Karyopharm Therapeutics Q4 2024 Earnings Call Transcript

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Provided by Quartr
February 19, 2025

There are 9 speakers on the call.

Operator

Good morning. My name is Joelle, and I

Speaker 1

will be your conference operator today. At this time, I would like

Operator

to welcome everyone to the Karyopharm Therapeutics Fourth Quarter and Full Year twenty twenty four 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 Tim Strong, Senior Vice President, Investor Relations and Corporate Communications.

Speaker 2

Thank you, Joelle, and thank you all for joining us on today's conference call to discuss Carrier Farm's fourth quarter and full year twenty twenty four financial results and recent company progress. We issued a press release this morning detailing our financial results for the fourth quarter and full year 2024. This release along with the slide presentation that we will reference during our call today are available on our website. For today's call, as seen on Slide two, I'm joined by Richard, Reshma, Sohanya and Lori, who will provide an update on our results for the fourth quarter twenty twenty four and recent clinical developments. Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995 as outlined on Slide three.

Speaker 2

Actual results may differ materially from those indicated by these forward looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent Form 10 Q or 10 K on file with the SEC and in other filings that we will 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 2

Please turn to Slide four.

Speaker 3

Good morning. Thank you, Brendan, and thank you all for joining us today for Theriault Farms Q4 twenty twenty four earnings call. In 2024, we delivered solid financial results, delivering on our range of guidance with a profitable U. S. Commercial organization and growing global demand in multiple myeloma.

Speaker 3

We continue to execute well on our cost reduction initiatives, reduce total expenses, particularly SG and A, while focusing resources on our Phase three clinical trials. Turning to Slide five, in 2025, we expect to grow EXPOVIO net product revenue, further reduce expenses and advance our transformative programs in myofibrosis and endometrial cancer, unlocking our innovation and growth strategy. Importantly, for 2025, we remain on track to complete enrollment in our Phase three SENTRI trial in the first half of this year and announce top line data in the second half of this year. Today, we are announcing modifications to our Phase three trial in endometrial cancer following discussions with the FDA in recent months. Our endometrial cancer data could become a key catalyst for us in 2026.

Speaker 3

First, let's focus on the transformational opportunity in 2025 to redefine the standard of care in myelofibrosis. As we think about our potential in myelofibrosis, it is worth remembering how we got here, which is outlined on Slide six. We've been taking deliberate steps over many years to put us in the position we are in today. This started with preclinical activity of myelofibrosis followed by demonstrating a clear monotherapy signal in the ESSENTIEL investigator sponsored trial that was presented at ASH in 2021. Following this, we initiated a Phase one study of selinexor in combination with ruxolitinib in JAK inhibitor naive patients.

Speaker 3

We presented data from this trial at ASH in both 2022 and 2023. This data demonstrated a strong signal of benefit for the combination of selinexor and ruxolitinib. Based on this signal, we received both Fast Track designation and orphan drug designation from the FDA and rapidly initiated our Phase three SENTRY trial. We also watched and learned as other clinical trials evolved and aligned with the FDA last year on a change in our co primary endpoint to absolute TSS. This was a very favorable change that we believe increases the probability of success of our Phase three SENTRI trial and a change that is strongly supported by leading KOLs and patient advocacy organizations.

Speaker 3

We continue to progress our Phase three SENTRI trial faster than historical benchmarks, while remaining incredibly focused on high quality clinical trial execution. As I noted earlier, we remain on track to complete enrollment in the first half of this year with top line data expected in the second half of twenty twenty five. As outlined on Slide seven, leading KOLs in myofibrosis including Doctor. 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 data.

Speaker 3

Finally, I cannot overstate how transformational this opportunity could be for our organization. As shown on Slide eight, we believe the peak revenue potential for selinexor in myofibrosis, if approved, is approximately $1,000,000,000 in The U. S. Alone. We are eager to see the outcome of our Phase three trial and the potential opportunity ahead.

Speaker 3

Now, I'd like to turn the call over to Reshma to discuss our programs in myelofibrosis, endometrial cancer and multiple myeloma. Reshma?

Speaker 1

Turning to Slide 10, as Richard mentioned, we are focused on delivering top line data from our Phase three SENTRY trial in myelofibrosis in the second half of this year. Let's start by reviewing the unmet need in JAK naive myelofibrosis on Slide 12. SOLINXOR's potential to help patients with myelofibrosis and our opportunity to redefine the standard of care as the first combination therapy. First, I think it is a helpful reminder that only approximately one third of ruxolitinib alone. As we have shared before, our Phase one data show that selinexor plus ruxolitinib more than doubled that SVR 30 five rate.

Speaker 1

Second, there has been a lack of new treatment options given that JAK inhibitors are the only approved class of therapies. Ruxolitinib has been the standard of care for over thirteen years as the potential first combination therapy in myelofibrosis. Selinexor plus ruxolitinib would be a convenient all oral therapy that the myelofibrosis community has clearly indicated interest in adopting given the rapid deep and durable spleen reductions in symptom improvement observed from the Phase one study. Third, there is minimal evidence of disease modification with JAK inhibitors. As we have discussed in the past along with the additive, it's not potentially synergistic clinical efficacy observed with selinexor and ruxolitinib, the combination also has the potential to enable disease modification.

Speaker 1

Let's now discuss why we believe selinexor as an Xp01 inhibitor is a rational mechanism to evaluate in patients with myelofibrosis starting on Slide 13. Selinexor prevents the nuclear export of various proteins and messenger RNA molecules. By doing so, it promotes the nuclear localization and activation of P53, an important tumor suppressor in MF given that ninety five percent of myelofibrosis patients are P53 wild type. We'll review our data in myelofibrosis momentarily. But before we do, I think it is worth remembering that in long term follow-up from analysis from SIENDO as shown on Slide 14, a median progression free survival of twenty eight point four months was observed in those patients with P53 wild type endometrial cancer.

Speaker 1

These clinical data further demonstrate selinexor can achieve in tumors that are P53 wild type. Moving to the data from our Phase one trial evaluating selinexor and ruxolitinib in JAK naive myelofibrosis patients as outlined on Slide 15. Amongst the 14 patients who received selinexor sixty milligrams plus rexolitinib, all the valuable patients achieved in SVR thirty five at any time and seventy nine percent of patients in the ITT population achieved in SVR 35 at week twenty four. Lean volume reduction is viewed as one of the most important factors by treating physicians given its correlation to overall survival. Turning to Slide 16, durability of response is also a key efficacy measure relevant to JAK naive patients.

Speaker 1

Our Phase one data demonstrate a one hundred percent probability of continuing response for both SVR35 and PSS50 over a median duration of follow-up of thirty two weeks and fifty one weeks respectively. This is particularly meaningful as it suggests that once patients achieve a response, they remain in response. This is a reason why leading physicians have indicated that the combination of selinexor plus rexolitinib should be initiated in all JAK naive myelofibrosis patients pending the outcome of our Phase three SENTRI trial. On Slide 17, the shift to absolute total symptoms score as as a co primary endpoint increases our overall confidence in the Phase three SENTRY trial. Using absolute TSS to assess the average improvement in symptoms over twenty four weeks has gained support from the FDA, investigators and patient advocacy groups as a more sensitive method to assess symptom improvement in myelofibrosis.

Speaker 1

On Slide 18, the depth of symptom improvement was sixty milligrams of selinexor plus ruxolitinib in our Phase one trial can be seen in comparison to historical data from ruxolitinib monotherapy. The average reduction, which signifies improvement in absolute TSS of 18.5 points with our combination compares favorably to the average of 11 to 14 reduction that have been observed with bruxolitinib alone in prior Phase three clinical trials conducted by others. The rapid deep and durable findings observed with SVR35 is also observed with average TSS as seen on Slide 19. This was seen as early as week four despite any side effects that the patients may have experienced from the treatments. These symptom improvements continued through week 24 demonstrating meaningful sustained symptom improvement for the entire six month duration evaluated.

Speaker 1

For the adverse events experienced, the most common were nausea, anemia, thrombocytopenia and fatigue. Even with this, you see very meaningful improvements in symptom scores over time. Turning to Slide 20, we continue to make strong progress towards our goal of enrolling three fifty patients into the SENTRI trial and remain on track to complete enrollment in the first half of this year. In summary, on Slide 21, I am eagerly anticipating the data from the SENTRI trial in the second half of twenty twenty five. Our clinical data thus far has shown deep spleen volume reduction over two times what has been seen with ruxolitinib mono therapy, robust symptom improvement, durable responses, a well established safety profile with approximately thirty thousand patients treated across multiple indications

Speaker 4

and

Speaker 1

the potential for patient convenience with an all oral combination. Now let's shift our focus to endometrial cancer, where we are providing an important update on our plans for our Phase three trial following dialogue with the FDA over the past few months on the evolving treatment landscape. The key highlights are on Slide 23. As you may recall, our original design for this trial involved enrolling two twenty patients with P53 wild type endometrial cancer regardless of MMR status. In late twenty twenty four and early twenty twenty five, we had productive discussions with the FDA, during which the FDA recommended we take into account the evolving standard of care, specifically checkpoint inhibitors that were approved in combination with chemotherapy followed by checkpoint inhibitor maintenance for patients with advanced recurrent endometrial cancer.

Speaker 1

In addition, the FDA acknowledged that the efficacy observed in the PMMR tumors is less than in DMMR tumors, consistent with the biology and mechanism of this class of therapies and suggested that we focus our trial population on patients with PMMR tumors. In light of this suggestion, we are introducing a new modified intent to treat population that will consist of approximately two twenty patients with PMMR tumors or patients who have DMMR tumors, but are medically ineligible to receive checkpoint inhibitors. Although this latter group may be small, we are including them given that this patient population has no other treatment options, as well as the encouraging data from the Sienda subgroup indicating that patients with P53 wild type tumors may benefit from selinexor regardless of MMR status. Given that roughly approximately eighty percent of patients enrolled to date meet the new eligibility definition, the ITT population will now enroll approximately two seventy six patients, which will enable us to maintain approximately two twenty patients in the MITT population, which are again P53 wild type PMMR or DMMR medically ineligible to receive a checkpoint inhibitor. As a result of the increased trial size, we now expect to have top line data in mid-twenty twenty six.

Speaker 1

We believe that the changes that we plan on implementing may provide us with the data we need to seek regulatory approvals in The United States and globally. Now let's revisit why P53 wild type is such an important biomarker that we believe can accurately identify patients who will benefit from selinexor therapy on Slide 24. Selinexor primarily functions by blocking the export of P53 from the nucleus to the cytoplasm. When P53 accumulates in the nucleus, it leads to disrupted DNA repair processes, cell cycle arrest and increased apoptosis. This mechanism is underscored by the antitumor effects in P53 dependent tumors, specifically in endometrial cancer.

Speaker 1

As seen on Slide 25, patients with both PMMR and P53 wild type tumors make up approximately fifty percent of all advanced or recurrent endometrial cancer cases, representing a very sizable group of patients. On Slide 26 from the long term follow-up of the ciendo exploratory subgroup data, selinexor has the potential to provide promising outcomes for advanced recurrent endometrial cancer patients with P53 wild type PMMR tumors with a median PFS benefit of thirty nine point five months observed with selinexor compared to the four point nine months observed with placebo corresponding to a hazard ratio of 0.36. Although we acknowledge the limitations of cross trial comparisons, it's important to note that the PFS improvement with selinexor in this subgroup exceeds the median overall survival achieved by checkpoint inhibitors in PMMR patients, emphasizing selinexor's substantial efficacy for these individuals. The safety data in endometrial cancer patients from the SIANDA trial is displayed on Slide 27. It's important to note that the adverse events associated with selinexor were generally manageable and well tolerated.

Speaker 1

Nausea, vomiting and diarrhea were the most frequently observed adverse events regardless of grade. Notably prophylactic dual antiemetics were not incorporated into the SANDO trial, whereas dual antiemetics for the first two cycles are required in EC-forty two and all of our Phase three trials including SENTRI. We anticipate the safety profile from our Phase three trials will be improved given the incorporation of these antiemetics as well as the lower starting doses of selinexor. 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 28, we outlined the updated study design for our EXPORT EC-forty two trial consistent with the key changes that I highlighted earlier.

Speaker 1

Given these changes and the increased number of patients we plan to recruit, we expect to report top line data in mid-twenty twenty six. Lastly, our Phase III EMN SPD trial is outlined on Slide 30. This trial aims to address the unmet needs 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 have completed enrollment in this trial with approximately 120 patients and intend to provide an update once we have concluded our engagement with regulatory agencies on this trial. I will now turn the call to Solania.

Speaker 1

Thank you, Reshma, and good morning. On Slide 32, I will discuss our commercial highlights for 2024. Exovio net product revenue was $29,300,000 for the fourth quarter, similar to what we delivered in the third quarter and up 16% compared to the fourth quarter of last year. I am very pleased with how our organization responded to increased competition that pressured revenue last year. For the year, we delivered within our guidance range for EXPOPIO with net product revenue of $112,800,000 up from $112,000,000 in 2023.

Speaker 1

This gain was achieved despite the introduction of new medications in the second half of twenty twenty three into what was already a highly competitive multiple myeloma market and also a substantial increase in our growth to net. Even with the increased competition, demand for EXPOVIO was consistent in 2024 versus 2023 with 60% of our sales coming from the community setting. Community physicians continue to find value in EXPOVIO as an oral, convenient, flexible therapy in a landscape with several complex medicines that are potentially challenging for many patients and community based physicians to access. In the academic setting, we continue to see EXPOPIO being used pre and post T cell therapies. And in January, the International Myeloma Working Group, a globally recognized myeloma expert committee, published updated recommendations for sequencing immunotherapies.

Speaker 1

This includes recommendations of EXPOVIO as a bridging option prior to CAR T and also as a treatment for patients who have disease progression following an anti BCMA treatment. These recommendations are built upon a growing body of evidence we have generated exploring the potential role for EXPOVIO in promoting an anti tumor immune microenvironment. Moving now to Slide 33, we received a number of reimbursement approvals internationally throughout 2024 that triggered additional regulatory milestone payments. And with these increasing number of approvals, we are seeing our underlying royalty revenues on international sales becoming more meaningful and will continue to grow over time. As Richard and Reshma both mentioned, our organization's biggest area of focus in 2025 is our Phase three readout in myelofibrosis and our commercial team is preparing for this opportunity.

Speaker 1

As outlined on Slide 34, we continue to believe that our peak revenue opportunity in The U. S. Alone is approximately $1,000,000,000 annually if approved with additional royalty and milestone revenue globally. On Slide 35, we outline why we believe we're so well positioned for a rapid launch in myelofibrosis. As we've 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.

Speaker 1

If selinexor is approved in combination with ruxolitinib, we could be the first combination therapy on the market. We would be an all oral therapy, which makes adoption much easier, especially in the community setting. On this point, we believe there is an eighty percent overlap between the physicians that we would target in myelofibrosis and the group of physicians that our organization is already calling on in multiple myeloma. And the same overlap applies to our patient support programs and medical affairs organization. This means two things.

Speaker 1

First, we should be able to launch rapidly because we have already trusted relationships with many physicians. Second, the upfront investment required for us to launch in mala fibrosis would be minimal since we can launch with our existing organization. Finally, in endometrial cancer shown on Slide 36, we continue to believe that we have a significant opportunity in the P53 wild type and PMMR patient population, which represents approximately fifty percent of advanced or recurrent endometrial cancer patients. Similar to what I outlined for myelofibrosis, there is a large overlap between the potential community based oncologists caring for endometrial cancer patients and those that we are already engaging with. Now bringing it back to our commercial focus for 2025, it will remain strongly on driving EXPOPIO revenue growth in 2025 following the success we delivered in the second half of twenty twenty four as well as planning for a successful launch in myelofibrosis if approved.

Speaker 1

Now I'm delighted to turn the call over to Lori for the first time to give an update on our financial results and guidance.

Speaker 5

Good morning, everyone, and thank you, Sohanya. It is a pleasure to be participating in my first Karyopharm earnings call. I look forward to getting to know many of you personally. 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, starting on Slide 38.

Speaker 5

Total revenue for the fourth quarter of twenty twenty four was $30,500,000 compared to $33,700,000 dollars for the fourth quarter of twenty twenty three. This decrease was primarily due to lower milestone related revenue from our licensing agreements. Total revenue for the year was $145,200,000 compared to $146,000,000 in 2023. U. S.

Speaker 5

Exboeo net product revenue for the fourth quarter of twenty twenty four was $29,300,000 compared to $25,100,000 for the fourth quarter of twenty twenty three. For the full year, U. S. Exboeo net product revenue was $112,800,000 compared to $112,000,000 in 2023. The gross to net discount for EXPOVIO in the fourth quarter and full year 2024 was 33.330.9% compared to 23.522.3% in the same periods in 2023.

Speaker 5

The increase in both periods was primarily driven by 340B utilization and Medicare rebates. We expect the gross to net discount to be similar in 2025 to 2024. And as seen in previous years, it is expected to be higher in the first quarter than our average for 2025. R and D expenses for the fourth quarter twenty twenty four were $33,300,000 compared to $39,400,000 for the fourth quarter of twenty twenty three and $143,200,000 for the year ended 12/31/2024 compared to $138,800,000 for the year ended 12/31/2023. The increase in R and D expenditure in both periods was attributable to the advancement of our pivotal Phase three studies, partially offset by a reduction '24 were $27,200,000 compared to $30,700,000 for the fourth quarter of twenty twenty three.

Speaker 5

SG and A expenses for the year ended 12/31/2024 were $115,400,000 compared to $131,900,000 for the year ended 12/31/2023. The decrease in both periods was due to reduction in headcount and contractors in connection with cost optimization efforts. On a combined basis, R and D and SG and A were $258,700,000 for the year towards the lower end of our guidance of two fifty five million dollars to $265,000,000 As a result, we delivered $12,000,000 of annual savings compared to 2023, while advancing three Phase three clinical trials. We continue to be very diligent in allocating our resources and pipeline prioritization, delivering additional cost savings in 2025, while continuing to advance our Phase three clinical trials and driving our commercial performance. We exited the year with cash, cash equivalents, restricted cash and investments of $109,100,000 compared to $192,400,000 as of 12/31/2023.

Speaker 5

Based upon our current operating plans, we are introducing guidance for the full year of 2025 as follows: total revenue of $140,000,000 to $155,000,000 consisting of U. S. Exboeo net product revenue and license, royalty and milestone revenue expected to be earned from our partners, primarily Medarini and Antigene. We are projecting U. S.

Speaker 5

ExboVio net product revenue to be in the range of $115,000,000 to $130,000,000 R and D and SG and A expenses will be in the range of $240,000,000 to $255,000,000 And finally, our guidance for cash runway remains unchanged. We expect our existing cash, cash equivalents and investments, the revenue we expect to generate from ex FOVIO net product sales and other license revenues and ongoing disciplined expense management and cost saving measures will be sufficient to fund our planned operations into Q1 twenty twenty six. This guidance does not include payment for the remaining twenty twenty five convertible notes and our $25,000,000 minimum liquidity covenant under our term loan. Considering the repayment of the 2025 convertible notes and the minimum liquidity covenant, we expect cash, cash equivalents and investments will be sufficient to fund operations into the fourth quarter of twenty twenty five. In summary, we are focused on the advancement of our Phase three clinical trials and driving commercial performance, while continuing to be very diligent when allocating our resources.

Speaker 5

We expect our 2025 operating expenses to be lower than 2024 as we recognize the full year benefits of our ongoing cost saving initiatives. We will actively engage in exploring various financing and business development activities to extend our cash runway to fund our operations into 2026 and beyond. I will now turn the call back to Richard for some final thoughts.

Speaker 3

Turning to Slide 40. In 2025, we expect to grow EXPOLIO net product revenue and advance our transformative programs in myofibrosis and endometrial cancer, working hard to unlock our innovation and growth strategy. Biofibrosis and endometrial cancer depending on the outcome of the data are both game changing opportunities for patients, our organization and our shareholders alike. As Laurie just stated, as we deliver on 2025, we will also be working to explore various financing and business development activities to strengthen our financial resources and extend our cash runway. In 2025, our number one priority is to deliver on myelofibrosis.

Speaker 3

As seen on Slide 41, we are on track to complete enrollment in the first half of this year and eagerly await sharing the top line data in the second half of the year. Pending positive data, we are excited by the opportunity to meaningfully improve clinical outcomes for myofibrosis patients with the support of leading physicians and patient advocacy organizations and rapidly bringing a combination of selinexor plus ruxolitinib to patients. 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. Operator?

Operator

Thank you. Your first question comes from Colleen Cousy with Baird. Your line is now open.

Speaker 6

Great. Thanks. Good morning and thanks for taking our questions. So for the myelofibrosis Phase three, I know you walked us through the data again, showed an 18.5 reduction in TSS for the combo versus 11 to 14 for Uxalone. So what reduction in TSS in the Phase three would help would make you reach that Sig?

Speaker 6

Just trying to figure out how much of a buffer your stats offer you in the Phase three? And then I have a follow-up, please.

Speaker 3

Yes, Pauline, thank you. For the first part of that, I think I'll turn to Reshma to talk to that and then let's follow-up on your second question.

Speaker 1

Yes. Thanks, Colleen. Great question. So when we look at our data, we really have a lot of room to be able to demonstrate not only clinical and significant benefit, especially when we look at that absolute TSS. The data suggests, right, and you alluded to that with our 18.5 improvement relative to the 11.11 to 14 improvement that we see with bruxolitinib in contemporary Phase III trials, we really could see a delta of three, four plus points.

Speaker 1

So we feel very comfortable that we can see a very meaningful difference and improvement in that absolute TSS. When we talk about the statistical aspect, we know from previous Phase three trials and I'll allude to the MANIFEST trial that STAT SIG was actually demonstrated with something far more I'm sorry, far more narrow. In fact, Daystar sat SIG with really only about a two point difference. So that gives you some context in terms of the data that we could provide from our Phase three, as well as the delta that would need to be seen to show STAT6IG. We haven't provided any of the details specifically from our Phase three trials.

Speaker 1

However, just note that we are using that information to really guide our powering assumptions as well as the delta that we can anticipate from this ongoing Phase three SENTRI trial.

Speaker 6

Super helpful. Thank you. And then

Speaker 1

can you give a little more color

Speaker 6

on the conversation that you had with the FDA around the endometrial study, kind of what drove the need for the meeting? And was there anything in the early PMMR data that made the FDA direct you towards just the DMMR population?

Speaker 1

Yes, absolutely. So as we announced back in December of twenty twenty four, we were engaged with the FDA, specifically evolving the treatment landscape in endometrial cancer. So back when we had discussed with the FDA in 2022 prior to the start of the trial, there were really no new available therapies. These patients were treated with carbotaxol for a fixed number of cycles followed by watch and wait, hence the incorporation of that placebo in that control arm. Fast forward to 2023, '20 '20 '4, we've now got introduction of multiple new therapies, including checkpoint inhibitors, whether it's pembrolizumab, dastardlimab, durvalumab available in combination followed by checkpoint inhibitor maintenance really for all patients with advanced recurrent endometrial cancer regardless of their MMR status.

Speaker 1

It was this evolving standard of care, I. E. The incorporation of the checkpoint inhibitors that led the FDA to have a discussion with them about how this trial, right, fit into this evolving treatment landscape. We really had some very productive discussions with the FDA. And ultimately what they recommended is to go after a patient population that unfortunately just doesn't benefit from the checkpoint inhibitors.

Speaker 1

And this is that PMMR patient population. PMMR patients with PMMR tumors represent the vast majority of endometrial cancer patients at eighty percent. With that said, and this is very consistent with the biology of the checkpoint inhibitors, the efficacy or the benefit that those patients achieve with the checkpoint inhibitors is very, very modest. So they recommended that we focus our patient population on that group of patients and conduct our Phase three as we currently are. They are very well of our data, right.

Speaker 1

So they appreciate from the CENDUS subgroup specifically in that PMMR P53 wild type population has a ratio of approximately 0.36 can be achieved with selinexor. So it really provides a potential new option for patients who are specifically P53 wild type PMMR that benefit can now rival what the checkpoint inhibitors are now specifically providing to the MMR patients.

Speaker 6

Great. Thank you. And does the inclusion of the MMR status, will that impact the rate of enrollment you think or will these patients already have kind of known their PMR or DMR status?

Speaker 1

Yes, really the latter. They are it is very much standard of care to test that MMR status. So this is really not an obstacle at all.

Speaker 6

Great. Thanks for taking our questions.

Speaker 3

Thanks, Colleen.

Operator

Your next question comes from Maury Raycroft with Jefferies. Your line is now open.

Speaker 7

Hi, good morning and thanks for taking my questions. Wondering for the SENTRI study, can you talk more about whether patient baseline profiles are tracking with your expectations? And is there any perspective you can share on baseline TSS and SVR35 and what you're seeing for discontinuation rates and potentially dose reductions for Rux or selinexor?

Speaker 1

Sure. Great question. So it is very much tracking with not only our Phase one patient population, but really the patient populations that have been enrolled as part of recent contemporary Phase three trials, including MANIFEST as well as TRANSFORM. So again, right, these are all JAK naive patients. Every single patient has to have a baseline platelet count of 100 or above.

Speaker 1

Again, this is very consistent with the enrollment criteria in our Phase one. Beyond that, when we look at the breakdown between dps status, intermediate one, intermediate two, high risk, driver mutations, baseline spleens, baseline hemoglobin and even baseline platelet counts, they really are very, very much tracking to again those three trials that I alluded to before, I. E. The Phase one, MANIFEST, as well as TRANSFORM. In terms of your other in regards to discontinuations, both treatment as well as study as well as dose modifications, so this is a blinded study.

Speaker 1

So we're not privy to any of that information by treatment arm. We haven't provided any additional blinded data beyond the demographics that I've provided earlier.

Speaker 7

Okay. I guess for those rates though, are you seeing are they tracking with your expectations for discontinuations with what you would expect?

Speaker 6

Yes. Yes, they are.

Speaker 7

Okay. And then maybe one other quick question. Just for absolute TSS endpoint for the SENTRI study, I believe fatigue is not included, but you're still measuring it. Just wondering if you could talk more about that, how FDA will assess and weigh fatigue and factor this into the approval decision process?

Speaker 1

Yes. So you're correct. So the MFSAF version four, collects information on seven different domains, fatigue being one of those domains. So we are collecting that information. However, for the primary analysis of absolute TSS, fatigue is going to be excluded.

Speaker 1

I'll note this is the same way that we evaluated the symptom improvement in our Phase one trial. We've had great conversations with the FDA regarding this. They are very much in alignment. And that's how we're going to proceed with the analysis again when the top line data report out in the second half of twenty twenty five. We'll always have that option right to incorporate fatigue at a later date if that's an analysis that we want to conduct.

Speaker 1

But again, the primary analysis will not include fatigue. Lastly, I'll just remind everybody that this is the same way that the original COMFORT trials were performed. So when ruxolitinib was approved based upon COMFORT one, COMFORT two, fatigue was also excluded. This was very similar to how fedratinib also evaluated their symptoms too. So there is multiple precedent in the domains included for overall symptom analysis.

Speaker 7

Got it. Okay. Thanks for taking my questions.

Speaker 3

Thank you, Mario.

Operator

Your next question comes from Peter Lawson with Barclays. Your line is now open.

Speaker 4

Hey, good morning. This is Alex on for Peter. Thank you for taking our questions. So I have two questions. One on ENDEMETRIEL.

Speaker 4

I guess you noted depending on the strength of the data, you would pursue regulatory approval. Can you walk us through your thinking here with respect to the bar for success? What would be a scenario where you seek approval versus a scenario where maybe you don't seek approval? And then my second question is on the SENTRI two study in JAK naive patients with moderate thrombocytopenia. I guess, have you submitted an abstract already for a medical meeting for this data?

Speaker 4

And then how much data could we expect to see? Thank you.

Speaker 3

Yes. Thanks for the question, Alex. I mean, I'll just address the second one first, and then I'll turn to Toreshman to address the first one on EC. But overall with regards to SENTRI two trial as we've shared, we'll be sharing some data in the first half of this year on initial set of patients. And we don't comment on whether or not we've submitted that yet for an abstract, but we're looking to share that data here in the first half of the year.

Speaker 3

And maybe, Reshma, if you can answer the second question with regards to EC and kind of the strength of the data and what we're looking to see.

Speaker 1

Yes, absolutely. So just stepping back to the C end of subgroup in which we evaluated the benefit and the risk of selinexor specifically in that P53 wild type subgroup, we saw very, very meaningful benefit. At the time of the top line results, we saw a more than ten month delta and approximately ten month delta when you compare the median PSS observed in the Selinexor arm as compared to the placebo arm. That in the context of a very safe and tolerable safety profile really suggests that the overall benefit risk of selinexor could be substantial for this patient population. That was a robust subgroup and we do expect that similar kind of profile to translate to our ongoing EC-forty two.

Speaker 1

With that said, I will remind everybody that in EC-forty two, the starting dose of selinexor is lower and we've incorporated dual antiemetics for the first two cycles. So what we could actually observe is very meaningful benefit, I. E. A median PFS delta of greater than six months, potentially even 10 as we saw before in the context of now even a better safety profile. I think that again would be a very meaningful outcome for this patient population.

Speaker 3

Thank you, Alex.

Operator

Your next question comes from Jonathan Chang with Leerink Partners. Your line is now open.

Speaker 8

Hi guys, good morning and thanks for taking my questions. First question, can you provide any color on how enrollment in the Phase three endometrial cancer study had progressed to date? And then second question, how should we be thinking about your cash runway guidance relative to the timelines of the Phase three studies and data readouts? Thank you.

Speaker 3

Sure. Thanks, Jonathan. Maybe for the first, I'll turn to Reshma and then we'll come back with Gory on the second part.

Speaker 1

Sure, Jonathan. And thanks for the question. Enrollment is going well in our endometrial cancer trial. We are now tracking to approximately two seventy six patients. It is a global trial where there is a lot of interest, right, in selinexor specifically in this novel population defined by their P53 status.

Speaker 1

So that interest is translating to robust enrollment and we're now looking at top line results in the middle of twenty twenty six.

Speaker 3

Laurie, do you want to amend the second part?

Speaker 5

Yes. Hi, Jonathan. Thank you for the question. And it's an important one that I know on understanding how we're going to extend our cash runway and to ensure that we can see the data readouts for these Phase three trials. The first thing I just want to make sure that I emphasize is we do understand the importance of being well capitalized.

Speaker 5

And the first thing that I want to make sure that I emphasize is we do have a profitable revenue generating business in multiple myeloma. So that starts our foundation. And as you mentioned, we have these two big data readouts coming in front of us. We have the one for myelofibrosis and then also for EC. So we are very well thinking through how are we going to be well capitalized going into these readouts.

Speaker 5

And as you know, there's a number of ways that we can look at financing and extending our cash runway. And these activities are similar to any other companies would explore, but we'll continue to look at business development, collaborations or strategic alliances, particularly on our early stage programs. For example, with eltonexor, we can look at for KPT $3.50 or KPT 9,274, which has a rare pediatric disease and orphan drug designation. We can take a look at extending our near term debt obligations or we can take a look at equity capital raises. We'll continue to evaluate all these options.

Speaker 5

We just want to make sure that we maximize the value for our shareholders proper path forward.

Speaker 8

Understood. Thanks for taking the questions.

Operator

Your next question comes from Brian Afram with RBC Capital Markets. Your line is now open.

Speaker 4

Hi, this is Kevin on for Brian. Thanks for taking our questions. Can you maybe just tell us a bit more on any particular characteristics of the DMMR population that is not eligible for checkpoint inhibitors and any reason to expect any different efficacies there? And just to add on to that, did you have any such patients in the SIENDO study? I'm just curious how they did on that study?

Speaker 4

Thank you.

Speaker 1

Great question. So these DMMR patients who are medically ineligible, no, there are not any unique characteristics about this patient population again. Is that patient population whose tumors are DMMR. Of course, they're going to be P53 wild type. This is again one of the key criteria.

Speaker 1

That medical ineligibility really just goes to some baseline medical history. By and large, these are comorbidities, autoimmune in nature that may preclude them from receiving a checkpoint inhibitor or a physician may have initiated treatment with the checkpoint inhibitor and then they unfortunately develop some kind of toxicity that requires them to permanently discontinue that checkpoint inhibitors. So it's really nothing about their underlying endometrial cancer or tumor type, that would make them eligible for this trial. It's really more about the comorbidities that again doesn't prevent them from receiving or continuing with that checkpoint inhibitor therapy. In terms of data from the SIENDO trial, no, I can't comment.

Speaker 1

We haven't gone back and taken a look at the SIENDO data. With that said, we don't expect there to be any difference too. I go back to the SIENDO subgroup, which really suggested that P53 is the driving factor that determines efficacy with selinexor. And the reason I highlight that is because when we look at the efficacy, specifically the hazard ratio by MMR status, both the PMMR as well as DMMR really demonstrated very robust improvement with hazard ratios in that 0.45 to 0.35 range.

Speaker 3

Thanks, Kevin.

Operator

Your next question comes from Ed White with H. C. Wainwright. Your line is now open.

Speaker 3

Good morning. Thanks for taking my questions. Just wanted to dive in a little bit more on your revenue guidance for 2025. Can you break it down on how you're thinking about growth in volume versus growth in price? Yes, thanks Ed.

Speaker 3

I'll turn to Solania to talk to that.

Speaker 1

Ed, thanks for the question. We feel confident about the guidance range we've put out there, $115,000,000 to $130,000,000 which where the midpoint represents approximately 11% revenue growth year over year. As we think about the drivers and the headwinds, our plan is to grow demand as well as revenue in 2025 year over year. Now our plan is to build upon the momentum that we've seen in the second half of twenty twenty four, where we grew demand in both the community and academic setting. And our plan is to again grow in 2025 versus 2024.

Speaker 1

As we think about the key headwinds in the space, of course, it's the ongoing competitive environment that we're in with two new potential entrants in 2025. Again, as we think about the role of EXPOVIO, it is distinctly positioned in the community setting in that second to fourth line as a flexible oral drug, as well as in the academic setting now that we have this growing body of evidence pre and post T cell therapy. The second key headwind really is gross to net. We expect it to be similar in 2025 to 2024, as Laurie mentioned, with Q1 having a higher gross to net than the average for 2025 consistent with our historical results. And in terms of sort of quarterly variability, we expect to see similar seasonal patterns that we have seen in the past.

Speaker 1

And so all these components are captured in the revenue guidance that we put out and we feel confident in delivering within that range.

Speaker 3

Okay. Thank you. And just a question on your R and D and SG and A guidance. Should we expect to see what we saw in 2024 as you are investing more in your Phase III studies that R and D should move a bit higher while you're still seeing SG and A cuts? Yes.

Speaker 3

Thanks, Ed. For that, I'll turn to Ori to talk to it broadly.

Speaker 5

Hi, Ed. For R and D, to be honest, it's going to be fairly comparable to 2024. As you know, we have the Phase three clinical trials that we're heavily investing in. Where we are seeing the reductions is on the SG and A, due to the cost optimization initiatives that we've put in place over the last two years and that's where we're seeing this significant decline in our operating expenses.

Speaker 3

Okay, great. Thank you for taking my questions. Thank you, Ed.

Speaker 4

There are

Operator

no further questions at this time. I will now turn the call over to Richard Paulson for closing remarks.

Speaker 3

Thank you, operator, and thank you everyone for joining us today. As I shared, we are focused and in 2025, our number one priority is to deliver on myofibrosis. As we move through the year, pending positive data, we are excited about the opportunity to meaningfully improve clinical outcomes for myelofibrosis patients and look to move forward and potentially bring this combination of selinexor plus ruxolitinib to patients. So once again, thank you for joining us for today's call and hope everyone has a great day.

Operator

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

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Earnings Conference Call
Karyopharm Therapeutics Q4 2024
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