My name is Ted Tenthoff. I'm a senior biotech analyst at Piper Sandler, and before I begin, I'm required to point out certain disclosures regarding the relationship between Piper Sandler and our next presenting company, Karyopharm, which are posted at the back of the room and also at the registration desk, so as you probably know, Karyopharm sells XPOVIO, or selinexor, which is a first-in-class oral Exportin-1 inhibitor for relapse refractory multiple myeloma and diffuse large B-cell lymphoma, mostly multiple myeloma. Karyopharm, importantly, is also developing selinexor for myelofibrosis and endometrial cancer, with important readouts in the new year. Here with us today from the company are Richard Paulson, President and CEO, and Dr. Reshma Rangwala, who's the Head of Research and the Chief Medical Officer, and also Lori Macomber, who's the Treasurer and CFO. Lori, I think you want to just start with some quick introductory comments.
Yes. So, bear with me as I do our disclaimers. Before we begin, I'll remind you that various remarks we'll make today constitute forward-looking statements as defined by U.S. securities law. 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 that we file with the SEC. Any forward-looking statements represent our views as of today only, and 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.
Great. Thanks, Lori. So, perhaps you guys can start off by describing the biology around Exportin-1 and how inhibiting this process kills cancer cells?
Yeah. Thank you so much, Ted. I can take that one. So, selinexor is what we call an XPO1 inhibitor, an Exportin-1 inhibitor. Exportin is a protein; think of it as a gate, but it's specifically located on the nucleus. And what this XPO1 inhibitor does is that it blocks the gate. And by blocking the gate, what we do is we retain really important proteins that control cancer development, cancer proliferation, tumor cell growth. What are these proteins that are retained within the nucleus? Really important tumor suppressors, including p53, also oncoproteins, glucocorticoids, relevant across multiple different kinds of cancers, both solid as well as hematologic in nature. Now, when we think of this mechanism specifically in the context of myelofibrosis, this is where XPO1, the benefit of XPO1, really is highlighted. We know that the current standard of care, by and large, just inhibits the JAK-STAT pathways.
It's an important pathway, but clearly not the only pathway that is relevant in myelofibrosis. What is relevant in myelofibrosis and what drives the pathophysiology, we know, is p53. p53 is very important in maintaining and keeping those cells at bay, but also NF-κB. NF-κB is what drives the symptoms that we see in these patients, also oncoproteins, including c-Myc. So, XPO1 has the benefit of inhibiting all of these relevant pathways applicable to myelofibrosis. And we've got some really key data coming out of many of our clinical trials suggesting that these pathways are inhibited. If we just look at the cytokine data, for example, we are seeing substantial decreases in cytokines relevant to symptom development. So, we know that the mechanism is tied specifically to the efficacy, and I'll certainly go into that in more detail in a few minutes.
That's super helpful background. I want to start with multiple myeloma, just because that is where selinexor, XPOVIO is currently approved, I think in more than 45 companies sold under different brand names across the globe. You guys reported third-quarter revenues around $32 million, guided $110 million-$120 million this year, which I think is back to slightly up versus last year. Where is selinexor primarily used today in relapse refractory multiple myeloma? Where is it used? And what do you see as potential drivers for that indication in the next year?
Yeah. Thanks, Ted. You know, so fortunately, we're continuing to expand a number of countries. We're now actually approved in over 50 countries around the world, with kind of three core partners helping to commercialize selinexor around the world and doing very well. In the U.S., as you mentioned, you know, we just delivered, I think, nice 8.5% year-over-year quarter growth. And, you know, we're working to continue to grow selinexor moving forward. And when you look at our multiple myeloma utilization in the U.S., about 60% of our utilization is in the community setting, where, you know, selinexor is positioned as a flexible, a very differentiated mechanism of action that's a convenient all-oral option for patients post anti-CD38, for patients who can't access or failed a T-cell engaging therapy. A really important treatment option in the community setting.
And then in the academic setting, again, selinexor, where about 40% of our utilization is, is increasingly positioned as a therapy which physicians are using pre and post T-cell engaging therapy. So, again, exciting opportunity for us, given our mechanism of action and given the importance of T-cell fitness in the academic setting.
Yep.
When we look at, you know, moving forward, we're going to continue to work to grow multiple myeloma. As you know, it's a very competitive space, but we believe we can continue to work to grow, you know, selinexor in multiple myeloma, where I think our transformational growth opportunities moving forward in the near term are myelofibrosis.
Yep.
As you mentioned at the beginning, we're so excited about our myelofibrosis opportunity, which is going to be reading out in March of next year. And then following that, endometrial cancer, which is going to read out in mid-2026. So, our focus right now is myelofibrosis and delivering that readout in March.
That's great, and Richard, that's a perfect segue to my next question, because myelofibrosis is a blockbuster opportunity. Maybe you can start off by, and Reshma, you went into this a little bit, maybe you can describe sort of the condition and the current standard of care, and then we'll get into the ESSENTIAL and the phase I SENTRY data.
Sure, and I might start with the first part, you know, because when you...
Of course.
When you look at myelofibrosis, what's important, there's really three main treatment drivers for physicians: it's spleen volume, it's constitutional symptoms, and it's anemia, and really, with spleen, with reducing the spleen being a key priority for physicians, when they look at what they want to treat. Now, unlike multiple myeloma, which we just discussed, where there are numerous frontline treatment options, there's a number of MOAs, there's a multitude of combinations. In frontline myelofibrosis, it's ruxolitinib.
One.
One. And it's been the standard of care for over a decade. And so, the majority of patients, especially looking at where we're targeting, kind of that intermediate to high-risk patient with platelets greater than 100,000, the large majority of patients are prescribed ruxolitinib. Going back to what I said when I started, what's most important? Reducing the spleen. Yet, when you look at ruxolitinib, three out of 10 patients actually achieve an SVR35. That means 2/3 do not achieve an SVR35. So, there's a significant opportunity to improve on the standard of care. And that's what we're working to deliver with selinexor plus ruxolitinib, working to establish it as the new standard of care, looking to address all three priorities in terms of improving spleen volume reduction, improving kind of symptoms, and really improving anemia for patients.
We have the potential, as Reshma has talked about, you know, just now in terms of how we work, to really deliver a new mechanism of action, a multi-targeted approach with the opportunity to be truly kind of transformational from a disease perspective. We're excited about the opportunity.
When you look at the data you've reported to date in the small ESSENTIAL study and then also in the phase I SENTRY arm, I mean, really remarkable results. Maybe you can touch on those, and we'll use that to segue into the ongoing phase III trial.
Yeah, absolutely. I mean, it's important to keep in mind that we've got a wealth of clinical trial data with selinexor in multiple different populations, both as a monotherapy but also in combination. So, let me touch on some of the monotherapy data first, because I think it truly highlights the potential of XPO1 inhibition in patients with myelofibrosis. To your point, the first clinical trial was something known as the ESSENTIAL trial. It was a single-arm study that was evaluating selinexor, again, as a monotherapy in a very heavily pretreated patient population. So, this is a patient population that was resistant, in some cases refractory, to standard of care ruxolitinib or prior JAK inhibitors. So, this is, again, a very difficult, you know, patient population to treat. You know, with that said.
Dr. Tantravahi, who was the principal investigator of the trial, observed a very meaningful, almost 30% SVR35 rate, right, which is, again, remarkable to observe in a patient population that really has no available therapies. That indicated that, yes, XPO1 potentially is a very fundamental mechanism in patients with myelofibrosis, and based upon those data, we then initiated another phase I study, now evaluating selinexor in combination with ruxolitinib, but in a very different patient population, specifically in a frontline patient population, so these patients, by and large, are newly diagnosed patients. All of them have platelet counts of 100 or above, and it's important to keep in mind, in those patients, those 14 patients that received the recommended dose of 60 mg of selinexor in combination with ruxolitinib, we saw a very meaningful 79% SVR35 rate. This is remarkable.
I say that because if you look at standard of care ruxolitinib, only about three in 10 patients or about 30% achieve that SVR35. So, the fact that we can more than double that SVR35 rate, again, reinforces the fact that XPO1 inhibition is a very fundamental mechanism. Hand in hand with SVR35, though, is symptom improvement. Symptoms are very debilitating in this patient population. I noted earlier before, the mechanism suggests that XPO1 can dampen these symptoms. And here, too, in our phase I, we see some very meaningful symptom improvement. When we look at it in absolute TSS, which is just the mean change in symptoms relative to baseline, here, too, we see an 18.5 point improvement at week 24. Compare that to ruxolitinib, which is really only in that about 11 point- 14 point.
Really encouraging data suggesting that the primary endpoints of both SVR35 and TSS substantially improved with selinexor, again, in combination with RUX.
And, Reshma, one of the things I love about this, too, is you demonstrated the single-agent activity. Now you really showed how adding it.
Exactly.
Synergistic mechanisms. So, I'm going to kind of segue that into the phase III SENTRY trial. Really excited for data in March. You guys have done a lot of work to get us here, including enrolling patients, starting to analyze the demographics of those patients. Maybe you can start by the trial design and, you know, kind of go into some of the analysis that you've done on the safety side and what that tells you. Yeah.
Yeah, absolutely. So, this phase III, again, is building off of that phase I combination trial. So, the patient population is going to be very similar in that these are frontline myelofibrosis patients who have not received a prior JAK inhibitor. All of them have platelet counts above 100,000. These patients, 353, were randomized in a two-to-one fashion to either the combination, again, this is selinexor 60 mg in combination with standard of care ruxolitinib or ruxolitinib plus placebo. These patients continue on therapy. The primary time point in which we analyze the two primary endpoints of SVR35 and absolute TSS is, again, at week 24. So, all patients followed up until week 24. The way we are analyzing those two endpoints is hierarchically. So, we have a strict 0.025 alpha. That 0.025 alpha is going to be used to test that SVR35 first.
If that's positive, then that full alpha is then going to be rolled down to absolute TSS. These are the two endpoints from a regulatory perspective. Arguably, these are the two endpoints that are most important to physicians as well as patients as well. However, we're testing a host of other endpoints, including SVR, absolute TSS at week 48, week 72. We're looking at PFS. We're looking at OS. And we're looking at a host of disease modification endpoints, including bone marrow fibrosis, cytokines, as well as VAS, and of course, safety, really to get a very comprehensive benefit-risk profile in this population. To your point, we've done a lot of work just analyzing, you know, what is some of the potential safety that we can glean from the combination. As part of the trial, we had a pre-planned futility analysis.
That pre-planned futility analysis was conducted earlier this year. The DSMB evaluated the efficacy and safety only in the first 61 patients that had been randomized to the trial, all of whom had been followed for at least 24 weeks. That futility analysis passed successfully. We took advantage of that cohort, though, and took a snapshot of the aggregate data. Of course, we are not privy to the data by each arm, but we were privy to the blinded data. We used that blinded information and then extrapolated what the likely AE profile is in the 40-some patients treated with the combination, largely because RUX safety is very well described, right? So, we used that safety profile. We knew it was a two-to-one randomization, and then, again, extrapolated the safety. And we're very encouraged by what we see.
We see a nice improvement in GI toxicities, something that is well described with selinexor. So, a really nice improvement in the overall rates and grades of nausea as well as vomiting. I think really encouraging, from my perspective, is what we see from the hematologic perspective. The hematologic perspective is very important to myelofibrosis patients and the physician, largely because ruxolitinib, unfortunately, exacerbates or worsens anemia. What we see with patients who are treated with the combination is potentially a lower grade three, four anemia rate at approximately 27% compared to the approximately 38% that's been described with ruxolitinib alone. So, potentially, what we could be seeing, the same, maybe even a better profile with the combination relative to what's been described with ruxolitinib.
This is important, too, because it keeps patients on therapy. It keeps them in the study.
Exactly. Exactly.
What should we expect from the phase III? Tell us about sort of powering assumptions. Because you do have the 0.025.
Yes.
Do you take any hits from the secondary endpoints or not? Yes. Walk us through.
Yeah, absolutely, so this has been designed as a superiority trial, so both the endpoints of SVR35 and absolute TSS have been powered to, again, show a superior outcome relative to ruxolitinib alone. From an SVR35 standpoint, you know, again, we're very, very encouraged by our phase I data, a more than doubling of the SVR35 rate, and keep in mind, this is the endpoint that physicians are absolutely most concerned by, right, because there is compelling data that suggests that the more rapid sustained ability to keep that spleen at bay potentially could correspond to long-term outcomes. They're very focused and, again, very encouraged by the data that we've seen with SVR35. In terms of symptoms, what they really want to see is just any kind of benefit over ruxolitinib. Again, the study is designed to show a statistical significant improvement.
From their standpoint, though, any kind of benefit above and beyond ruxolitinib, and I think our profile and the data that we've presented to date really could suggest we could hit that profile.
Yep. Well, very exciting. And the card's turning over in March.
Yeah, very soon.
So, not too long to wait. So, walk us through the market opportunity here, because it's really pretty exciting.
Yeah, thanks, Ted. I mean, as we mentioned and as you just heard, it's truly transformational for patients. It's also transformational for Karyopharm. And we do believe it's up to, you know, probably about approximately $1 billion, you know, in the U.S. alone in terms of a peak revenue opportunity. Internationally, obviously, additional royalties and milestones as well. And what's really important, you know, looking at a company our size, given that we already have a multiple myeloma franchise, we have the commercialization capabilities in place. We can launch rapidly, and there's a lot of overlap, 80% overlap, actually, with the customer base in terms of those prescribers for myelofibrosis and our existing coverage. I think what's also really important is when you look at patient and physician flow, patient flow, physician workflow, adopting selinexor plus ruxolitinib requires no changes in myelofibrosis. There's no additional testing.
There's no additional flow, so it's something which patients and physicians can also adopt rapidly within their existing workflow or their patient flow. Now, when you look at myelofibrosis, you know, currently in the U.S., there's a prevalent patient population of around 20,000 patients. What's really important is there's around 6,000 newly diagnosed intermediate to high-risk patients per year. Within that population, about 4,000 have platelets greater than 100,000. Now, in that population, rux is by far the standard of care currently. We've done, you know, some really good market research in the U.S. with physicians that show already, looking at our profile, there's a 75% intent to prescribe the combination for those patients intermediate to high risk with platelets greater than 100,000.
Now, when you look at other areas where new treatments have come and new treatments have added to the current standard of care, there's a lot of examples where you see it takes about two to three years to really achieve a peak patient share, but those therapies become the standard of care. And I think a great example, you know, is actually in AML with venetoclax plus HMAs, coming and adding to the standard of care and in two to three years becoming the standard of care, delivering great benefit to patients. So, we're excited about it. We're excited about the opportunity to really bring our commercialization capabilities to bear. And you mentioned it. You know, what's important also is that patients stay on therapy for a long duration of therapy. Right now, with ruxolitinib, you see about a 13-month duration of therapy.
We believe we have the opportunity to improve on that, as Reshma talked to, looking at the areas we're addressing. Looking at our early data, duration of response was really strong at 100% at the time the data cut off. So, we think a really strong opportunity to also have a really strong duration of therapy. So, again, we look at the opportunity, existing capabilities in place, really within the existing patient and physician, you know, flow with two approved drugs, improving on the standard of care. I think it's an exciting opportunity and one we can't wait to turn over in March and work to commercialize.
Absolutely. And I'm just going to pause there for a moment because this is an important part of the Karyopharm story. Any questions from the audience on myelofibrosis? Because your other opportunity is endometrial.
Endometrial, sure.
Yes. Thank you, and you guys are running the phase III XPORT-EC-042 trial. Tell us a little bit about this because you really do have two shots on goal next year.
Yeah. This is a really exciting opportunity for us, largely because it would be our first opportunity to get into a solid tumor, right? And our ability, again, to be able to go into solid tumors is just based upon the mechanism. In this case, what we're doing is we're leveraging p53, which is a really important tumor suppressor. p53 has been identified and discussed in endometrial cancer for a really long time. And essentially, what we are doing in this trial is that we are identifying patients whose tumors are p53 wild type. These patients are approximately a little bit more than half of all patients. We work with FMI Foundation Medicine. They use their NGS platform to identify patients who are p53 wild type. If they meet other inclusion/exclusion criteria, they're then randomized to either selinexor or placebo.
We continue to follow these patients until progression-free survival. All of these patients, again, they've completed their chemotherapy, randomized to selinexor, and we're really looking at our ability to delay PFS with selinexor, again, as compared to control or placebo. Why are we so excited about this opportunity? It's largely because we had a preceding phase III trial in a similar patient population. Now, this trial was an all-comers, irrespective of their p53 status. When we specifically looked at the cohort of patients who are p53 wild type, what we saw, especially with long-term follow-up, was a remarkable PFS benefit. In fact, in those patients who are pMMR, p53 wild type represents about 50% of all patients. That median PFS was 40 months. Compare that to placebo, which is only about 5 months, corresponding to a hazard ratio of around 0.36.
Keep in mind that 40 months PFS is actually longer than what's been observed for overall survival with the checkpoint inhibitors, another therapy that is available for these patients. So, it really suggests a remarkable ability to delay that time to tumor recurrence. This trial, again, is going to be looking at these p53 wild type patients. We have an MITT population that's going to be looking at the p53 wild type pMMR. If that's positive, we'll then be looking at all patients who are p53 wild type. The trial is enrolling at this time, and we expect the data in the middle of 2026.
Very exciting. So, two really cool shots on goal. I know most people are focused on myelofibrosis. It comes first, but we could have two wins. So, Lori, I want to bring you back into the conversation. In October, you guys entered into a multi-part financing financial restructuring that brought in new capital, issued new debt, converted some existing debt, and deferred interest payments. It was one of the more complicated structural deals that I've seen. It was actually very fun to kind of figure out all the pieces. Congratulations on executing that. Tell us where the cash is now, and what kind of runway do you have with that?
So, specifically, you were asking about the debt. We have $231 million of debt consisting of a term loan and two convertible notes. And as part of that refinancing, we were actually able to defer interest payments. So, those payments will not start again until the end of Q2 of 2026. And this is important because it gives us cash runway into quarter two of 2026, which allows us to get to our pivotal top-line data readout for phase III SENTRY trial in March.
Yep. That's it. Great. Well, I think we're out of time, but good luck. Break a leg. We're all pulling for you.
Thanks, Ted. Thanks for having us.