Earnings call transcript: Karyopharm Q2 2025 sees revenue decline amid strategic shifts

Karyopharm Therapeutics, with a market capitalization of just $34 million, reported a decline in revenue for its second quarter of 2025, with total revenue falling to $37.9 million from $42.8 million a year earlier. Despite this, the company saw a 6% year-over-year increase in net product revenue for XPOVIO, its flagship product. The company also faces liquidity challenges with a debt maturity looming in October 2025. In premarket trading, Karyopharm shares rose 0.57% to $3.962, though the stock has declined over 56% in the past six months. According to InvestingPro analysis, the stock appears undervalued based on its Fair Value calculations.

Key Takeaways

• Total revenue decreased to $37.9 million, down from $42.8 million in Q2 2024.
• XPOVIO net product revenue grew by 6% year-over-year.
• Net loss amounted to $37.3 million, or $4.32 per share.
• The company announced a 20% workforce reduction to optimize costs.
• Karyopharm is exploring strategic alternatives to address liquidity concerns.

Company Performance

Karyopharm’s performance in Q2 2025 reflected a challenging environment, as total revenue declined compared to the same period last year. The company is navigating a competitive landscape in the multiple myeloma market while identifying significant opportunities in the myelofibrosis sector. Despite the revenue drop, XPOVIO’s sales showed resilience, highlighting its potential in the company’s portfolio.

Financial Highlights

• Total revenue: $37.9 million, down from $42.8 million in Q2 2024.
• XPOVIO net product revenue: $29.7 million, up 6% year-over-year.
• Net loss: $37.3 million or $4.32 per share.
• Cash and equivalents: $52 million as of Q2 2025, down from $109.1 million at the end of 2024.

Outlook & Guidance

Karyopharm provided full-year 2025 revenue guidance between $140 million and $155 million, with XPOVIO net product revenue expected to range from $110 million to $120 million. The company is focused on advancing its pipeline, particularly in myelofibrosis and endometrial cancer, with three major data readouts anticipated in 2026. InvestingPro data reveals concerning financial health metrics, with analysts revising earnings estimates downward for the upcoming period. The company’s overall financial health score stands at 1.92 out of 5, labeled as "FAIR" by InvestingPro analysts.

Executive Commentary

CEO Richard Paulson emphasized the company’s strategic focus amid financial constraints, stating, "We are operating in a period of financial constraints with a near-term debt maturity in October." He also highlighted the potential to redefine the standard of care for patients, adding, "We believe we have the potential to redefine the standard of care for these patients."

Risks and Challenges

• Liquidity concerns with debt maturity in October 2025.
• Competitive pressures in the multiple myeloma market.
• Uncertainty surrounding the success of ongoing clinical trials.
• Need for strategic financing to support pipeline developments.
• Potential market saturation in targeted therapeutic areas.

Karyopharm’s strategic initiatives and focus on pipeline prioritization reflect its efforts to navigate financial challenges while capitalizing on growth opportunities in the myelofibrosis market. The company’s ability to manage its liquidity and execute its strategic plan will be crucial in the coming quarters. For a deeper understanding of Karyopharm’s financial position and growth prospects, access the comprehensive Pro Research Report available exclusively on InvestingPro, which provides detailed analysis of the company’s financial health, market position, and future potential.

Full transcript - Karyopharm Therapeutics Inc (KPTI) Q2 2025:

Ludi, Conference Operator: Good morning. My name is Ludi, and I will be your conference operator today. At this time, I would like to welcome everyone to the CurioPharm Therapeutics Second Quarter twenty twenty five Financial Results Conference Call. 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 over to Brendan Strong, Senior Vice President, Investor Relations and Corporate Communications. Please go ahead.

Brendan Strong, Senior Vice President, Investor Relations and Corporate Communications, Karyopharm Therapeutics: Good morning. Thank you for joining us on today’s conference call to discuss Karyopharm’s second quarter twenty twenty five financial results and recent company progress. We issued a press release this morning detailing our financial results for the 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 two, I’m joined by Richard, Rejma, Sohania and Lori, who’ll provide an update on our results for the 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 three. 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 ks 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 four.

Richard Paulson, CEO, Karyopharm Therapeutics: Thank you, Brendan, and thank you all for joining us today for Karyopharm’s Q2 twenty twenty five earnings call. Before we begin, as outlined on slide five, I want to address a topic that is on the minds of our employees, our partners, and our investors. We are operating in a period of financial constraints with a near term debt maturity in October. We are actively engaged with our lenders and advisors to enhance our liquidity and maximize value. Importantly, the fundamentals of our business remain strong with a profitable multi myeloma commercial organization that provides us with a solid foundation that we can build on with two potentially transformative Phase III readouts expected over the next twelve months.

These trials target diseases where patients have few treatment options and there is an opportunity to improve on existing therapies. Based on the strength of our data to date, we believe we have the potential to redefine the standard of care for these patients. This is the value that we are building toward and what drives our confidence in the long term trajectory of the company. With that, let’s get into our results for the quarter where we delivered solid commercial results and made exciting progress towards enrolling our pivotal Phase III trials in myelofibrosis and endometrial cancer. I am pleased to report that we expect to close new patient screening this week in our Phase III SENTRI trial in patients with JAK naive myelofibrosis.

This is a major milestone that is a result of many years of hard work and dedication from people throughout our organization, and I thank all of our teams. We greatly thank the patients and clinical trial sites that are participating in SENTRI. Importantly, SENTRI will be our first Phase III trial readout where we utilize a lower dose of selinexor combined with antiemetics during the first two cycles of treatment to improve the tolerability of selinexor as we work to enhance the patient experience. Through our strong clinical trial execution, we are seeing the benefits of both of these factors in the preliminary blinded safety data that Reshma will review today. We are eagerly anticipating top line data in March 2026.

Turning to slide six. Completing enrollment in our Phase III SENTRY trial is an important step on our over seven year journey to demonstrate the role that XPO1 inhibition may play in patients with myelofibrosis. The Phase III trial caps a growing body of evidence that has consistently demonstrated the potential for XPO1 in myelofibrosis. We are optimistic about the potential for selinexor plus ruxolitinib to redefine the standard of care for patients living with this disease and pending positive data, the transformational opportunity this represents for our organization. As outlined on slide seven, given the opportunity to improve the standard of care, leading KOLs, including Doctor.

John Mascarenas from Mount Sinai, who is the principal investigator for SENTRI, continue to highlight the need for new treatment options for patients with myelofibrosis. The depth and durability of response that Doctor. Masperanis mentioned in a recent interview with a patient advocacy organization plays to the strength of Finally, as shown on slide eight, we estimate the peak revenue potential for selinexor in myelofibrosis is up to approximately 1,000,000,000 annually in The U. S. Alone and believe that commercial uptake would be rapid.

We are very eager to bring this combination therapy to the market, pending the outcome of our data and future regulatory approvals. Now I’d like to turn the call over to Reshma.

Reshma, Chief Medical Officer, Karyopharm Therapeutics: Thank you, Richard. I will be sharing new blinded preliminary safety data with you today from our Phase III SENTRY trial that may support the potential of the combination of selinexor plus ruxolitinib, which may have a similar, if not more favorable safety profile than ruxolitinib alone. Before I get into the new data, let’s review why we believe selinexor as an XPO1 inhibitor is a rational mechanism to evaluate in patients with myelofibrosis starting on slide 10. Selinexor prevents the nuclear export of various proteins and messenger RNA molecules, thus inhibiting both JAK and non JAK pathways. The latter which includes the nuclear localization and activation of P53, an important tumor suppressor in myelofibrosis given that approximately ninety five percent of myelofibrosis patients are P53 wild type.

As Richard indicated, we believe that the combination of selinexor plus ruxolitinib has the potential to establish a new treatment paradigm for myelofibrosis patients by addressing each of the four key pillars of this disease as outlined on slide 11. While no assurances can be given, our confidence continues to strengthen as we receive and review additional data, including updated blinded safety data that I will be reviewing shortly. To set the stage, there has been a lack of new treatment options given that JAK inhibitors are the only approved class of therapies. Ruxolitinib has been the standard of care for over thirteen years. As the potential first combination therapy in myelofibrosis, selinexor plus ruxolitinib would be a convenient all oral therapy that the myelofibrosis community has clearly indicated interest in adopting given the rapid, deep and durable spleen reductions and symptom improvement observed from the phase one study.

Let’s now focus on the four key hallmarks in myelofibrosis. First, spleen volume reduction. I think it is a very helpful reminder that only approximately one third of patients achieve a spleen volume reduction of greater than thirty five percent with ruxolitinib alone. Our phase one data suggests that the combination could more than double the SVR35 rate with durable responses also seen. Second is symptom improvement.

Data from our phase one trial of selinexor in combination with ruxolitinib showed an average 18.5 improvement in absolute TSS at week twenty four, which suggests this combination could provide a meaningful improvement over the 11 to 14 improvement achieved by patients on ruxolitinib as observed in the phase three MANIFEST II and TRANSFORM-one trials. Third is hemoglobin stabilization and transfusion burden. The data that we presented in June at EHA show higher hemoglobin levels, lower transfusion burden, and much lower rates of all grade and grade three plus anemia in myelofibrosis patients previously treated with JAK inhibitor therapies who were randomized to selinexor compared to the physician’s choice arm, which included retreatment with the JAK inhibitor therapies including ruxolitinib. Fourth is disease modification. There is minimal evidence of disease modification with JAK inhibitors.

Data observed from selinexor monotherapy studies in a pretreated myelofibrosis population, as well as our phase one 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 12, we are pleased that our phase three SENTRY trial will be closing new patient screening this week. Importantly, based upon an initial review of the baseline characteristics of the patients enrolled to date, they are representative of the intended patient population. One notable characteristic is the baseline TSS, which when excluding fatigue may ultimately be higher than other phase three trials. An important trend that may suggest that our trial could be well positioned to report a greater improvement in absolute TSS.

In this new era of combination therapies, there have been challenges demonstrating meaningful symptom improvement above and beyond ruxolitinib. Based upon learnings from other trials, we believe we have optimized SENTRY for success. First, we changed the co primary endpoint of TSS fifty to absolute TSS, a more sensitive method by which to detect meaningful symptom improvement above and beyond ruxolitinib. Second, we have excluded the fatigue domain in the primary analysis of absolute TSS in alignment with the US FDA due to the difficulty in accurately assessing changes in this symptom. We are certainly not the first to exclude fatigue.

In fact, the pivotal trials that led to ruxolitinib and fedratinib approvals also excluded fatigue in their TSS fifty analyses. It’s also important to keep in mind that all of our studies have excluded fatigue and symptom analyses, including our phase one study evaluating the combination of selinexor and ruxolitinib as well as MF035 which evaluated selinexor as a monotherapy in previously treated MF patients. Finally, absolute TSS in the Phase three SENTRY trial will be analyzed using the mixed models repeated measure approach or MMRM. This differs from our Phase I, which given the limitations in sample size, could only evaluate the mean or average change at week twenty four. MMRM is viewed as a more sensitive and potentially more robust method by which to analyze absolute TSS.

The co primary endpoints in SENTRI are SVR35 and absolute TSS, which are tested sequentially. Some of the key secondary and exploratory endpoints that will also be analyzed include progression free survival, overall survival, hemoglobin stabilization, variant allele frequency reduction, improvement in bone marrow fibrosis and changes in cytokine levels. Now let’s review the encouraging preliminary blinded aggregate safety data from this trial. As these are preliminary data, please keep in mind that these data may not be reflective of the trial’s actual top line results. The data on slides thirteen and fourteen are from the first 61 patients that enrolled in the phase three portion of the century that have now been followed for a median of over twelve months.

These patients were included in the successfully passed futility analysis conducted in the beginning of the year. While only members of the DSMB had access to the unblinded efficacy and safety data from these patients, we have continued to track the safety events over time and took a snapshot of the blinded safety data from these 61 patients on 07/01/2025, which continued to look favorable. Let’s start by reviewing the adverse event summary on the left side of slide 13. The data on the sixty one patients shown in the table include patients randomized to either the combination of selinexor plus ruxolitinib or ruxolitinib in a two to one ratio. Because these are blinded data, we do not know the rates by each arm.

The second and third columns provide the treatment emergent adverse event summary or TEAE summary following a median follow-up of more than seven months or twelve months respectively. What you see in the summary is that many of the adverse events occur early with no meaningful increase in rates after the median of seven months of follow-up. In an effort to improve comparability, we then took our analysis one step further. Knowing that the sixty one patients were randomized two to one, we used the historical data on ruxolitinib to extrapolate the preliminary safety data for the approximately forty patients that received the combination, which is shown in the blue boxes on the right side of the slide. As you can see, the percentage of patients that have had at least one TEAE is approximately ninety seven percent, similar to what has been described for ruxolitinib.

However, when we focus on the grade three plus TEAE, the extrapolated data suggests that the rate may be slightly lower for patients on the combination versus ruxolitinib at approximately fifty three percent and fifty seven percent respectively. Looking at serious TEAEs, the extrapolated data suggests an even greater benefit for the combination therapy than ruxolitinib. Finally, the extrapolated rate of TEAEs leading to treatment discontinuation is only five percent to seven percent for the combination lower than the six to eleven percent range that has been historically reported for ruxolitinib, which we view as an encouraging observation. Let’s turn to the individual treatment emergent adverse events as shown on slide 14. We took the same approach with these data as the ones I just described on the prior slide.

Starting on the left, you’ll see the all grade blinded safety data on these sixty one patients with a median follow-up of more than seven months and again for more than twelve months. We also show two noteworthy grade threefour TEAEs at the bottom left, anemia and thrombocytopenia. Consistent with what I described on the prior slide, we see most TEAEs occurring within the first seven months of follow-up. Additional events are observed with the passage of time resulting in the rates of TEAEs modestly increased at twelve months of follow-up. The number that excites me the most is the extrapolated rate of grade threefour anemia at approximately twenty six percent.

The extrapolated rate of grade threefour anemia for the combination is meaningfully lower than the thirty seven percent historically reported for ruxolitinib. And while the extrapolated rate of all grade nausea is higher in the combination arm than ruxolitinib, the approximately sixty four percent is substantially lower than the approximately eighty percent rate that we reported in the phase one portion of this trial. We have recently presented compelling cytokine data that could explain in part the efficacy observed with selinexor. In addition, slide 15 shows pictographs of bone marrows evaluated at baseline and at week twenty four from a patient treated with the selinexor ruxolitinib combination and is further evidence of the potential disease modification that selinexor may induce in patients with myelofibrosis. These data were first presented by Doctor.

Harris Ali at the International Congress on myeloproliferative neoplasms in October 2024. This JAK inhibitor naive myelofibrosis patient was treated with selinexor sixty milligrams and ruxolitinib fifteen fifteen milligrams twice a day as per the USPI. Due to cytopenias, the ruxolitinib dose was decreased to suboptimal ruxolitinib doses five milligrams twice a day starting in cycle two. The patient achieved an SVR35 as early as week twelve and a TSF50 as early as week eight as a result of symptom reduction from a baseline of 42 points to 19.5 points at week eight. The efficacy observed in this patient can be explained in part by the meaningful change occurring in their bone marrow.

Specifically a 46% reduction in fiber density assessed by digital pathology was observed at week twenty four compared to base line samples as was a approximately 200% increase in erythroid progenitors, which are precursors of mature red blood cells. While this is a single patient experience, the increase in erythroid progenitors could also explain the potentially lower grade three plus anemia rates with the combination as compared to historical ruxolitinib data as I explained on the previous slide. 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 three 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 three plus anemia and thrombocytopenia are the same, if not better than ruxolitinib alone, it could also suggest decreased blood draws for the patient and reduced monitoring burden for physicians and healthcare staff.

I would also like to provide an update on our phase two SENTRY-two trial where we are evaluating selinexor as a monotherapy in JAK inhibitor naive myelofibrosis patients with moderate thrombocytopenia. Enrollment in this trial has been slower than anticipated given that the vast majority of sites enrolling on SENTRY-two are also enrolling patients into SENTRY. And we have asked sites to prioritize enrollment on SENTRI. In addition, patients with platelet counts between 50,100 represents only ten to fifteen percent of all JAK naive myelofibrosis. Now that SENTRI enrollment is completing, we plan on expanding the enrollment criteria to include all patients with platelet counts above 50,000 pending they meet all other eligibility criteria.

This should increase the number of patients that can participate in this trial. Our prior plan was to report preliminary data on a subset of patients from SENTRY-two in the first half of this year. Given the enrollment challenges and the changes we are making to the enrollment criteria, we now plan to report top line data from all patients that we enroll in the sixty milligram cohort of this trial in 2026. Now let’s shift our focus to endometrial cancer where P53 wild type is such an important biomarker. As seen on slide 17, patients with both MMR proficient and TP53 wild type tumors make up approximately fifty percent of all advanced or recurrent endometrial cancer cases representing a very sizable group.

Enrollment in the EXPORT EC042 trial is progressing steadily as seen on slide 18. And we continue to expect to report top line data in the 2026. I remain encouraged with the potential of selinexor to achieve clinically meaningful outcomes in the maintenance setting for patients with P53 wild type endometrial cancer. Lastly, our phase three EMN29 SPD trial is outlined on slide 20. This trial aims to demonstrate the potential of an all oral triplet treatment option for multiple myeloma patients that could also benefit those undergoing pre and post T cell engaging therapies.

We expect to report top line data from this event driven trial in the 2026. I will now turn the call to Sohania. Thank you, Reshma. On slide 22, I will discuss our commercial highlights for Q2 twenty twenty five. XPOVIO net product revenue was $29,700,000 this quarter, up 6% from the 2024.

Demand for XPOVIO was consistent in the 2025 versus the 2024, with the community setting continuing to drive approximately 60% of total U. S. Sales. As we all know, the multiple myeloma market is highly competitive and is becoming more competitive each year. Within this market, XPOVIO is positioned in the community as a flexible therapy with a differentiated mechanism of action, oral convenient option following treatment with an anti CD38 therapy, as well as in patients who cannot access or fail a T cell engaging therapy.

In the academic setting, XPOVIO is being increasingly used before and following T cell therapies. Taking our results for the first half of the year into account, including the atypical level of returns in the first quarter of this year, we expect net product revenue for full year 2025 will be in the range of $110,000,000 to $120,000,000 Finally, we continue to expand global patient access for selinexor and are now approved in various indications countries. This is translating into growth in royalty revenue from Menarini, Antigene and other international partners. Royalty revenue increased 28% to $1,600,000 in the 2025 compared to the 2024, reflecting increased global demand for XPOVIO and NexpoVIO. With data from our Phase three SENTRY trial in sight, our commercial team is preparing for a very rapid launch in myelofibrosis if approved.

As outlined on slide 23, we continue to believe that our peak annual revenue opportunity in The US alone is up to approximately $1,000,000,000 with additional royalty and milestone revenue globally. As you think about this opportunity, keep in mind that the average real world duration for the current standard of care is approximately thirteen months. And given the data we have reported to date, we believe we may have an opportunity to extend this further when ruxolitinib is combined with selinexor. On slide 24, we outline why we believe we’re well positioned for a rapid launch in myelofibrosis pending positive data and approval. As we’ve shared previously, 75 of the physicians that we surveyed say that they intend to adopt a combination therapy in myelofibrosis if one becomes available.

If selinexor is approved in combination with ruxolitinib, we could be the first combination therapy on the market. We would be an all oral therapy, which makes adoption much easier, especially in the community setting. On this point, there’s an eighty percent overlap in the community between myelofibrosis and multiple myeloma prescribers that our organization is already calling on, which enables us to drive a rapid launch and minimizes the upfront investment required for the launch. Finally, in endometrial cancer, as shown on slide 25, we continue to believe that we have a significant opportunity in the p53 wild type and PMMR patient population, which represents approximately fifty percent of advanced or recurrent endometrial cancer patients. Similar to what I outlined for myelofibrosis, there is a large overlap between the potential community based oncologists caring for endometrial cancer patients and those we are already engaging with.

Now I’ll turn the call over to Laurie.

Lori, CFO, Karyopharm Therapeutics: Good morning, everyone, and thank you, Sahania. 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 27. Total revenue for the 2025 was $37,900,000 compared to $42,800,000 for the 2024. The decline was primarily attributable to $6,000,000 of non reoccurring license related revenue from our partners recognized during the 2024.

US XPOVIO net product revenue for the 2025 was $29,700,000 compared to $28,000,000 for the 2024. As expected, the rate of product returns this quarter reverted to historic levels following the atypical increase reported in the first quarter of this year. As a result, the gross to net provisions for XPOVIO in the second quarter were 26.8%, down from the 45% that we reported in the first quarter of this year and down from 29.3% in the 2024. The year over year decline was primarily driven by mix and lower 340B discounts in the 2025. We expect our gross to net provisions will remain relatively consistent with Q2 twenty twenty five for the remainder of the year.

R and D expenses for the 2025 were $32,800,000 down 15% when compared to $38,400,000 for the 2024. The decrease was due to a reduction in headcount and contractors related to our cost optimization initiative, combined with lower clinical trial and related costs, primarily from our Phase III clinical trial in multiple myeloma. SG and A expenses for the 2025 were $28,500,000 down 8% when compared to $31,100,000 for the 2024. The decrease was primarily due to the realization of previously implemented cost reduction initiatives. Interest expense was $11,200,000 in the 2025, up from $8,900,000 in the 2024.

As a reminder, we announced a refinancing in the 2024 that raised interest expense. However, there was only a partial quarter impact in the 2024. Last year’s refinancing also resulted in a $44,700,000 gain on the extinguishment of debt in the 2024. Other expense was $2,200,000 in the 2025 compared to $14,300,000 of other income in the 2024. These amounts were attributable to reoccurring noncash fair value remeasurements of embedded derivatives and liability classified common stock warrants related to the refinancing transactions in the 2024.

We reported a net loss of $37,300,000 or $4.32 per share on a GAAP basis. This figure includes $11,200,000 in interest expense related to our debt instruments, as well as approximately $2,000,000 in noncash losses from the remeasurement of embedded derivatives and liability classified common stock warrants. Our net loss from operations was $24,500,000 for the 2025. This operating result reflects the performance of our core business during the quarter. From an earnings per share perspective, our GAAP EPS includes both interest expense and mark to market impact of the warrant and derivative remeasurements.

We continue to be very diligent in allocating our resources and pipeline prioritization. We announced a roughly 20% reduction in our workforce in early July. You will start to see the financial impact of these actions when we report our results for the fourth quarter of this year. In twenty twenty -twenty twenty six, we expect these actions will lower our annual spend by approximately $13,000,000 We exited the 2025 with cash, cash equivalents, restricted cash, and investments of $52,000,000 compared to $109,100,000 as of 12/31/2024. Based on our current operating plans, our guidance for the full year of 2025 is

Total revenue of 140,000,000 to $155,000,000 consisting of U. S. XPOVIO net product revenue and license, royalty, and milestone revenue expected to be earned from our partners, primarily Metarini and Antigen. US XPOVIO net product revenue to be in the range of $110,000,000 to 120,000,000 R and D and SG and A expenses to be in the range of $240,000,000 to $250,000,000 And finally, 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 to the October 15 maturity of our senior convertible notes. Excluding the remaining $24,500,000 2025 notes maturity and $25,000,000 minimum liquidity covenant, we expect that our liquidity is sufficient to fund our planned operations into January 2026.

As we address this, we are working closely with our advisors, including CenterVue partners, to explore potential financing and strategic alternatives to enhance liquidity and maximize value. I will now turn the call back to Richard for some final thoughts.

Richard Paulson, CEO, Karyopharm Therapeutics: Thank you, Ori. Turning to slide 29. We continue to believe that myelofibrosis in endometrial cancer, depending on the data from our ongoing Phase III clinical trials, are both game changing opportunities for patients and our organization, with the myelofibrosis opportunity alone representing up to a potential $1,000,000,000 in peak annual revenue in The U. S. Alone.

To deliver on these opportunities, we are working with urgency and discipline to address our liquidity while keeping our focus squarely on the opportunity in front of us to bring meaningful, much needed innovation to patients and generate significant value. I’d like to thank our employees, our partners, and our investors for their continued support and belief in our potential. We look forward to updating you on our progress in the coming months. And I would now like to ask the operator to open the call up to the Q and A portion of today’s call. Operator?

Ludi, Conference Operator: Thank you. And ladies and gentlemen, we will now begin the question and answer session. To withdraw your question, please press 2. We ask that you please limit yourself to one question and one follow-up. With that, our first question comes from the line of Ted Tenthoff with Piper Sandler.

Please go ahead.

Ted Tenthoff, Analyst, Piper Sandler: Great. Thank you so much for taking my question. I guess my biggest question has to do really two, if I may. First, just on myelofibrosis. Everything seems to be pointing in right direction.

What’s your biggest worry about that potential readout? Is Jakafi doing better? What could be kind of the snake hiding in the bushes or the grass or whatever that could surprise us? And then the second question is just with really three big readouts next year with myelofibrosis, the export MMO 31 trial, and also endometrial. How how are you planning on sort of prepping and being ready for all of those data readouts at the same time?

Is that gonna cause any problems just in terms of processing everything? Thanks so much.

Richard Paulson, CEO, Karyopharm Therapeutics: Yeah, thanks Ted. A couple of great questions. I’ll take the second one first. And that’s a great opportunity that we’re excited about to have three big readouts in front of us and to be getting ready for potentially positive data across all those readouts is what we’re super excited about as an organisation. Obviously, you know, building on the foundation in multiple myeloma, I think that’s something which is kind of our bread and butter organisation is really ready for.

Myelofibrosis is a key area for us obviously, and you’ve heard us talk and we talked again today that, you know, there’s significant overlap in the prescriber base. So to be able to build on our foundation, leverage our commercial capabilities, and get out and start being able to get ready for myelofibrosis and ultimately launching it. You know, pending positive data, again, I think we’re well ready for and then, you know, endometrial cancer kind of largely the same, there’s a lot of overlap because a number of these patients both in myelofibrosis and endometrial cancer are seen in the community. So our organisation, our payer capabilities, our medical affairs capabilities, our commercial capabilities, all have a lot of synergy to be able to bring both myelofibrosis and endometrial cancer to patients rapidly. So that’s a good problem that we’re excited about and, you know, the organisation already is starting to work on getting ready for myelofibrosis, obviously is our next potentially transformative opportunity and we’re looking forward to updating you more on the future.

For the second part of the question, I’ll turn that over to Reshma, and I’ll talk with you about MF. Know, when we talk about our biggest worry, I think there’s just, you know, broadly I’ll say it’s just a high level of excitement, really a high level of excitement that we’re building on the foundation that’s being put in place with ruxolitinib, and so to be able to potentially combine with the standard of care and create a new standard of care for patients obviously is very exciting for us, especially, you know, given that that’s an all oral with two already approved medications. But I’ll let Reshma maybe share with you what her biggest worry is with regards to looking at the phase three readout with selinexor and ruxolitinib.

Reshma, Chief Medical Officer, Karyopharm Therapeutics: Yeah, thanks Richard and thanks Ted for the question. You know, it’s interesting, worry, I’m not sure I would couch it in those words. You know, as Richard was mentioning, right, we’ve been exploring myelofibrosis for so many years. I mean, seven plus years, both with preclinical data, obviously teasing apart the mechanism. We’ve got multiple clinical data sets.

We’ve got a phase one study evaluating the combination in this relevant patient population of JAK naive myelofibrosis. And I have to say, I like what we’ve got, right? We’ve shown some very, very compelling SVR data, SVR 35 at week twenty four that more than doubles what we’ve observed with historical ruxolitinib that leads to SVR rates in only approximately a third of all patients, even with symptom improvement. I’ll admit, right, symptom improvement has been the Achilles heels of so many phase three trials. With that said, I like the data that we’ve observed to date, both from a TSS 50 standpoint but also an absolute TSS that latter which shows an 18.5 improvement at week twenty four relative to baseline.

And again, I always contextualize that with some of the monotherapy data that also shows some very compelling TSS data as well. But beyond that, SVR and TSS are only two of the key hallmarks that we evaluate in myelofibrosis. I really am quite encouraged by the disease modification data, both of the cytokines as well as bone marrow fibrosis. Obviously the impact on hemoglobin stabilization, this really intriguing observation that we’re also including improving the safety, especially the grade three plus anemia rates relative to historical control. So I think when I step back, the phase three is gonna be the phase three but I think going into that phase three, I really again like what we see in that the combination really can meaningfully improve on not only the key endpoints of SVR35 and absolute TSS, but all of the areas that obviously are very relevant to the patient as well as their physician.

Ted Tenthoff, Analyst, Piper Sandler: That’s very helpful. And I share your enthusiasm. So, looking forward to the data readouts. Thanks so much.

Richard Paulson, CEO, Karyopharm Therapeutics: Thank you, Deb.

Ludi, Conference Operator: And your next question comes from the line of Colleen Cusi with Baird. Please go ahead.

Colleen Cusi, Analyst, Baird: Great. Good morning. Thanks for taking our questions. Helpful update on the baseline characteristics for the pivotal MF combo study. You spoke to higher TSS at baseline.

Can you talk about that a little

Reshma, Chief Medical Officer, Karyopharm Therapeutics: bit more and how you

Colleen Cusi, Analyst, Baird: think that’ll impact the results? And specifically, have you seen a ceiling effect with other trials?

Reshma, Chief Medical Officer, Karyopharm Therapeutics: Thanks Colleen. Great question. Some of the data, especially when we look at historical trials in this JAK naive myelofibrosis, it does suggest whether you’re looking at TSF 50 or absolute TSF, that the higher the baseline, the more likely you’re going to see that meaningful outcome, either a fifty percent improvement or that proportion of patients who can achieve that 50% improvement, or overall that average reduction in that mean TSS at week 24 relative to baseline. So the higher you can push it, the more likely again you can achieve a meaningful outcome. And so, these are just preliminary characteristics.

We have not enrolled all of our patients. So ultimately when we complete enrollment, we’ll take a snapshot of where that baseline TSS is. But I’m really encouraged where the evolution has been within this phase three trial, I. E. Again, pushing to higher baseline TSS.

So, yeah, excited to see where we are right now.

Colleen Cusi, Analyst, Baird: And one quick follow-up if I can. You touched on this a little bit, but can you just further explain the rationale again for why you think you’re seeing the lower rates of grade threefour anemia with the combination? And how important do you think that will be for physicians and potential uptake of the combination?

Reshma, Chief Medical Officer, Karyopharm Therapeutics: Yeah, it’s a really, really intriguing observation and I really do think that it’s probably due to the disease modification that is occurring with selinexor plus ruxolitinib. We’ve touched upon some really compelling cytokine data. This was back at EHA in June, when we looked at selinexor as a monotherapy in that previously treated population. What those data suggested is that it’s decreasing key cytokines that are involved in all aspects of anemia, specifically hepcidin, ferritin, etc. You see decreases in those rates.

Obviously, or potentially could be translating to lower grade three plus anemia. And really liking with what we see from the very preliminary data coming out of the bone marrow fibrosis too. A really marked decrease in that reticulin density. It suggests that you’re clearing out that marrow and potentially allowing for some repopulation of those key cells that ultimately can produce erythrocytes and lead to higher hemoglobin. So that also could not only lead to efficacy, I.

E. Higher hemoglobin, but also potentially translate to lower grade three plus rates. Early days, these are just hypothesis generating data. But I love the fact that we see these clinical outcomes married with these disease modification data that again can explain both the efficacy and safety aspects that we see in our trials.

Colleen Cusi, Analyst, Baird: Great. Thanks for taking our questions.

Richard Paulson, CEO, Karyopharm Therapeutics: Thank you, Colleen.

Ludi, Conference Operator: And your next question comes from the line of Peter Lawson with Barclays. Please go ahead.

Peter Lawson, Analyst, Barclays: Great. Thanks so much. Thanks for the updates. And just as we think about revenues and,

Richard Paulson, CEO, Karyopharm Therapeutics: kind of the drivers,

Peter Lawson, Analyst, Barclays: what was the contribution on the business of volume pricing versus inventory? And then how should we think about that for the the rest of the year? And then I have a follow-up.

Richard Paulson, CEO, Karyopharm Therapeutics: Yeah, thanks Peter. Inventory was relatively consistent across the periods. So I think as Johann has shared, there’s a balance. We saw improvement in the GTN, and that’s something that we obviously, you know, talked to last quarter when we had this one time, you know, returns issue, and so overall we also have seen demand be relatively consistent, So that’s kind of the balance in drivers.

Amy, Analyst, Jefferies: Great, thank you.

Peter Lawson, Analyst, Barclays: And then that fairly blinded safety data looks really encouraging for lower grade three anemia and discontinuation rates versus ruxolone. How confident are you that those kind of backing out of data sets will kind of hold once it’s unblinded?

Reshma, Chief Medical Officer, Karyopharm Therapeutics: It’s good question and Peter, I wish I had that perfect crystal ball. Sometimes crystal balls can be fuzzy, but with that said, I like the evolution that we’ve seen in these blinded safety data. We’ve taken a couple of snapshots. So we’ve taken advantage of these sixty one patients. They again were included as part of that futility analysis that the Data Safety Monitoring Board evaluated earlier this year.

With approximately six months of follow-up, we see a really nice evolution in that safety profile, especially when we extrapolate with historical ruxolitinib. And when we continue to follow those patients and took an updated snapshot as of July 1, we really see a similar kind of trend. Yes, numerically, we do see increases in some of these rates of AEs, whether it’s all grade or grade three plus, but a really nice compared to historical ruxolitinib. I think one of the key things, when I do these extrapolations or I should say, we as a team do these extrapolations, is that historical ruxolitinib safety data has been relatively consistent. So when we look at the MANIFEST Phase three trial versus the COMFORT, they span more than a decade.

And yet again, it’s interesting to see that that ruxolitinib safety data by and large is very consistent. So it allows us or it gives us a little bit more confidence when we extrapolate to what the combination is likely going to see as relatively stable. Ultimately, we’ll need to just see what the Phase III data demonstrates. But again, encouraged by this preliminary observation.

Peter Lawson, Analyst, Barclays: Great. Thank you so much.

Richard Paulson, CEO, Karyopharm Therapeutics: Thank you, Peter.

Ludi, Conference Operator: And your next question comes from the line of Maury Raycroft with Jefferies. Please go ahead.

Brian Abrahams, Analyst, RBC Capital Markets: Hi. This is Amy on for Maury. Thank you for taking our questions, and congrats on the quarter. I have two questions, one on the endometrial, the other on the SENTRI-two study. So for the endometrial Phase III, can you talk about the enrollment progress so far and what percentage of the target has already been enrolled?

And for the SENTRI-two, could you help us understand how the protocol amendment would help with enrollment of the study considering the Phase III SENTRI and this original SENTRI-two are not in the same population? And what is the bar for success now for this amended study? And what do you plan to show in the top line? And how should we contextualize the data with the new population? Thanks.

Reshma, Chief Medical Officer, Karyopharm Therapeutics: Yeah, thanks, Amy. So, I’ll take the first one. For endometrial cancer, enrollment is very steady. Is a unique study in that it’s a biomarker driven maintenance study. What we are seeing right now and aiming to complete is that what we call the top of the funnel, I.

E. The number of patients who have submitted samples to Foundation Medicine for assessment of their P53 status. We see nice flows of samples into that bucket and anticipate top line results in the 2026. So again, very encouraged by the progress made to date. We have not released any target enrollment as of today.

So, we’re not giving out any numbers. Again, we’re confident with what we are seeing at the top of the funnel, as well as the subsequent randomization that we are going to hit top line results in the 2026. In terms of SENTRI-two, so another good question. So let me just back up for a minute. So SENTRI-two is also looking at that JAK naive myelofibrosis patient population.

We’re evaluating selinexor as a monotherapy in a single arm cohort in this population. Now keep in mind that the population had been different and still is different than our combination trial, SENTRI the ongoing phase three, largely based upon their platelet count. So SENTRI-two is just enrolling patients who have baseline platelet counts between 5,100. SENTRI is enrolling patients with 100 and above. What we plan to do, so this hasn’t occurred yet, but what we plan to do is to amend the trial to allow all patients with baseline platelet counts of 50 all the way, there’s no limit to enroll as part of this trial.

So now that we are opening up that baseline platelet cap, we do anticipate that the enrollment is going to pick up relative to what we’ve seen to date. In terms of the bar, so because the amendment has not been issued yet, we don’t see any difference in the bar. So we do anticipate that the majority of the patients enrolled as part of the sixty milligram cohort are still gonna be that moderate thrombocytopenic population fifty to one hundred. This is a very high unmet need small population at approximately fourteen percent. Because there’s not really effective therapies for that population, that bar is anywhere above twenty five percent, right?

Twenty five to thirty percent relative to historical controls of approximately fifteen percent.

Colleen Cusi, Analyst, Baird: Thank you.

Amy, Analyst, Jefferies: Thank you, Amy.

Ludi, Conference Operator: And your next question comes from the line of Brian Abrahams with RBC Capital Markets. Please go ahead.

Amy, Analyst, Jefferies: Hey. Good morning, guys. Thanks for taking my questions. I guess maybe asking the safety question a little bit of a different way. I’m curious, like, what’s your view as to what the potential reasons why you’re seeing this possible overall difference in tolerability when you kind of look at the extrapolated safety rates versus the Phase I?

Is there anything you can tell us about the use of antiemetics in the study, whether patients are continuing to use them or stopping after those first two mandatory cycles? And then my second question is, there’s been some recent changes in FDA leadership at CEDAR, and I’m curious if you’ve had any updated communications with the agency, since your alignment on the new, co primary endpoints, for the Phase III, and your level of confidence that their position on, what’s going to be required, remains the same as your prior feedback. Thanks.

Reshma, Chief Medical Officer, Karyopharm Therapeutics: Thanks, Brian, for the question. So it really is a very nice evolution, both to historical ruxolitinib, but as you mentioned, also to the phase one data. And arguably, I think some of the greatest benefit is around those GI toxicity. It’s very well known with selinexor. But what we see in our phase three extrapolated data is a really nice improvement both with that nausea as well vomiting.

In that phase one, yes, we saw eighty percent of the patients experience any grade nausea, approximately fifty percent of the patients experiencing any grade vomiting. And what we are now potentially seeing in our phase three is reduction in both the nausea and vomiting from 80 to 64%, even vomiting from 50 to now close to what you see and expect with historical ruxolitinib around ten percent, twelve percent. I think you hit the hammer on the head, why do we see this? I think it’s really because of all the antiemetics. So in our phase one, antiemetic usage was not consistent.

So there was many patients unfortunately who did not take dual antiemetics. There were quite a few patients who only took one, there were some patients who didn’t take any. In our phase three, we’ve really tightened that requirement. Virtually all of those patients above ninety percent are taking those dual antiemetics for the first two cycles and then it’s optional thereafter. And I think it’s because of those required dual antiemetics, we see this improvement in nausea.

But I think the real, really nice improvement is again in that vomiting, about from fifty percent all the way down to ten percent. So a really nice improvement not only to the phase one, but again, relative to historical ruxolitinib. In terms of the FDA, lots of evolution going on with the FDA as we all With that said, no additional feedback. We got that feedback back in the 2024 around the endpoint change and have not gotten any additional feedback. Because everything is so documented, we feel confident in the position that the FDA will ultimately take on our Phase three when we meet with them hopefully next year.

Richard Paulson, CEO, Karyopharm Therapeutics: And Brian, I think, and just add to that, I think when I look at the agency, I think we feel really positive about the evolutions and how they’re focused on accelerating access to meaningful cures, treatments and diagnostics. And you know, just a couple months back we participated in a really valuable CEO listening tour with the Commissioner, and really appreciate the interactions, I think, and the evolution, so continuing to look forward to working positive with them to bring new medicines to patients.

Amy, Analyst, Jefferies: Really helpful, thank you. Thanks.

Ludi, Conference Operator: And your next question comes from the line of Jonathan Chang with Leerink Partners. Please go ahead.

Brendan Strong, Senior Vice President, Investor Relations and Corporate Communications, Karyopharm Therapeutics0: Hi, guys. Thanks for taking my question. Can you discuss the scenarios being explored to enhance liquidity and maximize value? What existing and or potential exposure opportunities are being considered in these scenarios? Thank you.

Richard Paulson, CEO, Karyopharm Therapeutics: Yeah, thanks, Jonathan. I mean, that side, you know, there’s really nothing more to add on this point beyond what we’ve stated in our eight ks in July and what we shared today in the press release and our 10 Q. As we’ve stated, we are exploring a full range of financing and strategic alternatives that are going to enable us to extend our cash runway or enhance liquidity and maximize value. We have engaged interview partners, which as you know is a real leader in this area to help us through this, and you know we don’t intend to discuss or disclose any further developments, know, unless and until our board has approved a real specific action or otherwise determined that further disclosure is appropriate. So that’s kind of where we are now and you know continuing to work on it obviously as we move forward and obviously with XPOVIO it encompasses the totality of XPOVIO.

Brendan Strong, Senior Vice President, Investor Relations and Corporate Communications, Karyopharm Therapeutics0: Got it, understood. Thanks for taking the

Amy, Analyst, Jefferies: question. Thanks Jonathan.

Ludi, Conference Operator: And I’m showing no further questions at this time. I would like to turn it back to Richard Paulson for closing remarks.

Richard Paulson, CEO, Karyopharm Therapeutics: Thanks, operator. I think as you heard today, our organization is very focused on delivering on the opportunities in front of us. As we’ve stated, we’re working with real urgency and with discipline to address our liquidity and keeping our focus squarely on the opportunities we have in front of us, which is why we do what we do every day and that’s to bring meaningful, much needed innovation to patients and to generate significant value. So once again, I’d like to thank our employees, our partners, our investors for their continued support and their belief in our potential. Thank you for joining the call today.

Ludi, Conference Operator: Thank you, presenters. And ladies and gentlemen, this concludes today’s conference call. Thank you all for joining. You may now disconnect.

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