Tech analysts at Jefferies. It's with great pleasure that I'd like to welcome the Karyopharm management team to our Jefferies conference. We've got the CEO Richard Paulson and the CMO Reshma Rangwala and they're going to be joining us for a presentation today. It's an exciting year for the company. They've got an ongoing phase III study in myelofibrosis and also a phase III in endometrial as well. They'll tell you more about those programs in their commercial program as well. I'll turn it over to Richard and Reshma. Thank you Maury and thanks to the Jefferies team for hosting us. As you mentioned, you know it's a very exciting time at Karyopharm. We're an innovation driven commercial stage oncology company with two transformative phase III's reading out in the very near term as we work to build on Multiple Myeloma foundation. Before I get into things, kind of a little housekeeping, remind you that various remarks we make today will constitute forward-looking statements as you see on the slide. Please refer to our most recent 10Q. As Maury mentioned and as I kicked off with, it's an exciting time, we're building on our profitable foundation of Multiple Myeloma with transformative opportunities of myelofibrosis and endometrial cancer. That's what we want to present today too, to really talk some more about myelofibrosis and show the journey we've been on. As we continue to create data and generate insights in myelofibrosis, it just continues to give us confidence in our ability to make a difference for myelofibrosis patients and bring the potential of a doublet in frontline myelofibrosis where innovation has not happened. Really if we think about over the last 10- 13 years with Jakafi really being the standard of care as is, very excited with top line data kind of expected towards the end of this year, early 2026. As we see, you know, this leads us to a potential peak opportunity of $1 billion plus. At the same time, you know, Reshma is going to talk to our endometrial cancer program which we expect to read out kind of mid next year. Again, a significant opportunity to make a big difference for patients. Especially as we focus on the p53 wild type pMMR patient population. When you think about the data that we've just shared recently, it continues to build our confidence in myelofibrosis. Our phase III program is focused on JAK naive patients. This data that we're sharing today and that we've recently shared is actually from a heavily pretreated, difficult to treat patient population and it's monotherapy data. This is from a trial that we actually started before we had the combo data. As we see this data moving forward, it continues to show the potential of Selinexor really to impact the four key hallmarks of myelofibrosis. Looking at spleen volume reduction, symptom scores, looking at hemoglobin and transfusion burden, really importantly disease modification potential. When you look at the impact on key cytokines and in very kind of safe and tolerable profile which we continue to improve on as we're using lower dose Selinexor. As we look at this data, I think it really gives us more insight into our potential to be synergistic and additive to the impact you see with ruxolitinib as a combination in the frontline setting. We think about our myelofibrosis journey. You know, it's been a journey that the company has been on for over seven years and as we kind of highlighted, it started early on with some preclinical activity. There is some IST and kind of difficult to treat patients who have already been exposed to JAK inhibitors. We started our combo trial. We had started also this phase II program as we got the data from the combo trial in the phase I and showed the efficacy that we have across SVR, TSS, and again the ability to positively impact hemoglobin and really across key cytokines. We stopped that program and as you see we're going to share the data from that data because it really enabled us to again show the monotherapy activity. We've continued to move forward, we've learned from other programs, made adaptations to our program to increase our probability of success, you know, and enrolling rapidly to really hopefully bring this to patients in the frontline setting as a novel combination and potentially become the standard of care in frontline myelofibrosis. If you touched on this, this is a transformative opportunity, really growing on a profitable Multiple Myeloma foundation. We have the commercialization capabilities in place. We take our capabilities and, pending positive data and a label, launch rapidly into myelofibrosis where again we have the potential to more than double the response rate. When you think about SVR35 as being response, you see about 30%-35% response from ruxolitinib and the potential to more than double that. At the same time, you know, physicians want to be able to have access to this kind of innovation which really improves the frontline treatment as rapidly as possible. That I think will enable rapid uptake and again, moving forward with our existing commercialization capabilities. That is what has us excited to deliver on the data, has us excited to deliver and potentially transform outcomes for patients. As we look at how we are doing that, going to invite Reshma up to take you through kind of the data journey. Again, how we see increasing confidence as we are sharing the data around our ability in myelofibrosis. Reshma. Thank you, Richard. I'm really excited, you know, about the opportunities we have with Selinexor in myelofibrosis and endometrial cancer. I think two of our indications that are our near term opportunities. When I look at myelofibrosis, it really comes down to the mechanism. What is it about XPO1 inhibition that really enables potential monotherapy activity in multiple populations with myelofibrosis? Also, that important additive, if not synergistic, activity when it's combined with other agents, including JAK inhibitors. The way I look at it is because XPO1, through lots of interrogation, preclinical work and teasing apart of the mechanism, it suggests that we are inhibiting the JAK-STAT pathway, which is noted on the left. In addition to the JAK-STAT pathway, we are also modifying and utilizing non-JAK pathways to enable cell death. This is going to include p53-driven cell death. p53, we know, is a very important tumor suppressor. p53 wild type is found in about 95% of myelofibrosis patients. We have very, very compelling clinical data in endometrial cancer that really suggests that Selinexor drives meaningful activity in p53 wild type. We are also leveraging cell cycle arrest. This ability to inhibit both JAK and non-JAK pathways again enables monotherapy activity. I will take you through some of that new data in a few. There is also this potential additive, if not synergistic, activity when we combine it with a JAK inhibitor. The key aspect that we are focused on with Selinexor is its ability to modulate the four key hallmarks of myelofibrosis. In myelofibrosis, we know these patients unfortunately suffer from very large spleens. We really want to drive rapid but durable spleen reduction. These patients also suffer from very severe symptoms, both stemming from their very large spleens as well as non-spleen related symptoms. We know that they suffer from a lot of cytopenias. Their bone marrow unfortunately is like concrete. They also have these huge surges in cytokines that also implicate anemia and perpetuate anemia converting into transfusion dependent states. Lastly, how do we modify the underlying disease, how do we reverse some of these processes so that it ultimately can drive meaningful spleen volume reduction, symptom improvement, cytopenia stabilization, but ultimately drive PFS improvement and overall survival improvement? If I look at our phase I combination data, these are the data I think in that seven plus year journey really solidified our conviction in XPO1 inhibition in myelofibrosis. Why do I say that? It's largely because of the degree of spleen volume reduction rates that we see with this combination. As Richard already alluded, Jakafi, ruxolitinib, is the standard of care for this patient population. Patients treated with Jakafi, about 30%-35% of those patients are going to achieve that important SVR35 rate. What we see in our combination study is that amongst the 14 patients treated with Selinexor 60 mg in combination with standard of care ruxolitinib, we more than double that rate. We go from 30%-35% to now 79% of those patients achieving that SVR35 rate. If you look at any time in that efficacy evaluable population, we see that every single one of those patients actually achieve that SVR35 rate. Coupled with those high% of patients is the durability, right? What these patients want to appreciate is that once they achieve that spleen volume reduction, that spleen volume reduction is going to be maintained. What we analyzed is standard durability of response through a standard KM curve. On the left hand side is a Kaplan Meier plot of the durability of response amongst those patients. Eleven patients who achieved that SVR35 and what we see is a 100% probability of duration. None of the patients at the time of this data cutoff had actually progressed. Interestingly enough we also see that with symptoms. When we look at TSS50, a very standard responder based analysis amongst the patients who achieved that TSS50, again 58% there too, none of the patients had actually progressed. Really important durability of response, both from an SVR as well as a symptom perspective, important evolution in myelofibrosis is how we analyze symptoms. Okay, as I mentioned before on the previous slide, convention has always been to look at symptom improvement. Again, total symptom score of at least 50% goes all the way back to the insight days when they developed Jakafi. Right. It was sufficient. When you are looking at Jakafi versus placebo and you just look at the percentage of patients that achieved that 50%, it's fine to show that improvement. What we now see though, in these modern trials in which we are looking at combination relative to active control, TSS50 no longer is a sensitive endpoint. You cannot detect a meaningful improvement above and beyond ruxolitinib. What we are now looking at is again using the same data, but analyzing all of the data observed over the course of those 24 weeks. By utilizing all of the data and the changes that occur within those 24 weeks, we can then aggregate and then assess the change relative to baseline. That ability, again, serves as a more sensitive way of detecting that improvement above and beyond RUX, which from a physician standpoint and from a patient standpoint, is what they really want to appreciate. There are two key phase III trials that read out at ASH 2023. This is going to be the MANIFEST trial, this is going to be the TRANSFORM trial. I highlight those trials only because they too were evaluating their relative combinations versus RUX alone in a very similar patient population as what we did. When you look at the RUX only arms, what you can appreciate is that RUX only, RUX monotherapy, led to anywhere between an 11-14 point improvement relative to baseline. Now look at our phase I data on the left hand slide. We now see an 18.5 improvement. It suggests almost a 4 point delta, more than 4 point delta, with the combination relative to RUX alone, mirroring that same kind of improvement that we also see with TSS50. If I look at the change in symptoms over time, it also suggests rapid and sustained symptom improvement. Right. We looked at the change in symptoms in four week intervals, and what we see is again very symptomatic at baseline. As early as week four, you. You see a rapid decline in symptoms, which represents an improvement that continues all the way to week 16, which is again sustained until week 24. Based upon those data, as Richard mentioned, we initiated this ongoing phase III trial. This is our MF-034 phase III trial of Selinexor in combination with ruxolitinib. Again, in that JAK-naive myelofibrosis population. 350 patients are planned, two-to-one randomization in a double-blind fashion to either combination versus ruxolitinib alone. Our primary endpoints are going to be two, so co-primary endpoints: SVR35 at week 24 and then again absolute TSS. Right, a more sensitive way of assessing that symptom improvement. This study is close to finishing enrollment. We are really looking forward to when that last patient is enrolled, which is going to enable top line results likely at the end of this year, beginning of next year. There was a futility analysis pre-specified that was conducted earlier this year. It was based upon both efficacy and safety. Very happy to announce that it passed, and the study. The DSMB concluded that the study should continue as planned without modification. Those are our phase I data. Those are sort of the trial that is almost complete. To give you more confidence about the activity that Selinexor and XPO1 can have in myelofibrosis, I do want to take you through these data from this MF-035 study. As Richard mentioned, this was a study that was started many years ago in a very different patient population. Arguably this is a much harder to treat patient population given the fact that they were already exposed to JAK inhibitors, at least six months of JAK inhibitors. This patient population was randomized in an open label setting to either Selinexor as a monotherapy versus physician's choice. Right. They were followed for SVR and multiple endpoints including symptom improvement. This is the demographics of this patient population. In total, at the time that we paused enrollment, 24 patients had been enrolled, 12 to the Selinexor arm, 12 to the physician's choice arm, heavily pretreated. An average number of two prior lines, up to four prior lines of therapies. This is also a very high risk patient population. I say that because if you look at those triple negative rates as well as high risk rates, substantially higher than what you would normally anticipate out of a myelofibrosis population. If you look at the spleen volume reduction, again it mimics and is consistent with what we have seen in the past with so many of our other trials in myelofibrosis. That XPO1 as a monotherapy drives meaningful spleen volume reduction in the vast majority of these patients. In fact, if you look at the waterfall plot on the right hand side of the screen, the green bars represent patients that were treated with Selinexor at any time. In this waterfall plot you will see 12 patients who are efficacy evaluable, again, treated with Selinexor. Importantly, every single one of those patients achieved some degree of spleen volume reduction, save for one patient. Now compare that to physician's choice, in which only half the patients experience some degree of spleen volume reduction. Already a notable difference, that then translates to SVR25 and SVR35 rates too. If you look at the bottom of the slide, you'll note that SVR25 was achieved in 67% of the patients treated with Selinexor as compared to only 38% in physician's choice. If you look at SVR35, there too, there's a doubling, 33% versus only 13%. An important part of this study was the fact that it allowed a crossover specifically for those physician's choice patients. Right? Now, these physician's choice patients had to meet predefined progression criteria, right? The majority of those patients, of which there were six, were treated with prior ruxolitinib at the time that they crossed over. They had already relapsed, they were already refractory to their prior JAK inhibitor. We really wanted to appreciate whether a patient who was already refractory to a JAK inhibitor could then have some degree of spleen volume reduction when they were then subsequently treated with Selinexor. What we did is we took each one of these patients, we just charted their spleen over time and then included them in the standard spider plot. What you can see at zero, this is going to be their baseline spleen at the time that they were randomized. The second column represents the maximum spleen volume reduction they achieved when they were treated with Physician's Choice or RUX. The third column represents their spleen growth at the time that they had progressed. The fourth column represents the rapid and meaningful spleen volume reduction that was then achieved when they were then subsequently treated with Selinexor. In fact, four out of five patients treated with that XPO1 inhibitor achieved that SVR25, suggesting that XPO1 could actually overcome, right, prior JAK inhibition? Likely, because it is recruiting those other pathways that are going to be relevant in myelofibrosis. The third aspect, symptoms. Right. Do we see symptom improvement with Selinexor monotherapy in this very hard to treat population? We looked at both TSS50 at week 24 as well as absolute TSS. Here too, you see that monotherapy activity. In fact, amongst the seven patients randomized to Selinexor, we see 29% achieved that TSS50 at week 24 and a very meaningful six point reduction relative to baseline. When you look at all patients treated with Selinexor, again a more heavily pretreated patient population, therefore you see an 18 and 4 point respectively. Another aspect that is important, again, the third hallmark is going to be cytopenias. What we really wanted to understand was can XPO1 stabilize their hemoglobin and reduce transfusion burden? To answer these questions, what we did is first off, just charted mean hemoglobin over time across the two arms on this chart. The green line represents those patients treated with Selinexor and blue are gonna be those patients treated with physician's choice, by and large ruxolitinib. Visually you could already see that the mean hemoglobin from the very start of treatment substantially higher for the Selinexor treated patients as compared to physician's choice. When you look at transfusion burden, I think these data are very meaningful. These are standard swimmers plots. Blue again represents those patients treated with physician's choice. The green represents those patients treated with Selinexor and each red dot represents a transfusion. Visually again, you can already see substantially more transfusions administered to those patients treated with physician's choice as compared to Selinexor. That translates to about half the number of units transfused for the Selinexor arm as compared to physician's choice. The question is why? Why is this happening with XPO1? As I mentioned earlier, it's because we believe XPO1 is modifying the underlying disease. Right? We know that this myelofibrosis, the pathogenesis stems from multiple different factors. We know that cytokines are going to play a key role here. Specifically IL-6, IL-8, TNF-alpha, hepcidin, each one of those alone and in combination really driving aspects of angiogenesis, pathogenesis and multiple aspects of anemia as well. What we had access to were plasma samples at week four from a subgroup of these patients. We compared those cytokine levels at week four relative to baseline and then charted those cytokines in this very standard dendrogram. In this chart, the purple represents a decrease in cytokines and the orange or red represents increase in those cytokines. What you will notice is again a very rapid decrease in those cytokines as early as week four. Again, very meaningful reductions in IL-8, IL-6, TNF alpha, and hepcidin. Specifically for Selinexor. For PC, you actually see an increase. Of course, this comes with a very manageable safety profile. If we look at all grade treatment emergent adverse events, we see nausea, which is a known side effect with Selinexor, experienced in only 33% of those patients. Thrombocytopenia, 33%, even grade 3 plus AEs, very manageable, very tolerable. It is important to note none of these patients actually needed to discontinue therapy as a result of this AE. Now let's just segue to endometrial cancer. Completely different disease type. Of course, endometrial cancer. This is the beauty of Selinexor is because of its mechanism, it enables this broad anti-cancer activity across multiple different tumors, including both solid as well as hematologic in nature. What we're leveraging in endometrial cancer is this really important biomarker in p53 wild type. It's an important tumor suppressor. By administering XPO1, you just block the gate exportin that is going to be important. Shuttle of proteins from the nucleus into the cytoplasm. These patients that are administered Selinexor just have active p53 retained within their nucleus, which ultimately drives apoptosis and cell death. If you look at endometrial cancer, more than 1/2 of all patients are going to be p53 wild type. We also know in endometrial cancer, another really important molecular entity is going to be their MMR status, right? So MMR proficient is identified in about 80% of all patients. MMR deficient patients are going to represent the remaining about 20% of all patients. If you look at the percentage of patients who are both pMMR and p53, about 1/2 or 50% of all endometrial cancer patients. Now the landscape has really evolved in the last couple of years in endometrial cancer largely because of the introduction with the checkpoint inhibitors, right? Multiple checkpoints, including dostarlimab, pembrolizumab, have been approved for all patients regardless of MMR status. With that said, though, there is a growing appreciation, both by investigators, physicians as well as the regulatory agency that the efficacy achieved by MMR status is very different. Checkpoint inhibitors, not surprisingly, have substantial benefit in that small DMMR population, where the benefit is far more modest is going to be in that pMMR population. That is really going to be that population that you'll see in a couple of minutes really has the greatest benefit with Selinexor. Let me take you through these data very quickly. This is going to be long term follow up data from a very large subgroup of p53 wild-type patients observed in a prior phase III SIENDO trial. In here you can see that Selinexor led to a very meaningful 28.4 median PFS compared to only 5.2 months PFS for placebo, translating to a hazard ratio of 0.44. This is that subgroup. Again, 50% of all patients who are going to be p53 wild type pMMR. Now you see a median PFS of 40 months. This is actually longer than the overall survival achieved by the checkpoint inhibitors. Forty months achieved by Selinexor, again PFS, compared to only 4.9 months for placebo, translating to a hazard ratio of 0.36. Of course, very excited about these data as well as the ongoing phase III trial that again is evaluating Selinexor as a monotherapy in the maintenance setting in these patients with p53 wild type endometrial cancer. 276 patients are planned, one to one randomization to either Selinexor as a monotherapy or placebo. Primary endpoint is going to be progression free survival as assessed by investigator. It's going to be evaluated first in this MITT population which largely represents pMMR p53 wild type and then it'll roll down into that larger ITT population which is going to include additional dMMR patients. That said. Thank you Reshma. I think as you just heard and as Reshma walked you through, it's a transformative time for us at Karyopharm. It's a transformative time, the potential to really dramatically improve outcomes for patients in myelofibrosis and endometrial cancer. Very excited about it. You know as we move through the year, we're continuing to focus on working to grow our core business in Multiple Myeloma. You know, delivering the complete enrollment as we said over the next couple months in our Century trial, seeing the top line data end of this year, early next year, moving forward and really getting ready for that commercial launch with that established commercial capability that we have. It's an exciting time for anybody in the organization to be getting ready to bring potential new standard of care to patients, and as we report out the data, excited for the potential there to move forward rapidly and bring this innovation to patients. At the same time, continuing to move forward with completing enrollment in our endometrial cancer program and reading that out in mid-2026. Thanks for the opportunity to share the story and excited to talk some more in the near future.