Brian Abrahams, Senior Biotech Analyst here at RBC Capital Markets. Our next presenting company is Karyopharm Therapeutics, represented by their CEO, Richard Paulson, and their Chief Medical Officer, Reshma Rangwala. Thank you guys so much for joining us. Thanks for having us, Brian. Maybe just to kick things off, big picture, can you give us the latest overview of the business, the latest commercial performance for Xpovio in myeloma? And then sort of, and maybe a little bit of an introduction on how you're planning to expand selinexor's label in other indications. Sure. Sure. Thanks, Brian. I mean, you know, Karyopharm is a commercial-stage, oncology-focused company with selinexor currently approved in multiple myeloma in the U.S. and over 40 countries globally. We're guided to revenue this year of $140 to $160 million globally. In the U.S., we just reported Q1 sales of $26 million, a nice kind of quarter-over-quarter growth of 4% in multiple myeloma. And what we're very excited about moving forward is what I think is a very transformative and very value-generating pipeline in terms of being able to enhance and create new standards of care for patients. We have three Phase 3 programs ongoing with selinexor, and each one of those, in totality, is supposed to read out over the next 18 months. And the Phase 3 programs are in myelofibrosis, which we can spend some more time on later in this discussion. In myelofibrosis, you know, looking at frontline patients in combination with ruxolitinib, where we believe we have the potential to be the standard of care. And our early data, you know, as Reshma can talk about, we think is very strong. In endometrial cancer, where we have a very unique patient population, and the majority of patients really building on molecular classification, which physicians are very interested in doing endometrial cancer, with selinexor providing, you know, very strong benefit to patients who are TP53 wild... whose tumors are TP53 wild type in endometrial cancer. And then in multiple myeloma, we want to expand in multiple myeloma with an all-oral combo, which would be selinexor in combination with Pom/dex. And again, I think to have an all-oral combination is a significant benefit to the community. And also, if we take selinexor and Pom together, we think they have the ability also to be T-cell sparing, which is very important, given the evolving role of, you know, T-cell therapies in multiple myeloma. So for us, as an organization, obviously, to be running a Phase 3, Phase 3s is significant. The organization is very focused on it and driving forward very strongly. And from a financing perspective, you know, we've been very excited. Just last week, we announced, you know, significant debt restructuring, taking the vast majority of our debt into 2028 and 2029, kind of well beyond our potential data readouts and well beyond potential label approvals. Really, I think, to get people to be able to focus on our pipeline and really unlock the value of our pipeline, you know, as we move forward. As an organization, we also have a really strong commercial capability. So that capability right now is, as I talked about, delivering our multiple myeloma revenue. When you look at multiple myeloma by itself and just our commercial capability, it's already profitable. But importantly, it also gives us the potential to be able to launch rapidly, as we look at potential new approvals moving forward with our Phase 3. So it's exciting times for us and very focused, and I think a transformative future over the next 18 months. Great. No, that was a fantastic overview. I wanna drill down on a lot of the clinical trial work, as well as the commercial prospects. But maybe just first, can you elaborate a little bit more on the debt restructuring? Because that, I know, was the most recent announcement. What went into your decision to restructure the debt, and what it means for the business and where you are with regards to capital needs and runway, vis-a-vis the upcoming catalyst? Yeah. So, yeah, as you mentioned, a significant, significant focus for the organization, really to ensure that our, our capital structure better mirror the potential we have in terms of our pipeline. So to be able to extend the vast majority of our debt into 2028 and 2029, you know, well beyond the data readouts and potential approvals, I think really enables, you know, people to focus on the data and the potential for us to, to launch in these indications. And, you know, we were able to take advantage of our, our debt trading at a discount. So we got a 25% discount in exchange, about $148 million for $111 million in new debt in 2029. And also, you know, as we looked at the transaction, we were able to enhance our, our cash position. We added about $30 million cash, which takes our cash runway into the end of 2025. Again, kind of beyond our data readouts. So from an organizational perspective, I think it was a great opportunity to address it at the right time. You know, usually, you want to address this before it becomes current. We did. And as an organization, we feel very good about how we've addressed it and moving forward. Great. Let's talk about myelofibrosis. Can you give us a sense of your expectations for the ongoing Phase 3 study of selinexor plus rux in MF? I guess, how are you thinking about both, I guess, the bar for spleen volume as well as symptom improvements? What you think you need to show and what you hope, what you expect to show? Yeah. Absolutely. So the ongoing Phase 3 trial is specifically recruiting a patient population that is JAK-naive myelofibrosis. So these JAK-naive myelofibrosis all have to have a baseline platelet count of 100 or above. We're enrolling across all DIP scores from INT-1 all the way to high risk, and we're going to enroll approximately 306 patients to either the combination of selinexor at the 60 mg dose in combination with standard of care, ruxolitinib versus ruxolitinib alone. We're focused on two main endpoints: SVR 35, very traditional in myelofibrosis, and also TSS 50. And what we aim to show is not only clinically significant improvement across both of those endpoints relative to Rux-... But we aim to show the best SVR and TSS 50 data. Why do I say that? Is because the Phase 1 data, I think, are very compelling. We evaluated a group of JAK-naïve patients, you know, treated them with a combination of selinexor and ruxolitinib. And what we demonstrated in that Phase 1/2 trial was a very impressive 79% SVR35, numerically, some of the highest numbers out there. For TSS50, it's equally impressive at about 58%. So, you know, I anchor around the data that we've already demonstrated, and I think in our Phase 1/2, we have that opportunity to also show very similar numbers that potentially can drive a best-in-class combination for this patient population. Great. Can you remind us the timing for this study? Yeah, absolutely. So right now, we're projecting top-line results in the second half of 2025. Any potential for an interim analysis? So, no. So, you know, we're looking at, you know, sort of the week 24 data from all of the patients- Right ... that have been enrolled in the trial. Okay. Right now, second half. Okay, great. And then I know you're also running a monotherapy study, looking at selinexor in the frontline- Yeah ... as an alternative to Rux. How did you come up with the design of that study, and what are you looking to show in order to support selinexor's activity? Yeah, absolutely. Great question. So this is a really unique opportunity for selinexor and XPO1 in general. It ties back to the mechanism, right? Yeah. The mechanism of XPO1 inhibition really demonstrates broad applicability across multiple cancers. Mm-hmm. But specifically in MF, what we are taking advantage of is that XPO1 inhibition targets both JAK and non-JAK pathways, so it potentially already has this monotherapy potential. We've seen this in preclinical data. We've also demonstrated this in clinical trials. So there was the ESSENTIAL trial, a Phase 2 study, that evaluated selinexor as a monotherapy in this pretreated patient population. I think, as we all appreciate, this is a very high unmet need patient population, and we demonstrated a 30% SVR35, so again, already demonstrates monotherapy activity. And the Rux doses in the combo were potentially subtherapeutic as well. Exactly. Yeah. Exactly. So we have a subgroup of patients, you know, treated with suboptimal, also showing very compelling SVR35 and TSS50. So this Phase 1 study, which is looking at Seli as a monotherapy in this JAK-naïve patient population, further demonstrates that activity. I think more importantly, though, when you look in the context of our ongoing Phase 3, monotherapy, activity gives flexibility to physicians, right? So they can discontinue the ruxolitinib largely because of AEs, but potentially not compromise their activity that they can gain from either SVR or TSS50, right? So it gives flexibility to patients. Seli monotherapy also expands our opportunity in that JAK-naïve space. If you look at patients with moderate thrombocytopenia of 50 to 100, in addition to the 100 and above, which we are demonstrating in that, you know, the Phase 3 trial, we have an opportunity to embed selinexor in about 90% of all JAK-naïve patients. In terms of selecting this patient population, I guess, how... What's the right way to think about the, I guess, balancing, you know, the unmet need of a slightly thrombocytopenic population with or slightly low, lower platelet population, with the potential for selinexor to have some thrombocytopenic toxicities? So when we look at ours, it's interesting. So yes, selinexor has demonstrated some thrombocytopenia. I will say it's not clinically significant thrombocytopenia. So yes, there are a couple of dose reductions, dose modifications that need to happen. The key aspect, though, is that patients are not being discontinued from treatment as a result of that thrombocytopenia. Then maybe also on the safety front, there, there's been some concerns about tox signals for other MF drugs in development. Mm-hmm ... that have been, or on the market, that have been under debate, things like AML transformation, peripheral neuropathy. What do you think the safety bar is for a new MF therapy, and where do you think selinexor could potentially fit in the- Would either of those toxicities that I mentioned be of any concern based on what you've seen? They're very rare- Yeah ... side effects, right? I think this is one of the huge advantages of selinexor. Yeah. So because it's a commercially available therapy, we've obviously treated multiple myeloma patients, as well as multiple other indications. If you aggregate across the entire experience, we've treated about 30,000 patients with selinexor, so we have a very well-described safety profile. Those rare risks just do not exist with selinexor. Right. I think we're very confident with our safety profile. Do you think you need to hit on both spleen and symptoms from a statistical significance standpoint to get approval? You know, I think likely, you know, that's my assumption, you know, right now, is that we do need to show benefit for SVR as well as symptoms. I think more importantly, that's what patients want, right? Yeah. You know, they want it, they want both spleen reduction as well as symptom improvement, and that's what we aim to show in our Phase 3. You started to outline the potential market positioning of where Seli could fit in in MF. I was wondering if you could expand on that a little bit. How are you seeing the MF market potentially evolving with the advent of, you know, additional JAK inhibitors, potentially a BET inhibitor? Where do you see selinexor fitting in? How big of an opportunity might this be to expand the sales potential? Mm-hmm.... Do you want to take it, Richard? Yeah, I think when you look at the evolution of the marketplace, you know, in market research we've done, I think and others have done, there's a clear intent by physicians to say, you know, if you can have combo therapy with significant improvement in SVR and then TSS, physicians will use that for their patients, which makes a lot of sense. And I think as you heard from Reshma, our intent is to show best-in-class data. So I think with the potential to show best-in-class data, with a very well-established and only improving safety profile, with bringing down the dose of selinexor, I think we have the large ability to be the leader in that marketplace. Obviously, we need to see our data readout, but that's our intent as we move forward, is to really be able to have a leading position in the myelofibrosis marketplace and in the frontline in combination with Rux. Good. Well, certainly, at least from what Incyte has demonstrated, it could be a large market. Maybe shifting gears to endometrial cancer. Yeah. I know we're coming up on some new data- Yeah. You're going to be presenting update to the endo data at ASCO. Yeah. Can you talk about, I guess, how the longer-term follow-up data continue to support selinexor's potential in this p53 wild-type endometrial cancer patient population? Yeah. Very, very excited for ASCO, which is coming up in a couple of short weeks. But I will say, like, we were invited to present this abstract. Vicky Makker from Memorial Sloan Kettering is going to be presenting on behalf of all of the investigators. And there's a lot of excitement, right? So the long-term follow-up data that we've previously presented has already shown a very impressive 27-month median progression-free survival for patients treated with selinexor and whose tumors are p53 wild type. We've also demonstrated really compelling efficacy when we look at that subgroup of patients who are both p53 wild type pMMR, but also p53 wild type dMMR. In that p53 wild type pMMR, we still have not observed a median progression-free survival. We continue to follow those patients, right? I think that's an opportunity with updates, is to, again, provide median progression-free survival in that important subgroup of patients. Yeah. Obviously, you know, we continue to mature the overall survival. There's new analyses too. So, you know, largely we've focused on efficacy in terms of PFS, OS, the safety profile. You know, we have opportunities to also start to incorporate quality of life, too, right? Quality of life, I think, better provides a compelling positive, very positive benefit risk, you know, for selinexor as a maintenance therapy. You know, ultimately, what we aim to demonstrate is that just like myelofibrosis, selinexor has the potential to show the best data, specifically in those high unmet need patient populations, including pMMR, and now this new novel subgroup of patients who are classified by their p53 status. Can you talk about maybe a little bit more about the commercial opportunity in endometrial? You alluded to it with some of these patient populations where you're seeing the biggest unmet need, but I guess, where do you see selinexor potentially fitting in? You know, how should we be thinking about the subgroup analysis, the pMMR, dMMR, what that means for the most addressable populations, and where... I guess, how are checkpoints used today in the maintenance setting? Where does selinexor fit in relative to those? So let me take the second one first, right? So there's a lot of evolution in the endometrial space. You know, I think as Richard alluded to earlier, you know, the evolution really is about the molecular underpinnings of their cancer, right? And I think the, probably the most important right now, you know, molecular entity is the patient's MMR status. So patients who are dMMR or MMR deficient- Yeah ... they represent, you know, sort of a small 20% of all advanced recurrent endometrial cancer. The larger groups, you know, that's, that's going to be classified as MMR proficient. There is a new standard of care, specifically for those patients whose tumors are dMMR. This is going to be a checkpoint inhibitor, specifically dostarlimab, in combination with chemotherapy, followed by dostarlimab maintenance. For those patients who are pMMR, there is no approved agent, right? So those patients, by and large, are still going to be treated with carboplatin for a limited number of cycles. Once they complete those number of cycles, they're just going to be followed with a watch and wait paradigm until they progress. That progression occurs very quickly, which is why people really do want to identify a new maintenance option and why selinexor is so compelling for that patient population. I will say, the checkpoint inhibitors, although they have demonstrated, you know, benefit in that pMMR, investigators, you know, unfortunately, don't think that it's compelling, right? And so I think they really are looking for newer agents, you know, where benefit can rival what has already been seen with the checkpoints in that dMMR patient population. Should we be looking for any significant updates in the ASCO abstracts next week, or will most of the updates, on, you know, quality of life, maybe PFS data for pMMR, those, will that... any OS trends, will that all come at the meeting? You'll have to come. We'll be there. You'll have to come. No, I think we have opportunities to sort of update across all of those key areas- Okay ... efficacy, safety, and quality of life. Okay.... Got it. And then, I guess, can you talk about the ongoing study? How has enrollment gone? How's the conduct gone? What are the timelines we should be looking for? Yeah, absolutely. So, you know, again, it, it comes back to the data. I think people are very, you know, physicians in general, investigators, you know, both in the U.S., ex-U.S., are very, very compelled and excited about the opportunity to not only identify a new patient population, you know, based upon their p53 status, but the potential opportunity to now incorporate selinexor as a new standard of care. That enthusiasm is very much translating into enrollment for the clinical trial. Right now, we are projecting top-line results in the first half of 2025. Great. And just before I move on to myeloma, maybe just also on study timelines, what should we be expecting to see from the frontline selinexor monotherapy MS study this year? I guess, how much data, how many patients, or I guess, how meaningful will that be this year? Will that be just a really early preliminary cut? Sure. So we just announced initiation of that trial last month. So with that said, you know, if I have to project what we can expect over the course of 2024, it's going to be initial data, right? So a few patients, some initial efficacy and safety from some earlier time points from that study. But, you know, keep in mind, this is a paradigm shift, right? You know, in myelofibrosis, it's all, it's all about the JAK inhibitors. This is the first time that a non-JAK inhibitor, and especially an XPO1, is going to be evaluated as a monotherapy. So lots of excitement and, and opportunities for selinexor there. Great. And then maybe just, before we wrap up, would love to touch on the multiple myeloma franchise, both from a commercial and, and clinical standpoint. Can you talk about some of the headwinds and tailwinds, for Xpovio, uptake and, and revenue ahead and in the commercial setting? And then, I guess, how you're looking to preserve and grow the revenue stream, how much of an inflection might we expect post that all oral data that you alluded to earlier? Mm-hmm. Yeah, I think as I, as I touched on at the beginning, you know, in Q1, revenue of about $26 million, we've guided to $120 million for the year, and, you know, really positive to see in Q1 that we had NRX growth in both the community and the academic setting. Now, that was offset, especially in the community setting, by the fact that in Q4 last year, we had lower NRX, so the refills were somewhat lower in Q1 this year, and we also had a, you know, higher GTN, which is typical in Q1. So as we look moving forward, I think the positive focus in the community is going to be continuing with the positioning we put in place, which is post anti-CD38, and we preferred Category 1 NCCN listing. Physicians, I think, are increasingly used to being able to use selinexor appropriately with dual antiemetics upfront, and we're seeing patients in the community setting in their oral lines really having nice duration of therapy. Then in the academic setting, you know, positive to see demand growth Q-over-Q. As we look in the academic setting, you know, the strategy we put in place is to generate a significant amount of data looking at the role of selinexor pre and post T-cell engaging therapy, which, I think as that continues, we're seeing physicians and kind of increasingly from the front of the stage, as we'd say at academic meetings, looking at the importance of what's the right kind of therapy to use before utilizing a T-cell engaging therapy. Selinexor data, I think, is looking very strong, and we're continuing to generate more data in that space, and I think that's where we're seeing increased utilization. At the same time, you know, for sure, we're going to continue to see it's a very competitive marketplace with, with the bispecifics, with the CAR-Ts, and so balancing those two. As we move forward, I think with XPD, our view is that that is going to be the leading, combo, regimen that we're going to see with selinexor moving forward. So it will help to generate mid to long-term growth, in multiple myeloma, an all-oral option, and it's at the low dose. I think what's really important is that that's at the low dose, and also it'll be the first Phase 3 in multiple myeloma, where we're using, you know, the dual antiemetics through the study. I think it would really give us the opportunity to promote, a different safety profile, to promote, the low dose. And, you know, Pomalyst is about a $2 billion backbone in the U.S.- Yeah. So very significant opportunity for us moving forward. And also, when you look at the complexity of all the different therapies that are out there, you know, physicians and then patients, especially, they need access to some therapies which are pretty, you know, easy to take, and they can take no matter where they are in the country. So to have an all-oral regimen with strong efficacy and tolerability, I think, is really important to drive growth. Great. Well, with that, we're out of time. So Richard, Reshma, thank you guys so much. Thank you. Thanks, Brian.