Karyopharm Therapeutics Inc. ($KPTI)

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. [Operator Instructions] 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, and 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 the combination of selinexor plus ruxolitinib. You can find the ASCO presentation plus the JCO paper in the Publications and Presentations section of our website. In addition, the slides that we'll be using during today's call are available in the Events and Presentations 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 -- excuse me, 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, Sohani and Lori. And then 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 2. 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 4.

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 4 years. And I got to say, I think this is probably my most proud day in those 4 years. It's the day that we get the opportunity to present, sorry, 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 were 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. But 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 1/3 or 30% of those patients. These diseases are -- these mechanisms, I should say, or these treatments, they are antiinflammatory. And as an antiinflammatory 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. And importantly, probably most importantly, is this early signal, 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 a proliferation of these malignant clones. Somatic mutations in stem cells lead to a clonal expansion of malignant progenitor cells. These have a bunch of sequela. This leads to bone marrow fibrosis, enlargement of the spleen, the symptoms that I just talked about as well as ultimately leading to shorter survivals. Current treatments like the JAK inhibitors, including ruxolitinib, again, are antiinflammatory. Yes, they do reduce spleen size to a certain degree, yes, they do improve symptoms, but 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, synergized 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 correlation, specifically patients who achieve an SVR35 may have longer overall survival as compared to those patients who do not. Karyopharm has been committed to myelofibrosis for over 7 years. We have built a foundation of data, including preclinical, nonclinical work, clinical data through our Phase I now through to Phase III data translational work and then, 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 but selinexor, I do believe has this potential to become a backbone therapy. We have the opportunity to look at other combinations that are relevant in myelofibrosis and potentially other patient populations, not only in myelofibrosis, but in other MPNs as well. With that said, I want to turn it over to Dr. John Mascarenhas.

Okay. Reshma, thank you very much. And thanks for inviting me here to today's event. I am John Mascarenhas, and we're going to review the results that we just presented for the SENTRY Phase III study of selinexor plus ruxolitinib in JAK inhibitor naive patients. I have tried 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. And this was consistent against all subgroups, and that will probably play into discussions about who would get the drugs and how it will be utilized. It was clear symptom improvement, and that was comparable to what we see with ruxolitinib. And I think it's unreasonable to expect better symptom improvement beyond what we get with ruxolitinib and the multiple trials have shown us that, that's the case. So the combination of seli and rux improve 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. So that, to me, fit very nicely. And then 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. And then the safety profile, I think, emphasizes that with the right amount of optimization of antiemetics, and I think just combining the drug actually with ruxolitinib offsets toxicity, and it's very manageable. And you can see patients through the treatment to induce that spleen response, which ultimately correlates with improved outcomes. And 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. And if you ask me why is this drug interesting and mechanistically why I'm very interested in the translational science, and there are probably 3 pathways that are most relevantly impacted by inhibiting XPO1, which is a settling mechanism between the nucleus and the cytoplasm, which is what selinexor does. And as a consequence, you are upregulating p53. So you're turning on p53. It's been well described with other therapies and preclinical modeling that p53 is suppressed in MF and MF CD34 cells. And 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 anticlonal 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 preclinically, and selinexor does execute that as well as reducing c-Myc and NF-kappa B. And 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. And we know and [indiscernible], who was the discussion for today, he nicely pointed out that this is a hematologic malignancy, but it's an inflammatory disease. And what you want to do is you want a therapy that is anticlonal 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. And what selinexor does is it really hits these 3 key clinical pathways and nicely complements with ruxolitinib in order to synergize with ruxolitinib. And I say ruxolitinib because that's the way the drug was studied, but -- 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. But 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 then 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 1 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 milligrams once a week, so not a high dose of selinexor, and that was determined by the Phase I study with 40 and 60 milligrams. And with an intentional dual antiemetic prophylactic regimen for the first 2 months that significantly reduces the incidence and severity of nausea and makes this combination quite tolerable and quite manageable. And 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 TSS50, I think it's a more sensitive way of gauging symptom improvement and discerning benefit, particularly in this setting. And then key secondary endpoints that will describe the overall survival, safety and VAF reduction. Here's a disposition as of February of this year. You can see the number of patients in the 2:1 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. So 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 2 arms. I'd like to make a 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, and I think maintaining that is pretty key to its efficacy. And then 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. And I would even argue that JAK inhibitors might just really be potentiating the effect of the partner like selinexor. And then you can see the median follow-up below. There's a lot of information on this slide as there normally is with baseline characteristics and a very large -- and this is a very large as to -- this is a rare disease, a very large study, a very robust study over multiple countries. So this is a really good, I think, sample of what it looks like to have MFN enroll and be treated with the combination therapy. And these are going to be more primary myelofibrosis that's more prevalent than post-TMP base that makes sense. The Intermediate 1 risk. We saw that with manifests are the patients that are out there. Those are the patients we treat. So that would make sense. JAK2V617F is more prevalent than [indiscernible], so it's enriched for those patients. But you see representation of all the driver mutations. And then you see the spleen volume and TSS scores, which are comparable to what you've seen in other studies. And 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. So this was all in line with and across different continents, all in line with what we would see with treatment of this patient population. The primary endpoint is shown nicely here. So nearly 50% of patients in the combination of SVR35 at 24 weeks versus 28%. So clearly statistically significant with the p-value with 3 zeros before the one. And then on the right, you can see the waterfall plots and each column is individual patient. The aqua makes the nice accent of the further depth in spleen response that we're seeing with the addition of of selinexor. And it follows throughout the entire waterfall plot. So it's not just some of the patients, you really see significant reduction beyond what you would see with ruxolitinib. And 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. That they will tell you that the spleen -- they can fill their own spleen, they will tell you, my spleen feels smaller, I can end over more I can move more easily, it's freeing actually. And no remark on that pretty quickly. And it does happen pretty quickly, which is this slide. So by week 12, you can already see that these 2 curves diverge. And 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. So it's rapid, it's deep and it's durable. And on the other side, you can see the SVR35 rates between the 2 arms compared at week 12, week 24 week 36. And at any time, the odds ratio is 2.59 of hitting SVR35, which favors the combination. So it clearly is not doing it 1 snapshot. It's quickly and sustained through the follow-up. And there's not one subgroup that drives it. So it was really consistent across the subgroups -- prespecified subgroups that we looked at in the study. And this -- I think this table specifically speaks to a question that comes up, which is if the drug was available, who would you use it? And this plot would suggest you could use it in everyone whose JAK inhibitor naive. There's not 1 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 therapies. 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. And what we're looking at here is SVR35 at week 24 rates broken down -- between the 2 is 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. And spleen responses are not just important, which I'm going to show you for -- to hit a regulatory endpoint. I think they're important for the patient, and I'm going to show you why in a second. But you can see that with the control arm, you're not hitting SVR35, yet you do hit it when you add selinexor to it. So 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. And of course, that's probably not surprising because we know selinexor has single-agent activity, it's been shown previously, but 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 that 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 rux that you could even dial back the dose of ruxolitinib. So it allows a little bit of freedom and ease of mind that you can still achieve your goal without concentrating working 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 ruxolitinib. This was just not necessary when you have an active combination partner in play. So this is the second co-primary endpoint of absolute change in TSS week 0 to week 24. At first glance you actually say, "Oh, negative because it's not superior." But 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 don't -- I fundamentally don't believe you can't. 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. So you still improve symptoms when you give the combination of seli and rux and this is also true across symptom domains. And then 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. And you see this with a median follow-up of 11.6 and 12.6 months in the 2 arms with a hazard ratio of 0.43. And this is really the first time we're seeing an outcome like this in a prospective study. And then you might ask yourself or we asked ourselves, well, what does this relate to? And this graph, I think, really becomes important. As I said at the at the talk, I actually think it becomes important even beyond this room in this discussion today. For the field, it becomes important because it's the first time prospectively in a trial -- a well-designed trial that faithfully follow these patients out that if you hit an SVR35 irrespective of treatment arms, at week 24, you're more likely to have a survival benefit. And 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. The 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. And of course, the VAF reduction, which is the driver mutation JAK2 MPL and [indiscernible] are considered important biomarkers of disease modification, modulation as they represent the disease burden. And it's maybe the different way, but complementary to spleen volume reduction. So 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. So if you reduce the spleen, you're reducing the burden of disease. So 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. And here you see it already at 6 months, 32% of the patients on the combination had a VAF reduction of 20% greater versus 24% with single agent rux. And it's only at 6 months. It's still early on. And that reduction was associated, as you can see on the right, with spleen volume reduction, which is what you would expect to see. So 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. So blasts or immature cells, they are the leukemic component of a chronic disease. We know from prognostic scoring systems that even having 1% blast present in the peripheral blood is an independent adverse prognostic marker for survival. So it would follow that if you could reduce the presence of circulating blast as an indirect measurement of disease control, or -- and that's what we're showing on the left with the combination in blue, so less frequent circulating -- less patients had circulating blast at those given time points whereas the control arm in orange, as you can see, is not the same. But 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 and that's the natural history, I would say, of the disease on ruxolitinib. Ruxolitinib is a great drug. I was -- I'm proud to have been part of the COMFORT effort. But at the end of the day, it's not a blast-clearing drug. It's not modulating the disease at the core. And I think this is just another example of disease modulation. And then safety. So again, I think if you think back about the earlier slide about how the [indiscernible] were picked up for reasons for discontinuation and there was really no difference in the way 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, 4, which we expected and is consistent with the profile of selinexor, serious TEAEs were the same between the 2. And I think that's important because that's what drives a lot of tolerability issues and discontinuation. And then ultimately, we didn't have a lot of deaths, less deaths actually in the combination arm and the placebo arm. I think this all speaks to the fact that it is 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. So to me, this made absolute sense. And here's the butterfly plot showing that the toxicities compared to each other. And 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 follows. 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. And otherwise, it's as advertised, it's what you would expect, and it's what we've come to expect and it's manageable. And again, the transformation rate remains low, 1.7%. So that is not a concern. So in conclusion, I hope I've made clear or obvious to you that seli, 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 ruxolitnib, you're not compromising that. And then 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. But the fact that SVR35 correlates with the survival benefit is not just important for the story, but important for the field. And then 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. So I think this does represent a novel treatment strategy for JAK-inhibitor-naive myelofibrosis patients. And 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 a late-breaking abstract, the fact back that is breaking up start [indiscernible], also, I think it points to the fact that the hematology community recognizes about the unmet need and the value here. And I would argue that, that's what's trying to be address unmet need. We've been doing the same thing for a long time. Single agent JAK inhibitors, you can serially change them. I think like most of oncology where you need to move the combination to get deeper, more meaningful responses is what we're looking for, and obviously, the committees that select these abstracts recognize the importance of that as well. So this is a -- I actually made this a long time 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 the clinical trial where you have lower risk -- so if you break it up into lower risk MF, that's low risk and Intermediate 1, higher risk means Intermediate 2 and high risk. And I will point out something that 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 like I'm going to you because you're lower risk for treats. You treat patients based on need, the need for treatment. There's symptoms, they're spleen, you want to reduce spleen. You want to control disease. That to me supersedes risk, just to Just to point out and something that's not always obvious. So 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. And 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 the 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 treatment options. So 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 selinexor and ruxolitinib would make sense. Also, on the other side, in the high-risk patients with its greater than 50,000, again, selinexor and rux started there as a combination upfront. I would also argue, and this came up in the discussion at today. One obvious need -- transplant remains the only curative option we have for these patients. So we want to get them to transplant, particularly if we have patients earmarked, but we want [indiscernible] optimize them for transplant. And part of optimization, transplanters want their patients to have small [indiscernible]. The outcomes are better, the grafting 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 particularly in the most rapid fashion possible, then you would probably go to your biggest guns upfront. That would be combination therapy. So the obvious thing to me, too, would be if you have a patient where their goal is transplant and the transplanters on board, that's an obvious indication that I would want to use your 2 strongest agents in combination upfront and synergize together. So one could see the combo being used across these places. What I don't have here which -- because this makes it all seem like it's upfront treatment. So upfront treatment is obvious, like that's what the trial does. But I will say that I don't know why 1 wouldn't make the argument that if you have someone on rux, which is patients are sitting on rux, maybe not optimized, you would add sell to the rux. So upfront, but also add-on strategy for those patients who are already on rux, maybe who leads into rux, whatever the case may be. I'll also go as far as saying not [indiscernible], I would go as far as saying, if I had a patient who was on momelotinib another JAK in the. I don't think that I would not give them the opportunity for selinexor and I wouldn't switch them to ruxolitinib put them on so I probably would just add selinexor to that JAK inhibitor backlog. So that's my own editorial. But this is one way one can envision what the NCCN guidelines could look like and the places which Sally could end up if it was incorporated and integrated.

Thank you, Mascarenhas. Dr. Mascarenhas to come back to join us for Q&A right away. And I think as you heard from Dr. Mascarenhas and from Reshma, there's significant unmet need in myelofibrosis. And with the data we now have with SENTRY, we see the opportunity for selinexor 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 as physicians make them aware of the data and help to ensure they are 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 us an ideal opportunity across the community. And again, you open a 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. And if you look overall at the opportunity, I mean we know the myelofibrosis marketplace is a multibillion-dollar marketplace. And again, not disagreeing with Dr. [indiscernible], but we're focused on upfront is the newly diagnosed patients. [indiscernible] 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. So 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 and 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 a 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. So before we start our Q&A, I'd also like to thank Dr. Mascarenhas really for his leadership in the 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 myofibrosis 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 myofibrosis. 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 in myelofibrosis. So with that, let's go to the Q&A. Maybe I'll ask Reshma and Dr. [indiscernible] to come join me here. And we see the hands. Brian, first, we're going to start here in the room. So Brian?

A question for us [indiscernible].

Three-part, Brian, you're challenging me here.

I know there's a lot of discussion at the presentation about whether the increase of guests seem to be higher in the [indiscernible] arm and 1 might expect. So I guess my questions are do you believe that would if so, why would you tend to conversate case? Can you tell us anything about the risk level of the patients to progress and and also what the other pocket referred to in the [indiscernible]? And then I guess what more would you want to see from the overall survivor [indiscernible]? Like if the death rate even down across the 2 [indiscernible], that makes you comfortable that this is a real treatment effect or would you need to see continue to separate over time to be perfectly comfortable that there wasn't some kind of [indiscernible] events that occurred [indiscernible]?

We just have this microphone working. So I probably just summarize the question a little bit, Brian, but I think maybe for you, Dr. [indiscernible] is to a little bit more into the OS. Are the rates higher than expected risk levels of patients or the other patient bucket? And what more would you like to see from an OS perspective?

So to answer that question about the rates of death. So I just want to keep pointing out what I've pointed out previously is that the data is the data. So like we have this data here. So we can try to pull it apart, which I appreciate is the tendency. But 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 and then the tendency is to try to get them to transplant. It's also unfortunately going to be a high likelihood of a 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. So 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 is driving those as whether the high-risk patients, the intimate one, I don't know. Reshma looked at the data more finally than I don't think that there was clearly a risk group that was defined in the disease. But I think that's also a function of like 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 of that criteria for it. And even, frankly, symptoms don't exactly fit into it either. So you can have symptomatic patients with a big spleen and they're scoring because they're younger and they score into me [indiscernible], but they functionally are sick patients that -- it's an incomplete [indiscernible]. So I think we have to be a little bit careful with saying, oh, the curves are -- how do we expand these curves is enriched for Intermediate 1 patient. I think it's in richer patients who were ill got on to the trial. We just call them Intermediate 1, but they clearly had to have a disease burden that warranted treatment. I think that's the important point. So 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 that's those are the outcomes that we see. So I don't really think it really is that different from what we would expect. And I would love to see the curves keep going. But 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 get this kind of -- you make a quick impact on the disease process. And we've had discussions at small groups like we do, do that at 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. But in other leukemias, we don't really take a lot leukemia. We kind of go in strong and try to induce the response early on because we know if you delay or if you half asset, you really don't get that benefit and the outcome is usually suffer. So it doesn't seem like outside of the expectation of treating blood cancer is 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. So to me, that makes sense. And then again, I think the fact -- I think particularly the fact that the SVR35 in this prospective data set associates with the survival sort of ties that in nicely. The driver [indiscernible] follows follow suit. So to me, I'm biased because I'm involved in the program. I've been looking at this, it makes sense to me. I mean, I feel like it's -- and 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.

[indiscernible]. I just wanted to ask as an pirating the JCO, it was [indiscernible] to last time the [indiscernible] a big percentage [indiscernible]. Just wondering flood products to difference?

Yes. So I think we'll turn to Dr. Mascarenhas again. This is Albert asked the question more about the PFS hazard ratio, the OS hazard ratio.

So I think it's probably as simple as survival is obvious. It's binary, either you're a live or your debt, whereas progression is a little bit more vague. You could try to define progression as spleen increase, leukemic transformation, but 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. So what makes MF complicated is MF is not -- it's not a monogenic disease. It doesn't have like CRs that we induce. It's just -- it's a very molecularly and biologically very complicated disease that corrupts the microenvironment of the bone marrow. You have displaced amount of places that small in nature in the spleen and the patients are really complicated. And no 2 patients look alike. They're very heterogeneous and very variable. So even trying to gauge responses or the concept of progression is really challenging across patients. So I think it's a very vague, blurry, ill-defined endpoint where survival is not. So I think that's why survival is easy to to make that determination. And we'll often say like, I'd rather survive than I'd rather be on the survival curve than the progression curve. So like if you're surviving, that's what haters obviously, maters the most.

A question for Dr. [indiscernible]. I said if you show the curves of the s. But what about [indiscernible], I mean, you gain [indiscernible] reduction impact if that's the driver of allele that relative noted to that reduction. We also -- can you talk about that?

Yes. So the next question is for Michael. Beautiful SVR35 curves according to Michael, which we love, but VAF, a driver and kind of your view on that and the difference we see?

Yes. So the driver VAF, many of us have have looked at as a surrogate for disease burden too. So I think if I think about data sets where that really seems to ring true, it would be, for example, in TV because it's it's JAK2V617F driven disease. You can kind of use it pretty reliably there. We've got prospective data from 2 independent studies, 1 with [indiscernible] interferon, 1 with ruxolitnib, demonstrating that if you reduce that VAF within like a year of treatment, in those studies, they used different cutoffs with like 50% if it's under a certain amount, 25% over, but it associates with outcomes like event-free survival and overall survival. So there is data out there that ties in that marker as a disease burden marker. So it is, I think, notable that in the combination, you see a more frequent 20% or greater decline in the VAF. Is that an incomplete picture because there's still more analysis that we'll go into looking at the sub-clonal mutations, but I think that's the 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. So it ties in a story that would -- is circular in the sense like you are reducing the spleen. As I said before, the screen is a reservoir for the malignant cell population. And I would think that the VAF should go down as a reflection of...

I guess the question is whether you thought respectively, there would have been a tighter correlation between [indiscernible].

Odds ratio was 3. So patients who achieved that greater than 20% had 3x likelihood of achieving that CR rates as compared to those patients who don't. So Yes. I would argue it's a nice correlation.

I thought it coreless pretty nicely.

You talk a lot about the lower rux doses [indiscernible] and [indiscernible]. Can you talked about big implications of that real [indiscernible]. And maybe the company can kitchen as well as like serious are there certain types of physicians that community docs maybe just are not comfortable using [indiscernible] doses so their patients are not getting full [indiscernible]. I guess where -- what does that mean with regards to where selling could fit in just the [indiscernible] sparing effect?

Yes. I think the question, which I'll turn to Dr. [indiscernible] on for sure because he want to treat 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, but Dr. [indiscernible]?

Yes. So we've actually done and published real-world database collect 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-milligrams based on platelet count. And for a long time, we were of the mindset that you really -- to optimize the patient on a JAK inhibitor, you have to maximize the dose. And that was the mantra. It was based off the COMFORT studies. And then you look at these claims like from Trinatics and other groups, and it's like 2/3 of the patients are on doses of 10 milligrams [indiscernible] a day or less. Those are suboptimal dose clinical trial to suboptimal doses. Now it really becomes interesting if you think about the SVR part. So we know and we have a beautiful graph from 1 of our analysis from the conference side that SVR is a dose-dependent phenomena. You have to dose up to hit that SVR. If you compromise the dose, you attenuate the SVR with rux. So you want to optimize your dose of rux. But in the community, that's not happening in the community. I don't even think innocent that really happens. I think it happens across -- it doesn't happen across the board. So 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. So to me, that's very attractive. If you just add sell to whatever dose they start with or even if they dose reduce, no big deal. If you keep them on that dose, you keep hitting them with the seli 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.

I just wonder if monetation that are on drop-down I think some of?

So the question is like in real world, quantitation of[indiscernible]?

I think -- yes, I mean we've looked at -- so defining suboptimal is also a little bit tricky. I will admit that in the sense like you have to know what the patient was like before they started rush to know what they were on rux.

[indiscernible].

Yes. I mean, ultimately, by 2.5 years, 50% of patients are off rocks by 5 years, 85% of patients are off rux. So rux is a great drug, but it doesn't take you the distance. And a lot of that is driven by inadequate response, progression of spleen regressive symptoms. So you're not controlling the clone well enough. So to try to answer your question, like, everyone kind of becomes suboptimal at some point in their clinical course. But 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. And that's if you treat them the right way. It's probably even higher out in real world if you're suboptimally treating.

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. So Joel, if you can open up the call for questions.

[Operator Instructions] Your first question comes from Maurice Raycroft with Jefferies.

Congrats on the update. For the OS data, I wanted to follow up on that. Wondering what's the ideal follow-up time to have a more derisk view on OS? And how do you expect 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, Mary, this is Reshma. I can take that question. So I think one of the advantages of the SENTRY trial is that it continues to follow overall survival. So patients and physicians remain blinded to the arm to which they are randomized. So 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 sort of like events can accrue over a course of a few years. So 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 1 to 2 quarters.

[Operator Instructions] Your next question comes from Jane Sureties with Cantor Fitzgerald.

I had 2 quick ones. I guess one -- the shorter one. For the folks that were on that 0 to 15 milligrams of rux per day, I mean, I don't know if you can provide any color on how many we're closer to that 0 mark. And if that at all in your mind kind of provides a bit of read-through for what we might see for SENTRY 2?

[indiscernible], this is Reshma, again. Yes, great question. So I will say the vast majority of those patients were in that 10 to 15 milligrams. And 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. But I think regardless of where within that 0 to 15, they landed, I think I'll go back to what Dr. Mascarenhas just mentioned, these are suboptimal dose of the ruxolitinib, right? I mean regardless of whether you're on 5 or closer to 15, these kinds of doses of ruxolitinib just do not optimally provide spleen volume response or adequate symptom improvement. So yes, and I think that's the key takeaway is that despite being on the low doses of rux, right, that SVR35 for the combination still remains very high, very meaningful at 50%.

And maybe I would also add just the way I would think of it, too, is I showed the graph of rates based on the platelet count -- or the rux dose rather. The way I interpret that is that selinexor will become sort of the great equalizer across dose rux doses you can optimize your spleen reduction. It almost doesn't matter to some extent. It's not -- it's probably not the main driver of the benefit is the way I would look at it. It's seli-driven, rux supported. So you don't need the full dose rux. So it kind of makes it nice because if you have -- because rux is dosed a different top-1 dose, it's all you can have different doses, it allows for a constant presence of selinexor across those doses of rux, we're still going to get that benefit. So it makes it almost easier to deliver in that way because you don't have to think about dosing the rux.

And your second question, [indiscernible] just -- go ahead.

Yes. I guess relatedly on this topic. I mean from the protocol, I remember that the general guidance was for GI-related events, select dose down for non-GI rux dose. I guess here for the lower categories on rux exposure, I mean it seems very skewed to the combination arm. I guess could any color be given in terms of why is that just kind of some of the general increases we saw in the heme tox side of things? Or was there anything else kind of driving that trend?

Go ahead, Reshma.

Yes. This is Reshma. Yes, the majority of the ruxolitinib is still going to be driven by the heme tox. Now with that said, the protocol also allows dose reductions across both drugs. So if you modify, let's say, nausea with the selinexor is still maintained, they may also reduce the ruxolitinib too. So 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.

Thanks, [indiscernible]. We're just right up on time. So 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 treatments and potential for patients with myelofibrosis. Thank you very much, and thank you for joining us today.

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