Karyopharm Therapeutics Inc. (KPTI) June 2026 Conference Transcript

Okay.

Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. I'd like to welcome the Carrier Farm team today. We've got Richard Paulson, the CEO, and Reshma Rangwala, the CMO. And it's an exciting time for the company. You guys were just at ASCO with the late breaker for myelofibrosis, and you've got a big phase three readout coming soon. We're going to do fireside chat format, so maybe for those who are new to the story, maybe give a brief intro to Caryopharm and talk about the key programs.

Yeah, sure. Thanks, Maury, and thanks to Jeffries for hosting us. As usual, right, just a little house cleaning. Certain statements might be forward-looking statements, so please refer to our latest 8K on filing. As you mentioned, Maury, it's a truly exciting and transformative time at Caryopharm, and Caryopharm is a commercial-stage oncology company, and we're pioneering nuclear export inhibition to develop differentiated therapies for oncology patients, and our lead compound, Salonexor, or Expovio, as it's known, is approved in multiple myeloma in over 50 countries around the world, and what's truly exciting and transformative is the work we're doing in myelofibrosis and endometrial cancer, and as you mentioned, in myelofibrosis, just coming straight from Chicago with a great oral presentation with Dr. Mascheranis on our phase three century data, also the simultaneous publication in the journal Clinical Oncology. And next week, we're at EHAW with Dr. Claire Harrison, also doing an oral presentation, one of the best of EHAW. So very excited about the work and the progress we're making in myelofibrosis and the opportunity to transform outcomes for patients in myelofibrosis. And as you mentioned, endometrial cancer as well. So just recently completed enrollment in our EC042 Phase 3 program. That data is very much on track to read out in the middle of this year, and very excited with the opportunity also to transform outcomes in the endometrial cancer space. So exciting and transformative times for us at Keriopharm. Yep, for sure.

It's a great intro, and you just mentioned the Century data at ASCO. Can you walk us through the key highlights and takeaways?

Yeah, absolutely. So, you know, thank you for the invitation. This is always a lovely conference. You know, Century, as Richard mentioned was truly a highlight for us, you know, not only at ASCO, but, you know, at CarioPharm. So Sentry was our phase three trial, specifically evaluating the combination of cell and XOR, which is an XPO1 inhibitor, with ruxolitinib. And this is going to be in your jack-naive myelofibrosis patient population. All of these patients had platelet counts, you know, greater than 100. It was a two-to-one randomization. And we were focused on multiple endpoints that are relevant in myofibrosis, so specifically your spleen volume reduction, symptom improvement. But we also looked at secondary endpoints, including overall survival, as well as multiple endpoints looking at disease modification. Can XPO1 inhibition in combination with ruxolitinib modify the underlying disease, which ultimately enables improved long-term outcomes, including overall survival. The key takeaways are something very unique in myelofibrosis and something that has never been seen before in a prospective trial. Specifically, what the combination demonstrated was that SVR35, so that spleen volume reduction of at least 35%, yes, it met statistical significance. It was highly significant with an almost doubling of the SVR35 rate with the combination as compared to ruxolitinib alone. Specifically, 50% of the patients achieved that SVR 35 at week 24. What we also saw was a very important kinetics with that SVR 35. So it occurred very rapidly as early as week 12, and it was sustained all the way out until week 36. But in addition to the spleen volume reduction, we also something that, again, has never been seen before, overall survival. And yes, this is a promising early signal in overall survival, but with that said, the OS hazard ratio was 0.43 with a nominal p-value of 0.0222. When we looked at the correlation between SVR 35 and overall survival, again, something very unique, has never been seen before. But SVR 35 predicted overall survival, really suggesting that SVR 35 can be used as a potential surrogate marker for long-term outcomes. Symptom improvement, although it was not statistically significant relative to RUX, from a patient perspective, we saw something very important. Symptom improvement at week 24 was improved relative to baseline, no detriment across the two arms. And of course, all of this is happening in the context of a very manageable safety profile.

Got it. It's a great deep dive into the data. So for those points that you mentioned, or potentially if there are others, I guess, are there a couple of incremental details that are going to influence how doctors view and use the drug commercial?

Yeah, absolutely. So one of the key takeaways that Dr. Mascarenas presented at ASCO was when you look at the SVR 35, of course, we were very interested. Physicians are very interested. Are there any specific patient populations that benefit more than others? The key takeaway is that no. We looked at multiple pre-specified subgroups, and across all of the subgroups, we showed very consistent benefit with the combination relative to Rux alone. A key subgroup that I want to highlight is specifically the SVR35 achieved by average ruxolitinib doses, right? And when we looked at the forest plot, we were specifically looking at mean ruxolitinib doses above and below 30 milligrams. And again, that subgroup was very consistent across the two. We did a deeper dive into that daily ruxolitinib doses, as low as 15 milligrams or less, all the way as high as greater than 35 milligrams, again, daily doses. And what we showed was a very consistent benefit across all of the different dose levels, really suggesting that selenexor is driving the efficacy, ruxolitinib is merely supporting it. This has huge implications out in the community in that physicians can feel confident that they can prescribe the combination despite very low doses of ruxolitinib and not compromise the efficacy, especially from an SVR 35, that can be achieved in that patient population. Second point is that we also showed the O.S. Kaplan-Meier curves. And those O.S. Kaplan-Meier curves, again, support that very meaningful early O.S. benefit in that the Kaplan-Meier separated as early as week as month nine and continue to separate all the way out until the follow-up. Lastly, I'll point out with overall survival is that the reasons for death is very consistent with that benefit that you would expect. Specifically, the proportion of patients who died due to progression and toxicity was double in the ruxolitinib arm or the control arm as compared with the combination. Again, really supporting this meaningful OS benefit that we observed.

Got it. All makes sense. And the data with the different dose ranges of RUX is very interesting. And I'm wondering if you double-click on the 0 to 15 range, do you see an absolute benefit, or the absolute TSS, do you see a clear benefit there on that?

We didn't look at TSS, right? I mean, I think TSS, I think one of the key takeaways from not only this trial, but multiple other trials that have evaluated combinations with ruxolitinib versus ruxolitinib alone, is that it's very difficult to achieve a statistical significant improvement, you know, versus RUX. I think the key takeaway is that there is no detriment, you know, to your question, no, we did not look at TSS, you know, my takeaway is, again, you know, these patients are benefiting in symptoms. systems. It's not important whether they achieve statistical significance, but, you know, they are benefiting from a symptom standpoint.

Got it.

Okay.

And if we focus on the OS signal from Sentry, you've got the hazard ratio of 0.43 at the top line. Help us frame how to interpret that. What was the median follow-up at the cutoff, and how should we think about the event count and stability of the signal?

Yeah. So, all great questions. So, you know, as I mentioned, it was a hazard ratio of 0.43 p-value nominal at 0.0222. The median follow-up at the time of the data cutoff was approximately 12 months across both arms. And that hazard ratio was based upon a total of 23 events observed across the two arms. The Kaplan-Myers really suggests that the signal is robust. the reasons for death, again, suggest that the benefit is very robust. With that said, the trial has been designed to continue to follow overall survival. So both the patients as well as the physicians remain blinded to the treatment arm, will continue to follow OS until maturity. But again, am I confident that this OS signal is going to persist with longer follow-up? Absolutely, I do, largely because, again, the data suggests that SVR, which is clearly substantially higher in the combination arm, can predict long-term survival.

Got it. And for OS, as the data matures, what milestones or time points are going to matter the most to KOLs and regulators? Is it going to be 18 months, 24 months?

Yeah, I don't anticipate that it's actually going to be time-based. I think it's going to be based upon a pre-specified number of events, right, like we do with any kind of, like, long-term benefit. So, you know, we haven't commented yet in terms of, like, how many events we need to see before, again, we provide additional data. But I do think it's going to be event-based and not time-based. But, you know, more to come as we continue to dive into those details.

Are there good analog studies where, based on the percentage of events, like could it be 20% events from another study that led FDA to stop a study or to view it as a meaningful OS signal?

In myelofibrosis, no. There are no good analogs only because nobody has demonstrated overall survival. We're the first ones. So, you know, I think this is something that we get to forge the path on and we'll define, and like I said, we'll define it at a future date.

Got it. Makes sense. And since the top line on OS, have you done deeper work on death events across the arms and any observations there?

Yeah, again, I just want to highlight, right, you know, sort of the reasons for death are very consistent with this very robust OS signal. So the progressions, so deaths due to progressions, again, almost double in the control arm as compared to the combination arm. Depths due to AEs, right, again, higher in the control arm as compared to the combination. Why is that last one so important? So let's take, for example, AEs, let's say due to leukemia, okay? So if it was higher in the combination arm relative to RUX, irrespective of what you saw with that SVR 35, you're not going to see a robust improvement. So the fact that both progressions as well as toxicity are higher in the control arm as compared to the combination, and again, it really supports that this OS signal is real.

Yeah, yeah, it makes sense. And you've also emphasized the VAF reduction as a potential disease-modifying signal. Maybe start with what you're seeing there in terms of VAF reduction, and how do you connect the outcomes there that matter to prescribers, such as SVR durability, symptom benefit, and transfusion needs, or OS?

Yeah. So VAF is variant allele frequency. It's a marker of clonal burden, right? Myelofibrosis is an abnormality in these hematic stem cells. VAF, so what we measured was the proportion of patients who achieved a greater than 20% VAAF reduction. And we looked at it multiple time points. What we reported on was specifically the VAAF reductions at week 24. And what we saw, again, is very consistent with the SVR35 as well as the OS in that we saw a very rapid decrease in that VAAF as high as 32% in the combination and arm relative to ruxolitinib. Very high. It's the rapidity at which we see this VAF reduction, which I think is very reflective in both the SVR35 as well as the OS. It suggests that there's a disease modification that is occurring specifically with Selenexor, and this is another one where we'll continue to follow. But again, it's the reason why, It's the mechanistic rationale as to why XP01 inhibition ultimately leads to these key efficacy outcomes.

Got it. Makes sense. And it seems like you're seeing a pretty consistent effect across all the patients in the study that are on combo. But just wondering for SVR35, for the VAP outcomes, are there any particular subgroups where you're seeing additional benefit or the benefit seems differentiated?

And I think this is the key takeaway, is that that benefit is very consistent across, right? And so when we talk about DIPs, which is a prognostic, very similar kind of benefit in patients with large spleen versus small spleens. Again, very consistent benefit. So it really suggests that the combination can be and should be used across all patients with treatment-naive or JAK-naive myelofibrosis. Treating early is key. right? Because our data also suggests that when you treat early, you can lead to a very rapid SVR 35. That ability to achieve a rapid SVR 35 is ultimately what's going to gain these long-term outcomes in terms of overall survival. So I do hope that physicians really appreciate this. Myelofibrosis is not an indolent disease. It's a severe, life-threatening disease. If we truly want to gain OS benefit in this patient population, we've got to treat aggressively up front. And that aggressive treatment, again, is what's going to lead to these OS gains.

Makes sense. And maybe talk about regulatory strategy and how you're thinking about FDA engagement here.

Yeah. So we're actively engaged with the FDA as well as, you know, we've had good engagements with the co-rapertor and rapporteur as part of the EMA too. Very encouraging conversations. We haven't, you know, we haven't disclosed the path forward, but we will so in the next one to two quarters.

Got it. What do you think the regulators are going to be focused on? Is it going to be OS maturity, symptoms, safety?

I think they're going to be looking at it all, right? You know, I think they're going to be looking at SVR 35. It's a very traditional endpoint. Lots of data, especially now coming out of Sentry, that really suggests that SVR 35 can predict overall survival. I think absolutely they're going to be looking at overall survival. As I mentioned, this is a key differentiator from Sentry as compared to any other trial in that, yes, you do see this overall survival benefit as early as the data cut off of February 20th. I think they're going to be looking at symptoms, right? Not just symptoms in the context of whether it met statistical significance, but again, the fact that we can still see this benefit at week 24 relative to baseline. And yeah, they will be looking at the safety profile. But again, I think Sentry demonstrated a very manageable and safe profile. This is not a new data set, right? So, you know, Selenexor is approved. It's been used to treat tens of thousands of patients. And I think the fact that you see this manageable safety profile with no new safety signals should not only give the regulators confidence, but physicians confidence too.

Yeah, makes sense. And do you see the regulatory path driven primarily by the century data? You mentioned Celinox or there's a lot of studies out there that FDA could want to check into. I guess, how do we think about the total data package?

Yeah, I think they're primarily going to be focused on the phase three century results. We also have our phase one data, right, that we'll be packaging into it. But I think those are going to be the two main data sets that they're going to focus on to evaluate the total benefit risk.

Got it. And since LNXOR is already approved, there may be the potential to get the guidelines updated for myelofibrosis. Post-ASCO and the publication, what are the true gating items for guideline consideration, and what's your best sense of timing for those updates?

Yeah, I think you mentioned it more, you know, having the ASCO presentation, having the JCO article, you know, those are the resources that the committees need, and from an NCCM perspective, Obviously, NCCN is an independent committee, so they'll follow their processes and not an area that we get engaged in. But I do believe, you know, with the data that's being presented now, with the data in JCO, gives the right tools for the committee to move forward with the potential NCCN listing. And I think it remains on track, as we've said. It's something we would expect in the second half of this year.

Got it. And if guidelines, the guidelines update happens before the approval, what should the market opportunity look like? What could penetration be, and is it going to be front-lined, or do you think there's going to be subsets of patients that end up in the combo?

Yeah, I think as we've heard from physicians, especially at ASCO now when they're looking at the data, they really believe, and I think they want access to cell and XOR-RUX combo across all groups of patients. I think Reshma has talked to that in terms of our benefits that we've seen in the trial, you know, the top line, the benefit we've seen across all subgroups. So, you know, the current iteration of the guidelines do have different populations. Our expectation would be looking at our data, that we'd have access across a broad range of patients. And then when you look at the potential, obviously, NCCN, especially for approved products, which is where NCCN is really applicable, is something that usually happens much more rapidly than a regulatory approval, an SNDA approval. So we would expect that, as we said, to happen sooner. And then I think, again, in this space, you look at the unmet need. I mean, you look at the benefit, as Rashma talked to, the importance of treating early, the importance of achieving that rapid, deep, sustained spleen volume reduction early and giving patients the opportunity for improved overall survival and the high end need. So in this space, you know, we're not competing. We're combining with ruxolitinib. So I would expect the uptake to be pretty rapid. And I think when you look at products that, you know, first get NCCN approval before potential regulatory approval, you can see somewhere around 50% of the peak first being achieved in NCCN.

Got it. That's helpful. And do you get to engage with NCCN directly on what the guidelines could look like, and are there different scenarios for the wording?

Yeah, I think the committee works independently, and so they evaluate data, they work to the data, so that's up to the committee. And obviously also, pending NCCN, And it's not an area that we actively, you know, promote to. It's really an area where physicians make their decisions independently for the right kind of patients.

Got it. And with the NCCN guidelines alone, do you think there could be any payer friction or do you think it should be pretty seamless?

Yeah, the good thing is, you know, with NCCN guidelines, it really enables payers, including Medicare, to make sure they provide coverage for appropriate patients. And obviously, we have, you know, appropriate, you know, support programs in place to help support physicians or patients, you know, based on their decisions. Got it.

Okay. So let's shift gears to endometrial. You've got the phase three study that's supposed to top line middle of this year. What would constitute a clear win at top line and how should we think about the HR threshold that defines clear success?

Yeah, great question. So really, really, really excited about this phase three trial. So, you know, before I get into the bar, EC042, which is this phase three trial, is specifically evaluating cell and XOR in the maintenance settings. So these are going to be, essentially think of them as your first line endometrial cancer patients. These are all p53 wild type as identified by NGS, Foundation Medicine's proprietary platform. These patients have all completed at least four to six cycles of induction chemotherapy. What we're going to be evaluating in the study is the primary endpoint of progression free survival. And we've got two patient populations that we're going to be evaluating the PFS. The first is this what I call ITT, modified ITT population. By and large, think of this modified ITT patient population are those patients whose tumors are both p53 wild type and MMR proficient, right? We do have a small subgroup of patients in that MITT that may be MMR deficient, medically ineligible to receive a checkpoint inhibitor. The second population is going to be the broader ITT population, all patients whose tumors are P53 wild-type. Now, the reason that we are looking specifically at that MITT first is because that P53 wild-type MMR proficient, they just don't benefit as well from the current available therapies. And I'm specifically alluding to checkpoint inhibitors, pembrolizumab, dostarlimab. Those two checkpoint inhibitors, yes, have been granted broad approvals regardless of their MMR status, but with that said, the data indicates, very consistent with the mechanism of the checkpoint inhibitors, that the benefit specifically in that PMMR population is just not as robust. In fact, there was a retrospective analysis from the RUBI trial, which was Dostarlamab's phase 3 trial, that demonstrated that in this same P53 wild-type PMMR population, Hazard ratio, again, was modest at around 0.77, right? With median deltas, very incremental, approximately less than three months. So that's really the bar that has been set, right? And so we really aim, you know, with EC042 is to improve upon that hazard ratio. This is what physicians want. And the CNDO data, especially from the long-term follow-up of that P53 wild-type PMMR, really suggest that Selenexor can meaningfully improve upon that hazard ratio.

Got it. And given that the CNDO study, the benefit deepened over time, how should we calibrate expectations for the initial cut that you show versus later mature?

So I'll highlight. So, you know, the Siendo data, again, which was the preceding Phase III trial from which ECO42 was based, at the time of the top-line results, which was in the beginning of 2022, suggested benefit, again, very robust, especially in that P53 wild-type population. With an approximate 11-months median follow-up, the median PFS across the two arms, the delta, was more than 10 months. Median PFS for the cell and XOR arm was 13.7 months versus only 3.7 months in the control arm, corresponding to a hazard ratio of 0.46. I think that should be the benchmark, the anticipation going into ECO42. You know, with that said, it could slightly change, hopefully improve, given that the median fault may be a little bit longer at the time of the top-line results for EC042.

Got it. Okay. So those are kind of the numbers from Siendo that are relevant, the 13.7 and 3.7. As standard of care has changed, maybe control arm goes up a little bit. Is that a possibility, or how do you think about that?

Maybe a little bit, right? So I think you hit on a very important fact. In EC042, we do allow prior checkpoint inhibitors, right? And yes, that checkpoint inhibitors prior to Selenexor may lead to an improvement on that placebo arm. With that said, I do think that is likely going to be incremental at best because the proportion of patients that received a prior checkpoint inhibitors is still very small at approximately 15%. It's a randomized trial. So those patients are likely going to be evenly distributed across the two arms. The other thing that I would say is that if it's going to lead to a slight boost in that placebo arm, I do anticipate it's also going to lead to that same kind of boost in the Selenexor arm. So from a hazard ratio perspective, I really don't think that there's going to be much difference.

Got it. Okay. And how do you think about probability of success in the MITT and then passing alpha to ITT?

I think it's very robust, right? And the reason I say is because the data from Siendo is from a very large subgroup, right? So this P53 wild-type population comprised about 50% of all of the Siendo patient population. And it's from a randomized control arm. So you've got benefit both in the Selenexor arm as well as the control arm. We've continued to follow Siendo as well. And what we've seen is that the data have only strengthened over time. So, you know, our confidence going into EC042 is very high because, again, we've got this very robust signal coming out of Sando.

Got it. And if the study is positive, how do you see adoption unfolding commercially?

Yeah, I think pending the study and positive data, I think we see adoption being quite rapid and strong. We saw that previously as the checkpoint inhibitors came for the DMMR patient population, as Reshma talked to. And as we know, you know, the benefit is much more marginal in the PMMR P53 wild-type population. So in this space, we do think the adoption will be quite rapid and definitely would enable us to become the standard of care in that PMMR P53 wild-type population.

Where do you think the initial uptake is going to come from? Is it going to be from community centers or academic centers?

I think there's all, you know, usually you'll see, you know, your opinion leaders, academic centers really driving the early adoption. But we also know in the community groups, there's some very, you know, large community groups with GYNOC specialists that we think would drive pretty strong rapid adoption as well. But traditionally, you'll see, yes, in the academic centers first, but I think pretty quickly, we'll also see the broad community. The benefit, of course, being that Celenex are already being approved and the commercial capabilities we have in place where we have that coverage already across the community groups. They have experience of using Selenexor at the lower doses with dual antiemetics. I think that'll even enable stronger uptake than you traditionally would see with a new indication in the community setting.

Got it. And for myelofibrosis and endometrial, with myelofibrosis, you've already got a sales team in place for multiple myeloma, so with the same call points. How do you think about those two opportunities side by side and just the amount of time it's going to take to get to meaningful revenue from either opportunity?

Yeah, I mean, I think both, as we've talked to, both are areas of high-end met need. Both are areas where we would expect to see pretty rapid adoption. Both, you know, are really multibillion-dollar marketplaces. So both have significant opportunity for us, and obviously the focus on improving outcomes for patients. And, you know, when you look at our capabilities, as you mentioned, I think broadly it's important to look from a medical and scientific affairs perspective. We have those capabilities across multiple areas. the access capabilities, the payer capabilities, the patient support, insurance capabilities, and then the sales force capabilities. And yes, you know, primarily across the myofibrosis space, we have the capabilities, the coverage in place. As we mentioned, in endometrial cancer, the majority of patients are also treated in the community, so that broad access. But I think when we look at the endometrial cancer opportunity, we would add additional resources to really ensure, you know, good strong coverage for the Gynonx. which are a pretty focused group, but it's an area where we'd want to add some additional resources to support that coverage and rapid adoption.

Got it. I think we've covered a lot. It's a great conversation. Maybe in closing, if you want to talk about cash runway assumptions and just highlight the key updates over the next six to 12 months, investors should be focused on.

Yeah, I mean, as we've talked to, we have cash runway, you know, late into Q3, really through the major milestones that we've just been talking about and value generating opportunities, you know continuing to look at our pathway in myofibrosis, continuing to have progress with regards to NCCN, with regards to data presentations at EHA, with regards to our path forward as we talked to with regulatory agencies which we will be able to clarify through Q2, Q3. So major value generation opportunities in the MF space and then endometrial cancer, EC042 you know very much on track to read out in the middle of this year well within our cash runway so I think significant opportunities to really generate value in our existing cash runway, and excited about the opportunities in front to transform outcomes for patients.

Got it. Richard Reshma, thanks so much for joining us today.

Thank you.