Good morning and welcome to the Cogent Biosciences webcast. I will now turn the call over to Christi Waarich, Senior Director of Investor Relations. Thank you, Operator. Today's call will cover our SM updates announced over the weekend and this morning. You can find the press releases in the Investors and Media section of our website at cogentbio.com. Before we get started, please be reminded that remarks made during this webcast may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about our planned regulatory submissions and timelines, as well as our anticipated commercialization and market opportunity for bezuclastinib. Please refer to our most recent filings with the Securities and Exchange Commission for a full discussion of risks and uncertainties associated with our business. With that, it's my pleasure to turn the call over to Andrew Robbins, President and Chief Executive Officer. Andy? Thanks, Christi. Good morning, everyone, and thanks to everyone for joining our call today. It's certainly been a very busy weekend for us down in Orlando, and we're excited this morning to review the full results from the summit trial that we're presenting at this year's ASH Conference, as well as announce for the first time positive top-line results from our APEX pivotal trial. Joining me on the call today are Cogent's Chief Medical Officer, Jessica Sachs, as well as our special guest, Dr. Lindsay Rein, Associate Professor of Medicine at Duke University. Dr. Rein will review the summit results that she shared at ASH on Saturday afternoon, and after highlighting a few additional takeaways from the summit study, I will walk us through the APEX top-line results. Before I turn the call over to Dr. Rein here on slide four, I would like to take a moment to recognize the amazing progress we've made at Cogent since this summer. In just the past few months, we've reported positive results from all three pivotal trials of bezuclastinib: the SUMMIT trial of bezuclastinib in non-advanced systemic mastocytosis patients, the PEAK trial of bezuclastinib with sunitinib for second-line GIST patients, and this morning, the APEX trial of bezuclastinib for advanced systemic mastocytosis patients. Based on these results, bezuclastinib has emerged with a profile that positions it for market leadership across all three patient populations, with a global annual market potential of over $7.5 billion. We are moving forward rapidly to build a fully capable commercial organization, and with plans to submit all three NDAs within the next several months, we are on a path to launch bezuclastinib in both systemic mastocytosis and GIST by the end of 2026. What I'd like to do now is invite Dr. Rein to help walk us through the very exciting SUMMIT clinical trial results that she presented on Saturday afternoon at ASH. Dr. Rein? Thank you. So again, thank you for the invitation this morning. I'm going to walk you through the results from the pivotal SUMMIT trial data. If we go to the introduction slide, this will be slide seven. I don't need to remind you, but non-advanced SM for the purposes of this study includes indolent smoldering and bone marrow mastocytosis subtypes. As we know, SM can be associated with debilitating symptoms, which affect quality of life and can be life-threatening, and those are listed there. And as a reminder, bezuclastinib is an oral potent and selective TKI, which has minimal brain penetration and spares closely related kinases due to its high selectivity for the D816V mutation. This allows us to minimize off-target effects such as bleeding, cognitive impairment, and edema. If you go to the next slide. So this is the outline of the summit study, which I won't focus on too much. I think everybody has seen this, but for the purposes of this presentation, we looked at the part two, which randomized patients in two-to-one fashion to bezuclastinib 100 milligrams daily versus placebo. Patients then rolled over into an open-label extension. We know that the primary endpoint, which was statistically significant, was the mean change from baseline in the MS2D2 total symptom score. And what I want to focus on a little bit more today is the key secondary endpoints. Again, all statistically significantly different, which included those listed there, greater than or equal to 50% reductions in various markers of mast cell disease, and then additional descriptions of the symptom change. If we go to the next slide, these are the patient demographics that were represented within the context of the SUMMIT study. I think I'm going to point out just a few pertinent populations. Number one, this study did include smoldering systemic mastocytosis patients, which is important. If you go to the bottom left, you'll note that a population of patients did receive prior KIT inhibitor therapy. That was slightly overrepresented in the bezuclastinib group in comparison to placebo. And the other notable difference within the context of this study was the fact that patients who received bezuclastinib did have a slightly higher baseline mean total symptom score as measured by the MS2D2. So again, that was 57.1 in comparison to 52.6 in the placebo-treated group. So if you go to the next slide, I'll review this quickly, but I think this has been discussed. So the primary endpoint was achieved within the context of this study through a rapid, durable, and statistically clinically meaningful symptom improvement for patients. So you can see here the mean change in total symptom score at week 24 was approximately nine points improved in patients who received bezuclastinib in comparison to placebo, with a p-value of less than 0.001. If you go on to the next slide, we can look a little further at this and look more specifically at the proportion of patients who achieved either a greater or equal to 30% or 50% reduction in their MS2D2 total symptom score, again in comparison to placebo. So on the left of the slide, you'll note the patients who received bezuclastinib. In blue, you'll see those patients who achieved at least a 30% reduction in their total symptom score, and on the green bars, you'll see those patients who achieved at least or greater than a 50% reduction. This is in comparison to placebo, and again, these differences are statistically significantly improved for patients who received bezuclastinib. If you go to the next slide, I think this is an important piece of information to note that the improvement in mean total symptom score change as measured by the MS2D2 was not specific or due to one domain of symptoms or one symptom, but rather occurred in totality across all symptoms that were measured as part of the MS2D2, so here you'll see all of the symptoms collected as part of this MS2D2, including those that were utilized to calculate the total symptom score as well as additional symptoms. The baseline mean score is listed on the top of the slide, and you'll see with the green bars statistically significant improvements in the mean total symptom score across a majority of these individual symptoms for the patients, and so again, indicating that the change and the primary endpoint change was due to a change across all symptoms. If you go to the next slide, we'll take a look a little bit more in depth at the markers of mast cell disease burden. So this is slide 13. We note that bezuclastinib significantly reduced serum tryptase, which again is a core indicator of mast cell burden. We see here that 95.4% of patients had at least a 50% or greater reduction in their serum tryptase. This was in comparison to no patients who received the placebo. I think interestingly, if you look to the bottom table there, you will note that almost 78% of patients normalized serum tryptase values within the timeframe of this study in comparison to no patients who were treated with placebo. An important change there. If you go to the next slide, you'll see the changes in bone marrow mast cell burden and the abnormal mast cell phenotype, again significantly improved in bezuclastinib treated patients. You'll note that 88.2% of patients had at least a 50% reduction in mast cell aggregates or clearance of those aggregates. This is in comparison to 25% of patients who achieved the same marker in the placebo-treated group. One might ask why there is a change in patients who received placebo. And I think the way to think about this is to look at the blue circles underneath the patients, underneath the lines of patients. So this is indicative of CD25 staining. As we'll note, patients with mastocytosis have abnormal CD25 staining. In the patients who received bezuclastinib, we see that a majority of these patients had a reduction in the abnormal CD25 staining, indicating effects of bezuclastinib on abnormal or diseased mast cells. This is in comparison to only three patients treated with placebo who saw the same change, which would indicate that bezuclastinib is acting on the abnormal mast cells. And the variation we see within the placebo group is due to marrow sampling and that heterogeneity, which we do see. If you go to the last slide, we'll round this out with changes in KIT D816V variant allele frequency or VAF. And again, you can see here 97.5% of patients achieved at least a 50% reduction when exposed to bezuclastinib. This is in comparison to 0% of patients who received placebo. I think global response across all markers of disease burden and those key secondary endpoints. If you go to the next slide, which is slide 16, I want to highlight two particular patient populations. This is the patient population for smoldering systemic mastocytosis, and then also the patients who received prior avapritinib. Although small, these subgroups are important, and patients here did demonstrate meaningful improvements, again, both in symptoms and objective measures of disease consistent with the global population that was seen within the context of the study. Nice and consistent data here. If we go to slide 17, I think you'll see an interesting and important correlation that has come from this study. Given the large size of the data set available and the large number of patients, we were able to correlate some of the changes in symptoms with the degree of mast cell burden. What we find is that the greater reduction in the markers of mast cell disease, so serum tryptase, bone marrow mast cells, and KIT D816V VAF, the greater the change in those markers was significantly correlated with greater reduction in symptom severity, again, as assessed by the MS2D2. This is really the first description of this type of correlation within a cohort of patients, again, given the size of the population available to be able to do this, and really suggests that there is a relationship here between symptom improvement and what we're seeing in terms of bezuclastinib's effect on the pathophysiology of the disease. We're going to go one slide further and look at the safety profile. So again, bezuclastinib demonstrated a favorable and manageable safety profile. If you look at the AEs, you can see they're listed in the table to the left. The most common AEs we saw, again, we see across many TKIs are hair color changes and altered taste. A majority of the treatment emergent AEs were low-grade and reversible with cessation of therapy. We saw that 11% of patients required dose reductions of bezuclastinib related specifically to changes in ALT and AST, so those measures of transaminases. 5.9% of patients ultimately discontinued, although we will note that these, again, changes in AST and ALT were reversible, did not result in any hospitalizations, and were not associated with any significant change in clinically significant liver dysfunction. So again, I think supporting a favorable toxicity profile. So if you go to the last slide, just to summarize, bezuclastinib really does represent a promising new treatment with evidence of disease modification in this patient population of broadly non-advanced SM patients. This includes smoldering SM in patients with previous KIT inhibitor therapy. We see, as we note, that the study met its primary endpoint, and we see further reductions and significant reductions in objective markers of disease listed there. This is the first demonstration of a significant correlation between this reduction in objective measures of disease and improvements in symptoms. We see ongoing tolerability of bezuclastinib in this patient population, with most treatment emergent AEs being low-grade and reversible. Great. So Dr. Rein, thanks very much for that excellent presentation and for helping us as an investigator on the study. So now I want to look here on slides 21 and 22. I'd like to encourage everyone listening to spend some time later this afternoon listening to Dr. Tracy George from the University of Utah and ARUP Laboratories present a very thorough review of the SUMMIT pathobiology results focused on the impact bezuclastinib has at a cellular level in non-advanced systemic mastocytosis patients. Broadly speaking, Dr. George will present evidence that treatment with bezuclastinib reduces dense mast cell aggregates, decreases the overall quantity of mast cells in the bone marrow, and targets the removal of neoplastic mast cells from these patients, as evidenced by reduction in cells with CD25 and CD30 expression. These data are expected to stimulate a conversation among the mastocytosis community about the importance of using objective measures of disease burden in non-advanced patients as a key component of goal-directed therapy. To expand on this point, on slide 22, you'll see that 55% of patients treated with bezuclastinib achieved a level of improvement so dramatic that they no longer meet the diagnostic criteria for the disease. This is an amazing finding in a majority of SUMMIT patients treated with only 24 weeks of bezuclastinib. Moving to the right panel on this slide, you'll see over two-thirds of bezuclastinib patients meet the complete remission definition of pure pathological response. These data are highly impressive and suggestive of the rapid and deep benefit bezuclastinib is providing these patients at a cellular level. Bringing Dr. George's presentation together with Dr. Rein, Cogent is excited to be the first to show that objective measures of disease burden appear clearly linked to symptomatic improvements reported by the patients. Now turning to some of the most exciting SUMMIT data, I'd like to share a brief preview of our upcoming 48-week long-term follow-up from this study. Here on slide 23, bezuclastinib shows clear continued deepening of symptomatic improvement throughout the first year of treatment as measured using total symptom score. You can see this impressive effect juxtaposed with avapritinib's 48-week total symptom score results, which show a flattening or plateauing of effect on symptomatic improvement beginning by week 28. In fact, as we saw at ASH, much longer follow-up data from the Pioneer trial showed no significant additional symptomatic benefit in avapritinib-treated patients after three years of therapy, with mean TSS reduction at three years of only 19 points from baseline. Bezuclastinib symptomatic improvement of 32 points at week 48 is the type of differential magnitude that non-advanced systemic mastocytosis patients are looking for as they search for a treatment that can return them to a normal quality of life. Then on slide 24, we look at the broad impact bezuclastinib is having on the lives of these patients, with 86% of patients treated with bezuclastinib reporting a clinically meaningful improvement in symptoms by week 48. As you can see, 56% of patients on bezuclastinib report greater than a 50% improvement in their symptoms at the same time point. Next, on the right panel, you'll see that patients originally randomized to placebo also show rapid notable improvements in symptoms once crossed over to bezuclastinib therapy. Adding all of these results together results in a bezuclastinib profile showcasing a very active, well-tolerated option for patients, which we believe has the opportunity to become the preferred standard of care following approval. Now turning to the results from APEX, our registration-directed trial of bezuclastinib in patients with advanced systemic mastocytosis. Here on slide 26, you'll see, contained within the blue line, 81 patients were enrolled in part two of the APEX trial at the 150 milligram daily dose, 68 of whom reported measurable C findings at baseline and therefore are evaluable for response on the modified IWG-MRT-ECNM criteria. On the subsequent slides, you will see a total of 81 patients analyzed for PPR and safety, while that subset of the 68 patients with measurable C findings will be included for analysis of the primary endpoint. Turning to slide 27, you will see the patient demographics and characteristics, which are generally representative of the broad ASM patient population. Of importance, the APEX trial enrolled a slightly higher proportion of aggressive systemic mastocytosis and mastocytopenia patients, along with a higher rate of patients with the S/A/R mutations compared to prior studies in the same patient population. Also of note, the APEX trial did allow a small number of patients with prior avapritinib treatment to enroll. On slide 28, you'll see the impressive clinical activity demonstrated by bezuclastinib in this patient population. On the primary endpoint of modified IWG-MRT-ECNM response, bezuclastinib achieved a 57% response rate, including 49% objective response rate when considering the subset of patients who achieved a partial response or better. It's important to note that these data were cut with a median duration of treatment of just over nine months, and at the time of data cut, multiple additional patients were in unconfirmed response pending further assessment. Looking at performance on pure pathological response, a key secondary endpoint of the APEX trial, you note that 80% of patients achieved a partial response or better, reflective of the rapid and deep activity bezuclastinib has on serum tryptase and mast cell burden in this patient population. To dive deeper into bezuclastinib's effects on these objective measures of disease burden, you'll see here on slide 29 a very impressive waterfall plot showing that nearly all patients have reduction in their mast cell burden. Looking across the bottom of the slide, you'll see this impressive activity applies also to bezuclastinib's effect on serum tryptase and D816V variant allele frequency, with 89, 89, and 91% of patients achieving greater than a 50% reduction on these objective measures of disease burden. Now turning to possibly the most exciting part of the APEX results for advanced systemic mastocytosis patients, the safety and tolerability profile on slide 30. You'll see here that in the trial, no patients treated with bezuclastinib needed to discontinue treatment for related adverse events, and only 14.8% of patients even required a dose reduction of bezuclastinib. With low rates of grade 3 thrombocytopenia and anemia, coupled with the non-hematologic safety profile presented in the table, we look forward to offering patients a new treatment option which delivers the powerful clinical activity they are looking for without the trade-off of high rates of edema, cognitive impairment, and bleeding risks associated with the current standards of care. Of particular note here on slide 30, only one patient reported a grade 3 transaminase elevation, and with dose reduction, that patient remains on bezuclastinib today. To summarize the APEX results, bezuclastinib showed a 57% ORR on the primary endpoint as measured by modified IWG criteria, along with an 80% ORR on the key secondary endpoint of PPR. But what makes bezuclastinib stand out in the advanced setting is the safety and tolerability profile, which should allow patients to enjoy the rapid and robust activity of a potent KIT inhibitor without all the risks associated with currently available treatment options, which lack the selectivity of bezuclastinib. The potential for us to unlock the ability to treat SM AHN patients with bezuclastinib and in AHN direct therapy is of particular interest for investigators in this community. We are excited to submit an NDA for bezuclastinib in advanced systemic mastocytosis patients during the first half of 2026. Now, before I open up the call for questions, I'd like to reiterate just what an amazing journey the last several months have been for Cogent. Bezuclastinib has now demonstrated across three separate pivotal trials that it can provide clear clinical benefit to systemic mastocytosis in GIST patients, all while delivering a well-tolerated safety profile reflective of its highly selective targeted approach. With an opportunity to submit three NDAs in the next several months, putting us on track for multiple launches in the second half of 2026, Cogent is positioned to make the leap to a profitable commercial biopharma company in the very near future. To finish up today, I would like to congratulate my Cogent colleagues on all the recent successes and particularly thank all of the investigators and patients who participated in the SUMMIT and APEX trials and believed in the potential of bezuclastinib. So now, Operator, I think we're good to open up the line for some questions. Thank you. Ladies and gentlemen, as a reminder to ask a question, you will need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, simply press star 11 again. Again, to ask a question, please press star 11. Please stand by for our first question. And I'm showing our first question in queue coming from the lineup. Andrew Berens with Leerink Partners. Hi, can you hear me? Yeah, we can hear you, Andy. Great. Thanks, Andy. Congrats on the data and all the progress. I guess on ISM, slides 12 through 15 are particularly striking and suggesting that these have a broad effect on symptoms and the biomarkers correlate with symptoms. It's different from what Ayvakit shared in the past. I'm wondering if the doctor could comment on whether she thinks this is going to translate into an improved quality of life for the ISM patients. And when both of these drugs are on the market, how will she decide which drug she's going to use when a new patient that's naïve to therapy presents to her clinic? And then I have a question on ASM after that. Okay. Dr. Rein, do you want to maybe tackle that one? Yeah. So I think the first part of that question was, how do these findings translate into improved quality of life? So I think they translate in various ways. So as somebody who treats patients with SM, I think obviously that the data that we've presented looking at the change in total symptom score says right there that patients do have an improvement in their quality of life, right? So if people feel better and are able to do the things that they want to do, go to work and function, spend time with families, do the activities they enjoy, that oftentimes inherently improves quality of life. And so I think what I find encouraging about this data that we present is that we see the change across symptoms. Again, so it's not one specific domain or symptom driving this improvement, but rather a global change. And that is important because, again, specifically within ISM, we do see such a heterogeneous disease presentation in these patients. So I think that's important. I think the other key takeaway, as you kind of tie it into the decrease in changes in mast cell burden, as an oncologist, for a lot of diseases, we have markers of disease that patients follow very closely. And I think there is a certain level of comfort from a patient perspective. I know from my own personal experience and then as a treating physician that patients really do feel comfort, and some feel better seeing positive changes in disease. And I think that's very logical. So I think from a quality of life and just well-being perspective, I think oftentimes seeing your tryptase go down or seeing your mutation go away, I think that positively impacts a patient's experience of their disease, which is really important for chronic disease. So I think that answers the first part of the question. I think the second part of the question was, how would you choose between agents? Is that correct? I just want to clarify that. Yes. So I think that is an excellent, excellent question. So I will say first, I think the most exciting piece to this entire process from my perspective is the fact that this is the potential for patients to have options. So I think I like facts and figures, and I think what we've presented and what I've shown here within the context of this data is that, again, there is a significant improvement in symptoms. There is a significant improvement in markers of disease. There is a correlation between those two, and there is a tolerable safety profile. So I think when you talk to patients and when I talk to patients about this, what I typically review is the facts and the figures. I review the data in a patient-friendly way, and then we make the choice for the patient to decide on an agent that is going to be effective and then also well-tolerated, and I think, again, the tolerability is important because these are chronic diseases, and patients do stay on these medications for a long time, so I do think the safety profile, which we've presented here, is quite encouraging. Okay. Thank you very much for the in-depth response. And then just on the ASM data, just wondering if Andy, if you can give us a little more color on the unconfirmed patients, the number of patients that have had a response and maybe that haven't confirmed yet but still may confirm, and then when we might see the 20 patients, the combination patients presented, and if you think those patients may eventually end up in the label? Okay. So thanks, Andy, for the question. I'll take the second part of it first. The cohort of patients that is allowing for concomitant use of bezuclastinib with AHN-directed therapies continues to be open for enrollment. We would expect to have data from that cohort probably closer to launch. It is not meant to be part of the registration trial, so we'll have to stay tuned for that later in 2026 or early 2027. With regards to your first question, without putting a specific number on it, what we can tell you is if you look at that chart on. I'm going to get the slide number wrong. And let me see. From the APEX data, slide 28, that shows you the sort of disposition of response by patients at the time of data cutoff. There's quite a few patients on the modified IWG column that are in stable disease or clinical improvement. I can tell you that a lot of those patients are already in response, several of whom are in complete response per the pure pathological criteria, and they're waiting resolution of C findings. Now, some of those C findings are due to the underlying mastocytosis disease. Some of them are probably due to the AHN disease. So it's hard to predict exactly which ones of those patients will eventually become responders. What I can tell you, there's of the patients that are on study remaining in stable disease and clinical improvement, we've gone through them sort of one by one. There are many that have the opportunity to still achieve a response per modified IWG. So we'll wait and give those patients some more time. They're assessed on a Q3-month basis up through the first year and then a Q6-month basis afterwards. We have seen patients in our dose escalation portion of the study respond for the first time as late as 16 months into therapy. We're going to give those patients a chance to get to their response before we try to report out on them. Great. Well, congrats again on all the progress and execution. Great. Thanks, Andy, for the questions. Thank you. And our next question coming from the lineup, Anupam Rama with J.P. Morgan, your line is now open. Hey, guys. Thanks so much for taking the question. One for Dr. Rein. Look, this question was almost just asked of you, and I know you called it a loaded question on stage on Saturday morning. I was just wondering if you could dig in a little bit on how you think about the segments of patients that might be more appropriate for bezuclastinib in both the non-advanced and advanced setting versus Ayvakit based on the totality of what you know today. And then, Andy and team, congrats on all the progress, man. Just wondering, what are the final gating steps here to getting that NDA submitted in non-advanced and the SUMMIT data? I think you've reiterated that that's happening this month. So thanks so much. Yeah. So, Anupam, I'll just take the second question quickly, and then I can ask Dr. Rein. I know people want her to say that she's going to prescribe bezuclastinib to everybody, so maybe we'll hear what she has to say. So the NDA for ISM is definitely going in December. So the gating at this point is honestly just editing to make sure everything is T's crossed and I's dotted, but we're at the very, very home stretch of getting that submitted. So that'll be sort of an any day type of thing. So, Dr. Rein, do you want to sort of speculate on, in the future, assuming bezuclastinib is approved and the FDA gives it the green light, how you would make decisions, understanding that you already answered that it's going to be a patient-involved decision on an individual basis, but globally, do you see bezuclastinib becoming a big component of your treatment in the future? So to answer the question, I think you kind of hit the nail on the head. So I think the question asked is, what is the patient population for this? And I think what the SUMMIT study, what we showed and what is shown so nicely in that slide, and I can get you the slide number. How's that? Slide 16. I think the important takeaway for me is that this particular agent has activity across a broad patient population for non-advanced SM. And so we have not included previously in studies patients with smoldering SM. These tend to be higher-risk patients. These are the folks that you watch more closely with higher concern for disease progression. This SUMMIT study also included patients who had had prior avapritinib exposure. And so I think the take-home message for me when I think about future use is really that this is potentially applicable and is applicable to the entire population of indolent SM patients, so a global population. So when I think about who's appropriate, I think the answer there is I think it's appropriate to consider this when you're treating patients with indolent SM. Great. Thank You for taking my question. Yeah, Anupam, maybe I'll add one thing, and Dr. Rein, we were discussing this offline at some point over the weekend. As we get further down the line and we show longer and longer-term follow-up of bezuclastinib in SUMMIT, I think we have the opportunity, as I sort of presented a preview of the 48-week data, to show more clear differentiation as what we're seeing from avapritinib over time is essentially no deepening of response outside of the skin domain. And what we're seeing preliminarily from bezuclastinib is continued deepening of symptomatic response across the domains, including as we saw here for the 24-week data and as we can hopefully present in the not-too-distant future, the 48-week data. Bezuclastinib is having a broad effect, not just within the skin domain, but the skin domain with the GI domain, with the CNS domain, with fatigue, with most severe symptom at baseline. And I think that's going to be very compelling for patients of, "Do I want a drug that has a quick bump on one domain, or do I want a drug that's going to help me across all of my symptoms deeply and continue to improve over time?" So look, we're at the beginning stages of this journey with the SUMMIT data, but we're certainly encouraged and excited to show how those data emerge in the future. And I think that's exactly what you share with patients, right? So I think from my perspective, again, facts and figures, I think what you show speaks. The data speaks for itself. Thanks again for taking our questions. Yeah. Thanks, Anupam. Thank you. Our next question coming from the line of Michael Schmidt with Guggenheim Securities. Hey, guys. Good morning. Thanks for taking my questions. And yeah, congrats on the data as well. Maybe just to follow up on SUMMIT. So just obviously not great to see consistency in effect, really, in treatment effect across all symptom domains, but are there any particular subsets in the score that is particularly burdensome for patients, particularly impactful to have improvement, perhaps relative to Ayvakit as we look at symptomatic improvement? So that's my first question. Anything that stands out there? And then, yeah, on the correlation with PD markers essentially and outcomes on slide 17, really interesting to see the correlation, especially with some of the measurable things like tryptase reduction. And I was just wondering in clinical practice, just having that correlation, can that be used to guide therapy in any way? For example, seeing perhaps some tryptase reduction first, but not yet a clinical response, and keeping patients on longer on therapy, having that additional measurement, can that be used in clinical practice to guide therapy? That was the other question I had. Great. Michael, I appreciate your questions. And I'll certainly ask Dr. Rein to comment a little bit on the second half of- or actually both questions. Maybe I'll take a stab first. So I think what we've heard over the last several years from our competitor is that there's really not a lot of good reason to look at the biomarkers. And really, what you should do is focus exclusively on symptomatic improvement and dose of drug based on how a patient says that they feel. But I think what our data set is suggesting, and we acknowledge that this is the beginning of this journey and it's going to take a while to adopt, is that there is a very strong reason to measure what's going on at a cellular level inside these non-advanced systemic mastocytosis patients to see if the drug you're using is having the intended effect. So fundamentally, we are prescribing these patients inhibitors of KIT mutations. Their disease is driven by a KIT mutation. Ergo, it follows that you would want to measure, is that drug doing what it's intended to do, which is remove the cells that have a KIT mutation? We think absolutely. We think that the data we're presenting this weekend and later this afternoon is highly suggestive that you would very much want to measure those things in the future as they will correlate over time with symptomatic improvement. But certainly interested to hear what Dr. Rein has to say. With regards to your first question on particular symptoms, I'll just remind folks that at baseline, we do measure what's called the most severe symptom in these patients in our study, and I think it was consistent PIONEER. The most frequent, most severe symptoms are really fatigue as well as sort of the collection of skin symptomology in these patients, and then after those first two across the gamut of certainly patients reporting CNS and GI and some of the other symptoms as the most severe, we're really encouraged by the level of improvement we're seeing on the most severe symptom at baseline matched to the broad improvement across domains, and we're excited to show how that emerges with longer-term follow-up. I think what Dr. Rein said before is it's nice to have a drug where you don't have to make a choice among several drugs depending on which symptom a patient has, but instead a drug that has that broad activity. So regardless of the most severe symptoms that are bothering a patient, you know that that drug is going to help whatever that most severe symptom is. So maybe I'll ask Dr. Rein if she wants to comment on either of those. Yes. I'll piggyback on that on the first part of the question, the symptoms. So I think that hits the nail on the head. So I think this speaks to the heterogeneity of patients with indolent SM. No one patient is alike. We do have folks who have mainly skin findings. We have folks who have mainly GI or gastrointestinal findings. And so again, I think this data shows in a lovely way that you get broad improvement across symptoms. And there really is not one specific symptom that is contributing to that change in total symptom score, the mean change in total symptom score. So for me, from a clinical perspective, this broad improvement, I think, is actually very important. So that's the first part of the question. The second part of the question was addressing the correlation and how we use it clinically. I don't know that we would use it or I would use it as a marker of disease or in choosing. I think what I take from this, the takeaway message for me when I look at the correlation between symptom improvement and change in markers of mast cell disease burden, I think to me, it just speaks to the fact that, again, the agent is active not only in the symptom domain, which is highly important for patients' quality of life, but also is modifying what's driving the disease. So as a hematologist and obviously as an oncologist, I think both aspects of that are very important. And the correlation for me suggests that this is really the therapy is targeting what is driving the pathology driving the disease. Great. Thank you. Thanks, Michael. Thank you. Our next question coming from the line of Christopher Raymond with Raymond James. Hey. Thanks for taking the question. Maybe one for Dr. Rein on the treatment choices here. I know you've answered a couple of previous questions on how you choose between these drugs once they're both on the market. But maybe just a question here on another wrinkle. A big part of the treatment decision tree with Ava is whether to updose from 25 to 50 milligrams. We've heard from a number of treating physicians that this can be an issue for patients who are worried about cognitive effects, etc. So maybe with both drugs on the market, how big of a factor is that for you? And how important would it be to not have to deal with that? And then I have a follow-up for management. All right. So I'm a rule follower by nature. So I prefer to prescribe per label. So I think for me, that's a consideration. So my general preference is to prescribe per label. So I think thinking about how I will utilize available agents, I will typically prescribe per label, which is how I would think about things moving forward. Oh, excellent. Okay. Thank you. Okay. And then maybe, Andy, so you guys now have objectively a superior drug to Ayvakit in both non-advanced and ASM here. I think we all know the price that's been set for Ayvakit. And I know you're not going to sort of talk about the price specifically, but you have flexibility here now given the different doses. Should we be thinking about a meaningfully different price point for these indications? Yeah. It's an interesting question, Chris, and as you know, Blueprint Medicines and now Sanofi have avapritinib priced at a flat strategy. So whether you order a bottle of 25 milligrams of avapritinib or 200 milligrams, it's the same price. It's a price per bottle, not per dose. We'll definitely monitor how this all evolves as we get closer to launch and put as much information as we can into the decision, and it's not just in our little corner of the universe within mastocytosis. It's broadly within all of the things that are going on with drug pricing, both in the U.S. and globally, thinking about the best way to maximize the value of bezuclastinib. I know this weekend is really about ASH and hematology and mastocytosis, but I can't help but point out that we also have a very exciting finding in second-line gastrointestinal stromal tumor patients. That, as you know, is at a significantly different dose of bezuclastinib in combination with another agent. It's a little bit complicated, but I think we're very prepared to move forward and come out with a price that is very competitive to what's available given the clinical data that we've generated for bezuclastinib. Great. Thanks so much. Thank you. And our next question coming from the line of Sam Slutsky from LifeSci Capital, your line is now open. Hey, good morning. Thanks for taking the questions and great work on the update. Just two for me. Just on the correlation between the PD markers and symptom benefit and non-advanced SM, any hypothesis on why your data shows this versus avapritinib didn't? And then I guess to this point, could it be possibly because you have more data points at deeper reductions to contribute to the analysis? And then the second question is for the patients who had prior avapritinib in both your advanced SM and non-advanced SM studies, just any general statements on how they did? Yes. Sam, thanks for the questions. So I think I'll take both of these and see if Dr. Rein has anything to add. I mean, the most obvious answer to your first question about differences in non-advanced mastocytosis, avapritinib versus bezuclastinib, is first principles is that avapritinib reduced their dose by 90% in order to spare the side effect profile that they generated in the advanced setting, which was the only acceptable way to develop that drug in the non-advanced or the indolent systemic mastocytosis population. At 25 milligrams, and we've discussed this before, we see avapritinib on KIT D816V as about an IC50 level inhibitor, whereas at our 100 milligram dose in the summit study, we're probably tickling IC90 concentrations. So I think that's reflective of the phase 3 data that they shared from PIONEER versus the phase 3 data we've shared from SUMMIT, where we're hitting the target and engaging the target. And at the 25 milligram dose, they just aren't, which is also, I think, reflective of their strategy to try to stimulate use of their drug off-label at higher doses. When patients are not seeing that symptomatic benefit, it's, in our opinion, due to the fact that they're at a dose that's far below what would be required to hit the mutant cell target. With regards to the prior Ava patients, I think Dr. Rein presented the prior Ava patients from the SUMMIT study looking highly consistent from a magnitude of effect size. That's encouraging because you'd expect that those prior Ava patients would have gotten some benefit from Ava before they entered the study and would have had some of their symptoms improved, albeit needing a washout period before starting. From the prior Ava patients in the APEX study, I can say that, again, they performed consistently with the overall patient population. So we don't see any reason why you wouldn't want to give bezuclastinib to patients that had seen prior Ava. But I think there's also a lot of evidence building, especially some of that longer-term data from SUMMIT, that there's no reason why you'd want to give Ava first and then wait to reserve Bezu for later. So I see the profile of bezuclastinib as a clear preferred choice long-term, post-commercial approval, of course, as a first-line agent in these patient populations. But it's also a very interesting choice for patients that are currently or had previously taken avapritinib and either didn't tolerate it or didn't see a deep benefit as a potential option to try bezuclastinib as well. So Dr. Rein, anything to add to those two? Yeah. I will just echo the prior avapritinib exposure patients. Again, very consistent data, very consistent response. So again, suggestive that this is a cell population who will respond as we've seen nicely outlined in that data. Great. Thanks, Sam, for the question. Appreciate it. Thank you. And our last question is coming from the line of Clara Dong with Jefferies. Hi. Thank you for taking our question. This is Ancian for Clara. Our question is regarding the APEX trial. Could you elaborate on the time to responses, like the median time to responses, and how to expect the ORR to evolve over time with longer follow-up? Thanks. Sure. So thanks for the question. And I think this is probably going to be our last question. So thanks to everybody for joining the call. And certainly, thanks to Dr. Rein for spending her time at a very busy conference with us this morning. With regards to time to response, I think you saw in our press release this morning that we said the median time to response in APEX was two months and that the duration of response is not yet mature, which suggests that these patients are having a deep, durable response. I did reference earlier in the call that from our dose escalation portion of APEX, we did see patients responding for the first time as late as 16 months on therapy. So we are going to give the patients on the registration trial a little bit more time. Obviously, they get as much time as they want. But from us, to judge the response rate, we did mention that there are multiple patients who, at the time of data cutoff on APEX, were already in unconfirmed response. That is additional over the response rates we've reported, not part of the response rates, importantly. So I do believe that the PR or better modified IWG response rates. I would expect those to migrate into the 50%-60% range from the APEX trial. And again, what we were expecting from APEX, given that avapritinib from PATHFINDER ran that trial at their clinically relevant dose of 200 milligrams, I would expect that Bezu and avapritinib, at their equivalent clinically relevant doses, would achieve similar levels of activity. The key difference on APEX that we presented today is a safety profile that looks significantly better than what avapritinib at 200 milligrams can deliver with notably lower levels of dose modification, dose discontinuation, noticeably lower levels of tolerability challenges that those patients face, and so that is really the key for the APEX study, is providing a potent KIT inhibitor without all that off-target toxicity that has been managed by investigators, physicians, and patients over the last several years. We're hoping to bring a choice that they don't have to manage those tolerability concerns and still achieve that same level of activity, so hopefully, that answers your question. Appreciate you calling in, and again, to Dr. Rein, thanks for spending time with us today. I think we're going to wrap up the call at this point, so thanks, everybody, for tuning in and listening. Appreciate it. Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.