Everyone, and thank you for joining Baird's Biotech Discovery Series. I'm Mike Perrone, Baird's Healthcare Specialist, and I'm pleased to be joined by Karyopharm Therapeutics President and CEO Richard Paulson, CMO and Head of Research Reshma Rangwala, CFO and Treasurer Lori Macomber, and Head of IR and Corporate Communications Brendan Strong, as well as Dr. Claire Harrison, Clinical Director at Guy's and St Thomas' NHS Foundation Trust. I'm also joined by my colleague, Baird's Senior Biotech Analyst Colleen Kusy, who will be moderating the discussion today. As a reminder, Baird's Biotech Discovery Series is an opportunity for investors to hear from interesting and innovative biotech companies in a fireside chat format. A few quick logistics: if you would like to submit a question, you can do so via the webcast portal, or you can email Colleen at ckusy@rwbaird.com. And before we begin, I'm required to remind attendees to please refer to the event calendar, published research, or Baird's website for important disclosures regarding the companies discussed during this event. I'll hand it over to Brendan briefly to read some compliance documents from his end. Great, thanks so much, Mike. Before we begin, I'll remind you that various remarks we will make today constitute forward-looking statements as defined by U.S. securities laws. 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 factor section of our most recent Form 10-Q filed with the SEC and in other future filings we may file with the SEC. Any forward-looking statements represent our views as of today only, and you should not rely on these forward-looking statements as representing our views after today. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so. With that, I'll turn it over to Colleen. Great, thank you, Brendan. Thanks, everyone, for dialing in. Thanks for bearing with us with some technical difficulties, and thank you so much to the Karyopharm team and to Dr. Harrison for joining us today. Really excited to dive in here, so maybe just start for the Karyopharm team. Let's just start with a brief company overview. I'm sure people are familiar with Karyopharm when multiple myeloma was the lead, but now we have some really exciting phase IIIs coming into the near term here, so I'll kick it over to you, Richard. Yeah, thanks, Mike, and thanks, Colleen, for having us today. As you know, and as I'm sure many of your listeners know, we are a U.S.-based, innovation-focused, commercial-stage oncology company that's very focused on areas of high unmet need. And we're passionate about positively impacting patient lives. Our lead compound focuses on XPO1 inhibition, and XPOVIO is commercialized, as you mentioned, in multiple myeloma. And in the U.S., we already have a well-established commercial organization with a profitable multiple myeloma franchise as our foundation. And internationally, selinexor is already approved in over 50 countries with our international partners. And as you mentioned, moving forward, we're very excited about two transformational phase III opportunities. First, in myelofibrosis, and second, in endometrial cancer. And both of those are going to read out over the very near term. And as you mentioned, today, we're going to focus on myelofibrosis, where we have the opportunity to really establish a new standard of care with selinexor plus ruxolitinib. And pending positive data, we have the capabilities in place to move forward and launch rapidly. And in fact, the timing of today's call is really important and relevant because a number of us, in fact, all of us, I think, on this call from the Karyopharm side and Dr. Harrison just returned from a very successful and a very busy American Society of Hematology conference where we heard a lot of excitement from physicians, from investigators, from patient advocates who are eagerly awaiting the next big readout on myelofibrosis. And that's the phase III SENTRY trial with results anticipated in March, which is coming quickly. It's only three months away. So we're excited to be on this call today to discuss the data and the commercial opportunity. We're very delighted to be joined by Dr. Harrison, who's a leading international voice in myelofibrosis and other MPNs, as well as a leading investigator in the phase III SENTRY trial and a key member of our trial steering committee. So thanks for having us. Yeah, that's great. A great overview. And so as you said, phase III data coming in March for selinexor plus ruxolitinib in myelofibrosis. So maybe just to tee up into that readout, let's talk about the data you guys have generated so far. So maybe let's start with just the XPO1 mechanism, kind of the scientific rationale there, and then the phase I data that you've generated so far in combination with rux. Sure, I can take that one, Colleen. And thank you for having us on our call today. So selinexor is an XPO1 inhibitor. XPO1 or exportins are these gates that we find on the nuclear pore. And what they do is they just regulate the shuttling of proteins from the nucleus into the cytoplasm. And these proteins are multiple. They include tumor suppressors like p53, p21, glucocorticoids, oncoproteins, a myriad of tumors, sorry, proteins that are really important in pathogenesis and tumor cell development. Now, when we think about MF in particular, there are a number of proteins that are important as part of MF pathogenesis, but also in symptom growth, symptom development, spleen growth, as well as anemia. We know that the JAK-STAT pathways and the JAK inhibitors, they really downregulate upstream of those JAK-STAT pathways. When we look at XPO1, they're going to modulate a number of other pathways that are very relevant in myelofibrosis. This is going to be the NF-kappa B pathway. This pathway is integral in the symptom development that many of these patients experience. We're going to talk about oncoproteins and oncoprotein downregulations. This is going to be important in that spleen growth. And then, of course, tumor suppressors, specifically p53, guardian of the genome. p53 wild type is going to be identified in approximately 90%-95% of all myelofibrosis patients. And this pathway is really integral in cell apoptosis and proliferation. So what we see with XPO1 alone, and especially in combination, is this multi-targeted approach that allows us to downregulate, again, upstream of the JAK-STAT pathway, and then, of course, many of the relevant pathways implicated in myelofibrosis. Given this mechanism and some of the very compelling preclinical and early clinical work, we initiated a phase I study that specifically evaluated the efficacy, safety, and some of the early disease modification readouts of selinexor in combination with ruxolitinib in patients who are frontline myelofibrosis. Think of these patients as newly diagnosed myelofibrosis patients. All of these patients had a platelet count of 100 or above. We evaluated two different doses within the phase Ia. So these are going to be the low doses of selinexor, either 60 milligrams weekly or 40 milligrams weekly of selinexor in combination with standard of care ruxolitinib. Ultimately, we chose the 60 milligram dose of selinexor in combination with ruxolitinib, largely because it maximized the efficacy that we observed in this population. Specifically in the ITT population, in that 60 milligram cohort, 79% of those patients achieved an SVR35 at week 24. This is a very meaningful rate, given the fact that ruxolitinib alone historically has led to rates of approximately 30%-35%. So the combination is more than doubling what we see with ruxolitinib alone. Similarly, also very intriguing and meaningful symptom improvement. Absolute TSS, which is just an average improvement in that symptom over time, suggested an 18.5 improvement relative to baseline. Again, compare that with historical ruxolitinib, where prior data have suggested anywhere between 11% and 14%. So there, too, a very meaningful outcome. And hand in hand with both of these is durability. So especially when we look at SVR35, we see that once patients achieve that SVR35, they maintain that SVR35. So you see these rapid, deep, but also durable spleen reductions hand in hand with really meaningful symptom outcomes, too. Fantastic. And if you could touch on the safety that you saw as well at some of these lower doses than where you've looked in multiple myeloma before. Yeah, absolutely. So some of the toxicities that we see and we observed, as part of our phase I, so we do see GI toxicity. This is a well-recognized toxicity with selinexor, specifically nausea as well as vomiting. With that said, though, we know that the nausea has a very particular kinetics. So it's transient in nature. So this nausea, if it occurs, is usually going to last about 24, maybe 36 hours. We also know that the nausea, and this is based upon our multiple myeloma experience, usually only lasts for about the first two cycles or eight weeks of a patient's therapy. So each event is very transient. The overall duration of the nausea is also very transient. I mention this because this AE, in my conversations with physicians, really doesn't preclude a patient from staying on therapy long term. Ultimately, that's what we want to see in order to be able to drive meaningful symptom and spleen outcomes. The other toxicities we see, yes, are going to be your hematologic toxicities. Our data suggests that's largely stemming from the ruxolitinib, though. Overall, though, again, this is a very manageable safety profile, very few treatment discontinuations. In fact, in our phase I data, only two patients discontinued therapy due to AEs. One was due to a thrombocytopenia, and another was due to a neuropathy. Great. And maybe just while we're on the subject of safety, if you could just touch on the blinded pooled phase III safety data you guys have shared so far to date and how that's looking versus rux alone expectations? Yeah, absolutely. So in our phase III study, we had a pre-identified, pre-built-in futility analysis. That futility analysis was for both efficacy as well as safety. And it was conducted after the first 61 patients who were randomized onto the trial, all of whom were followed for 24 weeks. That data was then provided to the DSMB. They evaluated again the efficacy, safety. Everything looked great. And so the study continued as planned. Now, we took advantage of that futility analysis, followed the patients for a little bit longer, and took a snapshot, again, of the aggregate blinded data. So we did not have access to the safety by arm. Again, it was amongst all of the 61 patients that had been randomized. And what we saw amongst those 61 patients was, again, what we believe is a very manageable and tolerable safety profile. So lower rates of nausea and vomiting as compared to what we experienced in our phase I. We saw some fatigue, but again, nicely improved from our phase I. We also saw some heme toxicity, but again, it seemed very manageable. The key takeaway, though, was our treatment discontinuations were very low. This is, again, treatment discontinuations due to AEs. Amongst all 61 patients, what we observed was only four patients had actually discontinued due to a TEAE. So these are, again, very low rates at approximately 7%. That aggregate data, again, really suggested a manageable safety profile. With that said, we wanted to take it one step further and really start to understand what was that evolving safety profile, specifically amongst the 40 patients treated with a combination. And in order to better understand that safety profile, what we did is just took advantage of historically defined and observed ruxolitinib safety data. Again, these are from the COMFORT trials, from the MANIFEST trial. We looked at the ruxolitinib alone and used that data as well as knowing that it's a two-to-one randomization to then extrapolate what we believe is the likely safety profile specifically for those 40-some patients treated with the combination. And there, again, suggested a nice evolution and a very manageable safety profile. Nausea had come down to approximately 64%. Vomiting, only approximately 11%. And I say that because that's the same rate that's been described with ruxolitinib alone. Grade 3-4 anemia is probably the most intriguing to me. So for ruxolitinib, what's been described is a grade 3-4 anemia rate as high as 37%. What we are extrapolating for the combination is a lower grade 3-4 rate at approximately 28%. So yes, despite being treated with a combination, a lower grade 3-4 anemia rate as compared to what's been described with ruxolitinib. And lastly, I'll just, again, mention those treatment emergent discontinuations. Again, very low numerically, potentially lower than even rux alone. So a nice evolution in the safety profile, potentially the same, maybe a little bit better than rux. We'll see once the phase III data are observed. Great. That's a really helpful overview of the data generated to date. So we'll pivot to Dr. Harrison now. Thank you so much for joining us today again, Dr. Harrison. So maybe just to start by way of introduction, if you wouldn't mind walking us through your background and your research focus. Hi. My name is Claire Harrison. I'm a professor of hematology and deputy chief medical officer at Guy's and St Thomas', which is a big hospital in London, actually opposite the Houses of Parliament. I've worked as a consultant here for just 25 years and started my career with research into ET, which is a related myeloproliferative neoplasm. My profile is really as a disease expert in this area. I've worked heavily and developed patient advocacy, but I've also been very fortunate to lead a number of the registrational trials. So I was the lead of the COMFORT-III trial, the COMFORT-II even. The COMFORT-III didn't exist. I'm a bit jet-lagged still coming back from Florida. So I was the lead for the COMFORT-II study. I led the JAKARTA-2 study with fedratinib. I led PERSIST-1, and I'm the co-study chair for MANIFEST-2. I treat a lot of patients with this condition and have got sight of quite a lot of data in the area. Even though I only practice in the U.K., we don't have access to all of the JAK inhibitors that colleagues in the U.S. do. I certainly see a big gap for patients and a big unmet need in the field of myelofibrosis. That's great. Very helpful background. And so maybe let's just start with your treatment paradigm for a typical myelofibrosis patient. So they come in, they get diagnosed. What's your typical first line of treatment, and how do patients typically respond? Generally, we would start by looking at the individual need of the patient and what their prognosis is because some patients present very, very early with low-risk disease and don't need treatment. I was reflecting that 14 years ago, I stood at ASH with Serge Verstovsek in an investor meeting for Incyte and said I thought 70%-80% of patients would have ruxolitinib at some point in their disease course. It's interesting to note that that actually is true today. 70%+, maybe 80% of patients with myelofibrosis have ruxolitinib as a frontline therapy. There are a few patients we would give momelotinib to. I mentioned we don't have access to pacritinib in the U.K., and fedratinib is really a second or third-line drug for me, based around tolerability issues, and also it does cause a lot more anemia. So more anemic patients, more thrombocytopenic patients would tend to get momelotinib, especially those with platelets sub-50. But the problem is actually, number one, not all patients respond to ruxolitinib, and number two, those responses aren't very durable. And so what happens over time is that we often have to adjust the dose of ruxolitinib because the patient either develops anemia, and we don't want them to have to come and have transfusion. We may add erythropoietin. If I was practicing in North America, I might be able to add luspatercept. But frankly, those drugs are not very successful, and underlying disease is progressing. So we end up on a lower and lower dose, and ultimately, we stop the drug and cycle through another JAK inhibitor. So what we would really be looking for is something that really does more than JAK inhibitor monotherapy that potentially modifies some of the underlying aspects of the disease and gives patients a deeper and more durable response. And ideally, also, if that's not too much to ask, is better tolerated. That's great. And once a patient progresses on ruxolitinib, what's your next course? I think you said you kind of cycle through other JAK inhibitors, but what's kind of your next course of action there? And what's the general prognosis for that patient after this failed rux? Okay. So I didn't mention, but there are a small percentage of patients that go on to stem cell transplantation. But even in my practice, and I'm quite keen to send patients if they're eligible for transplant, that would be less than 10% of patients. And I would usually send them, still treat them with ruxolitinib, and send them for transplant at the peak of response. And most of the time, the transplant is going, "Stop sending me patients, Claire. They don't do well. I don't want them. I'd rather you treated them medically." So after ruxolitinib, effectively, we're just scrambling around, cycling through other JAK inhibitors. We would, of course, try to put patients on a clinical trial if we can, but these patients are often multimorbid. Their median age at presentation is in the mid-60s. So once they've had three years of ruxolitinib, they're 70. The disease has other issues, so suppressed immunity made worse by JAK inhibitors. So oftentimes, we're moving towards more palliative treatment, and we're often clinging on to the ruxolitinib because we know it's a reasonable drug. But I would say I'm not looking for something that's good in the second line. I really want something that's better in the front line. I'd accept a second-line drug, but I was always taught you give your best option first. So I wouldn't give oral hydroxyurea to someone with acute myeloid leukemia. I'd give them a proper treatment. So I'm looking for a better front-line treatment, to be honest. Great. And maybe moving then to the phase I data that selinexor has shown so far in combo with rux that Reshma just walked us through, what are your impressions of the data that we've seen from selinexor so far? What stands out to you? Well, to be honest, when I started looking at selinexor, all my colleagues in my lab went, "That's going to be a difficult drug for your patients to tolerate," which I've heard before because I gave my patients panobinostat in a study. So I was looking very closely not only at efficacy but also at tolerability. So I think compared to the monotherapy data at higher doses, the dosing in the combination study with ruxolitinib is lower, appears well tolerated. And the depth and the quantity of patients that are getting past the 35% spleen volume is good. And this 35% spleen volume reduction is a key marker for us. We had shown previously from the COMFORT-II and COMFORT-I analysis that that is a key marker of a survival benefit for a patient. So I'm always happy to see more patients getting through that SVR35 with ruxolitinib, typically at 30%. So what we're seeing here is in small numbers, in an unrandomized study, data that looks good. Also, what looks good is symptom response and anemia response. And as I'm also a translational scientist, I'm also interested in seeing translational data, so data to what's happening with the mutation, data on what's happening in the marrow. And I'm also super happy to kind of think that I'm using a therapy that's logical for my patients. There's a biological rationale. That's helpful. And on safety, I guess maybe just kind of double-clicking there in terms of, have you seen with any of your patients kind of how tolerable the nausea is in those first couple of cycles and anything else that stands out? Sure. So I haven't been lucky enough to give selinexor in any of the previous studies, but we do have patients in the current study that we're all excited to see a readout for. And we also have a patient that is enrolling in the monotherapy study. But to be honest, in previous trials, we could usually tell which patient was on the combination. So with pelabresib, the patients get altered taste. It's a two weeks on, one week off cycle. So we're also asking them, "Do you feel any different in the last seven days of your cycle?" These patients, they are taking the antiemetics, but we haven't had any breakthrough vomiting, no GI toxicity. My patients are all beyond now cycle two, three. My patients have got good tolerability, and most of them seem at least to, I don't think any of them have reached the MRI point yet, but they do seem to clinically have good responses in terms of spleen. And just to say, with ruxolitinib, we often see that patients put on weight. With selinexor, I know in the myeloma setting that patients did often lose weight, but that wasn't seen in the combination study. So my patients are all maintaining weight nicely, which is also important. So I'm excited to be honest. That's great. Yeah, that's great. And I know you mentioned pelabresib and many of the other clinical trials you've been involved in historically. I know you had just, I think, discussed some of those, the 72-week follow-up from MANIFEST-2. Just kind of what's your view? Navitoclax didn't end up showing TSS, but did show SVR35, but I don't think that's moving forward. And then pelabresib, I think just kind of narrowly missed on symptoms, though I'm not sure there's a path forward for that drug either. But just curious your thoughts on either of those programs. Navitoclax isn't being taken forward, but I think the problem with that study was that Navitoclax causes a lot of thrombocytopenia, and so there was a lot of dose adjustment. Patients had to interrupt drug, and then there was also frequent interruption and dose alteration with ruxolitinib, which is problematic. For pelabresib, I was one of the clinicians who was involved in designing that study, and we were quite careful about dosing of ruxolitinib because we knew that pelabresib causes thrombocytopenia, and pelabresib missed on symptoms, but we did an analysis that basically showed that if they had discounted fatigue, because there is a ceiling effect with ruxolitinib on fatigue, and we know that fatigues are very difficult. I mean, right now, I would score on fatigue because I've just flown back from Florida, so if we had discounted fatigue, that study would have been more positive. So I think, and we've shown that ruxolitinib, for example, does reduce fatigue levels to the equivalent of a normal person who might be accompanying our patients in the waiting room. So we've seen the 96-week data for pelabresib at ASH. It was presented on Monday. It's a drug that delivers spleen and symptom responses, although we're starting to see a waning of the spleen response now at 96 weeks. So we'll continue to look at it. I suspect the data from the selinexor study will be compared by colleagues to the pelabresib study. And the only other thing to mention with regard to pelabresib is there was an imbalance with regard to leukemia. That appears to have leveled out now, but I think that will ring a small alarm bell when it comes to treating patients with earlier disease. Patients with intermediate one risk with a trajectory of eight to 10 years, we might think twice as investigators in putting a patient on a drug like pelabresib, even though it's played out to be probably not a problem. It will probably just make us think a little bit. Great. That's really interesting, and we're going to dive into the SENTRY design in a second, but actually, while you're talking about some of the intricacies of the dosing of these other studies, does anything stand out to you, Dr. Harrison, for SENTRY in terms of the dose adjustments for selinexor and rux or how that might impact the trial? I think just to go back to what I said about Navitoclax and thrombocytopenia, I didn't actually put patients in TRANSFORM-1. I was the lead investigator on the REFINE study, and we saw a lot of thrombocytopenia. We haven't seen more thrombocytopenia with selinexor compared to with ruxolitinib. So I've looked at that very carefully because I know that that's limiting, and that's often the reason why we dose-reduce ruxolitinib. And I know that colleagues are looking at sort of mean dose of ruxolitinib, and that's important. But just to also say that the symptom responses with selinexor monotherapy are very striking. So I think we can be reasonably reassured. We're going to have to see how it looks when we get the results, and we're all excited to get them. But I think that the design of the study is robust. Patients going on are robust. The data from the monotherapy and combination that we used to design the study is robust. And the early safety look that Reshma was referring to earlier is reassuring. And my patients, which are the things that I can judge on the most, they're all still on the same dose of ruxolitinib, and we haven't had to dose adjust. And the other thing, just to say, sorry for talking a lot, is that dosing of selinexor is very straightforward. It's one flat dose. So it's not complicated for investigators to manage. That's super helpful. And so maybe let's dive into the SENTRY study design a little bit more, maybe for the Karyopharm team. Just kind of walk us through the trial design there and then the two co-primary endpoints, including the somewhat recent change to the absolute TSS. Sure. I can take this one, Colleen. So it's a very easy, conventional sort of combination trial in myelofibrosis. So again, these are going to be those front-line patients. They're all going to be JAK naive, very similar patient population to either enrolled on MANIFEST-2 or even TRANSFORM-1. It's a two-to-one randomization in a double-blind fashion to either selinexor plus ruxolitinib. Again, this is the 60 milligrams of selinexor in combination with standard of care ruxolitinib or ruxolitinib plus placebo, total of 353 patients. The primary endpoint is going to be specifically evaluated at week 24. And there's two endpoints: SVR35 and then absolute TSS. The way that the stats is going to work is that the full alpha is going to be allocated to SVR35. And then if that's positive, the full alpha will then be rolled down to absolute TSS. We are looking at a host of other efficacy endpoints, including hemoglobin stabilization, hemoglobin improvement. We're looking at long-term endpoints for both absolute TSS as well as SVR35, specifically at week 48 and beyond. We're looking at PFS, OS, and then a number of disease modification endpoints. So really a robust efficacy profile as well as long-term data coming out of the trial. Okay, great. And so I think Dr. Harrison actually touched on this. Some of the other studies, pelabresib included fatigue and TSS, but I believe you're excluding that, correct? Maybe just talk through that decision. Yeah, that's correct. So it's important to keep in mind that our entire development program in myelofibrosis has always excluded fatigue, whether this is our phase I trial evaluating selinexor plus ruxolitinib, our 005, so this is that monotherapy study in a previously treated patient population. And again, this ongoing phase III, again, all excluded fatigue. And one of the reasons that we did that is that we looked at precedent, right? So we know that for both ruxolitinib as well as fedratinib, the pivotal trials that ultimately led to their approvals were all based upon modified TSS, which again excluded fatigue. And the rationale was exactly how Dr. Harrison mentioned. It's just a very, very difficult domain to accurately assess and especially assess improvement relative to placebo. So we've excluded it. Of course, we've talked to the FDA about excluding fatigue. And again, just to reiterate, that's how our Absolute TSS will be conducted for the primary endpoint. Great. And then so just help us understand what would be a successful result here in terms of what the study is powered to show for SVR35 and TSS? Sure. So both of the endpoints, again, SVR35 and Absolute TSS are powered greater than 80%. SVR is actually greater than 90%, where our assumptions are 70% for the combination relative to 40% for ruxolitinib alone. Again, conservative assessments based upon the data we've observed in our phase I as well as historical ruxolitinib. For Absolute TSS, again, greater than 80% power. And that assumes a four-point delta across the two arms as well as a standard deviation of 13. There too, we believe those assumptions are conservative, just given the fact that Absolute TSS for ruxolitinib across a host of a number of trials suggests a pretty modest improvement relative to our 18.5. Also, it's important to note that our standard deviation is actually running smaller than the 12 that has been included in our trial. So again, we believe that both of them have a really good chance of success once the data read out in March. Okay, great. And I know you recently shared on the phase III earnings call the baseline TSS. So maybe just to kind of talk about, hit on that point and what that might mean for the patients in the study. Sorry, you mean absolute TSS? Yes, or at baseline. Baseline characteristics in the study. Baseline characteristics, yeah. So this was an online abstract that was included as part of ASH just this past weekend. And we're really encouraged by the baseline demographics. So by and large, when we look at baseline spleen, baseline platelets, baseline hemoglobin, percentage of patients who are transfusion dependent versus independent, primary versus secondary, and then breakdown by DIP status, they're all very consistent with what we have seen in other phase III trials and also very consistent with what we saw in our phase I trial. The one variable that is a little bit different is going to be that baseline TSS in that the baseline TSS in our phase III is actually running a little bit higher. These patients are more symptomatic. Probably what we are going to see is that without fatigue, the baseline TSS in our phase III probably could be the highest of any other phase III trial. We did this purposefully, largely because we believe, again, based upon some data, that the higher the baseline TSS, the more likely we're going to see a meaningful outcome from our phase III results in March. Great. Super helpful, and Dr. Harrison, did you have any thoughts on the baseline characteristics they've shared so far, specifically on that kind of higher TSS at baseline and how those patients might respond? Well, I think my kind of simple mind is actually if you're looking for a 50% reduction or a high absolute mean change, you're actually likely to have more accuracy if you have a higher TSS, and it also gives the opportunity to show in more detail. I think it's also interesting given that fatigue's being excluded and given the difficulties, as I've mentioned, we have in getting beyond the benefit of ruxolitinib for fatigue. I think that's a happy omen in some ways. Of course, we are just going to have to see how this plays out. We are making sure our patients are recording their symptom scores. We do give them a lot of training in doing that. I think it's reassuring. It's good. I mean, if we have patients entering with a symptom score of four, it's pretty difficult to get to two. As I said before, if I gave everyone one of those symptom scores, we would all probably score at least one or two on many of those parameters. So I think it's good. I think otherwise what we're seeing for those patients is a good readout. It's nice to have a peek into a kind of totally blinded. That's reassuring. Yeah. That's helpful, and in terms of SVR35 that we'll see in the top-line readout in March, is there any threshold, Dr. Harrison, that you're looking for, or is really just a statistically positive study probably the most important? Statistically positive is good, right? Because that means it's a positive study. It can be very good. What we know with ruxolitinib is, in COMFORT-I, the response rate was about 40%. In COMFORT-II was about 30%, and that's probably because the COMFORT-II primary endpoint was at week 48. We know that with pelabresib and with navitoclax, it was roughly double. So I would expect and hope to see something that hits or exceeds that. If we look at the data from the combination, it's actually very impressive. It's hitting sort of 80%, but of course, we just have to see when we treat a more diverse group of patients, and there is a diverse range of centers that have entered patients in this trial because the enthusiasm is high and it's open globally, so that means that the results will be reflective of a bit more of the global population, which is important. So I would expect to see more 60% or more, to be honest. I don't feel that I need to see spleen responses that are 50% reduction. As I mentioned before, our mark is 35% and more patients getting that benefit. It would also be good to see more patients getting the benefit of symptoms as well. So the absolute change in symptoms that was seen in the previous studies was 18. In the pelabresib study, we saw a difference that was, I think, 14 or 15. So again, it's important for me as a clinician to know my patients are going to benefit and they're going to tolerate the drug well. So if I can see patients that are benefiting from both symptoms and spleen, we've shown that for pelabresib, it would be good. Great. And are there any other endpoints beyond SVR 35 and symptoms that you'll be paying attention to in this top line readout? In the top line, yes, so a few things. Number one is hemoglobin, so we know that anemia is a strong prognostic factor. If I ask a medical student, "What do I use to test for prognosis?" for any heme malignancy, anemia is a prognostic factor, and what we know in myelofibrosis is if we can keep a patient's hemoglobin up or keep them independent of transfusions, that's actually also a good prognostic marker, so for me, it means the patient's out of hospital, not needing frequent dose interruptions, they're not needing transfusions, and their prognosis is good. I would also be very interested to see, of course, tolerability, how many patients are staying on, because that's important. You can have the best regimen, but if it's not tolerable and your patients can't carry on taking it, it's not good. So we'll get a sense of that in ASCO when the results are hopefully going to be presented, I understand. But also, increasingly, the BDI is on other surrogate markers of really hitting the basic biology. So improvements in the proportion of driver mutations, otherwise known as allele burden or variant allele frequency VAF, will be important to see. Preliminary studies with navitoclax, imetelstat, and others have shown that a modest VAF reduction is also linked to survival benefit. And there's a biological reason why we might see that. Also interested in cytokines. Cytokines also, they correlate with the well-being of our patients, but they also have a correlation with survival benefit. So these are all readouts that we're being promised as a steering committee. And logically, we should see with selinexor, looking at its mode of action against key pathological drivers of disease. Also really interested in its effect on apoptosis, P53 pathway, which is a difficult pathway. So if we can see a benefit in terms of survival and less leukemia, that would be good. But it's hard to read that out because it's not a common event and it's something that happens over time. Okay. Super helpful. And I realize this might be a hard question to answer, Dr. Harrison, since we haven't seen the data yet. But in a world where there's positive phase III data, this combination is approved, how would you expect you would potentially use a selinexor + rux combination in your practice? Okay. Well, the first thing to say is that I was always taught, and I'm quite long in the tooth now. I've said I've been a consultant for 25 years, that you should give your best therapy first. So if the patients in this study enjoy a better chance of getting SVR35, a good symptom benefit, and a better hemoglobin, and hopefully as we get more readouts from the study that is durable, we won't see that so much in the primary efficacy. But over time, as we see that it's durable and we're getting reimbursement in our countries, I would be giving this combination to the majority of my patients. So the patients who are eligible for ruxolitinib with myelofibrosis, don't forget we give ruxolitinib to patients with polycythemia vera and other indications. So I would be wanting to give a combination that was superior to ruxolitinib monotherapy to all the patients that I would be giving ruxolitinib to. Okay, great. That's super helpful. And from a monitoring perspective for this combination, is there anything that you expect would be more challenging than what you're doing for ruxolitinib alone, or would this be a pretty easy logistical addition to your treatment paradigm? I think it should be at least as easy. Of course, we have to talk to patients about nausea, but what I've observed from my patients in the study, as long as they comply with the antiemetics, and it's only once a week, it should be fine. I'm very lucky, and all my colleagues in the U.K. are very lucky. We have clinical nurse specialists who call the patients a couple of days after they've started treatment and can remind them. I think the other important thing is when we start ruxolitinib, we expect a 10%-20% drop in hemoglobin, and we sometimes have to monitor patients very frequently for that, and we sometimes actually start patients on a suboptimal starting dose of ruxolitinib as a consequence. If we truly see this improvement of hemoglobin with the combination, it will actually make it easier to start patients, and we may well be able to give them what we know is a more effective dose of ruxolitinib, so in short, I don't think we will need to monitor patients more. I also think that many hematologists and many community clinicians who treat these patients, they're not like me, they also treat patients with myeloma, so they'll be used to using selinexor, so for them, it will just be thinking about it in combination with ruxolitinib, a drug that's been around, as I said already, 14 years, so I don't think it will be that difficult, and also, you're not having to multiply dose adjust, which should be fine. That's super helpful. And actually, that was another question I was going to ask in terms of, obviously, you are a major KOL in this space, so obviously, you're very up to date. How would you expect a community physician might approach a combination therapy versus rux monotherapy? Do you think they would favor towards similarly best drug earlier? Or how would a community physician take that? I think they were probably taught the same way I was taught, give your best upfront. I also think they'll be very aware of the limitations of monotherapy with a JAK inhibitor. They will have seen patients get some benefit and then fail, and I would also say, for this study, we have plenty of referrals into our center from the community. Do you have a trial option that's good for this patient that's better than ruxolitinib alone? The study recruited very fast, so the community is interested. It's not only KOLs like myself who are recruiting patients. We have to have them referred in, and just lastly, the patient community in this field is extraordinarily active. It works very well in partnership with the clinicians. My patients frequently come in with a world of stuff that they've read or they've watched a video. I've seen you online. You said this. I think this. Do you agree? They're really well-informed or they'll have a caregiver who's well-informed. They're excited. They want to know more. So of course, there is some education that needs to happen. I'm not saying there isn't. But MPN sessions at ASH and other meetings are stacked out. Frequently, people stack their back. We run a lot of education events. And we now have, in the modern world, we can do webinars like this and spread news both to patients but also to clinicians. So I think the field's hungry for something better. Great. And you touched on this actually in your earlier remarks that your multiple myeloma colleagues had kind of maybe warned you a little bit on the safety, and thankfully, it looks like the lower dose has been much better tolerated. Did your multiple myeloma colleagues have any thoughts on efficacy? Or do you see any read-through really from the multiple myeloma efficacy that we've seen into myelofibrosis, or is it really based on the MF data we've seen? That's interesting. I think you'd have to say it's based on the MF data. It's like cousins from the same family that it's a different lineage. I think you can read out on toxicity, and we can see the data for efficacy, but we can also see the logic. What I don't like as a clinician is if a company comes to me and says, "Oh, I fancy trying this X inhibitor in combination with ruxolitinib," because we know there's a gap, but there's a strong kind of biological rationale here, which I think people can see from the kind of more global action on XPO1, apoptosis, cytokines, NF-kappa B, etc. And so there is some commonality there with myeloma, but I think predicting response and seeing what we're seeing is sort of totally different. Yep. Okay. Super helpful, and maybe to transition to the company then, with this great backdrop, how are you looking at the market opportunity for selinexor or in combination with ruxolitinib in front line? Yeah. Thanks, Colleen. I mean, I think as we just heard from Dr. Harrison, this is truly a transformative opportunity for patients and I think a transformative opportunity for Karyopharm. And as we've talked to, I think in the U.S. alone, we do see this as up to approximately kind of a $1 billion peak revenue opportunity. And obviously, internationally, there will be additional royalties and milestones with our partners. And what's really important is when you look at a company like ours, we have the capabilities in place to launch rapidly, and that's critically important as we hear about the unmet need. There's a lot of overlap in our customer base. I think you heard from Dr. Harrison, a lot of referrals in from the community. So when you look, there's about 80% overlap actually in the U.S. alone in terms of our existing coverage in the community with those myelofibrosis prescribers. And I think you also heard what's really important is when you look at kind of patients' and physicians' workflow to adopt selinexor plus ruxolitinib, it requires no change in myelofibrosis, no additional testing, no changes. And that's really important for the uptake. So this is a combination that patients and physicians can adopt rapidly within their existing workflow, which is really important. And if you look at the numbers with myelofibrosis, there's a prevalent population in the U.S. of approximately 20,000 patients. There's about 6,000 newly diagnosed intermediate to high-risk patients each year. And within that population, around 4,000 have platelets greater than 100,000. And across the population, we've heard and we know that ruxolitinib is a standard of care. We've done some market research already in the U.S., and already with the profile that physicians are seeing, they indicate about a 75% intent to prescribe, and I think you heard it from Dr. Harrison. People are taught to use their best options first, not to wait, so when you look at that together, look at the opportunities to move forward, I think it aligns really well with what we see in other areas and other examples where when new medicines have come and been added to standards of care and really improved, you kind of reach a peak share pretty rapidly in probably two to three years, and there's some great examples, and one that comes to mind is in AML, where we take venetoclax plus HMAs, and in two to three years, that became the standard of care, delivering great benefit to patients. So super excited to have the opportunity to hopefully transform that standard, and I think you also heard about the importance of patients for duration of therapy, and we've heard the median patients on therapy means about 13 months in the U.S., a number of patients also two to three years, so we think we have the opportunity to improve on that, again, with good duration, so opportunity is strong. Patient need is there. We fit into the existing workflow for physicians. We have the capabilities to launch rapidly, so we're super excited to turn that data card over in March and hopefully move forward from there. Absolutely. And maybe, Lori, while we have you too, let's touch on the finances. You recently closed a multi-part financing deal to extend this cash runway. Maybe just walk us through that deal and what the current cash runway looks like. Sure. Thanks, Colleen, and I'll touch on this at a high level because I know we're getting close to the time here. Actually, we were really excited and delighted to be able to announce this comprehensive refinancing package. It had various components with it with additional capital. We also equitized debt that was becoming due in October. We were able to negotiate deferral of interest payments as well as royalty payments, and on a pro forma basis, this provided us with about $78 million in cash, which is important because that extended our cash runway beyond this anticipated phase III myelofibrosis readout, and it actually provides us cash going into quarter two of 2026. Super helpful. And yeah, I know we are quickly running out of time. I feel like we've covered a ton. So I appreciate you keeping that so brief, Lori. I know that was a big deal that you guys raised. So maybe just in these last couple of minutes for the Karyopharm team, if you could just leave us why you're so excited about this MF opportunity that's coming up in this very near term and what that could mean for the future of Karyopharm and why investors should be paying attention to this. Yeah, Colleen, I think as we've heard from Dr. Harrison, there's a high unmet need, and people want the opportunity to improve on the current standard of care. Patients need that opportunity. Physicians want the opportunity, and the opportunity to use selinexor plus rux is one that really fits into the existing workflow, so we're confident we've done everything we can to kind of optimize the trial. We've also heard about all the work we've done in terms of optimizing the design of the trial and doing everything we can to increase the probability of success for our phase III SENTRY trial. We like the strength of our data, where we have preclinical data. We've heard makes a lot of sense from a preclinical perspective, from a scientific, from an MOA perspective. Our phase I data, our phase II data, and the blinded and extrapolated phase III safety data are all very encouraging. And I think all pointing to selinexor having the potential to really play a foundational role in myelofibrosis. And with that, we've talked about the opportunities being substantial and the fact that we have the capabilities in place in the U.S. We have partners in place internationally to be able to execute quickly and move forward and make this available to patients as rapidly as possible pending positive data. So we eagerly await to have that data in March. And with that, again, Colleen, thank you for hosting us. And I really appreciate Dr. Harrison with her jet lag being able to join us after just being out in Orlando as well. I think, again, for investors, it's an exciting time to really see Karyopharm moving to our next phase of growth with transformative trials in myelofibrosis and then endometrial cancer as well. Absolutely. Well, awesome. Well, thank you so much for that recap. Thanks to the whole Karyopharm team for joining. Especially a huge thank you to Dr. Harrison for sharing all of her expertise in this area. So thanks, everyone, for tuning in. Thank you. Thank you.