Karyopharm at Jefferies: Pioneering Trials in Cancer Treatment

On Thursday, 05 June 2025, Karyopharm Therapeutics Inc (NASDAQ:KPTI) presented at the Jefferies Global Healthcare Conference 2025, shedding light on its significant strides in the treatment of myelofibrosis and endometrial cancer. The company is focusing on phase 3 trials that could potentially transform patient outcomes, while also addressing challenges in a competitive oncology market.

Key Takeaways

• Karyopharm’s phase 3 trials in myelofibrosis and endometrial cancer are poised to significantly impact patient care.
• The myelofibrosis program targets a $1 billion+ peak opportunity, with data expected by late 2025 or early 2026.
• The endometrial cancer program is advancing, with data readout anticipated in mid-2026.
• CEO Richard Paulson and CMO Reshma Orangwala emphasized the transformative potential of selinexor in combination therapies.

Financial Results

• Karyopharm estimates a peak opportunity exceeding $1 billion for its myelofibrosis program.
• The company is focused on expanding its core multiple myeloma business, leveraging its profitable foundation.

Operational Updates

• The phase 3 trial for myelofibrosis (MF034) is nearing full enrollment, with completion expected soon.
• Enrollment for the endometrial cancer program is ongoing, aiming for a data readout by mid-2026.
• Karyopharm has commercial capabilities ready for a rapid market launch, pending positive trial results.
• A futility analysis for the MF034 trial was successfully passed, allowing the study to proceed as planned.

Future Outlook

• Karyopharm anticipates top-line data from the myelofibrosis phase 3 trial by the end of 2025 or early 2026.
• The company aims to establish new standards of care in myelofibrosis and endometrial cancer.
• Completion of enrollment in the SENTURY trial is expected within the next few months.

Quotes from Leadership

• Richard Paulson, CEO, stated, "It’s a very exciting time at Karyopharm. We’re an innovation-driven commercial stage oncology company with two transformative phase 3s reading out in the very near term."
• Reshma Orangwala, CMO, highlighted, "What we see in our combination study is that amongst the fourteen patients treated with selinexor sixty milligrams in combination with standard of care ruxolitinib, we more than double that rate."

Readers are encouraged to refer to the full transcript for a more detailed understanding of Karyopharm’s strategic initiatives and future plans.

Full transcript - Jefferies Global Healthcare Conference 2025:

Maury, Tech analyst, Jefferies: Tech analyst at Jefferies. It’s with great pleasure that I’d like to welcome the Karyopharm management team to our Jefferies conference. We’ve got the CEO, Richard Paulson and the CMO, Reshma Orangwala. And they’re going to be joining us for a presentation today. It’s an exciting year for the company.

They’ve got an ongoing phase three study in myelofibrosis and also a phase three in endometrial as well. And they’ll tell you more about those programs and their commercial program as well. And so I’ll turn it over to Richard and Ruffin.

Richard Paulson, CEO, Karyopharm: Thank you, Maury, and thanks to the Jefferies team for hosting us. And as you mentioned, you know, it’s a very exciting time at Karyopharm. We’re an innovation driven commercial stage oncology company with two transformative phase 3s reading out in the very near term as we work to build on our multi myeloma foundation. And so before I get into things, kind of a little housekeeping. I’ll remind you that various remarks we make today will constitute forward looking statement, as you see on the slide.

And please refer to our most recent 10 Q. So as Maury mentioned, and as I kicked off with, it’s an exciting time. We’re building on our profitable foundation of multiple myeloma, with the transformative opportunities of myelofibrosis and endometrial cancer. And that’s what we want to present today, too, is to really talk some more about myelofibrosis and show the journey we’ve been on, and as we continue to create data and generate insights in myelofibrosis, just continues to give us confidence on our ability to make a difference for myelofibrosis patients and bring the potential of a doublet in frontline myelofibrosis, where innovation has not happened, really, if we think about over the last ten to thirteen years, with Jakafi really being the standard of care. That is very excited with top line data kind of expected towards the end of this year, early ’twenty six.

And as we see, you know, this leads us to a potential peak opportunity of a billion dollars plus. At the same time, you know, Reshma is going to talk to our endometrial cancer program, which we expect to read out kind of mid next year. Again, a significant opportunity to make a big difference for patients, especially as we focus on the p53 wild type PMMR patient population. So when we think about the data that we’ve just shared recently, you know, it continues to build our confidence in myelofibrosis. And our phase three program is focused JAK naive patients.

This data that we’re sharing today and that we’ve recently shared is actually from a heavily pretreated, difficult to treat patient population. And it’s monotherapy data. And this is from a trial that we actually started before we had the combo data. And as we see this data moving forward, it continues to show the potential of selinexor really to impact the four key hallmarks of myelofibrosis. Looking at spleen volume reduction symptom scores, looking at hemoglobin and transfusion burden, really importantly, disease modification potential when you look at the impact on key cytokines, and in a very kind of safe tolerable profile, which we continue to improve on as we’re using lower dose selinexor.

So as we look at this data, I think it really gives us more insight into our potential to be synergistic and additive you see with ruxolitinib as a combination in the frontline setting. And we think about our myelofibrosis journey, know, it’s been a journey that the company has been on for over seven years. And as we kind of highlighted, it started early on with some clinical activity, with some IST and kind of difficult to treat patients who’ve already been exposed to JAK inhibitors. We started our combo trial. We had started also this phase two program.

As we got the data from the combo trial in the phase one and showed the efficacy that we have across SVR, TSS, and again, the ability to positively impact hemoglobin, and really across key cytokines. We stopped that program. And as you see, we’re going to share the data from that data because it really enabled us to again show the monotherapy activity. We’ve continued to move forward. We’ve learned from other programs, made adaptations to our program to increase our probability of success, you know, and are rolling rapidly to really hopefully bring this to patients in the frontline setting as a novel combination and potentially become the standard of care in frontline myelofibrosis.

And as you touched on, you know, this is a transformative opportunity really growing on a profitable multiple myeloma foundation. We have the commercialization capabilities in place. We take our capabilities and pending positive data in the label, launch rapidly into myelofibrosis where, again, we have the potential to more than double the response rate. When you think about SVR thirty five as being response, you see about thirty percent to thirty five percent response from ruxolitinib the potential to more than double that. At the same time, you know, physicians want to be able to have access to this kind of innovation, which really improves the frontline treatment as rapidly as possible.

So that, I think, will enable rapid uptake and, again, moving forward with our existing commercialization capabilities. That’s what has us excited to deliver on the data, has us excited to deliver and potentially transform outcomes for patients. And as we look at how we’re doing that, I’m going to invite Reshma up to take you through kind of the data journey, and again, how we see increasing confidence as we’re sharing the data around our ability in myelofibrosis. Reshma?

Reshma Orangwala, CMO, Karyopharm: Thank you, Richard. I’m really excited, you know, about the opportunities we have with selinexor in myelofibrosis and endometrial cancer. I think two of our indications that near term opportunities. When I look at myelofibrosis, right, it really comes down to the mechanism. What is it about XPO1 inhibition that really enables potential monotherapy activity in multiple populations with myelofibrosis, but also that important additive, if not synergistic activity when it’s combined with other agents including JAK inhibitors.

And the way I look at it is because lots of interrogation, preclinical work and teasing a part of the mechanism, it suggests that we are inhibiting the JAK STAT pathway, which is noted on the left. But in addition to the JAK STAT pathway, we modifying and utilizing non JAK pathways to enable cell death. This is going to include p53 driven cell death. P53 we know is a very important tumor suppressor. P53 wild type is found in about ninety five percent of myelofibrosis patients.

And obviously we have very, very compelling clinical data in endometrial cancer that really suggests that selinexor drives meaningful activity in p53 wild type. And of course we are also leveraging cell cycle arrest. So this ability to inhibit both JAK and non JAK pathways, again, enables monotherapy activity. And I’ll take you through some of that new data in a few minutes, but also this potential additive if not synergistic activity when we combine it with a JAK inhibitor. The key aspect that we are focused on with selinexor is ability to modulate the four key hallmarks of myelofibrosis.

And in myelofibrosis, we know these patients unfortunately suffer from very large spleens, so we really want to drive rapid but durable spleen reduction. These patients also suffer from very severe symptoms, both stemming from their very large spleens as well as non spleen related symptoms. We know that they suffer from a lot of cytopenias. Their bone marrow unfortunately is like concrete. They also have these huge surges in cytokines that also implicate anemia and perpetuate anemia converting into transfusion dependent states.

And lastly, how do we modify the underlying disease? How do we reverse some of these processes so that it ultimately can drive meaningful spleen volume reduction, symptom improvement, cytopenia stabilization, but ultimately drive PFS improvement and overall survival improvement. If I look at our phase one combination data, these are the data I think in that seven plus year journey really solidified our conviction in XPO1 inhibition in myelofibrosis. Why do I say that? It’s largely because of the degree volume reduction rates that we see with this combination.

So as Richard already alluded, Jakafi ruxolitinib is the standard of care for this patient population. Patients treated with Jakafi, about thirty percent, thirty five percent of those patients are going to achieve that important SVR 35 rate. What we see in our combination study is that amongst the fourteen patients treated with selinexor sixty milligrams in combination with standard of care ruxolitinib, we more than double that rate. We go from thirty to thirty five to now seventy nine percent of those patients achieving that SVR 35 rate. And if you look at any time in that efficacy evaluable population, we every single one of those patients actually achieved that SVR thirty five rate.

Coupled with those high percentage of patients is the durability, right? What these patients want to appreciate is that once they achieve that spleen volume reduction, that spleen volume reduction is going to be maintained. What we analyzed is standard durability of response through a standard Kilometers curve. On the left hand slide is a Kaplan plot of the durability of response amongst those patients, 11 patients who achieved that SVR 35. And what we see is a 100% probability of duration.

None of the patients at the time of this data cutoff had actually progressed. But interestingly enough, we also see that with symptoms. So when we look at TSS 50, a very standard responder based analysis amongst the patients who achieved that TSS 50, again fifty eight percent, there too none of the patients had actually progressed. So really important durability of response both from an SVR as well as a symptom perspective. Important evolution in myelofibrosis is how we analyze symptoms.

Okay? So as I mentioned before on the previous slide, convention has always been to look at symptom improvement. Again, total symptom score of at least 50%. It goes all the way back to the insight days when they developed Jakafi, right? And it was sufficient.

When you are looking at Jakafi versus placebo and you just look at the percentage of patients that achieved that fifty percent, it’s fine to show that improvement. What we now see though in these modern trials in which we are looking at combination relative to active control, TSS fifty no longer is a sensitive endpoint. You cannot detect a meaningful improvement above and beyond ruxolitinib. So what we are now looking at is again using the same data but analyzing all of the data observed over the course of those twenty four weeks. By utilizing all of the data and the changes that occur within those twenty four weeks, we can then aggregate and then assess the change relative to baseline.

That ability again serves as a more sensitive way of detecting that improvement above and beyond rux, which from a physician standpoint and from a patient standpoint is what they really want to appreciate. There are two key phase three trials that read out at ASH twenty twenty three. This is going to be the MANIFEST trial. This is going to be the TRANSFORM trial. I highlight those trials only because they too evaluating their relative combinations versus rux alone in a very similar patient population as what we did.

And when you look at the rux only arms, what you can appreciate is that rux only, rux monotherapy, led to anywhere between an 11 to 14 improvement relative to baseline. Now look at our phase one data on the left hand slide. We now see an 18.5 improvement. So it suggests almost a four point delta, more than four point delta with the combination relative to ruxolone, mirroring that same kind of improvement that we also see with TSS fifty. If I look at the change in symptoms over time, it also suggests rapid and sustained symptom improvement, right?

So we looked at the change in symptoms week four, you see a rapid decline in symptoms, which represents an improvement that continues all the way to week sixteen, which is again sustained until week twenty four. Based upon those data, as Richard mentioned, we initiated this ongoing phase three trial. So this is our MF034 phase three trial of selinexor in combination with ruxolitinib, again in that JAK naive myelofibrosis population. Three fifty patients are planned, two to one randomization in a double blind fashion to either combination versus ruxolitinib. And our primary endpoints are going to be two, so co primary endpoints, SVR 35 at week 24, and then again absolute TSS, right?

A more sensitive way of assessing that symptom improvement. This study is close to finishing enrollment. Enrollment. We are really looking forward to when that last patient is enrolled, which is going to enable top line results likely at the end of this year, beginning of next year. There was a futility analysis pre specified that was conducted earlier this year.

It was based upon both efficacy and safety. Very happy to announce that it passed and the study, the DSMB concluded that the study should continue as planned without modification. So those are our phase one data. Those are, you know, sort of the trial that is almost complete. But to give you more confidence about the activity that selinexor and XPO1 can have in myelofibrosis, I do want to take you through these data from this MF035 study.

As Richard mentioned, this was a study that was started many years ago in a very different patient population. So arguably this is a much harder to treat patient population given that the fact that they were already exposed to JAK inhibitors, at least six months of JAK inhibitors. This patient population was randomized in an open label setting to either selinex selinexor as a monotherapy versus physician’s choice, right? And they were followed for SVR and multiple endpoints including symptom improvement. This is the demographics of this patient population.

In total at the time that we paused enrollment, twenty four patients had been enrolled. 12 to the selinexor arm, 12 to the physician’s choice arm. Heavily pretreated, so an average number lines up to four prior lines of therapies. This is also a very high risk patient population. I say that because if you look at those triple negative rates as well as high risk rates, substantially higher than what you would normally anticipate out of a myelofibrosis population.

If you look at the spleen volume reduction, again it mimics and is consistent with what we have seen in the past with so many of our other trials in myelofibrosis. And that XPO1 as a monotherapy drives meaningful spleen volume reduction in the vast majority of these patients. In fact, if you look at the waterfall plot on the right hand side of screen, the green bars represent patients that were treated with selinexor at any time. In this waterfall plot, you will see 12 patients who were efficacy evaluable, again treated with selinexor. And importantly, every single one of those patients achieved achieved some degree of spleen volume reduction, say for one patient.

Now compare that to Physician’s Choice in which only half the patients experienced some degree of spleen volume reduction. So already a notable different that then translates to SVR 25 and 35 rates too. So if you look at the bottom of the slide, you’ll note that SVR 25 was achieved in sixty seven percent of the patients treated with selinexor as compared to only thirty eight in Physicians Choice. If you look at SVR35, there too there’s a doubling, thirty three percent versus only thirteen percent. Now an important part of this study was the fact that it allowed a crossover specifically for those physician’s choice patients.

Now these physician’s choice patients had to meet predefined progression criteria. And the majority of those patients of which there were six were treated with prior ruxolitinib. So at the time that they crossed over, they had already relapsed. They were already refractory to their prior JAK inhibitor. So we really wanted to appreciate whether a patient who was already refractory to a JAK inhibitor could then have some degree of spleen volume reduction when they were then subsequently treated with selinexor.

So what we did is we took each one of these patients, right, we just charted their spleen over time and then included them in the standard spider plot. And what you can see at zero, this is going to be their baseline spleen at the time that they were randomized. The second column represents the maximum spleen volume reduction they achieved when they were treated with Physicians Choice or ROX. The third column represents their spleen growth at the time that they had progressed. And then the fourth column represents the rapid and meaningful spleen volume reduction that was then achieved when they were then subsequently treated with selinexor.

In fact, four out of five patients treated with that XPO1 inhibitor achieved that SVR 25 suggesting that XPO1 could actually overcome, right, prior JAK inhibition likely because it’s recruiting those other pathways that are going to be relevant in myelofibrosis. The third aspect, symptoms, right? Do we see symptom improvement with selinexor monotherapy in this very hard to treat population? We looked at both TSS 50 at week twenty four as well as absolute TSS. Here too you see that monotherapy activity.

In fact, amongst the seven patients randomized to Selinexor, we see twenty nine percent achieve that TSS 50 at week twenty four and a very meaningful six point reduction relative to baseline. When you look at all patients treated with selinexor, again a more heavily pretreated patient population, therefore you see an eighteen and four point respectively. Another aspect that is important, again the third hallmark is going to be cytopenias. What we really wanted to understand was can XPO1 stabilize their hemoglobin and reduce transfusion burden? And to answer these questions, what we did is first off just charted mean hemoglobin over time across the two arms.

On this chart, the green line represents those patients treated with selinexor and blue are going be those patients treated with physician’s choice, by and large ruxolitinib. Visually you can already see that the mean hemoglobin from the very start of treatment substantially higher for the selinexor treated patients as compared to physician’s choice. When you look at transfusion burden, I think these data are very meaningful. So these are standard Swimmers plots. Blue again represents those patients treated with Physicians Choice.

The green represents those patients treated with selinexor. And each red dot represents a transfusion. Visually again you can already see substantially transfusions administered to those patients treated with Physicians’ Choice as compared to selinexor. And that translates to about a half the number of units transfused for the selinexor arm as compared to Physicians’ Choice. So the question is why is this happening with XPO1?

And as I mentioned earlier, it’s because we believe XPO1 is modifying the underlying disease, right? And we that this myelofibrosis, the pathogenesis stems from multiple different factors. We know that cytokines are going to play a key role here, specifically IL-six, IL-eight, TNF alpha, hepcidin, each one of those alone and in combination really driving aspects of angiogenesis, pathogenesis, and multiple aspects of anemia as well. What we had access to were plasma samples at week four from a subgroup of these patients. And we compared those cytokine levels at week four relative to baseline and then charted those cytokines in this very standard dendrogram.

In this chart, the purple represents a decrease in cytokines and the orange or red represents increase in those cytokines. And what you will notice is again a very rapid decrease in those cytokines as early as week four. So again, very meaningful reductions in IL-eight, IL-six, TNF alpha and hepcidin specifically for selinexor for PC, you actually see an increase. And of course this comes with a very manageable safety profile. So if we look at all gray treatment emergent adverse events, we see nausea which is a known side effect with selinexor experienced in only thirty three percent of those patients, thrombocytopenia thirty three percent, even grade three plus AEs, very manageable, very tolerable.

And it’s important to none of these patients actually needed to discontinue therapy as a result of this AE. Now let’s just segue to endometrial cancer. So completely different disease type, of course, right? Endometrial cancer. And this is the beauty of selinexor is because of its mechanism, it enables this broad anticancer activity across multiple different tumors, including both solid as well as hematologic in nature.

What we’re leveraging in endometrial cancer is this really important biomarker in p53 wild type. It’s an important tumor suppressor. By administering XPO1, you just block the gate, Exportin that is going to be important shuttle of proteins from the nucleus into the cytoplasm. So these patients that are administered selinexor just have active p53 retained within their nucleus, which ultimately drives apoptosis and cell death. If you look at endometrial cancer, more than half of all patients are going to be p53 wild type.

We also know endometrial cancer, another really important molecular entity is going to be their MMR status, right? So MMR proficient is identified in about eighty percent of all patients. MMR deficient patients are going to represent the remaining about twenty percent of all patients. If you look at the percentage of patients who are both PMMR and P53, about half or fifty percent of all endometrial cancer patients. Now landscape has really evolved in the last couple of years in endometrial cancer largely because of the introduction with the checkpoint inhibitors, right?

So multiple checkpoints including dostarlimab, pembrolizumab have been approved for all patients regardless of MMR status. With that said though, there is a growing appreciation both by investigators, physicians, as well as the regulatory agency that the efficacy achieved by MMR status is very different. So checkpoint inhibitors, not surprisingly, have substantial benefit in that small DMMR population. Where the benefit is far more modest is going to be in that PMMR population. And that’s really going to be that population that you’ll see in a couple of minutes really has the greatest benefit with selinexor.

Let me take you through these data very quickly. This is going to be long term follow-up data from a very large subgroup of p53 wild type patients observed in a prior phase three SEENDO trial. Here you can see that selinexor led to a very meaningful 28.4 median PFS compared to only five point two months PFS for placebo, translating to a hazard ratio of 0.44. This is that subgroup again, fifty percent of all patients who are going to be p53 wild type PMMR. Now you see a median PFS of forty months.

This is actually longer than the overall survival achieved by the checkpoint inhibitors. Forty months achieved by selinexor, again PFS, compared to only four point nine months for placebo, translating to a hazard ratio of 0.36. Of course, very excited about these data as well as the ongoing phase three trial that again is evaluating selinexor as a monotherapy in the maintenance setting in these patients with p53 wild type endometrial cancer. Two seventy six patients are planned one to one randomization to either sell you as a monotherapy or placebo. Primary endpoint is going to be progression free survival as assessed by investigator.

It’s going to be evaluated first in this

Richard Paulson, CEO, Karyopharm: largely

Reshma Orangwala, CMO, Karyopharm: represents PMMR, P53 wild type. And then it’ll roll down into that larger ITT population which is going to include additional DMMR patients. That said.

Richard Paulson, CEO, Karyopharm: Thank you, Raishma. So I think as you just heard, and as Raishma walked you through, it’s a transformative time for us at Karyopharm. It’s a transformative time with the potential to really dramatically improve outcomes for patients in myelofibrosis and endometrial cancer. So very excited about it. You know, as we move through the year, we’re continuing to focus on working to grow our core business in multiple myeloma, you know, delivering the complete enrollment, as we said, over the next couple months in our SENTURY trial, seeing the top line data end of this year, early next year, moving forward, and really getting ready for that established commercial capability that we have.

It’s an exciting time for anybody in the organization to be getting ready to bring potential new standard of care to patients. And as we report out the data, excited for the potential there to move forward rapidly and bring innovation to patients, and at the same time, continuing to move forward with completing enrollment in our endometrial cancer program and reading that out in mid-twenty twenty six. So thanks for the opportunity to share the story, and excited to talk some more in the near future.

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