Good afternoon. My name is MJ, and I will be the conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics Investor Event at AACR 2023. I would now like to turn the call over to Elhan Webb of Karyopharm. Elhan? Thank you. Good afternoon, everyone, and thank you all for joining us today for Karyopharm's Analyst Event at AACR. Copy of the slides that we are being presented are also available on our investor relations website. I'm joined today by my colleagues, Richard Paulson, our President and CEO, and Dr. Reshma Rangwala, our Chief Medical Officer. We are also very pleased to be joined today by a recognized thought leader in the area of hematology, Dr. John Mascarenhas, M.D., Professor of Medicine at the Icahn School of Medicine at Mount Sinai, where he serves as Director of the Center of Excellence for Blood Cancers and Myeloid Disorders. Before we begin, I would like to remind you that various remarks we'll make today constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995, as outlined on slide three. Actual results may differ materially from those indicated by these forward-looking statements, FLS, as a result of various important factors, including those discussed in the Risk Factors section of our most recent Form 10-K, which is on file with the SEC and in other filings that we may make with the SEC in the future. Any FLS represent our views as of today only. While we may elect to update them at some point in the future, we specifically disclaim any obligation to do so, even if our views change. Therefore, you should not rely on these FLS as representing our views as of any later date. It is now my pleasure to introduce Richard Paulson, our CEO. Richard? Thanks, Elhan, good morning. Good afternoon, everyone. We are delighted that you're able to join us today to review the updated data that was presented earlier today at the American Association for Cancer Research annual meeting. Before turning the call over to Dr. Reshma Rangwala, our Chief Medical Officer, I wanted to say how excited we are about this data and what it may mean for our ability to help patients with myelofibrosis. As Reshma will discuss, selinexor and ruxolitinib appear to be working synergistically, resulting in improvement in both the spleen response and total symptom score for patients with myelofibrosis. Based on these data, we are planning to move forward with a Phase III study of selinexor plus ruxolitinib in patients with JAK-naïve myelofibrosis. Towards the end of our presentation today, Dr. Mascarenhas will review our planned study design for the trial. In light of the compelling combination data we are presenting today and the significant opportunity both commercially and to help patients in the frontline myelofibrosis setting with ruxolitinib, which is a $2 billion-plus marketplace, we've decided to concentrate our efforts on this frontline setting. As we focus our capital allocation and resources on the frontline, we have stopped enrollment in our XPORT-MF-035 study of selinexor as a monotherapy in the second-line setting. In addition, we are looking to explore other frontline opportunities, such as novel combinations, to benefit the greatest number of myelofibrosis patients. I will now turn the call over to Reshma to discuss the treatment landscape and the data that we presented earlier today. Reshma? Thank you, Richard. In turning to slide 6, over 20,000 people are living with myelofibrosis in the United States, with another 17,000 in the EU. Currently, JAK inhibitors are the only available therapies for patients with myelofibrosis. The current standard of care for treatment-naive patients is Jakafi or ruxolitinib, which was approved over 10 years ago. Less than half of all patients respond to this agent. Response duration is generally limited. Importantly, key subgroups of patients generally do not benefit from this therapy, including male patients or patients who start on ruxolitinib doses of 15 milligrams or less. Spleen volume reductions of 35% or greater are observed in less than a quarter of the patients in each of these two important subgroups. Additionally, thrombocytopenia and anemia are the leading cause of JAK inhibitor treatment discontinuation. Clearly, the current standard of care leaves a large opportunity to transform frontline treatment of myelofibrosis patients, especially in the context of these latest data. Based on the data that we presented in our poster earlier today, the combination of selinexor, which inhibits XPO1, and ruxolitinib, which inhibits JAK, appears to have the potential to shift the treatment paradigm for patients with JAK-naive myelofibrosis. In particular, our data show rapid, deep, and sustained spleen response and robust symptom improvement across all subgroups, including male patients. The combination is generally tolerable with a manageable side effect profile, enabling sustained therapy with the number of patients in our study on therapy for more than a year. Finally, we see evidence of disease modification, including rapid normalization of platelets and increase in hemoglobin levels, offsetting the thrombocytopenia and anemia, which often results in ruxolitinib alone treatment discontinuations. On slide seven, you will see that selinexor has the potential to inhibit multiple pathways downstream of JAK, including AKT, STAT, and ERK, as well as multiple cargo proteins involved in the regulation of cell growth and survival. These features suggest selinexor may be active as a monotherapy as well as show additives if not synergistic activity in combination with both JAK inhibitors as well as agents with novel MOAs. Turning now to slide eight, you can see the design of the Phase I 034 Study. This is a Phase I study evaluating the safety and efficacy of either a 40 or 60 milligram dose of selinexor in combination with ruxolitinib in patients with JAK-naive myelofibrosis. In this study, we completed enrollment of the Phase I portion and dosed 24 patients in total. 10 patients were assigned to the selinexor 40 milligram dose, and 14 patients were assigned to the 60 milligram dose. The data cut for the efficacy and safety analysis was February 24th, 2023. All patients were dosed for more than 24 weeks prior to the data cutoff. As outlined on slide nine, you can see the definitions of the safety and efficacy populations we are presenting today. Specifically, the safety population consists of all patients who received at least one dose of selinexor. The efficacy evaluable population includes all patients who received at least one dose of selinexor and had spleen volume or symptom response evaluations at 12 or 24 weeks. Patients who did not have a spleen or symptom assessment at that time point were excluded from the denominator. The intent to treat population includes all patients treated with at least one dose of selinexor. For the TSS analyses, patients who did not have any symptoms at baseline were excluded. Slide 10 includes the patient characteristics at baseline. A few notable items that I would like to highlight. One, the overall baseline characteristics are generally consistent with the JAK-naïve patient population. Second, men represented more than half of the patients in the study, and they were relatively well-balanced across the two doses. Third, the majority of patients in the study had risk scores based upon the Dynamic International Prognostic Scoring System, or DIPSS, in the intermediate two or high categories, and nearly half had high risk of genetic mutations. Lastly, the median ruxolitinib starting doses were fairly similar across the 40 and 60 milligram doses of selinexor at 17.5 and 15 milligrams respectively. Turning to slide 11 are the SVR35 results broken down by dose. In the efficacy evaluable and ITT populations, the SVR35 rates at week 24 achieved in the 60 mg dose cohort were 92% and 79% respectively, which is almost double compared to the rates achieved at 40 mg. These reductions occurred rapidly with an 83% SVR35 rate observed at week 12 for patients in the efficacy evaluable population treated with the 60 mg selinexor dose. The waterfall on slide 12 shows the spleen volume response. The green bars represent the patients treated with 40 mg selinexor, while the blue bars denote patients treated with 60 mg. As you can see, 100% of the evaluable patients treated with selinexor 60 mg achieved a spleen volume response of 35% or more at any time, indicating a clear dose response across the 40 and 60 mg doses. Moving to slide 13 are the subgroup data in patients treated with selinexor 60 mg. In general, you can see that efficacy was similar across all of the subgroups that were evaluated. Highlighted in orange are two important subgroups. Specifically, the response rates for men and women in the ITT population were similar at 78% and 80% respectively. Recall what I mentioned earlier that only 25% of men achieve an SVR35 at week 24 on ruxolitinib alone. Similar efficacy was also observed by Rux starting dose. Patients in the ITT population who were treated at starting doses of 15 or 20 milligrams of ruxolitinib achieved an SVR35 of 75% as compared to 83% amongst patients treated with five or 10 milligrams of ruxolitinib. As we turn to slide 14, I will now pivot to our data showing that the combination's meaningful ability to lower total symptom scores by 50% or more. Consistent with the SVR35 data, treatment with the 60 milligram dose showed greater symptom improvement compared to patients treated with the 40 milligram dose. At week 24, for patients who received 60 milligram dose of selinexor, TSS50 was observed in 78% of the efficacy evaluable population and 58% of the ITT population. Here, too, you see rapid improvement in symptoms with approximately 80% of the efficacy evaluable patients treated with 60 milligrams achieving a TSS50 as early as week 12. On slide 15, we show graphs of major spleen and cytokine-related symptoms across the MFSAF or Myelofibrosis Symptom Assessment Form domains, evaluating the improvement in median symptom scores with both the doses of selinexor. Similar to the TSS50 scores, substantial improvement relative to baseline is observed across all domains at the 60 milligram dose, indicating that symptom improvement is stemming from symptoms derived from both the spleen and cytokines. Looking at the data on slide 16, we show a really unique subgroup analysis from patients that were enrolled in this Phase I portion of the O34 study. The patients included in this analysis had their ruxolitinib dose reduced to fivemilligrams as early as Cycle 2 and remained on that dose for the remaining duration of their therapy. 5 milligrams of ruxolitinib is considered a subtherapeutic dose. Patients who are treated with this dose generally do not experience spleen reductions or symptom improvements. Despite this, all patients achieved spleen volume reductions and all patients evaluable at week 24 achieved an SVR35. Similarly, symptom score improvement was observed in all patients with five out of six patients achieving a 50% or greater improvement in their total symptoms. These data suggest that XPO1 is a fundamental mechanism in myelofibrosis. Looking at the swimmer's plot on slide 17, you can see the treatment durations for both dosing regimens. As of the data cutoff, the median duration of selinexor treatment was 31.5 weeks for the 40 milligram cohort and 38 weeks for the 60 milligram cohort. Notably, we had two patients as of the data cutoff in the 60 milligram dose cohort that had been treated for more than one year. Given that patients continue to stay on therapy, we will continue to update these results with future analyses. Slide 18 shows a breakdown of adverse events. The side effect profile across the two dose levels were relatively similar, with the most common adverse events including nausea, anemia, fatigue, and thrombocytopenia. The most common Grade 3-4 AEs were anemia, thrombocytopenia, and neutropenia. Two patients discontinued therapy due to treatment-related AEs, thrombocytopenia and peripheral neuropathy. Both of these events occurred in patients treated with the 60 milligram dose. While between 70%-78% of patients experienced nausea, the vast majority of these events were Grade 1 and transient, with the majority of these events resolving within two cycles. Furthermore, we know that prophylactic antiemetics are very effective in controlling both the severity and rates of nausea. Amongst the patients who received one prophylactic antiemetic, nausea rates both decreased and occurred at only a Grade 1 severity. We anticipate that these rates will further decrease in the Phase III study, which will incorporate mandatory dual antiemetics for the first two cycles. Lastly, even though some patients experienced nausea and vomiting, patients generally did not experience weight loss. In fact, as seen on slide 19, there was a median absolute weight gain of 2.5 kilograms observed at week 24 in patients treated with selinexor 60 milligrams. Turning our attention to hemoglobin levels on slide 20, we found the potential for disease modification as median hemoglobin levels returned to baseline over time. This trend is unique with the addition of selinexor to Rux, given that with Rux alone, hemoglobin levels drop after treatment initiation and tend to stay low. On slide 21, we see rapid normalization of platelet levels between Cycles 2 to 3. A finding, again, which may be evidence of disease modification and is important for patients as thrombocytopenia is the number one reason for Rux discontinuation. On slide 22, I will walk you through a case study of a 76-year-old male with primary myelofibrosis, a DIPSS intermediate-1 score, and a JAK2 positive mutation. On the far left, you will see the patient's spleen at baseline prior to initiation of 60 milligrams of selinexor and 15 milligrams of ruxolitinib. At the second cycle, the patient's ruxolitinib dose was reduced to 5 milligrams due to grade two thrombocytopenia, while the selinexor dose remained at 60 milligrams. In the center image at 12 weeks, you will see the patient's spleen volume was reduced by approximately 54% and total symptom score by more than 50%, as shown in the graph at the bottom of the slide. In the far right image, you will see the spleen volume was further reduced at week 24, reaching an approximately 55% reduction relative to baseline, and his total symptom burden continued to improve. This patient gained four kilograms of weight at week 24 compared to baseline. It's worth noting that this patient was given an antiemetic at the beginning of treatment and no adverse events around nausea were collected over the course of the study. As of the data cutoff, this patient remained on selinexor 60 mg and ruxolitinib 5 mg for over 62 weeks. In conclusion, as we turn to slide 23, we believe this combination treatment has the potential to transform frontline myelofibrosis treatment paradigms. Both the selinexor 40 mg and 60 mg were generally well-tolerated and manageable. Only two treatment-related discontinuations were observed, one for peripheral neuropathy and 1 for thrombocytopenia. Rapid, deep, and sustained spleen response and robust symptom improvement were found in patients treated with selinexor 60 mg in combination with ruxolitinib. In the ITT population, SVR35 at week 24 was approximately 79% and TSS50 at the same time point was approximately 58%. Furthermore, 100% of evaluable patients treated at the 60 mg dose level achieved an SVR35 at any time. Responses were consistent regardless of gender or ruxolitinib starting dose. SVR35 and TSS50 were also observed in patients who were rapidly dose-reduced to 5 milligrams of ruxolitinib, which is considered a suboptimal dose. We saw symptom improvement across all of the MFSAF domains for patients treated with the 60 milligram dose. Disease modification was observed as evidenced by rapid normalization of platelets and stabilization of hemoglobin levels. Based upon the safety and efficacy profiles across the two dose levels, selinexor 60 milligrams in combination with ruxolitinib is the recommended dose that we are planning to incorporate into our Phase III study, the details of which will be presented by Dr. John Mascarenhas. With that said, I am pleased to introduce Dr. John Mascarenhas, Professor of Medicine at the Icahn School of Medicine at Mount Sinai, where he focuses on blood cancers and myeloid disorders. He is a distinguished key global opinion leader in the field of hematology and oncology. Dr. Mascarenhas will discuss the treatment landscape and review the design of our planned Phase III trial, for which he will serve as the study's Principal Investigator and which we are planning to initiate later this quarter. Dr. Mascarenhas? Okay, Reshma, thanks for the introduction. I'm truly excited to join the Karyopharm team today for this presentation, and I am quite enthusiastic about the development of selinexor in myelofibrosis. As the team can attest, I had not been enthusiastic initially. In fact, I was skeptical in the ability to deliver this medication in myelofibrosis. I really think that the data that we're seeing coming out of the Phase II study or the expansion study with the combination has really changed my mind and changed the attitudes of many people that are watching the space carefully. I'm excited to watch this move forward and to participate actively and enthusiastically. With that, I'll begin. I'm John Mascarenhas, and I'm an investigator in MPNs. I have a long history of doing this, and I'm excited about novel therapies, and this is one therapy that has definitely caught my attention. What I hope to do is give you a disease background and a sense of where we are today as we lead into the registration Phase III study. Starting in slide 26, this is an overview of MPNs, which are hematologic malignancies that originate at the level of the hematopoietic stem cell. Then broadly, there's the Philadelphia chromosome negative and then positive. The Philadelphia chromosome positive is CML. The negative diseases that lack the BCL-2 translocation that are of interest are myelofibrosis, polycythemia vera, and essential thrombocythemia. Today, we're focused on myelofibrosis, the worst of the pack in terms of prognosis and outcomes, and the most challenging both from a biologic and a clinical level. In slide 27, it gives you a overview of the disease in terms of the subtypes. There's primary, and then there's secondary that originates either from an antecedent essential thrombocythemia or polycythemia vera diagnosis. These are diseases that are considered uncommon by NCI criteria and are probably, I think, underestimated, but probably somewhere between one to two new cases per year. It is slightly more common in men. The median age is around 65 years, although you can meet patients that are diagnosed even in their 30s. It's driven in most part by three driver mutations, JAK2, V617F in about 60% of patients, calreticulin mutation in about 25%-30% of patients, and about 5%, MPL mutation, which involves a thrombopoietin receptor, and about 10% of patients are triple negative or don't have a discernible driver mutation. The etiology of myelofibrosis is really complex and not well understood. On slide 28, I'm showing you, in general, the prognosis and mortality. We know that there are certain features of myelofibrosis that are prevalent, such as anemia in 40% of patients at presentation. In fact, a quarter of patients are already requiring red blood cell transfusional support, and that is a major factor in prognostication. There are a number of different prognostication tools that are used to help risk stratify our patients in order to apply a risk-adapted treatment approach. Here I'm giving you one example of a dynamic risk stratification tool that allows us to put patients based typically on five clinical variables, age, leukocytosis, anemia, blasts, and systemic symptoms into categories termed high risk, intermediate 2, intermediate 1, and low risk, with survivals that range from less than two years in high-risk patients to almost 20 years in low-risk patients. There's quite heterogeneity across the myelofibrosis disease spectrum. Unfortunately, about a quarter of patients with myelofibrosis will transform from what is essentially a chronic leukemia to an acute leukemia, which has a poor prognosis and limited treatment options. Patients with myelofibrosis often due to their age and competing comorbidities, have a lot of clinical burden and often are not candidates for stem cell transplantation, which is the only curative option for patients with myelofibrosis. On slide 29, in its broadest terms, I'm showing you the four key hallmarks of myelofibrosis, which involve extramedullary hematopoiesis, driving splenomegaly, so increased spleen volume. That affects abdominal pain and early satiety and leads to weight loss, as well as constitutional or systemic symptoms that are driven by cytokine inflammatory state, which also lead to morbidity and contribute to mortality. The cytopenias from the bone marrow failure aspect, the anemia and thrombocytopenia that lead to debility and risk for bleeding. The name of the disease is myelofibrosis is typified by fibrosis, reticulin and collagen fibrosis in the bone marrow, which again contributes to the cytopenias and the disease process. About a quarter of the patients are asymptomatic, most patients at some point in the clinical course will have progressive symptoms that are quite debilitating. On slide 30, I'm showing you what is the example of these massive spleens that these patients have to carry around. These spleens are typically, you know, 5 to 8 times the size of a normal spleen. It's in the left upper quadrant of the abdomen. It contributes to a lot of discomfort, challenges in breathing, getting comfortable walking, wearing clothes normally, and frank pain in many cases. This is a very debilitating aspect of the disease. A lot of the therapies are focused on reducing the size of the spleen and improving patient symptomatology. On slide 31, I'm showing you one of the risk scoring systems. There are a number that are in play. This is the Dynamic International Prognostic Scoring System that uses a number of different clinical variables that I mentioned previously, but also incorporates clinical features like thrombocytopenia, the need for red blood cell transfusion receipt, and an unfavorable karyotype. Again, providing risk groups that put patients into discrete risk groups that often factor into treatment, which is slide 32. This is adapted from the NCCN guidelines in which we follow to treat patients with any malignancy, but specifically myelofibrosis. The higher risk patients, those that fall in the usually in the intermediate to high risk groups within our scoring systems, particularly if they have symptom burden and spleen burden, are patients that we're looking to have therapeutic effect and intervention. It is stratified by platelet count, so those with less than 50,000 platelets. If they're not a transplant candidate, which transplant remains the only viable curative option. pacritinib is the only JAK2 inhibitor available for these patients and very effectively can address spleen and symptom burden. In patients greater than 50,000, we have ruxolitinib since 2011 and fedratinib since 2019 to address spleen and symptom, and then one can use alternative JAK inhibitors if they do not have a beneficial effect or lose that initial effect with those JAK inhibitors. There's an algorithm for treating anemia if anemia is the predominant clinical feature of patients at the time of presentation. On slide 33, this is a cartoon that solidifies the theme and the pathobiological theme of myelofibrosis, which converges on hyperactivity of the JAK-STAT signaling pathway that results in this inflammatory state and this proliferative myeloid malignancy. These are driven by, again, mutations involving the mutant CALR, the JAK2 V617F, and the thrombopoietin MPL mutation, all of which converge on this central JAK-STAT pathway. That's important to understand as we explore the different therapies that are available. That is what I'm doing on slide 34. On the left, the approved JAK inhibitors for in the U.S. for myelofibrosis. Rux is for patients greater than 50,000, fedratinib as well, and pacritinib less than 50,000. On the right, momelotinib just presented data at ASH of 2022 for follow-up from their randomized Phase III MOMENTUM study, which has positive results as a second-line agent to address anemia and symptom burden in patients who were previously treated with ruxolitinib. On slide 35, many of you are probably familiar with ruxolitinib or Jakafi based on the COMFORT studies, COMFORT-I on the left, COMFORT-II on the right. These were the randomized Phase III studies that led to the approval of ruxolitinib. On slide 36, you can see that approval was based on very potent reduction in spleen. The, the green waterfall plot on the left shows SVR spleen volume reduction with the dotted line showing those that met the regulatory endpoint of 35% or greater, which was achieved in 42% of patients, as opposed to progression of spleen on the right in the gray bars, for patients treated with placebo. Likewise, on the right, symptom improvement was deep and rapid with ruxolitinib, and worsened for those patients treated with placebo, and this was essentially irrespective of whether you were JAK2 mutated or wild type. On slide 37, I'm comparing across trials with all the caveats that exist when one does that. I'm acknowledging that up front. What I'm, what I'm showing you here is if one were to simply look at how does this compare and contrast across the two trials, Phase I II on the left for ruxolitinib approval, then the Phase I data that was presented previously by Reshma with combination selinexor 60 milligrams and ruxolitinib, either starting dose of 15 or 20 milligrams. One can see that there is even though the numbers are more limited on the right with the selinexor study, there is deep spleen response here that's appreciated across the patients that are evaluable for this response assessment. This is easily twice of what we would normally see in patients treated with single agent ruxolitinib. This is a very encouraging finding very early on in the development of selinexor for myelofibrosis. On slide 38, I'm going back to the COMFORT-I study for ruxolitinib just to highlight the fact that we do see on-target expected grade 3/4 thrombocytopenia, anemia, neutropenia of 13%, 45%, and 7%. This is expected, very easy to manage. On slide 39, you can see that the kinetics of the thrombocytopenia is about a 40% median reduction from baseline and then stays reduced through the course of the treatment with ruxolitinib. It does not go back to baseline. It sort of has this depressed effect while on ruxolitinib, whereas the anemia basically natters around week 12 and then stays 1 gram per deciliter below the starting point with single-agent ruxolitinib. On slide 40, I'm showing you one of the more important slides within this deck, it is the fact that you optimize, or you begin to optimize, I should say, the effect of spleen reduction, and symptom improvement at a minimum dose of 10 milligrams twice a day. Less than that, you're really getting very little activity to no activity. It's really a ineffective dose. The optimal dose in effect for single-agent ruxolitinib is really somewhere closer to 15 milligrams twice daily. Even at 15 milligrams twice daily, I would even argue even at 25 milligrams twice daily, you can see the median change in spleen volume is about 40%. You're not getting the deep responses that we see when you combine ruxolitinib with a drug like selinexor. Slide 41 makes an important point. This was from an analysis from the Phase I/II study that was conducted by a cohort of patients that were treated at MD Anderson. The deeper the spleen response by palpation, the better the survival. This sort of solidified the idea that reducing the spleen has not simply a cosmetic effect or improvement for the patient here and now, but also the potential to improve survival down the line. It acts as a surrogate biomarker for an outcome measure, such as survival. On slide 42, I demonstrate from the pooled analysis of the COMFORT studies that there was a modest improvement in survival with ruxolitinib in green compared to in dark blue, those patients that were on placebo or BAT who crossed over, then compared to the dotted blue line, which is a rank-preserving structural failure test, mapping out patients who would've received ruxolitinib in an imaginary cohort if they had never crossed over. One can appreciate that there is an improvement in survival. It's not based on histopathologic or molecular remissions, but in improvements in spleen, symptom, cachexia, and performance status. Next on slide 43, what happens to patients once they get ruxolitinib? They do have improvements. Unfortunately, by meeting the three years, half the patients by three years, I should say, have come off treatment. It's been shown now in multiple studies, even in a shorter timeframe, in the commercial space. Two-thirds of the patients come off ruxolitinib for reasons that include lack of initial response, loss of response, or ruxolitinib-related adverse events. A quarter of patients come off due to frank progression of disease to acute myeloid leukemia. On slide 44, I show you that those patients who do discontinue unfortunately have a poor outcome with a median overall survival of about 14 months. This has been shown now in a number of different papers, probably five different independent analysis that confirm this bad, this bad patient population and outcome. This is particularly true for patients with lower platelets or patients who develop clonal evolution on ruxolitinib. Fedratinib on slide 45 is the second approved selective JAK2 inhibitor tested in Phase III on the left, the JAKARTA study, and Phase II on the right, the JAKARTA2, as a second-line agent. I will highlight on slide 44, sorry, on slide 46 that at the 400 milligrams once daily, which is the approved dose of fedratinib, 36.5% of patients with this single agent achieved a spleen volume of 35% or greater. You can see on the right the kinetics of the change in symptom burden over time with fedratinib at 400 milligrams, the approved dose. On slide 47, I show you the toxicity profile of fedratinib from the JAKARTA study. What I just want you to focus in on is on the left-hand side, a fedratinib 400 milligram daily dose, the Grade 3/4 toxicities, and the frequent grade, all grade, GI tox of diarrhea, and nausea, particularly also with vomiting. This is a frequent toxicity that we see with FLT3 inhibitors in our field, particularly with fedratinib and even pacritinib. Easy to manage, typically in the first couple of cycles. Antiemetics can be immensely helpful in mitigating this toxicity and keeping patients on the drug. It's rarely a reason for discontinuation. Despite this GI toxicity, most patients do fabulously well with fedratinib, particularly in the second line, where it's typically used, and GI tox is not a common reason for discontinuation. You'll also see myelosuppression is a common theme with the JAK inhibitors that we use and with therapies in general in this, in this field. Anemia and thrombocytopenia, grade 3/4 of 43% and 17%. Very common, very expected. Slide 48 now moves to pacritinib, the third JAK2 inhibitor approved in March 2022, and I'll ask you to look at the PERSIST-2 on the bottom. This is the pivotal randomized Phase III study that promoted the drug in the less than 100,000 platelet population, and patients could have seen a prior JAK2 inhibitor. Pacritinib 200 milligrams twice daily in the middle was the arm that ultimately led to the approval at that dose. On slide 49, I show you in this patient population that's low platelets, less than 100,000, 22% met the primary endpoint of spleen volume reduction compared to 3% with BAT. Even in those patients with the unmet need of 50,000, pacritinib delivered a 30% spleen volume reduction rate versus 3%. On slide 50, you can see the toxicity profile is similar in many ways to fedratinib. Again, you see this GI toxicity, it's a recurrent theme here. Rarely leads to discontinuation, easy to manage with an antiemetic or antidiarrheal, and something that hematologists are very accustomed to treating. Bleeding was perhaps more frequent in patients who were treated with pacritinib than those that were treated with best available therapy. On slide 51, this is a very broad overview of drugs that are in clinical development for myelofibrosis that are in late stage. It includes pelabresib, the pan-BET inhibitor, in an upfront Phase III study. Navitoclax, the BCL-2/BCL-XL inhibitor in both an upfront and a second-line study. Parsaclisib, that was in both upfront and second line, is now relegated to the upfront. This is a PI3K inhibitor. Selinexor that has rapidly joined this group from exciting early Phase data to an upcoming Phase III registration study. On slide 52, I make some conclusions that I think you'll appreciate from this presentation. One is that MF is an aggressive hematologic malignancy, involving the stem cells. It's intimately linked to inflammation. Molecules that decrease inflammation do have beneficial effect on these patients. We have a certain degree of an appetite for toxicity that's acceptable in this leukemia, this chronic form of leukemia, in which the median survival in many patients can be measured on the order of two years. The unmet need exists to improve upon the depth and initial response of a JAK inhibitor and extend that benefit and ultimately survival. JAK inhibitors do afford our patients benefit, but unfortunately, they don't cure our patients, and outcome is dismal when dose reduced or the drug has to be stopped, which ultimately happens in the majority of patients. Over the next three years, I'm really optimistic that we will see a paradigm shift to the upfront combination therapy approach as being explored with the selinexor. Given the novel agents in late-stage development, I really think that a new era of treating myelofibrosis is ahead. I think that the opportunity to exploit non-JAK2 inhibitor sequencing, such with the drugs like imetelstat or MDM2 inhibitor like navtemadlin offer, other opportunities as well to treat patients down the line. I'm very encouraged by the selinexor data in the JAK inhibitor-naïve patients as we've seen so far. I do think it has the potential to improve on existing JAK inhibitor-based approaches, but perhaps even in the future as combinations with other novel agents. I think this drug would be best explored as a combination in the upfront JAK inhibitor-naïve space, which sets us up for slide 53, which is the Phase IIII design for the selinexor plus Rux study, which would include JAK inhibitor-naïve patients with intermediate and higher risk myelofibrosis, a total of 306 patients. That will be randomized in a 2-to-1 fashion to Rux plus selinexor at 60 milligrams once weekly in 28-day cycles. Ruxolitinib will be dosed based on the platelet count per the prescribing label, versus placebo plus ruxolitinib. The co-primary endpoints of this rigorous study will be spleen volume response rate of 35% or better at week 24, and symptom improvement of 50% or better at week 24, with a key secondary endpoint of anemia response at week 24. There will be randomization, a stratification rather, at randomization based on DIPSS score, spleen volume, and baseline platelet count, which is pretty standard in MF studies. With that, I will end on slide 54, which is questions and answers, and hand it back to Reshma. Thank you very much, Dr. Mascarenhas. Really appreciate, that very thorough, review of the treatment landscape and of course, incorporation of our data. With that said, operator, can we open it up to questions? Of course. Thank you. We will now begin the question and answer session. To ask a question, you may press star then one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw from the question queue at any time, please press star then two. At this time, we will pause momentarily to assemble our roster. Today's first question comes from Peter Lawson with Barclays. Please go ahead. Great. Thank you. Thanks for taking my questions. I guess the question initially for Dr. Mascarenhas. You mentioned your skepticism around the STORM study. Just curious why you had that level of skepticism initially and kind of how you think this data could stack up versus the talazoparib combination? You know, my initial skepticism was really, you know, one of probably naivety. Not really thinking that a drug like selinexor, which I watched being developed in multiple myeloma as my colleagues, Ajay Chari and others here were pivotal in that process. I would talk to them and see the data as they were presenting it was a situation where I thought, well, you know, in myelofibrosis, which the patients are quite symptomatic at baseline, have a lot of fatigue and cytopenias, this would be a challenging drug, an active drug, but a challenging drug, and a mechanistically rational drug, but challenging drug to deliver due to toxicity concerns. I think that was clearly laid, at least in my mind, clearly laid by the combination data that we saw presented. You know, the reality is that I would say two things. One thing is the data that's presented allays that concern, period. The other thing that I think is also quite true across the board is that as a field of investigators and in drug development, I think our appetite for toxicity is different today than it might have been, you know, 15, 20 years ago in a sense of the appreciation of the disease, you know, the malignant nature of this disease, the poor outcomes of patients with this disease. You know, myelosuppression, low blood counts, even GI toxicity, particularly GI toxicity that's manageable, as this GI toxicity profile appears to be manageable, like the toxicity profile that we see with FLT3 inhibitors is outweighed by the clinical benefit that we see. I'm a firm believer in the combination therapy approach. I do think that we have historically waited too long for patients to get progressive disease and be harder to treat and harder to rescue. The idea of taking active agents like selinexor that again are mechanistically sound, have good preclinical data and now emerging early-Phase clinical data and taking it to patients earlier on, I absolutely think is the right way to treat these patients. The toxicity profiles that I had once been concerned about really are not a reason for concern. I'm looking forward to, you know, to treating patients on this Phase III study. You know, I do think there may be some toxicity differences between the arms, but I'm quite confident that the clinical benefits will outweigh any of those toxicity concerns. Got you. Thank you. Let me just address your other comment regarding its comparison to pelabresib. You know, I'm careful to compare across, you know, studies, particularly at this juncture. You know, I don't see these as competing agents or even competing approaches. You know, I think in myelofibrosis, which is quite a heterogeneous disease state, with, you know, a lot of opportunities to capitalize on different drugs with differing mechanisms of action and perhaps not, you know, in some ways not differing mechanisms of action. Some of the drugs that I think are most exciting in this field are drugs that downregulate pathways that are relevant, like NF-κB and upregulate p53. These are pathways that are relevant to selinexor and it would lead to reason to believe that there would be benefit, that would be, you know, mechanistically shared with some of these other agents that have excited me and others in the field. I am, you know, I'm unable to compare it. Obviously, I don't think anyone can head to head at this point to pelabresib. I do think that there's reason to believe that there's a lot of space open to develop multiple drugs that can have a combinatorial effect, you know, with ruxolitinib and other JAK inhibitors actually. Again, you know, a statement I made, in the conclusion, I also think, you know, which is very forward-looking and I realize that is I think, you know, as we learn more and hopefully gain approvals of these drugs in combination with Ruxolitinib, I think there's also opportunities down the line for novel combinations, which would also be exciting, at least from my perspective as a clinical investigator. Good. Thank you. Just a question for Reshma or Richard, just around the discontinuation rates. What were they at the 60 and 40 milligram level? Kind of what drove the decision between 40 and 60 milligrams? Sure. Hi, Peter. Thank you for the question. You know, at week 24, that's the time point in which we are focused on in this presentation. In the 60 milligram dose level, only two patients discontinued prior to week 24. One patient discontinued because they transformed to AML unfortunately. Another patient discontinued because they fortunately had the opportunity to go on to a stem cell transplant. You know, by and large at week 24, patients were not discontinuing therapy, which is key, right? Because we need them to stay on therapy. Ultimately, that's gonna drive their SVR and TSS50 data, TSS50 response. Gotcha. Okay. Thank you so much. The next question comes from Maury Raycroft with Jefferies. Please go ahead. Hi, thanks for doing this presentation and for taking my questions. I was gonna ask about the Phase III design, if you can confirm that FDA has cleared your go-forward use of the 60 mg selinexor dose, and can you talk about powering for the Phase III and also enrollment timeline expectations? Sure, Maury. I can take that question. This is Reshma. We've had great discussions with the FDA, and we've incorporated, of course, all of their feedback into our design, and really excited, right, to initiate this study in the first half of this year. In terms of the powering assumptions, we haven't disclosed those data. You know, with that said, again, you know, many of our assumptions are built around the efficacy that we've observed in the 60 milligrams, specifically in the ITT patient population, in which 79% of the patients achieved an SVR35 and a 58% of the patients achieved a TSS50 at week 24. You know, what we're doing is we're comparing those responses to what Ruxolitinib has historically seen, you know, with SVRs and TSS50 in that 42%-46% range. Got it. Anything you're seeing about enrollment, timeline expectations for the Phase III at this point? We haven't yet. You know, again, we're focused on initiating the trial in the first half of this year. You know, once we get into, the early stages of the activation, we'll certainly be able to provide more color on those enrollment timelines. Got it. For your Phase I, you had some suboptimal use of ruxolitinib that you guys talked about, and the Phase III recommends following the prescribing information for RUX, adjusting dose by platelet count. Can you remind on what led to the suboptimal dosing in the Phase five for RUX? Will the Phase III protocol also allow any suboptimal use of RUX? Yeah. Great question. In the subgroup analysis, we identified seven patients whose ruxolitinib doses were reduced down to 5 milligrams, and that reduction occurred primarily within the first to second cycle. The reason for those dose reductions were primarily due to heme toxicities, so either due to thrombocytopenia or anemia. Investigators, again, were reducing that ruxolitinib all the way down to 5 milligrams. In the cases of these seven patients, they then stayed on that 5 milligrams for the duration of that therapy. In terms of the dose modifications in the Phase III, yes, we will allow investigators to modify the treatments, the doses as necessary. If, again, if a patient experiences a thrombocytopenia and anemia, and they do deem that a modification or reduction is important and necessary, we certainly will allow them to do that. Got it. Okay. Thanks for taking my questions. I'll hop back in the queue. The next question comes from Chris Raymond with Piper Sandler. Please go ahead. Hi. This is Nicole Gabreski on for Chris. Thanks for taking the question. One just around the TSS50 score. It seemed to decline from week 12 to week 24 in both dose groups and in both the efficacy evaluable and ITT analysis groups. I guess was there anything in particular that drove that? Secondly, I guess we were a bit surprised by the difference in reduction in SVR35 just between the two dose groups. As it relates to your endometrial cancer program, I guess, you know, what gives you confidence that we won't see a similar degradation of efficacy as you move to a lower dose in your Phase III XPORT-EC-042 study? Great question. Hard to say, you know, why there's this slight change in the numbers between week 12 and week 24. You know, with that said, very encouraged by the TSS results, you know, observed at the 60 milligrams at week 24. I think as you appreciate, right, that's the time point in which we need to show significant improvement compared to Rux alone. Again, very encouraged by that 58% that we see at week 24, compare that to Rux's around 46%. Again, shows a very meaningful improvement there. In terms of the XPORT-EC-042, XPORT-EC-042 also incorporates a 60-milligram dose. It's down from 80 milligrams, which was the dose that was incorporated in SIENDO. You know, we're incorporating a 60-milligram dose, again, dosed weekly in the XPORT-EC-042 endometrial trial. Again, the same dose that we are incorporating into our Phase III myelofibrosis program in which we're combining selinexor and ruxolitinib. Okay. Thanks. The next question comes from Colleen Kusy with Baird. Please go ahead. Hi. Good afternoon. Congrats on the updates, and thanks for taking our questions. First question on TSS50. At ASH, the TSS50 you were showing was quite a bit lower for the ITT compared to what you're showing in this update. Can you just talk about those patients that were non-responders previously and what they're doing now? Yeah, absolutely, Colleen. Great question. Thank you. At ASH, we only included patients who filled out their symptom form. We did have six patients that because they didn't fill out their symptom form, we couldn't include them in the denominator of that efficacy evaluable analysis. What we did identify is that many of those symptoms were collected by the physicians and incorporated as part of the patient's charts. We were able to go back to the physicians, to the investigators, collect that data, and then we've incorporated that updated information as part of this TSS50 analysis that you see here. Much more robust data now for TSS50, again, gives us confidence around that 58% that we are presenting in the 60 milligram in the poster today. Great. That's helpful. Thank you. For Dr. Mascarenhas, on the weight gain that we saw in this trial, can you put that into perspective in terms of what you'd expect your RUX monotherapy patients, and how important is weight gain for these MF patients? Okay, thanks. Weight gain is definitely important. Unlike, like polycythemia vera, which is a related disease where we're not looking to gain weight with ruxolitinib, in myelofibrosis, these patients are typically underweight and cachectic from the disease. It was understood, you know, many years ago when we first started developing RUX that you do get this reversal in cachexia and weight gain. You do get improvements even in other metabolic parameters like cholesterol, and albumin, et cetera. You do see this improvement, and that weight gain is considered favorable. I think what is important about and what got my attention about the selinexor data, and again, sort of allayed my concerns about tolerability, is patients must be doing better, generally speaking, with this combination, including their appetite and ability to eat. The GI tox is obviously not getting in their way because of that curve, you know, demonstrates a favorable weight gain. I would say this is exactly what you'd wanna see, you know, no better, no worse than what you see with ruxolitinib, but maybe most importantly, you see it. If the drug was, and this was, again, was my initial concern was, you know, would the patient be able to tolerate the drug from a GI perspective, you know, asthenia, and would they, you know... I think weight loss or, no weight gain would suggest that that was a complication. To me, this curve is a very reassuring aspect of the data that's been presented. Awesome. Thank you. One last one for me. For the Phase III trial design, realize, you're not sharing the powering assumptions yet, but can you just clarify with the co-primary endpoints, do you need to hit both SVR35 and TSS50 or just one? We need to hit both. Got it. Thank you for taking our questions. The next question comes from Jonathan Chang with SVB Securities. Please go ahead. Hi, this is Matt Cowper on for Jonathan Chang. Thanks for taking my question, and congratulations on the data. Just a couple from me. The first one sort of touched on a little bit already, but in terms of, you know, dose reductions and sort of modifications for the ruxolitinib, you kind of said that in the first two cycles, these patients are being reduced to five. For the patients that you have, you know, out past a year, are these patients that had seen reductions or modifications in either of the therapies, or are they sort of, you know, tolerable, like very tolerant to it and just continue going, or do you have patients that are like sort of long-term that have had this dose-reduced suboptimal sort of Rux? Just any sort of color on that. I have a follow-up question on that. Sure. I can provide a little bit of color on that question. By and large in the protocol, we provided guidance around two main buckets of AEs. For the hematologic toxicities, we did recommend that investigators dose reduce the ruxolitinib, hence the reason that you see this reduction in the ruxolitinib for some of these patients all the way down to 5 milligrams. For the non-heme toxicities, we recommended that they dose reduce the selinexor. You can see that either one of the doses or either one of the drugs was being managed based upon the toxicities that were being observed. I will say we do have patients who are on therapy for a substantial amount of time, even at these low doses of ruxolitinib. In the patient case that I described during my presentation, that patient, as of the data cutoff, had been on therapy as of 62 weeks, and they had maintained that efficacy of approximately 55% reduction in their SVR on a 5 milligrams Rux dose only. Their selinexor dose was higher. You can see that patient's efficacy can be maintained even though the reductions in these therapies needed to occur. Perfect. Thanks so much for providing some color on that. The last or the question is maybe for Dr. Mascarenhas. To what extent is this patient population representative of a typical or real-world treatment-naive myelofibrosis population? Thanks. Yeah, I mean, I think, I think this is the, you know, this is pretty much the real-world experience of what you would get, in the office when you see patients with myelofibrosis, right? I think it's a pretty good representation. It's a good representation of what we see. I think it's a good snapshot of what to expect, in a Phase III, randomized setting as well. In the interest of time, please limit your questions to one question and one follow-up. The next question comes from Eric Joseph with JP Morgan. Please go ahead. Hi, this is Noah An for Eric. Thanks for taking our question. Just a quick one from us. What subgroups treated on standard of care do you observe suboptimal responses that might benefit the best from the Rux-selinexor combination in the Phase III trial? I can start out with this one. This is Reshma. It's a great question. You know, in our evaluations of the data, specifically the ruxolitinib data, we were very intrigued by the fact that there's a couple of subgroups that may not benefit with ruxolitinib, and this is primarily around gender, in which we see male patients not achieving SVR 35 to the same degree as female patients. We also noted that SVR 35 and TSS 50 were also lower in patients who were started on lower doses of ruxolitinib, specifically at 15 milligrams. When we looked at our subgroup data, again, we looked across multiple sub-subgroups, as presented in our, my presentation later today. Again, very encouraged by the fact that when we looked at the efficacy across all of the subgroups, including by gender and by Rux starting dose, the efficacy was very consistent, which really suggests that the combination can provide benefit to those male patients and to patients who need to be dosed at lower doses of ruxolitinib, again, in contrast to what you see with Rux alone. Dr. Mascarenhas, any thoughts from your end? No, I mean, I agree with you. To me, what's probably, you know, most intriguing is that you can get these deep responses, you can maintain the patients on lower doses of ruxolitinib. One can imagine, you know, this could be an approach that might have a universal appeal to many different patients. It, you know, I don't know that we have a clear subgroup in which this would be, you know, a preferential therapy. It could just be a therapy that's used agnostic of, you know, of sex, driver mutation or other clinical features. Great. Thank you. The next question comes from Ed White with H.C. Wainwright. Please go ahead. Good afternoon. Congratulations on the data. You had mentioned that the patients that were reduced, on the JAK inhibitor. What about, selinexor? Were any of the patients on the 60 milligram dose reduced? Great question, Ed. Yes, we did have patients who were dose reduced with selinexor. The protocol did allow dose reductions from 60 to 40 if they started on 60 and then even 40 to 20. By and large, right, the majority of the dose reductions were just occurring from 60 to 40. Yes, that modification was permitted in the protocol. it's gonna be allowed also in the Phase III? Yes, absolutely. Okay. In the Phase III, you mentioned some of the stratifications. Will the patients be stratified by gender as well? No, we're not. The three stratification factors are gonna be around their DIPSS scores, platelet levels, and then also spleen volume. We decided not to incorporate gender as one of the stratification factors. Okay, great. Thanks for taking my question. The next question comes from Brian Abrahams with RBC Capital Markets. Please go ahead. Hey, good afternoon, guys. Thanks so much for taking my questions. I'm wondering, I guess, first off, are there any more patients that might be coming through to potentially provide more definitive point estimates around the powering assumptions with respect to spleen response and particularly TSS or perhaps any interims in the Phase III that could enable upsizing? Then maybe as a follow-up along those lines for Dr. Mascarenhas, I'm curious as the principal investigator, your views on the trial design here. It looks like the TSS50 looks somewhat comparable to other promising late stage MF therapies, but the size of the Phase III here looks to be quite a bit smaller. I guess I'm curious if there's anything maybe with regards to randomization or population that gives you confidence that in the powering for the Phase III here with this, with these, with this end? Thanks. Yeah. I can start off with that one. Great question. Again, there's not gonna be any additional data coming from the Phase I, so all of the patients initiated treatment more than 24 weeks. These are the data that we presented today are the 24-week data for both SVR and TSS 50 by dose. Again, for the 60 and the 40 milligrams. Again, very encouraged by the 79 and 59% that we see in the ITT for the SVR and TSS 50s, respectively. In terms of any additional analyses, we haven't disclosed that information at this time. You know, just a high-level overview that Dr. Mascarenhas presented a few minutes ago. Dr. Mascarenhas, any comments from your side? No. I don't, I don't think I can add anything beyond that. Okay. Fair enough. Thanks so much. Seeing no further questions in the queue, I would like to turn the call back over to Mr. Richard Paulson for closing remarks. Thank you, operator, and thank you to everyone for joining us today and asking your questions. A special thank you to Dr. Mascarenhas for joining us today and all of our employees that helped make today possible. Once again, we are very excited about the selinexor data in frontline myelofibrosis and working hard to bring this potential new treatment option to patients as rapidly as possible. Have a great evening, everyone. The conference is now concluded. Thank you for your participation. You may now disconnect.