate a wide range of pathological effects, as you can see here. The mast cells, by releasing histamine, tryptase, chymase, and other lipid mediators, have a rapid response. So this is the immediate response, which can lead to acute bronchoconstriction, which leads to asthma, acute sinus impact, which can lead to allergic rhinitis, but also conjunctivitis. Then there is anaphylaxis, and these are really acute impacts upon contact with the allergen. In this thing, you can have hives, you can have flushing, all those symptoms are very acute. And then there is this release of long-term mediators, cytokines, chemokines that impact other cells, such as you can see your neutrophils, eosinophils, basophils, and others, and even the connective tissue fibroblasts and others. Then that creates what we call Th2 inflammation and inflammation, long-term inflammation, and that results in other diseases, the chronic gastrointestinal diseases. Also impacts, for example, bone. There is osteoporosis, osteopenia, that is impacted by histamine and other mast cell mediators. So again, the impact of the mast cells can be seen as an acute impact, and then a long-term impact in different diseases. So I'm particularly interested in the chronic impacts of mast cells. And, you know, I used to run an asthma clinic, and I understand how bad these patients can be because their lungs are permanently changed due to the overactive inflammation that occurs there. I know that there are patients where the mast cells actually contribute quite a bit to that. But maybe to dive a little more deeply into the impact of the immune system, we've learned a lot from systemic mastocytosis. So can you talk us through a little bit about some of the changes we're seeing in the immune cell population? Yes. In mastocytosis, what we have known for the last 30 years or more is that mast cells can accumulate in different organs, and they can accumulate in the skin, they can accumulate in the bone marrow, and can be distributed to other organs such as the gastrointestinal tract, or liver, and spleen. And that has been a major understanding. Very recent understanding implicates other cells that can be impacted by the long-term release of mast cell mediators. We have here, in the left side, the mast cells releasing all those mediators and the long-term impact on the T cells, which can be due to the release of through the [T cell] activation Fc, FcR, and the Ig receptor, the IgG receptor, and other receptors. But in the right side, we see the consequences of that. And you see, for example, in the healthy donors, we don't have an impact of mast cells in other immune cells such as T cells and other naive cells. But here we see that systemic mastocytosis patients have an increase in naive CD4 T cells. And this is critical because that will also have an impact in inflammatory tissues such as the respiratory, gastrointestinal tissues. And again, we see that there is a diminution of central memory T cells, and that also will have an impact. So again, mast cell mediators are modulating the landscape of inflammation in mastocytosis patients. Yeah. When I, when I spoke to Dr. Orfao about these data, you know, these are the circulating levels of these T cells, and, and part of his explanation for this is that these T cells have really relocated to the site of inflammation where the mast cells are. And so, I know there's more data coming on that, but it really goes to the simplest term, it's just not normal. So can you talk us... So if you think about this occurring over many months and years, you can imagine a very dysregulated system. Can you talk a little bit about how mast cells play in pathogenesis? And, and I understand sometimes they are the main culprit, other times there are more cells instead. So can you dive into that a little bit more? Yes. Yes, and we have here the distribution, the upper part of distribution in diseases and conditions that are mast cell-dependent, in which we have identified the mast cells, in which we have actually seen them in the tissue and measured the mediators. In the right side, we have mast cell-associated diseases, in which we actually have seen a new direct way in which mast cells impact those two diseases. For example, in mast cell-dependent diseases, systemic mastocytosis, very clear and monoclonal mast cell activation syndrome, that mutated mast cells increase the mast cell mass. They relocate to different tissues. They inflame those tissues. And there is also a disease in which the mast cell mass is not increased, and mast cells are activated. Idiopathic mast cell activation syndrome, some forms of hereditary angioedema, in which patients have family members affected. In these diseases, the mast cell is really the central effector. We have here also that in some allergic diseases such as type two asthma, we have seen an increase in mast cells in the musculature of those patients. When we dissect patients who have died of asthma, we have seen that in the muscle of the bronchi, there is more mast cells. There's also chronic urticaria, nasal polyps, anaphylaxis, high impact anaphylaxis, in food allergies, in allergic rhinitis, and also allergic conjunctivitis. In those, we have actually the signature of the mast cell. We turn to the mast cell-associated diseases. This is the interesting part in which in the last few years, we have been unfolding that mast cells do have a role in, irritable bowel syndrome, in eosinophilic disorders, in idiopathic pulmonary fibrosis, and [SIBO], because we have seen that indirectly, some of the mast cell blockers, mediator blockers, may have actually had a beneficial and potentially beneficial in, psoriasis, dermatitis, chronic colitis, and other viruses. In all those diseases, there is tissue distribution of an increased mast cell, and we really don't know, as we were talking about, what is the phenotype of those mast cells, and what do they release, and how can we address them in those, mast cell-associated disorders? Yeah. And so when I think about treatment of all these, the wide variety of diseases, and mast cells play a different role in different diseases, I can imagine that some of these, particularly those on the left, might be more suited for single agents that could address mast cell biology directly, while you might need combinations for those diseases on the right. Can you comment on that? And then one other aspect is, I also believe that if you have a therapeutic way of dialing to the right amount of mast cell inhibition, it would allow you to address a wide variety of diseases. Can you just comment on that approach? Right. And so, for example, in the left side, we have the diseases in which decreasing the number of mast cells will be beneficial, such as in systemic mastocytosis, decreasing the number of the mast cells and decreasing the impact in the tissues. In other mast cell-associated diseases, tuning down the level of mast cell activation and the impact of the interactions between mast cells and the other cells will definitely be something in conjunction that would be addressing potentially a much better way than just addressing only inflammation without the mast cells. So I do think that in the right side, we have really growing evidence that mast cells can be complementary in the treatment of those diseases. Okay. Can we dive a little bit more deeply into asthma? And, you know, I know that we know a lot more about asthma than when I ran that clinic, 20 years ago. My understanding now is that there's asthma that is associated with allergic conditions, and then asthma that might or may not be associated with allergic conditions, there's like Th2 asthma. Can you talk a little bit about the relative role of mast cells in those two types of asthma and what evidence we have so far that this, that approach might work? Well, you know, asthma is such a complex disease, and we try to make it simple. When I was a fellow, we said it is allergic and non-allergic, and now you see in the left side of the slide that there is a lot of plethora, a very complex plethora of interacting cells that play this disease. So, just like, from the aboveground vision of asthma, we thought that what we call Th2 asthma is what we call a, an asthma with Th2 inflammation, allergic versus non-allergic, in which initially we thought that mast cells had only the allergic part. So mast cells have IgE, and IgE can bind allergens. Allergens can be from dust mites, indoor pollen to the rest, and that will activate the mast cell, and that will release the mediators, inflammation go on. That's what we have, actually a really good version, now of an allergic asthma. In that regard, mast cells need to be targeted, or at least we could target the mast cell mediators. In the non-allergic asthma, which is, an asthma that we have been able to identify, the mast cell is actually talking to other cells. There are other components, such as IL-33, IL-25, TSLP, and others, and especially other cells, basophil, ILC2, T cells, Th2 cells, that actually release their own kind of mediators. But mast cells receive, as we were mentioning, directly to them with cell-cell contacts with all these cells, and the fibroblasts, and the eosinophils, and the neutrophil cells. But also they are having a release of mediators that have a long-term impact in those tissues. So we can actually see a very good example in the right side. In the right side, one of the conundrums of asthma is that there's asthma and there's severe asthma, and our understanding of severe asthma is just unfolding. We see here that our preoccupation is to treat patients who have severe asthma. We already have, as mentioned before, and through the work of the great work of Dr. Austen, with these mediators that now we can target. But what about severe asthma? So we have here that in this slide from our group, Dr. Cahill, our division, that describe how they treated severe asthma patients with KIT blocker, imatinib, tyrosine kinase. And we see that in the red, the change in the tolerance to allergen challenge and also the decrease in tryptase was really significant with imatinib. And so this is kind of a proof of concept that targeting mast cells and targeting KIT was actually able to make a difference in severe asthma, which is really, really the frontier about treating, patients with asthma. So we can inhibit IgE medication—excuse me, IgE-mediated activation. We can deplete mast cell numbers, but then we may need a combination of targeting mast cells in the, in the, the very difficult asthma. Yeah. And this is a great start in terms of proof of concept that addressing mast cells can help in asthma. I understand that imatinib is not the best KIT-type inhibitor, and a more targeted one might help us quite a bit more. I just wanted to dive into one more disease that you mentioned earlier, which is eosinophilic esophagitis. It's called eosinophilic, but I guess the understanding from you that I've gotten is that it may be that mast cells play either a large or maybe even a more important role. Can you say a little about that? Yes. I'm actually not happy with the name. It should be mast cell eosinophilic esophagitis. So those are diseases in the gastrointestinal tract that we have in the last, I would say, 10 years, and thanks to one of our colleagues, Dr. Marc Rothenberg, who did a full time identifying eosinophil as the, the prime, cell. But when studies have been unfolding, we have seen, and we have here, in the left side, that not only the eosinophils are, increased, but mast cells are increased in this disease. And so they all hand in hand. The mast cells are increased significantly in those patients with eosinophilic disorders, not only esophagitis, gastritis, and other, parts of the intestine. And then the mast cells, also in the right side, are degranulating. So not only are they present, but they are active. The pathogenesis of the diseases now is thought to be a combination of eosinophils coming to the site and then mast cells being there and degranulate... and so depleting the mast cells there makes sense. Controlling the mast cell regeneration makes sense. And those diseases, it is clear already now a proof of concept that only addressing eosinophils will not make the difference. We have to address eosinophils and mast cells in all these eosinophilic disorders. But your hope is that by addressing mast cells in addition to what we already have for EoE, we can really deepen the response and improve? Mast cells are extremely important cells, as we mentioned before, they raise the immune system, but also the adaptive immune system. They are placed in strategic locations in every single organ. They protect us from the environment, coming from the pollen, the dust mites, the cat, but also in our bowels, by the foods that people become allergic. So I think it makes a lot of sense, in this area where we have single cell RNA, where we have all these incredible tools, and we can actually target mast cells either by targeting their receptors or their signal transduction to look into diseases in which we have now evidence that mast cells can participate. Well, Dr. Castells, I want to thank you for a rapid but extremely deep journey through what mast cells do and what overactive mast cells can cause. And you, you've taught us again how powerful they are, that they are social cells, and that they can lead to many different disease manifestations over time. And that, again, is why I believe that we are in an inflection point for patients and for the therapeutic areas that involve mast cells. So at Blueprint, we are very focused on tunable ways to address mast cells. As you know, Blueprint, it has a track record of creating exquisitely specific inhibitors with very few off-target effects and allowing us to treat patients and address cell biology that's very specific. So what I want to do next now is turn it over to Percy Carter, our Chief Scientific Officer, to explain more about the Blueprint approach to this biology and some of the tools that we've developed. Thank you, Becker, and thank you, Dr. Castells, for joining us this morning for this presentation. So on the next slide, by way of background, I'd like to remind you of the long track record of success that Blueprint Medicines has had, has had over its past history, bringing forward two approved medicines, actually, in the first 10 years, of the company's history, Avapritinib and pralsetinib. During this time period and more recent time period as well, the company has been able to maintain approximately 80% success rate from IND filing to clinical proof of concept. And over this time period through the end of last year, we've brought forward 17 development candidates for nomination for clinical development. As shown in the center of this slide, we are currently focusing our scientific expertise in two areas. The first, allergy and inflammation, which is clearly the subject of the talk today, as well as in oncology. You're aware, obviously, of our role in bringing forward Avapritinib and our continued role and we're thrilled with the continued progress of the commercialization and distribution of to patients in need. We have Elenestinib, a molecule also indicated for the treatment of systemic mastocytosis, currently in clinical study. And then the subject of today's talk, BLU-808, a wild-type KIT inhibitor, indicated for the treatment of mast cell-mediated disorders. It's important to highlight also our CDK2 franchise, led by BLU-222, a molecule currently in clinical study in the context of HR-positive, HER2-negative breast cancer resistant to treatment with CDK4/6 inhibitors. We're very excited at ASCO in a few short weeks to provide an update on the progress with BLU-222 in combination with Ribociclib and Fulvestrant. We also recently announced at the JP Morgan Healthcare Conference our advancement of BLU-956, another CDK2 inhibitor, as well as our activities with a CDK2 degrader program. Looking to the future, we have a broad research portfolio. One of the key philosophical underpinnings of this portfolio is that we use the right modality to target a biological target in the context of the disease, where we feel that provides a key control node over that disease. We look forward to providing additional descriptions of these programs in the future. So now it's 2023, let's refocus our attention on the mast cell. So you've seen this diagram before, and obviously, one of the things we want to highlight here is the crucial role and central role that KIT plays as a regulator of mast cell activation, proliferation, and survival. Dr. Castells and Dr. Hewes nicely highlighted how mast cells drive disease and exacerbate inflammation. You've already heard that we have a track record of success in mast cell drug development. As we go to the next slide and talk about that track record, you can see we've brought forward four programs for the treatment of disorders mediated by KIT specifically. So Avapritinib in the upper left-hand part of this slide, and Elenestinib in the lower left, those inhibitors of the D816V mutant form of KIT, the key genetic driver of systemic mastocytosis. In the upper right, a molecule that we partnered with IDRX, and now referred to as IDRX-73. This is an inhibitor of KIT Exon 13, indicated for the treatment of gastrointestinal stromal tumors. And then in the lower right, the molecule that we're going to focus on today, BLU-808. So all together, one of the three that three clinical-stage, highly selective and potent KIT inhibitors designed by our scientific team. So moving to the right, next slide, we want to set up this diagram, which I think, Becker has nicely already spoken to. What we want to emphasize here is, as we move into the data with BLU-808, we want to keep in mind the notion that when we designed this molecule, a program that we started three years ago. One of our concepts at the outset was that we would be able to provide inhibition ranging from sort of IC50 level inhibition, which you know, illustrated on the slide, would be achieved at a relatively low dose of the drug and would reduce mast cell activation, but not significantly impact mast cell number. But then it would have a safety index that would allow us to move to higher doses and higher circulating concentrations, which would more profoundly impact mast cell activation and reduce mast cell number. And as we think about different diseases, and Professor Castells and Dr. Hewes nicely highlighted this, in some diseases, we may want to be closer to the right end of the spectrum, and in other diseases, as we're combining with other agents, we want to be closer to the left end of the spectrum. With that, let's move to the next slide, where we can review the profile of BLU-808. These data, and in fact, the data that I'm going to show you on the next three slides after this, were reported at the recent AAAA I conference that my colleague, Cassie, mentioned at the outset of the talk. You can find a direct link to the poster of the AAAA I conference on our Blueprint webpage. So I direct you there if you'd like to have more details on any of the things discussed here. So looking at BLU-808, we can see the molecule is fully potent, having a cellular activity of 0.4 nanomolar in the phospho-KIT assay. It's also a potent blocker of KIT-dependent proliferation of cells at 1.3 nanomolar. And then we'll talk further about its ability to inhibit mast cell activation, as indicated in primary cells of the inhibition of CD63 expression and histamine degranulation. Let's talk about the selectivity, and Becker has highlighted that this has been a long-time focus of the company and continues to be central to our approach to drug discovery projects. Which is to say, we bring forward molecules that specifically target one aspect of the biology. These, a crucial node in this impact. Here you can see as part of that, this molecule is fully selective in the kinase assay. Here we see we have 10 score at three micromolar, 0.04. And relative to specific off targets that have plagued wild-type KIT inhibitors in the past, namely PDGFR alpha, beta, as well as SLIT3 and CSF1R, we see excellent selectivity exceeding 300-fold in all instances, and even higher for several of them. And importantly, also, as we think about where we want this molecule to act, as Dr. Castells has mentioned, we want this to be in the periphery, right in the tissues, but not in the brain, so we kept the Kpu of the molecule low by design. And then lastly, I'll note that the team did an excellent job, working to eliminate all metabolic liabilities of the molecule, to avoid potential drug-drug interactions and to optimize the clearance of the molecule, as well as the absorbable availability. Such that we believe we're bringing forward a molecule with the potential for once daily oral dosing in patients that might... As was mentioned previously, we remain on track for IND submission in the second quarter of this year, and then we'll plan to initiate a healthy volunteer study after that, as we'll talk about in a moment. So on the next slide, let's go through three slides. We'll start off with a three-slide data review, here again, from the poster. So these, these first two panels are from the experiment set up the same way. Which is to take CD34-positive mast cells derived from primary cells from healthy human donors and to examine their response to KIT inhibition at different concentrations, going from low on the left to higher concentrations on the right, after activation with IgE and anti-IgE. And what you can see is, regardless of the endpoint used, whether that's CD63 expression or histamine release, we see a nice consistent, dose-responsive inhibition with a normal profile. On the next slide, slide 28, we show you some results of live cell imaging from basically the same experiment. When we look at the next slide, what we can see is the green fluorescent imaging, which actually highlights for you a key disruption of the membrane that occurs when histamine is released from the mast cell. And so when we look on the left-hand side of the slide, which are the vehicle-treated cells, we can see that, first of all, the cells are all alive. And secondly, many of the cells have this green ring around them. What that green ring is, is that's the consequence of the mast cell degranulating histamine into the media after stimulation. If I draw your attention to the right-hand part of the slide, you'll see the right-hand part of the slide, which has now been treated with an antihistamine, looks very similar to the vehicle-treated group. You see lots of green rings around these cells. And that's because, of course, antihistamines don't block histamine degranulation. They work on the histamine receptor downstream, and so as you'd expect, no impact on that. Then the key panel, of course, is the center panel, where we can see the impact of administration of a relatively low concentration of just 10 nanomolar in the cell system. And what we can see is dramatic reduction of histamine degranulation of these cells, showing that in a live cell context where we're preserving cell vitality, we can block the activation via a project. Okay, so on the next slide then, we'll finish the brief data review with a description of the in vivo context. So the left-hand panel here just shows you a reduction in mast cell number, achieved at different concentrations of BLU-808 in otherwise healthy rats. What you can see is the first part of that concentration response curve is relatively shallow, as you would expect, and then becomes very steep at the end as we achieve full inhibition of KIT and non-activated mast cell. This is very similar back to that tunability slide that I referenced to you before. I'll mention two other experiments that are not shown on this slide, but are shown in the poster that's referenced on the slide. The first is that in this in vivo context, we can show that [BLU-808] nicely blocks in a dose-dependent fashion the activation of mast cells by SCF, the KIT ligand. And furthermore, we can show that in the context of a disease model, asthma, the OVA human sensitization, and then the challenge model, we can show again a nice dose-dependent response. We can get a free poster for those data. Then with that, we'll conclude the overall discussion by talking about the development plans for BLU-808, a molecule that we believe has the potential to revolutionize the treatment of allergy and inflammation. As I've mentioned, it's a highly selective and potent oral wild-type KIT inhibitor, which we believe has first-in-class impact. KIT is a well-validated target in chronic urticaria, and so therefore, it follows that our development plan begins with healthy volunteers and then will move to patients with chronic urticaria as the two key initial proof points. In healthy volunteers, we'll look to establish the kinetics of the molecule, tolerability of the molecule, as well as demonstrating crucial pharmacodynamic modulation in that study. That will be a key de-risking event for the compound in its development paradigm. We'll then move to examine the activity of the molecule in chronic urticaria. Then after that, as we begin our registrational studies in chronic urticaria, we can explore the wide array of diseases that Becker and Dr. Castells spoke about earlier in the presentation. Some of these we'll approach as monotherapy, and some of which we'll approach combination therapy. And with that, it remains me to thank the Blueprint scientists at Blueprint R&D, who have done just an extraordinary job moving forward this program. It's just remarkable, and it's a real privilege to work with them every day. And I'll now turn the talk back over to our head of research and development, my colleague, Fouad Namouni, to manage the questions. Thank you, Percy. Thank you, Becker, and thank you, Dr. Castells, for your presentations. I think we are ready now for the Q&A session. Operator? Thank you. At this time, I would like to remind everyone, in order to ask a question, to please press star, then the number 1 on your telephone keypad. We will pause for a moment just to compile the Q&A register. Your first question comes from the line of Brad Canino from Stifel. Great, thank you, and this was a helpful discussion today. I've got two questions on the potential product profile of 808, and first, a biology question to Dr. Castells. Do we know if inhibition of KIT alone without depletion of the mast cells will be effective at preventing the degranulation that can match the biologic effect we've recently seen with the antibody depleters? I guess underlying this question is if other pathways beyond KIT and its ligand could lead to degranulation. Thank you. Thank you, Brad, and this is Fouad, and I think your question is whether or not blocking KIT is enough to prevent and inhibit degranulation or are there other stimulatory pathways that would circumvent this path and stimulate the mast cell. Dr. Castells? Yes, that's an interesting question. For example, if we look at chronic spontaneous urticaria, there is no trigger that we can actually assess that would work. And yes, anti-IgE has worked in that avenue. So targeting KIT makes a lot of sense in these cells to potentially work the same way that we have seen with blocking through IgE. I do think that other diseases, such as asthma, allergic rhinitis, conjunctivitis, and even eosinophilic esophagitis is the same. The KIT has a tonic cyclic tuning of mast cell activation, that by blocking it, definitely mast cells will be able to turn off their machinery. Whether eliminating that makes sense, at this moment, we will see that in the future. We will see how we can tune the control versus just tuning the ability to navigate it. Thank you, Dr. Castells, and I think the other part of Brad's question, maybe Becker, you can add here, is depletion versus inhibition of the function of the mast cell. Can you tell us a little more about that? Yeah, I, I think first of all, we've shown in systemic mastocytosis that you can increase the function of the mast cells, and you can have really tremendous improvement in symptomatology. And we believe that that is somewhat similar to what you can do in chronic urticaria and a number of different diseases. I think it's important to remember that it's not just the presence of the mast cells, but it's really the, what they release and the impact on the, on the local environment and distal environment. And so our intent is not to simply go in and block and deplete the mast cells. We don't think that that's the right therapeutic approach, even for, for the, the diseases that are specifically driven by mast cells, but particularly in combination for the more complex diseases. Okay. If I could just squeeze in one more. I mean, notably absent from this discussion was neutrophil counts, which I think is one of the larger debates among the antibody companies. Are you currently thinking about any potential for a differential neutropenia effect with BLU-808, and is that gonna be context specific? Any comments would be helpful. Thank you. Thank you, Brad, and we'll hand over this question to you, Percy. Yeah. Thank you, Brad. No, so neutropenia does not remain a point of concern for us, although it is, of course, a point that we monitor in all of our toxicology studies, and we'll also obviously monitor in the intervention healthy volunteer studies. But it's not. I wanted to make a comment about just the biology. So, one thing that Dr. Castells has taught me is that mast cells retain very high levels of KIT throughout their development. That's not true of the other lineages. And the other thing to remember about neutropenia specifically is you really need to be able to turn that effect on and off quickly, particularly in the context of an infection. A small molecule gives you the opportunity to do that. Thank you. The next question comes from Michael Schmidt of Guggenheim. Your line's open. Hey, guys. Good morning. Thanks for taking our questions. And yeah, nice, nice overview on the 808 opportunity. Could you perhaps talk a bit more about some of the mechanistic differences between targeting wild-type KIT and MRGPRX2, and perhaps MRGPRX4, where we've obviously seen an acquisition earlier this week? And how perhaps some of those mechanistic differences might impact the potential disease biology and the opportunity for these oral agents. Thanks so much. Thank you, Michael, for the question on the mechanistic differences between targeting the control, effector target like KIT versus targeting other targets on the mast cell like MRGPRX2. I think I will start with Dr. Castells, and then maybe Percy, you can add after that. Dr. Dr. Castells? From a biology standpoint of view, KIT is expressed in all mast cells. We have seen today through our talk that there are many types of mast cells, at least six types that have been described and potentially more. All of them express KIT. So every cell, every mast cell in every tissue does have KIT. If we target KIT, the impact will be in all the tissues that. Mast cells. MRGPRX2 expression is different. MRGPRX2 expression has been shown to be really highly, significantly impacted in the skin. So skin mast cells do have a lot of MRGPRX2. It has been shown by many groups now. But others, other cell types and other tissues that contain mast cells, we are unfolding, you know, what the expression, the capacity, and the functionality of those MRGPRX2 receptors. So again, MRGPRX2 receptor is potentially more tissue-driven, disease-driven than a universal KIT, which is expressed by all mast cells. Thank you, Dr. Castells. Yes, so I would only echo what Dr. Castells has said. So the role of an MRGPRX2 inhibitor is going to be more restricted to the skin compartment, right? And so that's the current focus on development of atopic dermatitis area of those small molecules. We're not. MRGPRX4 is not pertinent in this particular context and concept. As we think about a KIT inhibitor, just to extend what Dr. Castells has said, we look at this as again, in the context of being able to combine KIT inhibition with a variety of different agents, the breadth of clinical utility, I think, is achieved, is substantial in my point of view. Thank you, Dr. Castells. Thank you, Percy. Thank you. Thank you. We now have Reni Benjamin of Citizens JMP. Hey, great. Thanks for taking the questions, and thanks for the overview. You know, maybe for Dr. Castells, you know, as you're thinking about key side effects, you know, that you would like to be on the lookout for, is there anything in particular that would cause a red flag in your eyes as the therapy gets into clinical studies? And maybe just related to that, you know, in a world where maybe there's multiple KIT inhibitors on the market, whether it's antibody or small molecule, what kind of factors or characteristics would lead you to choose one over the other? Thank you. Thank you, Ren, two good questions. Let me start with your first questions around the presence of multiple KIT inhibitor on the market and how they are gonna be different. I really think if we go back to our slide 30, the effect of KIT is central to the mast cell. And yet there are few research and development opportunities looking at developing KIT when you compare, like in chronic urticaria, to a number of other areas like, in, in cytokines or antihistamines or leukotrienes and so on. Now, at Blueprint, we have been working on the mast cell for more than 10 years, and we have studied the biology of the mast cell, understanding what's key to its survival, what's key to its activation, and degranulation through our experience in systemic mastocytosis and our knowledge that applies more and more today to AYVAKIT. So what we bring is really the know-how of what we believe will be the best-in-class and a first-in-class molecule to tackle a number of inflammatory diseases. Percy shared how good is the profile of our BLU-808 in terms of selectivity, in terms of potency, and more to come as we enter the clinical trials. Now, to your other question around what we think about in terms of side effects or adverse events as we are in a phase where we are entering soon the clinical trial, I would start by saying the profile that Percy shared is really pristine, so we're happy with that. But Percy, can you talk about what's on your mind as we go through the clinical trials as well? Yeah, you know, the KIT biology has been well known for many, many years. What we're looking for is the ability to gradually turn on the KIT inhibition and tune it to the level that you want it to be at for the various disease. We know that if you give high doses of KIT inhibitors, you will eventually hit the bone marrow. We know that there is a side effect that will occur. And all of these things are certainly things that we can watch for in the clinical trials. But we've also shown that, in preclinically, and we've seen clinically with Avapritinib, that the therapeutic effect can come before those side effects do. And really defining that therapeutic window with an exquisitely targeted specific inhibitor, it's where we think the therapeutic window will be well-defined and the clinical benefit. Thank you, bye. Your next question comes from Laura Prendergast of Raymond James. Hi, guys. This is really helpful. I just have two questions. First, you know, thinking about a clinical algorithm, specifically in CSU, you know, like, ideally, how long would a patient be on an oral KIT inhibitor? You know, for example, if after 12 weeks you see the symptoms resolve, would you maybe consider a lower dose maintenance therapy, or would this just be, you know, given during a flare-up? And then, my second question is in relation to tryptase and its ability to be a biomarker in this disease. I know in ISM, you know, there's not really a correlation with symptom burden, but, would there be so in CSU and how you guys are thinking about possibly using that as a biomarker? Thank you. Thank you, Laura. Let me start with your second question, then Becker will answer your first question on the duration of treatment and the maintenance with patients as an example for chronic urticaria. I think tryptase is the byproduct of activated mast cells, and you can take it even to the next level. Some studies measure not only all tryptase, but the mature tryptase versus the total tryptase, and telling us what - whether the mast cell is really activated or just the mast cell being resting on the ground in a given tissue. I think tryptase is telling us, increasing tryptase in an experiment as pharmacodynamic marker in this case is important, and we expect to show decrease in tryptase in our healthy volunteer study. I, I think it's telling us that we are really acting on the key cell, which is the mast cell. Whether or not it correlates clinically with a disease that, you know, has been there for some time, has mast cells, but has a lot of inflammation around it, it's really a difficult question to answer. I I mean, Dr. Castells, you wanna add something to this? Yeah, no, I think that I would agree with that. In addition to that, we have had patients, patients who have the extra tryptase copies, and it's going to be an interesting study to find out, you know, how many of the patients with chronic idiopathic urticaria have had, and how much then the tryptase can be impacted by a KIT inhibitor. So I think that there's a lot of subtleties, and potentially, there may not be a direct correlation with decrease in tryptase and decrease in symptoms. So we will have additional questionnaires and additional things that will measure that impact. Thank you. Thank you. And Laura, for us, we—given that there is a clear, a clinical proof of concept with using an antibody in this disease, showing that we are affecting the mast cell with a good safety and a good pharmacology profile is a major inflection point for the development of BLU-808. And then for the maintenance or the duration of treatment in patients, as an example, in chronic urticaria, beyond the 12 weeks, which always just for an endpoint to see whether you improve this based on the log, I would ask Becker Hewes to attend and answer the question. Yeah. I will provide my thoughts and then I'll ask Dr. Castells to comment, because she's the expert in the room. But, I think of chronic urticaria as not one disease, it's multiple diseases. There are autoimmune causes, there are idiopathic causes, and the duration of treatment depends on the duration of symptoms in these patients. There are some patients who will have spontaneous remission after a number of years, and then there are others that continue to have persistent symptoms and require multiple lines of therapy for years beyond that. So I think at the end of the day, it depends on the patient. I think that your question about whether starting with a high dose and then moving to a low dose is possibly needed in some patients. I think that's a great thought. You know, getting the disease in check, and then treating for longer is certainly a strategy to be considered. I don't believe you need to decrease the cell, though. And so I think that by stopping the degranulation and decreasing the activity of these cells as we've seen with some of the practices, you could then go to a more maintenance dose. There will be some patients that have more episodic disease, though, and they could have intermittent treatment with involved. Yeah, that, that's a really interesting question. I do think that the biology of chronic idiopathic urticaria is not well known. And one of the interesting things is that the females are more affected. And there is a very interesting impact of dietary or hormones and a lot of things that impact women. And so there is, you know, the if you look at the natural history, there's acute episodes that can last from months to years, and there is regressions, and then those episodes can surface back. So as Becker was indicating, you know, treatment initially for 12 weeks will make a lot of sense. And then as we see the disease fluctuate, we can address that. But again, I think it's something that nobody is actually paying attention to that, but 80% of the impact of Chronic Idiopathic Urticaria is in females. And I think that that deserves, you know, further research. Thank you. Thank you, Dr. Castells. Thank you both. Yeah, thank you. That was very... We now have Mark Byrne of TD Cowen. Great. Thanks for taking my questions. Maybe just following up on, on that tryptase discussion and, and just kind of trying to dial in KIT. Dr. Castells, you mentioned, you know, the kind of different subsets of, of mast cells that are kind of being elucidated now. Is your sense that all subsets are kind of equally sensitive to KIT inhibition, or are there important differences there? And, and then how should we think about that from this kind of dosing paradigm, for the company that you're putting forward of, you're kind of dialing in exactly what you want as opposed to kind of just hitting KIT really hard, in all places? Thank you, Mark. The question is around, there are, from a biology perspective, a number of subsets for mast cells. Are they all sensitive the same way to KIT inhibition? What does that imply in terms of signaling? Dr. Castells. Thank you. The question is quite interesting because we know that all mast cells express KIT, but we don't know if they are all sensitive to KIT inhibition the same way. The frequency of KIT expression in the mast cell is different. The mucosal mast cells express less KIT as opposed to connective tissue mast cells that express more KIT. So that, addressing diseases in which, for example, in the skin where mast cells have more KIT and express more, probably will require, you know, a higher dose of a KIT inhibitor versus diseases in which we have mast cell in the mucosa of the gastrointestinal tract, where they have less KIT, less expression, and that would require less doses. Again, a tunable inhibition of KIT, which is highly dependent on the disease that we're treating, because every mast cell is different in all those tissues. Thank you, Dr. Castells. Becker, anything? Yeah, Mark, I asked a similar question of Larry Schwartz, the grandfather of tryptase a couple of days ago. You know, his honest answer is, we don't know some. The other thing to remember is in some of these complex diseases, it's not just the mast cell, and there may be some of the mediators that a mast cell secretes. So you can inhibit KIT, and you still need to have the right combination. So having a really combinable agent is going to be important. Thank you, Becca. Okay. That's helpful. And then maybe just following up on that, I guess I appreciate the complexity of tryptase and that it's not a, you know, maybe it's a good binary, are you hitting the target, but not great quantitative biomarker. But it, are there other biomarkers you are going to be more focused on kind of to try out, dial in, that you're making sure you're, you know, testing the right doses once you move into patients with specific diseases? Or is it going to have to just necessarily be more of a trial and error and see what you find out from a clinical endpoint? Your question around, are there other biomarker, other PT marker. I think tryptase is a good marker to really reflect all the mast cells. There are other things we'll be looking at and sharing at the right time, Mark. But at the end of the day, in these very complex diseases, the clinical data will really tell us how important the clinical activity and will show how positive the best in-class profile through 808 will pan out. I will ask Dr. Castells, I mean, if you have additional ideas to share this anyway. Yeah. Tryptase, again, is a marker of mast cell burden, but also mast cell activation. And our test do not allow us to differentiate between how many mast cells we are actually killing versus how many mast cells are not activating. But there are other, certainly other markers such as histamine, such as prostaglandins, and I think those markers are in the making to being looked upon. You know, leukotriene E4, prostaglandin E2, and metabolites are readily available for us to look at them. So potentially, in future studies, those other mast cell markers could be of very good help. Thank you, Dr. Castells. Thank you. We now have Derek Archila with Wells Fargo on the line. Hey, guys. Good morning. Thanks for taking the questions, just two from us. I guess, in terms of your strategy for establishing proof of concept with 808, I guess, are you planning a more traditional phase 2 trial, or would you look to add, you know, a patient cohort to the phase 1 to get more rapid POC? And then the second question, just in reference to slide 23, you talk about combination approaches for mast cell diseases. I guess, you know, with 808, what makes sense in your view, and do you have any preclinical data for any potential combos? Thanks. Thanks, Derek. Very good questions. I will start and ask the team here to add, too. So, for us, it is important to show POC, not only in chronic urticaria, but in a number of other diseases, and hopefully as quickly as possible. First step is we need to generate some very good preclinical data in preclinical model. We have already reported data on urticaria models. We reported data on asthma models in our presentation at Quad AI. We continue to do preclinical work for very well-validated models to show that we have a base to really go to the clinic and do POC. I think there are a number of conditions where we very quickly will try to show some POC to have clarity on what is the full scope of the opportunity of helping patients with BLU-808, and then decide on the registrational development and go from there. Becker? Yeah, Derek, with respect to the clinical program, so the first in human study will be healthy volunteers to rapidly get to the effective doses, both the single and multiple dosing. And the plan is for that to inform a parallel patient study that we can start as soon as we have the appropriate signals, and I look forward to sharing more details on that in the future. The other thing to think about is that chronic urticaria is not the only disease in our sights, and our ability to test multiple indications kind of in parallel is something that we're building out in our clinical plan. And I'll let Percy speak more to if there's anything else about proof of concept preclinically. What I would say is that showing that we can impact the mast cell in a specific disease area in animals by itself is a complex thing, much less in combination in preclinical models. So really showing we can impact the mast cells and then going to the clinic is the way to show that. Thank you, Becker. The other part of your question, Derek, was around slide 23 and the combination strategy. I can tell you when Percy Carter and his team started thinking about three years ago, the design of this molecule, combinations was in mind, and this is why the profile of selectivity has been made really pristine. I think there is some combination thinking and work. I would ask Percy to answer the combination questions. Yeah, yeah, I'm very happy to. Thanks for the question, Derek. So, I would sort of break it down into two parts. So for some of these diseases, there are existing therapies which we would not want to remove, you know, the, from the patient's, regimen. So, you know, you can think about asthma, where, you know, our intention would not be to remove a long-acting, medicine, corticosteroids, right? So, so clearly there, in that context, we would, we would at least initially study in combination with those agents. For other diseases, there are opportunities for, novel, novel combinations with different mechanisms. Although, as usual, we remain quiet about what we're doing in our research portfolio, what I'll say is in the context of the mast cell, we're working on programs that affect both directly the KIT axis, as well as those that would be complementary to KIT acting mechanisms. And so we look forward to discussing that more in the future. Thank you, Percy. We now have the next question from Salveen Richter of Goldman Sachs. Thanks for taking our question for the helpful call. This is Tommy on for Salveen. So clearly there is a breadth of indications here, and so beyond chronic urticaria, how are you thinking about which to prioritize in the medium to long term, including your comments about combination strategies? And could this be an area where you would consider partnerships? Thank you. Thank you for the question. Very good question. So two questions. One is, beyond urticaria, what are the next, or the multiple next indications in the app? The second question is around potential partnership and how to bring this together. I would ask back a bit before, but I would just say that, as I mentioned earlier, chronic urticaria, there is actually a clinical POC out there, based on an antibody inhibiting wild-type KIT. So that is really making the case for this target very solidly, probably better than many targets, other targets, to move fast and build to chronic urticaria. As I mentioned earlier, I think we'll be looking at a number of POCs in terms of diseases, other diseases, to really understand what we can do with BLU-808 before moving to other work in the registrational space. It will generate as much data as we can to inform what is the full scope and opportunity for BLU-808. Yeah, I think that chronic urticaria is a great indication to de-risk the molecule and provide proof of concept that 808 is the right one, and we can define the doses where we see various levels of maximum inhibition. And that will open the gate to these other indications, both the ones that are mast cell-driven and those that require combination. With respect to combinations, we will look at a wide variety of molecules that are approved. And, you know, in terms of partnership, what we've done in the past with, for example, with A straZeneca, is we've had an agreement to provide a drug throughout to explore the proof of concept as a combination is safe and effective. But it's too early to speculate on how we'll set that up. Thank you, Becker. Obviously, we always talk to potential partners to get access to, you know, some medicines to combine with and do some work more in the future. I mean, I remind all of us, we are just, you know, about to file the IND of BLU-808 and start in the healthy volunteer study, so 30 days, but very promising opportunity. Thank you, Becker. Your next question comes from Matt Biegler of Oppenheimer. Oh, great. This actually might be tagging on to the last question, but we wanted Dr. Casale's thoughts on the importance of eosinophils and basophils. You know, are these subsets more bystanders, whereas mast cells are kind of the orchestrator, or can they also drive certain disease pathogenesis? And if so, kind of what would those indications be where maybe combinations are more important? Thanks. So. Thank you so much. Yeah, you know, this is a very intense area of research. Eosinophilic, like eosinophilic disorders, were thought to be essentially, pathogenic eosinophils entering the tissues and then releasing whatever mediators. Within the last five years or more, we have found that there is a partnership, an intense partnership with mast cells in those eosinophilic disorders. So in this particular arena of the gastrointestinal disorders, mast cells and the eosinophilic cells have a similar importance. And whether their interactions are cell-cell interactions or through mediators is actually not known, so intense research is going into this arena. Working mast cells in eosinophilic disorders makes a lot of sense, and there is already some proof of concept that that is going to be helpful. Basophil is different. Basophils are increased in chronic idiopathic urticaria. There is also some influence of basophil in asthma. So again, where there is evidence of diseases in which they can participate, it makes sense to address both of them. I have to say that basophil do have the same content in the granules. They have a little bit of chymase, which I described when I was doing my PhD thesis. They do have histamine, and they do have similar mediators as mast cell. So it's difficult to differentiate between the release from mast cells and eosinophil. But it makes sense to partnership with the basophil cells in different diseases. Thank you. Thank you, Dr. Castells. Thanks. We now have Ami Fadia with Needham. Hi, good morning, and thanks for the very informative presentation. I wanted to understand, you know, on, on slide 18, you talk about a variety of different diseases and, you know, some being mast cell-dependent and others being mast cell-associated. How do you plan to go about really kind of understanding how 808 needs to be tuned and, and developed either in sort of as a monotherapy or in combination, to really kind of understand, you know, and then prioritize some of these different diseases that you've highlighted here? Thank you. Thank you, Ami. I think the question is around the number of diseases, whether they are mast cell-dependent or mast cell-associated, and how are we thinking about BLU-808, and where to use it as monotherapy, where to use in combination, as the molecule was also designed for combination purposes profile. So maybe before that, Dr. Castells, can you really highlight one more time the mast cell-dependent versus the mast cell-associated? Yes. Thank you so much. The mast cell-dependent diseases are diseases in which we already know that mast cells are either increased in number, such as mastocytosis, or that we have been able to measure mast cell mediators, such as asthma, or food allergies or chronic urticaria. So, mast cell increasing number or mast cell mediators, mediators have been actually measured, and those are mast cell-dependent disorders. And in those, it makes sense to either decrease the number of the mast cell or at least try to block their signal transduction, activation, and then reduce the activity of the mast cell. Mast cell-associated diseases is a different landscape, where the interaction between the cells that are thought to be pathogenic, whether eosinophil or T cells, in gastrointestinal disorders or other disorders, for example, in idiopathic pulmonary fibrosis, we have found that mast cells are around those cells, and then their interactions may be direct or indirect. So, tackling the part of the mast cell in those diseases will require a lot of tuning, but also a lot of associated therapies such that the mast cell is part of it, but it's not the central and the essential actor. Thank you, Dr. Castells. And, Ami, the way we are thinking about where monotherapy and where combination with eight-oh-eight is driven, obviously, by the biology of the disease, and it's driven by standard of care, and it's driven by what we'd like to include. I'm gonna use one example that actually both Percy and, Becker used earlier, is type two asthma, a very complex disease, where Dr. Castells showed that really the mast cells are key players there. But these patients are chronic patients, severe asthma. A lot of remodeling happens, a lot of cross talks between the innate and adaptive immune system, and sometimes inflammation takes as, if I can say, a life on its own. This is your typical disease where patients are receiving corticosteroids. It will be in combination strategies in type two asthma. When you think about, as an example, chronic urticaria, I think you know that it is a disease where you can have a deep effect on the disease just by targeting the mast cell as a monotherapy. More to come from our development plan strategy over the next months and years. But I think what I'm really happy about is the way eight-oh-eight was designed is very much amenable to combinations. We now have Peter Lawson from Barclays. Hi, this is Alex for Peter. Thank you for taking our question. Just could you give us a sense for the timing of the healthy volunteer study, how long, you know, that would take to complete, when we could see some data? And then for the proof of concept study in chronic urticaria, how big would that study be? You know, how many patients do you need to get the proof of concept, and what would be the relevant clinical endpoints to think about here? Thank you. Thanks, Alex. I mean, the first question around the timing of healthy volunteers, and I mentioned earlier, we are about by the end of this quarter to submit the IND, and then upon clearance, we will be starting the healthy volunteer study, which things that we typically do all the time. From a POC study perspective, size and endpoints, I think it's too early to really start talking about the design of our POC study. But the good thing in chronic urticaria, I mean, the endpoints are rather standardized, and the proof of concept was with a wild-type data has already been shown, the use of a monoclonal antibody in the seed. So we are very excited to just execute as rapidly as possible our SAD/MAD study and show some PD markers, because with that, I think we're heading to a place where we not only believe, we have patients that we believe will be differentiated in terms of a small molecule, bringing a different value proposition for the patient compared to other types of modalities. Thank you. We have our last question from the line of David, David Lebowitz from Citi. Thank you very much for taking my question. Could you comment on the expression of KIT across other cell types beyond mast cells and the selectivity of 808? Thank you, David. I would—the question is around the expression in other types of cells. I really think what we are trying to get at is the on-target toxicity that you would expect when you are blocking it in this type of strategy. And I would ask about the expression of KIT, Dr. Castells, and then Becca, thinking in terms of on-target toxicities. Thank you. In the bone marrow, many cells that are immature, that come from myelopoiesis do express KIT. As the cells mature, all the cells lose the expression of KIT, and the only cells that are mature that retain KIT are mast cells. And as I mentioned before, all the cells in the mature state that populate all the tissues who contain KIT are mast cells. And so targeting the wild-type KIT in mast cells can be very tunable. And in the bone marrow, the only cells that will have KIT would be very immature cells. Well, it leads to Becker, in terms of the studies they have done to assess, you know, what would be the potential toxicity in those cells. Yeah. I think, as I said earlier, you know, you turn up KIT inhibition as high as you can, you're going to hit a number of different cell types. But really having a wide therapeutic window with a very targeted molecule, I think that that will allow us to define a therapeutic window much more effectively. And I'll just remind everyone that Gleevec has been on the market for many, many years and has shown inhibition, and in some cases, depletion of mast cells without causing bone marrow suppression. So there's clearly a KIT therapeutic window where you can get inhibition mast cells without bone marrow. Thank you, Becker. Thank you, Dr. Castells. Thank you. I would like to turn it back to Mr. Namouni for any final remarks. Thank you. As we have seen today, the mast cell is a powerful target in allergy and inflammation, with an enormous potential to address diseases where there is a major medical need. Through our demonstrated experience with mast cells, Blueprint is in a great position to make a difference in mast cell-associated diseases. Before closing, I would like to thank our team at Blueprint Medicines, who have been driving the research and development effort in the mast cell area, in partnership with key leading experts in this field of mast cell disorders, as represented today, with us, Dr. Castells. Thank you, Dr. Castells, and thank you all for your attention today.