Great. Welcome to the next session of TD Cowen's Chronic Urticaria Summit, where we're really happy to have with us from Blueprint Medicines, Chief Scientific Officer Percy Carter, as well as Cassie Saito, the director, who's one of the directors of IR, who I'm sure many of you on the line have interacted with in the couple of years since she joined the team. So with that, I do have a question list that I will work through with Percy and Cassie, that my team has come up with, but we would really appreciate, you know, input from investors, and we will certainly ask those questions as well. You can submit those either through the chat function at the top of your screen, or you can email me directly at marc.frahm@tdsecurities.com, and then I will kind of layer those questions in as we go through the list. But maybe to start out with Percy, you want to just kind of give a high-level overview of just why mast cells are so important to urticaria, but maybe just a little bit larger view across I& I indications for wild-type inhibition of mast cells. Yeah, happy to do so, Marc, and thanks for having us at the event. Appreciate the opportunity to speak to you and the group. So yeah, I mean, mast cells are super important cells as we know. You know, originally, we think of them as cells with a defensive origin, right? And so when we think about the tissue compartments in which they appear, they tend to be sort of externally facing compartments, so you know, the skin, the lungs, the GI tract. And so when we think about kind of what disease processes we're worried about, where excessive mast cell activity plays a role, it tends to be in those same, you know, compartments, right? So skin, lung, GI. I mean, I think famously, when people think about mast cells, they think about, you know, acute allergic events, right? Everybody thinks about, you know, that bee sting or... And certainly, urticaria itself is a disease that plenty of people are familiar with. It's particularly in the not even in the chronic form, but just in the acute form, right? Many teenagers have it, so on and so forth. And you see, most oftentimes where you see it is in that sort of classic stress response. Somebody has a high-stress response to an event, and then they actually literally break out in hives, right? And you can see that. And that's all mast cell-driven, just sort of classic degranulation, you know, histamine, tryptase out there. What I would say when we think about disease process, although what I just described can certainly play a role, particularly in the context of, say, an attack for asthma, an asthmatic patient, or a situation with somebody with allergic rhinitis, so it can be a prompting event, an acute phase event. You know, we know, and particularly we at Blueprint know from our experience in systemic mastocytosis, that mast cells also, beyond this kind of, you know, rapid response, there's also an early response and then even a late-phase response. Those responses can lead to, you know, actual tissue damage, remodeling, barrier disruption, things like that, sort of effects that chronically can lead to real sort of degradation in the integrity of those compartments in which the diseases occur. Okay. In Blueprint's view, are all mast cells the same, or are there kind of important subtypes that may have kind of different disease-specific manifestations that we need to think about? It's a good question, so we know the answer to your question is no, not all mast cells are the same, so, you know, period. We know that's the answer to your question. The second part of your question is actually more difficult to answer, and that's actually part of why we're excited about KIT as a target, right? Because KIT is a master regulator and control switch for mast cells, and so we're sort of covering, you know, we're gonna have the ability to impact diseases in all of those tissue compartments, but it's a great question, and I think, you know, continued research is going to sort of help the field ultimately provide a more nuanced answer to the second part of your question. Okay. And then maybe as we start diving into getting to specific diseases, you know, the main focus of this summit, but maybe a little bit broader to other urticaria, like CIndU and things like that. What% of patients you want to walk through kind of the epidemiology and, in particular, what% of patients Blueprint really believes are in need of a truly novel therapy? And then importantly, and then I'll follow up from there. Maybe we'll just start with that number. Sure. So, I mean, I think the treatment algorithm for urticaria is well understood in terms of the front line, right? I mean, so the first thing that's done is to once you really sort of know a patient has chronic urticaria, you look to understand whether they're gonna respond to antihistamines, right? And typically, that's done in a high-dose fashion, right? So it's, I think it's, you know, really, like, four times the traditional antihistamine dose to see how well the patients respond to that. And some, you know, double-digit percentage of patients actually will respond to that, Marc, and, you know, will have their chronic urticaria controlled, at least for the time being. The disease, as I'm sure you know, you know, is chronic in nature and can have a sort of a time period of flaring, ranging from two to, you know, sort of twenty years. And patients can progress over that time period such that therapies that were effective in the beginning, you know, lose their effectiveness later on. And so, you know, when we think about a medicine, a potential medicine as powerful as wild-type KIT inhibition, and specifically BLU-808, a small molecule wild-type KIT inhibitor, selective over, you know, other kinases, if we look at something like that as really being able to help patients that are not doing well on that initial line of therapy. Then, I'm sure, I mean, you're at an urticaria conference. I'm sure you're well aware of the other therapies that are then explored in second line and so on and so forth, as antihistamines fail. We look at wild-type KIT as being able to have a role in that same space, you know, post-initial antihistamine treatment. Okay, and you, Blueprint has kind of proposed this dual track over time, maybe within indications, but also across different indications of, you know, some patients needing kind of the most potent KIT inhibition that's really driving kind of broad killing of mast cells throughout the body, versus maybe other patients need a, a bit less, drug and are more you're more trying to tune for just kind of inhibiting the, mast cells. Just within urticaria, like, what percent of patients do you think need one versus the other kind of KIT approach? Yeah, I haven't actually conceptualized it in the context of percentage of patients within urticaria, again, in part because the disease can, you know, can change over time. But, I guess the way I would think about it is that this question that you've asked is actually one of the central things that we'll explore in our clinical trial. So let's just maybe take a step back and just think about your question. If we can think about it more broadly, if you'll permit me to do that- ... and think about it and just say, well, how do we want to cover wild-type KIT activity in urticaria, and what I would say is that we know that clinical proof of concept has been provided from the antibodies, right? Which provide effectively, you know, enormous coverage of wild-type KIT, leading, as we know, to mast cell depletion, right? So that's one example of an, sort of an extreme kind of level of coverage. What we don't yet know is whether or not, with the fine-tune control that you can have from a small molecule therapy with what we project to be, well-behaved, once-daily, you know, pharmacokinetics, with oral dosing, whether or not, in fact, if we provided, say, we'll pick a number, let's say IC75 inhibition, whether, in fact, actually just sitting on top of that every day, whether or not that would be sufficient. So that experiment's not been run by anybody, right? And so we actually don't know. That may well be sufficient, in fact. In fact, in our animal models, we can in fact see that there is a, you know, the kind of, you know, sort of sigmoidal response-type relationships that you'd like to see with, you know, sort of plasma coverage and sort of biological effect. So it may well be that a lower coverage level is sufficient, and we'll certainly look to test that. And then, the final concept I think that many are wondering about, ourselves included, is given the time period to sort of recycle the mast cell once apoptosis has been triggered, is there even a paradigm where you could, for example, use a loading dose and cycle to a lower dose for maintenance over what could be as long as, you know, two months kind of thing, because you've in fact knocked the mast cell population back so sufficiently? So I think all three of those dosing paradigms are potentially of interest. The one has clinical validation. I think the key thing with 808 is that 808 allows us. It gives us the flexibility to explore all three of those. Yeah. Maybe in your preclinical assays, you know, you've done a little bit of that work, right? Of exploring kind of different levels of inhibition and what that means for, you know, how the mast cells react. Just can you think about what are the scale differences in inhibition that you need to drive kind of profound killing versus just inhibiting just kind of driving constant inhibition of mast cells? Right. So I think as you get to that sort of... let's just, we'll use IC90 as a, you know, don't hold that to me as, don't hold me to that as a quantitative measure. But, you know, in that area of coverage is where you start to see, very, very meaningful, loss of the mast cell population, right? That occurs, of course, not instantly. As you know, that takes several days for that to manifest itself, right? So that's something you observe in vivo after several days. And I think this is an important point when we go back to what we said before about sort of, you know, sort of acute phase and early phase and chronic phase and whatnot. We've already shown, and, Cassie posted some nice videos. We've also got the mast cell webinar, which you can look at online, where we can show that, you know, in a matter of sort of seconds to that sort of minute timeframe with live-cell imaging, you can show that with no impact on mast cell vitality, you can completely shut down mast cell activation, right? So we know that in short periods of time, if you just want to impact mast cell activation, you can. Over long periods of time, as you move to that higher coverage level, let's again just use IC90 as a kind of a rule of thumb, you do see the substantial apoptosis. And certainly, at that point, you have profound activity in whatever model you want to test it in, right? You know, in an acute model, you know, comparing to, like, SCF inhibition, you of course block that. You know, in a more chronic model, like the ovalbumin in an asthma model, which we published in AAAAI earlier this year, you see good effect there, too. But in terms of to drive that kind of acute inhibition, is that still acutely IC90 or- No, no, so you can- IC50, IC50 is enough? Yeah, absolutely. So it's whatever. It's really whatever you want. So if you want to block sort of 50% of kind of the response, you can sort of titrate it down, and you sit on that, and you do. And in a short periods of time, you get well-behaved inhibition. And we were pleased with that because not every, you know, not every kinase works in that kind of fashion. But in this case, we've been able to show that 808 inhibiting wild-type KIT provides a nice sort of dose-dependent response across a range of models. And again, we've put some of that data out there. Okay. And maybe on this angle of wild-type KIT inhibition, you know, Ayvakit obviously is, you know, selective for the mutant form, but that's found in systemic mastocytosis. But, you know, there is, at some level, some inhibition of wild-type KIT that's gonna happen, right? Like, do you have a sense for, you know, at the approved doses, like, what level of wild-type KIT inhibition are you likely kind of just giving patients as a side effect, essentially, of Ayvakit? Is that, like, 5% inhibition, 50%? I wouldn't want to put a quantitative measure on that. What I would say is that the approved 25 milligram dose for you know indolent systemic mastocytosis you know at that dose certainly avapritinib is a selective D816V inhibitor. Okay. And do you have a sense from, you know, from some of that dose-ranging work of Ayvakit, and that may be informed by preclinical work for both Ayvakit and 808, just to drive some of these wild-type KIT toxicities of on heme compartment, taste effects, CNS effects, hair color, like, what level of inhibition do you need to get... Yeah, starts driving the, those? Is it IC90 again, or, Yeah. Something like that. Yeah, that's a great question. You know, the list of things that you articulated, we associate those, and we've observed those preclinically at high doses. And in fact, actually, it seems as if actually, in fact, there is even a bit of a separation between the impact on the mast cells and the impact on those other compartments. But in any event, it really is occurring at the high-dose pharmacology. It's a high-dose pharmacology phenomenon. Okay. And is it really Cmax driven? Is it exposure, you know, AUC? Yeah … cumulative exposure over time? Yeah, like- We haven't done a rigorous study of that. You know, that requires, as you know, very specialized studies to pull that apart. What I would say is just stepping back at it. I would think of it as a time over coverage, kind of, you know, time over inhibition level. Okay. That's helpful. You know, any other aspects of kind of Ayvakit's development and kind of the studies you've been able to actually do in humans as a result, you know, that now being an approved drug, it making it all the way through, that kind of inform your understanding of KIT that's really relevant to thinking about 808? I have, I mean, certainly, I mean, not to be too basic about it, but at the simplest level, you can say that systemic mastocytosis just highlights what a powerful cell the mast cell is in regards to driving disease processes, right? You can see when it's chronically active, just how much destruction it can do. And likewise, on the positive side, you can see if you can tamp that down by inhibiting D816V, the mutant that's driving that activity, you can see the kind of benefit you can provide to patients. So I think at the most simplistic level, you can see the power of KIT as a controlling element for the mast cell in that system. I think beyond that, you can also see the relevance, you know, the unfortunate symptomatology of mastocytosis, but again, it confirms many of the things we've talked about before, you know, issues in the, issues in the skin, issues in the GI, you know, itching, things of this nature, and again, you can see the impact avapritinib has by inhibiting D816V KIT and turning off that chronic activation. You can see the benefits it has in those compartments, so I would say that avapritinib provides a nice proof of concept for the role of KIT in the mast cell and the role of mast cell in driving, you know, disease pathology in those compartments we talked about before. I think- Okay, it- If I can just add, Marc, I think it's also a really nice example of the tunability approach that we're really excited about with BLU-808. So as you know, we have five different doses available of Ayvakit, you know, and that can really be tuned to address the patient that is in front of the provider. Okay. Any learnings from Ayvakit, just how to think through mast cell biology and importance biomarkers that, you know, can really apply to the development of 808? So I think in terms of. Well, what I would say is, beyond what we just described, certainly, we understand how to study many of the, you know, acute effects of mast cell activation. When we think about the wild-type KIT program, I think we're exploring still more broadly, a broader set of biomarkers because of the way we're approaching its development. But yes, I mean, and the short answer to your question is yes. You know, studying avapritinib has allowed us to become expert at studying many of the sort of biomarkers associated with KIT activation. Okay, with fear of opening old wounds of the SM development, but just around tryptase, there's a debate also in urticaria of how useful of a PD marker that is. You know, how is Blueprint approaching it? Is it more quantitative here because you don't have the confounding effect of some cells are mutant, some cells are not, and you know, here it's all coming from the same type of mast cell? Right. So I think we're gonna learn more about that. I think what we know is, at the extreme end, if you kill mast cells, you reduce tryptase, right? So we know that as a benchmark on the extreme end. As you know, the tryptase assay that's used clinically is a total tryptase assay, so you're measuring a collection of it, a collection of molecules, not all of which are really relevant from a disease perspective. So I would say that you wouldn't. It's hard to imagine that you would study KIT inhibition without measuring tryptase. Point one. Point two, I think it's very difficult to draw a quantitative relationship when you're operating below sort of maximal inhibition over a more prolonged period of time. It's difficult right now, a priori, to predict the quantitative relationship between tryptase reduction, and again, that total tryptase assay versus activity. Okay. And so, I mean, certainly at that highest level, you can think about, like, just very significant reductions of tryptase being important, or obviously, then you can also look in the skin for, you know, changing mast cell count, right? But for that two- You can look at- Yeah. You can look at positives, yep, absolutely. Yeah, yeah. But for the tunability piece, right? Like this potential for using some lower doses that maybe aren't gonna kill cells as much, what's a relevant PD marker? Like, how do you go about selecting which doses make the most sense to kind of study more fully in patients? Is there a good PD marker, or is it just gonna have to be empirically found with, you know, clinical symptom scores and things like that? Yeah, well, so that's a great question, and so I'll just come back to the premise that we started earlier in the discussion with, which is we're breaking new ground here and exploring this sort of submaximal area, right? More in a more detailed fashion. And so to support that, we have a number of biomarkers that we've not discussed publicly and aren't gonna, you know, talk about here in this conference that we're looking to understand whether or not, in fact, actually there is a biomarker we would prefer for, one, we're operating in that submaximal space. And so I think that this is something that as we move through and complete the single ascending dose trial and the multiple ascending dose trial, and we start to report out that data we can comment on that more, in more detailed fashion. Okay. Then maybe as you were designing 808, you know, thinking through the kind of profile, like what was the most important kinase-- what were the most important kinases to kind of, to try to avoid that relate, you know, naturally things that hit KIT tend to hit as well, you know, when you were designing 808? Yeah, that's a good question. So when we think about wild-type KIT, there are a few kinases that have tended historically to ride along with it. And we certainly worked to make sure that those were not impacted by BLU-808. So things that you think of, PDGFR alpha is a great example. FLT3 is another one that tends to be associated. CSF1R, likewise, tends to be associated. So when we look at BLU-808, you know, we have multiple hundreds of fold selectivity over all of those kinases that I just mentioned. I mean, as is always the case, also marked with a Blueprint kinase program, we did look to optimize broad kinome selectivity, so not just the ones I specifically mentioned, which we did specifically study, but also overall kinome selectivity. you know, we were pleased we got our kinome S-score. The team did a great job with this. The team drove the kinome S-score at a concentration of three micromolar down to 0.047, which is very, very highly selective across the broad kinome. Okay. In thinking through that selectivity, you know, obviously, you would expect at the highest doses, you will start to see these KIT, the on-target AEs of hemotox or things like that, hair color changes. But, you know, if there were to be an off-target AE found, just based on kind of preclinical data, like what is that what would that most likely be, and kind of what kinase might that be coming from? Yeah, we optimized the molecule. Again, given the clinical validation of KIT, we actually optimized the molecule to allow us to dose safely at IC90. And so the necessary, you know, consequence of that is that wild-type KIT... we anticipate that those are the first safety signals we're gonna see, so... Okay. And then maybe, you know, based on the knowledge we do have about the molecules, understanding they're not 100% complete, just how does 808 stack up against some of the other KIT inhibitors that are out there in terms of selectivity, in your mind, selectivity and other important, you know, factors for, you know, for ultimate performance in the clinic? Yeah, I mean, we don't have, as I think you just mentioned, we don't have sort of a rigorous sort of side-by-side comparison across a full range of compounds there. But based on what we've seen, we're very confident that 808 is, you know, fully selective and fully potent. We don't see any weakness in that regard. Obviously, the pharmacokinetics have not been published for any of the molecules and we haven't described the clinical data either, but based on our projections from preclinical work, as we described at AAAA I, we're confident in that profile as well. So I think we'll be able to better- we'll probably be able to better answer your question, you know, as a field in several months' time. Okay. So the phase I, you know, the IND's cleared, it's underway. Can you speak to maybe the starting dose and how much you think you likely need to dose escalate to, to actually get to maybe first that kind of non-homeopathic type of dose that you know maybe is getting to the beginning of that tunability scale, and then how much further to get to the you know the full coverage type of level? Yeah. So we don't. You know, we're obviously not speaking about specific doses. It's an active clinical trial, right? So we're not talking about specific doses. But what I would say conceptually is, there's nothing unusual here relative to a traditional normal healthy volunteer study, right? So we're starting in a normal healthy volunteer patient population. As is always the case, you know, patient safety is preeminent in our minds, right? So we're studying, you know, tolerability, and we have, you know, obviously the appropriate monitoring in that regard. We're studying pharmacokinetics. We're studying, I mentioned, a series biomarkers, tryptase apparently being one of them. And, you know, we look forward to that. At the appropriate point, as is always the case in the normal healthy volunteer trial, you know, we'll switch to the multiple ascending dose arm of that, and, you know, we'll escalate in both cases. I think we can say with confidence that, you know, we, you know, you can sort of reasonably infer from all the comments I've made previously in this, given that we want BLU-808, and we believe 808 can cover all sorts of dosing paradigms, we need- you know, we really want to be able to dose up to IC90 in these trials, right? So I think you can make that as a reasonable inference because we've designed the molecule with the ability to do that. Okay. And is moving from SAD dosing to MAD dosing, and then, ultimately MAD dosing of healthy volunteers to starting to enroll some patients with urticaria, is that entirely... Are both of those steps entirely gated just on safety, or do you need to see, like in SAD dosing, some of biomarkers starting to move a little bit to want to move to MAD and vice... and then again, from MAD to patients? Yeah, I think we, we're expecting to, again, observe kinetics, tolerability, as you just mentioned, safety. We're anticipating that we'll [monitor] biomarkers, and then we'll look at the totality of that data and select doses for study in patients, and as we've mentioned before, I mean, urticaria, and you just referenced as well, urticaria patients are definitely, you know, part of our focus in that early patient population data. I wouldn't want to describe here any specific cut-offs or anything of that nature, but again, we'll look at the totality of that data set across tolerability, kinetics, and biomarker responses. Okay. And this is a Percy question, but maybe also a Cassie question. Just what's gating to showing data to the investor, the investment community, but then ultimately the medical community, too? Is it just healthy volunteer data showing you're getting to what you believe to be good exposures? Do you need to start actually having some data in urticaria patients? Just, how's the disclosure, strategy? That's a Cassie question. I mean, obviously everyone is excited about this, as are we. So we have guided to sharing initial data, you know, early next year. That's not formal guidance, but just I think based on the cadence of initiating the healthy volunteer study, as we announced on the 2Q call. You know, that's certainly reasonable timing to expect, and we will provide more information when we have it. Okay. Is it likely to include patient, patients, or just, you know, is healthy volunteer just so important that, yeah, that's more than enough to warrant talking to everybody about it? You know, it's interesting, and I think following on, you know, the conversation today, you know, the inhibition of wild-type KIT in chronic urticaria has been de-risked by others. So we really feel that being able to show, as Percy described, a molecule that has a good safety profile and PK and PD that are, you know, acting as expected, that that data in and of itself should be significantly de-risking for the program. If we can demonstrate that we have a well-behaved molecule, and it's doing what we expect in a disease that is fairly well understood, I think that's a good sign. But Percy, please add. No, I think you just described it perfectly, Cassie. We look at the normal healthy volunteer study as a significant de-risking event for the compound. Okay. Yeah, this whole conversation has been focused on KIT, but of course, that's not the only target on mast cells. Just your thoughts on other targets out there that are being actively pursued by competitors, but maybe you would also have some interest. You know, MRGPRX2, Siglec, you know, there's BTK. It's just how do you kind of view KIT fitting in with these other targets? Yeah. So I think, you know, actions speak the loudest, so I think our decision to pursue KIT as our primary mast cell target based on the experience that we talked about before in systemic mastocytosis, you know, tells you our sort of starting position, which is if you could go after... You know, the first target you would go after is a wild type KIT, you know, period. Academically, right, I have the word science in my title, right? So academically, I'm very interested in MRGPRX2. I'm very interested in Siglec-6. I'm very interested in BTK, and at a field level, I'm glad that as a field, we're investing in all those targets and looking forward to continued, you know, discussion of those mechanisms. Okay. Is Blueprint interested pre-clinically in additional targets or, you know, for these indications? Or, you know, do you view- We have a- ... KIT as so important that, like, "Look, if we hit this with 808, we don't really need anything else? Right. Yeah, it's a good question. So, what I would say is at Blueprint, we have a deep interest in KIT biology, and that's plain for everybody to see. We also have a broad interest, I think, in allergy and inflammation, and BLU-808 is a great example of a molecule that's gonna allow us to explore a number of indications. However, to your point, we do have an entire pre-clinical program that includes other targeted biology within the KIT axis and beyond the KIT axis. And I think we're interested in the mast cell broadly construed, and we're also interested in the immune system broadly construed. And so we look forward, you know, at the appropriate moments in the future, to be able to talk about that work. Great. And then with Ayvakit, you did, I mean, maybe not the next day, but, you know, not that far behind, put an additional molecule in the clinic, and now that's. Should we expect additional wild-type KIT inhibitors to ultimately enter the clinic, or, is that not part of the plan, unless you kind of see something with 808 that makes you want another asset in the clinic? Right. So I won't answer the question directly with a yes or no, but what I'll say is you can see in multiple programs historically, you just referenced a great example of elenestinib, but you've also seen recently with CDK2, and you've seen that also with our EGFR program with BLU-701 and BLU-945. You know, we, in general, look to make sure that we've fully covered our the risk associated with any given molecule. Okay. Unfortunately, that is all the time we have for today, so we're gonna have to cut it off there. But thanks a lot for joining Percy and Cassie, as well as all the investors online, and stay tuned. I think the next session is starting. The next fireside is in about a half hour. Thank you, Marc. All right, thank you. Yep.