Karyopharm Therapeutics Q4 2025 Earnings Report

Karyopharm Therapeutics EPS Results

• Actual EPS: -$2.23
• Consensus EPS: -$2.26
• Beat/Miss: Beat by +$0.03
• One Year Ago EPS: N/A

Karyopharm Therapeutics Revenue Results

• Actual Revenue: $34.08 million
• Expected Revenue: $33.16 million
• Beat/Miss: Beat by +$919.00 thousand
• YoY Revenue Growth: N/A

Karyopharm Therapeutics Announcement Details

• Quarter: Q4 2025
• Date: 2/13/2026
• Time: Before Market Opens
• Conference Call Date: Thursday, February 12, 2026
• Conference Call Time: 8:00AM ET

Karyopharm Therapeutics (NASDAQ:KPTI) (NASDAQ: KPTI) is a clinical-stage biopharmaceutical company focused on discovering and developing novel first-in-class drugs that target the nuclear export protein XPO1. The company’s lead product, selinexor (marketed as XPOVIO), is an oral selective inhibitor of nuclear export (SINE) compound approved for treatment of multiple myeloma and diffuse large B-cell lymphoma. In addition to selinexor, Karyopharm’s pipeline includes second-generation SINE compounds and combination studies in solid tumors and hematologic malignancies.

Founded in 2008 and headquartered in Newton, Massachusetts, Karyopharm has built a research platform around modulation of nuclear export pathways. The company conducts clinical trials both domestically and internationally, working with regulatory agencies in the United States and Europe. Through strategic collaborations, Karyopharm seeks to expand the therapeutic reach of its SINE technology into other areas of oncology and potentially neurodegenerative diseases.

Karyopharm is led by Michael Kauffman, M.D., President and Chief Executive Officer, who co-founded the company and has guided its transition from preclinical research to commercial-stage operations. Under his leadership, Karyopharm has forged partnerships with global pharmaceutical firms to advance pipeline candidates and ensure broader patient access. The company maintains a scientific advisory board composed of experts in cancer biology, translational medicine and drug development.

Karyopharm Therapeutics Q4 2025 Earnings Call Transcript

Key Takeaways

• Positive Sentiment: Phase 3 myelofibrosis readout in March 2026: Karyopharm expects top-line data from its frontline selinexor + ruxolitinib (CENTURY/SENTRI) trial next month, positioning the combo to be the first frontline combination and a potential major value driver if positive.
• Positive Sentiment: Phase 3 endometrial cancer data mid‑2026: The EXPORT‑EC042 trial remains on track for mid‑2026 top‑line results, supported by promising long‑term SIENNA subgroup data in P53 wild‑type/pMMR patients that Karyopharm highlights as a meaningful expansion opportunity.
• Negative Sentiment: Near‑term cash runway into Q2 2026: The company ended 2025 with ~$64.1M in cash and says existing liquidity funds operations only into the second quarter, and it is actively evaluating financing and strategic options to bridge to and beyond upcoming readouts.
• Positive Sentiment: Commercial performance and 2026 guidance: Xpovio net product revenue grew to $114.9M in 2025, management expects $115M–$130M in 2026 and continues to position Xpovio in community and peri‑T‑cell engager settings as a durable commercial foundation.

Presentation

[Operator]

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 Q4 and full year 2025 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 call over to Brendan Strong, Senior Vice President, Investor Relations. Please go ahead.

[Brendan Strong, VP of Investor Relations and Corporate Communications at Karyopharm Therapeutics]

Good morning, and thank you all for joining us on today's conference call to discuss Karyopharm's Q4 and full year 2025 financial results and recent company progress. We issued a press release this morning detailing our financial results for the Q4 and full year 2025. This release, along with a slide presentation that we will reference during our call today, are available on our website.

[Brendan Strong, VP of Investor Relations and Corporate Communications at Karyopharm Therapeutics]

For today's call, as seen on slide two, I'm joined by Richard, Reshma, Sohanya, and Lori, who will provide an update on our results for the Q4 and full year 2025 and discuss recent clinical developments. Before we begin our formal comments, a reminder 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.

[Brendan Strong, VP of Investor Relations and Corporate Communications at Karyopharm Therapeutics]

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.

[Brendan Strong, VP of Investor Relations and Corporate Communications at Karyopharm Therapeutics]

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 five.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Thank you, Brendan, 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.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Today, Selinexor has an established, durable commercial foundation in multiple 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.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

In myelofibrosis, we remain on track to share top-line data from our phase three 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.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

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 three XPORT-EC-042 trial in mid-2026.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

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 Q2, which aligns with key near-term clinical milestones.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

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.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

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, Sowjanya, 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?

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Thank you, Richard. I'm incredibly excited by the near-term opportunity to read out two phase three 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

As seen on slide eight, 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-κB, p53, and fibrosis-inducing pathways.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

As a result, frontline treatment with monotherapy JAK inhibitors do not adequately address the relevant drivers of pathogenesis in myelofibrosis. On slide nine, our confidence in selinexor's potential in myelofibrosis is based upon a substantial body of preclinical, non-clinical, translational, and clinical efficacy, as well as safety data sets.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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-κB, PI3 kinase, AKT, mTOR, and TGF-beta.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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 three plus anemia. First, spleen volume reduction. Note that only approximately 1/3 of patients achieve a spleen volume reduction of greater than 35% with ruxolitinib alone. In contrast, our phase one data suggests that the combination could more than double the SVR35 rate at 79%. Second is symptom improvement.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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 11-14 points achieved by patients on ruxolitinib, as observed in the phase MANIFEST-2 and TRANSFORM-1 trials.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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+ anemia. The data that we presented in June at EHA from our phase two 035 monotherapy trial showed lower rates of all grade and grade 3+ anemia for the selinexor arm, as compared to physician's choice in myelofibrosis patients previously treated with JAK inhibitor therapies.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Our initial blinded safety data from the first 61 patients enrolled in SENTRY also suggests lower rates of Grade 3+ 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Data observed from selinexor monotherapy studies in a pretreated myelofibrosis population, as well as our phase one 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Turning to slide 12, we are eagerly awaiting the readout from our phase three 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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 three 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Let's now turn our attention to endometrial cancer on slide 15. In the phase three EXPORT-EC042 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Our phase three 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

As discussed previously, the long-term follow-up data from our phase three 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Let's review some of our long-term follow-up data from our last phase three 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 three trial.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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 pre-specified 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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 three trial. As you look at these data, keep in mind that SIENDO was evaluating 80 mg of selinexor once weekly, and while antiemetics were used at times, the mandated use of dual antiemetics during the first two cycles of therapy was not part of the clinical trial protocol.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

This is a key difference when you think about the design of our current phase three, where we are using a lower dose of selinexor at 60 mg once weekly, and dual antiemetics are mandated during the first two cycles of therapy.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

That takes us to slide 19, which contains the trial design of our phase three EXPORT EC042 trial, where selinexor 60 mg is being evaluated as a maintenance therapy in patients with P53 wild-type endometrial cancer.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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 three trials to establish new standards of care in two areas of high unmet need. I will now turn the call to Sohanya.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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 Q4 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 to 130 million of Xpovio net product revenue in 2026.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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 achieve a spleen volume reduction of 35% or more, with 2/3 of patients not adequately responding.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

As Reshma outlined, our data highlights the 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.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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 US alone.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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 US Oncology and Florida Cancer Specialists, and approximately 200 other large community accounts.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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, two-thirds of patients still fail to reach SVR 35 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.

[Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development at Karyopharm Therapeutics]

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.

[Lori Macomber, CFO and Treasurer at Karyopharm Therapeutics]

Good morning, everyone, and thank you, Sohanya. Turning to our financials on slide 29. Total revenue for the Q4 of 2025 was $34.1 million, an increase of 11.8% compared to the Q4 of 2024. For the year, total revenue was $146.1 million, a slight increase from 2024.

[Lori Macomber, CFO and Treasurer at Karyopharm Therapeutics]

U.S. XPOVIO net product revenue for the Q4 of 2025 was $32.1 million, an increase of 9.6% compared to the Q4 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 Q4 and 31.2% for the calendar year 2025.

[Lori Macomber, CFO and Treasurer at Karyopharm Therapeutics]

License and other revenue was $2 million in the Q4 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.

[Lori Macomber, CFO and Treasurer at Karyopharm Therapeutics]

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 Q4 of 2025 were $27.7 million, a decrease of 17% from the Q4 of 2024.

[Lori Macomber, CFO and Treasurer at Karyopharm Therapeutics]

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 three myelofibrosis and endometrial cancer programs.

[Lori Macomber, CFO and Treasurer at Karyopharm Therapeutics]

Selling, general, and administrative expenses were $22.8 million for the quarter, a decrease of 16% compared to the Q4 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.

[Lori Macomber, CFO and Treasurer at Karyopharm Therapeutics]

Taken together, our loss from operations improved by approximately 43% in the Q4 of 2025 compared to the Q4 of 2024, and improved 24% in the full year 2025 compared to 2024. Interest expense was $12.6 million in the Q4 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.

[Lori Macomber, CFO and Treasurer at Karyopharm Therapeutics]

Other expense was $10 million in the Q4 of 2025, compared to $10.1 million of other income in the Q4 of 2024. For the full year, other income was $0.2 million, compared to $28.4 million of income in the full year of 2024. This non-operational item is primarily driven by recurring non-cash fair value remeasurements of embedded derivatives and liability-classified common stock warrants related to the refinancing transactions completed in the Q2 of 2024 and the Q4 of 2025.

[Lori Macomber, CFO and Treasurer at Karyopharm Therapeutics]

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 non-cash and non-operational in nature.

[Lori Macomber, CFO and Treasurer at Karyopharm Therapeutics]

As a result, we reported a net loss of $102.2 million, or $5.71 per share on a GAAP basis in the Q4 of 2025, and a net loss of $196 million, or $17.93 per diluted share for the full year of 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 non-cash in nature. Excluding these items, our underlying operating performance continues to demonstrate meaningful improvement.

[Lori Macomber, CFO and Treasurer at Karyopharm Therapeutics]

Finally, we ended the year with $64.1 million in cash, cash equivalents, restricted cash, and investments, compared to $109.1 million as of 31 December 2024. Based on our current operating plans, our guidance for the full year of 2026 is as follows: Total revenue of $130 to 150 million, consisting of XPOVIO net product revenue and license, royalty, and milestone revenue expected to be earned from our partners, primarily Menarini and Antengene.

[Lori Macomber, CFO and Treasurer at Karyopharm Therapeutics]

XPOVIO net product revenue to be in the range of $115 to 130 million. R&D and SG&A expenses to be in the range of $230 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 Q2 of this year. I will now turn the call back to Richard for some final thoughts.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

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 multiple 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.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

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 three 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.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

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]

Thank you. And ladies and gentlemen, we will now begin the question-and-answer session. To ask a question, you may press star followed by one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, you may press star followed by two, and we kindly ask you to please limit yourself to one question and 1 follow-up. With that, our first question comes from the line of Colleen Kusy with Baird. Please go ahead.

[Colleen Kusy, VP and Senior Equity Research Analyst at Baird]

Great. Good morning. Thanks for taking our questions, and congrats on all the progress. We're excited for the upcoming data we'll see next month. Maybe if we can start there, you know, obviously, the 60 mg data has, you know, that we've seen so far has been best-in-class.

[Colleen Kusy, VP and Senior Equity Research Analyst at Baird]

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 on 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 one? Thank you.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Yes. Thanks, Colleen. I think obviously our dose is focused on the 60 mg and looking at our phase three 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 mg in combination with Rux. Reshma?

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Yeah. Thank you, Colleen. Yeah, thank you, Colleen and Richard. So it goes back to our phase one data, in which we evaluated both the 60 mg as well as 40 mg. And when you look at the efficacy and safety, there's a clear benefit-risk in favor of the 60 mg cohort as compared to the 40, largely due to the fact that efficacy, both from an SVR as well as TSS, was maximized in the 60 mg group as compared to the 40mg group.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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 mg as compared to 40 mg, but you don't see that substantial dose response as compared to, again, what I described in the efficacy. In total, again, when you look at the efficacy and safety data, it really is in favor of that 60mg group.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Layer in the pharmacokinetic data, and there, too, exposures are higher with that 60 mg group as compared to the 40 mg. Really, the totality of the data from the clinical, efficacy, safety, clin pharm. And then, of course, we've got multitude of, you know, preclinical data, translational PD markers that really suggest that 60 mg, is the right dose in myelofibrosis, hence the reason that we've taken that forward in our phase three.

[Colleen Kusy, VP and Senior Equity Research Analyst at Baird]

Great. That's super helpful. Thank you. 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. Would think, obviously, follows your strategy of enrolling highly symptomatic patients, but just curious your thoughts on the read-through there.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Yeah. Thanks, Colleen. Yeah, I think you highlighted it really, it, it does talk to the, the importance of having the right patient population in the trial, which I think we've delivered very well. Overall, really, the continued investment in myelofibrosis space really talks about the unmet need and the significant value that, that's in the myelofibrosis market.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

You know, I think as we look at it, you know, regarding the EU, I think Novartis has indicated they, they may be moving forward and, and filing there. That may indicate that the EU regulatory agencies are, are more, more focused on, on SVR35 and potentially showing, you know, more regulatory flexibility, less focused on symptoms.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

You know, given our top-line readout data is gonna 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. You know, given the fact that Novartis has indicated that they would run another trial for the U.S., you know, that trial wouldn't read out for a number of years and gives us a significant amount of time to establish ourself well and become the standard of care in frontline myelofibrosis.

[Colleen Kusy, VP and Senior Equity Research Analyst at Baird]

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? Thank you.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

I'll take the first question, and then I'll pass over the IP to Richard. But, you know, 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Eltanexor has already been evaluated in a phase I/II trial, so we do have some, you know, 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.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Yeah, and from a patent perspective, obviously it's early days yet with regards to our overall strategy there. You know, right now with eltanexor, the patent, it 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, you know, into 2039. Lots of opportunity for us as we continue to move forward and develop in that space.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Great. Thanks so much for taking our questions. Excited for the data next month.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Thanks, Colleen.

[Operator]

Thank you. And the next question comes from the line of Yanni Souroutzidis with Cantor. Please go ahead.

[Yanni Souroutzidis, Research Analyst at Cantor]

Hi, folks. Appreciate the updates here. Great to see the progress and timelines 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 AEs like the nausea, anemia, and thrombocytopenia?

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Hey, Yanni. Thanks for the question. So no, we haven't updated anything beyond what we've publicly disclosed in the past. You know, what we've said in the past is, you know, the baseline demographics as 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

You know, with that said, though, we did have an opportunity to update the TSS in approximately 350 patients. Again, you know, 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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-hem toxicities, including the GI toxicities, nausea, as well as...

[Yanni Souroutzidis, Research Analyst at Cantor]

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, and how in line it is with the, the label?

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Absolutely. The selinexor dose, it can be reduced, so it can go from 60 mg to 40 mg to 20 mg, and then yes, you know, 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 USPI.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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-hem toxicity, then we suggest that they modify selinexor dose so we try to keep it very easy for the investigator, just based upon the kind of AE that the patient experiences.

[Yanni Souroutzidis, Research Analyst at Cantor]

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

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Yeah, I can talk to that. Yeah, I mean, overall, obviously, our registration enabling trial is our phase three 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.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

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 two 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.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

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, you know, pending positive data with our phase three frontline combination with RUX, our view would be, you know, to read out the phase two data and look at that as an opportunity to really expand from a guideline perspective.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Enable physicians much more flexibility, and the opportunity to establish, you know, 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?

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

No, nothing. That's, that's great.

[Yanni Souroutzidis, Research Analyst at Cantor]

Perfect. All right, guys, really appreciate the updates and best of luck here in the near, near term.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Thanks, Yanni.

[Operator]

The next question comes from the line of Brian Abrahams with RBC Capital Markets. Please go ahead.

[Brian Abrahams, Senior Biotechnology Analyst and Global Sector Head of Healthcare Research at RBC Capital Markets]

Hey, good morning. Thanks for taking my question, and look forward to an exciting next couple of months. You reported the phase three baseline characteristics at the ASH conference in an abstract. It looks like if you look at the risk status, if you look at spleen volume, the baselines, the baselines, the patient population looks somewhat milder than what was in the phase one, two.

[Brian Abrahams, Senior Biotechnology Analyst and Global Sector Head of Healthcare Research at RBC Capital Markets]

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 two. Can you maybe talk about what some of those similarities, but also differences might mean with regards to you know the potential to show as wide a delta in the phase three? Thanks.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Sure. Thanks, Brian. You are correct, right? You know, sort of like if you compare the patient populations in the phase three, phase one, I would agree it is, it's a little bit milder. I think the other aspect that is different is even the baseline hemoglobin, right? So it was approximately 10 grams, median was 10 grams in the phase one. It's approximately 11 grams in the phase three. I think by and large, right, yes, this potentially could be a less sick patient population.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

You know, with that said, though, I don't think it's gonna have any impact on the efficacy, right? I say that because even when we look at the subgroups from our phase one, from an SVR perspective, there really is a very nice consistency, including across all of the depths, 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 gonna have far more, difficult to treat disease versus those that are, have a little bit more mild disease. Yeah.

[Brian Abrahams, Senior Biotechnology Analyst and Global Sector Head of Healthcare Research at RBC Capital Markets]

No, that, that's really helpful. Thanks. 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, in the case that you show statistically significant spleen reductions, but don't quite show, get the statistical significance, on, on symptoms what, what would be the bar to still potentially proceed with a filing, assuming there aren't any safety surprises or anything like that?

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Sure. You know, our goal is to really show statistical significance for both SVR as well as absolute TSS, right? You know, those are the bars that are included in our statistical analysis plan, as well as, you know, discussed with the FDA. We think that profile against statistically significant improvement, both for the SVR, 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Even 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, you know, multiple datasets, multiple, you know, meta-analyses, that really suggest that the deeper, the more rapid, the more durable the SVR that can be achieved...

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

The more that it may correlate with long-term outcomes. They're very focused on that spleen volume reduction, and while they say, yes, symptoms are important, you really for them, they just want to see some kind of benefit above and beyond ruxolitinib. 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.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

You know, I think that's very encouraging from their perspective and a 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, you know, striving to achieve here.

[Brian Abrahams, Senior Biotechnology Analyst and Global Sector Head of Healthcare Research at RBC Capital Markets]

Got it. That, that's super helpful. And then maybe one more, if I could squeeze it in. Could 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? Thanks.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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

[Brian Abrahams, Senior Biotechnology Analyst and Global Sector Head of Healthcare Research at RBC Capital Markets]

Thanks again.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Thank you, Brian.

[Operator]

The next question comes from the line of Maury Raycroft with Jefferies. Please go ahead.

[Maurice Raycroft, Senior Equity Research Analyst at Jefferies]

Hi, good morning. Thanks for taking my questions. Maybe as a follow-up to one of the earlier ones, for the, the 61 patients in the futility analysis group in SENTRY, what can you say about dose reductions you saw for selinexor or, 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 compare to your phase one, and how the Rux dose reductions could compare to other myelofibrosis phase three studies?

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Sure. Great question, Maury so I haven't commented on the dose reductions from the first 61 patients, specifically for the ruxolitinib, largely because, you know, as you know, the starting dose is gonna be very variable, again, based upon the patient's baseline platelet count, extrapolating, you know, 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. Again, it's not meaningful output at this time.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

You know, let's just wait until the top-line data. Now, with that said, though, you know, we have mentioned that the selinexor dose intensity, so whether it's selinexor or placebo, does look really good. And amongst the 61 patients, the mean relative dose intensity was greater than 95%.

[Maurice Raycroft, Senior Equity Research Analyst at Jefferies]

Got it. Okay, that's helpful. Maybe just two quick clarification questions. For the first 61 patients, is there anything more you can say about where those patients were recruited from, which regions they came from?

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Sure. They were globally. They were gonna—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 yeah, just assume that this is going to be a population largely recruited again within Europe as well as North America.

[Maurice Raycroft, Senior Equity Research Analyst at Jefferies]

Got it. Okay. Knowing that the date is going to be in March is really helpful. Just wondering if you're saying whether it's going to be earlier or later in March?

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

No, I think guiding to March is pretty strong. So feel very good about that and continues to progress well, and we'll read the data out in March.

[Maurice Raycroft, Senior Equity Research Analyst at Jefferies]

Got it. Okay, thanks for taking my questions.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Thanks, Maury.

[Operator]

Your next question comes from the line of Jonathan Chang with Leerink Partners. Please go ahead.

[Jonathan Chang, Senior Research Analyst at Leerink Partners]

Hi, guys. Thanks for taking my question. Just one. What are the key reasons for confidence in hitting on the TSS endpoint of the SENTRY study? Thank you.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Sure, Jonathan. Great question. I think there's multiple different aspects that give us confidence. You know, I go back to, you know, the studies, the phase one study's original secondary endpoint was TSS 50, right? When we had the opportunity to look at TSS 50 amongst that ITT, numbers were quite strong at approximately 59%, relative to historical ruxolitinib data that have read out, you know, sort of in the mid-40 so a really nice improvement there.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

We then looked at absolute TSS or the observed mean change at week 24 relative to baseline these are gonna be the actual, values, not estimated, which is what is gonna be coming from the phase three. 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 11-14 points so from a clinical perspective, you really have evidence of meaningful TSS improvement from both TSS 50 as well as absolute TSS.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

Now, the other part that really should be taken into consideration is the cytokine data, right? So I mention that because we know that the pro-inflammatory cytokines is what really drives the symptom development in the first place.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

When we look at cytokine levels on treatment relative to baseline, regardless of whether you look at it from the phase one population, which was JAK-naïve, 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 four. So the fact that you see that cytokine decrease again explains why you also see that associated clinical benefit.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

I think, like, really, those, you know, are, are gonna 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 TSS 50, which we know is very crude measurement of symptom benefit, to a much more sensitive methodology in absolute TSS, which is, again, gonna look at that mean change over time.

[Reshma Rangwala, EVP, Chief Medical Officer and Head of Research at Karyopharm Therapeutics]

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, it's just a very, very difficult domain to meaningfully evaluate. 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.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Then, Jonathan, I'll just close that because I think as Reshma has talked to, we feel very good about that. And then, as we've said, feel very pleased with the patient population we've enrolled, right? It's consistent with the population we had planned.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

As we set our targets to ensure we had, you know, a meaningful baseline TSS, we've delivered on that with the TSS scores, you know, 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.

[Jonathan Chang, Senior Research Analyst at Leerink Partners]

Understood. Thank you.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

Thanks, Jonathan.

[Operator]

We have no further questions at this time. I would like to turn it back to Richard Paulson for closing remarks.

[Richard Paulson, President and CEO at Karyopharm Therapeutics]

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 three 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.

[Operator]

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

Participants

Executives

• Brendan Strong, VP of Investor Relations and Corporate Communications
• Lori Macomber, CFO and Treasurer
• Reshma Rangwala, EVP, Chief Medical Officer and Head of Research
• Richard Paulson, President and CEO
• Sohanya Cheng, EVP, Chief Commercial Officer and Head of Business Development

Analysts

• Brian Abrahams, Senior Biotechnology Analyst and Global Sector Head of Healthcare Research at RBC Capital Markets
• Colleen Kusy, VP and Senior Equity Research Analyst at Baird
• Jonathan Chang, Senior Research Analyst at Leerink Partners
• Maurice Raycroft, Senior Equity Research Analyst at Jefferies
• Yanni Souroutzidis, Research Analyst at Cantor