Karyopharm Therapeutics, Inc. Aktie

Good morning. My name is Anas, and I'll be your conference operator today. At this time, I would like to welcome everyone to Karyopharm's Second Quarter 2026 Financial Results Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request. I would now like to turn the conference over to Brandon Strong, Senior Vice President, Investor Relations.

Good morning, and thank you all for joining us on today's conference call to discuss Karyopharm's second quarter 2026 financial results and recent company progress. We issued a press release this morning detailing our financial results for the second quarter of 2026. This release, along with the slide presentation that we will reference during our call today, are available on our website. For today's call, as shown on slide 2, I'm joined by Richard, Reshma, Sohanya, and Lori, who will review our second quarter financial results, provide an update on the significant progress we've made advancing our myelofibrosis program, discuss the clinical and regulatory momentum supporting our planned sNDA submission, and review our financial position and capital allocation priorities.

Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995, as outlined on slide 3. 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 factors section of our most recent Form 10-Q or 10-K on file with the SEC and in other filings we may make with the SEC in the future. Any forward-looking statements represent our views as of today only.

While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so, even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any later date. I'll now turn the call over to Richard. Please turn to slide 5.

Thank you, Brandon, and good morning, everyone, and thank you for joining us today. The second quarter marked the beginning of an important new chapter for Karyopharm as we advanced selinexor from a compelling and differentiating Phase 3 data set toward our planned supplemental new drug application under the FDA's Accelerated Approval Pathway for patients with myelofibrosis. Over the past several months, we've remained focused, moved with urgency, and executed against an ambitious plan, generating and presenting the SENTRY data, publishing the results in the Journal of Clinical Oncology, working collaboratively with the FDA to establish a regulatory pathway as we prepare our planned submission.

The SENTRY study demonstrated statistically significant, rapid, deep, and sustained spleen responses, together with preliminary overall survival findings and evidence of potential disease modification. These findings have now been presented at leading international scientific meetings, published in a peer-reviewed journal, and continue to generate strong interest globally among the hematology community. Taken together, we believe these data reinforce the potential for selinexor to fundamentally change the treatment of patients with myelofibrosis. That same focus, urgency, and commitment to execution continues to guide every step as we advance into the next phase of our myelofibrosis program.

Turning to slide 6, as we announced in July, we remain on track to submit our sNDA in August as we complete the final elements of our submission in collaboration with the FDA. Our interactions with the agency continue to be constructive, and we remain focused on delivering a high-quality submission. Our confidence in this opportunity continues to be grounded in both the consistency of the SENTRY data and our constructive regulatory engagement. If approved, selinexor in combination with ruxolitinib would be the first approved combination therapy for patients with myelofibrosis, introducing a novel therapeutic mechanism for the treatment of this disease.

Turning to slide 7, while our focus today is on the important progress we've made in myelofibrosis, I'd also like to briefly address the top-line results from our Phase 3 XPORT-EC-042 study and the actions we've taken following those results. While we were disappointed that the study did not achieve statistical significance for its primary endpoint in the mITT population, I want to thank the patients, investigators, and study teams whose commitment made this important trial possible. Although we observed a numerical improvement in median progression-free survival favoring selinexor, the study did not meet the statistical threshold required to support our development plans in endometrial cancer.

Following these results, we made the deliberate decision to sharpen our focus on hematology with our opportunities in myelofibrosis and multiple myeloma, where we believe selinexor has the greatest potential to improve patients' lives and create long-term shareholder value. While we continue to follow patients in the near term, we are meaningfully reducing planned investment in endometrial cancer. Moving forward, our priorities are clear. Advancing our myelofibrosis program through the regulatory process, continuing to grow our multiple myeloma business, and leveraging the commercial, medical, and market access capabilities we have built over many years to a rapid and efficient launch in myelofibrosis if approved.

As we execute against these priorities, we are equally focused on disciplined capital allocation. As we'll discuss, we are actively evaluating a range of financing opportunities and strategic alternatives with the objective of maximizing long-term shareholder value while preserving strategic flexibility as we advance our myelofibrosis program through these important milestones. We are approaching this with the same focus, urgency, and discipline that have characterized our execution over the past several months.

Looking ahead, we believe the company is entering 1 of the most important periods in its history. Turning to slide 8, over the coming quarters we expect several important milestones, beginning with the potential inclusion in the treatment guidelines in Compendia, our planned sNDA submission in myelofibrosis this month, followed by potential FDA filing acceptance of the sNDA, and its potential to be accepted for priority review and ultimately a potential approval and launch as early as the first quarter of 2027.

Additionally, we remain on track to report top-line data from the 60 milligram cohort of the Phase 2 SENTRY-2 study in the second half of this year, which we expect will further establish the role of selinexor in myelofibrosis. We are entering this next phase with a clear strategy, a focused organization, and an established hematology platform that positions us well for what lies ahead. With that, I'll turn the call over to Reshma, who will discuss the clinical and regulatory foundations supporting our planned submission for the first ever combination and why we believe selinexor is a necessary novel therapeutic mechanism that has the potential to fundamentally change the treatment of patients with myelofibrosis. Reshma?

Thank you, Richard. As Richard discussed, we believe selinexor has the potential to fundamentally change the treatment of patients with myelofibrosis. I'd like to spend the next few minutes discussing why we believe the scientific evidence supporting that opportunity has continued to strengthen, why it supports our planned sNDA submission, and how we continue to build the clinical foundation for selinexor in myelofibrosis. Turning to slide 10, the biological rationale for combining XPO1 and JAK inhibition is compelling. STAT activation is a key driver of malignant clone proliferation, splenomegaly, and disease-related symptoms, while XPO1 activity is important for malignant cell survival. By targeting these complementary pathways simultaneously, we believe selinexor has the potential to complement JAK inhibition and improve outcomes beyond symptom control alone.

Turning to slide 11, myelofibrosis remains a disease with a high unmet need given clinical activity with the currently approved therapies is modest. As a result, spleen volume reduction of at least 35% is observed in less than 1 third of patients. Overall survival improvements are limited, and meaningful modifications of the underlying disease is not observed. Turning to slide 12, a distinctive profile has been observed from the SENTRY trial, given the compelling SVR35 results that are rapid, deep, and sustained, a promising OS signal, a first-of-a-kind prediction between SVR35 and OS, and a safe and manageable adverse event profile. These data appear to support SVR35 as a reasonably likely surrogate endpoint, enabling an sNDA under the accelerated approval pathway.

Turning to slide 13, at week 24, a nearly double spleen response rate was observed with the combination of selinexor plus ruxolitinib versus ruxolitinib alone. What's particularly important is the quality and kinetics of that response. As shown on slide 14, the responses were rapid, emerging as early as week 12, and deep, with greater average spleen volume reductions relative to baseline observed with the combination. Both response rates and depth of response were sustained through week 36.

Importantly, as seen on slide 15, the benefit was consistent across pre-specified patient subgroups, reinforcing the robustness of the treatment effect in the vast majority of frontline myelofibrosis patients. Especially important is a subgroup analysis by ruxolitinib dosing as seen on slide 16. Even with average suboptimal doses of ruxolitinib less than 15 milligrams per day, SVR35 rates with the combination were as high as 50% compared to 0 observed with ruxolitinib alone, indicating that with the combination, SVR35 is driven by selinexor and supported by modest doses of ruxolitinib. From a clinical practice standpoint, these data suggest that ruxolitinib dose reductions may not compromise efficacy when combined with selinexor.

As shown on slide 17, at the time of the top-line analysis, the overall survival hazard ratio was 0.43, and patients continued to be followed as these data mature. On slide 18, a post hoc landmark analysis demonstrated that irrespective of treatment, SVR35 at week 24 predicted overall survival. This observation is further reinforced by the longer term follow up from the Phase 1 trial on slide 19, in which the same relationship between SVR35 and overall survival is observed.

On slide 20, the importance of the SVR35-OS relationship becomes even clearer when viewed in the context of the broader myelofibrosis literature. Over the past several years, a substantial body of retrospective evidence from Phase 3 JAK inhibitor trials has demonstrated that greater SVR35 rate differences observed across the 2 arms correlate with improved overall survival. SENTRY now provides an important opportunity to build on that body of evidence as the first Phase 3 trial that prospectively demonstrates the same relationship and establishes SVR35 as a potential surrogate endpoint for overall survival. This underscores the importance of treating patients with the combination early in the disease course, increasing the likelihood an SVR35 reduction is observed, thus potentially maximizing overall survival.

On slide 21, we also observed higher rates of variant allele frequency reduction with selinexor plus ruxolitinib as early as week 24. These molecular findings are important because VAF reduction was associated with a greater likelihood of achieving SVR35, providing additional biological evidence that is consistent with the clinical findings. Taken together on slide 22, the rapid, deep, and sustained spleen responses, the promising overall survival findings, the relationship between SVR35 and survival, and the molecular data all point in the same direction.

We believe this unique and compelling profile strengthens the scientific rationale for SVR35 as a meaningful predictor of long-term survival. It is the combination of this growing body of evidence, the strength of the SENTRY data, and the significant unmet need in myelofibrosis that formed the basis of our scientific discussions with the FDA regarding the role of SVR35 in supporting our planned sNDA submission. We believe the FDA's written feedback indicating that SVR35 appears to qualify as a reasonably likely surrogate endpoint to predict overall survival represents an important scientific and regulatory milestone. Importantly, this builds upon years of scientific evidence supporting the relation between SVR35 and long-term outcomes, together with the prospective randomized evidence generated through SENTRY.

Our planned submission will be based on the week 24 SVR35 results. We intend to use additional long-term overall survival data from the ongoing SENTRY trial to verify clinical benefit, a requirement under the accelerated approval pathway to later convert to traditional approval. While our immediate priority is our planned submission, we continue to explore the broader role of selinexor in myelofibrosis. On slide 23, the ongoing SENTRY-2 study provides an opportunity to further characterize the activity of selinexor as a monotherapy and explore the potential flexibility of XPO1 inhibition in combination with additional JAK inhibitors.

This study will help us better understand the intrinsic contribution of selinexor and continue to define the broader role of XPO1 inhibition across the treatment of patients with myelofibrosis. As Richard noted, we expect top-line data from the 60-milligram cohort of SENTRY-2 during the second half of this year. We believe the strength and consistency of the evidence generated through SENTRY, together with our continued clinical development efforts, provide a strong scientific foundation for our planned sNDA submission, and reinforce our belief that selinexor has the potential to fundamentally change the treatment of patients with myelofibrosis. With that, I'll turn the call over to Sohanya.

Thank you, Reshma. Turning to slide 25, my focus today is on why we believe Karyopharm is well positioned to commercialize this opportunity. Importantly, we're not preparing to build a commercial organization from the ground up. We're leveraging an established hematology platform that we have built over many years through the commercialization of XPOVIO. On the scientific side, we have clinical development experience, active medical and scientific affairs teams, investigative relationships, and growing visibility across the myelofibrosis community. On the commercial side, we have established coverage in both community and academic hematology, key account capabilities, and market access expertise. And through KaryoForward, we have an existing patient support platform designed to help patients and caregivers navigate access, reimbursement, and treatment initiation. Importantly, these capabilities already work together today in multiple myeloma and can now be leveraged to support the potential expansion of selinexor into myelofibrosis, which is a significant strategic advantage to enable a rapid and efficient launch.

Turning to slide 26, Q2 was a breakout quarter with top-tier recognition across leading global oncology platforms. As Richard discussed, the SENTRY data have now been presented at ASCO and EHA, published in the Journal of Clinical Oncology, and continue to be discussed at scientific meetings throughout the hematology community. Importantly, while commercial promotion begins only following regulatory approval, scientific engagement is already well underway. The Medical and Scientific Affairs Organization is already deeply engaged within the myelofibrosis community. Following ASCO and EHA, our medical and scientific affairs teams have continued scientific exchange with investigators and treating physicians, participated in regional educational programs and scientific symposia, and continued building upon the relationships established throughout the SENTRY clinical development program.

We see significant engagement and thoughtful discussion surrounding the SENTRY results, particularly the rapid, deep, and sustained spleen responses, the promising overall survival findings, and the potential for disease modification. Furthermore, the structure of the myelofibrosis market is also well aligned with our existing footprint as shown on slide 27. Approximately 70% of patients are treated in the community setting and 30% in academic centers. Across both settings, the majority of patients are concentrated within a manageable group of treatment centers. This concentration allows us to focus our resources on the physicians caring for the majority of patients and to deploy our existing organization efficiently.

Our physician segmentation work has also given us a detailed understanding of the high-volume, innovation-oriented physicians most likely to adopt a new combination approach early. These physicians place significant importance on achieving rapid, deep, and sustained spleen responses and are actively considering how treatment may influence longer-term outcomes. There is also opportunity for prevalent patients treated with a JAK inhibitor to benefit from the combination therapy. We hear physician interest in the ability of selinexor to maintain spleen responses even when ruxolitinib doses are reduced, which is clinically relevant given how frequently dose adjustments occur in practice.

Finally, as we turn to slide 28 and looking at the commercial opportunity in myelofibrosis, we believe selinexor plus ruxolitinib has the potential to generate up to approximately $1 billion in peak annual revenue in the U.S. alone. Approximately 20,000 patients are currently living with myelofibrosis in the U.S. with roughly 4,000 newly treated frontline patients each year with no approved combination therapy in frontline myelofibrosis. Let's now review our multiple myeloma performance, which continues to provide the commercial and operational foundation for the broader hematology platform I have described.

As shown on slide 30, we delivered another quarter of strong commercial execution with XPOVIO U.S. net product revenue of $30.8 million. Underlying demand remained relatively consistent with the second quarter of last year, despite an increasingly competitive treatment landscape. This performance reflects the resilience of our multiple myeloma franchise and importantly, the strength of the relationships our commercial organization has built with hematologists and oncologists across both community and academic practices. Turning to slide 31, we continue to believe XPOVIO is well positioned for sustained performance.

Our focus remains on the community setting, which represents approximately 60% of our U.S. business, where physicians continue to value XPOVIO as a differentiated and convenient oral therapy. In addition, XPOVIO continues to occupy a unique position in the evolving treatment landscape surrounding T-cell engaging therapies, providing physicians with flexibility both before a CAR-T therapy and following progression on a T-cell engaging therapy. Our commercialization capabilities position us to continue to build on the foundation of multiple myeloma and, importantly, drive a transformative launch in the multi-billion dollar myelofibrosis marketplace. With that, I'll turn the call over to Lori to review our financial results and discuss how our disciplined capital allocation strategy supports the opportunities ahead.

Thank you, Sohanya, and good morning, everyone. Turning to slide 33, I will focus on our second quarter financial performance, our financial outlook, and the actions we're taking to support the important milestones Richard outlined. Starting with revenue, total revenue for the second quarter was $33.4 million compared to $37.9 million in the prior year period. The reimbursement of development-related expenses at the end of 2025, which reduced revenue by approximately $6.5 million compared with the prior year quarter. U.S. XPOVIO net product revenue was $30.8 million compared to $29.7 million in the prior year period. Underlying demand remained consistent, and our gross to net rate of 26.6% was comparable to the second quarter of 2025.

Turning to expenses, we remain focused on disciplined execution. R&D expenses were $29 million and SG&A expenses were $25.9 million, down 12% and 9% respectively year over year. This reflects our continued prioritization, disciplined investment, and focus on advancing our highest value late-stage programs with our Phase 3 trials having completed enrollment. We also continue to maintain disciplined alignment of prelaunch investments with clinical and regulatory milestones. Net loss was $67 million for the quarter, compared to $37.3 million in the prior year period. As a reminder, net loss includes non-cash mark-to-market adjustments related to our financing structure.

From an underlying operating perspective, performance improved with approximately an 8% reduction in loss from operations, reflecting stable net product revenue and continued expense discipline. Turning to the balance sheet, we ended the quarter with $65.4 million in cash, cash equivalents, restricted cash, and investments. Based on our current operating plan, we expect our existing liquidity, including cash, cash equivalents, and investments, together with anticipated cash flow from net product revenue and license and other revenue, to fund our current operating plans into September 2026.

On September 10, 2026, a $15.8 million principal payment is due under our Senior Secured Term Loan Facility. If that payment is made without additional financing or a waiver from our lenders, we expect our cash, cash equivalents, and investments will fall below our $10 million minimum liquidity covenant, which would constitute an event of default under the term loan. Importantly, our immediate priority is to address this and strengthen our financial position and provide the flexibility needed to continue executing our myelofibrosis strategy. Every capital allocation decision we make is intended to support the important clinical, regulatory, and commercial milestones ahead while maintaining disciplined execution across our multiple myeloma business and maximizing long-term value for patients and shareholders.

Turning to guidance, we are reaffirming our full year 2026 outlook. We continue to expect total revenue in the range of $130 million to $150 million. It's license and other revenue consisting entirely of royalties over the next 2 quarters and U.S. XPOVIO net product revenue of $115 million to $130 million. We continue to expect combined R&D and SG&A expenses of $230 million to $245 million in 2026, excluding certain one-time costs that we may incur associated with our endometrial cancer program and evaluating financing opportunities and or strategic transactions.

As a result of our decision to prioritize myelofibrosis and multiple myeloma, we are actively reducing investment across the endometrial cancer program, and we expect our cost structure to decline over time. A greater financial benefit will be realized in 2027 as we continue patient follow-up for the near-term and evaluate the evolving data set together with responsibly completing the remaining clinical and operational activities associated with the XPORT-EC-042 trial. In the near term, third quarter expenses may be modestly higher than the second quarter. This reflects a unique transition period for the company as we simultaneously advance our myelofibrosis program, implement the organizational changes associated with our decision to prioritize myelofibrosis and multiple myeloma following the XPORT-EC-042 top line results, and the costs we may incur to evaluate financing opportunities and strategic alternatives. With that, I will turn the call back over to Richard. Thank you.

Before we open the call for questions, I'd like to leave you with 1 final thought. Karyopharm is entering 1 of the most important periods in our history. We have a compelling opportunity in myelofibrosis, a regulatory path forward, an experienced hematology organization prepared to support a potential launch, if approved, and a team that has consistently demonstrated the ability to execute with focus, urgency, and discipline. We also recognize the importance and urgency of this moment, and that is why we are acting with discipline, not only in advancing our myelofibrosis program, but also in how we allocate capital and evaluate the financing opportunities and strategic alternatives discussed today.

Every decision we make is guided by a single objective, maximizing long-term value for patients and shareholders. I'd like to thank our employees for their extraordinary dedication, our investigators and collaborators for their partnership, and most importantly, the patients and families who have placed their trust in Karyopharm by participating in our clinical trials. We appreciate your continued support and look forward to updating you on our progress over the coming quarters. And with that, operator, we'd now be pleased to take your questions. Thank you.

[Operator Instructions]

Your first question comes from Edward Tenthoff with Piper Sandler. Please go ahead.

I just had some questions with respect to what still had to be done for the sBLA or sNDA, considering obviously that selinexor is already approved in multiple myeloma. You know, how much of the filing is already done and is there anything you'll say you need to compile on the clinical side, any sites that need to be revisited, or does all that already seem to be taken care of with the current approval?

Thank you, Ted. I'll turn to Reshma to go into that in more detail.

Yes, thank you, Ted and Richard. So Ted, the team has actively been working on the sNDA, by and large, the vast majority has already been put together. It's ready to go. 1 of the key pieces that we are just aligning and finalizing with the FDA is just around the confirmatory data piece, right? So I think as we all appreciate under accelerated approval, we are provided an approval, a label, but we do need to provide clinical benefit at some point in the future.

And so right now our discussions really have been focused on using the mature overall survival observed from SENTRY. We're finalizing the statistical analysis plans, again, aligning on those last details, which is something that is required before we submit the sNDA. So great productive conversations with the FDA, and we still are very much on track to submit the sNDA in August.

That's really helpful. Just to make sure I understand, so you'll use the OS data from the ongoing SENTRY as the confirmatory data set?

That is correct. We designed SENTRY intentionally from the very beginning to follow all the way for overall survival so that study continues with patients' sites blinded. They continue on treatment. They continue to provide scans as well as OS data. So yes, we are going to leverage that maturing OS to confirm the benefit, which is going to occur likely years from now, but that is going to serve as the confirmatory data set. We believe, you know, upon alignment with the FDA.

That's really helpful. Thanks, Reshma. Well, good luck.

Thank you. Your next question comes from [ Yannis Souroutzidis ] with Cantor. Please go ahead.

I guess just a quick question on kind of what is the right way to think about the feasibility here of future operations. Is accelerated approval absolutely needed, or do you believe that inclusion in the NCCN committee could provide sufficient revenues to address the debt and operating needs? And I have a quick follow-up.

Yes, thanks, Yanni. You know, I think as we've talked to, there's really, you know, a few of those milestones happening very much in the near term. And obviously, given that we're already an approved agent, you know, NCCN is very important, and I think it's something which, as we know, physicians utilize a lot. I think we've talked to that previously where, you know, with NCCN in similar situations, if NCCN is all that you achieve, usually products will achieve about 50% of what their peak may be.

But obviously, our goal is to enable as broad access as possible. 1 component is NCCN. The other component, as we've talked to, is really continuing to advance down the regulatory pathway. So, you know, I think both of those are occurring very, very positively over the near term. And I think both would be very positive for us in terms of, you know, being able to fund operations and obviously being able to enable patients to get access to selinexor and ruxolitinib in myelofibrosis.

Yes, appreciate it. And then just, I guess, relatedly to, you know, appreciate the transparency on kind of the upcoming payment required and the debt covenants there. I guess, is there a sense of what would be kind of the stopgap in your mind to kind of position the company well financially from a liquidity perspective to make it through these near-term milestones? And, you know, ideally, I would imagine make it through at least the first half or end of 2027.

Yes, I think, you know, as we've seen before, our lenders have consistently been very, very supportive with us and I don't have any reason to believe that they won't continue to do so. And so I think as we announced, we are working on a range of financing opportunities and strategic alternatives. We're in direct dialogue with our lenders with respect to these options. And I think obviously our goal is to work with lenders and potential equity investors and find a way to, you know, enhance our liquidity, extend the runway as we have these really important milestones, you know, in front of us in the second half of 2026. So I think, you know, we'll be able to continue to execute on that and find the right balance as we move forward.

Understood. All right. Thanks so much.

Thanks, Yanni.

Thank you. Your next question comes from Brian Abrahams with RBC Capital Markets. Please go ahead.

You mentioned in milestones the potential for inclusion of selinexor in the compendia in the back half of this year. That seems pretty rapid if the NCCN meeting is happening just this week. So I'm just curious if you're hearing anything emerging from the meeting that gives you confidence and maybe you could remind us of the process there. And then maybe just secondly, just curious if in your dialogue you're hearing any insights from the FDA on whether, and how open they might be to priority review.

Sure, thanks, Brian. I'll address the first part and I'll turn to Reshma for the second part. You know, obviously, you know, NCCN is an independent committee and an independent body. So, you know, they'll go through their process and evaluate. Importantly, we've put the right components in place in terms of our, you know, ASCO presentation, our EHA presentation, our Journal of Clinical Oncology manuscripts. I think all the right components are there, and we hear a high level of interest from opinion leaders to be able to get access to selinexor plus ruxolitinib. I think we're on track, as we said, to see that in the second half this year. I'll turn to Reshma to talk to the FDA.

Yes, thanks, Brian. You know, so as I mentioned, you know, really great productive conversations with the FDA. In terms of priority review, not necessarily. So this is, you know, a request that we need to make with the FDA at the time that the application is submitted. They have approximately 60 days to review that request, and then they'll provide that update shortly thereafter. So no specific insight, but we do believe that we have a strong package, potentially a differentiating profile, a need for a combination therapy. So hopefully they will review it and expedite the PDUFA date that will enable an approval sometime early next year.

Super helpful. Thanks so much.

Thanks, Brian.

Thank you. Your next question comes from Maury Raycroft with Jefferies. Please go ahead.

Maybe I'll just ask 1 on the term loan negotiations. Lori, you mentioned potential for a waiver. What do those discussions look like and what could updated obligations look like if there's a waiver and what is the likelihood of that? Then I've got a follow-up question.

Sure. Maybe, Maury, I'll address that 1. I mean, just at a high level, we're not going to obviously go into the details of the conversations and negotiations. But I think, as we mentioned, the lenders have been consistently supportive with us. And again, I think we don't have any reason to believe that they won't continue to do so. So, good, productive conversations and working on the right solution as we move forward. And obviously, that's something that we're very focused on and working to achieve rapidly.

Understood. That's helpful. And then for NCCN compendial listing, I guess, what's your plan to get patients from your clinical studies on the paid drug? And do you have a sense of proportion of patients from your studies that would make that switch early on with only the NCCN compendial listing?

Sure. Well, I think on our study, as we mentioned, we look to see our study continue, right? So our study continues. Patients are blinded. Clinicians are blinded. We have a blinded study team inside Karyopharm. So we would look to see our study continue. And I think, as Reshma mentioned, we're looking to see that to be the confirmatory data from an accelerated approval perspective. So our focus would be to make sure we're really working with the sites, investigators, patients, et cetera, to continue patients on our Phase 3 program.

Understood. Okay, thanks for taking my questions.

Thanks, Maury.

Thank you. Your next question comes from Michael King with Rodman & Renshaw. Please go ahead.

Just a little further granularity on the filing and the interaction with the FDA. I just wondering, given the recent interaction with the Type B and C meetings and the updated analysis that you presented at ESMO, I just wonder if any part of the data set that you're going to submit could be considered to be a major amendment. Obviously, this would be very impactful for the approval timeline. So I'm just wondering how you're thinking about submitting the data to the agency.

Yes, let me turn to Reshma for that part.

Yes, thanks, Michael. Great question. So the sNDA, you know, under the accelerated approval is really going to be based upon the week 24 data. So the week 24 that we really believe is compelling and differentiating, of course, is going to be that SVR35 data. Not only at week 24, that's the time point at which the primary analysis was conducted, but the kinetics really suggest something very differentiating. So, of course, that SVR35 at week 12, 24, 36 shows that sustained SVR, of course, the overall survival data, the post hoc analysis with the relationship between SVR35, OS, the disease modification data and the safety. So that's the profile, again, very compelling at week 24. And again, we'll form the basis for that for the sNDA.

Okay, and no 48-week data to be submitted then, is that correct?

That's correct. We're going to really focus on the week 24 data. Now, there are some patients that have been followed for week 48. You know, we'll provide that data as well, but, you know, the primary focus is really going to be on the week 24.

Okay, and can you say whether you'll include the pre-specified OS confirmatory analysis in that submission?

Yes, absolutely. That's part of the differentiating package. And that OS data that we observed and, of course, presented at ASCO, EHA, and was included in the JCO really was the basis for that post-hoc analysis that allowed us to show that relationship between SVR35, OS. So it is a very important data point. Of course, we'll continue to follow patients on overall survival. And as mentioned earlier, we'll use those data to ultimately confirm the benefit in the future.

Great. Thanks for taking the questions.

Thanks, Michael.

Thank you, Michael. There are no additional questions in the queue. I will turn it back to Richard for some closing remarks.

Thank you, Operator, and thank you everyone for joining us today and your continued interest in Karyopharm. I guess we've highlighted, you know, we very much look forward to providing you additional updates on our regulatory and financing developments very much in the near future. So, once again, thanks for joining us.

Ladies and gentlemen, this concludes your conference call for today. Thank you for participating. You may now disconnect. Have a great day.

All right, BiotechTV. We're in Stockholm, Sweden, at the 2026 EHA Annual Conference. That's the European Hematology Association. So that's all about blood diseases, including blood cancers. And I'm with a company right now publicly traded in the U.S. that's had a medicine on the market for multiple myeloma for years. And this could be a big year for them because they could increase the number of indication that this is used for by 1 or maybe even 2, depending on how some data plays out. So we're going to talk all about that.

It's Karyopharm Therapeutics, and this is Richard Paulson, the CEO. It's good to see you.

Good to see you, Brad. Thanks for having us.

Yes. So the drug is -- the brand name is XPOVIO. It was approved in 2019 for multiple myeloma, selinexor. And the first -- what we're here to talk about at EHA is a condition called myelofibrosis. Let's start with what is that? And like what's the unmet need for a new medicine?

Yes. Thank you, Brad. I mean myelofibrosis is a rare blood cancer, which has overall survival in your intermediate to high-risk patients of only 4 to 5 years. It's a progressive disease, which you see kind of the proliferation of clonal cells. You see bone marrow scarring. Patients have large spleens. They have kind of abnormal blood cell production and also constitutional symptoms, which overall, unfortunately, again, kind of leads to this progression and poor overall survival.

The unmet need is really driven again by the overall survival being only 4 to 5 years in intermediate to high risk, and the fact that there's really only been one class of therapies for these patients, that's the JAK inhibitors. They were approved over 15 years ago. They provide spleen volume reduction of about 1/3, for about 1/3 of patients, 30%, 35%, minimal disease modification. And so patients tend to then get some initial response, but then you start to see the spleens growing and patients progressing. So we obviously want to address that to work to really improve spleen volume reduction, improve overall survival for patients.

All right. So you've run a Phase III. You presented the data for the first time at ASCO a week ago. And so you're kind of doing an encore here. I'll pass it to you. Tell us like what the highlights of the data were and what you believe the significance are.

Yes. Super excited about the data. And as you mentioned, we presented at ASCO. We had a simultaneous publication in the Journal of Clinical Oncology presenting here tomorrow. And when you look at the data, the data really is driven by this really strong spleen volume reduction of SVR35 that we saw. Statistical significance, SVR35 at week 24, almost doubling what you see with ruxolitinib alone and then this promising overall survival signal we saw also very early with a greater than 50% reduction in risk of death.

And really what's important in the data are a couple of things. What you see is it's kind of the kinetics of our spleen volume reduction. And so you see our spleen volume reduction is really rapid, deep and sustained. So as early as week 12 we have a more than doubling of spleen volume response was 48% versus 20% with rux alone. At week 24, 50% spleen volume reduction versus 28%. And then sustained through week 36, we're at 40% or 47% actually versus 23%.

So really, the rapidity and the depth and the duration of spleen volume reduction is critically important. And then again, being the first study to show early in myelofibrosis compared to ruxolitinib alone to show this signal of overall survival, I think is very promising and what people are very excited about in the field.

Yes. One thing to note is that the trial had co-primary endpoints. The spleen reduction was one of those. One of them was like a symptom score, and you did not hit stat sig on that. What do you like when people ask you about that, like what do you have to say?

Yes. I mean, as you said, we didn't hit stat sig. We didn't see an improvement versus ruxolitinib alone. What's really important for physicians and patients is we did show meaningful improvement and very similar improvement to rux versus baseline. So patients with selinexor plus rux also showed a meaningful improvement versus baseline. And that's what's important for patients from a symptom perspective and something that I think as we look at the kind of the overall data with the spleen volume reduction with a similar symptom improvement to the overall survival, I think is very promising to kind of transform the field and improve outcomes for patients.

Yes. I mean I'm far from an expert in this space, but I do know we also call overall survival the gold standard in cancer period and you have a trend. How will you continue following that and seeing how that solidifies over time?

Yes. We're going to continue following it. We're committed to following this space, and it's important we've designed our trial so that patients and clinicians continue to be blinded. So we're going to continue to follow overall survival and then find the right time points to report it out when it's meaningful. It's not going to be a report every month. But I think as we continue to look, we are going to report that out, and that's, I think, what the field is very interested in.

Okay. And then here, too, you've said in your press release, it hasn't been presented yet, so we can't like talk in detail about it. But you believe you have like that the spleen volume reduction is like basically like a diagnostic that or a predictive value in terms of the overall survival. Is that right?

Yes. And this is something that's been in the field for over a decade where you've seen a growing body of literature where the better spleen volume response and the longer spleen volume response you have leads to better overall outcomes. We have the opportunity, I think, now to be the first study to show that prospectively versus rux, which is the gold standard. So I think we're going to continue to look at that.

I think a couple of things that are really important that we're talking to here is kind of irrespective of the ruxolitinib dose, you continue to see that with selinexor plus rux, you achieve that spleen volume response, which is critically important as you have to manage that with patients in the clinic. And also, we're going to be sharing some of the data from our Phase I where patients have obviously had the opportunity to be followed up longer, where we continue to see that predictive nature of spleen volume response leading to improved overall survival. So exciting and looking forward to the presentation tomorrow.

All right. Let's talk about next steps. And there's kind of 2 things that people are talking about. So again, this is a drug that's on the market right now for something else. And there's these things that we have called the NCCN guidelines where physicians get together and kind of publicly say this is the right course of treatment for something. So I know that you're hoping to be included in that for myelofibrosis. Is that completely out of your control? Like tell us like what that process is and whether you have any input in it at all and what the potential time line is?

Yes. It's a great question. And NCCN guidelines, I think are really important for clinicians to stay up to speed and have the ability to use medications across multiple groups of patients and really be reviewed by their peers and shared to help people understand new developments. But selinexor, as you said, have been on the market already for a while. We've treated over 40,000 patients. The safety profile is well understood. And so what's important for NCCN committees is they want to have peer-reviewed journals. They want to have presentations. So the ASCO presentation, Journal of Clinical Oncology publication really important.

I think -- so the committees, they work independently. They will look at the data and make their decisions. But yes, we hope to be included on there. We think it would be important. We hear from many clinicians they'd like to see us included on there. So I think that's the beauty of already being an approved medicine. Obviously, it's not an area we can commercially promote to, but it is an area which many clinicians look to, to make sure that they can stay up to speed and utilize already approved medicines as rapidly as possible.

Yes. And then how about FDA? Can you say anything about your filing plans?

Yes. I mean we've shared that we've had good productive conversations with FDA. We've also had productive conversations with our rapporteur and co-rapporteur in Europe. So we're going to continue those conversations, and we want to be able to provide a more meaningful update through Q2 and Q3 very shortly.

All right. So myelofibrosis is potentially the second indication. And then you have a big trial that's scheduled to read out sometime in the middle of this year for endometrial cancer, specifically in the maintenance setting. And fingers crossed for you. No pressure. I've seen analyst reports that suggest a success could almost double your stock, and we won't plan for this, but if it's less than a success, this is like a true binary event. So people should take note of that.

Tell us what you've done in endometrial cancer up to this point, and why an XPO1 mechanism is a good mechanism for endometrial cancer?

Yes. It's a great question. And I think it just builds on where we already are. As you mentioned, we're already an approved medicine. So revenue guidance this year was $130 million to $150 million. Obviously, in myelofibrosis, significant opportunity, and that's going to continue moving forward. And then endometrial cancer. So I don't look at it as binary because I think we have multiple opportunities that we're really have shots on goal.

And so I think in endometrial cancer, it is the #1 kind of gynecological cancer for women, still unfortunately, one of the leading causes of death for women. And in the endometrial cancer area, we had a trial a few years back called SIENDO, which we read out and the trial initially was designed to study the whole patient population and provided benefit, but a marginal benefit for the whole patient population. But what we did identify is a biomarker-driven patient population, so really personalized medicine. And those patients whose tumors are p53 wild-type really had really strong response with selinexor as a maintenance treatment in the endometrial cancer space. And it's really driven by p53 wild-type.

So p53 wild-type is a key tumor suppressor protein. We retain that tumor suppressor protein in the nucleus so it can kill the cancer cells. And what we saw in that data overall across all p53 wild-type patients was a meaningful hazard ratio of 0.44, PFS to the top line, 13.7 versus 3.7 months. It's really meaningful data, which has continued to improve. And as we look at that data continuing to improve, I think it's an opportunity for us to meaningfully improve outcomes for these women.

Okay. So you've completed enrollment in that, right? And your guidance is like summer, is...

Yes, it's coming up soon, right? So we're in summer. And so yes, our guidance continues -- it's event-driven trials. So obviously, we've had to be a little bit more flexible to make sure we can adapt. But we continue to have very strong belief that guidance is going to deliver that data shortly in the middle of 2026.

Okay. Well, I always say we always plan for success.

Thank you.

And of course, with an important cancer like that, we're wishing you the best of success. So good luck with myelofibrosis. A very important indication on its own, and good luck with that as well. It's very nice to meet you.

Yes. Thank you. Thanks for having us.

Thank you.

Good morning. My name is Joelle, and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics Conference Call to discuss today's Phase III SENTRY presentation at ASCO. [Operator Instructions] Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Brendan Strong, Senior Vice President, Investor Relations.

All right. Good afternoon, everyone, and thank you all for joining us on today's conference call to discuss the Phase III SENTRY trial of selinexor plus ruxolitinib in patients with myelofibrosis that was presented by Dr. John Mascarenhas in a late-breaking oral presentation at ASCO this morning.

We issued a press release this morning with the highlights from our Phase III SENTRY results presented at ASCO. As part of this, we're delighted that the SENTRY results were simultaneously published this morning in the peer-reviewed Journal of Clinical Oncology. These important milestones demonstrate the importance and relevance of this data on the opportunity to improve outcomes for myelofibrosis patients with the combination of selinexor plus ruxolitinib.

You can find the ASCO presentation plus the JCO paper in the Publications and Presentations section of our website. In addition, the slides that we'll be using during today's call are available in the Events and Presentations section of our website.

For today's call, we are honored, we are absolutely honored to have Dr. John Mascarenhas, one of the world's leading experts in myelofibrosis and the principal investigator of our Phase III SENTRY trial. Dr. Mascarenhas is Professor of Medicine at the Icahn -- excuse me, at the Icahn School of Medicine at Mount Sinai, and Director of the Center of Excellence for blood cancers and myeloid disorders. Dr. Mascarenhas just delivered the late-breaking oral presentation at ASCO this morning, and will be discussing the importance of these results and the potential benefit to patients on our call today.

I'm also joined by Richard, Reshma, Sohani and Lori. And then before we begin our formal comments, I'll just remind you that various remarks we will make today constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995 as outlined on Slide 2. 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 Factors section of our most recent Form 10-Q on file with the SEC and in other filings we may make in the future with the SEC. Any forward-looking statements represent our views as of today only. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any later date.

I'll now turn the call over to Reshma. Please turn to Slide 4.

Thank you so much, Brendan. On behalf of all of Karyopharm, my name is Reshma Rangwala, I'm the Chief Medical Officer at Karyopharm. I've been at Karyopharm for a little over 4 years. And I got to say, I think this is probably my most proud day in those 4 years. It's the day that we get the opportunity to present, sorry, the very important Phase III data from our SENTRY trial. This is the combination of selinexor plus ruxolitinib. Simultaneously, we had the opportunity to publish the data as part of JCO. And we just issued a press release in which we were also going to be presenting the data at EHA, picked as one of the top abstracts to be reported at that very important congress.

This is a great day, not only for Karyopharm, of course, our physicians who are treating myelofibrosis, but most importantly, our patients who suffer from myelofibrosis. The SENTRY results really matter in myelofibrosis, just given where we are in the treatment landscape for myelofibrosis. For the past 15 years, these patients who are frontline myelofibrosis have been treated with JAK inhibitors. It started with ruxolitinib, arguably a very meaningful game changer for this patient population. But with that said, I think we all appreciate there are limitations in not only ruxolitinib, but the other JAK inhibitors that have come subsequently, including pacritinib, momelotinib as well as fedratinib.

Why do I say that? I say that because the most important aspect of this patient's disease is their very large spleen, right? We know the JAK inhibitors do reduce spleen size, but I would argue that it's relatively modest. The rates of patients who achieve that important SVR35 is still quite low, only approximately 1/3 or 30% of those patients.

These diseases are -- these mechanisms, I should say, or these treatments, they are antiinflammatory. And as an antiinflammatory agent -- class of agents, yes, they also improve symptoms. What's missing though is this meaningful improvement in overall survival. The SENTRY data, as Dr. Mascarenhas is going to take everybody through, really is that game changer. You see these very meaningful improvements in SVR35 as rapid as week 12, sustained all the way out to week 36. It occurs in conjunction with meaningful improvement in symptoms at week 24 relative to baseline. And importantly, probably most importantly, is this early signal, promising signal in overall survival. This is a game changer for a patient population that needs to live longer beyond the median 4 to 5 years that are currently seen with the JAK inhibitors.

We know that myelofibrosis is really characterized by a proliferation of these malignant clones. Somatic mutations in stem cells lead to a clonal expansion of malignant progenitor cells. These have a bunch of sequela. This leads to bone marrow fibrosis, enlargement of the spleen, the symptoms that I just talked about as well as ultimately leading to shorter survivals.

Current treatments like the JAK inhibitors, including ruxolitinib, again, are antiinflammatory. Yes, they do reduce spleen size to a certain degree, yes, they do improve symptoms, but we don't see meaningful disease modification. That disease modification is key if ultimately we want to develop new therapies that improve overall survival. Once a patient becomes refractory to JAK, unfortunately, prognosis becomes even shorter. We need new therapies that introduce new mechanisms that can be combined with ruxolitinib, synergized with these therapies and ultimately improve long-term outcomes.

Lastly, I will say what we also need are new endpoints in myelofibrosis. Yes, traditionally, we see SVR35, we see TSS or an improvement in their symptom scores. We need to look beyond these endpoints at overall survival, other endpoints that can show the benefit. One of the benefits of this trial and unique aspects of this trial is the prospective identification of SVR's ability to predict overall survival. These data build upon published literature that have also demonstrated the same correlation, specifically patients who achieve an SVR35 may have longer overall survival as compared to those patients who do not.

Karyopharm has been committed to myelofibrosis for over 7 years. We have built a foundation of data, including preclinical, nonclinical work, clinical data through our Phase I now through to Phase III data translational work and then, of course, continuing to monitor the safety, not only in myelofibrosis, but in other disease types. This is only the beginning for us at Karyopharm. Yes, this is an important combination but selinexor, I do believe has this potential to become a backbone therapy. We have the opportunity to look at other combinations that are relevant in myelofibrosis and potentially other patient populations, not only in myelofibrosis, but in other MPNs as well.

With that said, I want to turn it over to Dr. John Mascarenhas.

Okay. Reshma, thank you very much. And thanks for inviting me here to today's event. I am John Mascarenhas, and we're going to review the results that we just presented for the SENTRY Phase III study of selinexor plus ruxolitinib in JAK inhibitor naive patients. I have tried to make this point very clear. I think the key takeaways are summarized very nicely here. To me, it's very obvious that the combination of selinexor and ruxolitinib induce a very rapid, deep and sustained spleen volume reduction. I think that's probably the crux of why we see this benefit in MF. And this was consistent against all subgroups, and that will probably play into discussions about who would get the drugs and how it will be utilized.

It was clear symptom improvement, and that was comparable to what we see with ruxolitinib. And I think it's unreasonable to expect better symptom improvement beyond what we get with ruxolitinib and the multiple trials have shown us that, that's the case. So the combination of seli and rux improve symptoms to the same degree as rux would, you don't compromise symptom benefit. Number 3 is we did see this overall signal for survival within 11- to 12-month follow-up. That correlates with spleen volume reduction, which was more frequent and deeper with the combination. So that, to me, fit very nicely.

And then to tie in at a molecular level that there's this disease modification, a biomarker that the field concentrates on that has been shown when reduced in MPNs to be associated with outcomes like OS is the reduction in driver VAF, which was seen to a greater degree, a greater frequency with the combination than single agent. And then the safety profile, I think, emphasizes that with the right amount of optimization of antiemetics, and I think just combining the drug actually with ruxolitinib offsets toxicity, and it's very manageable. And you can see patients through the treatment to induce that spleen response, which ultimately correlates with improved outcomes. And I do think this represents an opportunity to use selinexor with rux as a novel treatment approach, as a combination therapy approach for patients with JAK inhibitor naive myelofibrosis.

And if you ask me why is this drug interesting and mechanistically why I'm very interested in the translational science, and there are probably 3 pathways that are most relevantly impacted by inhibiting XPO1, which is a settling mechanism between the nucleus and the cytoplasm, which is what selinexor does. And as a consequence, you are upregulating p53. So you're turning on p53. It's been well described with other therapies and preclinical modeling that p53 is suppressed in MF and MF CD34 cells. And that's the point I want to really make is that the reason why I think that this is an active drug is because it's anticlonal and a lot of that is based on these mechanisms that you target and induce apoptosis and cell cycle arrest if you can turn on p53 in that hematopoietic stem and progenitor cell population that's been shown preclinically, and selinexor does execute that as well as reducing c-Myc and NF-kappa B. And NF-kappa B particularly is a pathway of interest and multiple therapies have hinged on reducing NF-kappa B regulated gene sets that contribute to inflammatory cytokine expression.

And we know and [indiscernible], who was the discussion for today, he nicely pointed out that this is a hematologic malignancy, but it's an inflammatory disease.

And what you want to do is you want a therapy that is anticlonal and at the same time is reducing the inflammatory cues that help promote the disease, sustain the clone and prime the microenvironment for continued disease. And what selinexor does is it really hits these 3 key clinical pathways and nicely complements with ruxolitinib in order to synergize with ruxolitinib. And I say ruxolitinib because that's the way the drug was studied, but -- the trial was designed, but I actually think this would combine nicely with other JAK inhibitors, and we're going to explore that as well. But today's topic is SENTRY upfront treatment based on preclinical rationale, a Phase I study that got a lot of attention within the field based on very significant spleen responses and symptom improvement that then inspired the SENTRY Phase III study, which is this randomized Phase III study, global, 20 countries, many investigators, many committed people that saw this through that enrolled Intermediate 1 risk or higher primary or post-ET PV/MF patients with at least a platelet count of 100,000 and measurable spleen and symptom burden.

Patients were randomized in a 2:1 fashion to seli 60 milligrams once a week, so not a high dose of selinexor, and that was determined by the Phase I study with 40 and 60 milligrams. And with an intentional dual antiemetic prophylactic regimen for the first 2 months that significantly reduces the incidence and severity of nausea and makes this combination quite tolerable and quite manageable. And I think that's another important point when thinking about this combination.

ruxolitinib was dosed by platelet count and the placebo was the control arm with rux. The co-primary endpoints were SVR35 at week 24, pretty standard endpoint, and then absolute change in TSS from baseline at week 24. If you're wondering why that instead of the binary TSS50, I think it's a more sensitive way of gauging symptom improvement and discerning benefit, particularly in this setting. And then key secondary endpoints that will describe the overall survival, safety and VAF reduction.

Here's a disposition as of February of this year. You can see the number of patients in the 2:1 fashion that were randomized to the experimental arm. 36% and 35% of patients had discontinued treatment. You can see the reasons why discontinuation is here. Now this is captured by electronic case report forms. And if you look at the reasons why, the site was putting in for discontinuation. I think I'll point out something quite important, which is 9% and 8.6% of patients discontinued for adverse events. So if there's concerns about toxicity, that was not a major driver with the combination for discontinuation.

Also importantly, the rate of leukemic transformation, which has been a concern in this patient population, which is part of the natural history of the disease, was low, 1.7% and equal between the 2 arms. I'd like to make a point that there's the ability to maintain the dose intensity of selinexor. Again, I would say that speaks to tolerability and manageability. 51.7 median weekly dose of selinexor, and I think maintaining that is pretty key to its efficacy. And then I think what's really interesting and maybe subtle is the fact that the median daily dose of rux was 23 versus 29, suggesting that you may not need the full dose of ruxolitinib to garner the actual benefit here that seli is probably driving a very significant proportion of it. And I would even argue that JAK inhibitors might just really be potentiating the effect of the partner like selinexor. And then you can see the median follow-up below.

There's a lot of information on this slide as there normally is with baseline characteristics and a very large -- and this is a very large as to -- this is a rare disease, a very large study, a very robust study over multiple countries. So this is a really good, I think, sample of what it looks like to have MFN enroll and be treated with the combination therapy. And these are going to be more primary myelofibrosis that's more prevalent than post-TMP base that makes sense. The Intermediate 1 risk. We saw that with manifests are the patients that are out there. Those are the patients we treat. So that would make sense. JAK2V617F is more prevalent than [indiscernible], so it's enriched for those patients. But you see representation of all the driver mutations. And then you see the spleen volume and TSS scores, which are comparable to what you've seen in other studies. And I would say from my own practice, these are what you would see if patients are presenting in need of treatment that would normally get, let's say, commercial single-agent JAK inhibitor.

So this was all in line with and across different continents, all in line with what we would see with treatment of this patient population.

The primary endpoint is shown nicely here. So nearly 50% of patients in the combination of SVR35 at 24 weeks versus 28%. So clearly statistically significant with the p-value with 3 zeros before the one. And then on the right, you can see the waterfall plots and each column is individual patient. The aqua makes the nice accent of the further depth in spleen response that we're seeing with the addition of of selinexor. And it follows throughout the entire waterfall plot. So it's not just some of the patients, you really see significant reduction beyond what you would see with ruxolitinib. And I can say anecdotally, when treating patients, it's pretty obvious, too, because the rapidity in which the spleen goes down, and the depth is pretty remarkable and patients can notice it. That they will tell you that the spleen -- they can fill their own spleen, they will tell you, my spleen feels smaller, I can end over more I can move more easily, it's freeing actually. And no remark on that pretty quickly. And it does happen pretty quickly, which is this slide. So by week 12, you can already see that these 2 curves diverge. And this slide is pretty key, I think, to understanding the kinetics and maybe why selinexor has this differentiating capacity here in this upfront setting.

You get this rapid reduction in SVR and that -- it's deepened over time and sustained. You don't lose it. So it's rapid, it's deep and it's durable. And on the other side, you can see the SVR35 rates between the 2 arms compared at week 12, week 24 week 36. And at any time, the odds ratio is 2.59 of hitting SVR35, which favors the combination. So it clearly is not doing it 1 snapshot. It's quickly and sustained through the follow-up.

And there's not one subgroup that drives it. So it was really consistent across the subgroups -- prespecified subgroups that we looked at in the study. And this -- I think this table specifically speaks to a question that comes up, which is if the drug was available, who would you use it? And this plot would suggest you could use it in everyone whose JAK inhibitor naive. There's not 1 particular group that you would target that this could work across patient subtypes, which is important as we think about our patients that could benefit from combination therapies.

This is a really interesting slide that I think caught a lot of attention from those on the steering committee and physicians who treat patients with myelofibrosis that are interested in this space. And what we're looking at here is SVR35 at week 24 rates broken down -- between the 2 is broken down by the dose of ruxolitinib. What I want you to focus on is the fact that here when we're looking at low doses of ruxolitinib, you do not expect -- I don't expect because I don't see it, you don't really expect to see spleen responses. And spleen responses are not just important, which I'm going to show you for -- to hit a regulatory endpoint. I think they're important for the patient, and I'm going to show you why in a second. But you can see that with the control arm, you're not hitting SVR35, yet you do hit it when you add selinexor to it.

So even at low doses where the expectation and the reality is you don't hit SVR35 at week 24, you're seeing it with selinexor. And of course, that's probably not surprising because we know selinexor has single-agent activity, it's been shown previously, but it really makes a point that this is not a rux-driven event that this is a combination event and doesn't even require the full dose of ruxolitinib. In fact that the SVR rates, if you look across, remain consistent across the doses of ruxolitinib, which is, again, from my perspective, as a physician treating these patients and thinking about the implementation of a combination therapy in the community setting, too, it makes it kind of easy to think about you don't need to be worrying about what dose of rux you're on. You just get them on a dose of rux that you could even dial back the dose of ruxolitinib. So it allows a little bit of freedom and ease of mind that you can still achieve your goal without concentrating working on maximizing the dose of ruxolitinib, which has been what has been ingrained in the way we treat MF, which is dose up and try to maximize dose of ruxolitinib. This was just not necessary when you have an active combination partner in play.

So this is the second co-primary endpoint of absolute change in TSS week 0 to week 24. At first glance you actually say, "Oh, negative because it's not superior." But I would say positive because you improve symptomatology. And that's all that matters. I'm not looking to improve symptoms beyond what ruxolitinib can do as a single agent because I don't -- I fundamentally don't believe you can't. Every trial we do shows that you cannot. Even the FDA, I think, realizes that probably doesn't really make sense anymore. This graph demonstrates that you don't compromise symptom improvement, which is obviously important to treating patients, and it's comparable to giving single agent ruxolitinib.

So you still improve symptoms when you give the combination of seli and rux and this is also true across symptom domains.

And then this becomes an important slide, and I'll go back to the SVR part in a second. There was a survival signal, albeit early on, that's driven mainly by disease progression adverse events in the control arm. And you see this with a median follow-up of 11.6 and 12.6 months in the 2 arms with a hazard ratio of 0.43. And this is really the first time we're seeing an outcome like this in a prospective study. And then you might ask yourself or we asked ourselves, well, what does this relate to? And this graph, I think, really becomes important. As I said at the at the talk, I actually think it becomes important even beyond this room in this discussion today. For the field, it becomes important because it's the first time prospectively in a trial -- a well-designed trial that faithfully follow these patients out that if you hit an SVR35 irrespective of treatment arms, at week 24, you're more likely to have a survival benefit. And to some extent, this is not new news. I think many of us in the field believe this to be true and other analysis that have been done with COMFORT studies and real-world studies have all suggested this, but prospectively, we're showing it here. The SVR35 at week 24 associates with survival benefit, which again, I'm trying to tell a story that you get more SVR35 with the combination, you get it faster and deeper and sustained without the need for dialing up rux to achieve it.

Additionally, we like to think of other biomarkers of disease response. And of course, the VAF reduction, which is the driver mutation JAK2 MPL and [indiscernible] are considered important biomarkers of disease modification, modulation as they represent the disease burden. And it's maybe the different way, but complementary to spleen volume reduction. So I will point out something that we rarely say at meetings, but maybe it's worth pointing out is that the disease in large part sits in the spleen. So if you reduce the spleen, you're reducing the burden of disease. So to me, that's not a very difficult concept to understand. It should track with, and you would expect to see reductions in disease burden by other measures. And here you see it already at 6 months, 32% of the patients on the combination had a VAF reduction of 20% greater versus 24% with single agent rux. And it's only at 6 months. It's still early on. And that reduction was associated, as you can see on the right, with spleen volume reduction, which is what you would expect to see. So it's a nice, I think, way of tying it all in.

This was an analysis that I think also speaks to the fact that there's probably multiple aspects of selinexor that are affecting multiple aspects of the disease and peripheral blood blasts are another one. So blasts or immature cells, they are the leukemic component of a chronic disease. We know from prognostic scoring systems that even having 1% blast present in the peripheral blood is an independent adverse prognostic marker for survival. So it would follow that if you could reduce the presence of circulating blast as an indirect measurement of disease control, or -- and that's what we're showing on the left with the combination in blue, so less frequent circulating -- less patients had circulating blast at those given time points whereas the control arm in orange, as you can see, is not the same. But on the right, even perhaps more interestingly, you see a suppression of the presence of blasts with the combination whereas you can see that, that's not true and that's the natural history, I would say, of the disease on ruxolitinib.

Ruxolitinib is a great drug. I was -- I'm proud to have been part of the COMFORT effort. But at the end of the day, it's not a blast-clearing drug. It's not modulating the disease at the core. And I think this is just another example of disease modulation.

And then safety. So again, I think if you think back about the earlier slide about how the [indiscernible] were picked up for reasons for discontinuation and there was really no difference in the way the teams were assessing, the reason for discontinuation from the study, I think talking about tolerability. In fact, we can maintain the dose intensity with selinexor. If you look at treatment emergent adverse events, although they were more frequent Grade 3, 4, which we expected and is consistent with the profile of selinexor, serious TEAEs were the same between the 2. And I think that's important because that's what drives a lot of tolerability issues and discontinuation.

And then ultimately, we didn't have a lot of deaths, less deaths actually in the combination arm and the placebo arm. I think this all speaks to the fact that it is manageable. You have to know what you're doing, prophylax the patient, and this study knew what they were doing. I also think that there's an element of when you give a JAK inhibitor and you downregulate inflammation it often makes partners look better, that people tend to feel better and tolerate things better. So to me, this made absolute sense.

And here's the butterfly plot showing that the toxicities compared to each other. And again, as you would expect, some more myelosuppression, but we deal with myelosuppression in hematology offices, including thrombocytopenia and neutropenia. There was not a significant signal of bleeding and infection that follows. So that's important. Anemia was not worse. It was the same. That's also important, maybe more important. So anemia and transfusion dependence are known adverse prognostic markers. You do not worsen it with the addition of selinexor. And otherwise, it's as advertised, it's what you would expect, and it's what we've come to expect and it's manageable. And again, the transformation rate remains low, 1.7%. So that is not a concern.

So in conclusion, I hope I've made clear or obvious to you that seli, rux in this randomized Phase III global study nicely showed that you beat out single agent rux from a spleen reduction perspective, both in its rapidity, depth and durability, and that you get a mean change in symptom score, which is important to patients, but it's not the end all be all. That mimics what you see with ruxolitnib, you're not compromising that. And then maybe most intriguingly and most I think excitingly, you see the survival benefit. That's already obvious at this point. We'll have to follow it out for more events to make sure that it continues in that direction. But the fact that SVR35 correlates with the survival benefit is not just important for the story, but important for the field. And then following suit that the higher rates of VAF reduction, again, speak to the idea of disease modification and a safety profile and toxicity chart that I showed you also consistent with the known profiles of both agents.

So I think this does represent a novel treatment strategy for JAK-inhibitor-naive myelofibrosis patients. And as you're probably aware, the full manuscript with the details of the study that I can't provide with you right now are available at JCO right now, which is really exciting to have that published simultaneously.

I think the fact that it's published simultaneously, the fact that this got a late-breaking abstract, the fact back that is breaking up start [indiscernible], also, I think it points to the fact that the hematology community recognizes about the unmet need and the value here. And I would argue that, that's what's trying to be address unmet need. We've been doing the same thing for a long time. Single agent JAK inhibitors, you can serially change them. I think like most of oncology where you need to move the combination to get deeper, more meaningful responses is what we're looking for, and obviously, the committees that select these abstracts recognize the importance of that as well.

So this is a -- I actually made this a long time or a version of this. But this is a schema of what it could look like out there in the real world setting outside of the clinical trial where you have lower risk -- so if you break it up into lower risk MF, that's low risk and Intermediate 1, higher risk means Intermediate 2 and high risk. And I will point out something that I think is important, particularly if people are trying to understand and wrap their heads around this. These risk scores, we don't treat patients based on these risk scores. I've never met a patient like I'm going to you because you're lower risk for treats. You treat patients based on need, the need for treatment. There's symptoms, they're spleen, you want to reduce spleen. You want to control disease. That to me supersedes risk, just to Just to point out and something that's not always obvious.

So if you have a lower risk patient and those are like the Intermediate 1 almost 60% of the patients who are symptomatic and they're coming to you, and I see them all the time. And just because you're Intermediate 1, doesn't mean you're not at high risk for having symptoms and spleen burden and in need of treatment. I think we have the star there that selinexor and ruxolitinib could be a consideration and an option for those patients beyond what is already listed in the NCCN as treatment options. So I started there to say, well, that's what the study would tell us, right? If you go by evidence-based medicine, that's where selinexor and ruxolitinib would make sense. Also, on the other side, in the high-risk patients with its greater than 50,000, again, selinexor and rux started there as a combination upfront.

I would also argue, and this came up in the discussion at today. One obvious need -- transplant remains the only curative option we have for these patients. So we want to get them to transplant, particularly if we have patients earmarked, but we want [indiscernible] optimize them for transplant. And part of optimization, transplanters want their patients to have small [indiscernible]. The outcomes are better, the grafting is more robust. It is a prerequisite of sorts to get into the door for a transplant. Well, if you want to optimize that as particularly in the most rapid fashion possible, then you would probably go to your biggest guns upfront. That would be combination therapy. So the obvious thing to me, too, would be if you have a patient where their goal is transplant and the transplanters on board, that's an obvious indication that I would want to use your 2 strongest agents in combination upfront and synergize together.

So one could see the combo being used across these places. What I don't have here which -- because this makes it all seem like it's upfront treatment. So upfront treatment is obvious, like that's what the trial does. But I will say that I don't know why 1 wouldn't make the argument that if you have someone on rux, which is patients are sitting on rux, maybe not optimized, you would add sell to the rux. So upfront, but also add-on strategy for those patients who are already on rux, maybe who leads into rux, whatever the case may be. I'll also go as far as saying not [indiscernible], I would go as far as saying, if I had a patient who was on momelotinib another JAK in the. I don't think that I would not give them the opportunity for selinexor and I wouldn't switch them to ruxolitinib put them on so I probably would just add selinexor to that JAK inhibitor backlog. So that's my own editorial. But this is one way one can envision what the NCCN guidelines could look like and the places which Sally could end up if it was incorporated and integrated.

Thank you, Mascarenhas. Dr. Mascarenhas to come back to join us for Q&A right away. And I think as you heard from Dr. Mascarenhas and from Reshma, there's significant unmet need in myelofibrosis. And with the data we now have with SENTRY, we see the opportunity for selinexor really transform the frontline myelofibrosis landscape, potentially become a backbone for myelofibrosis treatment across many lines of therapy and with potentially many partners. Right now, the focus is with selinexor and ruxolitinib.

As you know, our focus is to say how do we rapidly bring this to patients as rapidly as possible. Significant unmet need. We have the capabilities in place. We have the capabilities in place with a very strong global medical and scientific affairs organization, which is there to help educate, work together as physicians make them aware of the data and help to ensure they are informed about the opportunities to advance treatments for their patients. Pending commercialization, we also have the commercial capabilities in place to help ensure we can again rapidly bring these to patients across the community. I think as you heard from Dr. Mascarenhas the ability, given the flexibility and given the ability of selinexor to work across all the different dosages we see with ruxolitinib makes us an ideal opportunity across the community. And again, you open a community, that's where the majority of patients are. 70% of patients are in the community treated across large community centers, so very focused community center group, and as well in the key academic institutions, where we see, again, a very focused group of physicians where we can rapidly engage and provide the opportunity for patients to benefit from selinexor plus ruxolitinib.

And if you look overall at the opportunity, I mean we know the myelofibrosis marketplace is a multibillion-dollar marketplace. And again, not disagreeing with Dr. [indiscernible], but we're focused on upfront is the newly diagnosed patients. [indiscernible] about 7,000 newly diagnosed patients per year that intermediate to high-risk patient population really brings us with a target patient population per year of about 4,000 patients.

So again, for us, as an organization, we're very excited. We're committed to continue to move forward and to really ensure we can help make selinexor a foundational therapy in myelofibrosis to benefit patients with myelofibrosis. The data, as we've heard, really supports selinexor's role across myelofibrosis. There's a high unmet need. We're engaged with the FDA and with global regulatory agencies with regards to our data and filing plans and the team and our partners and Dr. Mascarenhas are delivering at breakneck speed because of the need for patients. Late-breaking oral presentation we just heard at ASCO, a simultaneous publication with a late breaking, one of the best oral presentations at EHA as it's been voted on, and then working towards potential compendia inclusion here in the second half of 2026.

So before we start our Q&A, I'd also like to thank Dr. Mascarenhas really for his leadership in the study for sharing his perspective and for sharing the data and what this means in terms of a really important advance in myelofibrosis, for the myofibrosis community and the fact that this is an opportunity that should be available to patients, to physicians and to caregivers to see the benefits of myofibrosis.

I also want to really recognize and thank the patients, the families, the caregivers, the investigators, the broader clinical trial teams. it's a village to make a trial like this come to light. And all of our Karyopharm employees together to make this study possible. Deeply grateful for their commitment as we advance treatment options for patients in myelofibrosis. So with that, let's go to the Q&A. Maybe I'll ask Reshma and Dr. [indiscernible] to come join me here. And we see the hands.

Brian, first, we're going to start here in the room. So Brian?

A question for us [indiscernible].

Three-part, Brian, you're challenging me here.

I know there's a lot of discussion at the presentation about whether the increase of guests seem to be higher in the [indiscernible] arm and 1 might expect. So I guess my questions are do you believe that would if so, why would you tend to conversate case? Can you tell us anything about the risk level of the patients to progress and and also what the other pocket referred to in the [indiscernible]?

And then I guess what more would you want to see from the overall survivor [indiscernible]? Like if the death rate even down across the 2 [indiscernible], that makes you comfortable that this is a real treatment effect or would you need to see continue to separate over time to be perfectly comfortable that there wasn't some kind of [indiscernible] events that occurred [indiscernible]?

We just have this microphone working. So I probably just summarize the question a little bit, Brian, but I think maybe for you, Dr. [indiscernible] is to a little bit more into the OS. Are the rates higher than expected risk levels of patients or the other patient bucket? And what more would you like to see from an OS perspective?

So to answer that question about the rates of death. So I just want to keep pointing out what I've pointed out previously is that the data is the data. So like we have this data here. So we can try to pull it apart, which I appreciate is the tendency. But I do think that probably what you're seeing is, if I had to guess, where you would see the separation of curves. If you don't have good disease control, like if rux is inefficient or insufficient in controlling the disease in a patient who's got a big spleen and symptom burden and then the tendency is to try to get them to transplant. It's also unfortunately going to be a high likelihood of a poor outcome if patients are that sick, not responding and then have to get rushed off to transplant and then the transplant-related mortality can be high.

So some of it may just be a function of not controlling the disease. And I think that, that's kind of in line with what we see. I think we have to be careful, and to get to your other question about who is driving those as whether the high-risk patients, the intimate one, I don't know. Reshma looked at the data more finally than I don't think that there was clearly a risk group that was defined in the disease. But I think that's also a function of like if you think about what defines or what constitutes a risk group, interestingly, spleen doesn't fit into that risk group, so -- into that definition of that criteria for it. And even, frankly, symptoms don't exactly fit into it either.

So you can have symptomatic patients with a big spleen and they're scoring because they're younger and they score into me [indiscernible], but they functionally are sick patients that -- it's an incomplete [indiscernible]. So I think we have to be a little bit careful with saying, oh, the curves are -- how do we expand these curves is enriched for Intermediate 1 patient. I think it's in richer patients who were ill got on to the trial. We just call them Intermediate 1, but they clearly had to have a disease burden that warranted treatment. I think that's the important point.

So I think that those curves are those curves and probably can be explained by what happens to the patients because they're not responding well to single-agent rux and they're going on to other therapies and that's those are the outcomes that we see. So I don't really think it really is that different from what we would expect. And I would love to see the curves keep going. But I think that probably even the curves like this, if they stay like this, still tell us something important, which is if you intervene -- and maybe the answer is you intervene early and intently and deeply then you get this kind of -- you make a quick impact on the disease process. And we've had discussions at small groups like we do, do that at sort of -- MF is a chronic leukemia. We never really call it that way. We call it a neoplasm, which denotes it, but it's really a chronic leukemia. It's an inflammatory leukemia. But in other leukemias, we don't really take a lot leukemia. We kind of go in strong and try to induce the response early on because we know if you delay or if you half asset, you really don't get that benefit and the outcome is usually suffer.

So it doesn't seem like outside of the expectation of treating blood cancer is that something -- if you have an approach that's intense and more effective at controlling that clone, you're probably just going to have a better outcome. So to me, that makes sense. And then again, I think the fact -- I think particularly the fact that the SVR35 in this prospective data set associates with the survival sort of ties that in nicely. The driver [indiscernible] follows follow suit. So to me, I'm biased because I'm involved in the program. I've been looking at this, it makes sense to me. I mean, I feel like it's -- and if I think about patients i see, it's a course or an outcome that would make sense to me.

I don't know if that answers this.

[indiscernible]. I just wanted to ask as an pirating the JCO, it was [indiscernible] to last time the [indiscernible] a big percentage [indiscernible]. Just wondering flood products to difference?

Yes. So I think we'll turn to Dr. Mascarenhas again. This is Albert asked the question more about the PFS hazard ratio, the OS hazard ratio.

So I think it's probably as simple as survival is obvious. It's binary, either you're a live or your debt, whereas progression is a little bit more vague. You could try to define progression as spleen increase, leukemic transformation, but progression is also a lot of other things that we don't always understand like progression of cytopenias, progression of symptomatology. And it's defined different ways in different studies, and it's not consistent across studies. So what makes MF complicated is MF is not -- it's not a monogenic disease. It doesn't have like CRs that we induce. It's just -- it's a very molecularly and biologically very complicated disease that corrupts the microenvironment of the bone marrow. You have displaced amount of places that small in nature in the spleen and the patients are really complicated. And no 2 patients look alike. They're very heterogeneous and very variable.

So even trying to gauge responses or the concept of progression is really challenging across patients. So I think it's a very vague, blurry, ill-defined endpoint where survival is not. So I think that's why survival is easy to to make that determination. And we'll often say like, I'd rather survive than I'd rather be on the survival curve than the progression curve. So like if you're surviving, that's what haters obviously, maters the most.

A question for Dr. [indiscernible]. I said if you show the curves of the s. But what about [indiscernible], I mean, you gain [indiscernible] reduction impact if that's the driver of allele that relative noted to that reduction. We also -- can you talk about that?

Yes. So the next question is for Michael. Beautiful SVR35 curves according to Michael, which we love, but VAF, a driver and kind of your view on that and the difference we see?

Yes. So the driver VAF, many of us have have looked at as a surrogate for disease burden too. So I think if I think about data sets where that really seems to ring true, it would be, for example, in TV because it's it's JAK2V617F driven disease. You can kind of use it pretty reliably there. We've got prospective data from 2 independent studies, 1 with [indiscernible] interferon, 1 with ruxolitnib, demonstrating that if you reduce that VAF within like a year of treatment, in those studies, they used different cutoffs with like 50% if it's under a certain amount, 25% over, but it associates with outcomes like event-free survival and overall survival. So there is data out there that ties in that marker as a disease burden marker. So it is, I think, notable that in the combination, you see a more frequent 20% or greater decline in the VAF. Is that an incomplete picture because there's still more analysis that we'll go into looking at the sub-clonal mutations, but I think that's the first nice look at an early time point that there's a difference in those outcome measures and that the reduction in the VAF associates with the reduction in spleen volume.

So it ties in a story that would -- is circular in the sense like you are reducing the spleen. As I said before, the screen is a reservoir for the malignant cell population. And I would think that the VAF should go down as a reflection of...

I guess the question is whether you thought respectively, there would have been a tighter correlation between [indiscernible].

Odds ratio was 3. So patients who achieved that greater than 20% had 3x likelihood of achieving that CR rates as compared to those patients who don't. So Yes. I would argue it's a nice correlation.

I thought it coreless pretty nicely.

You talk a lot about the lower rux doses [indiscernible] and [indiscernible]. Can you talked about big implications of that real [indiscernible]. And maybe the company can kitchen as well as like serious are there certain types of physicians that community docs maybe just are not comfortable using [indiscernible] doses so their patients are not getting full [indiscernible]. I guess where -- what does that mean with regards to where selling could fit in just the [indiscernible] sparing effect?

Yes. I think the question, which I'll turn to Dr. [indiscernible] on for sure because he want to treat patients. Lower rux dose intensity and what that really means from a practice implication, whether it be in the academic or the community and maybe specifically more in the community setting, but Dr. [indiscernible]?

Yes. So we've actually done and published real-world database collect claims-based database, where you can see that the doses of rux that are used in the community are far below the active doses that were explored like in the comfort sizes. 15 and 20-milligrams based on platelet count. And for a long time, we were of the mindset that you really -- to optimize the patient on a JAK inhibitor, you have to maximize the dose. And that was the mantra. It was based off the COMFORT studies. And then you look at these claims like from Trinatics and other groups, and it's like 2/3 of the patients are on doses of 10 milligrams [indiscernible] a day or less. Those are suboptimal dose clinical trial to suboptimal doses. Now it really becomes interesting if you think about the SVR part.

So we know and we have a beautiful graph from 1 of our analysis from the conference side that SVR is a dose-dependent phenomena. You have to dose up to hit that SVR. If you compromise the dose, you attenuate the SVR with rux. So you want to optimize your dose of rux. But in the community, that's not happening in the community. I don't even think innocent that really happens. I think it happens across -- it doesn't happen across the board. So what is attractive here is it doesn't matter. You can have a patient on a suboptimal dose of rux, you don't minimize or compromise that SVR outcome.

So to me, that's very attractive. If you just add sell to whatever dose they start with or even if they dose reduce, no big deal. If you keep them on that dose, you keep hitting them with the seli every week, and you're going to get them to where they need to be.

If there aren't any other questions in the room right now -- go ahead, Mike.

I just wonder if monetation that are on drop-down I think some of?

So the question is like in real world, quantitation of[indiscernible]?

I think -- yes, I mean we've looked at -- so defining suboptimal is also a little bit tricky. I will admit that in the sense like you have to know what the patient was like before they started rush to know what they were on rux.

[indiscernible].

Yes. I mean, ultimately, by 2.5 years, 50% of patients are off rocks by 5 years, 85% of patients are off rux. So rux is a great drug, but it doesn't take you the distance. And a lot of that is driven by inadequate response, progression of spleen regressive symptoms. So you're not controlling the clone well enough. So to try to answer your question, like, everyone kind of becomes suboptimal at some point in their clinical course. But if you would ask me a question of what do we anticipate if we started 100 people on rux at 18, 24 weeks, somewhere around probably 40% of patients alone will be suboptimal. And that's if you treat them the right way. It's probably even higher out in real world if you're suboptimally treating.

All right. We're happy to come back and take questions in the room. I know there's some questions on the line as well. So Joel, if you can open up the call for questions.

[Operator Instructions] Your first question comes from Maurice Raycroft with Jefferies.

Congrats on the update. For the OS data, I wanted to follow up on that. Wondering what's the ideal follow-up time to have a more derisk view on OS? And how do you expect OS to be viewed by the FDA? And are there any specifics they have defined around the OS parameters for what they would want to see?

Thanks, Mary, this is Reshma. I can take that question. So I think one of the advantages of the SENTRY trial is that it continues to follow overall survival. So patients and physicians remain blinded to the arm to which they are randomized. So as the study continues, as we observe additional OS events, of course, we have that opportunity at a future later date to update, not only the overall survival, which is important, but other markers of disease modification, including VAF and other areas. We haven't defined at this point when we want to do that next OS evaluation. I think importantly is that it's got to be a meaningful update, right? This is a patient population in which sort of like events can accrue over a course of a few years. So we really want to look at it prospectively, define a meaningful number of events so that when we do update the OS, people can interpret it quite robustly.

Actively engaging with the FDA, really productive conversations. We have not gone into details about what they want from the OS perspective. Hopefully, we'll have more clarity that we can share with you in the next 1 to 2 quarters.

[Operator Instructions] Your next question comes from Jane Sureties with Cantor Fitzgerald.

I had 2 quick ones. I guess one -- the shorter one. For the folks that were on that 0 to 15 milligrams of rux per day, I mean, I don't know if you can provide any color on how many we're closer to that 0 mark. And if that at all in your mind kind of provides a bit of read-through for what we might see for SENTRY 2?

[indiscernible], this is Reshma, again. Yes, great question. So I will say the vast majority of those patients were in that 10 to 15 milligrams. And keep in mind, this is average daily dose, right? So they were on the higher end of the spectrum. I don't have the exact breakdown, something I can certainly look into. But I think regardless of where within that 0 to 15, they landed, I think I'll go back to what Dr. Mascarenhas just mentioned, these are suboptimal dose of the ruxolitinib, right? I mean regardless of whether you're on 5 or closer to 15, these kinds of doses of ruxolitinib just do not optimally provide spleen volume response or adequate symptom improvement. So yes, and I think that's the key takeaway is that despite being on the low doses of rux, right, that SVR35 for the combination still remains very high, very meaningful at 50%.

And maybe I would also add just the way I would think of it, too, is I showed the graph of rates based on the platelet count -- or the rux dose rather. The way I interpret that is that selinexor will become sort of the great equalizer across dose rux doses you can optimize your spleen reduction. It almost doesn't matter to some extent. It's not -- it's probably not the main driver of the benefit is the way I would look at it. It's seli-driven, rux supported. So you don't need the full dose rux. So it kind of makes it nice because if you have -- because rux is dosed a different top-1 dose, it's all you can have different doses, it allows for a constant presence of selinexor across those doses of rux, we're still going to get that benefit. So it makes it almost easier to deliver in that way because you don't have to think about dosing the rux.

And your second question, [indiscernible] just -- go ahead.

Yes. I guess relatedly on this topic. I mean from the protocol, I remember that the general guidance was for GI-related events, select dose down for non-GI rux dose. I guess here for the lower categories on rux exposure, I mean it seems very skewed to the combination arm. I guess could any color be given in terms of why is that just kind of some of the general increases we saw in the heme tox side of things? Or was there anything else kind of driving that trend?

Go ahead, Reshma.

Yes. This is Reshma. Yes, the majority of the ruxolitinib is still going to be driven by the heme tox. Now with that said, the protocol also allows dose reductions across both drugs. So if you modify, let's say, nausea with the selinexor is still maintained, they may also reduce the ruxolitinib too. So I think you've got a double whammy, so to speak for the ruxolitinib, it's going to be the primary driver for the hematologic toxicity, but you can also modify for the non-heme tox as well.

Thanks, [indiscernible]. We're just right up on time. So I want to thank again Dr. Mascarenhas for an amazing presentation twice today now that he's delivered it and being available for Q&A. And again, just your unwavering commitment to working incredibly hard to advance treatments and potential for patients with myelofibrosis. Thank you very much, and thank you for joining us today.

Ladies and gentlemen, this concludes your conference call for today. We thank you for participating and ask that you please disconnect your lines.

Good morning, everybody. My name is Kelsey, and I will be your conference operator for today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics First Quarter 2026 Financial Results Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request.

I would now like to turn the call over to Mr. Brendan Strong, Senior Vice President, Investor Relations. Please go ahead.

Good morning, and thank you all for joining us on today's conference call to discuss Karyopharm's first quarter 2026 financial results and recent company progress. We issued a press release this morning detailing our financial results for the first quarter of 2026. This release, along with a slide presentation that we will reference during our call today, are available on our website.

For today's call, as seen on Slide 2, I'm joined by Richard, Reshma, Sohanya and Lori, who will provide an update on the results for the first quarter, highlight the importance of the results from our Phase III SENTRY trial in myelofibrosis and provide an update on our endometrial cancer program and related commercial opportunity.

Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995 as outlined on Slide 3. 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 Factors section of our most recent Form 10-Q or 10-K on file with the SEC and in other filings we may make in the future with the SEC. Any forward-looking statements represent our views as of today only. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any later date.

I'll now turn the call over to Richard. Please turn to Slide 5.

Good morning, and thank you for joining us today. Karyopharm continues to execute through an important period for the company with recent and upcoming milestones that we believe can unlock meaningful growth opportunities and shape our next phase. Over the past several quarters, we have focused our organization around 3 priorities: Advancing our late-stage clinical programs, maintaining our commercial foundation in multiple myeloma and managing the business with discipline as we approach significant value-creating milestones. Since our fourth quarter call, we have made meaningful progress across our key 2026 priorities, including reporting top line results from our Phase III SENTRY trial in myelofibrosis, completing enrollment in XPORT-EC-042 in endometrial cancer and strengthening our balance sheet through the financing completed in Q1.

With these milestones and data in hand, we are now focused on the next phase of execution, advancing our regulatory and scientific engagement for SENTRY, preparing for the EC-042 top line data readout and continuing to manage the business with financial discipline. SENTRY showed a compelling and differentiated profile for selinexor in combination with ruxolitinib, including rapid, deep and sustained spleen volume responses accompanied by a promising overall survival signal and evidence of potential disease modification, including greater reductions in variant allele frequency as early as week 24. These findings reinforce the potential of selinexor plus ruxolitinib to address an important gap in frontline myelofibrosis treatment where treatment options remain limited and the need for therapies that can improve long-term outcomes remain high. We are very encouraged by the level of interest and enthusiasm we are hearing from the myelofibrosis KOL and patient group communities following the SENTRY readout.

Our next major catalyst is XPORT-EC-042 in endometrial cancer, where enrollment is now complete, and we continue to expect top line data in mid-2026. This is a biomarker-driven program focused on patients with TP53 wild-type endometrial cancer, particularly those with pMMR tumors where there remains a significant unmet need and no approved personalized biomarker-driven maintenance therapy. Commercially, we believe we have a strong foundation to build from. Our deep relationships across community and academic accounts and capabilities in sales, marketing, market access, patient support and medical affairs can be leveraged across future potential launches. In both endometrial cancer and myelofibrosis, we see concentrated treatment landscapes and clear unmet need.

Financially, we remain disciplined. We ended the quarter with increased liquidity following our financing in March, and we continue to manage spending with a clear focus on the clinical and regulatory milestones that matter most. Our current operating plan provides us with sufficient flexibility through our major near-term clinical and regulatory catalysts, including SENTRY next steps and the EC-042 top line readout, funding us into late Q3 2026.

With that context, today's call will first cover the SENTRY highlights and next steps, followed by a deeper discussion of the upcoming XPORT-EC-042 readout, our commercial readiness and our financial performance with guidance.

I'll now turn the call over to Reshma. Reshma?

Thank you, Richard. Before we dive into myelofibrosis and endometrial cancer, I want to take a step back and ground everyone in the biology of XPO1 inhibition and why we believe this novel mechanism has the potential to meaningfully improve outcomes for patients across both diseases as outlined on Slide 7. What's particularly compelling about XPO1 inhibition is that it allows the drug to simultaneously impact multiple highly relevant oncogenic pathways. Selinexor selectively binds to XPO1, a key nuclear export protein and blocks the transport of critical regulatory proteins out of the nucleus. By doing so, selinexor drives the retention and activation of tumor suppressor proteins such as p53, FOXO, T21 and IkappaB within the nucleus where they can exert their anticancer effects.

This effect is particularly notable for myelofibrosis and endometrial cancer, given that greater than 95% and 50% of these tumors, respectively, are p53 wild-type. At the same time, it reduces the activity of oncogenic signaling pathways, including NF-kappa-B, which is of relevance to myelofibrosis. Induction of cell cycle arrest independent of the p53 pathway is also critical pathway important to both endometrial cancer and myelofibrosis. The net effect is a coordinated biological response, including decreased tumor cell proliferation, increased apoptosis and ultimately, the potential for durable disease control. We believe this multi-pathway mechanism is a key differentiator for selinexor and underpins the breadth of activity we've observed across multiple cancers, including both MF and EC.

With that backdrop, let's turn to myelofibrosis and why we believe the SENTRY data are so compelling as outlined on Slide 9. There remains a clear opportunity to improve upon the current standard of care. While JAK inhibitors have been an important advancement and remain the only approved class, we continue to see relatively rates of spleen volume reduction, limited impact on long-term survival and minimal evidence of true disease modification. As such, there is an unmet medical need for therapies that go beyond symptom control and deliver deeper, more durable benefit and improve long-term outcomes like overall survival.

Moving to Slide 10. As I presented a few weeks ago, we're very encouraged by the top line results from our Phase III SENTRy trial. The combination of selinexor plus ruxolitinib delivered rapid and clinically meaningful spleen volume reduction as early as week 12. Importantly, that benefit was sustained through week 36. The co-primary endpoint of SVR35 at week 24 was 50% for the combination compared to 28% for ruxolitinib alone, corresponding to a statistically significant p-value of less than 0.0001.

Our second co-primary endpoint was symptom improvement at week 24. While the difference in absolute TSS was not statistically significant, patients in both arms experienced important and similar improvement from baseline. What we find particularly exciting is the intriguing signal of overall survival, arguably the most important outcome for patients with myelofibrosis. The combination of selinexor and ruxolitinib is the first potential treatment in myelofibrosis to suggest an overall survival improvement relative to standard of care. At the time of the top line data, the overall survival hazard ratio was 0.43 with a nominal p-value of 0.0222. In addition, post-hoc analyses demonstrate that SVR35 predicts OS, consistent with published analyses in other myelofibrosis trials that have also shown the same.

These findings underscore the importance of achieving rapid, deep and sustained SVR35. The greater proportion of patients on the combination arm at 32% who experienced a variant allele frequency reduction of at least 20% may be indicative of an underlying effect on the disease biology, raising the potential for true disease modification. The rapidity at which we see these VAF reductions reflect the anticlonal attributes of selinexor and mirrors both the substantial improvement in SVR35 as early as week 12, and the early improvements in overall survival.

Lastly, the combination demonstrated a generally manageable tolerability profile that was consistent with what we understand about each agent individually. We did not observe any new safety signals. Importantly, with the use of the lower dose of selinexor and dual antiemetics, we've seen an improved tolerability compared to the Phase I study. We believe the combination of the XPO1 inhibitor, selinexor, and ruxolitinib delivers a very compelling and differentiated product profile with the potential to improve outcomes for patients with myelofibrosis.

Turning to Slide 11. We're excited that these data have been selected for a late-breaking oral presentation at ASCO, and we expect to have a manuscript published in a peer-reviewed journal in the middle of 2026. Overall, we remain very encouraged by the SENTRY results and look forward to productive discussions with the FDA.

Let's now turn to endometrial cancer and why we're so excited about selinexor's potential to address a clear and meaningful treatment gap, particularly for patients with p53 wild-type MMR proficient tumors. As highlighted on Slide 13, this is a large and well-defined patient population. Approximately half of the patients are p53 wild-type and about 80% have MMR proficient tumors. Importantly, this is not a niche segment. It represents a substantial proportion of the overall endometrial cancer patients whose unmet need remains high. Equally important, molecular classification is already embedded in the standard of care today. That means clinicians are routinely identifying these patients in practice, which we believe positions selinexor very well for real-world adoption if our Phase III data are positive and pending regulatory approval.

On Slide 14, we believe we have an opportunity to define a personalized biomarker-driven maintenance treatment option for patients with p53 wild-type endometrial cancer. Today, patients with advanced or recurrent EC have no personalized biomarker-driven maintenance-only therapy. And although checkpoint inhibitors are approved in combination with chemotherapy followed by checkpoint inhibitor alone, patients whose tumors are both p53 wild-type and MMR proficient gained the least benefit. The RUBY trial, which evaluated dostarlimab in combination with chemotherapy in advanced or recurrent EC patients showed a marginal PFS improvement of only 0.77 in patients whose tumors were NSMP or p53 wild-type MMR proficient. This highlights the profound unmet need for the subgroup that comprises approximately 50% of all endometrial cancer patients and underscores the urgency to identify p53 wild-type directed therapies. It also highlights the substantial benefit that potentially could be observed with selinexor in patients with p53 wild-type tumors and especially those whose tumors are both p53 wild-type and MMR proficient.

As seen on Slide 15, the top line data in the p53 wild-type subgroup of the SIENDO study showed a very strong PFS signal with a median PFS in the selinexor arm of 13.7 months versus 3.7 months for placebo, translating to a hazard ratio of 0.41.

As you can see on Slide 16, with long-term follow-up, the median PFS benefit for the selinexor arm extends to 28.4 months, corresponding to a hazard ratio of 0.44. And when we focus on the patients whose tumors are p53 wild-type MMR proficient, the data become even more compelling.

As shown on Slide 17, the median PFS approaches 40 months at long-term follow-up with a PFS hazard ratio of 0.36. These results compare very favorably to the RUBY data in which the MMR proficient p53 wild-type subgroup showed a PFS hazard ratio of 0.77. Taken together, what we see is not only a strong initial signal, but a benefit that deepens and becomes more meaningful over time. That's the dynamic we're aiming to replicate in XPORT-EC-042. To demonstrate a clear PFS advantage at top line, we also anticipate that the PFS benefit may continue to strengthen as the data mature.

The safety profile on Slide 18 is from the long-term follow-up from SIENDO. Given that the dose of selinexor was 80 milligrams in the SIENDO trial and prophylactic dual antiemetics for the first 2 cycles were not mandated, we have an opportunity to observe a better safety and tolerability profile in the ongoing 042 trial. Similar to the SENTRY trial, we've been very deliberate in optimizing both the dose and supportive care.

In the EC-042 trial, selinexor is dosed at 60 milligrams once weekly, and we've mandated dual antiemetics during the first 2 cycles, which is when patients are most likely to experience nausea and vomiting. There is the potential that with an improved safety profile, patients stay on treatment longer, translating to improved efficacy. Overall, we feel very good about how the program has evolved in delivering a more optimized and patient-friendly treatment approach.

Finally, turning to Slide 19. As Richard mentioned, I'm very pleased that we have successfully completed enrollment in our Phase III XPORT-EC-042 trial. We enrolled 257 patients in the intent-to-treat population, with approximately 220 patients in the modified intent-to-treat population, which is the primary analysis population for the study. As a reminder, our statistical plan is designed to be both rigorous and efficient. We will first assess progression-free survival in the mITT population. And if that analysis is statistically significant, the alpha will then pass down sequentially to the full ITT population.

As we approach the prespecified number of PFS events that will trigger the primary analysis, we remain on track to report top line results in the near term. Stepping back, I'm incredibly excited about the opportunity in front of us, not only in endometrial cancer, but also in myelofibrosis. In both areas, we have the potential to establish new standards of care and deliver meaningful benefits for patients where significant unmet need remains.

I will now turn the call to Sohanya.

Thank you, Reshma. As shown on Slide 21, we delivered strong net product revenue growth this quarter, driven primarily by favorable gross to net dynamics, which Lori will cover in more detail. Underlying demand for XPOVIO was lower compared to the first quarter of 2025, reflecting the impact of new competitive entrants. This is not new territory for us. We've successfully navigated competitive dynamics and returned to drive demand growth.

Turning to Slide 22. There are 2 ways that XPOVIO is positioned that we believe sets us up for future growth amidst an evolving and competitive landscape. First, our focus remains on the community setting, which represents approximately 60% of total U.S. sales, where many community-based physicians and patients value XPOVIO as a flexible and convenient oral option in the second to fourth line.

Second, our distinct positioning for XPOVIO as a differentiated mechanism of action in the peri T-cell engaging therapy setting allows selinexor to be used in patients prior to a CAR-T, which is an important position given anticipated future expansion of CAR-Ts and also in patients progressing on a T-cell engaging therapy. Therefore, despite an evolving competitive landscape, we remain confident in our ability to drive growth in XPOVIO net product revenue.

Now if we turn to Slide 23, if we look at our future potential launches in myelofibrosis and endometrial cancer, these are areas where there is strong overlap with community-based accounts with fewer treatment alternatives and higher unmet need than the multiple myeloma market. As we prepare for these potential launches, I would like to underscore the strength and value of our highly experienced teams. We have established capabilities across sales, marketing, market access and medical affairs, all of which can be utilized to educate on the relevant disease states. This allows us to prepare for launch with minimal incremental investment preapproval and only modest additional spend post launch.

Let's now discuss the potential commercial opportunity in both myelofibrosis and endometrial cancer, starting with myelofibrosis on Slide 25. In myelofibrosis, the only treatment options that patients currently have are JAK inhibitors with ruxolitinib monotherapy being the standard of care for the past 15 years and only about 1/3 of patients that receive ruxolitinib achieve a spleen volume reduction of 35% or more with 2/3 of patients not adequately responding.

Slide 26 provides an outline of the potential market opportunity. selinexor plus ruxolitinib targets a sizable U.S. myelofibrosis market with roughly 20,000 patients living with the disease and limited approved options beyond JAK inhibitors. With around 7,000 newly diagnosed first-line patients annually, about 4,000 of whom are addressable, we see a clear path to meaningful adoption. We believe the combination of selinexor and ruxolitinib has the potential to deliver up to approximately $1 billion in U.S. peak annual revenue. Our sales organization is well positioned for a potential launch in myelofibrosis. We have deep relationships with the key accounts where the majority of patients are treated.

As outlined on Slide 27, 70% of myelofibrosis patients are treated in the community setting and 30% are treated in academic centers. Across both settings, the majority of patients are treated in a concentrated group of accounts, which enables us to move quickly and execute a focused high-impact launch, if approved.

Turning now to Slide 28. We're energized by the opportunity to reshape frontline myelofibrosis treatment by pairing selinexor with the current standard of care and pending approval to drive rapid uptake and potentially transform patient outcomes.

Turning to Slide 30. I'd like to share how we are thinking about the commercial opportunity in endometrial cancer, which is the most common gynecologic malignancy in the United States with 17,000 newly diagnosed advanced or recurrent patients each year and incidence and mortality rates on the rise. As Reshma mentioned, we believe we have a clear opportunity to establish selinexor as the standard of care in patients whose tumors are p53 wild-type and pMMR. These patients comprise approximately 50% of all endometrial cancer patients. As we look at other therapies that have driven meaningful benefit in the treatment landscape, for example, the uptake of checkpoint inhibitors in dMMR endometrial cancer and PARP inhibitors in the maintenance setting in ovarian cancer. They achieved peak share within 18 to 24 months of launch.

Similarly, given the high unmet need for maintenance therapy in p53 wild-type patients as well as our established commercial capabilities, we would expect adoption to be rapid. On duration, our assumptions are influenced by the fact that this would be a maintenance option. While we don't equate PFS directly with duration, the strength of our PFS data from SIENDO gives us confidence that patients can remain on therapy for an extended period. Putting this together, this represents a significant opportunity within a multibillion-dollar marketplace.

Turning to Slide 31. In summary. From a commercial perspective, if approved, Selinexor is positioned to rapidly transform treatment in p53 wild-type endometrial cancer. We're very encouraged by the opportunity ahead and confident in our commercial readiness to support successful launches.

With that, I'll turn the call over to Lori starting on Slide 33.

Thank you, Sohanya, and good morning, everyone. I will focus on the key highlights from our first quarter financial performance and how those results position us relative to our full year expectations.

Starting with revenue. Total revenue for the first quarter was $35.1 million compared to $30 million in the prior year period. U.S. XPOVIO net product revenue was $29.2 million compared to $21.1 million last year. This increase was driven by a decrease in gross to net, which was 21.8% this quarter versus 45% in the first quarter of 2025 that was impacted by an atypical product return adjustment. Our gross to net reflected lower realized discounts and returns this quarter. Excluding these adjustments, our underlying gross to net was approximately 26% this quarter.

Turning to expenses. We remain focused on disciplined execution. R&D expenses were $33.8 million and SG&A expenses were $26.7 million, both relatively consistent year-over-year. This reflects our continued focus on prioritizing investment in our highest value clinical programs while maintaining overall cost controls. Net loss was $22.4 million for the quarter compared to $23.5 million in the prior year. As a reminder, net loss includes noncash mark-to-market adjustments related to our financing structure. From an underlying operating perspective, performance improved meaningfully with a 20% reduction in loss from operations, driven by the increase in total revenue and continued expense discipline.

Turning to the balance sheet. We are managing the business with a clear focus on our clinical catalysts and ended the quarter with $91.2 million in cash, cash equivalents and restricted cash, which includes the approximately $50 million raised this quarter. Based on our current operating plan, we expect our existing liquidity to fund operations into late in the third quarter of 2026. We remain focused on prudent capital management as we advance our pipeline and prepare for our upcoming Phase III readout in endometrial cancer.

Turning to guidance. We are reaffirming our full year 2026 outlook. We continue to expect total revenue in the range of $130 million to $150 million with license and other revenue consisting entirely of royalties over the next 3 quarters and U.S. XPOVIO net product revenue of $115 million to $130 million. Finally, we also continue to expect combined R&D and SG&A expenses in the range of $230 million to $245 million in 2026. Overall, we believe our first quarter performance and operating discipline position us well to deliver against our full year expectations in 2026.

With that, I'll turn the call back over to Richard.

Thank you, Reshma, Sohanya and Lori. As we have discussed today, Karyopharm has made meaningful progress against the priorities we laid out entering 2026. Across both myelofibrosis and endometrial cancer, we believe the story is consistent. Selinexor has a differentiated mechanism of action. The clinical programs have been refined based on experience and the commercial opportunities are meaningful. We have also worked hard to optimize how selinexor is used, including dose selection and proactive supportive care with the goal of delivering the right balance of efficacy, tolerability and real-world usability.

Looking ahead, our focus is clear. We are advancing the next steps for SENTRY, including FDA engagement, presentation of the data at ASCO, publication planning and potential Compendia inclusion. In endometrial cancer, we are preparing for the XPORT-EC-042 top line readout in mid-2026, which we believe represents a major potential value-creating catalyst for Karyopharm. Across the business, we will maintain operational and financial discipline as we execute while continuing to evaluate opportunities to strengthen our financial position and extend our runway. We have an important few months ahead, and we are focused on executing with urgency, discipline and a clear commitment to bring meaningful new treatment options to patients in 2 areas of high unmet need.

We'll now open the call for questions. Operator?

[Operator Instructions] Your first question comes from Brian Abrahams from RBC Capital Markets.

Congrats on all the progress. So maybe just on the MF study. I guess I'm wondering, have you done any additional work since the top line presentation to look into some of the deaths that occurred for patients on the placebo rux arm relative to the seli plus rux arm, anything standing out that wasn't apparent at all initially? And then anything -- like, I guess, what should we be expecting beyond these initial top line data you reported at ASCO?

Yes. Thanks, Brian. I think overall, again, we'll have a totality of our results as we shared at ASCO, but I'll turn to Reshma to expand on that.

Yes. Thanks, Brian, for the question. So absolutely, we're looking at the deaths that occurred, specifically the 23 deaths that were reported at the time of the top line. We haven't provided greater granularity in terms of the types of deaths or the deaths across the 2 arms. I mean with that said, when I look at them, they're very consistent with what you would expect, right, not only in MF, but other oncology trials, right? So we're going to see a lot of deaths due to progression of disease, adverse events, et cetera. So nothing inconsistent with what you would expect and more to come, right? As we continue to evaluate these data, we'll certainly look at opportunities in which we can present it at upcoming medical congresses.

And your next question comes from Ted Tenthoff from Piper Sandler.

Great. Thank you very much, and thanks for all the updates. Really an exciting time for Karyopharm and you guys just keep on fighting. So I appreciate that. I'm looking forward to the endometrial cancer data coming up. My question is on myelofibrosis and looking forward to the presentation at ASCO. Can you give us a little bit more information about the potential timing or sort of preparation that you're doing for the meeting with the FDA? And when could we find out sort of where their head is on a potential sNDA?

Yes. Again, I think overall, Ted, as we've shared, we're very pleased with the results and we feel the SENTRY data is very compelling and meaningful for MF patients. And I'll turn to Reshma again to kind of expand on our planned engagement with the agency.

Yes, absolutely. And thank you, Ted, for the question. I just want to reiterate what Richard said. I think we're very compelled by the profile that we saw at the time of the top line results. It's not just about the spleen, right? We know that other Phase III trials have shown these spleen reductions. I think what is so compelling is that it's occurring in conjunction with this very promising overall survival signal, again, as early as the data cutoff. And then it's reflected by this rapid VAF reduction, which again is a potential signal of disease modification. And we believe this is happening because of the unique aspects of XPO1 that are specifically targeting the clone, causing this anticlonal activity and again, reflected in the clinical endpoints of SVR, OS and then, of course, this disease modification as well.

We look forward to engaging with the FDA. They've been strong partners with us from the very beginning of the SENTRY trial, and we hope to elaborate on our next steps over the course of the next couple of quarters?

Great. Excellent. Looking forward to the presentation at ASCO.

And your next question comes from Colleen Kusy from Baird.

It's Nick on for Colleen. Congrats on the progress. Just for myelofibrosis, could you discuss the gating factors for potential compendia inclusion for selinexor? And is seli is included on guidelines in the future, could you discuss how you view this opportunity versus an approval? And I just had a quick follow-up after that as well.

Sure. I'll take the first part of the question, and thank you, Nick, for this important question around compendia. So we know that NCCN and other compendia, they are independent bodies. With that said, from our understanding, they're constantly looking at the literature, whether it's published literature, presented data, whether new treatments should be incorporated as part of their guidelines. And we do expect that they will be well aware of the data that we present at ASCO in the next couple of weeks.

And then any publication that we do anticipate should be published in the middle of the year. So we anticipate because, again, of the importance of these data that they will be convening either ad hoc or one of their scheduled meetings. And then hopefully, fingers cross, they agree the data are compelling and will be incorporated into the guidelines. I'll let Richard take the second part of your question.

Yes. Nick, on the second part, and I think as you know, in myelofibrosis, they are only using one class of therapies. And again, ruxolitinib being approved over 15 years ago and really a high unmet need for these patients. As Reshma has touched on, it's very typical in these areas with new data to work to get that guideline listing pretty rapidly. And if you look at analogs over the years, rituximab, bevacizumab, gemcitabine, et cetera, and they generated meaningful revenue based on physicians deciding to prescribe based on NCCN guidelines. So given the strong unmet need, I think you typically see -- if you only achieve NCCN listing without a label, products can achieve approximately about 50% of what peak may be if they had a label.

So obviously, this isn't an area that we would actively promote to, but it's an area where physicians can choose to use the medicine to make sure they're fulfilling the best interest of the patients.

Great. And then just on the follow-up for the endometrial for -- with 257 patients enrolled in the ITT, that was just a bit under the 276 number originally you said. Does that still provide sufficient powering to show statistics in the broader ITT population?

Yes, yes. No, I really appreciate the question, Nick. So when we originally incorporated this new mITT population, again, that mITT population, by and large, consists of these patients who are going to be p53 wild-type and pMMR. Yes, you can anticipate a small subgroup of patients whose tumors are going to be dMMR and they're also medically ineligible to receive a checkpoint inhibitor. But by and large, just assume this is going to be your p53 wild-type MMR proficient subgroup. When we originally incorporated that mITT, we assumed just based upon a proportion that, that 220 that we were targeting for that important mITT would likely equate to approximately 276 patients in that ITT.

What we found though is that the proportion was a little bit different. We are still very much targeting the 220 for the mITT. That's the key population for the FDA. And based upon the distribution, we landed up with 257 patients for the ITT. Because the benefit of selinexor is driven by the P53 status and not the MMR status, yes, we are very well powered to show both meaningful benefit in the mITT as well as ITT populations.

Our next question comes from Ioannis from Karyopharm.

I don't think Ioannis is at Karyopharm, but Ioannis, thank you for the question.

It's aspirational. No, great to hear the continued operational execution here. Yes, I guess just two quick ones. Now that, that enrollment has completed here for the trial, just looking back at the SIENDO results for endometrial, obviously, the outcomes really improved with additional follow-up. And so curious if you can at least kind of directionally guide us in terms of thoughts on where median follow-up would fall here for this trial? Is it going to be kind of closer to what we saw for SIENDO top line or maybe closer to the 30-plus month follow-up for the longer-term data cut?

Yes. I appreciate the question, Ioannis. So we anticipate that it's probably going to be in between the 2. So we had a top line results, which showed a median PFS specifically in that p53 wild-type subgroup of about 13.7 months and the placebo arm was 3.1 months. We then performed a subsequent cut that demonstrated the median PFS had increased to approximately 22 months. And then, of course, the most recent data, that long-term follow-up increased again to the median PFS of about 28 months.

So over those 3 cuts, we anticipate EC-042 to likely land in between the top line and the second cut. Now we'll see ultimately when we cut the data, it's going to be driven by when the events occur, right? But that is my anticipation going into the top line results of EC-042.

Got it. Okay. Very helpful. And then a quick follow-up on myelofibrosis. I guess with SENTRY-2, I think, slated to also put out data later this year, how does that kind of integrate with the effort here to get a publication out and potentially be included in compendia listing?

Yes. Really exciting trial. I love this trial, right, because it really demonstrates or hopefully will demonstrate monotherapy activity of selinexor in a frontline population. I do want to reiterate, it's not exactly the same population of SENTRY-2, largely because we do allow patients with platelet counts as low as 50,000 to be enrolled. So slightly different. But again, it allows us to better understand monotherapy activity of selinexor because investigators have that opportunity to add a JAK inhibitor as early as week 12, we also get some really important combination data.

My hope is with this trial is that we can significantly change the landscape in MS, right? JAK inhibitors have always been thought to be the backbone. My hope is that we change and -- we now change the paradigm to XPO1 inhibitors as that backbone. Important data, I think it's going to be relevant for the patient community as well as the physician community. We look forward to presenting the data in the second half of 2026. And then absolutely, if the guideline committee choose to adopt and incorporate that as part of the NCCN, obviously, that's up to them. But potentially, and again, pending the data, it could be a meaningful opportunity for this patient population.

And your next question comes from Maurice Raycroft from Jefferies.

Congrats on progress. Just wondering, when you meet with FDA on SENTRY, do you plan to share a more mature OS cut or other specific analyses? And who are you going to bring with you to the meeting? And is there more an ex-U.S. interaction strategy that you can share? Do you plan to meet with FDA first? Or do you want to align interactions with FDA and EMA?

Yes. Thanks, Maurice, for the question. Give me a chance to present the data at ASCO first. I don't want to get ahead of ourselves. I think there's going to be a lot of really important data that Dr. Mascarenhas is going to present on behalf of all the investigators of SENTRY. And keep in mind, right, just as we reported a few weeks ago, even the SVR data, right, sort of like not only shows week 24 data, but you also got some initial glimpses at week 36 as well. So we do have a little bit longer follow-up as part of SVR as part of those top line results. We haven't commented on any future data cuts, right? But I will say that the study was designed to follow for long-term outcomes, especially for overall survival.

So patients and physicians remain blinded to the arm to which they were randomized. They continue on treatment. They continue again on the arm to which they were assigned, and will continue to follow up for overall survival. We haven't guided on when those subsequent steps or presentations will occur, but that's an opportunity based upon the trial design. In terms of the FDA 2, right, so as I mentioned earlier, we look forward to providing updates over the course of the next 2 quarters. At this point, we're not providing any granular details around any of our conversations either with the FDA or the broader rest of world regulatory agencies.

And overall -- and our team overall, Maurice, is working well with our partners and globally. And as Reshma touched to here in the U.S. in terms of preparing for an sNDA and preparing and working with the regulatory agencies around the world to really advance this rapidly given the high area of unmet need for these patients.

Got it. That's helpful. And maybe a quick follow-up. For EHA, we're seeing the SENTRY-2 placeholder abstract there. But the time -- the guidance for data second half, I guess, will EHA, is that still -- is the data going to be at EHA? Or can you clarify on that point?

Yes. So that is a trial in progress. So [indiscernible] going to be at EHA. So that abstract, yes, that's just going to be a trial in progress. And yes, we anticipate data from that trial again in the second half of this year.

And your next question comes from Jonathan Chang from Leerink Partners.

First, can you remind me what dose is used in the 042 study and how that compares to the SIENDO study? And what gives you confidence in the 042 study dose? And as a follow-up to that, can you remind me what the safety profile in SIENDO look like? And what gives you confidence that patients can stay on selinexor in the maintenance setting for an extended period of time?

Yes. I really appreciate the question, Jonathan. So in SIENDO, we had a dose of 80 milligrams of selinexor. So these patients took 80 milligrams once weekly, dual antiemetics was not consistently used in that protocol. The reason I mentioned both of those is because both of those differentiate with EC-042. So in EC-042, the ongoing Phase III trial, we optimized the dose. The dose is going to be the same as SENTRY in that it's now 60 milligrams of selinexor again, dosed weekly. And in the EC-042, we also require the incorporation of dual antiemetics prior to each dose for the first 2 cycles. And we did that because we know nausea and vomiting are known side effects of selinexor because of the kinetics, i.e., the onset usually occurs in the first 2 cycles. We mandated again just for those first 8 weeks. And then, of course, it's optional thereafter.

How did we pick the dose? We really looked at a comprehensive data set. So again, we know in SIENDO that the median dose was 60 milligrams. The majority of the dose reductions occurred very early, largely because of the nausea, vomiting and hematologic toxicity. We also looked at comprehensive clin pharm data. And this is really where the AUCs when we look at 80 milligrams, AUCs achieved with 80 milligrams. At 60 milligrams, there's a lot of overlap in terms of the progression-free survival that was observed across those 2 data points.

So yes, a lot of confidence that, that 60 milligrams should be able to improve the safety profile of selinexor. This improvement in the safety profile is going to enable patients to stay on longer and hopefully drive what could be even potentially better efficacy than what we observed as part of SIENDO. One other thing that I will mention is that we know that the 60 milligrams does improve the safety and tolerability profile. I say that because of our SENTRY data, right? So SENTRY again, incorporated 60 milligrams in combination with ruxolitinib from that data set, very pleased to see reductions both in the rates as well as grades, especially of these GI toxicities of nausea and vomiting that have been well observed with selinexor.

[Operator Instructions] And your next question comes from Ted Tenthoff.

I didn't realize that there were openings at Karyopharm. I had to submit my resume as well, especially in the commercial group since that's going to be expanding. And that was kind of my follow-up question for -- what additional prep are you guys doing both from a drug supply side as well as what kind of additions need to be made to the commercial organization if EC hits and if we get on compendium or ultimately get approval in myelofibrosis, how does that change the organization?

Yes, I'll start at a high level, Ted, great question. And I would love to talk, of course, if you're interested. But I'll turn to Sohanya for the later part. But overall, the organization is really well established and obviously, has been working over the last couple of years to make sure we leverage the strong capabilities we've built from a supply perspective, a very solid supply chain, very solid manufacturing here in the U.S. and well ready to drive and support uptake for endometrial cancer and myelofibrosis as we continue to work to achieve labels and be able to commercialize in both those areas. But I'll turn to Sohanya because meaningful work has been already in progress and meaningful opportunities as we move forward.

Thanks, Richard. Yes, I'm very proud of the established team that we've set up, and there is a significant amount of prelaunch activities underway right now. So I'll break it down into 2 components. The global medical and scientific affairs obviously have been engaging strong with KOLs, strong presence at congresses, really understanding the treatment landscape and gathering those insights. From a commercial landscape, we've been extremely busy developing messaging, both promotional branded messaging, payer messaging, key account mapping, segmentation and so on. So lots of work going on. Again, as Richard mentioned, we have very strong capabilities. And then from a customer-facing model standpoint, there is very strong overlap at the key accounts and coverage in the key accounts. Specifically in myelofibrosis, it's a very concentrated group of accounts.

So we should be able to hit the ground running. In terms of endometrial cancer and the sales force coverage, again, strong coverage at key accounts, both in the academic and community medical oncology setting. In terms of the specialty gyn-oncs, there'll obviously be an incremental increase in sales coverage. But this is -- this specialty gyn-onc group really is also a very concentrated group of treating physicians. So we're very excited coming from a position of strength here and ready to have you join our team.

And your last question comes from Michael King from Rodman & Renshaw.

A couple of quick ones, if I may. Just wondering, the data that we'll see at ASCO, how closely is that going to map to -- I mean I always know the FDA gets a lot more data than what we see in public. But just as far as the data analysis and the timing is concerned, how much more will the -- will you take -- I guess the question, will you take another cut at the data before you present it to the FDA after investors and your peers see it at ASCO?

Yes. Thanks for the question. So we're not commenting on the data that we're presenting to the FDA, right? In general, as I mentioned earlier, we'll provide greater clarity on our interactions with the FDA and next steps over the course of the next couple of quarters. I'm really excited about ASCO, right? I mean this is the first time the data are going to be presented by publicly. I mean, obviously, really proud of the team for all the work that they've put into it, really excited to see Dr. Mascarenhas, one of the leading KOLs present these data on behalf of all the SENTRY investigators. And I think it's a great opportunity for people to really appreciate, right, sort of the benefit that selinexor in combination with ruxolitinib can provide to this population and the key differentiating aspects of this combination relative to other treatments that have been evaluated in myelofibrosis and certainly the current standards of care. So I hope you can be there live. I think it's going to be a great show.

I wouldn't miss it for all the money.

That's awesome. That's great. That's great. But yes, I think it's going to be a really great opportunity, especially for the patients.

Well, to pick up on your comment about precedent, FDA is a precedent-driven organization and all the approved MF drugs have had some kind of a glitch in their data set. I mean, so you guys didn't hit SVR35, but you did hit VAF, you did hit survival. I just want to -- if you can just help us put it into context relative to approvals for things like pacritinib, momelotinib, et cetera.

Sure. So we know that pacritinib and momelotinib, those are 2 great examples because while their focus also was on SVR and TSS, pacritinib clearly got an accelerated approval on SVR only, really important precedents because I think it highlights the FDA's appreciation and the importance of SVR as an important endpoint in myelofibrosis. In momelotinib, I think that example is also very relevant. Although those trials were also focused on SVR, TSS, those trials didn't necessarily show benefit as per their statistical analysis plan.

In this situation, the FDA definitely showed flexibility, I would say creativity, in identifying populations and other endpoints that clearly demonstrate that unmet need. So I provide those examples because it shows that this FDA is willing to look at the totality of the data, the data beyond just what's included as part of the primary endpoint. They're willing to look at other measures of clinical benefit and potentially provide a path forward for those meaningful treatments.

And there are no further questions at this time. Mr. Richard Paulson, President and Chief Executive Officer, you may continue.

Thank you, operator, and thank you again to everyone for joining us today and for your continued interest in Karyopharm. As you've heard, we are very encouraged by the progress we have made across our late-stage programs and remain very focused and disciplined in our execution through the next stage of important milestones. Most importantly, we remain committed to advancing selinexor's potential to bring meaningful new options to patients with both endometrial cancer or in the areas of endometrial cancer and myelofibrosis. And as we've heard, we look forward to seeing many of you at ASCO during our oral presentation of our SENTRY results. Thank you for joining us today.

Ladies and gentlemen, this does conclude your conference call for today. We thank you very much for your participation, and you may now disconnect. Have a great day, everyone.

Good morning. My name is Jenny, and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics' call to discuss top line results from the Phase III SENTRY trial. There will be a question-and-answer session to follow. Please be advised that this call is being recorded at the company's request.

I would now like to turn the conference call over to Brendan Strong, Senior Vice President, Investor Relations.

Good morning, and thank you for joining us on today's conference call to discuss the results from our Phase III SENTRY trial, evaluating selinexor in combination with ruxolitinib in myelofibrosis. Today's news is many years in the making, and we're delighted that you're able to join our call today. We issued a press release this morning with top line efficacy and safety data from SENTRY. We also issued a press release to announce a financing that provides us with $30 million at closing with additional funding if the associated warrants are exercised. These releases, along with the slide presentation that we will reference during our call today, are available on our website.

For today's call, as seen on Slide 2, I'm joined by Richard and Reshma, who will be presenting; and Sohanya and Lori, who are also joining for Q&A. We're also joined today by Dr. John Mascarenhas; Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of the Center of Excellence for Blood Cancer and Myeloid Disorders. Dr. Mascarenhas is one of the world's leading experts on myelofibrosis and the principal investigator of our Phase III SENTRY trial. We're very pleased that you will hear directly from him on the importance of our results and the potential benefit to patients.

Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995, as outlined on Slide 3. 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 Factors section of our most recent Form 10-K on file with the SEC and in other filings that we may make with the SEC in the future. Any forward-looking statements represent our views as of today only. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so, even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any later date.

I'll now turn the call over to Richard. Please turn to Slide 5.

Good morning, and thank you for joining us today. Today, we are excited to share top line results from our Phase III SENTRY trial, evaluating selinexor in combination with ruxolitinib in patients with JAK inhibitor-naive myelofibrosis. These data represent an important milestone for Karyopharm and more importantly, for patients living with this serious disease.

Myelofibrosis remains a disease with significant unmet need. Current therapies deliver modest spleen responses, limited evidence of disease modification, and JAK inhibitors remain the only approved class of therapies. There is a clear need for new treatment options that can improve outcomes for patients, particularly overall survival. From an efficacy perspective, the study met the first of its 2 co-primary endpoints. Selinexor plus ruxolitinib delivered a statistically significant improvement in spleen volume reduction.

In addition, the combination showed rapid, deep and sustained spleen volume response rates compared to ruxolitinib alone. And as many of you know, spleen reduction is a critical clinical outcome in myelofibrosis and one that physicians focus on closely in practice. While the difference on the absolute TSS endpoint was not statistically significant, patients in both arms experienced important and similar symptom improvement from baseline.

Additionally, the combination showed a promising overall survival signal as well as evidence of potential disease modification reflected by greater reduction in variant allele frequency in the combination arm. Taken together, we believe these findings represent an important and encouraging clinical profile. In addition, no new safety signals were identified in the study, the safety and tolerability profile was consistent with the known profiles of selinexor and ruxolitinib individually. Importantly, selinexor's differentiated XPO1 inhibition targets a broader disease biology in a way that we believe is complementary to JAK inhibition.

Taken together, we believe these results support the potential of selinexor as a meaningful new option for patients with myelofibrosis and mark an important step forward for Karyopharm.

With that, I'd like to turn the call over to Reshma, who will review the top line results from SENTRY in greater detail. And then Dr. Mascarenhas will share his perspective on why he believes these results are important. Reshma?

Thank you, Richard. Before getting into the data, I'd like to remind you of the contribution that XPO1 inhibition may offer in myelofibrosis as seen on Slide 7. XPO1 inhibition simultaneously targets multiple biologically relevant pathways in myelofibrosis that may be additive, if not synergistic with JAK inhibitors. These include inhibition of NF Kappa beta, activation of the p53 pathway and decreases in clonal cell division via inhibition of oncoproteins. Together, these effects may contribute to spleen volume reduction, reductions in variant allele frequency, a measure of mutational burden and potential improvement in long-term outcomes, including overall survival.

Turning to Slide 8. I will briefly review the key elements of the Phase III SENTRY trial design. SENTRY enrolled JAK-naive or frontline myelofibrosis patients, all of whom, who had baseline platelet counts of greater than 100,000. Patients were randomized in a 2:1 ratio to selinexor 60 milligrams in combination with ruxolitinib dosed per label or ruxolitinib in combination with placebo. In total, 353 patients were randomized. The trial had 2 co-primary endpoints, a SVR35 and Absolute TSS, both evaluated at week 24. The endpoints were evaluated at a one-sided alpha of 0.025, and were tested sequentially.

The trial also included multiple secondary and exploratory endpoints, including overall survival as a secondary endpoint, and variant allele frequency, or VAF reduction as an exploratory endpoint.

Moving to the data on Slide 9. The first co-primary endpoint of SVR35 at week 24 was met. The benefit was highly significant with an almost doubling in SVR35 rates observed with the combination versus ruxolitinib alone at 50% versus 28%, respectively, translating to a p-value of less than 0.0001.

The kinetics of these response rates were as important. Turning to Slide 10, at week 12, the SVR35 rates were already 49% versus only 20% observed with ruxolitinib alone. Furthermore, the response rates were sustained at week 36 with SVR35 rates of 47% for the combination versus only 23% for ruxolitinib alone. Taken together, these results speak to the rapid and sustained benefit of the combination on SVR35 rates.

On Slide 11, in addition to this rapidity of response, we see that the spleen volume reduction was deeper with the combination compared to ruxolitinib. Over time, the combination arm led to greater reductions in spleen size.

Turning to symptoms as seen on Slide 12, the mean change in total symptom score at week 24 was similar across the 2 arms with an approximate 10-point improvement observed with the combination and an 11-point improvement observed with ruxolitinib. Importantly for patients, the combination led to very similar symptom improvement relative to baseline.

One of the most encouraging findings in our study is the promising overall survival signal observed, which is shown on Slide 13. Overall survival is arguably the most important endpoint in any clinical trial. The combination demonstrated a greater than 50% reduction in the risk of death compared to ruxolitinib. At a median follow-up of approximately 12 months, the rate of overall survival events observed with the combination was less than half the rate observed with ruxolitinib alone at 4.7% and 10.2%, respectively, corresponding to a hazard ratio of 0.43 and a nominal p value of 0.0222.

We believe the magnitude and early emergence of this signal is particularly notable, and this may be one of the only trials to show a signal of overall survival benefit compared to ruxolitinib alone. We will continue to follow this very promising signal to maturity. Furthermore, a post-talk analysis suggests that SVR35 as early as week 12 may predict overall survival. These data are consistent with the multiple analyses done with JAK inhibitors, which show a similar correlation, potentially validating spleen volume reduction as a surrogate for overall survival and highlighting the importance of achieving a rapid SVR.

As seen on Slide 14, variant allele frequency, or VAF in myelofibrosis measures the percentage of blood cells carrying a specific driver mutation including JAK2, CALR or MPL and reflects the malignant clonal burden. VAF reduction of the relevant driver mutations in myelofibrosis, again, including JAK2, MPL and CALR is evidence of potential disease modification. VAF reductions greater or equal to 20% at week 24 was observed in 32% of the evaluable combination-treated patients versus 24% of ruxolitinib-treated patients.

Notably, these reductions occurred early and may reflect the rapidity of the spleen volume reduction and the promising signal observed in overall survival. We believe these differentiating findings highlight the relevance of the XPO1 inhibition in myelofibrosis. The safety profile of the combination was manageable, as seen on Slide 15. The safety and tolerability profile was consistent with the known safety profiles of selinexor and ruxolitinib individually, both of which are marketed drugs and have been used to treat tens of thousands of patients. No new safety signals have been observed.

The 5 most common treatment-emergent adverse events observed with the combination were either hematologic or GI in nature, including thrombocytopenia at 59%, anemia at 57%, nausea at 57%, constipation at 32% and neutropenia at 27%. I do like that when combining both drugs, we do not see an increase in anemia. And in fact, we see a slightly lower rate of all grade anemia in the combination versus ruxolitinib.

Notably, the nausea rates, a known side effect of selinexor was lower than what was reported in the Phase I of SENTRY due to incorporation of prophylactic antiemetics. Grade 3 plus treatment-emergent adverse events were observed in approximately 70% of patients treated with the combination versus 50% treated with ruxolitinib. Treatment-emergent adverse events leading to discontinuation were 14.5% versus 8.6%. These rates are very consistent with other combination therapies commonly used in the treatment of cancer indications.

Finally, confirmed leukemic transformations were the same at 1.7% in each arm. In conclusion, on Slide 16, the combination of the XPO1 inhibitor selinexor and ruxolitinib demonstrates an encouraging product profile that has the potential to improve outcomes for patients. Importantly, we see rapid near doubling in sustained SVR35 rates, similar improvement in symptoms, relative to ruxolitinib from baseline and a promising signal in overall survival.

The early and notable reductions in VAF levels greater or equal to 20% relative to baseline highlight a potential mechanism driving these key efficacy outcomes. I would now like to turn the call over to Dr. John Mascarenhas to talk about the importance of these results and the potential implications in the treatment of myelofibrosis.

I will start on Slide 18 by level setting the discussion around SENTRY by highlighting the clinical hallmarks of myelofibrosis, which define both disease burden and treatment goals. The 4 key features of MF are first and foremost, splenomegaly, which is a function of extramedullary hematopoiesis due to aberrant MF stem cell trafficking and represents a fundamental complication of this chronic and progressive neoplasm. This contributes to frank discomfort in the abdomen, and also can lead to early satiety and contribute to weight loss.

Second, cytopenias include anemia and thrombocytopenia, which are a function of the bone marrow failure aspect of MF and worsen with time and limit treatment options and have been shown to associate with poor prognosis. Third, progressive bone marrow fibrosis, the underlying histopathologic driver of the disease attributed to activated MF megakaryocytes and the consequence of highly inflamed bone marrow microenvironment.

And the fourth feature of substantial symptom burden, including fatigue, night sweats and weight loss, which reduce quality of life and negatively impact functioning. With that context, I would like to comment on the top line results from the SENTRY study reported on this call, which I believe are compelling and promising. We observed rapid and sustained spleen volume reductions with the combination of seli and rux with faster, deeper and more sustained SVR rates compared to placebo and rux in this randomized study. This was clearly superior to rux alone as anticipated by the Phase I data and as credentialed by the mechanism of action of seli in hitting multiple disease-relevant pathways, such as p53 activation that preclinical data suggests would synergize with rux. The spleen is a clinical biomarker of disease burden and SVR is an important outcome measure, initially set forth by the COMFORT studies, and one in which JAK inhibitors have been focused on achieving in clinical trials.

Here, we can see that a rational combination strategy delivers greater SVR than rux alone. In addition, we are seeing an encouraging signal in overall survival, favoring the combination, which is ultimately the endpoint that matters most to patients, caregivers, clinicians and regulatory agencies. The correlation of SVR with overall survival reinforces both the importance of it delivering an on-target activity and attaining spleen response for immediate benefit to the patient, but with added potential benefit of disease course modification.

What is also notable is the greater reduction in variant allele frequency of driver mutation, which still early suggests we may be impacting the underlying biology of the disease, not simply managing symptoms. This also aligns nicely with the clinical outcome of greater SVR with the combination. These results highlight clinically meaningful endpoints. The trial achieved strong spleen responses and promising overall survival outcomes. While total symptom score was not statistically different between the 2 arms, we importantly see no detriment with the combination, and there was a meaningful improvement in symptoms relative to baseline.

From a clinical perspective, maintaining or improving symptom control while enhancing spleen response and disease modification with potential overall survival benefit is what we seek to accomplish with combination therapy in the frontline MF setting.

Finally, I want to emphasize the rationale behind the combination approach by adding selinexor, an approved agent in multiple myeloma, with a well-established safety profile to ruxolitinib, we're introducing a novel and relevant mechanism of action. This combination has the potential to go beyond what JAK inhibition alone can achieve, which is well established over many trials of 4 approved JAK inhibitors and may meaningfully improve survival outcomes for patients, which are only modestly achieved with single-agent JAK inhibitors. Taken together, these findings support the potential for seli and rux as first-line combination approach to the treatment of myelofibrosis.

Turning to Slide 19, we can look back at other studies for reference of the importance of spleen reduction, most notably in the 2023 Minerva real-world retrospective study in Italy of 154 patients with myelofibrosis treated with ruxolitinib, spleen responses were achieved in a substantial proportion of patients, approximately 68%, typically within the first 24 weeks of therapy. Importantly, achieving a spleen response by palpation was strongly associated with improved overall survival. This was independent of baseline risk as measured by DIPSS.

As important as attaining spleen response at a landmark analysis of 24 weeks is those patients, who maintain spleen response had the most favorable survival outcomes, whereas those who lost response experienced outcomes comparable to nonresponders. So it is not sufficient to simply attain the endpoint of 24 weeks, but the real benefit is in maintaining it over time. These findings underscore spleen reduction is not only a marker of clinical benefit, but also a meaningful prognostic indicator, linking durable spleen responses with longer survival in real-world practice.

The landmark analysis of the SENTRY study at 12 and 24 weeks reinforces the potential to rapidly achieve SVR and maintain this clinical outcome, which in the ad hoc analysis of SENTRY data, irrespective of treatment arm, would support a relationship between SVR and overall survival. I believe that this prospective data from a Phase III study not only validates the Italian retrospective data set, but also has the potential to support credentialing SVR as a surrogate for overall survival in MF therapeutic development. Obviously, following this data out further is paramount to confirm the validity of this exciting finding.

Finally, Slide 20 shows the current NCCN guidelines for the treatment of MF with low risk on the left and higher risk on the right. What I want to point out is that the subcategory of platelets greater than 50,000, in addition to the availability of 4 JAK inhibitors in which ruxolitinib is most frequently used, it would be possible to imagine that a combination approach such as ruxolitnib and selinexor would be commercially available and NCCN endorsed, giving the provider and patient the option to choose an active initial treatment regimen with the highest probability of optimizing disease response and attaining SVR while not compromising symptom benefit in order to maximize potential for overall survival benefit.

I believe the combination should be available to all patients, although this may not be the preferred treatment selection for every patient. I look forward to presenting the greater data set from the pivotal trial at upcoming meetings. And thank you.

Now I will turn it back to Richard.

Thank you, Dr. Mascarenhas. In closing, as outlined on Slide 22, we believe the SENTRY top line results represent an important milestone for Karyopharm and an encouraging step forward for patients living with myelofibrosis. These results suggest the potential to improve on key dimensions of treatment benefit in a disease where patients and physicians continue to need better options. We observed rapid, near doubling and sustained spleen responses, similar symptom improvement relative to ruxolitinib, a promising overall survival signal and evidence of potential disease modification reflected by reductions in VAF.

Taken together, we believe these findings represent an important and encouraging clinical profile. From here, we plan to meet with the FDA to discuss the totality of the SENTRY data and our potential sNDA filing plan. We also intend to present Phase III SENTRY data at an upcoming medical meeting and submit a manuscript to a peer-reviewed journal.

Beyond SENTRY, we remain focused on advancing export EC-042 in endometrial cancer, which remains on track for top line data in mid-2026 and represents a significant opportunity for Karyopharm. Importantly, the financing that we announced this morning extends our cash runway into late Q3, enabling us to deliver on a second major inflection point with our top line EC-042 results, while continuing to execute in each of these areas.

Before we start Q&A, I want to recognize and thank the patients, families, caregivers, investigators and the broader clinical trial teams whose participation made this study possible. We are deeply grateful for their commitment. I would also like to thank Dr. John Mascarenhas for his leadership in this study and for sharing his perspective that these results represent an important advance for the myelofibrosis community and one that should be available to patients and physicians. Thank you again for joining us today.

We'll now open the call for questions.

[Operator Instructions] Your first question is from Ed Tenthoff from Piper Sandler.

Congratulations on the impressive data. I know a lot of work has gone into getting here. And pleased to see the emerging OS signal. I'm curious about absolute total symptom score, and I know this is still the top line. I'm wondering if you have a concept of what maybe was the difference that sort of left those measures comparable between the 2 arms at an individual line level? Was there anything that really stood out?

Yes. Thanks, Ed. Maybe I'll turn to Reshma to touch on that.

Yes. Thank you, Ed. Great question. So I do want to emphasize, I think the really important aspect of this trial demonstrated very meaningful benefit in terms of TSS for the combination arm relative to baseline. It was a 10-point improvement, really indicating that these patients at week 24 do feel substantially better relative to baseline.

Now as I mentioned on the call, while we're disappointed that it did not just superiority relative to the placebo arm, I think it really highlights the variability that you see in the TSS and why it may not be -- it potentially may not be the best marker of improvement in a trial such as myelofibrosis. We are certainly looking into the individual domains and trying to understand whether there was a specific contribution from one of the domains for the overall results, but again, I'm just very encouraged by the improvement relative to baseline.

And Dr. Mascarenhas, anything you would add to that?

No, I mean, I would agree with Reshma. I think it's really a reflection of what to expect in this setting of a Phase III randomized study, where the control arm is active. We have numerous studies that demonstrate that ruxolitinib and other JAK inhibitors are quite potent in reducing symptom burden likely by reducing inflammatory cues. So I think the real question for people like myself that are investigators across the board in these trials is, is it realistic to expect improvement upon symptom burden in this setting?

I think from my perspective, if you're not worsening symptom burden, but delivering improvements to that individual in terms of their symptom burden relative to ruxolitinib, that's a win. So it is -- in some ways, it shouldn't be shocking that we see this phenomenon over and over again. I think it's a reflection of the disease and the fact that it's really probably not realistic to improve upon symptom burden in this setting from baseline to ruxolitinib at 24 weeks.

But the real question is, can you deliver other meaningful endpoints like spleen reduction and other biomarkers that would suggest disease modification? So my attention is more focused these days on those outcomes. The spleen as we see that spleen is meaningful, that spleen reduction is not simply a regulatory endpoint, but is probably a clinical outcome measure that is associated with survival. So in my mind, rapid deeper spleen responses is really the endpoint of interest, and we want to make sure we're not adding symptomatology or detracting from quality of life, but at least matching what ruxolitinib can deliver.

So I'm not sure I'm disappointed by this result in the sense that I think it's a hard bar to overcome. And I think it's like any other study. It's hard when you go from a Phase I study to a Phase III study, broad study across multiple countries, different investigators different reporting structures, there's always going to be that potential to not hit in a measurable way here. So not surprising in some ways, but still reassuring that the most important primary endpoint was met.

Your next question is from Colleen Kusy from Baird.

Congrats on the updates. If you could just speak to the level of confidence that the FDA would approve this given the historical precedent of needing to hit on both SVR35 and TSS? And then just kind of what -- can you talk about what the NCCN guidelines next steps would look like? And if Dr. Mascarenhas could chime in on how he thinks physicians might view not approved, but included in NCCN guidelines and use expectations there?

Yes. Thanks, Colleen. Maybe I'll start with Reshma on the first part, and then I'll turn it to Dr. Mascarenhas.

Yes. Thanks, Colleen. So I think overall, once again, we are very encouraged by the profile that has been demonstrated from this trial. As John mentioned, as I reported in the prepared remarks, the early -- the sustained -- the substantial proportion of patients that achieved that SVR really demonstrates that meaningful benefit layer on top of this very promising early overall survival signal and a manageable safety and tolerability profile really suggests a positive benefit-risk. And we look forward to engaging with the FDA on the totality of that data.

So we plan on finalizing our steps with the FDA and the sNDA path forward, hopefully, in the next 6 months. In the meantime, we look forward to presenting the data in an upcoming medical congress and publishing the data that hopefully will enable NCCN guidelines, although that is an independent body that ultimately determines whether they want to incorporate in the guidelines. I'll hand it over to Richard.

Yes. Dr. Mascarenhas, your thoughts from NCCN perspective?

Well, I think the -- I'll first say that I think it's hard to -- as an investigator in this field, I find it a little bit challenging to necessarily predict what the FDA will evaluate and assess data results. I think the FDA will be interested in the survival benefit here because I think that's obviously important. And the relationship between SVR. I think that will translate into the community and likely be reflected in NCCN endorsement that would then at least give providers the opportunity to combine it with rux in the real-world commercial setting, even if it's not approved off-label as this can be seen already with drugs like luspatercept, which is approved in MDS for transfusion-dependent lower-risk MDS, but has Phase II data in MF and soon to be release full data set in MF in the Phase III setting, but is already used in the commercial setting based on NCCN endorsement.

So selinexor is an approved drug. It's already out there. Many people in the community have some use and some understanding of the drug from myeloma. So it's not impossible to imagine the utilization of selinexor in the community setting even with rux to deepen the spleen response based on the data we've seen here at SENTRY. So I could see a path forward in this way.

Your next question is from Brian Abrahams from RBC Capital Markets.

Just wondering if you could comment on the causes of deaths here in the study, any patterns or timing there? And then maybe for Dr. Mascarenhas, do you think 36 weeks is long enough for spleen benefits of this degree to translate to the overall survival signal of this magnitude?

Sure, Brian. So the causes of death, we've looked into it, and they're very consistent with what you would expect with myelofibrosis, especially across the 2 arms. So there's no pattern that we see either amongst the deaths, or any kind of, I would say, discrepancies across the 2 arms.

The other aspect that I just want to highlight is that when we look at the ruxolitinib arm especially the 18-month overall survival landmarks, they're very consistent with what's been published, especially with ruxolitinib in their overall survival data. So nothing out of the blue. We don't see that ruxolitinib over underperforms. Those data, again, really suggest that this could be a very promising signal in overall survival.

And Dr. Mascarenhas, for the second part of the question?

So I'm encouraged by the fact that you see not simply this rapid reduction in spleen volume, which I think speaks to the fact that there's true synergy between selinexor and ruxolitinib as the preclinical modeling would show in the Phase I data would demonstrate. So that was reassuring to see.

It was also reassuring to see that it predicted -- so response at 12 weeks also predicted response at 24. It maintained at 24, and then you continue to see that response at 36. Obviously, it's always nice to continue to see the response beyond 36 weeks, but you don't see the same degree of rapidity depth and maintenance of response with ruxolitinib. You do -- you start to lose that over time.

So I do think that, that's important. And obviously, I'm happy that Karyopharm is committed to following this out longer to demonstrate the continued maintenance of that SVR and to observe differences in survival, which at this early time point, I think, is very encouraging to see already. I think the totality of this spleen data would suggest that there is, in fact, a relationship, not necessarily that a smaller spleen lets people live longer, but it is a biomarker. It's a clinical readout for on-target disease modulation that likely over time is going to read out as an improvement in outcomes.

Your next question is from Ioannis Souroutzidis from Cantor.

Congrats on the data again. I just had a question on the OS signal. Obviously, it's only 23 events, and so I think that's roughly 93% of the patients are still censored. And I guess, could you walk us through how you expect to kind of communicate updates there on how those survival curves might mature? And then speak to how these patients are getting therapy subsequent to the study as well, just to understand kind of the follow-through there and how that might affect overall survival in the long term?

Yes, absolutely, Ioannis. So we absolutely need to continue to follow the OS signal out to maturity. There is no crossover in the study. So that hopefully will allow us to better detect a meaningful overall survival as the patients continue on therapy. We haven't communicated sort of like how we're going to follow or when we're going to communicate out those OS events, but we'll continue to look at it and find an appropriate venue in which to ultimately publish those more mature overall survival deaths.

In terms of the subsequent therapy, so this is another marker that we follow very closely. So we do collect all of the subsequent therapies. Right now, it's relatively small or a small number of patients are getting those subsequent therapies. So in addition to the overall survival data, we'll likely comment on the subsequent therapies, and their impact on that overall survival.

One quick follow-up, if you don't mind, for Dr. Mascarenhas. I couldn't help, but notice that there was a recent study that you kicked off looking at selinexor with pacritinib. And just kind of curious what was the impetus there and inspiration for doing that?

I'm so glad you asked that question. So that is -- that's an exciting study as well. I think it complements very nicely the SENTRY study and the results. So if you think about MF as a disease spectrum and in the NCCN guidelines, in particular, it segregates patient baseline platelet count. And this study was focused on the patients that had a -- which is the majority of patients that had adequate platelets of greater than 100,000. There's substantial data that would suggest that the patients with cytopenias, thrombocytopenia anemia, have a different clinical course and a poorer outcome and are not able to enjoy the full benefit of ruxolitinib.

And that's where drugs like pacritinib, which is a multikinase inhibitor, spares JAK1, hits IRAK1 as well as FLT3 and other enzymes, I think, are important to the disease process, and then also combines very nicely and neatly with selinexor in preclinical modeling. So the idea there is, can we capture the spectrum of patients? So rux perhaps with seli in the patients who have adequate blood counts at baseline, and then rux -- selinexor plus pacritinib in patients with lower counts, anemia and thrombocytopenia.

So I look forward to that study. That study is a MPN research consortium study, so it's an investigator-initiated study, which Karyopharm and Sobi have generously provided a drug for. And we hope to start that study through multiple centers in the U.S. starting in May. And I think it just adds to the volume of data that will help bring attention to combination therapies.

And I will put in that there are other ongoing studies, which I think are exciting. For example, selinexor upfront, and then adding at a later time point if spleen and symptom is not met, combinations of ruxolitinib, pacritinib or momelotinib really trying to explore different ways of combining seli, well, or maybe not even combining seli, maybe seli upfront, but combining seli to optimize response across the JAK inhibitor spectrum. So I think the more data, the better, it also just helps reinforce when a prescriber is seeing patients that might not all look uniform, how best to tailor the therapy. And that for a complex disease that's really attractive.

Your next question is from Maury Raycroft from Jefferies.

Congrats on the update. The SVR35 benefit is compelling. I guess if the base case is compendia listing in the U.S. can Dr. Mascarenhas talk more about the relevant patient population? Would it be used for patients with severe splenomegaly at baseline? How big is that population? And based on the combos overall profile, would treatment be durable or more of an induction type of treatment up to 24 or 36 weeks?

So I think the -- so the answer is if you -- and we have to look at this data more carefully. And I think at upcoming meetings when we have the opportunity as a community to really go through it, we'll be able to parse out and understand whether there are predictors of response to the combination. Right now, the response looks uniform across all different type -- subtypes of MF. So there's not really one patient profile that I can glean at this point would be the patient profile to use combination. So it could be used in any patient upfront.

I think what you will likely find particularly as therapies are introduced into practice is an adoption that will likely start in many cases with the patients who come really advanced, big spleens, high symptom burden. I think those are sort of the natural patients where you would probably pick a combination upfront. But it's not clear to me that there is a profile, whether it's driver mutation, spleen volume, risk score that would suggest that this is the population for combination.

And in some cases, it might be comorbidities that might influence treatment decisions. So for example, if someone has underlying severe IBS or IBD, perhaps a combination with selinexor might not be the optimal choice for that patient. If a patient has a platelet count of 50,000 at baseline, perhaps rux and seli may not be the best choice for that patient. And that's again, to go back to the previous question, that's why exploring combinations with pacritinib, for example, would allow us for a more broader usage of combination therapy.

Just to finish, and no, so I don't know that I would necessarily -- I think it's an interesting concept of induce a response, and then maybe back off of it. I think on an individual basis, we'll have to see how patients respond to the combination balancing benefit and toxicity, but I think what we've learned in this field is you do want to induce a response and maintain a response. And I think that would require continued therapy with the combination. At least at this time point, that's the way it's been developed and explored, that's probably the best way to continue using it.

Got it. And maybe one other follow-up question. If you guys can just provide more perspective into the Grade 3 plus AEs and what trends you're seeing across the two arms. And specifically, how do these compare across both arms on anemia and thrombocytopenia?

Yes. Good question, Maury. So again, the Grade 3 plus AEs were observed in 14.5% of the combination versus 8.6% in ruxolitinib alone. Again, very consistent, as I mentioned, of other combinations, not only in myelofibrosis, but also in other oncology combination therapies. While we haven't specified the actual Grade 3 plus AEs, and the most common Grade 3 plus AEs, they're still going to be GI as well as hematologic in nature.

I think the really important aspect for me, and maybe John can comment as well, is that, overall, this is a very manageable profile, regardless of that 14.5%. And the reason I say that is because it's still enabled to this very rapid and sustained SVR that we see with the combination patients, and we also see this very promising overall survival signal. Again, two things that you wouldn't see if toxicity was a challenge for this combination.

And Dr. Mascarenhas, is there anything you'd add to that?

Well, I think we've learned with time how to optimize the delivery of selinexor. So at 60 milligrams once weekly with adequate prophylaxis. And I have to say you have to tailor that prophylaxis to that patient. And I think awareness is really important to be aware of that potential toxicity, so you can optimize that potential toxicity is really important. So it is deliverable. I think if we didn't see these spleen responses and survival benefit, then one could question that the balancing act between toxicity and efficacy here. But I think if you look at the full data set, the GI toxicity is overcome by the clear benefit in spleen reduction and that exciting signal for survival.

Your next question is from Jonathan Chang from Leerink Partners.

This is Albert Agustinus on for Jonathan Chang. Congrats on the data. Just a small one for me. Based on your prior interactions with FDA and historical precedents, to what extent do you expect the FDA to weigh on this OS signals against TSS endpoint during the review? And how will this translate to the confidence in your upcoming meeting?

Yes. I mean, overall, as I mentioned previously, we're encouraged by the profile that has been established with the combination, right? We see these very rapid sustained SVR. As John mentioned, it is a likely clinical biomarker for long-term outcomes. You layer on that, we see this very promising overall survival signal in the context of a very manageable and tolerable safety profile. So we look forward to engaging with the FDA and engaging with next steps.

And our last question is from Michael King from Rodman and Renshaw.

I'll add my congratulations on the outcome. I'm just wondering if you could just comment a bit more on OS. How are you defining the maturation of the data, when will that read out? Is there a specific event number that you're looking to achieve? And will you wait to speak with FDA until you have more maturity on the OS endpoint?

Yes. So overall survival is a prespecified secondary endpoint. Again, we see this very promising overall survival signal. We're going to continue to follow OS in the study. We do not have a predefined number of events, but we'll continue to look at the data and present the data as it continues to mature.

There are no further questions at this time. I will now hand the call back to Richard Paulson for the closing remarks.

Thank you, operator, and thank you, everyone, for joining us today. I think as we all well know and as we heard again today, myelofibrosis remains a disease with significant unmet needs. And the current therapies really deliver modest spleen responses with limited evidence of disease modification, and JAK inhibitors really remain the only approved class of therapy.

So there's a clear need for new treatment options that can improve outcomes for patients, particularly overall survival. I think, as we've shown, these data represent an important milestone for Karyopharm and more importantly for patients and caregivers and physicians, living with this very serious myelofibrosis disease. So we're focused on working together as we work to try to bring selinexor to patients with myelofibrosis. Thank you for joining us today.

Ladies and gentlemen, the conference has now ended. Thank you all for joining. You may now disconnect your lines. Goodbye.

Good morning. My name is Ludy, and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics Fourth Quarter and Full Year 2025 Financial Results Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request.

I would now like to turn the call over to Brendan Strong, Senior Vice President, Investor Relations. Please go ahead.

Good morning, and thank you all for joining us on today's conference call to discuss Karyopharm's fourth quarter and full year 2025 financial results and recent company progress. We issued a press release this morning detailing our financial results for the fourth quarter and full year 2025. This release, along with a slide presentation that we will reference during our call today, are available on our website. For today's call, as seen on Slide 2, I'm joined by Richard, Reshma, Sohanya and Lori, who will provide an update on our results for the fourth quarter and full year of 2025 and discuss recent clinical developments.

Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995 as outlined on Slide 3. 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 Factors section of our most recent Form 10-Q or 10-K on file with the SEC and in other filings that we may make with the SEC in the future. Any forward-looking statements represent our views as of today only. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any later date.

I'll now turn the call over to Richard. Please turn to Slide 5.

Thank you, Brenden, and good morning, everyone. Thank you for joining us today. Here in 2026, Karyopharm is in a defining phase, marked by important late-stage clinical milestones, continued disciplined execution and the opportunity to meaningfully expand the impact and scale of our oncology franchise. Today, selinexor has an established durable commercial foundation in multi myeloma within a highly competitive treatment landscape. That business continues to support the company and provide important experience as we advance into new treatment areas. Looking ahead, we see the most significant near-term driver of value in myelofibrosis with endometrial cancer representing a subsequent opportunity to further expand the franchise. In myelofibrosis, we remain on track to share top line data from our Phase III SENTRY trial in March. SENTRY was designed to address a clear unmet need by evaluating selinexor as part of a combination approach in a setting where treatment options remain limited. Over time and through clinical experience, we've meaningfully optimized how selinexor is used, including dose refinement and proactive supportive care, resulting in a more manageable and predictable tolerability profile. As we approach this important data readout, our organization is energized and well positioned to deliver on this opportunity.

In endometrial cancer, we remain on track to report top line data from our Phase III XPORT-EC-042 trial in mid-2026. This biomarker-driven program targets a defined patient population with limited effective treatment options and represents an important opportunity to expand the long-term commercial profile of the franchise beyond hematological malignancies. From a financial perspective, we continue to manage the business with discipline. As previously disclosed, our cash runway extends into the second quarter, which aligns with key near-term clinical milestones. We have been deliberate in how we sequence spend across the portfolio, and we are actively evaluating a range of financing and strategic options to maintain flexibility and align capital decisions with value creation.

With that context, I'd like to first turn the call over to Reshma, our Chief Medical Officer, who will provide a detailed update on our clinical programs and upcoming milestones. Following Reshma, Sohanya, our Chief Commercial Officer, will discuss how we are preparing from a commercial and go-to-market perspective. Then Lori, our Chief Financial Officer, will review our financial results and discuss our financial guidance for 2026. After those updates, we'll return for additional discussion and Q&A. Reshma?

Thank you, Richard. I'm incredibly excited by the near-term opportunity to read out two Phase III trials that could establish new standards of care in two areas of high unmet need. Let's start with myelofibrosis, where we will have data next month. As seen on Slide 8, I'd like to emphasize the substantial need for new treatment options for patients with myelofibrosis. JAK inhibitors are the only approved therapies. And while they may decrease symptom burden and lead to very modest spleen reduction, relevant JAK inhibitors, including ruxolitinib, the standard of care in frontline myelofibrosis do not target all of the relevant pathways implicated in myelofibrosis, including Nf-kappa beta, p53 and fibrosis-inducing pathways. As a result, frontline treatment with monotherapy JAK inhibitors do not adequately address the relevant drivers of pathogenesis in myelofibrosis.

On Slide 9, our confidence in selinexor's potential in myelofibrosis is based upon a substantial body of preclinical, nonclinical translational and clinical efficacy as well as safety data sets. These data suggest XPO1 inhibition is a key mechanism that may facilitate potential synergy with ruxolitinib and other drugs relevant in myelofibrosis. This multi-targeted approach enables treatment of the underlying mechanisms that lead to myelofibrosis, and we believe may lead to meaningful efficacy across the key treatment drivers as well as a generally safe and manageable side effect profile.

As seen on Slide 10, while JAK inhibitors directly inhibit the JAK/STAT pathways, multiple other pathways downstream of JAK/STAT support malignant clone proliferation and survival, bone marrow fibrosis, cytokine storms and proliferation of abnormal megakaryocytes. These pathways include Nf-kappa beta, PI3-kinase, AKT, mTOR and TGF-beta. A multifaceted approach with dual XPO1 and JAK inhibition simultaneously target upstream and downstream effectors of the JAK/STAT pathway, ultimately enabling apoptosis or cell death of the malignant clones.

Let's now focus on the key treatment drivers in myelofibrosis as seen on Slide 11, spleen reduction, symptom improvement and lower rates of grade 3+ anemia. First, spleen volume reduction. Note that only approximately 1/3 of patients achieved a spleen volume reduction of greater than 35% with ruxolitinib alone. In contrast, our Phase I data suggests that the combination could more than double the SVR35 rate at 79%. Second is symptom improvement. Data from this trial also showed an average 18.5-point improvement in absolute TSS at week 24 relative to baseline, which suggests this combination could provide a meaningful improvement over the 11 to 14 points achieved by patients on ruxolitinib as observed in the Phase III MANIFEST-2 and TRANSFORM-1 trials. Keep in mind that our 18.5-point improvement excludes fatigue, whereas the numbers from the other trials include fatigue. So in reality, the difference could be even greater. Third is lower rates of grade 3 plus anemia. The data that we presented in June at EHA from our Phase II 035 monotherapy trial showed lower rates of all grade and Grade 3 plus anemia for the selinexor arm as compared to physicians' choice in myelofibrosis patients previously treated with JAK inhibitor therapies. Our initial blinded safety data from the first 61 patients enrolled in SENTRY also suggests lower rates of grade 3 plus anemia when selinexor is combined with ruxolitinib compared to historical ruxolitinib data. Meaningful improvement of these treatment drivers require disease modification or elimination of the underlying mechanisms leading to development of an enlarged spleen, constitutional symptoms and worsening cytopenias. Data observed from selinexor monotherapy studies in a pretreated myelofibrosis population as well as our Phase I combination data in JAK inhibitor naive myelofibrosis suggests meaningful reductions in key cytokines critical to myelofibrosis pathogenesis, symptom development and anemia as well as improvements in bone marrow fibrosis, increases in erythroid progenitors and mutational burden. Improvement in these markers of disease modification may explain why selinexor alone and in combination may lead to improvement in the key hallmarks of the disease, including enlarged spleen, cytopenias and symptoms.

Turning to Slide 12. We are eagerly awaiting the readout from our Phase III SENTRY trial next month. As we have previously discussed, we believe that we have done everything within our control to optimize SENTRY for success, including focusing on the relevant symptom domains and the analysis of TSS that can be most accurately evaluated in a randomized trial analyzing TSS by estimating the mean change in TSS at week 24 relative to baseline, also referred to as absolute TSS as well as recruiting a more symptomatic patient population. As previously discussed, the mean baseline TSS without fatigue in approximately 350 patients is approximately 22.5, which could be the highest baseline TSS observed in a frontline myelofibrosis Phase III trial.

Depending on the outcome of our data in myelofibrosis, we also have a significant opportunity to expand into other myeloproliferative neoplasms as outlined on Slide 13. This includes the potential to expand into polycythemia vera and essential thrombocythemia with eltanexor, our leading next-generation XPO1 inhibitor.

Let's now turn our attention to endometrial cancer on Slide 15. In the Phase III XPOR-EC-042 trial, the number of PFS events observed to date are consistent with our projections, giving us confidence in our ability to share top line data in mid-2026. In light of the near-term proximity of these data, I wanted to go back and remind everyone about the treatment landscape, our data from our last trial and recap our current trial design. Our Phase III trial is recruiting patients with p53 wild-type endometrial cancer. Given that checkpoint inhibitors are entrenched in the treatment landscape for patients with DMMR tumors, the trial has been updated to first evaluate the primary endpoint of PFS in patients with p53 wild-type PMMR tumors or p53 wild-type DMMR tumors, but medically ineligible to receive a checkpoint inhibitor. If positive, PFS will then be evaluated in all patients with p53 wild-type tumors. As discussed previously, the long-term follow-up data from our Phase III SIENDO trial indicated that women in the exploratory subgroup with p53 wild-type endometrial cancer and PMMR tumors, roughly half of all patients experienced a progression-free survival with selinexor as a maintenance therapy following chemotherapy, which exceeds the overall survival that checkpoint inhibitors have demonstrated in the same population.

Let's review some of our long-term follow-up data from our last Phase III trial in endometrial cancer. Slide 16 shows a very encouraging signal in the p53 wild-type subgroup with a hazard ratio of 0.44 and a median PFS benefit of 28.4 months, largely due to the early separation of the curves. These data have only strengthened with time and suggest a similar trend may be observed in our ongoing Phase III trial. These results were even more impressive in the subgroup of patients with p53 wild-type PMMR tumors.

As shown on Slide 17, the long-term follow-up data from this prespecified exploratory subgroup showed a hazard ratio of 0.36 and a median PFS benefit of 39.5 months. Similar to the broader p53 wild-type subgroup, the PFS benefit has only improved with increased follow-up. Slide 18 shows the safety profile at the time of the long-term follow-up, which is something that we will expect to improve when we report data from our ongoing Phase III trial. As you look at these data, keep in mind that SIENDO was evaluating 80 milligrams of selinexor once weekly. And while antiemetics were used at time, the mandated use of dual antiemetics during the first two cycles of therapy was not part of the clinical trial protocol. This is a key difference when you think about the design of our current Phase III, where we are using a lower dose of selinexor at 60 milligrams once weekly and dual antiemetics are mandated during the first two cycles of therapy.

That takes us to Slide 19, which contains the trial design of our Phase III XPORT-EC-042 trial, where selinexor 60 milligrams is being evaluated as a maintenance therapy in patients with p53 wild-type endometrial cancer. The primary endpoint for the trial is progression-free survival as assessed by the investigator. As I mentioned earlier, event accrual is consistent with our projections, and we remain on track to share top line data in mid-2026. I am incredibly excited by the opportunity presented by both of these Phase III trials to establish new standards of care in two areas of high unmet need.

I will now turn the call to Sohanya.

Thank you, Reshma. As shown on Slide 21, our commercial organization executed well in 2025 within the highly competitive multiple myeloma market. XPOVIO net product revenue grew to $32.1 million in the fourth quarter of 2025 and $114.9 million for full year 2025. We expect to continue to deliver revenue growth this year and are guiding towards $115 million to $130 million of XPOVIO net product revenue in 2026. Demand for XPOVIO was consistent year-over-year in 2025 with the community setting continuing to drive approximately 60% of total U.S. sales. XPOVIO continues to be positioned in both the community and academic settings as a flexible therapy with a differentiated mechanism of action, oral convenient option. Additionally, given the emergence of new T-cell engaging therapies, and our growing body of evidence around the role of selinexor in potentially preserving the T cell environment, XPOVIO continues to be utilized in the peri T-cell engaging therapy setting.

Let's turn to Slide 23. As we work to expand beyond multiple myeloma, let's now focus on myelofibrosis, where selinexor has the potential to play a very different role where the patient populations, competitive dynamics, the dose of selinexor and potential impact on patients are fundamentally different. This is why our commercial opportunity in myelofibrosis is so much greater. Taking a closer look at dosing and patient population differences between the two diseases, it's important to recognize that the side effect profile often associated with XPOVIO stems largely from its use at higher doses in multiple myeloma following our initial approval. Those historical concerns don't accurately reflect how selinexor is expected to be used at a lower dose with dual antiemetics in frontline myelofibrosis if approved. The other fundamental difference between the two diseases is the unmet need and competitive landscape. In myelofibrosis, the only treatment options that patients currently have are JAK inhibitors with ruxolitinib monotherapy being the standard of care for the past 15 years and only about 1/3 of patients that receive ruxolitinib achieved a spleen volume reduction of 35% or more with 2/3 of patients not adequately responding. As Reshma outlined, our data highlights our opportunity to meaningfully improve patient outcomes by increasing the proportion of patients that achieve rapid, deep and durable spleen volume reduction as well as symptom improvement and lower rates of grade 3+ anemia, while also potentially modifying the underlying disease.

Slide 24 provides an overview of our opportunity to be the new market leader with the first ever frontline combination therapy as we combine with the current market leader to offer better outcomes for patients. As you look at the overall prevalent market, there are 20,000 patients living with myelofibrosis in the U.S., which represents a multibillion-dollar marketplace with approximately 6,000 newly diagnosed patients each year. Our commercial efforts will focus on the approximately 4,000 newly diagnosed patients with intermediate to high-risk myelofibrosis that have a platelet count above 100,000. Based on the market research that we have conducted, 75% of physicians expressed intent in treating patients with a combination therapy. For duration, we're assuming that we can improve upon the 13-month real-world duration of treatment for ruxolitinib. Taking all of this into account, we believe that our peak revenue opportunity may approach $1 billion annually in the U.S. alone.

Turning to Slide 25. We have the capabilities in sales, market access, marketing and medical affairs to support a launch in myelofibrosis. The team that we have assembled has deep experience in hematological oncology and rare disease launches. This group, plus the robust teams that support them will allow us to launch rapidly. Our current sales organization has deep relationships and experience with accounts that will be key to our launch.

As outlined on Slide 26, 70% of myelofibrosis patients are treated in the community setting. The majority of these patients are treated at five large community networks such as U.S. Oncology and Florida Cancer Specialists and approximately 200 other large community accounts. Academic institutions represent the other 30% of patients and more than 70% of these patients are treated at the top 50 academic institutions. Importantly, a majority of the top 50 academic institutions are participating in SENTRY and/or SENTRY-2. So the clinical care teams that work with myelofibrosis patients in these institutions are already very familiar with selinexor plus ruxolitinib for frontline myelofibrosis patients. As we focus on the concentrated group of accounts outlined on this slide, we believe this will allow us to launch rapidly.

Turning now to Slide 27. We're energized by the opportunity to reshape frontline myelofibrosis treatment by pairing selinexor with the current standard of care. Today, 2/3 of patients still fail to reach SVR35 on ruxolitinib, an unmistakable unmet need. Our selinexor-ruxolitinib combination is a convenient all-oral regimen. Our teams are already engaging the key accounts, positioning us for a fast, efficient launch. Just as importantly, selinexor fits seamlessly into existing workflows, no new testing, no operational hurdles, no disruption to how patients receive care. That simplicity makes adoption far easier with positive data and regulatory approval, we'll be ready to drive rapid meaningful uptake and deliver a therapy with the potential to change the trajectory for patients.

Now I will turn the call over to Lori.

Good morning, everyone, and thank you, Sohanya. Turning to our financials on Slide 29. Total revenue for the fourth quarter of 2025 was $34.1 million, an increase of 11.8% compared to the fourth quarter of 2024. For the year, total revenue was $146.1 million, a slight increase from 2024. U.S. XPOVIO net product revenue for the fourth quarter of 2025 was $32.1 million, an increase of 9.6% compared to the fourth quarter of 2024. For the year, U.S. XPOVIO net product revenue was $114.9 million, an increase of 1.9% from 2024. Gross to net provisions for XPOVIO were 26.9% in the fourth quarter and 31.2% for the calendar year 2025. License and other revenue was $2 million in the fourth quarter and $31.2 million for the full year 2025. Keep in mind, our full year revenue included $15 million of R&D reimbursement from Menarini, and 2025 was the last year we will receive this reimbursement. The remaining $16.2 million in 2025 was related to royalties or milestones earned from our international partners, including Menarini.

Turning to expenses. We remain disciplined in managing operating expenses and allocating capital to our pipeline. This focus continues to translate into solid quarterly and full year financial performance. Research and development expenses for the fourth quarter of 2025 were $27.7 million, a decrease of 17% from the fourth quarter of 2024. For the full year, research and development expenses were $125.6 million, a decrease of 12% from 2024. These decreases were driven largely by lower personnel costs following previously implemented cost reduction initiatives and focused clinical trial expenses as we prioritize capital allocation to our Phase III myelofibrosis and endometrial cancer programs. Selling, general and administrative expenses were $22.8 million for the quarter, a decrease of 16% compared to the fourth quarter of 2024. For the full year, SG&A expenses were $105.2 million, a decrease of 9% from 2024. These decreases primarily reflected the continued benefits of our cost reduction initiatives. Taken together, our loss from operations improved by approximately 43% in the fourth quarter of 2025 compared to the fourth quarter of 2024 and improved 24% in the full year 2025 compared to 2024. Interest expense was $12.6 million in the fourth quarter and $45.8 million for the full year. Both amounts were an increase from the comparable periods in 2024, reflecting higher outstanding debt and higher interest rates as part of our refinancing in October. Other expense was $10 million in the fourth quarter of 2025 compared to $10.1 million of other income in the fourth quarter of 2024. For the full year, other income was $0.2 million compared to $28.4 million of income in the full year 2024. This nonoperational item is primarily driven by reoccurring noncash fair value remeasurements of embedded derivatives and liability classified common stock warrants related to the refinancing transactions completed in the second quarter of 2024 and the fourth quarter of 2025. This, combined with the $62.4 million loss on the extinguishment of debt in 2025 compared to the $44.7 million gain on the extinguishment of debt in 2024, were the primary contributors to the higher net loss and lower earnings per share in 2025 versus 2024. Importantly, both items are noncash and nonoperational in nature. As a result, we reported a net loss of $102.2 million or $5.71 per share on a GAAP basis in the fourth quarter of 2025 and a net loss of $196 million or $17.93 per diluted share for the full year 2025. More than half of the full year loss was driven by below-the-line items, including the loss on extinguishment of debt and interest expense, which are largely noncash in nature. Excluding these items, our underlying operating performance continues to demonstrate meaningful improvement. Finally, we ended the year with $64.1 million in cash, cash equivalents, restricted cash and investments compared to $109.1 million as of December 31, 2024. Based on our current operating plans, our guidance for the full year 2026 is as follows: Total revenue of $130 million to $150 million, consisting of U.S. XPOVIO net product revenue and license royalty and milestone revenue expected to be earned from our partners, primarily Menarini and Antigene. U.S. XPOVIO net product revenue to be in the range of $115 million to $130 million. R&D and SG&A expenses to be in the range of $230 million to $245 million. We expect our existing liquidity, including the revenue we expect to generate from XPOVIO net product sales as well as revenue generated from our license agreements will enable us to fund our current operating plans into the second quarter of this year.

I will now turn the call back to Richard for some final thoughts.

Thank you, Reshma, Sohanya and Lori. As we've discussed today, Karyopharm is well positioned as we approach pivotal data that will inform the next phase of the company. We have a durable commercial foundation in multi myeloma, and we are approaching pivotal data from our late-stage clinical programs that have the potential to significantly expand the role and impact of our oncology franchise, beginning with myelofibrosis in March and extending into endometrial cancer in the middle of this year. We've continued to refine how our programs are developed and executed, applying clinical experience, optimizing how our therapies are used and ensuring our Phase III programs reflect what we believe is the right balance of efficacy and tolerability for the settings we are targeting. From a capital perspective, we remain disciplined and deliberate. We are managing the business with a clear focus on near-term value-creating milestones while maintaining flexibility and optionality as we consider financing and longer-term strategy. Ultimately, our priorities are straightforward: execute well, generate high-quality data and allow these results to define the next phase of the company. We believe this approach best serves patients, investigators and shareholders alike.

We'll now open the call for questions. Operator?

[Operator Instructions] With that, our first question comes from the line of Colleen Kusy with Baird.

Congrats on all the progress. Very excited for the upcoming data, we'll see next month. Maybe we can start there. Obviously, the 60 mg data has -- that we've seen so far has been best-in-class. I think as a lot of people are doing a little bit more work ahead of the readout. There's been some questions coming up from investors just on the 40 mg dose and the data we've seen there. So maybe just can we start there? Just any notable difference in exposure? Anything else you think is driving that difference in activity that you've seen for the 40 mg versus the 60 mg in the Phase I?

Yes. Thanks, Colleen. I think, obviously, our dose is focused on the 60 milligrams and looking at our Phase III trial. But I'll let Reshma maybe just talk to that broadly, but I think people should be very focused on the data, efficacy, safety and tolerability we have with the 60-milligram in combination with rux. Resh?

Yes. Thank you, Colleen and Richard. So it goes back to our Phase I data in which we evaluated both the 60 milligram as well as 40 milligram. And when you look at the efficacy and safety, there's a clear benefit risk in favor of the 60-milligram cohort as compared to the 40 mg, largely due to the fact that efficacy, both from an SVR as well as TSS was maximized in the 60-milligram group as compared to the 40-milligram group. Now when you look at the safety, though, you don't see as stark of a difference, right? Numerically, yes, both the heme and non-hemes are slightly higher with the 60 milligram as compared to 40 mg, but you don't see that substantial dose response as compared to, again, what I described in the efficacy. So in total, again, when you look at the efficacy and safety data, it really is in favor of that 60-milligram group. Then layer in the pharmacokinetic data and there too, exposures are higher with that 60-milligram group as compared to the 40 mg. So really, the totality of the data from the clinical efficacy, safety, clinharm. And then, of course, we've got a multitude of preclinical data, translational PD markers that really suggest that 60 milligrams is the right dose in myelofibrosis. Hence, the reason that we've taken that forward in our Phase III.

Great. That's super helpful. And then obviously, you guys are the first potential combination in frontline MF, which is an exciting opportunity. Novartis, a potential competitor potentially just kind of announced some new plans moving forward in MF. Just kind of curious your thoughts on the read-through there. We think obviously follows your strategy of enrolling highly symptomatic patients, but just curious your thoughts on the read-through there.

Yes. Thanks, Colleen. Yes, I think you highlighted it. Really, it does talk to the importance of having the right patient population in the trial, which I think we've delivered very well. And overall, really the continued investment in myelofibrosis space really talks about the unmet need and the significant value that's seen in the myelofibrosis market. So I think as we look at it, regarding the EU, I think Novartis has indicated they may be moving forward and filing there. That may indicate that the EU regulatory agencies are more focused on SVR35 and potentially showing more regulatory flexibility, less focus on symptoms. But given our top line readout data is going to happen in March, we would look to be filing rapidly with our data, obviously engaging in both the U.S. and globally. And so I think this really gives us the opportunity to establish ourselves pending positive data as the standard of care in frontline myelofibrosis. Given the fact that Novartis has indicated that they would run another trial for the U.S., that trial wouldn't read out for a number of years and gives us a significant amount of time to establish ourselves well and become the standard of care in frontline myelofibrosis.

Awesome. And then one more quick one, if I can. Just if you could expand the comments a little bit about the strategy for eltanexor and other MPNs if MF is positive. Just what the strategy would look like there, and what the IP is, could you remind us for eltanexor versus selinexor?

Yes, I'll take the first question, and then I'll pass over the IP to Richard. But yes, eltanexor is a second-generation XPO1 inhibitor. So just like selinexor, it too is going to inhibit XPO1. It has a couple of differentiating properties, specifically lower IC50s as well as lower penetration through the blood-brain barrier that has opportunities to lower the dose, potentially dose more frequently, also have a better safety profile. Eltanexor has already been evaluated in a Phase I/II trial. So we do have some very encouraging preliminary data, albeit in other tumors outside of the MPNs. I think where we look as the next opportunity is to go beyond MF, right? We know that MF is just one of multiple MPNs. We've got some really interesting preclinical data that also suggests that XPO1 may be relevant in other MPNs, including PV as well as ET. And so that, I think, would be our next opportunity is to expand again beyond MF and start to look at some of these other more chronic diseases like the ones that I just mentioned.

Yes. And from a patent perspective, obviously, it's early days yet with regards to our overall strategy there. But right now, with eltanexor, the patent goes into mid-2034. But as a reminder, we haven't yet applied for any patent term extension or patent term adjustment, which would extend it into 2039. So lots of opportunity for us as we continue to move forward and develop in that space.

And the next question comes from the line of Ioannis Souroutzidis with Cantor.

Appreciate the updates here. Great progress and time lines remain intact. Just had a question with regards to the blinded safety data. And just given that you've been able to provide baseline characteristics on a blinded basis with the trial now fully enrolled, curious if there's been an opportunity to kind of refresh that look, and if there's been any kind of material change there with regards to discontinuation rates or other -- as like the nausea anemia and thrombocytopenia.

Hi, Ioannis, thanks for the question. So no, we haven't updated anything beyond what we've publicly disclosed in the past. So what we've said in the past is the baseline demographics is disclosed in the ASH abstract, which included approximately 320 patients, was very consistent with our expectations for a population to be enrolled in a frontline myelofibrosis. With that said, though, we did have an opportunity to update the TSS in approximately 350 patients, again, something that I've commented before in the past. And that TSS evolution, that baseline TSS evolution without fatigue is, again, really nice. It's approximately 22.5, potentially could be the highest baseline TSS, which is something that we were actively striving for throughout the clinical trial. In terms of the blinded safety data, no, we haven't done a refresh. We're looking forward to the data next month where we can definitively look at the data across the two arms. Those two, I think, are very encouraging and potentially suggest that patients treated with the combination could have lower grade 3+ anemia. This is again based upon extrapolations relative to historical ruxolitinib data as well as very manageable non-heme toxicities, including the GI toxicities in nausea as well as [Audio gap]

Elaborate there, what is kind of the general protocol, and if there's any kind of high-level view that you can provide with regards to rux dosing, and how in line it is with the label?

Absolutely. So the seli dose can be reduced. So it can go from 60 mg to 40 meningitis to 20 mg. And then yes, of course, if the AEs persist, it can be discontinued. Those dose modification guidelines are well specified within the protocol. The ruxolitinib dose modifications are really based upon the country's local label, right, which, by and large, are very consistent with the U.S. PI. So the starting dose is going to be based upon the patient's baseline platelet count and then any kind of dose modifications, including reductions, interruptions and even discontinuations, again, should be followed per the USPI. So we're very strict about that in our protocol. Now given the fact that this is a combination therapy, what we suggest to our investigators is to modify based upon what I call the flavor of the AEs. So if a patient first experiences a hematologic toxicity, for example, anemia, thrombocytopenia, very well described for ruxolitinib, we guide them to modify the ruxolitinib dose first, again, per the USPI. If they experience a non-heme toxicity, then we suggest that they modify selinexor dose. So we try to keep it very easy for the investigators just based upon the kind of AE that the patient experiences.

Got it. Okay. And one last quick one. Just with regards to SENTRY-2, could you comment there a little bit on just kind of the strategic thought there and kind of the utility of that data, and what you're hoping to show, and how that might tie in with future label expansions within MF?

Yes, I can talk to that. Yes. I mean overall, obviously, our registration-enabling trial is our Phase III frontline combination with ruxolitinib. But really importantly, when we look at the overall efficacy and I think the activity of selinexor, we've seen in a number of our trials really strong monotherapy data. And also, we do know that it's important to be able to expand beyond ruxolitinib in the future, potentially with selinexor to really play a foundational role across myelofibrosis first and potentially across other MPNs. So our Phase II is really one where we're letting patients start at platelets greater than 50,000, so 50,000 and above as we just modified the protocol. And within that, it's starting with selinexor as a treatment monotherapy. And then you have the opportunity for patients to be able to add on other JAK inhibitors depending on the need. So they may not need to. But if they do need to, they can add on their JAK inhibitors. And we do know that selinexor is a drug that's able to be partnered with many other drugs. So I think pending positive data with our Phase III frontline combination with rux, our view would be to read out the Phase II data and look at that as an opportunity to really expand from a guideline perspective, enable physicians much more flexibility and the opportunity to establish selinexor in combination with multiple JAK inhibitors and/or selinexor to be able to treat patients potentially as a monotherapy. But again, that's an opportunity to expand in the future and an area that I think we're quite excited about and is moving forward well. Anything you would add on to that, Reshma?

No, nothing. That's great.

And the next question comes from the line of Brian Abrahams with RBC Capital Markets.

Look forward to an exciting next couple of months. You reported the Phase III baseline characteristics at the ASH conference in an abstract. And it looks like if you look at the risk status, if you look at spleen volume, the baseline -- the patient population looks somewhat milder than what was in the Phase I/II. And then while the -- I think you pointed out that the TSS score is actually substantially higher, there is a pretty wide range, including patients going down to scores as low as 2. So can you maybe talk about what some of those similarities, but also differences might mean with regards to the potential to show as wide a delta in the Phase III?

Sure. Thanks, Brian. So you are correct, right? Sort of like if you compare the patient populations in the Phase III, Phase I, I would agree, it is a little bit milder. I think the other aspect that is different is even the baseline hemoglobin, right? So it was approximately 10 grams. The median was 10 grams in the Phase I. It's approximately 11 grams in the Phase III. So I think by and large, right, yes, this potentially could be a less sick patient population. With that said, though, I don't think it's going to have any impact on the efficacy, right? And I say that because even when we look at the subgroups from our Phase I from an SVR perspective, there really is a very nice consistency, including across all of the dips from INT 1 all the way up until high risk and even by hemoglobin. So I think it really suggests that there can be meaningful benefit across all of the different subsets of patient populations to, of course, people that are going to have far more difficult-to-treat disease versus those that are -- have a little bit more mild disease, yes.

No, that's really helpful. And then do you have any sort of updated feedback from either KOLs or from regulators on -- that's maybe shaped your view on what might be a reasonable threshold for symptomatic improvement just in the case that you show statistically significant spleen reductions, but don't quite show -- get to statistical significance on symptoms. What would be the bar to still potentially proceed with the filing, assuming there aren't any safety surprises or anything like that?

Sure. So our goal is to really show statistical significance for both SVR as well as absolute TSS, right? Those are the bars that are included in our statistical analysis plan as well as discussed with the FDA. We think that profile, again, statistically significant improvement, both for the SVR and TSS in the context of a very manageable safety profile is really the ideal profile for a new combination therapy, the only combination therapy that would be available for these patients with MF. Take it one step further. When we talk to our KOLs, right, they do emphasize that SVR is going to be their primary treatment driver, largely because there are multiple data sets, multiple meta analysis that really suggests that the deeper, the more rapid, the more durable the SVR that can be achieved, the more that it may correlate with long-term outcomes. So they're very focused on that spleen volume reduction. And while they say, yes, symptoms are important, really for them, they just want to see some kind of benefit above and beyond ruxolitinib. So again, I think even if you have that outcome in which SVR is positive, TSS is numerically improved, that is a profile that they would be very happy with and clearly would even advocate for the NCCN guidelines to adopt. So I think that's very encouraging from their perspective and very important voice, right, in the MF space. From a regulatory perspective, they've never commented, right? They've never commented on what that minimum delta would be. I think, again, I think statistical significance is what we're striving to achieve here.

Got it. That's super helpful. And then maybe one more if I could squeeze it in. Can you just remind us on the regularity of, I guess, DSMB or interim safety looks here and whether or not you would expect that would pick up on any imbalances in the transformation?

Yes. So the DSMB does evaluate the data on a regular basis, approximately every 4 to 6 months. It's something that we do across all of our clinical trials. And yes, they would. They get the totality of the safety data from all AEs, Grade 3, 4 SAEs and of course, transformations as well. So far, they haven't mentioned anything. And as I mentioned previously, even with the futility analysis, right, they did suggest that the study continues without modification.

And the next question comes from the line of Maury Raycroft with Jefferies.

Maybe as a follow-up to one of the earlier ones, for the 61 patients in the futility analysis group in SENTRY, what can you say about dose reductions you saw for selinexor and/or ruxolitinib? And even though you've been clear that we shouldn't rely too much on extrapolating based on these patients, can you contextualize how the dose reductions compared to your Phase I, and how the rux dose reductions could compare to other myelofibrosis Phase III studies?

Sure. Great question, Maurice. So I haven't commented on the dose reductions from the first 61 patients, specifically for the ruxolitinib largely because, as you know, the starting dose is going to be very variable, again, based upon the patient's baseline platelet count, extrapolating the rux dose intensity and the dose reductions in the context of a blinded safety data, where that starting dose is very variable, again, can be very challenging. And so again, it's not meaningful output at this time. Let's just wait until the top line data. Now with that said, though, we have mentioned that the selinexor dose intensity, whether it's selinexor or placebo does look really good. And amongst the 61 patients, the mean relative dose intensity was greater than 95%.

Got it. Okay. That's helpful. And maybe just two quick clarification questions. For the first 61 -- for the 61 patients, is there anything more you could say about where those patients were recruited from, which regions they came from?

Sure. They were globally. So they were -- they're globally recruited primarily North America as well as EU and probably a few more. I don't have the exact numbers, I will say, but I anticipate more patients coming from North America just because those were the first sites activated. But yes, just assume that this is going to be a population largely recruited again within Europe as well as North America.

Got it. Okay. And for -- knowing that the data is going to be in March is really helpful. Just wondering if you're seeing whether it's going to be earlier or later in March?

I think guiding the March, it is pretty strong. So we feel very good about that and continues to progress well, and we'll read the data out in March.

And your next question comes from the line of Jonathan Chang with Leerink Partners.

Just one. What are the key reasons for confidence in hitting on the TSS endpoint of the SENTRY study?

Sure, Jonathan. Great question. I think there's multiple different aspects that give us confidence. So I go back to the studies -- the Phase I study's original secondary endpoint was TSS50, right? And when we have the opportunity to look at TSS50 amongst that ITT, numbers were quite strong at approximately 59% relative to historical ruxolitinib data that have read out sort of in the mid-40s. So a really nice improvement there. We then looked at absolute TSS or the observed mean change at week 24 relative to baseline. These are going to be the actual values, not estimated, which is what is going to be coming from the Phase III. Those numbers, too, very strong with an 18.5 improvement, substantially better than what's again been described for ruxolitinib, where the improvement was only 11 to 14 points. So from a clinical perspective, you really have evidence of meaningful TSS improvement from both TSS50 as well as absolute TSS. Now the other part that really should be taken into consideration is the cytokine data, right? So I mentioned that because we know that the pro-inflammatory cytokines is what really drives the symptom development in the first place. And when we look at cytokine levels, on treatment relative to baseline, regardless of whether you look at it from the Phase I population, which was JAK-naive treated with the combination or even from our monotherapy study in which we evaluated selinexor as a monotherapy in that previously treated population, you really see very meaningful and rapid reductions in those cytokine levels as early as week 4. So the fact that you see that cytokine decrease, again, explains why you also see that associated clinical benefit. So I think like really those are going to be the key reasons why I have that confidence. I think the other aspects that we can't lose sight on is the FDA gave us the opportunity to change out the endpoint, right, from TSS15, which we know is very crude measurement of symptom benefit to a much more sensitive methodology in absolute TSS, which is, again, going to look at that mean change over time. And then the last part that I'll just emphasize is that we are looking at TSS without fatigue. And the reason we are doing that is, again, there's precedence with evaluating without fatigue. It was established by both ruxolitinib as well as fedratinib, but we also know that fatigue is just a very, very difficult domain to meaningfully evaluate. So I think, again, being able to incorporate absolute TSS without fatigue as the key measure of improving symptoms is really a significant opportunity to be able to show that significant improvement relative to rux alone.

And then, Jonathan, I'll just close that because I think as Reshma has talked to, we feel very good about that. And as we've said, feel very pleased with the patient population we've enrolled, right? It's consistent with the population we had planned. And as we set our targets to ensure we had a meaningful baseline TSS, we've delivered on that with the TSS scores that appear to be higher than MANIFEST and substantially higher than TRANSFORM, which again is what we intended to do. So I think we've set up the trial as well as we could and are extremely excited about reading this out next month in March.

And we have no further questions at this time. I would like to turn it back to Richard Poulson for closing remarks.

Thank you, operator, and thank you, everyone, again, for your time and your continued interest in Karyopharm. As you just heard, we are extremely excited to be reading out our top line Phase III data in the frontline myelofibrosis with selinexor in combination with rux, and we look forward to engaging with you in March as we read that out. Thank you for joining us today.

Thank you. Ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect.

Good morning. My name is Ludy, and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics Third Quarter 2025 Financial Results Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request.

I would now like to turn the call over to Brendan Strong, Senior Vice President, Investor Relations and Corporate Communications. Please go ahead.

Good morning, and thank you all for joining us on today's conference call to discuss Karyopharm's third quarter 2025 financial results and recent company progress. We issued a press release this morning detailing our financial results for the third quarter of 2025. This release, along with a slide presentation that we will reference during our call today, is available on our website.

For today's call, as seen on Slide 2, I'm joined by Richard, Reshma, Sohanya, and Lori, who will provide an update on our results for the third quarter of 2025 and discuss recent clinical developments.

Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995, as outlined on Slide 3. 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 Factors section of our most recent Form 10-Q or 10-K on file with the SEC and in other filings that we may make with the SEC in the future.

Any forward-looking statements represent our views as of today only. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any later date. I'll now turn the call over to Richard. Please turn to Slide 4.

Thank you, Brendan, and thank you all for joining us today for Karyopharm's Q3 2025 Earnings Call. As we turn to Slide 5, I'm pleased to share that this has been a very productive quarter for Karyopharm, one defined by meaningful clinical progress and strengthened financial flexibility that together set the stage for our next chapter of growth.

In Q3, we completed enrollment in our Phase III SENTRY trial in frontline myelofibrosis, marking a pivotal moment for Karyopharm. SENTRY represents a significant opportunity to redefine the standard of care for patients with myelofibrosis through the combination of selinexor plus ruxolitinib as a potential all-oral treatment option. With top-line results expected in March, we believe this trial could establish a new paradigm for how myelofibrosis is treated and further validate the relevance of XPO1 inhibition in hematological malignancies.

The power of XPO1 inhibition is multidimensional. It simultaneously targets multiple pathways that enable malignant cell growth and proliferation. Targeting these relevant pathways concurrently overcomes the limitations of targeted therapies, such as ruxolitinib, a JAK inhibitor that mostly delivers symptomatic benefits that many consider palliative. This unique and potentially foundational mechanism could establish XPO1 inhibition as a key mechanism in myelofibrosis with further potential across the broader MPN landscape.

In October, we made significant progress in strengthening our financial foundation. Through comprehensive refinancing and capital restructuring, we secured approximately $100 million of financial flexibility and additional capital, extending our cash runway into the second quarter of 2026.

Turning to our financial performance. Our profitable multi myeloma commercial organization provides a solid foundation on which to build. In the third quarter, we delivered total revenue of $44 million, an increase of 13% year-over-year, and U.S. net product revenue grew 8.5%, reaching $32 million. This growth reflects the continued strength of XPOVIO in multiple myeloma and the disciplined execution of our commercial and operational teams. Importantly, we delivered this level of growth while continuing to reduce expenses.

As we look ahead, our recent financing enables us to continue with focus and conviction around 3 core priorities. First, advancing our late-stage clinical programs, SENTRY and EC-042, which we believe have the potential to be truly transformative for patients and the company. Second, driving continued growth across our XPOVIO franchise; and third, maintaining financial discipline as we execute on our strategy and position Karyopharm for sustained success.

Taken together, these underscore the momentum and transformation underway at Karyopharm. We are executing with clarity and purpose as we advance our mission to pioneer innovative cancer therapies that can meaningfully improve the lives of patients and deliver long-term value for all our stakeholders. As our next major milestone is the top-line myelofibrosis data from SENTRY, we will focus much of today's discussion on the science supporting this program and the significant commercial opportunity ahead. Now I'd like to turn the call over to Reshma to review our science.

Thank you, Richard. There is a substantial need to develop new treatment options for patients with myelofibrosis. As shown on Slide 7, this disease is heterogeneous and is defined by 4 hallmarks or defining features. These hallmarks include an enlarged spleen, abnormal blood cell production, bone marrow fibrosis, and constitutional symptoms. Furthermore, the median overall survival for intermediate to high-risk myelofibrosis patients is only 4 to 5 years.

Lastly, JAK inhibitors are the only approved therapy for myelofibrosis. And while they may decrease symptom burden and lead to very modest spleen reduction, relevant JAK inhibitors, including ruxolitinib, the standard of care in frontline myelofibrosis, do not target all of the relevant pathways implicated in myelofibrosis, including NF-kappa beta, p53, and fibrosis-inducing pathways. As a result, treatment of frontline myelofibrosis patients with monotherapy JAK inhibitors do not adequately address the relevant drivers of pathogenesis in myelofibrosis.

On Slide 8, our confidence in selinexor's potential in myelofibrosis is based upon a growing body of preclinical, nonclinical, translational and clinical efficacy and safety data sets. These data suggest XPO1 inhibition is a key mechanism that may facilitate potential synergy with ruxolitinib and other drugs relevant in myelofibrosis. This multi-targeted approach enables treatment of the underlying mechanisms that lead to myelofibrosis, and we believe may lead to meaningful efficacy across the key treatment drivers as well as a generally safe and manageable side effect profile. This is supported by our blinded safety data, which I will take you through in a few slides as well as our substantial safety database with selinexor, where approximately 30,000 patients have been treated in clinical trials and in the post-market setting. This underscores our confidence in the ongoing Phase III SENTRY trial.

As seen on Slide 9, while JAK inhibitors directly inhibit the JAK-STAT pathways, multiple other pathways downstream of JAK-STAT support malignant clone proliferation and survival, bone marrow fibrosis, cytokine storms and proliferation of abnormal megakaryocytes. These pathways include NF-kappa beta, PI3-kinase, AKT/mTOR, and TGF-β, a multifaceted approach with dual XPO1 and JAK inhibition simultaneously target upstream and downstream effectors of the JAK-STAT pathway, ultimately enabling apoptosis or cell death of the malignant clones.

Let's now focus on the key treatment drivers in myelofibrosis as seen on Slide 10, spleen reduction, symptom improvement and lower rates of Grade 3+ anemia. First, spleen volume reduction. As a reminder, note that only approximately 1/3 of patients achieved a spleen volume reduction of greater than 35% with ruxolitinib alone. In contrast, our Phase I data suggests that the combination could more than double the SVR35 rate at 79%. A substantial proportion of patients achieving an SVR35 is coupled with very encouraging durability, specifically a 100% duration of response as of the data cutoff.

Second is symptom improvement. Data from this trial also showed an average 18.5-point improvement in absolute TSS at week 24, which suggests this combination could provide a meaningful improvement over the 11 to 14 points achieved by patients on ruxolitinib as observed in the Phase III MANIFEST-2 and TRANSFOR-1 trials. Third is lower rates of Grade 3+ anemia. The data that we presented in June at EHA from our Phase II 035 monotherapy trial showed lower rates of all grade and Grade 3+ anemia in myelofibrosis patients previously treated with JAK inhibitor therapies. Blinded safety data from the ongoing Phase III SENTRY study suggests a similar trend.

Meaningful improvement of these treatment drivers requires disease modification or the elimination of the underlying mechanisms leading to development of an enlarged spleen constitutional symptoms and worsening cytopenias. Data observed from selinexor monotherapy studies in a pretreated myelofibrosis population as well as our Phase I combination data in JAK inhibitor-naive myelofibrosis suggest meaningful reductions in key cytokines that are critical to myelofibrosis pathogenesis, symptom development and anemia as well as improvements in bone marrow fibrosis, increases in erythroid progenitors and mutational burden.

Turning to Slide 11. We are super excited that our Phase III SENTRY trial has completed enrollment with top line data expected in March 2026. The co-primary endpoints in SENTRY are SVR35 and absolute TSS, which are tested sequentially. As we have discussed before, it is important to reemphasize based upon learnings from other myelofibrosis trials that we believe we have optimized SENTRY for success.

In alignment with the FDA, we changed the co-primary endpoint of TSS50 to absolute TSS and exclude the fatigue domain in the primary analysis of absolute TSS due to the ambiguity of patients' assessment of their fatigue. We are certainly not the first to exclude fatigue. In fact, both the pivotal trials that led to ruxolitinib and fedratinib approvals also excluded fatigue in their TSS50 analyses. Encouragingly, amongst approximately 350 patients enrolled in SENTRY, the mean baseline TSS, excluding fatigue is approximately 22.5. Note that the 21.9 that you will see in our ASH abstract today was preliminary data and before enrollment was completed. Our mean baseline of approximately 22.5 compares favorably to other comparable trials.

Importantly, as you compare our number to other trials, please remember other Phase III trials may include fatigue in their baseline scores. How does the fatigue domain affect the score? Given that in the Phase III MANIFEST-2 trial, the average fatigue score at baseline was approximately 5 points. Our baseline score, if we included fatigue, would be approximately 5 points higher, which gives us confidence in the patient population that we have enrolled.

Shifting back to our trial design, absolute TSS in the Phase III SENTRY trial will be analyzed using the mixed models repeated measure approach, or MMRM, which is viewed as a more sensitive and potentially more robust method by which to analyze absolute TSS. Now let's review the encouraging preliminary blinded aggregate safety data from this trial. As these are preliminary and blinded data, please keep in mind that this data may not be reflective of the trial's actual top line results. The data on Slide 12 are from the first 61 patients that enrolled in the Phase III portion of SENTRY that have now been followed for a median of over 12 months. These patients were included in the successfully passed futility analysis conducted in the beginning of the year.

We have continued to track the safety events over time and took a snapshot of the blinded safety data from these 61 patients on July 1, 2025, which continue to look favorable. The most common TEAEs are provided for the first 61 patients randomized to the trial and include patients randomized to both the combination of selinexor plus ruxolitinib or ruxolitinib arms in a 2:1 ratio. Because these are blinded data, we do not know the rates by each arm.

In an effort to improve comparability, we then took our analysis one step further. Knowing that the 61 patients were randomized 2:1, we used the historical data on ruxolitinib to extrapolate the preliminary safety data for the approximately 40 patients that received the combination, which is shown in the orange boxes in the middle of the slide. The number that I am most optimistic by is the extrapolated rate of Grade 3/4 anemia. At approximately 26%, the extrapolated rate of Grade 3/4 anemia for the combination is meaningfully lower than the 37% historically reported for ruxolitinib. Grade 3/4 thrombocytopenia rates are relatively similar, with 9% suggested for the combination treated patients compared with the approximately 6% reported for ruxolitinib alone.

Finally, the extrapolated rate of treatment-emergent adverse events leading to discontinuation is only approximately 5% to 7% for the combination, lower than the 6% to 11% range that has been historically reported from ruxolitinib, which we view as an encouraging observation. We are very encouraged about these data and what it could mean for patients if we see something similar in the top-line results in the Phase III SENTRY trial. Specifically, it could suggest a combination therapy that has a safety profile similar, if not potentially better than standard of care ruxolitinib, given that both Grade 3 plus anemia and thrombocytopenia are similar, if not better, than ruxolitinib alone, could suggest decreased blood draws for the patient and reduced monitoring burdens for physicians and health care staff.

As we await our Phase III data, it is informative to review a case study on Slide 13 that shows meaningful efficacy, overall tolerability, and the potential for disease modification. This patient is enrolled in the Phase I combination study of selinexor and ruxolitinib and has been on the study treatment for over 3.5 years. This 81-year-old female was diagnosed with myelofibrosis secondary to polycythemia vera. She initiated treatment with selinexor 60 milligrams in combination with ruxolitinib in March 2022. Her baseline spleen volume was 2,058 cubic centimeters for TSS without fatigue at baseline was 7, and variant allele frequency burden or VAF was 83%, meaning that 83% of her cells had a cancer-driving mutation.

She achieved an SVR35 and TSS50 at week 24 and complete resolution of her symptoms by approximately week 52. Furthermore, her VAF levels decreased to 0, signifying eradication of the cancer-driving mutation. To this day, she still continues on therapy with minimal side effects, with more than 3.5 years on therapy. This patient exemplifies the potential a multi-pathway approach can deliver in a disease as complex as myelofibrosis. XPO1 inhibitors' unique ability to simultaneously target multiple relevant pathways suggest their foundational potential in all patients with MS as well as other myeloproliferative neoplasms. I will now turn the call to Sohanya.

Thank you, Reshma. As shown on Slide 15, our commercial organization executed well this quarter within the highly competitive multiple myeloma market. XPOVIO net product revenue in Q3 grew 8.5% year-over-year to $32 million. Demand for XPOVIO was consistent year-over-year, with the community setting continuing to drive approximately 60% of total U.S. sales. XPOVIO is positioned in both the community and academic settings as a flexible therapy with a differentiated mechanism of action, oral convenient option, and increasingly used in the third line in patients before a T cell therapy or in patients who cannot access these complex therapies. Additionally, it is used in the fourth line plus setting once patients progress on a T cell therapy. Based on our results year-to-date, we are confident in our ability to deliver within our full year guidance range of $110 million to $120 million.

Now turning to myelofibrosis outlined on Slide 17. We are excited to be working towards a potentially transformative commercial launch that we expect will redefine the way that frontline myelofibrosis patients are treated. Our conviction is driven by the high unmet need in myelofibrosis, combined with the fact that there has been no real innovation in the market beyond JAK inhibitors over the past 14 years.

Ruxolitinib has been the standard of care for more than a decade and is being used in the vast majority of intermediate to high-risk patients, even though fewer than 35% of these patients achieve an SVR35. Physicians and patients want to see deep and durable reduction in spleen volume. And as Reshma discussed, the data from our Phase I trial highlights our potential in this area, with selinexor plus ruxolitinib helping more than twice as many patients achieving a spleen volume reduction of 35% or more. In addition, many patients experience constitutional symptoms and anemia, both of which negatively affect patient quality of life. And these are areas where we believe the selinexor plus ruxolitinib combination may make a meaningful difference. So, this presents us with a significant opportunity to improve upon the standard of care in combination with the market leader.

Slide 18 provides an overview of our potential commercial opportunity. We have the opportunity to redefine the standard of care, expand the market, and lead with a new frontline combination therapy that may offer very differentiated results for patients. This isn't an incremental change in the treatment landscape. It is a potentially transformational change for patients. Here are some figures that help inform our view that selinexor's peak revenue opportunity could be up to approximately $1 billion annually in the U.S. If you look at the overall prevalent market, there are 20,000 patients living with myelofibrosis in the U.S., which represents a multibillion-dollar marketplace.

As we look at the opportunity for patients that can benefit from selinexor plus ruxolitinib, there are approximately 4,000 newly diagnosed patients each year in the U.S. with intermediate to high-risk myelofibrosis that have a platelet count above 100,000. This is our target market. Most of these patients receive ruxolitinib today. 75% of U.S. physicians showed an intent to treat with combination therapy based on third-party market research. There is a clear appetite among physicians to evolve from a monotherapy to a combination treatment approach.

Finally, the real-world duration of therapy for ruxolitinib is approximately 13 months. Our assumption is that the combination of selinexor plus ruxolitinib would be used for at least 13 months. Looking at all of this together, you will see that our peak revenue opportunity may approach $1 billion annually in the U.S. alone. As we prepare for potential commercialization, we have spent the past year speaking with leading KOLs at academic medical centers as well as community-based physicians and have received overwhelming support for the need to improve upon the current standard of care. Our position in the market, if approved, will be very clear and focused. If you're going to prescribe ruxolitinib to a patient with newly diagnosed myelofibrosis, prescribe selinexor plus ruxolitinib instead.

Finally, our existing commercial capabilities are highly synergistic in myelofibrosis and prepare us for a rapid and successful launch, as shown on Slide 19. We have market access, a patient support hub, scientific and medical affairs, marketing, and a sales team with deep relationships with potential prescribers. In the academic setting, we already call on all the key institutions. In the community setting where a majority of newly diagnosed myelofibrosis patients are treated, there's approximately 80% overlap with our existing customer base. Pending positive data and subsequent regulatory approval, our commercial team will be ready to drive rapid and strong uptake as we bring this transformative therapy to patients. Now I'll turn the call over to Lori.

Good morning, everyone, and thank you, Sohanya. Turning to our financials. Since we issued a press release earlier today with the full financial results, I will focus on the highlights and reviewing our guidance for 2025 on Slide 21.

Total revenue for the third quarter of 2025 was $44 million, an increase of 13.4% compared to $38.8 million in the third quarter of 2024. U.S. XPOVIO net product revenue for the third quarter of 2025 was $32 million, an increase of 8.5% compared to $29.5 million in the third quarter of 2024. Gross to net provisions for XPOVIO were 27% in the third quarter, consistent with the second quarter of 2025 and down from 31% in the third quarter of 2024. We expect gross to net provisions to remain relatively consistent with the third quarter levels in the fourth quarter of 2025.

License and other revenue was $12 million in the third quarter, up nearly 30% from third quarter of 2024, primarily driven by higher milestone revenue from our partner, Menarini. This included the final amount of revenue that we will record from Menarini related to the $15 million of annual R&D reimbursement. In the fourth quarter, our license and other revenue will primarily be royalty revenue since we do not expect to achieve any significant additional milestones in Q4 2025.

Turning to expenses. We continue to be very disciplined in managing our operating expenses and prioritizing our pipeline investments, including additional cost reduction initiatives that we implemented in the third quarter. Research and development expenses for the third quarter of 2025 were $30.5 million, down 16% compared to $36.1 million in the third quarter of 2024. The decrease was primarily driven by lower clinical trial and related costs for selinexor in multiple myeloma, reflecting the reduced scope of our Phase III trial, as well as lower personnel and stock-based compensation expenses resulting from previously implemented cost reduction initiatives.

Selling, general, and administrative expenses were $26.6 million for the quarter, down 4% compared to $27.6 million in the third quarter of 2024. The decrease was primarily attributable to the continued realization of our cost reduction initiatives. Taken together, our loss from operations improved by approximately 42% in the third quarter of 2025 compared to the third quarter of 2024. Interest expense was $11 million in the third quarter of 2025 compared to $11.4 million in the third quarter of 2024.

Other expense was $7.4 million in the third quarter of 2025 compared to $3.8 million of other income in the third quarter 2024. This nonoperational item is primarily driven by reoccurring noncash fair value remeasurements of embedded derivatives and liability classified common stock warrants related to the refinancing transactions completed in the second quarter of 2024. We reported a net loss of $33.1 million or $3.82 per share on a GAAP basis. More than half of this loss is driven by below-the-line items, including interest expense, which is almost entirely noncash at this point and the $7.4 million of noncash mark-to-market adjustments that I just mentioned. Excluding these items, our underlying operating performance continues to show meaningful improvement.

Finally, prior to the receipt of approximately $36 million of gross proceeds from the financing transactions that we announced in October, we ended the third quarter with $46.2 million in cash, cash equivalents, restricted cash and investments compared to $109.1 million as of December 31, 2024.

On a pro forma basis, after deducting transaction-related expenses, we would have had approximately $78 million in cash. Importantly, from a cash perspective, our interest payments do not start again until June 2026, and our royalty payments do not begin again until the third quarter of 2026. Based on our current operating plans, our guidance for the full year 2025 is as follows: total revenue of $140 million to $155 million, consisting of U.S. XPOVIO net product revenue and license, royalty and milestone revenue expected to be earned from our partners, primarily Menarini and Antengene; U.S. XPOVIO net product revenue to be in the range of $110 million to $120 million.

We are lowering our range of R&D and SG&A expenses to $235 million to $245 million, down from $240 million to $250 million. With the financing that we announced last month, we expect our existing liquidity, including the revenue we expect to generate from XPOVIO net product sales as well as revenue generated from our license agreements will be sufficient to fund our planned operations into the second quarter of 2026.

I will now turn the call back to Richard for some final thoughts.

Thank you, Lori. Before we close on Slide 23, I want to emphasize how far Karyopharm has come and where we're heading. This quarter reflects clear execution against our priorities and the progress we've made has positioned us to enter 2026 with confidence. With SENTRY enrollment complete, a strong commercial foundation and a reinforced balance sheet, we are focused squarely on what matters most, delivering 2 potentially transformative Phase III readouts that could reshape the future for patients with myelofibrosis and endometrial cancer.

Our team's dedication, scientific rigor and focus on patients continue to drive everything we do. We believe the opportunities ahead are significant, and we are executing with purpose and discipline to realize them.

Thank you for your continued support and confidence in Karyopharm. We look forward to updating you as we advance towards these important milestones. I would now like to ask the operator to open the call up to the Q&A portion of today's call. Operator?

[Operator Instructions] Our first question comes from the line of Peter Lawson with Barclays.

I guess first is just around the MF data that we're seeing March '26. If you could just kind of walk through what we should see if it's like SVR PFS and OS trends if that's going to be staged across other medical meetings in 2026. And then a follow-up question would just be around the size of the sales force. I know you've kind of talked about 80% overlap, but interested to see how many you would add or dedicate to MF and also the kind of the ex-U.S. strategy.

Thanks, Peter. So maybe the first part, Peter, are you asking about when we plan to share the data post March? It wasn't quite clear the question in the first part.

Just the level of detail we'd see in -- for MF, whether it's SVR, TSS, OS trends and then -- or if it's kind of spread across the year kind of thing.

Sure. Yes, I'll turn to Reshma for that first part, and then I'll turn to Sohanya for the second part with regards to our commercial capabilities.

Yes. Thanks, Peter. This is Reshma. So, the top line results, you're correct, expected more to 2026. I anticipate at this point, really just providing again sort of those top line details. So, you're correct, the primary endpoints of SVR35 at week 24, absolute TSS, potentially, right, some other secondary endpoints, including hemoglobin and/or disease modification. And then, of course, we'll touch upon safety. But we'll get granular as we get closer to that milestone.

Peter, as far as the sales force, as you mentioned, very strong overlap, particularly in the community setting, of course, with our current organization. And in the academic setting, we already call on those accounts. So, we expect really minimal additions to our commercial structure. Our capabilities are already highly synergistic. As far as ex-U.S., we'll continue to work with our ex-U.S. partners to drive launches in each of the countries and additional royalty and milestone revenues globally.

And your next question comes from the line of Ted Tenthoff with Piper Sandler.

Congrats on all the progress both on the clinical side and financial side. Can you remind us, are there any milestones associated with data or warrants or things like that for the recent financial restructuring that could extend that capital beyond the second quarter? And are there any geographies where you don't currently have distributors in place for myelofibrosis?

Thanks, Ted. Maybe on the first part, are you just asking about milestones from a financing perspective with regards to positive data? Or maybe just clarify that part of the question.

Yes. So, milestones were there any warrants or anything like that, that could trigger to extend the June or the 2Q deadline. I was trying to remember back.

From a pure warrant or financing perspective, no specific triggers with regards to positive MF data. Obviously, pending positive data, we think that will be a very, very strong inflection and value point for us. And on the second part with regards to our partnerships globally, no, we have well-established partners for selinexor globally. And as Sohanya mentioned, I think they're very excited and engaged and looking forward to positive data and moving forward with a registration strategy and commercialization strategy globally, which we would be able to do. With the exception, one market we still don't have partnered is Japan. That would be the only additional market we would look to partner with in the future moving forward.

And your next question comes from the line of Colleen Kusy with Baird.

Congrats on all the progress. Hopeful for the baseline TSS number, 22.5%, I think you said, Reshma, quite a lot higher than what you had enrolled in the Phase I, I believe. And based on the data that you had at AACR in 2023, it actually looks like fairly similar response for TSS above and below 20, which could just be due to the small end, but just curious how you would expect that might impact the read-through from Phase I to the pivotal Phase III? And then I'll have a follow-up after.

Yes. It's a great question, Colleen. I think we're very encouraged by how the baseline TSS is evolving. As you mentioned, 22.5%, approximately 22.5 in almost the full ITT. I think you're right. Sort of the Phase I, it's small. So, we're very encouraged by those numbers. Clearly, it suggests that absolute TSS as well as TSS50 can be achieved with the combination relative to historical ruxolitinib data. I think what we were trying to accomplish in the Phase III was to drive that baseline TSS without fatigue as high as possible. And so again, very encouraged with that 22.5%, especially as I compare it to other contemporary trials in which that 22.5 likely is higher than even those. So, it really suggests that we could see a potentially meaningful improvement for absolute TSS with our combination versus ruxolitinib alone.

That's super helpful. And then in that same AACR update, it looks like there was some variability in response for platelet count above and below 200,000, which again could just be driven by small end. But curious if you have the baseline platelet count and what your kind of thoughts are on the activity based on platelet count.

Yes. We're seeing more than half of the patients with baseline platelet counts above 200 which again is what I would expect. There's nothing biological or mechanistic that would suggest that platelet count is a key variable that would impact the overall SVR35 rate or even the absolute PSS. So again, it's a number we're watching. It's a baseline characteristic that I think is very consistent with other Phase III trials. In general, that variable as well as all of the other variables are in line with what we would expect and again, very encouraged with how this patient population is enrolled and who they represent across the frontline myelofibrosis population.

And your next question comes from the line of Maurice Raycroft with Jefferies.

Congrats on the progress. So, ASH abstracts are coming out pretty soon. Just confirming, it sounds like your Phase III baseline data is going to be at ASH. Can you talk more about what's in the abstract and then what is going to be at the conference?

Yes. Thanks for the question, Maurice. So, the ASH, so it's going to be an abstract only. We're not going to present an additional poster. So, any additional data in the full ITT is going to be presented with the top line results in March of 2026. So, when the data come out in about 20 minutes, really, what you're going to see is just the baseline characteristics amongst 320 patients. So, this is a subset. These were the available patients at the time of the data cutoff. And as I mentioned on my prepared remarks as well as with some of the questions today, just very encouraged with how that patient population has evolved and again, very consistent with what we would expect.

And maybe as a follow-up, for the slightly lower treatment-emergent adverse events leading to discontinuation for the 61 patients in the blinded safety review. Can you comment on whether that rate is mostly in line with what you're seeing for the full study? I guess, any additional perspective there that you could share?

Yes, great question. So, one of the things that I'm very encouraged by is that we've followed these 61 patients and taken a snapshot across their AE summary, including their treatment discontinuation rates as well as the specific AEs as well as a couple of Grade 3 plus AEs. And what I'm encouraged by, again, is that despite whether we look at a 7-month median follow-up or even a 12-month median follow-up, rates, including treatment-emergent discontinuation rates are remarkably stable, right? So, it really suggests that a majority of the events, including discontinuations potentially are occurring early, and we don't continue to see this accumulation as the patients are followed over time. Now what the top line results are going to show, we'll see at the top of the -- at the time that we report the top line results, but again, very encouraged by how the 61 patients are evolving.

Your next question comes from the line of Brian Abrahams with RBC Capital Markets.

Congrats on all the progress. I wanted to drill down a little bit more on some of the market research findings, in particular, the high 75% intent to treat with the combo in frontline MF. I'm curious if you could talk a little bit more about sort of the types of patients that you're hearing physicians would try on a combo. Ruxolitinib initially, whether or not some of the payer feedback maybe you've been getting the early payer feedback has been aligned with what you're hearing from physicians in terms of the degree of frontline use. And then with the space expected to evolve and more targeted treatments like mccarls and more targeted JAKs, what impact do you think that might have on the way selinexor is ultimately positioned should it be successful in Phase III?

Yes. Thanks, Brian. Maybe I'll start kind of with the second part of your question, and I'll turn it over to Sohanya to talk to. I think broadly, in myelofibrosis, as you know and as Sohanya talked about, there's been really no new innovation in the front line, only JAK inhibition in myelofibrosis. So, there's significant opportunity across the whole space to improve outcomes for patients and to bring new innovation to patients, which is exactly what we're focused on. We're bringing a novel MOA such as selinexor and XPO1 inhibition, which we think can have a really meaningful benefit to patients. And when we look across the space again, I think the data we've shown, as we've talked about, we've been working on myelofibrosis for over 7-plus years. Reshma talked about the breadth of our data and showing impact as a monotherapy and obviously, as a combination.

And I think what we're excited about, obviously, is to work to deliver that positive Phase III trial and then to continue expanding in MPNs as well as with selinexor, with eltanexor, our novel second-generation XPO1 inhibitor and a whole suite of XPO1 inhibitors that we have, which we think may be able to have an impact across a broad range of MPNs. With regards to the CALR, we need to wait. We haven't seen any data in myelofibrosis. So again, I think there's a lot of opportunity for innovation and improvement. And what we're excited about again is in the very near-term to read out a potentially positive trial in a combination with such an impact for patients. And I'll let Sohanya talk to that because that's really what our market research indicates when we talk about the 75% intent to prescribe that combination therapy upfront for treatment-naive patients.

Thanks, Richard. Just to kind of add a little bit more to that. The target patient in the market research would be the newly diagnosed intermediate to high-risk patient with greater than 100,000 platelets. And the market research kind of just a little bit of background was comprised of both community and academic physicians. The proportions were in line with what we've seen in real world, the majority community physicians that are treating newly diagnosed myelofibrosis patients. So, the value proposition for selinexor is very simple, clear and focused.

If a prescriber is already prescribing or planning to prescribe rux alone for a newly diagnosed myelofibrosis patient upon approval, they will then just do a seli plus rux combination. So, we are not competing with ruxolitinib, which is the standard of care go-to treatment for our target patient population. We're simply an addition with ruxolitinib, the current market leader. As we look at the sort of payer environment, we don't anticipate any kind of pushback with the payers. And generally, as Richard pointed out, there really has been little innovation beyond the JAK inhibitors. So, there's a tremendous appetite to move these physicians from a monotherapy to a combination treatment approach.

And our last question will come from Jonathan Chang with Leerink.

Just regarding the commercial potential launch in myelofibrosis, can you discuss any relevant learnings from the multi myeloma experience?

Yes. I think broadly, Jonathan, the learnings from our multi myeloma experience really have been built in into the trial design, where in multi myeloma came to the marketplace, as you know, at a much higher dose at 80 milligrams twice weekly or 160 milligrams. And what we've learned over the past number of years is the importance and the ability to use selinexor at a lower dose. And we've obviously built that in with our trial now being at 60 milligrams once weekly. And we've also learned the importance of the dual antiemetics to use for the first couple of cycles as patients initiate therapy on XPO1 inhibition. We know that the nausea is transient and gets better over time. So, we've seen both those learnings over our multiple myeloma experience. We've built that in already to the design of the trial.

And so, I think moving forward and what we've seen already and what Reshma has shared in the blinded safety data is really the benefit to patients, the benefit overall to the tolerability profile. And as we saw from the very low TAE discontinuations, the benefit for patients. And I think the case study Reshma talked to with the patient on the combination for over 3.5 years and so benefiting really talks to the outcomes for patients from those learnings we've built in. So, we feel very positive about the learnings we've built in and the potential to transform outcomes for myelofibrosis patients in the front line.

Yes. I would add that the kind of biggest differentiating point between the 2 landscapes is the degree of competition. Myeloma, highly competitive with overlapping competitors across classes, very different situation in myelofibrosis, really little to no innovation beyond the JAK inhibitors. Also, I would say the myelofibrosis space is primed to be what the myeloma space was over a decade ago. Over a decade ago in myeloma, they were using monotherapies and then evolving to doublets. That is the level of transformation, I think we're about to see in myelofibrosis. The second point is given that we have established a commercial organization that has worked very closely with community physicians who will be the majority of prescribers for the newly diagnosed patients, there's a high degree of synergy, and we expect to launch rapidly with myelofibrosis.

And that concludes today's question-and-answer session. I would like to turn it back to Richard Paulson for closing remarks.

Thank you, operator, and thank you to everyone again for joining us on today's call. As you can tell, we are very excited about our prospects to redefine the current standard of care for the majority of frontline myelofibrosis patients. We look forward to sharing top line data with you in March and pending future regulatory approvals, our organization is well prepared to rapidly deliver on the commercial opportunity. Once again, thanks for joining today.

Thank you. And ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect.