Good morning. My name is Joelle and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics conference call to discuss today's phase III SENTRY presentation at ASCO. 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 now like to turn the call over to Brendan Strong, Senior Vice President, Investor Relations. All right. Good afternoon, everyone, thank you all for joining us on today's conference call to discuss the Phase III SENTRY trial of selinexor plus ruxolitinib in patients with myelofibrosis that was presented by Dr. John Mascarenhas in a late-breaking oral presentation at ASCO this morning. We issued a press release this morning with the highlights from our Phase III SENTRY results presented at ASCO. As part of this, we're delighted that the SENTRY results were simultaneously published this morning in the peer-reviewed Journal of Clinical Oncology. These important milestones demonstrate the importance and relevance of this data on the opportunity to improve outcomes for myelofibrosis patients with a combination of selinexor plus ruxolitinib. You can find the ASCO presentation plus the JCO paper in the Publications and Presentation section of our website. In addition, the slides that we'll be using during today's call are available in the Events and Presentation section of our website. For today's call, we are honored. We are absolutely honored to have Dr. John Mascarenhas, one of the world's leading experts in myelofibrosis and the principal investigator of our phase III SENTRY trial. Dr. Mascarenhas is 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. Mascarenhas just delivered the late-breaking oral presentation at ASCO this morning and will be discussing the importance of these results and the potential benefit to patients on our call today. I'm also joined by Richard, Reshma, Sohanya, and Lori. Before we begin our formal comments, I'll just remind you that various remarks we will make today constitute forward-looking statements for the 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 forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent Form 10-Q on file with the SEC and in other filings we may make in the future with the SEC. Any forward-looking statements represent our views as of today only. While we may elect to update these forward-looking statements 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 forward-looking statements as representing our views as of any later date. I'll now turn the call over to Reshma. Please turn to slide four. Thank you so much, Brendan. On behalf of all of Karyopharm, my name is Reshma Rangwala. I'm the chief medical officer at Karyopharm. I've been at Karyopharm for a little over four years, and I got to say, I think this is probably my most proud day in those four years. It's the day that we get the opportunity to present the very important phase III data from our SENTRY trial. This is the combination of selinexor plus ruxolitinib. Simultaneously, we had the opportunity to publish the data as part of JCO, and we just issued a press release in which we are also going to be presenting the data at EHA, picked as one of the top abstracts to be reported at that very important congress. This is a great day, not only for Karyopharm, of course, our physicians who are treating myelofibrosis, but most importantly, our patients who suffer from myelofibrosis. The SENTRY results really matter in myelofibrosis, just given where we are in the treatment landscape for myelofibrosis. For the past 15 years, these patients who are frontline myelofibrosis have been treated with JAK inhibitors. It started with ruxolitinib, arguably a very meaningful game changer for this patient population. With that said, I think we all appreciate there are limitations in not only ruxolitinib, but the other JAK inhibitors that have come subsequently, including pacritinib, momelotinib, as well as fedratinib. Why do I say that? I say that because the most important aspect of this patient's disease is their very large spleen. Right? We know the JAK inhibitors do reduce spleen size, but I would argue that it's relatively modest. The rates of patients who achieve that important SVR35 is still quite low, only approximately one-third or 30% of those patients. These mechanisms or these treatments, they are anti-inflammatory, and as an anti-inflammatory agent, class of agents, yes, they also improve symptoms. What's missing, though, is this meaningful improvement in overall survival. The SENTRY data, as Dr. Mascarenhas is going to take everybody through, really is that game changer. You see these very meaningful improvements in SVR35 as rapid as week 12, sustained all the way out to week 36. It occurs in conjunction with meaningful improvement in symptoms at week 24 relative to baseline. Importantly, probably most importantly, is this early promising signal in overall survival. This is a game changer for a patient population that needs to live longer beyond the median 4 to 5 years that are currently seen with the JAK inhibitors. We know that myelofibrosis is really characterized by proliferation of these malignant clones. Somatic mutations in stem cells lead to a clonal expansion of malignant progenitor cells, and these have a bunch of sequelae. This leads to bone marrow fibrosis, enlargement of the spleens, these symptoms that I just talked about, as well as ultimately leading to shorter survivals. Current treatments like the JAK inhibitors, including ruxolitinib, again, are anti-inflammatory. Yes, they do reduce spleen size to a certain degree. Yes, they do improve symptoms, we don't see meaningful disease modification. That disease modification is key if ultimately we want to develop new therapies that improve overall survival. Once a patient becomes refractory to JAK, unfortunately prognosis becomes even shorter. We need new therapies that introduce new mechanisms that can be combined with ruxolitinib, synergize with these therapies, and ultimately improve long-term outcomes. Lastly, I will say what we also need are new endpoints in myelofibrosis. Yes, traditionally we see SVR35, we see TSS or an improvement in their symptom scores. We need to look beyond these endpoints at overall survival, other endpoints that can show the benefit. One of the benefits of this trial and unique aspects of this trial is the prospective identification of SVR's ability to predict overall survival. These data build upon published literature that have also demonstrated the same correlations. Specifically, patients who achieve an SVR35 may have longer overall survivals as compared to those patients who do not. Karyopharm has been committed to myelofibrosis for over seven years. We have built a foundation of data, including pre-clinical, non-clinical work, clinical data through our phase I, now through phase III data, translational work. Of course, continuing to monitor the safety not only in myelofibrosis but in other disease types. This is only the beginning for us at Karyopharm. Yes, this is an important combination, selinexor, I do believe, has this potential to become a backbone therapy. We have that opportunity to look at other combinations that are relevant in myelofibrosis and potentially other patient populations, not only in myelofibrosis, in other MPNs as well. With that said, I want to turn it over to Dr. John Mascarenhas. Reshma, thank you very much. Thanks for inviting me here to today's event. I'm John Mascarenhas, we're going to review the results that we just presented for the SENTRY phase III study of selinexor plus rux in JAK-inhibitor-naive patients. I try to make this point very clear. I think the key takeaways are summarized very nicely here. To me, it's very obvious that the combination of selinexor and ruxolitinib induce a very rapid, deep, and sustained spleen volume reduction. I think that's probably the crux of why we see this benefit in MF. This was consistent against all subgroups, and that will probably play into discussions about who would get the drug and how it would be utilized. It was clear symptom improvement, and that was comparable to what we see with ruxolitinib. I think it's unreasonable to expect better symptom improvement beyond what we get with ruxolitinib, and multiple trials have shown us that that's the case. The combination of seli and rux improves symptoms to the same degree as rux would. You don't compromise symptom benefit. Number 3 is we did see this overall signal for survival within 11 to 12 month follow-up that correlates with spleen volume reduction, which was more frequent and deeper with the combination. That to me fit very nicely. To tie in at a molecular level that there's this disease modification, a biomarker that the field concentrates on that has been shown when reduced in MPNs to be associated with outcomes like OS, is the reduction in driver VAF, which was seen to a greater degree, a greater frequency with the combination than single agent. The safety profile, I think, emphasizes that with the right amount of optimization of antiemetics, I think just combining the drug actually with ruxolitinib offsets toxicity, and it's very manageable. You can see patients through the treatment to induce that spleen response, which ultimately correlates with improved outcomes. I do think this represents an opportunity to use selinexor with Rux as a novel treatment approach, as a combination therapy approach for patients with JAK inhibitor-naive myelofibrosis. If you ask me why is this drug interesting and mechanistically why, I'm very interested in translational science, there are probably three pathways that are most relevantly impacted by inhibiting XPO1, which is a shuttling mechanism between the nucleus and the cytoplasm, which is what selinexor does. As a consequence, you are upregulating p53. You're turning on p53. It's been well described with other therapies and pre-clinical modeling that p53 is suppressed in MF and MF CD34 cells. That's the point I want to really make, is that the reason why I think that this is an active drug is because it's anti-clonal, and a lot of that is based on these mechanisms that you target and induce apoptosis and cell cycle arrest if you can turn on p53 in that hematopoietic stem and progenitor cell population. That's been shown pre-clinically, selinexor does execute that, as well as reducing c-MYC and NF-kappa B. NF-kappa B particularly is a pathway of interest and multiple therapies have hinged on reducing NF-kappa B regulated gene sets that contribute to inflammatory cytokine expression. We know, Andrew Kuykendall, who was the discussant for today, he nicely pointed out that this is a hematologic malignancy, but it's an inflammatory disease. What you want to do is you want a therapy that is anti-clonal and at the same time is reducing the inflammatory cues that help promote the disease, sustain the clone, and prime the microenvironment for continued disease. What selinexor does is it really hits these three key clinical pathways, and nicely complements with ruxolitinib in order to synergize with ruxolitinib. I say ruxolitinib because that's the way the drug was studied, the trial was designed, but I actually think this would combine nicely with other JAK inhibitors, and we're going to explore that as well. Today's topic is SENTRY upfront treatment based on preclinical rationale, a phase I study that got a lot of attention within the field based on very significant spleen responses and symptom improvement that inspired the SENTRY phase III study, which is this randomized phase III study, global 20 countries, many investigators, many committed people that saw this through, that enrolled intermediate one risk or higher primary or post-ET/PV MF patients with at least a platelet count of 100,000 and measurable spleen and symptom burden. Patients were randomized in a 2:1 fashion to seli 60 mg once a week, not a high dose of selinexor, and that was determined by the phase I study with 40 and 60 mg. With an intentional dual antiemetic prophylactic regimen for the first two months that significantly reduces the incidence and severity of nausea and makes this combination quite tolerable and quite manageable, I think that's another important point when thinking about this combination. ruxolitinib was dosed by platelet count and the placebo was the control arm with rux. The co-primary endpoints were SVR35 at week 24, pretty standard endpoint, and then absolute change in TSS from baseline at week 24. If you're wondering why that instead of the binary TSS 50, I think it's a more sensitive way of gauging symptom improvement and discerning benefit, particularly in this setting. Key secondary endpoints that we'll describe are overall survival, safety, and VAF reduction. Here's the disposition as of February of this year. You can see the number of patients in a two-to-one fashion that were randomized to the experimental arm, 36% and 35% of patients had discontinued treatment. You can see the reasons why discontinuation is here. Now, this is captured by electronic Case Report Forms, and if you look at the reasons why the site was putting in for discontinuation, I think I'll point out something quite important, which is 9% and 8.6% of patients discontinued for adverse events. If there's concerns about toxicity, that was not a major driver with the combination for discontinuation. Also importantly, the rate of leukemic transformation, which has been a concern in this patient population, which is part of the natural history of the disease, was low, 1.7% and equal between the two arms. I'd like to make the point that there's the ability to maintain the dose intensity of selinexor. Again, I would say that speaks to tolerability and manageability. 51.7 median weekly dose of selinexor. I think maintaining that is pretty key to its efficacy. I think what's really interesting and maybe subtle is the fact that the median daily dose of rux was 23 versus 29, suggesting that you may not need the full dose of ruxolitinib to garner the actual benefit here, that seli is probably driving a very significant proportion of it. Now, I would even argue that the JAK inhibitors might just really be potentiating the effect of the partner like selinexor. You can see the median follow-up below. There's a lot of information on this slide, as there normally is with baseline characteristics in a very large, just to rare disease, very large study, very robust study over multiple countries. This is a really good, I think, sample of what it looks like to have MF and enroll and be treated with a combination therapy. These are going to be more primary myelofibrosis, that's more prevalent than post-ET/PV, so that makes sense. The intermediate one risk, we saw that with COMFORT. These are the patients that are out there. These are the patients we treat, so that would make sense. JAK2 V617F is more prevalent than CALR and MPL, so that it's enriched for those patients. You see representation of all the driver mutations. Then you see the spleen volume and TSS scores, which are comparable to what you've seen in other studies. I would say from my own practice, these are what you would see if patients are presenting in need of treatment that would normally get, let's say, commercial single-agent JAK inhibitor. This was all in line with, and across different continents, all in line with what you would see with treatment of this patient population. The primary endpoint is shown nicely here. Nearly 50% of patients in the combination arm met SVR35 at 24 weeks versus 28%. Clearly statistically significant with a P value with three zeros before the one. On the right, you can see the waterfall plots and each column is an individual patient. The aqua makes the nice accent of the further depth in spleen response that we're seeing with the addition of selinexor. It follows throughout the entire waterfall plot. It's not just some of the patients. You really see significant reduction beyond what you would see with ruxolitinib. I can say anecdotally, when treating patients, it's pretty obvious too, because the rapidity in which the spleen goes down and the depth is pretty remarkable, and patients can notice it. They will tell you that the spleen, they can feel their own spleens, they will tell you, "My spleen feels smaller. I can bend over more easily. I can move more easily." It's freeing, actually. They'll remark on that pretty quickly. It does happen pretty quickly, which is this slide. By week 12, you can already see that these two curves diverge. This slide is pretty key, I think, to understanding the kinetics and maybe why selinexor has this differentiating capacity here in this upfront setting. You get this rapid reduction in SVR, and that it's deepened over time and sustained. You don't lose it. It's rapid, it's deep, and it's durable. On the other side, you can see the SVR35 rates between the two arms compared at week 12, week 24, week 36. At any time, the odds ratio is 2.59 of hitting SVR35, which favors the combination. It clearly is not doing it one snapshot. It's quickly and sustained through the follow-up. There's not one subgroup that drives it, so it was really consistent across the subgroups, pre-specified subgroups that were looked at in the study. I think this table specifically speaks to a question that comes up, which is if the drug was available, who would you use it in? This plot would suggest you could use it in everyone who's JAK inhibitor naive. There's not one particular group that you would target that this could work across patient subtypes, which is important as we think about our patients that could benefit from combination therapy. This is a really interesting slide that I think caught a lot of attention from those on the steering committee and physicians who treat patients with myelofibrosis that are interested in this space. What we're looking at here is SVR35 at week 24 rates between the two arms broken down by the dose of ruxolitinib. What I want you to focus on is the fact that here, when we're looking at low doses of ruxolitinib, you do not expect, I don't expect because I don't see it, you don't really expect to see spleen responses. Spleen responses are not just important, which I'm going to show you to hit a regulatory endpoint. I think they're important for the patient. I'm going to show you why in a second. You can see that with the control arm, you're not hitting SVR35, yet you do hit it when you add selinexor to it. Even at low doses where the expectation and the reality is you don't hit SVR35 at week 24, you're seeing it with selinexor. Of course, that's probably not surprising because we know selinexor has single-agent activity. It's been shown previously. It really makes a point that this is not a rux-driven event, that this is a combination event and doesn't even require the full dose of ruxolitinib. In fact, the SVR rates if you look across, remain consistent across the doses of ruxolitinib, which is, again, from my perspective as a physician treating these patients and thinking about the implementation of a combination therapy in the community setting too, it makes it kind of easy to think about. You don't need to be worrying about what dose of Rux you're on. You just get them on a dose of ruxolitinib. You could even dial back the dose of ruxolitinib. It allows a little bit of freedom and ease of mind that you can still achieve your goal without concentrating, worrying on maximizing the dose of ruxolitinib, which has been what has been ingrained in the way we treat MF, which is dose up and try to maximize dose of Rux. This would suggest not necessary when you have an active combination partner in play. This is the second co-primary endpoint of absolute change in TSS, week 0 to week 24. At first glance, you say, "Oh, negative, because it's not superior." I would say positive because you improve symptomatology, and that's all that matters. I'm not looking to improve symptoms beyond what ruxolitinib can do as a single agent because I fundamentally don't believe you can. Every trial we do shows that you cannot. Even the FDA, I think, realizes that probably doesn't really make sense anymore. This graph demonstrates that you don't compromise symptom improvement, which is obviously important to treating patients, and it's comparable to giving single-agent ruxolitinib. You still improve symptoms when you give the combination of seli and Rux, and this is also true across symptom domains. This becomes an important slide, and I'll go back to the SVR part in a second. There was a survival signal, albeit early on, that's driven mainly by disease progression, adverse events in the control arm. You see this with a median follow-up of 11.6 and 12.6 months in the two arms with a hazard ratio of 0.43. This is really the first time we're seeing an outcome like this in a prospective study. You might ask yourself, or we asked ourselves, "Well, what does this relate to?" This graph, I think, really becomes important. As I said at the talk, I actually think it becomes important even beyond this room and this discussion today. For the field, it becomes important because it's the first time prospectively in a well-designed trial that faithfully follow these patients out, that if you hit an SVR35, irrespective of treatment arm, at week 24, you're more likely to have a survival benefit. To some extent, this is not new news. I think many of us in the field believe this to be true, and other analysis that have been done with COMFORT studies and real-world studies have all suggested this, but prospectively, we're showing it here, that SVR35 at week 24 associates with survival benefit, which again, I'm trying to tell a story that you get more SVR35 with the combination. You get it faster and deeper and sustained without the need for dialing up rux to achieve it. Additionally, we like to think of other biomarkers of disease response. Of course, the VAF reduction, which is the driver mutations JAK2, MPL, and CALR are considered important biomarkers of disease modification, modulation as they represent the disease burden. It may be the different way, but complementary to spleen volume reduction. I will point out something that we rarely say at meetings, but maybe it's worth pointing out, is that the disease in large part sits in the spleen. If you reduce the spleen, you're reducing the burden of disease. To me, that's not a very difficult concept to understand. It should track with, and you would expect to see reductions in disease burden by other measures. Here you go. You see it already at six months, 32% of the patients on the combination had a VAF reduction of 20% or greater versus 24% with single-agent rux. It's only at six months. It's still early on. That reduction was associated, as you can see on the right, with spleen volume reduction, which is what you would expect to see. It's a nice, I think, way of tying it all in. This was an analysis that I think also speaks to the fact that there's probably multiple aspects of selinexor that are affecting multiple aspects of the disease and peripheral blood blasts are another one. Blasts are immature cells. They are the leukemic component of a chronic disease. We know from prognostic scoring systems that even having 1% blasts present in the peripheral blood is an independent adverse prognostic marker for survival. It would follow that if you could reduce the presence of circulating blasts as an indirect measurement of disease control. That's what we're showing on the left with the combination in blue. Less patients had circulating blasts at those given time points, whereas the control arm in orange, you can see is not the same. On the right, even perhaps more interestingly, you see a suppression of the presence of blasts with the combination, whereas you can see that that's not true. That's the natural history, I would say, of the disease on ruxolitinib. Ruxolitinib is a great drug. I'm proud to have been part of the COMFORT effort. At the end of the day, it's not a blast-clearing drug. It's not modulating the disease at the core. I think this is just another example of disease modulation. Safety. Again, I think if you think back about the earlier slide about how the eCRFs were picked up for reasons for discontinuation, and there was really no difference in the way that the teams were assessing the reason for discontinuation from the study. I think talking about tolerability, in fact, we can maintain the dose intensity with selinexor. If you look at treatment-emergent adverse events, although they were more frequent, Grade 3 or 4, which we expected and is consistent with the profile of selinexor, serious TEAEs were the same between the two. I think that's important because that's what drives a lot of tolerability issues and discontinuation. Ultimately, we didn't have a lot of deaths, less deaths actually in the combination arm than the placebo arm. I think this all speaks to the fact that it is a manageable. You have to know what you're doing, prophylax the patient, and this study knew what they were doing. I also think that there's an element of when you give a JAK inhibitor and you downregulate inflammation, it often makes partners look better, that people tend to feel better and tolerate things better. To me, this made absolute sense. Here's the butterfly plot showing the toxicities compared to each other. Again, as you would expect, some more myelosuppression, but we deal with myelosuppression in hematology offices, including thrombocytopenia and neutropenia. There was not a significant signal of bleeding and infection that followed, so that's important. Anemia was not worse. It was the same. That's also important. Maybe more important, so anemia and transfusion dependence are known adverse prognostic markers. You do not worsen it with the addition of selinexor. Otherwise, it's as advertised. It's what you would expect, and it's what we've come to expect, and it's manageable. Again, the transformation rate remains low, 1.7%. That is not a concern. In conclusion, I hope I've made clear or obvious to you that selinexor and rux in this randomized phase III global study nicely showed that you beat out single-agent rux from a spleen reduction perspective, both in its rapidity, depth, and durability, and that you get a mean change in symptom score, which is important to patients, but it's not the end-all be-all. That mimics what you see with ruxolitinib. You're not compromising that. Maybe most intriguingly and most, I think, excitingly, you see the survival benefit. That's already obvious at this point. We'll have to follow it out for more events to make sure that it continues in that direction. The fact that SVR35 correlates with the survival benefit is not just important for this story but important for the field. Following suit that the higher rates of VAF reduction, again, speak to the idea of disease modification and a safety profile and toxicity chart that I showed you, also consistent with the known profiles of both agents. I think this does represent a novel treatment strategy for JAK inhibitor-naive myelofibrosis patients. As you're probably aware, the full manuscript with the details of the study that I can't provide with you right now are available at JCO right now, which is really exciting to have that published simultaneously. I think the fact that it's published simultaneously, the fact that this got late-breaking abstract, the fact that it's a late-breaking abstract at EHA also, I think, points to the fact that the hematology community recognizes the unmet need and the value here. I would argue that that's what's trying to be addressed here is unmet need. We've been doing the same thing for a long time. Single-agent JAK inhibitors, you serially change them. I think like most of oncology, where you need to move to combination to get deeper, more meaningful responses is what we're looking for. Obviously, the committees that select these abstracts recognize the importance of that as well. I keep going, right? You're right. Wait, no, I'm not done. I'm not done. Well, there's. Hold on. I actually made this a long time ago, or a version of this, but this is a schema of what it could look like out there in the real-world setting outside of a clinical trial where you have lower risk. If you break it up into lower risk MF, that's low risk and intermediate 1, higher risk means intermediate 2 and high risk. I will point out something I think is important, particularly if people are trying to understand and wrap their heads around this. These risk scores, we don't treat patients based on these risk scores. I've never met a patient where like, "I'm going to treat you because you're low risk for treat." It's not how. You treat patients based on need, the need for treatment, their symptoms, their spleen. You want to reduce spleen, you want to control disease. To me, supersedes risk, just to point out, and something that's not always obvious. If you have a lower risk patient, and those are like the intermediate 1, almost 60% of the patients who are symptomatic, and they're coming to you, and I see them all the time. Just because you're intermediate 1 doesn't mean you're not at high risk for having symptoms and spleen burden and in need of treatment. I think we have that star there, that selinexor and ruxolitinib could be a consideration and an option for those patients, beyond what is already listed in the NCCN as a treatment option. I started there to say, well, that's what the study would tell us, right? If you go by evidence-based medicine, that's where seline rux would make sense. On the other side, in the high-risk patients with platelets greater than 50,000, again, selinexor and rux starred there as a combination up front. I would also argue, and this came up in the discussion today, one obvious need, transplant remains the only curative option we have for these patients. We want to get them to transplant, particularly if we have a patient who's earmarked, but you want to optimize them for transplant. Part of optimization, transplanters want their patients to have smaller spleens. The outcomes are better. The engraftment is more robust. It is a prerequisite of sorts to get into the door for a transplant. Well, if you want to optimize that as best, and particularly in the most rapid fashion possible, then you would probably go with your biggest guns up front, and that would be combination therapy. The obvious thing to me, too, would be if you have a patient where their goal is transplant and the transplanter's on board, that's an obvious indication that I would want to use your two strongest agents in combination up front and synergize together. One could see the combo being used across these places. What I don't have here, because this makes it all seem like it's upfront treatment. Upfront treatment's obvious. That's what the trial tells. I will say that I don't know why one wouldn't make the argument that if you have someone on rux, which those are patients who are sitting on rux, maybe not optimized, you would add seline to the rux. Upfront, but also add-on strategy for those patients who are already on rux, maybe who ease into rux, whatever the case may be. I'll also go as far as saying, not Karyopharm, I would go as far as saying, if I had a patient who was on momelotinib or another JAK inhibitor, I don't think that I would not give them the opportunity for selinexor, and I wouldn't switch them to rux to put them on selinexor. I probably would just add selinexor to that JAK inhibitor backbone. That's my own editorial, but this is one way one can envision what the NCCN guidelines could look like and the places which seline could end up if it was incorporated and integrated. We need more applause. Yes. Thank you, Dr. Mascarenhas. Dr. Mascarenhas will come back to join us for Q&A right away. I think as you heard from Dr. Mascarenhas and from Reshma, there's significant unmet need in myelofibrosis. With the data we now have with SENTRY, we see the opportunity for selinexor to really transform the frontline myelofibrosis landscape, potentially become a backbone for myelofibrosis treatment across many lines of therapy and with potentially many partners. Right now, the focus is with selinexor and ruxolitinib. As you know, our focus is to say, how do we rapidly bring this to patients as rapidly as possible. Significant unmet need. We have the capabilities in place. We have the capabilities in place with a very strong global medical and scientific affairs organization, which is there to help educate, work together with physicians, make them aware of the data, and help to ensure that they're informed about the opportunities to advance treatments for their patients. Pending commercialization, we also have the commercial capabilities in place to help ensure we can, again, rapidly bring these to patients across the community. I think as you heard from Dr. Mascarenhas, the ability, given the flexibility and given the ability of selinexor to work across all the different dosages we see with ruxolitinib, makes this an ideal opportunity across the community. Again, you look in the community, that's where the majority of patients are. 70% of patients are in the community, treated across large community centers, so very focused community center group, and as well in the key academic institutions, where we see, again, a very focused group of physicians where we can rapidly engage and provide the opportunity for patients to benefit from selinexor plus ruxolitinib. If you look overall at the opportunity, we know the myelofibrosis marketplace is a multi-billion dollar marketplace. Again, not disagreeing with Dr. Mascarenhas, but what we're focused on upfront is the newly diagnosed patients, where we know there's about 7,000 newly diagnosed patients per year. That intermediate to high-risk patient population really brings us with a target patient population per year of about 4,000 patients. Again, for us as an organization, we're very excited. We're committed to continue to move forward and to really ensure we can help make selinexor a foundational therapy in myelofibrosis to benefit patients with myelofibrosis. The data, as we've heard, really supports selinexor's role across myelofibrosis. There's a high unmet need. We're engaged with the FDA and with global regulatory agencies with regards to our data and filing plans. The team, and our partners, and Dr. Mascarenhas are delivering at breakneck speed because of the need for patients. Late-breaking oral presentation we just heard at ASCO, a simultaneous publication with JCO, late-breaking, one of the best oral presentations at EHA, as it's been voted on, and then working towards potential compendia inclusion here in the second half of 2026. Before we start our Q&A, I'd also like to thank Dr. Mascarenhas really for his leadership in this study, for sharing his perspective, and for sharing the data and what this means in terms of a really important advance in myelofibrosis for the myelofibrosis community, and the fact that this is an opportunity that should be available to patients, to physicians, and to caregivers to see the benefits of myelofibrosis. I also want to really recognize and thank the patients, the families, the caregivers, the investigators, the broader clinical trial teams. It's a village to make a trial like this come to light, and all of our Karyopharm employees together to make this study possible. Deeply grateful for their commitment as we advance treatment options for patients with myelofibrosis. With that, let's go to the Q&A. Maybe I'll ask Reshma and Dr. Mascarenhas to come join me here. We see the hands. Brian, first we're going to start here in the room. Brian? Thank you. It's a three-part question, John, and that's for Mascarenhas. Three-part, Brian, you're challenging me here. I know there was a lot of discussion at the presentation about whether the rates of deaths seem to be higher in the rux alone control arm than one might expect. I guess my questions are, A, do you believe that's true, and if so, why would you hypothesize that's the case? B, can you tell us anything about the risk level of the patients who do progress and die? C, what more would you want to see from the overall survival curves? Like if the death rate evens out across the two arms, does that make you comfortable that this is a real treatment effect, or would you need to see deaths continue to separate over time to be perfectly comfortable that there wasn't some kind of fluke of events that occurred? We just have this microphone working, so I'll probably just summarize the question a little bit, Brian. I think maybe for you, Dr. Mascarenhas, to go a little bit more into the OS. Are the rates higher than expected? Risk levels of patients, what are the other patient bucket? What more would you like to see from an OS perspective? To answer that question about the rates of death. I just want to keep pointing out what I've pointed out previously, is that the data is the data. We have this data here, so we can try to pull it apart, which I appreciate is the tendency. I do think that probably what you're seeing is if I had to guess where you would see the separation of curves, if you don't have good disease control, like if rux is inefficient or insufficient in controlling the disease in a patient who's got a big spleen and symptom burden, then the tendency is to try to get them to transplant. It's also unfortunately going to be a high likelihood of poor outcome if patients are that sick, not responding, and then have to get rushed off to transplant, and then the transplant-related mortality can be high. Some of it may just be a function of not controlling the disease, and I think that that's kind of in line with what we see. I think we have to be careful, and to get to your other question about who's driving those deaths, whether they're the high-risk patients or the intermediate one. I don't know. Reshma's looked at this data more finely than I. I don't think that there was clearly a risk group that was defining the disease. I think that's also a function of if you think about what defines or what constitutes a risk group, interestingly, spleen doesn't fit into that risk group, so into that definition or that criteria for it. Even frankly, symptoms don't exactly fit into it either. You can have symptomatic patients with a big spleen, and they're scoring because they're younger and their score is intermediate 1, but they functionally are sick patients that it's incomplete. I think we have to be a little bit careful with saying, "Oh, how do we explain these curves? It's enriched for intermediate 1 patient." I think it's enriched for patients who were ill who got onto the trial. We just called them intermediate 1, but they clearly had to have a disease burden that warranted treatment. I think that's the important point. I think that those curves are those curves and probably can be explained by what happens to the patients because they're not responding well to single-agent rux, and they're going on to other therapies, and those are the outcomes that we see. I don't really think it really is that different from what we would expect. I would love to see the curves keep going. I think that probably even the curves like this, if they stay like this, still tell us something important, which is if you intervene, and maybe the answer is you intervene early and intently and deeply, then you make a quick impact on the disease process. We've had discussions as small groups, like we do that sort of MF is a chronic leukemia. We never really call it that way. We call it a neoplasm, which denotes it, but it's really a chronic leukemia. It's an inflammatory leukemia. In other leukemias, we don't really tickle the leukemia. We kind of go in strong and try to induce a response early on because we know if you delay or if you half-ass it, you really don't get that benefit, and the outcomes usually suffer. It doesn't seem like outside of the expectation of treating blood cancers that something, if you have an approach that's intense and more effective at controlling that clone, you're probably just going to have a better outcome. To me, that makes sense. Again, I think particularly the fact that the SVR35 in this prospective dataset associates with the survival ties that in nicely. The driver VAF, it all just follows suit. To me, I'm biased because I'm involved in the program, and in looking at this, it makes sense to me. I feel like if I think about patients I see, it's a course or an outcome that would make sense to me. I don't know if that answers this. This is from Claire Rogers. I just want to ask about the PFS hazard ratio in the JCO. It was 0.97 compared to the OS hazard ratio, that big% was 4.3. I'm just wondering what drives the difference. Yeah. I think we'll turn to Dr. Mascarenhas again. Albert asked a question more about the PFS hazard ratio, the OS hazard ratio. I think it's probably as simple as survival is obvious. It's binary. Either you're alive or you're dead, whereas progression is a little bit more vague. You could try to define progression as spleen increase, leukemic transformation, progression is also a lot of other things that we don't always understand, like progression of cytopenias, progression of symptomatology, and it's defined different ways in different studies, and it's not consistent across studies. What makes MF complicated is MF is not a monogenic disease. It doesn't have CRs that we induce. It's a molecularly and biologically very complicated disease that corrupts the microenvironment of the bone marrow. You have displaced myelopoiesis that's malignant in nature in the spleen, the patients are really complicated. No two patients look alike. They're very heterogeneous and very variable. Even trying to gauge responses or the concept of progression is really challenging across patients. I think it's a very vague, blurry, ill-defined endpoint, where survival is not. I think that's why survival is easy to make that determination. We'll often say, "I'd rather be on the survival curve than the progression curve." If you're surviving, that's what obviously matters the most. I think this is a question for Dr. Mascarenhas. I know you showed the huge curves of the SVR35, but what about VAF? Again, VAF reduction, if that's the driver allele, that the relative magnitude of that reduction would be also an outcome. Can you talk about that? Yeah. The next question is from Michael. Beautiful SVR35 curves according to Michael, which we love. VAF, a driver, and kind of your view on that and the difference we see. Yeah. The driver VAF, many of us have looked at as a surrogate for disease burden, too. I think if I think about datasets where that really seems to ring true, it would be, for example, in PV, because it's a JAK2 V617F-driven disease. You can kind of use it pretty reliably there. We've got prospective data from two independent studies, one with ropeginterferon, one with ruxolitinib, demonstrating that if you reduce that VAF within a year of treatment. In those studies, they use different cutoffs, but 50% if it's under a certain amount, 25% over. It associates with outcomes like event-free survival and overall survival. There is data out there that ties in that marker as a disease burden marker. It is, I think, notable that in the combination you see a more frequent, 20% or greater decline in the VAF. That's an incomplete picture because there's still more analysis that we'll go into looking at the subclonal mutations. I think that's a first nice look at an early time point that there's a difference in those outcome measures, and that the reduction in the VAF associates with the reduction in spleen volume. It ties in a story that is circular in the sense like you are reducing the spleen. As I said before, the spleen is a reservoir for the malignant cell population, and I would think that the VAF should go down as a reflection. I guess the question is whether you thought prospectively there would've been a tighter correlation between the VAF and the SVR? Odds ratio was three. Patients who achieved that greater than 20% had three times likelihood of achieving SVR rates as compared to those patients who don't. Yeah, I would argue it's a nice correlation. Yeah. I thought it correlates pretty nicely. Brian. You talked a lot about the lower rux dose intensity and association or sparing effect. Can you talk about the implications of that in real-world practice? Maybe the company can pitch in as well on this. Are there certain types of physicians, like community docs, who maybe just are not comfortable using full rux doses, and so their patients are not getting the full benefit? I guess, what does that mean with regards to where Celie could fit in, just this rux sparing effect? Yeah, I think the question, which I'll turn to Dr. Mascarenhas on for sure, because he's the one who treats patients. Lower rux dose intensity and what that really means from a practice implication, whether it be in the academic or the community, and maybe specifically more in the community setting. Dr. Mascarenhas. We've actually done and published real-world database, claims-based database, where you can see that the doses of rux that are used in the community are far below the active doses that were explored, like in the COMFORT sizes, 15 and 20 mg based on platelet count. For a long time, we were of the mindset that really to optimize a patient on a JAK inhibitor, you have to maximize the dose. That was the mantra. It was based off the COMFORT studies. You look at these claims from TriNetX and other groups, and it's like two-thirds of the patients are on doses of 10 mg twice a day or less. Those are suboptimal doses. Clinical trial doses are suboptimal doses. It really becomes interesting when you think about the SVR part. We know, and we have a beautiful graph from one of our analysis from the COMFORT studies, that SVR is a dose-dependent phenomenon. You have to dose up to hit that SVR. If you compromise the dose, you attenuate the SVR with rux. You want to optimize your dose of rux. In the community, that's not happening. It's not even the community. I don't even think in academia that really happens. I think it doesn't happen across the board. What is attractive here is it doesn't matter. You can have a patient on a suboptimal dose of rux. You don't minimize or compromise that SVR outcome. To me, that's very attractive. You just add cellie to whatever dose they start with, or even if they dose reduce, no big deal. You keep them on that dose, you keep hitting them with the cellie every week, and you're going to get them to where they need to be. If there aren't any other questions in the room right now. Go ahead, Mike. No, no. I just wondered, John, for the rest of 830, quantification of that are on rux now that are having suboptimal? The question is, in real world quantification. I think, yeah. Defining suboptimal is also a little bit tricky, I will admit that, in the sense, you have to know what the patient was like before they started rux to know what they were on rux. Sure. We just keep on getting symptoms. I mean. Yeah. Ultimately, by two and a half years, 50% of patients are off rux. By five years, 85% of patients are off rux. Rux is a great drug, but it doesn't take you the distance. A lot of that is driven by inadequate response, progression of spleen, regressive symptoms. You're not controlling the clone well enough. To try to answer your question, everyone becomes suboptimal at some point in their clinical course. If you would ask me a question of what do we anticipate if we started 100 people on rux at 18, 24 weeks, somewhere around probably 40% of patients alone will be suboptimal. That's if you treat them the right way. It's probably even higher out in real world if you're suboptimally treating them. All right. We're happy to come back and take questions in the room. I know there's some questions on the line as well. Joelle, if you can open up the call for questions. Thank you. Ladies and gentlemen, we will now begin the question and answer session. Should you have a question, please press star 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 star two. If you're using a speakerphone, please lift the handset before pressing any keys. We request that our callers limit their questions to one main question and one follow-up. Your first question comes from Maury Raycroft with Jefferies. Your line is now open. Hi. Congrats on the updates and thanks for taking my questions and hosting this. For the OS data, I wanted to follow up on that. Wondering what's the ideal follow-up time to have a more de-risked view on OS, and how do you expect the OS to be viewed by the FDA, and are there any specifics they have defined around the OS parameters for what they would want to see? Thanks, Maury. This is Reshma. I can take that question. I think one of the advantages of the SENTRY trial is that it continues to follow overall survival. Patients and physicians remain blinded to the arm to which they are randomized. As the study continues, as we observe additional OS events, of course, we have that opportunity at a future later date to update not only the overall survival, which is important, but other markers of disease modification, including VAF and other areas. We haven't defined at this point when we want to do that next OS evaluation. I think importantly is that it's got to be a meaningful update, right? This is a patient population in which events can occur over a course of a few years. We really want to look at it prospectively, define a meaningful number of events so that when we do update the OS, people can interpret it quite robustly. Actively engaging with the FDA, really productive conversations. We have not gone into details about what they want from the OS perspective. Hopefully, we'll have more clarity that we can share with you in the next one to two quarters. Got it. Okay. Thanks for taking my questions. Ladies and gentlemen, as a reminder, should you have a question, please press star one. Your next question comes from Yanni Souroutzidis with Cantor Fitzgerald. Your line is now open. That was pretty good. Wish I could be there. Congrats on the data today. I had two quick ones. I guess one, the shorter one. For the folks that were on that zero to 15 mg of rux per day, I don't know if you can provide any color on how many were closer to that zero mark. If that at all, in your mind, provides a bit of read-through for what we might see for SENTRY-2. Hi, Yanni. This is Reshma again. Yeah, great question. I will say the vast majority of those patients were in that 10 to 15 mg. Now keep in mind, this is average daily dose, right? So they were on the higher end of the spectrum. I don't have the exact breakdown, something I can certainly look into. I think regardless of where within that 0 -1 5 they landed, I'll go back to what Dr. Mascarenhas mentioned. These are suboptimal doses of ruxolitinib, right? Regardless of whether you're on five or closer to 15, these kinds of doses of ruxolitinib just do not optimally provide spleen volume response or adequate symptom improvement. Yeah, and I think that's the key takeaway is that despite being on these low doses of rux, right, that SVR35 for the combination still remains very high, very meaningful at 50%. Maybe I would also add just the way I would think of it too is, I showed the graph of SVR rates based on the platelet count or the rux dose rather. The way I interpret that is that selinexor becomes sort of the great equalizer. It's across rux doses that you can optimize your spleen reduction. It almost doesn't matter to some extent. It's probably not the main driver of the benefit, is the way I would look at it. It's selinexor driven, rux supported. You don't need the full dose of rux. It kind of makes it nice because rux is dosed at different, it's not one dose fits all. You can have different doses. It allows for a constant presence of selinexor across those doses of rux, and you're still going to get that benefit. It makes it almost easier to deliver in that way because you don't have to think about dosing of rux. Got it. Your second question, Yanni? We just have Yeah, go ahead. I guess still relatedly on this topic. From the protocol, I remember that the general guidance was for GI-related events, selinexor gets dosed down for non-GI, ruxolitinib does. I guess here, for the lower categories on ruxolitinib exposure, it seems very skewed to the combination arm. I guess, could any color be given on in terms of why? Is that just some of the general increases we saw on the heme tox side of things, or was there anything else driving that trend? Go ahead, Reshma. This is Reshma. No, the majority of the ruxolitinib is still going to be driven by the heme tox. With that said, the protocol also allows dose reductions across both drugs. If you modify, let's say, nausea with the selinexor, it's still maintained. They may also reduce the ruxolitinib, too. I think you've got a double whammy, so to speak, for the ruxolitinib. It's going to be the primary driver for the hematologic toxicity, but you can also modify for the non-heme tox as well. Got it. Okay. Okay, thank you. Thanks, Yanni. We're just right up on time. I want to thank, again, Dr. Mascarenhas for an amazing presentation twice today now that he's delivered it, and being available for Q&A, and again, just your unwavering commitment to working incredibly hard to advance treatment and potential for patients with myelofibrosis. Thank you very much, and thank you for joining us today. Ladies and gentlemen, this concludes your conference call for today. We thank you for participating and ask that you please disconnect your lines.