Karyopharm Therapeutics Q1 2025 Earnings Call Transcript

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Provided by Quartr
May 12, 2025

There are 10 speakers on the call.

Operator

Good afternoon. My name is Chloe, and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics First 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.

Operator

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

Speaker 1

Thank you, Chloe, and thank you all for joining us on today's conference call to discuss Karyopharm's first quarter twenty twenty five financial results and recent company progress. We issued a press release after the market closed detailing our financial results for the first quarter of twenty twenty five. This release, along with a slide presentation that we will reference during 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 will provide an update on our results for the first quarter of twenty twenty five and review new data that we are sharing for the first time today in myelofibrosis. 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.

Speaker 1

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 and 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.

Speaker 1

Please turn to slide four. Thank you, Brandon, and thank you all for joining us today for Karyopharm's Q1 twenty twenty five earnings call. As we continue to execute on our innovation and growth strategy, we are pleased that our Phase III SENTRY trial in patients with JAK naive myelofibrosis has passed its pre specified futility analysis and continues as planned without modifications. We are very focused on completing enrollment in this trial, while also advancing enrollment in our Phase III trial in endometrial cancer, as outlined on slide five. As we have discussed in the past, we have a profitable commercial organization in multiple myeloma that can be leveraged to drive rapid commercialization if we receive approval in additional disease areas.

Speaker 1

Turning to slide six, we are excited to share with you today new clinical data which further strengthens our conviction in selinexor's potential in combination with ruxolitinib in JAK naive myelofibrosis patients. The data that Reshma will take you through is selinexor monotherapy data in a heavily pretreated, hard to treat population from our randomized Phase II Export MF035 trial. The data are very encouraging because they continue to show selinexor may have an impact across each of the four key hallmarks of the disease. When combined with other clinical and preclinical data we have shared previously, this tells a consistent story which supports our belief that the combination of selinexor plus ruxolitinib has the potential to meaningfully improve patient outcomes and redefine the standard of care in myelofibrosis. We look forward to sharing data with you from our Phase III SENTRY trial, which is evaluating selinexor in combination with ruxolitinib toward the end of this year or in early twenty twenty six.

Speaker 1

We have now enrolled approximately eighty percent of the three fifty patients that we are targeting for this study and expect to complete our targeted enrollment in the JuneJuly timeframe. As we think about our potential in myelofibrosis, it is worth remembering how we got here, which is outlined on slide seven. We have been taking deliberate steps over many years to put us in the position we are in today. We continue to progress our Phase III SENTRY trial faster than historical benchmarks, while remaining incredibly focused on high quality clinical trial execution. As outlined on slide eight, leading key opinion leaders in myelofibrosis, including Doctor.

Speaker 1

Ram Paul from Memorial Sloan Kettering and Doctor. Mascarenas from Mount Sinai, continue to highlight the need for new treatment options for patients with myelofibrosis and are encouraged by the strength of our phase one combination data. Finally, we continue to believe that the commercial opportunity in myelofibrosis is transformational. As shown on slide nine, if approved, we believe the peak revenue potential for selinexor in myelofibrosis is up to approximately $1,000,000,000 in The US alone. Based on our market research, including discussions with leading key opinion leaders on our Phase I data, and the fact that we are looking to combine selinexor with the existing standard of care, we believe that commercial uptake would be rapid.

Speaker 1

We are eager to see the outcome of our Phase III trial and the potential opportunity ahead. Now I'd like to turn the call over to Reshma.

Speaker 2

Thank you, Richard. Before I get into the new data, let's quickly review why we believe selinexor as an XPO1 inhibitor is a rational mechanism to evaluate in patients with myelofibrosis starting on slide 11. Selinexor prevents the nuclear export of various proteins and messenger RNA molecules 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. Let's start by reviewing the unmet need in JAK naive myelofibrosis on slide 12, selinexor's potential to help patients with myelofibrosis, and our opportunity to redefine the standard of care as the first combination therapy.

Speaker 2

To set the stage, there has been a lack of new treatment options given that the 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

Speaker 3

myelofibrosis. First, let's look

Speaker 2

at spleen volume reduction. I think it's a helpful reminder that only approximately one third of patients achieve a spleen volume reduction of greater than 35% with ruxolitinib alone. As we have shared before, our phase one data show that selinexor plus ruxolitinib more than doubles that SVR35 rate. Second is symptom improvement. As a reminder, 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 a meaningful improvement over the 11 to 14 improvements achieved by patients on ruxolitinib as observed in the phase three MANIFEST II and TRANSFORM-one trials.

Speaker 2

Third is hemoglobin stabilization and transfusion burden. The new data we will be reviewing today shows higher hemoglobin levels, lower transfusion burden, and much lower rates of all grade and grade three plus anemia in patients randomized to selinexor compared to physician's choice, primarily JAK inhibitors, including ruxolitinib. Fourth is disease modification. There is minimal evidence of disease modification with JAK inhibitors. The new monotherapy data shows substantial reduction in key cytokines that are critical to myelofibrosis pathogenesis, symptom development and anemia.

Speaker 2

We believe this data likely indicates that selinexor is having an impact on the underlying disease, which enables both monotherapy as well as additive, if not potentially synergistic benefit when combined with other therapies, including ruxolitinib. Turning to slide 13, our EXPORT MF035 trial is a randomized Phase two trial that is evaluating selinexor monotherapy versus physician's choice. The study was designed to evaluate the efficacy and safety of selinexor in a more heavily pretreated myelofibrosis population. Importantly, this trial allows for patients to crossover from physician's choice to selinexor if their spleen met predefined progression criteria. To be eligible for the trial patients needed at least six months of prior exposure to a JAK inhibitor.

Speaker 2

This trial was originally designed to randomize 112 patients. However, we stopped enrollment in 2023 to focus our resources on our ongoing phase three SENTRY trial. Slide 14 contains the baseline characteristics for the 24 patients that we enrolled in the trial. Keep in mind that this trial enrolled a very different patient population than the patients we are enrolling in our phase three SENTRY trial. Patients in this trial were heavily pretreated with an average of two prior lines of therapy with some patients having up to four lines of prior therapy.

Speaker 2

This is also a very frail high risk population. I would direct your attention to the fact that seventeen percent of patients are triple negative and twenty one percent are high risk. Furthermore, these patients are generally cytopenic with hemoglobin levels between nine and ten. Five of these patients were transfusion dependent prior to enrolling in the trial. Slide 15 contains the spleen volume reduction observed in this trial.

Speaker 2

We evaluated the maximum SVR experienced at any time in the efficacy evaluable populations. The eight patients shown in blue were treated with physician's choice. The patients represented by the solid green bars in the middle of the slide were randomized to selinexor. The additional five patients in the textured green bars on the far right were patients that progressed on physician's choice and crossed over to selinexor. As is clear on this slide, spleen volume reduction was greater in those patients that received selinexor at any time compared to the group that received physician's choice.

Speaker 2

In fact, all but one patient in the selinexor arm achieved some degree of spleen volume reduction, whereas only half of the patients in the physician's choice arm experienced a decrease in spleen volume. Thirty eight percent of the evaluable patients in the physician's choice arm achieved an SVR twenty five at any time, whereas sixty seven percent in the selinexor arm, including patients that crossed over achieved an SVR twenty five. For SVR thirty five rates were more than double for selinexor. Thirteen percent of patients in the physician's choice arm achieved this level of spleen volume reduction or greater compared to thirty three percent in the selinexor arm. Slide 16 contains a very compelling spider line graph that looks at the impact that selinexor has on spleen size on patients that crossed over and thus had progressed on prior therapy.

Speaker 2

Of the six patients who crossed over from physician's choice to selinexor, five were evaluable and are showed on the slide. Four of these five patients received ruxolitinib as a physician's choice prior to crossover. So in fact, the spider line graph really demonstrates selinexor's effect on the spleen size in ruxolitinib refractory patients. The first column is represented by the Y axis represents the baseline spleen level for each patient. The second series of data points represents the maximum reduction of spleen volume on physician's choice or ruxolitinib.

Speaker 2

The third series of data points represent the spleen volume growth experienced at the time of progression. The fourth series of data points then represents spleen volume relative to baseline after the patients cross over to selinexor. The interpretation of these data are very clear. Each patient that crossed over to selinexor demonstrated clear and meaningful reductions in their spleen volume after crossing over, likely indicating that selinexor is targeting pathways beyond the JAK STAT pathway enabling both monotherapy activity as well as additive if not synergistic activity when combined with ruxolitinib. Similar to spleen volume reduction, we also see meaningful symptom improvement with selinexor monotherapy.

Speaker 2

As you see on slide 17, there was no improvement in symptoms for the patients randomized physician's choice. In contrast, the seven efficacy evaluable patients randomized to selinexor reported a 5.9 improvement in absolute TSS at week twenty four and twenty nine percent achieved a TSS 50. If you look at all patients treated with selinexor, including those that crossed over, this group reported a three point seven point improvement in absolute TSS and eighteen percent achieved a TSS 50 at week twenty four. Please note that all of these figures exclude the fatigue domain, which is consistent with how we are calculating absolute TSS in our Phase three SENTRY trial. As we have previously discussed, we have aligned with FDA on this approach and it is consistent with the COMFORT and Jakarta trials that led to approvals for ruxolitinib and fedratinib respectively.

Speaker 2

Turning to slide 18, we show how hemoglobin levels changed over time. Patients randomized to selinexor are shown in green. Patients on physician's choice are shown in blue. Visually, you can see that hemoglobin levels are substantially higher in the selinexor arm throughout the study duration. Let's take this a step further and look at transfusion burden as shown on slide 19.

Speaker 2

Starting with the swimmers plot on the left, we use the same colors from the prior slide. Patients randomized to selinexor are in green. Patients randomized to physician's choice are in blue. And patients that crossed over to selinexor are shown in the yellow extensions at the end of the blue lines. The red dots represent transfusions.

Speaker 2

Five patients were transfusion dependent at baseline, three in the physician's choice arm and two in the selinexor arm. Notably, patient four thousand one hundred twelve-three in the selinexor arm was transfusion dependent prior to randomization. Visually, you can see right away that patients that start on Physician's Choice received many more transfusions. Why? It is likely because XPO1 inhibition is modifying the underlying disease and helping the patients produce more healthy bone marrow.

Speaker 2

We expect to be able to answer this question more definitively with the results from the phase three SENTRY trial. Now we ask ourselves why are we seeing higher hemoglobin levels and less transfusion? Let's look at slide 20, which outlines the key cytokines that are relevant in myelofibrosis. Starting with myelofibrosis pathogenesis IL-six and IL-eight are relevant to malignant mutated clonal expansion, hepatosplenomegaly, and bone marrow angiogenesis. IL-six and IL-eight also affect constitutional symptoms and drive inflammation as does TNF alpha.

Speaker 2

Anemia is affected by IL-six, hepcidin and TNF alpha which plays a role in suppressing normal hematopoiesis and also blocks iron availability. Please keep all of this in mind as we review slide 21. We obtained plasma samples at baseline and again at week four on a subset of the patients that participated in the trial. Five from the selinexor arm and five from the physician's choice arm. We plotted the cytokine changes using a standard dendrogram plot.

Speaker 2

Blue and purple hues represent a decrease in cytokines. Red and peach hues represent an increase. The decreases are what we are looking for. As you look at the slide, please focus on the box in the middle of the screen. This is where the four cytokines that are relevant to myelofibrosis are shown.

Speaker 2

You'll see the arrows pointing to IL-six, IL-eight, hepcidin, and TNF alpha. For these four key cytokines, we are seeing clear reductions as early as week four in the selinexor arm, while there are increases in the cytokines in the physician's choice arm. In the blue box at the bottom, you can see the actual percentage changes including a 37% median reduction in IL-eight, 29 median reduction in IL-six, 25% median reduction in TNF alpha, and a 30% median reduction in hepcidin for those patients in the selinexor arm. In contrast, three of the four medians increased for the physician's choice arm. These data suggest that selinexor is modifying the underlying disease, something that JAK inhibitors have not been able to adequately demonstrate.

Speaker 2

Let's now turn to the safety data on slide 22. Selinexor continues to demonstrate a manageable safety profile. Selinexor similar to physician's choice for both all grade and grade three plus AEs. In particular, nausea was only 33% in the selinexor arm compared to physician's choice. Similar rates of thrombocytopenia were observed across the two arms.

Speaker 2

A notable exception is anemia, where both all grade and grade three plus anemia are meaningfully decreased in the selinexor arm compared to physician's choice. Specifically, all grade anemia was twenty five percent in the selinexor arm compared to fifty eight percent in the physician's choice arm and grade three plus anemia was seventeen percent in the selinexor arm compared to fifty eight percent in the physician's choice arm. These data are notable given that we are not only seeing higher hemoglobin levels and lower transfusion burdens, I discussed on the prior slides, but also lower anemia AEs in our safety data further suggestive of disease modification. Lastly, I'll note that none of the patients randomized to selinexor discontinued treatment due to an adverse event. Turning to slide 23, we are pleased that our phase three SENTRY trial successfully passed its pre specified futility analysis.

Speaker 2

The DSMB recommended that the study continue as planned without modification following a review of safety and efficacy data in the first sixty one patients, all of whom were followed for at least twenty four weeks. In the study, we continue to make strong progress towards our goal of enrolling three fifty patients. We expect to complete enrollment very shortly in the June timeframe. With the data that I just shared with selinexor monotherapy in a hard to treat heavily pretreated patient population, I'm very encouraged with the consistency that is being observed across our multiple clinical and preclinical data sets. These data continue to suggest that the combination of selinexor plus ruxolitinib has the potential to be clinically additive if not synergistic in a JAK naive patient population, thus leading to substantially higher SVR and TSS improvements as compared to each agent alone as observed in our phase one combination study.

Speaker 2

Together with the hemoglobin stabilization and lower transfusion burden, as well as the potential for disease modification, the data continue to suggest selinexor is affecting each of the four key hallmarks of myelofibrosis. We look forward to continuing to demonstrate this with the upcoming results from our Phase three SENTRY trial and building upon selinexor's well established safety profile with over thirty thousand patients treated across multiple indications and the potential for patient convenience with an all oral combination. Now let's shift our focus endometrial cancer where P53 wild type is such an important biomarker. As seen on slide 25, 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 of patients. Selinexor primarily functions by blocking the export of P53 from the nucleus to the cytoplasm.

Speaker 2

When P53 accumulates in the nucleus, it leads to disrupted DNA repair processes, cell cycle arrest and increased apoptosis. 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. On slide 26, we outlined the study design for our ongoing EXPORT EC042 trial. Enrollment in the trial is progressing steadily and we continue to expect to report top line data in the middle of twenty twenty six. Lastly, our Phase three EMN29 SPD trial is outlined on slide 28.

Speaker 2

This trial aims to address the unmet need of patients with multiple myeloma by offering an all oral triplet treatment option 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 first half of twenty twenty six. I will now turn the call to Silhanya.

Speaker 3

Thank you, Reshma. On slide 30, I will discuss our commercial highlights for Q1 twenty twenty five. We delivered 5% demand growth in Q1 year over year, although net product revenue was $21,100,000 and was adversely impacted by a $5,000,000 increase in the product return reserve due to atypical returns of expired product, primarily eighty milligrams and one hundred milligram XPOVIO units. These higher dose units were purchased by clinics and hospitals following the 2020 approval of the XPOVIO one hundred milligram triplet combination. The majority of XPOVIO that is prescribed today are forty milligrams and sixty milligram doses, and we expect product returns will be similar to historical levels in future quarters.

Speaker 3

As we look at the key drivers of demand in Q1, we delivered year over year growth in prescriptions across both academic and community settings of care, with the latter contributing to 60% of our sales. The multiple myeloma market remains highly competitive, and we are expecting additional new entrants this 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 compared to last year, we're seeing increasing use of XPOVIO immediately before and following T cell therapies. We expect to continue to display resilience in a competitive multiple myeloma market.

Speaker 3

And in light of the atypical level of returns in the first quarter, we now expect to be tracking towards the lower end of our guidance range for net product revenue of 115,000,000 to 130,000,000 Moving to slide 31, we continue to expand global patient access for selinexor, which is translating into growth in royalty revenue from Menarini, Antigene, and other international partners. Royalty revenue increased 57% to $1,700,000 in the first quarter of twenty twenty five compared to the first quarter of twenty twenty four, reflecting increasing global demand for XPOVIO and XPOVIO. As we now move to potential new indications, our commercial team is preparing for a very rapid launch in myelofibrosis, if approved. As outlined on slide 32, we continue to believe that our peak annual revenue opportunity in The U. S.

Speaker 3

Alone is up to approximately a billion with additional royalty and milestone revenue globally. On slide 33, we outline why we believe we are so well positioned for a rapid launch in myelofibrosis. As we have shared previously, seventy five percent 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.

Speaker 3

On this point, there is 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 34, we continue to believe that we have significant opportunity in the p53 wild type PMMR patient population, which represents approximately fifty percent of advanced or recurrent endometrial cancer patients. Similar to what I outlined for myelofibrosis, there's a large overlap between the potential community based oncologists caring for endometrial cancer patients and those that we're already engaging with. Now I'll turn the call over to Lori.

Speaker 4

Good afternoon, everyone, and thank you, Suhanya. 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 36. Total revenue for the first quarter of twenty twenty five was $30,000,000 compared to $33,100,000 for the first quarter of twenty twenty four. U. S.

Speaker 4

XPOVIO net product revenue for the first quarter of twenty twenty five was $21,100,000 compared to $26,000,000 for the first quarter of twenty twenty four. A decrease in net product revenue was due to an increase in the gross to net provision primarily related to the higher dose product returns recorded in the first quarter of twenty twenty five, resulting in a $5,000,000 increase in the product return reserve compared to the first quarter of twenty twenty four. Related to this, the gross to net provisions for XPOVIO in the first quarter was 45% compared to 29.3% in the same period in 2024. We expect our gross to net provisions will return to historic levels starting in the second quarter. R and D expenses for the first quarter of twenty twenty five were $34,600,000 compared to $35,400,000 for the first quarter of twenty twenty four.

Speaker 4

The decrease was due to reduction in headcount and contractors related to ongoing cost optimization initiatives, partially offset by increased clinical trial activity related to our pivotal Phase III study in mild fibrosis. SG and A expenses for the first quarter of twenty twenty five were $27,400,000 compared to $29,500,000 for the first quarter of twenty twenty four. The decrease was due to a reduction in headcount and contractors in connection with cost optimization efforts. We continue to be very diligent in allocating our resources prioritization while striving to deliver additional cost savings in 2025 and continuing to advance our phase three clinical trials and driving our commercial performance. We exited first quarter twenty twenty five with cash, cash equivalents, restricted cash, and investments of $70,300,000 compared to $109,100,000 as of 12/31/2024.

Speaker 4

As a reminder, cash burn is typically highest in the first quarter of each year. Based on our current operating plans, our guidance for the full year of 2025 is as follows. 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 Metarene and Antigene.

Speaker 4

U. S. XPOVIO net product revenue to be in the range of 115,000,000 to $130,000,000 As a result of the atypical level returns in the first quarter, we now expect total revenue and net product revenue will be towards the lower end of these ranges. R and D and SG and A expenses to be in the range of $240,000,000 to $255,000,000 And finally, we expect our existing cash, cash equivalents and investments, the revenue we expect to generate from Excovio net product sales, and other leases revenues and ongoing disciplined expense management will fund our planned operations into early Q1 twenty twenty six. This guidance does not include payment for the remaining 2025 convertible notes and our $25,000,000 minimum liquidity covenant under our term loan.

Speaker 4

Considering the repayment of the 2025 convertible notes and the minimum liquidity covenant, we expect cash, cash equivalents, and investments will fund operations into early Q4 twenty twenty five. In closing, we are exploring various opportunities to extend our cash runway and are focused on the advancement of our Phase III clinical trial, driving commercial performance, and continuing to be very diligent when allocating our resources. I will now turn the call back to Richard for some final thoughts.

Speaker 1

Turning to slide 38. As Lori mentioned, we are exploring various opportunities to extend our cash runway as we are focused on delivering the potentially transformational opportunity ahead of us in myelofibrosis, while also continuing to advance our Phase III trial in endometrial cancer and deliver solid commercial results. Myelofibrosis and endometrial cancer, depending on the outcome of the data, are both game changing opportunities for patients, our organization, and our shareholders alike. We are working hard to unlock our innovation and growth strategy and are very excited by our growing body of data and what it can mean for patients with myelofibrosis. Thank you again for joining us today, and I would now like to ask the operator to open the call up to the Q and A portion of today's call.

Speaker 1

Operator?

Operator

Thank you. Ladies and gentlemen, we will now begin the question and answer please press star followed by the two. I would like to advise everyone to have a limit of one question and one follow-up. And if you are using a speakerphone, please lift the handset before pressing any keys. One moment, for your first question.

Operator

And your first question comes from the line of Colleen Tissy from Baird. Please go ahead.

Speaker 4

Hi, good afternoon. Thanks for

Speaker 5

taking our questions. Congrats on the continued progress and the new data. Thanks for all the updates. So, the futility analysis, can you

Speaker 4

talk about what that was based on and what the options were? Could the study have been upsized if the DSMB had suggested it?

Speaker 1

Yeah, thanks Colleen. I'll let Reshma go into the details of that from the futility analysis. Resh?

Speaker 2

Yeah, thanks Colleen for the question. So there was a futility analysis that was conducted earlier this year. And it was specifically based upon efficacy and safety that was observed in the first sixty one patients, all of whom were followed for twenty four weeks. For the efficacy, the DSMB had the unblinded data for both SVR35 in that cohort as well as absolute TSS. Those efficacy analyses had pre specified thresholds.

Speaker 2

Essentially, the thresholds amounted to no worsening for the combination relative to ruxolitinib alone. For the safety, again, they were also provided the unblinded safety data from that cohort and there was no pre specified bars for that analysis. That was really based upon their qualitative assessment of the totality of that safety data. As you noted, they passed the futility and recommended that study just continues as planned as we are now doing. Enrollment is now expected to complete in the JuneJuly timeframe.

Speaker 5

That's helpful. Thanks. And then I believe in prior quarters, you talked about a two point delta in average TSS being in a stat sig range for MANIFEST II. I think on your slide you talk about the powering the primary endpoints about a four point delta on TSS. So can you just talk about what you're expecting to need to hit on TSS for it to be a positive study?

Speaker 2

Sure, so great questions. These are just our assumptions. So with three fifty patients, we are assuming a delta of four across the two arms and a standard deviation 12 for each of these two arms. Incorporating those assumptions, the overall power for hitting on absolute TSS is going to be greater than 80%. So these are just our assumptions.

Speaker 2

In reality, as you know, the data can differ. We still maintain that a clinically meaningful outcome is just improvement for the combination above and beyond what ruxolitinib alone demonstrates. But, you know, again, that four point delta and standard deviation of 12 are just, again, the stat assumptions that drive the overall power.

Speaker 5

Got it. That's helpful. And if I can

Speaker 4

squeeze in one more quick one. The enrollment looks to be

Speaker 5

slightly behind schedule for the phase three myelofibrosis entry study.

Speaker 2

Can you speak to some of the

Speaker 5

enrollment dynamics you're seeing that's putting you kind of towards the end, the bottom half of the range? Thanks.

Speaker 1

Yeah, I think, you know, enroll. Go ahead, go ahead.

Speaker 2

Sorry. Yeah, sorry. We stepped over each other, but good question again, Colleen, you know, sort of like when we put together the enrollment curves, we were really looking at a lot of data, especially historical trials, TRANSFORM as well as MANIFEST. We were getting a lot of information from the sites and really understanding sort of that competitive intensity or lack thereof that is occurring in the field of myelofibrosis specifically in this patient population. I will admit, sort of like what we've seen in the last few months, especially in 2025, suggests that it's a little slower than expected.

Speaker 2

Things are still very robust, both from screening as well as enrollment. But again, a little slower than what we had anticipated, which is what is driving that slight delay in the enrollment timeframe.

Speaker 5

Got it. That's helpful. Thanks for taking our questions.

Speaker 1

Thanks, Colleen.

Operator

Thank you. And your next question comes from the line of Maury Raycroft from Jefferies. Please go ahead.

Speaker 6

Hi, this is Amy on for Maury. Thank you for taking our questions. We have two questions for the myelofibrosis Phase III trials. The first one is, can you talk about your assumptions to getting into the full enrollment in this June and July? Will you do a press release when you achieve the target enrollment?

Speaker 6

And also, can you talk more about the baseline characteristics of the patients today, or will you provide more colors on the baselines when the trial is fully enrolled? I have a quick follow-up after this one.

Speaker 1

Yeah, can take the first part of that. You know, our expectations and where we are now is really aligned with what Reshma talked to. We're 80% enrolled. We have visibility into the number of people in our screening and pre screening process. So, you know, we expect to complete enrollment in the JuneJuly timeframe, as Raishma shared.

Speaker 1

And when we do complete our target enrollment, yes, we will share that in a press release. Maybe for the second part of the question, I'll turn that over to Raishma for some of baseline characteristics that we're seeing in the trial.

Speaker 2

Yeah, sure. So for the baseline characteristics, and then again, this is just a quick snapshot, I mean, to your question, you know, will we provide the baseline characteristics for the full population? Yeah, absolutely, and we anticipate being able to do so in the next few months after enrollment is completed. With that said, to just give a little bit of visibility, the patient population by and large is going to be similar to our phase one trial. Again, these are gonna be your JAK naive myelofibrosis patients.

Speaker 2

All of the patients have to have a baseline platelet count above 100. With that said, they're a little less cytopenic than what we saw in our phase one. So their baseline hemoglobins are slightly higher than what we saw in our phase one. Also baseline platelet counts are slightly higher than what we saw in our phase one. Breakdown by dips is very consistent with what you would expect for a JAK naive myelofibrosis population.

Speaker 2

I think the one key difference is going to be baseline symptom scores. So in our phase one population, we didn't have any requirement for that baseline TSS. In our phase three, we do. So patients do need to be symptomatic. We actually have a threshold.

Speaker 2

So overall, you are going to see higher baseline TSSs for this population, again, as compared to the phase one.

Speaker 6

Thank you. That's very helpful. The follow-up is, can you talk a little about, if you see anything, the patient compliance in the daily measurement of the TSS score, and how does that compare to your expectations and other myelofibrosis Phase III trials? And what are yep, that's it.

Speaker 2

I can take that one as well. So compliance is really good. So this is something that we've been laser focused on from the very beginning of the trial. So we use an ePro vendor, an electronic PRO vendor who follows the data, alerts goes out to the patients, we're notified if a patient doesn't happen to complete one of their daily TSSs. It just gives us visibility in terms of the data such that if a patient were to miss something, we're able to go ahead and talk to the site and ensure that that patient gets back on track.

Speaker 2

So overall that compliance, we're really happy with that very high compliance on those daily TSS forms. In terms of how that's comparing to other trials, I don't know. I'm not aware of any data regarding the compliance from other phase three trials including manifest transform. Again, I got to say I'm very happy with where we are right now with our phase three.

Speaker 6

That's very helpful. Thank you so much.

Speaker 1

Thank you, Amy.

Operator

Thank you. And your next question comes from the line of Ted Tenthoff from Piper Sandler. Please go ahead.

Speaker 7

Great, thank you very much. Two questions, if I may. Firstly, when it comes to multiple myeloma, what really is driving utilization now? And what are some of the potential marketing synergies between the existing sales force and if we hopefully get positive myelofibrosis data? How would that, you know, sort of jumpstart your sales efforts in MF?

Speaker 7

Thanks.

Speaker 1

Yeah, thanks, and I'll take the second part of that and then I'll turn it back to Sohani to take the first part. You know, when you look at our existing commercialization capabilities and the alignment or synergy with myelofibrosis, we have about eighty percent overlap. So a significant number of patients are seen in the community. We have strong capabilities across our commercial team, across our access team, across our global medical and scientific affairs teams. So I think there's a really high level of synergy that would enable us to move forward rapidly with really minimal additional investments.

Speaker 1

And I'll turn to Sohania to take the question on the first part about multiple myeloma.

Speaker 3

Thanks, Ted, for the question. So, we were really pleased with the resilience of the team and ability to grow demand in an increasingly competitive marketplace year over year, so 5% growth in Q1. And as you look at sort of the underlying drivers of that growth, importantly, we were able to grow in the community setting as well as in the academic setting. If you kind of break it down into the two settings of care in the community setting, we continue to be used as a flexible combination therapy, a convenient oral, about fifty to sixty percent of our patients are in that earlier line, second to fourth line setting, primarily treated in the community setting, following an anti CD38 therapy. But also importantly, for patients that come to the community that either fail a T cell engaging therapy or just are not ineligible or don't have access to it.

Speaker 3

Now, switching to the academic setting, we're positioning XPOVIO with our increasing body of evidence in that pre and post T cell engaging therapy setting, and we're seeing increasing use there, which really led to the growth in the academic setting in Q1 year over year. Again, it's a highly competitive landscape, as you know, but we continue to have a unique positioning as a differentiated mechanism of action, both in the community and academic settings. And again, to reinforce to your second point, what Richard mentioned, obviously a high level of synergy in the positions we already call on, but our capability, infrastructure that we have built in the past five years really sets us up well for a rapid launch in myelofibrosis if approved.

Speaker 7

Great. Thank you for all that extra color.

Speaker 1

Thanks, Dan.

Operator

Thank you. And your next question comes from the line of Peter Lawson from Barclays. Please go ahead.

Speaker 8

Hey. Thanks so much. Thanks for taking the question. Just on the the return product, in 1Q. So that's $5,000,000 What's what's the normal run rate of return product?

Speaker 8

And are there any further risks of revenue shortfall or return product in 2Q and 3Q that we should be thinking about?

Speaker 1

Yeah. Thanks, Peter. At a high level, no. And I'll get Laurie to go into the details, but I think as Reshma and Laurie both talked to, this really is, you know, five million atypical impact from high dose returns, and Laurie, maybe you can just expand on that.

Speaker 4

Yes, hi Peter. So if you think about these returns, they were to support the Boston launch, which we talked about, which was really our sales in '21 and '22. So if you think about it, that's over 220,000,000 in sales, and this impact was less than 2%. So if it when and then when you look going forward, I think it's important to know that these atypical returns, these high doses, this is the expiry window that opened for the these returns. Going forward, as Sahana mentioned, it translates more to the forty and the sixty milligram doses that we're seeing.

Speaker 4

So we don't expect this to carry on into future quarters. And so we really do believe this is isolated to this quarter when this window opened and relative to all of the sales, it still was below 2%. And then we expect going forward, we'll continue to kind of get back to our more historic levels that we see for doses more in the forty and sixty milligrams.

Speaker 8

Thank you. Laurie, you mentioned about extending the cash runway. How are you thinking about further authorization between business development, equity raises, and restructuring?

Speaker 4

So it's a very important question. How are we planning on extending our cash runway? I mean, we understand the importance of being well capitalized. As Richard mentioned, and I both mentioned on the call, we are exploring various alternatives to extend that cash runway. We'll continue to evaluate our cash runway and financial position, basically how best can we deliver these Phase III clinical trials and get to these top line data readouts.

Speaker 4

But beyond this, I cannot really provide specific details at this time.

Speaker 8

Okay. Thank you so much.

Speaker 1

Thank you, Peter.

Operator

Thank you. And your next question comes from the line of Jonathan Chang from Leerink Partners. Please go ahead.

Speaker 1

Hi. This is Albert Agustinos dialing in for Jonathan Chang. Thanks for taking my question. Will you be able to give us reasons for confidence that you can still reach your revenue guidance? Thank you.

Speaker 1

Yeah. I think, you know, as as you heard, you know, from Sonia and you heard from Lori, we're guiding towards the lower end of our revenue guidance given the impact, this 5,000,000 impact of our atypical high dose returns. You heard with regards to our US business, 5% demand growth year over year. We heard very strong growth from our global partners. So yes, we believe we're going be seeing ourselves deliver in the lower end of our guidance from a global revenue perspective and from a US revenue perspective.

Speaker 1

Thank you. That's very helpful. Thank you.

Operator

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

Speaker 9

Hi team, this is Kevin on for Brian. Thanks for taking our questions. Just had a follow-up on the futility analysis. Can you remind us if this was pre specified before the study expansion and co primary endpoint change and if or if it was something maybe that the FDA, you know, was asking about with the protocol amendment? And then just speaking of FDA, have you had any further interactions with the agency in the meantime?

Speaker 9

And just maybe how would you characterize those interactions? Thank you.

Speaker 2

Yeah, thank you, Kevin. I can take that one. So yes, this was pre specified and this futility analysis was part of the trial from the very beginning, so from the initial protocol. Nothing that has happened either with the endpoints or even in the increase in the trial size from 300 to three fifty, you know, prompted incorporation of that futility analysis. In terms of the FDA conversations, sort of like, as we've mentioned in the past, the bulk of them were really around that endpoint change, specifically the change from TSS 50 to absolute No additional conversations at this time, and we're just, again, looking forward to completing enrollment and providing top line results at the end of this year, beginning of 'twenty six.

Speaker 8

Great. Thank you.

Operator

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

Speaker 1

Thank you, operator, and once again thank you everyone for joining us today. As you heard through the call, we are very focused and very excited about the transformational opportunity we have ahead of us in myelofibrosis very much in the near term, as the team's focus on completing enrollment through JuneJuly and reading up the top line data through the end of this year or early next year. The consistency we see in the strength of our data that Reshma shared again today in a difficult to treat, more severe patient population with multiple lines of therapy, has continued to build our confidence and strength in the potential for selinexor plus ruxolitinib to become the new standard of care, pending positive data in JAK naive patients. So once again, you for joining us.

Operator

Thank you. And this concludes today's call. Thank you for participating. You may all disconnect.

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Key Takeaways

  • Phase III SENTRY trial in JAK-naive myelofibrosis passed its pre-specified futility analysis and is ~80% enrolled, with completion expected in June-July and top-line data by late 2025/early 2026.
  • Phase II Export MF035 monotherapy data show selinexor achieved more than double the SVR35 rates versus physician’s choice, meaningful symptom improvement, higher hemoglobin levels, lower transfusion burden, and significant reductions in key cytokines, all with a manageable safety profile and reduced anemia rates.
  • Q1 net product revenue for XPOVIO was $21.1 M (up 5% year-over-year in demand) despite a $5 M increase in product return reserves; global royalty revenue rose 57%, and 2025 guidance is $115–130 M U.S. net product revenue and $140–155 M total revenue, now expected at the lower end due to atypical returns.
  • Cash, cash equivalents, restricted cash, and investments totaled $70.3 M at quarter end, with typical Q1 burn; the company expects funding into early Q1 2026 (or Q4 2025 including debt covenants) and is exploring options to extend its cash runway.
  • Pipeline advancement includes a Phase III trial in p53 wild-type endometrial cancer (top-line mid-2026) and a Phase III multiple myeloma triplet trial (top-line H1 2026), while myelofibrosis market potential in the U.S. could reach up to $1 billion if approved.
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