Good morning. My name is Cindy, and I'll be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics call. There will be a question-and-answer session to follow. Please be advised that this call is being recorded at the company's request. I would like to turn the call over to Elhan Webb, Senior Vice President, Investor Relations. Thank you, Cindy, and thank you for all joining us on today's conference call to discuss Karyopharm's phase III SENTRY trial in myelofibrosis. We issued a press release this morning to provide an update on our SENTRY trial and also posted a presentation on our website that we will reference during our call today. Before we begin our formal comments, I'll remind you that various remarks we'll make today constitute forward-looking statements, FLS, for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995, as outlined on slide two. Actual results may differ materially from those indicated by these FLS as a result of various important factors, including those discussed in the risk factors section of our most recent Form 10-Q and in other filings that we may make with the SEC in the future. Any FLS represent our views as of today only. While we may elect to update these FLS at some point in the future, we specifically disclaim any obligation to do so, even if our views change. Therefore, you should not rely on these FLS as representing our views as of any later date. I will now turn the call over to Reshma Rangwala, our Chief Medical Officer and Head of Research. Please return to slide three. Good morning. Thank you, Elhan, and thank you all for joining us today. We are excited to provide a very favorable and important update on the design of our phase III SENTRY trial in myelofibrosis. As we will discuss on the call today, we believe the change in the co-primary endpoint to Absolute TSS further increases our confidence in our phase III clinical trial, is aligned with the FDA's goal to use more patient-friendly endpoints in clinical trials and is supported by leading investigators and patient advocacy organizations. As you can see on slide four, joining us on the call today are two of the leading experts in myelofibrosis, Dr. Raajit Rampal, Director of the Center for Hematologic Malignancies and Director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, and Dr. John Mascarenhas, Principal Investigator of the phase III SENTRY trial and Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of the Center of Excellence for Blood Cancers and Myeloid Disorders. Dr. Rampal will provide an overview of the myelofibrosis landscape, discuss the advantages of using Absolute TSS as our new co-primary endpoint, and also share his perspectives on why this change is helpful based upon observations from other clinical trials. Dr. Mascarenhas will then discuss XPO1 inhibition and provide his perspectives on our phase I data in myelofibrosis that have been presented previously. Following each of their presentations, I'll ask each of them a few questions. I will then discuss the study design of our phase III SENTRY trial and then open the call for questions. Turning to slide five, we are advancing a late-stage pipeline built around selinexor and XPO1 inhibition, leveraging the strength of our foundation in multiple myeloma. We remain very excited about our ongoing work in evaluating selinexor as a potential maintenance therapy in endometrial cancer and also using it in combination with pomalidomide and dexamethasone in multiple myeloma. But today is going to be all about our myelofibrosis program and the phase III data that we expect to share with you in the second half of 2025. As we have discussed in the past and as outlined on slide six, our current phase III studies of selinexor use substantially lower doses of selinexor than the ones that were used when selinexor was first approved for use in multiple myeloma. We believe this is worth remembering since the side effect profile, specifically some of the nausea that patients experience, is lessened with these lower doses as well as the incorporation of prophylactic antiemetics for the first two cycles. With that, I will now turn the call over to Dr. Rampal. Dr. Rampal? Thank you, Reshma, and good morning, everyone. Let's start on slide eight. Just to give you a background, my intention with these slides is to give you a brief introduction to the disease, the current modalities, the limitations of those modalities, and some of the perspectives that we have on the clinical studies that we do in this disease. Advancing to slide nine, myelofibrosis is a progressive disease, and there are a number of different manifestations that we deal with regards to our patients who have the disease. The principal things that cause patients' discomfort, but also ultimately can lead to morbidity and mortality, include progressive constitutional symptoms, progressive organomegaly, principally hepatomegaly and splenomegaly, and progressive bone marrow failure, which results in cytopenias like anemia and thrombocytopenia. Let's advance to slide ten. So when we think about the current landscape of therapeutics for myelofibrosis, it is varied. There are a number of different agents that we have that we use to treat different things. But really, at the end of the day, two major things that arise to significance are symptomatic splenomegaly and the constitutional symptoms. And for those for at least more than the past decade, JAK inhibitors have been the standard of care for the treatment of these symptoms and issues. As I will talk about, there are significant limitations to the efficacy of JAK inhibitors, and that necessitates the investigation of other agents. Let's advance to slide 11. So when we think about clinical trials as it pertains to myelofibrosis, in the JAK inhibitor era, really two things have been the major endpoints of studies, the first being spleen volume reduction. Spleen volume reduction of 35% has been the benchmark that has been utilized for the approval of the current JAK inhibitor arsenal that we have. Why is that important? Obviously, as I mentioned, this is a symptomatic issue for patients. It does decrease their quality of life. In fact, the spleen volume response, or SVR, does in fact correlate with overall survival in both retrospective and prospective studies. The retrospective studies of the COMFORT trials clearly did demonstrate an association between survival and spleen volume reduction. Let's advance to slide 12. A prospective observational study, which led to a model called the RR6 model, demonstrated that there were essentially three variables associated with an increased risk of death in patients who were on JAK inhibitor therapy. One of these, the second issue here, splenomegaly reduction by less than 30% by palpation at three and six months had a hazard ratio of 2.26. There is an association with not achieving spleen reduction and patients doing worse. I think to all of us, this certainly justifies spleen volume response as an endpoint in clinical trials for patients. Let's advance to slide 13. The symptom burden issue has also been of prominence. As we talked about, this is a prominent issue for our patients. They are often heavily symptomatic. The issue has been, how do you adjudicate this? The total symptom score has been the tool that has been utilized for clinical studies, and there's some various forms of this. How you actually measure that is sort of part of the issue that is the heart of the call today. There are ways to look at this using absolute total symptom score reduction, where you're actually just looking at the numerical difference from a baseline score to the endpoint of the study. But there's also the TSS50, which has been used more prominently. And this measures the proportion of patients with a 50% reduction in the total symptom score. It's also important to note that not all trials have used the same version of the TSS in looking at responses, and that makes this a little bit of a more complicated issue. Let's go to slide 14. So slide 14 is the actual MPN or myelofibrosis symptom assessment form that patients fill out. You see that the symptom domains are listed on the left hand of the slide. The question asks the patient, "What was your worst level of this symptom in the last 24 hours?" Patients score this on a scale of 0 to 10. You can imagine if you were to fill this out that there could be quite a bit of variability that you might report on a day-to-day basis. But the thing that is perhaps the most fickle out of all of this is fatigue. Fatigue can vary for any number of reasons that aren't related to disease, right? If somebody has a bad night's sleep, as an example, that could increase your fatigue. So fatigue is a relatively fickle thing, and I'll talk about that more in a moment. Let's go to slide 15. As it pertains to the JAK inhibitors and their inadequacy, as I mentioned before, obviously in the U.S., we have four FDA-approved JAK inhibitors that are listed here. And I won't get into much of the detail on this slide except for the bottom, which is the spleen volume response by 35%. Again, with the argument that spleen volume response does associate with survival, if you actually look at the SVR35 achieved by JAK inhibitors, it ranges from 22%-41.9%, i.e., the majority of patients are not achieving SVR35. And this tells us that we do need to utilize or study drugs that are able to get us a higher SVR as one of the things to think about going forward. Next slide, slide 16 at this point. And indeed, ruxolitinib duration of therapy is often less than two years, and when patients discontinue, they do poorly. So again, this justifies the principle that ruxolitinib and other JAK inhibitors do achieve a certain degree of efficacy that is good for our patients, but it is not where we need to be, and therefore we need other agents. Let's go to slide 17. So to kind of illustrate some of this, I want to use the MANIFEST-2 data as a discussion point. And the goal here is not to dig into the MANIFEST-2 data, but rather to use it in an illustrative manner. And as you recall, the MANIFEST-2 study was for treatment naive patients with myelofibrosis who were randomized to ruxolitinib and pelabresib or ruxolitinib and placebo. And the primary endpoint here was SVR35, as we talked about this, I think, is a well-justified thing. But the key secondary endpoints here were absolute change in TSS and the TSS50. I think looking at that data is informative. Let's go to slide 18. Without a doubt, when compared to ruxolitinib alone, it is very clear from MANIFEST that the SVR was significantly increased by the combination of ruxolitinib and pelabresib. I think this helps justify this as an endpoint. Let's go now to slide 19. As we think about symptoms, there were two different scores used. Again, the total symptom score, absolute change, which is, again, just looking at the numerical change from baseline to week 24 using the scoring system that I've shown you a few slides earlier. From this analysis, there was a numerical advantage for the combination therapy, and the p-value just missed here. By contrast, same patients, if you look at the TSS50, again, this is a question asking what proportion of patients had a 50% reduction in the total symptom score. Here you see, again, the difference is not even close to statistical significance, even though numerically there's some difference here, and that does tell you that these two tools do not align and don't necessarily give you the same degree of information, and so that is, I think, part of the problem with regard to how we measure total symptom score. Let's now go to slide 21, so one of the interesting analyses that was presented at the European Hematology Association meeting with regard to pelabresib was to try to understand what do these symptom scores actually mean and how do you put them into context. One way to do this, and what was done, is that there was a study years ago from 2015 that did actually look at the symptom burden using the symptom assessment scores in patients who do not have MPNs, because certainly many people without MPNs have fatigue or can have other symptoms like abdominal discomfort. What was the analysis done here, presented on the slide, is that you see the baseline values for the patients in the MANIFEST-2 study in green, and then their week 24 results. More or less, for most of these symptoms, both drugs were able to reduce the symptom burden. The blue line represents non-MPN patients. These are "normal controls," but if you look at the domain of fatigue, what you will notice is that both drugs, the pelabresib combination is in dark blue line, and ruxolitinib is in the light blue line. You see that both drugs are able to actually reduce fatigue to the level of normal controls, and it's interesting because from this paper, they do quote that about 53% of people who go to their primary care physician go for a complaint of fatigue. So fatigue is a problematic measurement. It's a problematic thing to measure as a symptom associated with the disease, but you really can't divorce it from other factors that associate with fatigue, and that the drugs that we have are doing a pretty good job of approximating fatigue to that of the normal non-MPN population. And in fact, if you look at the modified TSS and you exclude fatigue as one of the domains, then the Absolute TSS change becomes statistically significant. Is that a legitimate thing to do? The answer is yes, because this has been done by other registrational trials. So to kind of conclude my section here, it's clear that we need newer drugs. There is an unmet need in this patient population, number one. Number two, it is clear that the SVR remains an important endpoint. And that number three, the total symptom score also is an important endpoint. However, there are challenges in how you measure it. And there are clear advantages to not including things like fatigue that are really difficult to adjudicate. And the modified TSS may be a way to better define that, which we'll talk about in a moment. I will turn this back over to Reshma. Thank you so much, Dr. Rampal. This was very, very helpful. Just one follow-up question for you. So I liked the illustration of using the MANIFEST trial to compare the Absolute TSS versus the TSS50. Yes, if you look at the p-value, the Absolute TSS was closer as compared to TSS50. What do you think about going forward in future trials, such as the SENTRY, of picking one of those two endpoints, specifically the Absolute TSS? Do you think the Absolute TSS is a better way to assess symptoms as compared to TSS50? Yeah, no, I think this is a key question, right? And there's a couple of things to think about. One is that we're looking at a binary versus a continuous variable. And symptoms are a continuous variable. I think the analogy would be to say, if somebody has a headache and we say, "Well, tell us your scale of pain on a scale of 1 to 10," but we're going to decide that if your headache pain level is less than 4, you don't really have a headache. This is kind of akin to what we're doing, which is we're saying that you could have a 49% reduction in your symptom burden, but that doesn't count, that you're a non-responder, as far as the symptom profile occurs. We are missing a lot of data by using the TSS50 as a tool, whereas the Absolute TSS gives you more granularity. It gives you the actual change, numerical change that occurs, and is not giving you an arbitrary cutoff of saying, "This is a response, and this is not a response," because the response of 50% or more versus less than 50% means different things to different patients. So I think that is the challenge of TSS50 and why the Absolute TSS may be a better tool to look at responses in clinical trials going forward, as well as in SENTRY. Again, thank you so much for sharing your perspectives on these questions. I'm now going to turn the call over to Dr. John Mascarenhas to discuss selinexor's mechanism of action and review the data from our phase I clinical trial of selinexor plus ruxolitinib. Dr. Mascarenhas? Okay, Reshma, thanks. Thanks for the introduction and the invitation to speak today to the group with Raajit. I'm going to take us through, A, what is selinexor, and it's probably not new news to most listeners today, and then B, what is the data that we have with combination ruxolitinib in myelofibrosis that basically sets the tone for the expectations for the phase III study. So with that, I'm going to move to slide 23, which is an illustration of XPO1 inhibition, as I would indicate, is a rational intervention for MF patients. So selinexor is a novel XPO1 inhibitor. It blocks nuclear export of many proteins and even messenger RNA molecules, thereby increasing nuclear localization and activation of, for example, P53 and other tumor suppressor pathways and decreases cytoplasmic activation of multiple proliferative and profibrotic pathways relevant to MF pathobiology. So what we are seeing with selinexor is the way I would sort of look at it, a drug that has a combination effect on multiple relevant pathways, as we try to illustrate here. Pathways that we know are relevant, that are targeted by other molecules that are in clinical development, that are covered comprehensively here with selinexor. Dr. Mascarenhas? Can you hear me? Yeah, yeah, there we go. Thank you. Okay, sorry, I don't know why that is. Multiple pathways that are relevant, and TP53 being one of the main pathways, that's wild type and dysregulated, and when activated, regulates both cell cycle arrest and apoptosis. Other pathways that I don't have listed here, like TGF-β1, which is a main fibrogenic cytokine and also a negative regulator of hematopoiesis and megakaryopoiesis specifically. Addressing both the malignant stem cell population and the tumor microenvironment to promote more normal hematopoiesis and reduce malignant hematopoiesis. Slide 24. Taking that, keeping that in mind, what is the data that we've seen so far with selinexor, the XPO1 inhibitor plus ruxolitinib? Here's top line data in slide 24 from the phase I result. I'm going to, I'm not going through all the data in detail. I'm just really showing you the highlights that are important that set the stage for the phase III trial. And I want the listeners to look specifically at the intention to treat line that's highlighted at week 24, which is oftentimes the regulatory endpoint landmark analysis. And you can see at week 24, in 11 out of the 14 patients, a 78.6% SVR35. And again, Raajit showed you historically what we expect from JAK inhibitors in various phase III studies. And this is probably one of the higher SVR35s we've seen in combination in the upfront setting. So this is taking combination therapy, trying to build upon the success of ruxolitinib to deepen spleen response, which is effectively done here in the majority of patients that are treated with selinexor plus ruxolitinib. Then looking at TSS50, which was the way it was evaluated in the phase I, you see a 58.3% TSS50. So 58% of patients had a 50% reduction in their TSS. And I can tell you from treating patients with myelofibrosis, this is a significant improvement in their symptom burden, aligned with a significant reduction in their spleen. Now, if one looks to the right of the slide to understand, what does this look like in terms of the reduction, the Absolute TSS reduction? So as Raajit has pointed out, probably reflects a more robust way of looking at improvement in symptoms in patients with myelofibrosis. At week 24, you have a reduction of 18.5 points on the scale. So that's a, in the world of myelofibrosis and symptom burden, that's a very significant reduction in symptom burden. This is a very symptomatic disease driven by many factors, including the inflammatory milieu that is significantly heightened in myelofibrosis. Now, down below, we also highlight that this is a drug that has a well-known, well-described toxicity profile. Keeping that in mind, with very aggressive prophylaxis, for GI prophylaxis, one can significantly reduce the amount of GI toxicity that can be seen with selinexor, including nausea and diarrhea. This is, I think, key to part of the understanding and discussion of how this drug would roll out in myelofibrosis in combination. Because if one is aware of toxicity that can emerge and is proactive about managing that toxicity, the drug can be delivered very effectively. The toxicity that we see with selinexor is mostly seen in the first couple of cycles. That's also a key point to remember, is that this is toxicity that can be managed proactively and is not toxicity that persists through the dosing of selinexor, which is in this study, once a week, low dose, so 40 mg and 60 mg. I'm just showing you the 60 mg, the recommended phase II dosing, 60 mg once a week with aggressive prophylaxis can significantly reduce toxicity and enable continuous administration. Because it's the continuous administration, ultimately in combination with ruxolitinib, that's going to afford the patient's benefit. With that, I'm going to move on to the next slide, which is slide 25. This slide was included to make an important point, which is when combining a novel agent, any novel agent with ruxolitinib, one wants to understand what is the relative contribution of the new agent to both spleen reduction and symptom reduction. And this slide really nicely highlights that even in the patients that were receiving lower doses of ruxolitinib, doses that if you look historically have very minimal effect on spleen and symptoms. So for example, 5 mg, 2x a day, you can see on the left, there's still significant reduction of spleen volume. So despite the presence of a low dose ruxolitinib, this tells you that selinexor is actively synergizing at this low dose and inducing significant spleen response. On the right, total symptom score reduction can be seen, again, same principle, significant reduction in symptom burden at low doses of ruxolitinib, in which you do not normally expect to see such responses. So, despite the low doses of ruxolitinib, one can get significant reduction in both spleen and symptom burden. Again, highlighting the clear activity of this drug and the synergistic potential of selinexor plus ruxolitinib. So we're going to move on to slide 26. This slide is included to, I think, highlight and enforce, again, an important point that I know Dr. Rampal and I think about when we are involved in clinical trials or evaluating clinical trial results. It's what is the durability of these responses? Because it's not sufficient to be able to simply hit a response and then lose a response. In a chronic disease, you need to maintain that response. And what we're showing here is that the median duration of response on the left for SVR 35 and on the right for TSS50 is durable, very durable, with follow-ups that are noted 32 weeks and 51 weeks respectively. So it's not a phenomenon of hitting a response and then losing a response because of dose modifications or low doses of ruxolitinib. These are patients who can maintain the response. Ultimately, there are regulatory endpoints that are important, and we'll talk more about the importance of the change in Absolute TSS as a regulatory endpoint for approval at week 24. We're also invested in durability. What this slide is highlighting is it's not simply a regulatory endpoint that is being achieved here. It's the prospect for durable maintenance of those responses that would then ultimately translate to overall improvement in the outcomes of patients with these chronic yet progressive diseases. That's a, I think, a key important point of the phase I data that I look forward to follow up when we ultimately read out the phase III study. With that, I'm going to end my part of the presentation and hand it back to Reshma. Thank you so much, Dr. Mascarenhas. This is a really helpful overview. So as the principal investigator, why are you so positive about the change from the TSS50 endpoint to the new Absolute TSS? And does your confidence in the outcomes of the trial change with this update in the endpoint? So I think Raajit answered that question beautifully. And I think it's understanding what we're looking at. We know that ruxolitinib as a first-in-class, first JAK inhibitor is a very effective drug in terms of improving symptom burdens in patients with myelofibrosis. So the bar is very high when you treat patients with ruxolitinib. It is high enough that it is likely that any drug combined with ruxolitinib will face the same challenge and difficulty of clearing that bar when looking at TSS50%. And I think most people who are following this field will recognize very quickly that that's a theme that we've seen in upfront setting with combination therapy for myelofibrosis. Now, I think the change, which I also think signals the FDA's appreciation of these challenges and the FDA's desire to see drugs move forward for patients with myelofibrosis, to the absolute mean change in TSS reflects an understanding that that bar is probably unrealistic and not one that can easily be overcome with a trial that has been conducted, for example, like TRANSFORM, MANIFEST-2, so I think the change that we're seeing here in this endpoint really signifies something that's even greater than what we're talking about this trial, sort of a coming to terms with what needs to be done in order to truly appreciate the benefit that we can provide patients with these combinations of therapy. Again, I'll still make the point, though, that I think we often put a lot of emphasis on symptoms because that's a regulatory endpoint. But as Raajit pointed out very nicely with the slide set too, is that we can't forget that these drugs and selinexor with ruxolitinib has demonstrated very significant spleen reduction. And if you were to speak to physicians that treat myelofibrosis, although I don't think any physician would deny that there is an absolute satisfaction in seeing patients' symptoms decline, whether it's measured by TSS50 or the absolute change, but the objective reduction in spleen volume tied into survival is really key. And here with selinexor, we're seeing very deep spleen responses with this very big delta in terms of reduction in TSS50 at TSS at week 24. So my confidence in this, and you're going to explain the study design for the phase III with respect to this TSS, I think really is phenomenal. I mean, it signifies a new era of evaluation of combination therapy. Great. Thank you. Thank you Thank you so much. I would now like to conclude by reviewing the trial design for SENTRY shown on slide 27. As mentioned, we are changing one of the co-primary endpoints from TSS50 to Absolute TSS following alignment with the U.S. FDA. The two co-primary endpoints will be SVR 35 and Absolute TSS, and they're going to be tested sequentially. Specifically, SVR 35 will be tested first, and if positive, the alpha will then be rolled down to Absolute TSS. In addition, we have proactively increased the sample size to 350 patients, allowing us to further strengthen the statistical powering of the study. The very strong enrollment we have seen to date enables us to increase the sample size while maintaining the timelines that we have previously outlined. We remain on track to report our top-line results in the second half of 2025. All of the other key aspects of the trial, including the two-to-one randomization, the stratification factors, the dose of 60 mg for selinexor, and the administration of dual antiemetics prior to each dose for the first two cycles remain unchanged. In closing, we believe the changes we have announced today increase our confidence with our phase III trial, further increase our statistical powering, and are strongly supported by key opinion leaders in the myelofibrosis community at large. We remain incredibly excited about the potential for selinexor to be the first add-on therapy to be used in combination with ruxolitinib in patients with myelofibrosis, if supported by the data from SENTRY. We eagerly await reporting top-line data from this phase III trial in the second half of next year. With that, we would be happy to take your questions, Operator, to open up the call to the Q&A portion of today's call. Operator? Thank you. Ladies and gentlemen, we will now begin the question and answer session. Should you have a question, please press the star followed by the number one on your touch-tone phone. You will hear a prompt that your hand has been raised. Should you wish to decline from the polling process, please press the star followed by the number two. If you're using speakerphone, please lift the handset before pressing any keys. One moment, please, for your first question. First question from Brian Abrahams. Please go ahead. Hi, this is Kevin on for Brian. Thanks for taking our question. So this is for Dr. Rampal and Dr. Mascarenhas. Can you tell us more on maybe the type of variability we can expect to see in Absolute TSS changes in this population? And do you think the powering of the study should mitigate any potential for outliers influencing the mean one way or another of the Absolute TSS change? Thank you. Thanks, Kevin, for your question. I'm going to hand it over to Dr. Rampal. Yeah, it's an interesting question, right? And if one looks at some of the historical data, looking at, for example, MANIFEST in terms of the amount of variability, there really isn't that much variability that we see in the Absolute TSS changes, which is interesting and remarkable, right? Because patients do start with different baseline values of the Absolute TSS. So I don't anticipate or expect that we're going to see wide variance in the Absolute TSS. And of course, adding more patients and powering the study, as was discussed, I think will only give more confidence in those results going forward. Dr. Mascarenhas, is there anything you want to add? No. I mean, I think I totally agree with Raajit. All right. Thank you. Next question, Operator? Next question from Maury Raycroft. Please go ahead. Hi, this is Amy on for Maury. I was wondering, can you comment on how the enrollment is going given the increased number of patients? And what are the updated powering assumptions for the new trial design? And what would we need to see in the spleen reduction and the Absolute TSS to give us more confidence? And also, is the FDA still assessing the TSS50 and put a lot of weight on it? Thank you. Thank you, Amy, for your question. So I'll take your first questions. So as I mentioned in the call, the enrollment is very strong. And largely, that's driven by the enthusiasm from investigators who are participating in the trial. This is a global trial. They're putting their patients on, and this is leading, again, to very strong enrollment, which is going to enable data in the second half of 2025. Raajit, Dr. Rampal, do you want to take the next question about what you want to see in regards to SVR and Absolute TSS from this combination? Yeah, sure. I think that there's a couple of different ways to look at it. But if we think about what we've seen with combination therapies that have been reported out this year, right? Thinking about TRANSFORM and MANIFEST, spleen volume reduction akin to those or greater than that would be a reasonable place to go. And with regards to the Absolute TSS reduction, it isn't entirely clear what magnitude would need to be met. Obviously, it would need to be significant, but does the magnitude need to be eight or 10? In my mind, if I think about this on a practical level, right? Any change that is significantly different that demonstrates to me that benefits the patient, number one. And number two, if that is occurring in the context of also achieving a greater SVR, then that, to me, as a kind of composite, is really what I'd want to see as the deliverable from a combination therapy, thinking about putting this into a patient in clinic if it were to be approved. So it's really achieving an SVR close to what we saw with other combinations while also showing that the Absolute TSS favors the combination. That's the practical answer. And I think that the early data that was shown from the phase I is encouraging in that regard. All right. Thank you so much, Dr. Rampal. Dr. Mascarenhas, I know Amy had a follow-on question just in regards to how the FDA views both of these endpoints and specifically the weight they put on symptom evaluation. I think as we've been saying, there are historically two endpoints that have had to be hit for drug development and approval in myelofibrosis. If you ask the question, where did these endpoints come from and what do they mean? They come from the era of JAK inhibitors. JAK inhibitors are very effective in reducing spleen and improving symptoms. If you were to then ask the question, what's the value of these endpoints? I think there's obviously value in making our patients feel better. I can tell you, and I know Raajit would agree, there is a real satisfaction of having someone who feels unwell and rapidly making them feel better. Patients also want to have more deeper enduring benefits from their therapy. That's where I think my view differs perhaps from the way the FDA views this. I think the FDA is interested, understandably, in intangible benefits, and symptom improvement is a tangible benefit that they value, whereas I don't know that they appreciate what I think many of us see, which is the link between spleen volume reduction and outcomes that are truly meaningful at the end of the day to our patients with chronic progressive diseases, and that's overall survival, so for me, my focus actually is on the spleen more than the symptom, and I totally agree with Raajit that as long as we're not adding a therapy that detracts from the symptom improvement with ruxolitinib and goes in the wrong direction, I'm not as interested in how much more additional symptom improvement we get. I think it's icing on the cake, but I'm interested in the fuller effect of the combination therapy. And I do think that the spleen volume response is a clinical biomarker for those outcomes that really matter. And what I'm encouraged by with the data we've seen with phase I, and I think we are going to see that in the phase III, is that we do get these perhaps doubling or more than doubling of spleen volume response with the addition of a drug like selinexor at a low dose. And we do get improvement of symptoms beyond what is seen with ruxolitinib, particularly as measured by the absolute mean change in TSS. So I think that this is a regulatory requirement, but at the end of the day, getting that spleen very small and maintaining that on therapy, I think, is really key and fundamental to moving these drugs forward in a meaningful way. Okay. Thank you very much. Yeah, very helpful. Your next question from Peter Lawson. Please go ahead. Thank you so much. Thanks for taking my question. So I guess just continuing that dialogue with the physicians on the call, just what's the current trend? Do you think Absolute TSS is going to replace TSS50 longer term? Is that what's kind of bubbling up with trial designs currently being put in front of the FDA? Thanks, Peter. I'll hand it over to Dr. Mascarenhas to tackle that one. So I think it can, yes. I mean, I think the fact that we're seeing in this trial a rollout of change in TSS, absolute value in TSS as a primary endpoint reflects the FDA's appreciation of the challenges that we've seen and their willingness to be dynamic and flexible as we try to move drugs forward. I think the reality is that within this trial, we'll also demonstrate that delta between the two arms, that that change that you see between ruxolitinib and rux plus selinexor is clinically meaningful too, that that can be tied in and anchored into Patient Global Impression of Change, things that can also support that that's a meaningful delta between the two. I do think that this probably marks an era where I don't know that it will be mandatory that TSS50 remains the key primary or secondary endpoint in trials going forward. I think that's a good thing. I'm happy about that. Do you think because there is that change, do you think there's pushback from peers if they're looking at TSS50 versus Absolute TSS? I think it's a good question because the reality is that TSS50 has been the main way of assessing drugs. I don't think that means that we can't change and modify the way we've been doing this. I think most people who've been following this field carefully and are invested in it and are really interested in seeing things move forward will recognize what Raajit showed is absolutely true, which is the TSS50 was adequate, particularly early on in the era of these monotherapy JAK inhibitors with comparator arms that were inert placebo, but is probably not able to adequately reflect meaningful differences between arms when there is an active monotherapy JAK inhibitor. So I do think that there's a general acceptance of that. I think the fatigue part is really important. I mean, you can't really improve fatigue beyond what a non-MF patient's fatigue level is. That's not realistic. So I think these modifications reflect a growing realization that the TSS50 played an important role and served its purpose early on in the era, in the first 10 years, I would say, of the JAK inhibitor approval process. But I think many investigators, many sponsors, many patient advocacy groups would agree that it's probably not the best method of comparing across active arms of therapies and that we have to rise to the occasion. We have to be adaptable. I think that the FDA appreciates that. And again, I just see it as a positive change. And I don't know that the FDA is going to require TSS50 in any form or fashion if the absolute mean is there as a key endpoint and is met with statistical power. Gotcha. Thank you. Just final question. If this combination gets approved, are there particular groups of MF patients you think would benefit the most from the combination versus other JAK inhibitor options? Yeah. If that question is still directed to me, I'll take a stab at it. I mean, I think the reality is that we're looking at upfront therapy in intermediate and high-risk patients that have measurable spleen and symptom burden. Whether there will be a signal where one subset of patients in stratification are more obviously positively affected by the combination than single agent, we'll have to see when the results come out. But I think the way these trials are designed and the way we're approaching this is a general movement from monotherapy upfront to combination across the board for patients where you would intend to use a JAK inhibitor, that you would combine drugs that are active to try to get the deepest response upfront with the idea that we could then maintain it for a longer period of time. Because what we want to avoid is the eventual loss of response or inadequacy of response with single agent JAK inhibitor that can occur in patients and extend the benefit in a more durable way. And I think attaining deepest responses upfront is probably the best bet at this point with a drug like selinexor to achieve that goal. So to answer your question, no, I don't know that we know which subsets of patients, and it would be sort of for all newcomers that are in need of intervention. Thank you so much. Really appreciate it. Your next question from Jonathan Chang. Please go ahead. Hi guys. Good morning. Thanks for taking the questions. First question, can you discuss your level of confidence on the data readout remaining in the second half of 2025 despite the increase in the study size? Second question, what should we be expecting at ASH this year? And maybe last question for the docs on the call, how would you compare the tox profile of ruxolitinib to other treatment options in MF? Thank you. Yeah. Thanks for your questions, Jonathan. So our confidence remains high, right? Sort of as I mentioned, the enrollment is really strong. I think investigators are really convinced by the phase I data. They're compelled by the SVR, the TSS50, as well as the absolute. It really suggests that the efficacy that can be achieved with the combination supports a potential new combination therapy. As such, they're really driving their patients onto the trial. I think the other aspect that's important to just note is that currently in the MF space, in the JAK naive myelofibrosis patient population in particular, there are really no other combination trials. We're the only combination trial. So there's not a lot of other competition. There's actually no competition for a similar patient population, again, also supporting that strong enrollment. Because we see that strong enrollment, we're still expecting top-line results in the second half of 2025, even with the small increase in the sample size. In terms of your next question about ASH that we haven't disclosed, what we can expect at ASH, I think those titles are coming out soon in the next few days. So I won't spill the beans on anything about ASH. In terms of the last question, so the toxicity profile of rux versus the other therapies currently in development, maybe Dr. Rampal, I'll hand that one over to you. Yeah. I guess the question was about rux toxicity versus the other JAK inhibitors. I think that we certainly do not see the extent of GI toxicity that we see with other drugs like fedratinib or pacritinib as an example. And I think that sort of helps as we think about this combination therapy, right? Because as Dr. Mascarenhas talked about, there are known GI side effects with selinexor, but those can be mitigated. But the fact that you have a drug like ruxolitinib that does not have these types of side effects makes the combination much more, I think, easy to think about in given patients. We do see cytopenias, anemia and thrombocytopenia, as we do with any JAK inhibitor, although the anemia does tend to get better over time with ruxolitinib. I think the only other side effect that we do see are occasionally infectious complications, but those can also be easily mitigated. We have a vast amount of experience with ruxolitinib, and I think we are well attuned to the potential toxicities, which are not that common aside from the hematologic effects that we see. But I think that also gives confidence, as I said, in combination therapy with selinexor because there really aren't overlapping non-hematologic toxicities. Understood. Thanks for taking the questions. Next question from Ed White. Please go ahead. Hi. Thanks for taking my question. Just a question on timing. Why change the endpoint now? What has changed since you started the trial? Why didn't you begin with Absolute TSS as an endpoint? Yeah. Thanks, Ed, for your question. It's a great one. I think as we've always maintained, we're in a very favorable position to be able to watch, learn, understand, discuss, obviously, with our KOLs, really understand what the patients need, and use those learnings to be incorporated into our phase III trial. This update to Absolute TSS is the perfect example of just that, right? There has been this evolution over the course of the last couple of years in terms of how we need to best assess symptom improvement. TSS50, as Dr. Rampal so eloquently laid out, had been the traditional endpoint. Some of the more recent trials, including MANIFEST as well as TRANSFORM, incorporated the Absolute TSS, and I think there's good data to suggest that Absolute TSS is a more sensitive and therefore powerful way to assess symptom change over time. So again, these are opportunities for us to learn, be able to incorporate. We've had very productive conversations with the FDA, and now this opportunity to go ahead and change one of the key endpoints to Absolute TSS, which, as I mentioned, I think increases our overall confidence in the outcomes of the phase III SENTRY trial. Okay. Thanks. And just a last question for me on the timing. So the timing hasn't changed from the second half of 2025 for data, but that's a six-month window. Does the timing actually move further out in that window, or is there absolutely no change to timing? And then also on cost, just wanted to know if there's any material change to cost of the trial? Yeah. So the second half of 2025 is when we expect top-line results. We haven't guided further within that half as to when we can expect data. But right now, firmly on track to report top-line results in the second half of 2025. For the cost, maybe I'll hand it over to Richard. Yeah. Thanks, Reshma. No. I mean, Ed, overall, it's very marginal cost to the total cost of the trial, given that all our sites are open and moving forward, and it's a small number of patients. So marginal cost. And really, as Reshma talked to you and as we've heard from Dr. Rampal and Dr. Mascarenhas, it really helps to increase confidence with the trial as we move forward. Okay. Thanks for taking my question. Again, should you have a question, please press star followed by the number one on your touch tone phone. Yeah. I think, Operator, given the timing, I think we will wrap up. So, thank you to Dr. Rampal, Dr. Mascarenhas, and Reshma, and all of you again for joining today's call. And we're excited about today's news and what this could mean for patients. And we look forward to reporting our top-line data in the second half of 2025 and speaking with you again next week on Tuesday as we discuss our Q3 results. Have a great day, everyone. And thanks again for joining us. Ladies and gentlemen, this concludes today's conference call. We thank you for participating and ask that you please disconnect your lines.