Okay, we're going to go ahead and get started. Thanks for joining us for our last session of the morning. My name is Chris Raymond. I'm a senior biotech analyst here at Piper Sandler. It's my pleasure to introduce our next presenting company, which is Karyopharm Therapeutics. We have with us the President and CEO, Richard Paulson, and CMO, Reshma Rangwala, so just to go over the format, a little housekeeping: this is a fireside chat. It's meant to be very informal, so if anybody in the audience has any questions, just raise your hand. I'll make sure it gets asked and answered, so we have time for Q&A. But before we do that, maybe, Richard, if you could just sort of level set the conversation, a little introduction for those who don't know Karyopharm, about the company, the story, and the setup going forward. That would be great. Great. Thank you, Chris. Thanks for hosting us. And great to have everyone here this morning. And before I get started, a little housekeeping: the various comments we make today may constitute forward-looking statements. So please refer to our risk factors in our SEC filings. Karyopharm is a commercial stage, innovation-based company. And our foundation is in multiple myeloma. But we're also rapidly advancing a late-stage pipeline, which is very exciting as we're moving forward. And if I talk to our foundation from a commercial perspective in multiple myeloma, this year we've guided to deliver net revenue of about $145 million-$155 million. And we're very pleased that through the year we've actually delivered three consecutive quarters of net revenue growth in our multiple myeloma franchise. And in fact, in the last quarter, Q2 to Q3, delivered double-digit demand growth. We're going to be working to continue delivering and working to deliver our growth as we move forward, making a very competitive multiple myeloma landscape with a profitable multiple myeloma franchise, which obviously gives us a commercialization capability, which strengthens us as we move forward and look at our potential, looking at the evolution of our pipeline. I think when we look at our pipeline, obviously there's three programs we have in our pipeline. It's first building on the multiple myeloma franchise. So our Phase 3 program with selinexor PomDex an all -oral combination, which we're very excited about, that's continuing to move forward well. Second, it's in the myelofibrosis area, looking at our combination with ruxolitinib. I'm sure we're going to spend some time talking to that. We've had some really exciting evolution over the past month or so, which we announced. We'll spend some time looking at how we've evolved the endpoints, make positive evolution in conversations with the FDA, and really evolving with the evolving landscape in myelofibrosis to evolve our endpoints to SVR35 and absolute TSS, which we believe gives us a strong opportunity and increases the probability of success for us to be the first combination therapy approved to myelofibrosis. I think in the myelofibrosis area, as we know, ruxolitinib has been the standard of care for well over a decade. You still have less than half the patients which are really responding. I think there's a great opportunity to improve on that. We're excited the trial's moving forward very strongly, with enrollment planned to be completed in the first half of next year and data readout in the second half of next year as well. We can spend some time talking to that. Our third program is our endometrial cancer program, EC-042. In that program, as we shared this morning in a press release, we're engaged in some conversations with the FDA and upcoming meeting. Currently, we're not going to go into conversation on the EC-042 program or answer any questions about it, and look forward to updating people as we work through those conversations in the very near future. As an organization, when you bring back the foundation, as we said, building on our foundation of multiple myeloma, moving forward with the commercialization capability, a very strong development capability, advancing our pipeline, the next 12-18 months is very exciting at Karyopharm. Great. So no endometrial questions. No, I'm kidding. I was going to lead with that. But that was a great intro. And we will leave it at that. So maybe just dive into myelofibrosis then, if you don't mind. So you mentioned some encouraging data that you've had. Talk a little bit about that, the most recent data cut you presented and the relevance. You mentioned rux and the improvement that can be had over there. Help us understand how that data compares to ruxolitinib. I can take that one, so as Richard mentioned, I think we're really, really excited about where we are and the opportunity that we have with myelofibrosis. If I look at the landscape, there is a huge unmet need, and I know we sometimes talk about unmet need, but in myelofibrosis in particular, you can argue these patients really only have one meaningful therapy available to them. This is ruxolitinib or Jakafi, approved more than 10 years ago, and when it was approved, it demonstrated benefit when we look at two main traditional endpoints, so this is going to be SVR35 or spleen volume reduction of at least 35%, and the other endpoint is going to be something called TSS or total symptom improvement. Back then, they were looking at what's called 50, TSS 50, a 50% improvement in their symptoms relative to baseline. With that said, a majority of the patients do not benefit from ruxolitinib. And I'm specifically talking about JAK inhibitor naive or this treatment naive myelofibrosis population. If you look at the data, not only from the original COMFORT trials that led to their approvals, but even just larger real-world evidence use, only about a third to 40% of patients actually achieve a spleen volume reduction of 35%. Even when you look at symptom improvement, less than half of patients are actually achieving a symptom improvement. So really, it suggests to us that there is a lot more that we've got to do for these patients. And I think when I look at physicians, when I talk to physicians, when I look at the landscape, what is really demonstrated likely the most meaningful impact is we've got to move into a combination setting. I think this is really where selinexor data is so pronounced. If I look at selinexor, it's obviously a novel mechanism in myelofibrosis. It's an XPO1 inhibitor. That XPO1 inhibition lends itself to multiple mechanisms by which it leads to anti-tumor effect. It obviously is impacting downregulating that JAK-STAT pathway. But it also leverages positively the NF-kappa B pathway, which is integral in symptom improvement, p53, which is an important tumor suppressor, but even cell cycle arrest. So it's that multi-modality aspect, which makes XPO1 such a critical mechanism in myelofibrosis, obviously lends itself to potentially monotherapy activity. But then when we combine with other agents like ruxolitinib, may lead to potential synergism. So we led a Phase 1 trial. We looked at two different doses of selinexor. These, again, are low doses of selinexor, about a quarter of the dose of the originally approved doses. We looked at selinexor 40 milligrams, selinexor 60 milligrams, both dosed weekly, combined them with ruxolitinib, standard of care ruxolitinib, and again, treated this JAK naive patient population, and what we observed, especially in that 60 milligram dose, is a very meaningful benefit. 79% of that ITT population achieved that SVR35. If we look at any time that was specifically at week 24, if we look at any time, 100% of those patients actually achieved that SVR35. 79%, it more than doubles what you can expect from ruxolitinib alone. If I look at the symptom aspect, again, TSS 50, there are two very meaningful improvements. TSS 50 at week 24 was observed in 58% of that patient, so it really demonstrates a very meaningful outcome with the combination. If we look at other efficacy endpoints, you can also see the benefit durability. For a JAK naive patient, yes, what they achieve at week 24, six months, that's nice. What they want to understand is that what does my overall benefit look like? When we looked at durability, it indicated that amongst those patients that achieved a response, once they achieved that response, they stayed in response. So as of an August 2023 data cutoff date, actually none of the patients who experienced an SVR or TSS 50 response had progressed. Remarkable. So you see this very meaningful SVR35, obviously meaningful TSS 50, long-term durability, all in the context of a very manageable safety profile. The evolution that is occurring in myelofibrosis, though, is in how we evaluate symptoms. TSS 50, I think, has a lot of limitations. It's a binary, yes or no, you achieve this endpoint or response. In the combination setting, we need a more sensitive mechanism. And this is where absolute TSS has really become at the forefront, both from a regulatory perspective, but even sponsors and companies that are developing myelofibrosis therapies. And I think we'll get into it. But this is a very positive evolution for us in that we no longer need to look at TSS 50, but instead absolute TSS. Instead, I will hand it back over to you. OK. Yeah, so obviously a very active drug. I mean, clearly, you're seeing an impact. But one of the questions I get from investors is the side effect profile. Even at these low doses, you've got nausea, anemia, thrombocytopenia, and fatigue. And I think the GI side effects you guys mentioned are in the first two cycles. You manage them with antiemetics. But maybe expand a little bit more on you mentioned a manageable safety profile. What are docs telling you about the safety trade-off with the level of activity that you've seen? Yeah. I think it's a very fair question. So what we know with selinexor is that it has two flavors of toxicity. It's going to have your heme toxicity. It's going to have your non-heme toxicity. The heme toxicity, I got to say, when I talk to myelofibrosis docs, really hematologists in general, they're very aware of it. Largely, it's because that's the exact same thing they experience with ruxolitinib. Ruxolitinib causes profound anemia and thrombocytopenia to such a degree that many of these physicians actually need to discontinue ruxolitinib as a result. So they're very aware. They follow lab counts. They know when to modify or potentially even discontinue the ruxolitinib. None of that changes now when they are treating selinexor in combination with ruxolitinib. Interestingly enough, when we look at our combination data, if a patient experienced thrombocytopenia or anemia, we instructed them, modify the ruxolitinib dose first, modify, either hold, reduce. When they did that, by and large, the cytopenias resolved. It really suggests, again, that the heme toxicity is really stemming from that ruxolitinib component and not exacerbated or worsened when we add selinexor. The last thing I'll add about that is that only one patient actually discontinued due to thrombocytopenia. When we talk about the non-heme toxicities, you're absolutely correct. There's going to be your GI toxicities, nausea, vomiting. This is something that we know about selinexor. We know it's very dose-dependent. At our very high doses of 80 milligrams twice weekly, yes, patients were experiencing aggressive nausea and vomiting. Some patients needed to discontinue. I think what we've rapidly learned, though, over the course of the last two years is that we know that by substantially reducing the dose of selinexor, we can mitigate many of those issues, and then secondly, by incorporating dual antiemetics only for first two cycles, so it's really the dose, the incorporation of the dual antiemetics, which is now required in all of our Phase 3s. I will say we see a very meaningfully improved toxicity profile. When I talk to physicians today, including those multiple myeloma, there are those physicians that obviously are still treating or had experience with the higher regimens. Yes, toxicity is by and large sort of their concern. It's interesting when I talk to physicians now who know to treat with the lower dose, who know to incorporate, no longer are the discussions around toxicity. It's a completely different drug. I think they're now very much focused on the efficacy or the benefit that selinexor can provide. OK, excellent. Let's talk about your Phase 3. So XPORT-MF-034, this is evaluating selinexor in combination with ruxolitinib. And this is specifically treatment-naive patients. Just on the design here, I think you guys made some news recently after discussing with the FDA an update to your co-primary endpoint. Talk a little bit about that and how this decision sort of impacts that trial and maybe through the lens of a physician, why that was important. Yeah, great question. So as I was mentioning before, Jakafi set the precedent. Symptom score, symptom improvement is important. But the way they were going to evaluate it is, again, TSS 50. I got to say, it's a somewhat arbitrary measure, 50% improvement relative to baseline. I think what we have realized, especially in the context of two Phase 3s that read out at ASH last year, is that there are substantial limitations in TSS 50, especially because the modern contemporary trials are now evaluating combination relative to an active control, which is ruxolitinib. So as such, what we are trying to observe is a very meaningful improvement above and beyond what an active comparator is already providing. The bar is set extremely high when we're looking at this binary TSS 50. And I think we saw the results. I think the proof is really in the pudding. Neither one of those two trials had a positive TSS 50 outcome. It didn't mean that symptoms weren't improved. They just didn't meet that threshold that was required based upon that analysis. Interestingly enough, both of those trials also incorporated absolute TSS as part of their evaluation. What is absolute TSS? So absolute TSS is now looking at the average symptoms over the course of 24 weeks relative to baseline. So it's no longer looking at just what happens at week 24 and comparing it to baseline. It's looking at the average over time and comparing it to baseline. Because it's looking at the average over time, it's a far more sensitive and comprehensive way of assessing symptom improvement above and beyond ruxolitinib. Why is that important? Because for the patient, for the physician, what they want to know is that, yes, can I achieve some symptom improvement above and beyond ruxolitinib? Physicians, they're focused on SVR35. Very large spleen, very debilitating to the patient. There are data, multiple different data sets that correlate spleen volume shrinkage with overall survival. So that's the marker of benefit they are really focused on. So they want to achieve that SVR35. What they also want to provide to their patients is also, yes, some degree of symptom benefit above and beyond ruxolitinib. So it's a really nice way of being able to provide that information, again, to physicians, but also to patients, too. And just to follow up on that, Chris, I think the second part of your question was how are physicians or investigators feeling about it. As we've shared the evolution and the endpoint, it's an area that they're super excited about. They've been engaging. They've been, I think, working to shift the endpoints. They've been working to really, as Reshma talked to, show that SVR35 is very important, critical for them. They also want to show that patients are getting better in their symptoms, which absolute TSS does. I think there's a lot of excitement that we were able to get this evolution and moving forward the field. OK. Great, so I think another aspect of the study that you released was the upsizing, so 306 patients to 350. I know that it's to increase statistical power, but maybe just touch on the discussions that led to that decision and how you arrived at that number. Yeah, that's right. So the two aspects go hand in hand. So the change from TSS 50 to absolute TSS already has a positivity to it. We were already confident in our TSS 50 data. Evolving from TSS 50 to absolute TSS only increases our confidence. To further enhance that, yes, we marginally increased the size of our trial from 306 to 350. For us, it was an easy decision. Enrollment has been going very well on the trial. And I think for multiple reasons, we are looking at completing enrollment in the first half of 2025. By going from 306 to 350, none of those milestones change. So there's a lot of upside. It increases the confidence of the POS coming out of the trial without impacting at all any of our milestones. So maybe just on timing, to your point, Reshma, enrollment's going really well. And you now have this new sort of endpoint to look at. You guided previously to the second half of 2025 as a readout. Any sort of push, pull that you can describe in terms of meeting that timing? Not really, not at this point. We're not guiding further within each of these two halves. Again, I'll just continue to emphasize sort of enrollment is on track. Why is this happening? Sort of like I think, one, KOLs are really resonating positively with the data. Since the announcement of this change from TSS 50 to absolute TSS, I think their confidence has only increased. So I think they're very enthusiastic. Obviously, they're supporting the trial and enrolling their patients who are JAK-naive onto the trial. I think the other big factor is that we're the only combination in town right now. There are no other Phase 3s that are being evaluated in this JAK-naive population. So we've got this very open environment, a lot of excitement around our data. Yeah, and I think that that's really fueling the enrollment. OK, so maybe just a little bit on the setup here. So second half 2025, we get the press release. You've got the co-primary endpoints of SVR35. And these are being tested sequentially, right? Correct, yeah. And so maybe just what would you need to see, I guess, on SVR35 and then on this absolute TSS? There's stat-sig, and then there's clinically meaningful. Any sort of thoughts there in terms of what you guys are looking for? Sure. I mean, SVR35, again, in our Phase 1 data, we already demonstrated a very meaningful 79%. Give a little bit of wiggle room to that. When I talk to physicians, I think anywhere above 60% would be, again, very meaningful and I think be a transformation for how we think and treat patients with myelofibrosis. In terms of absolute TSS, looking at the MANIFEST data, so the MANIFEST, again, they looked at both TSS 50 as well as absolute TSS. Their post-hoc analysis, so they, Raajit Rampal, Dr. Rampal at MSK, had an oral session in which they reevaluated absolute TSS. This time, they removed one of the key domains. So the MFSAF form, which is the form that patients fill out that ultimately leads to that TSS, includes many domains, seven domains, one of which is fatigue. When they excluded fatigue, lo and behold, they were stat-sig. Their delta that they saw between the two arms was only two points. Again, it already indicates that absolute TSS is a more robust measure of being able to demonstrate significant improvement in absolute TSS. I go back to my comment about what do physicians want to see. Physicians want to see any kind of improvement above and beyond ruxolitinib. You could argue that even with a delta of two, that would be above and beyond ruxolitinib. If I look at our own data, it really suggests we can more than double it because our absolute TSS we saw from the Phase 1 was actually suggested that you could see a delta of approximately four when you look at historical ruxolitinib arms. So I think just based upon the data, based upon how ruxolitinib alone is performing, I think we have a great shot of observing both statistical and clinically meaningful outcomes. OK, great. So your bread and butter is still multiple myeloma. And we've spent almost all of our time talking about MF. So I want to maybe just sort of maybe touch on this. You're in a Phase 3 study now at a lower dose, selinexor, at a lower dose with plus PomDex in relapse refractory myeloma. Just remind us of what you saw at that lower dose cohort that supports continuing at these lower doses, to your point, to deal with the toxicity at the original approved dose? Yeah, so SPD40, we evaluated this starting dose in two different cohorts of relapsed refractory multiple myeloma. One cohort was treated at 60 milligrams. Another cohort was treated at 40 milligrams. And what we observed is a very positive benefit-risk specifically in that cohort of patients treated at SPD40. Both the efficacy was substantially improved and safety was substantially improved. When I hone in on that SPD40, that PFS, that median PFS that we observed in that cohort was meaningfully longer than what I think any of us had anticipated. I got to say, when we started that EMN trial, SPD versus EPD, we expected a median PFS of approximately nine months. In this cohort, it was actually 11.2 months. So meaningfully improved. Why does this happen? I think it's because patients experience less toxicity. They're able to stay on therapy longer. Ultimately, that's going to drive longer longitudinal endpoints. We were able to leverage those data. Because we see a much longer median PFS, we were able to reduce the size of the trial to approximately 120. And enrollment is complete on that trial, but also lower the number of PFS events without compromising any of the power. So really a nice evolution. And at this point, yeah, we await for those PFS events to mature. You have a poster coming at ASH just next week on that. Maybe just remind us what you'll be sharing. Yes, so in another cohort, this is of multiple myeloma patients. One cohort treated at 40 milligrams, another 60, another 80 milligrams. Again, just looking at that efficacy, safety observed across those three cohorts. Punchline, again, SPD40 wins. OK, excellent. Well, I have a ton more questions, but no more time. So thanks for the great presentation. Thanks, Chris.