Q4 2024 Karyopharm Therapeutics Inc Earnings Call
Thank you.
Thank you joelle.
Speaker Change: Thank you all for joining us on today's conference call to discuss carrier farms fourth quarter and full year 'twenty 'twenty four financial results and recent company progress.
Speaker Change: We issued a press release this morning detailing our financial results for the fourth quarter and full year 2024.
Speaker Change: This release, along with a slide presentation that we will reference during our call today are available on our website.
Speaker Change: For today's call as seen on slide two I'm joined by Richard Rosemont, Sanya, and Lori who will provide an update on our results for the fourth quarter 2024, and recent clinical developments.
Speaker Change: 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 Change: 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.
Speaker Change: Any forward looking statements represent our views as of today only.
Speaker Change: 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.
Richard Rosemont: Now I'll turn the call over to Richard Please turn to slide four.
Richard Rosemont: Thank you Brendan and thank you all for joining us today for carrier if arms Q4, 'twenty 'twenty four earnings call.
Richard Rosemont: In 2024, we delivered solid financial results delivering on our range of guidance with our profitable U S commercial organization and growing global demand and multiple myeloma.
Richard Rosemont: We continue to execute well on our cost reduction initiatives.
Richard Rosemont: <unk> total expenses, particularly SG&A, while focusing our resources on our phase III clinical trials.
Richard Rosemont: Turning to slide five in 2025, we expect to grow exposure net product revenue further reduce expenses and advance our transformative programs in myelofibrosis and endometrial cancer unlocking our innovation and growth strategy.
Richard Rosemont: Importantly for 2025, we remain on track to complete enrollment in our phase <unk> trial in the first half of this year and announce topline data in the second half of this year.
Richard Rosemont: Today, we are announcing modifications to our phase III trial in endometrial cancer following discussions with the FDA in recent months.
Richard Rosemont: Endometrial cancer data could become a key catalyst for us in 2026.
Richard Rosemont: First let's focus on the transformational opportunity in 2025 to redefine the standard of care in myelofibrosis.
Richard Rosemont: As we think about our potential in myelofibrosis. It is worth remembering how we got here, which is outlined on slide six.
Richard Rosemont: We've been taking deliberate steps over many years to put us in a position we are in today.
Richard Rosemont: This started with preclinical activity in myelofibrosis.
Richard Rosemont: By demonstrating a clear monotherapy signal and the essential investigator sponsor trial that was presented at ash in 2021.
Richard Rosemont: Following this we initiated a phase one study of Selinexor in combination with rux, So isn't there been JAK inhibitor naive patients.
Richard Rosemont: We presented data from this trial at Ash in both 2022 and 2023.
Richard Rosemont: This data demonstrated a strong signal of a benefit for the combination.
Speaker Change: That one XOR and rux, who isn't it.
Speaker Change: Based on this signal we received both fast track designation and orphan drug designation from the FDA and are rapidly initiated our phase III century trial.
Speaker Change: 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.
Speaker Change: This was a very favorable change that we believe increases the probability of success of our phase III <unk> trial and a change it is strongly supported by leading kols and patient advocacy organizations.
Speaker Change: We continue to progress our phase III <unk> trial faster than historical benchmarks.
Speaker Change: Our 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 topline data expected in the second half of <unk>.
Speaker Change: 195.
Speaker Change: As outlined on slide seven leading kols in myelofibrosis, including Dr ramp ups from Memorial Sloan Kettering and Dr masquerading as from outside.
Speaker Change: Continue to highlight the need for new treatment options for patients with myelofibrosis and are encouraged by the strength of our data.
Speaker Change: Finally, I cannot overstate, how transformational this opportunity could be for our organization as shown on slide eight we believe the peak revenue for Nacho for Selinexor in myelofibrosis.
Proved is approximately $1 billion in the U S alone we.
Speaker Change: We're eager to see the outcome of a phase III trial in <unk> and.
Speaker Change: So opportunity ahead.
Speaker Change: Now I'd like to turn the call over duration.
Speaker Change: Our programs in myelofibrosis and.
Speaker Change: Endometrial cancer and multiple myeloma.
Speaker Change: Asthma.
Speaker Change: Turning to slide 10, as Richard mentioned, we are focused on delivering top line data from our phase III <unk> trial in myelofibrosis in the second half of this year.
Speaker Change: Let's start by reviewing the unmet need in JAK naive myelofibrosis on slide 12 follow next with potential to help patients with myelofibrosis and our opportunity to redefine the standard of care as the first combination therapy.
Speaker Change: First I think it is a helpful reminder, that only approximately one third of patients achieved the spleen volume reduction of greater than 35% with Russell at Nib alone.
Speaker Change: We have shared before our phase one data show that Selinexor, plus <unk> more than doubles that STR 35 rate.
Speaker Change: There hasn't been a lack of new treatment options given that JAK inhibitors are the only approved class of therapies Brookfield has been the standard of care for over 13 years as the potential first combination therapy in myelofibrosis, Selinexor, plus rock solid and it would be a convenient oral therapy, but the myelofibrosis <unk>.
Speaker Change: <unk> has clearly indicated interest in adopting given the rapid deep and durable spleen reduction symptom improvement observed from the phase one study.
Speaker Change: Third there is minimal evidence of disease modification with JAK inhibitors.
Speaker Change: As discussed in the past along with the additive if not potentially synergistic clinical efficacy observed with Selinexor in Rockville Loopnet. The combination also has the potential to enable disease modification.
Speaker Change: Let's now discuss why we believe selinexor as an X P. O. One inhibitor is a rational mechanism to evaluate in patients with myelofibrosis, starting on slide 13.
Speaker Change: Our next door prevents the nuclear export of various proteins and messenger RNA molecules by doing so it promotes the nuclear localization and activation of P. 53, an important tumor suppressor in MF given that approximately 95% of myelofibrosis patients are P 53 wild type.
Speaker Change: We will 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 C. N DAU as shown on slide 14.
Speaker Change: And progression free survival of $28 four months was observed in those patients with P. 53, Wild type endometrial cancer. These clinical data further demonstrate the benefit that selinexor can achieve in tumors that are P 53, wild type <unk>.
Speaker Change: Moving to the data from our phase one trial evaluating selinexor and <unk> and JAK naive myelofibrosis patients as outlined on slide 15.
Speaker Change: Most of the 14 patients who received Selinexor 60 milligrams plus rux the letting it all evaluable patients achieved an SVR 35 at any time and 79% of patients from the ITT population achieved an SCR 35 at week 24.
Speaker Change: Clean volume reduction is viewed as one of the most important factors by treating physicians given its correlation to overall survival.
Speaker Change: Turning to slide 16 durability of response is also a key efficacy measure relevant ticket naive patients our phase one data demonstrate a 100% probability of continuing a response for both SCR thirty-five MTS 50 over a median duration of follow up of 32 weeks and 51 weeks.
Speaker Change: Secondly.
Speaker Change: This is particularly meaningful as it suggests that once patients achieve a response. They remain in response. This is the reason why leading physicians have indicated that the combination of Selinexor plus rux, a loopnet should be initiated in all JAK naive myelofibrosis patients pending the outcome of our phase III <unk> trial.
Speaker Change: On slide 17, the shift to absolute total symptom score as a co primary endpoint increases our overall confidence in the phase III trial, using absolute TSS to assess the average improvement in symptoms over 24 weeks has gained support from the FDA investigators and patient advocacy groups.
Speaker Change: More sensitive method to assess symptom improvement in myelofibrosis.
Speaker Change: On slide 18, the depth of symptom improvement with 60 milligrams of Selinexor, plus rux or letting it in our phase one trial can be seen in comparison to historical data from Russell letting of monotherapy, the average reduction which signifies improvement in absolute TSS at 18 five points there were combination.
Speaker Change: Compares favorably to the average of 11 to 14 point reduction that had been observed with the <unk> balloon in prior phase III clinical trials conducted by others.
Speaker Change: The rapid deep and durable findings observed with SVR 35 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.
Speaker Change: Symptom improvement for the entire six months duration evaluated.
Speaker Change: The adverse events experienced the most common word nausea anemia, thrombocytopenia and fatigue, even with this he sees very meaningful improvements in symptom scores over time.
Speaker Change: Turning to slide 20, we continue to make strong progress towards our goal of enrolling 350 patients into the century 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 centrally trial in the second half of 2025.
Speaker Change: Our clinical data thus far has shown deep spleen volume reduction over two times, what has been seen with Brookfield Litton of monotherapy robust symptom improvement durable responses, a well established safety profile with approximately 30000 patients treated across multiple indications and the potential for patient.
Speaker Change: Convenience with an all oral combination.
Speaker Change: Now, let's shift our focus to endometrial cancer, where we are providing an important update on our plans for a phase III 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.
Speaker Change: 220 patients with P 53, wild type endometrial cancer, regardless of MMR status in late 2024, and early 2025, 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 <unk>.
Speaker Change: Combination with chemotherapy, followed by checkpoint inhibitor maintenance for patients with advanced recurrent endometrial cancer.
Speaker Change: In addition, the FDA acknowledged that the efficacy observed in the P. M. M. R tumors is less than in DMR tumors consistent with the biology and mechanism of this class of therapies and suggested that we focus our trial population on patients with P. M. M. R tumors in light of the suggestion we are introducing.
Speaker Change: Our new modified intent to treat population that will consist of approximately 220 patients with P. M. M R tumors or patients who have D. M. M. R 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 <unk> subgroup, indicating that patients with pes of 53 wild type tumors, they benefit from Selinexor, regardless of the MMR status.
Speaker Change: Given that roughly approximately 80% of patients enrolled to date meet the new eligibility definition. The ITT population will now enroll approximately 276 patients which will enable us to maintain approximately 220 patients in the M. I T. T population, which are again P 53, one.
Speaker Change: Type P M M R or D. M M R medically ineligible to receive a checkpoint inhibitor.
Speaker Change: As a result of the increased trial size. We now expect to have top line data in mid 2026, we believe that the changes that we plan on implementing and they provide us with the data we need to seek regulatory approvals in the United States and globally.
Speaker Change: Now, let's revisit why P 53, wild type is such an important biomarker that we believe can accurately identify patients who will benefit from selinexor therapy on slide 24.
Speaker Change: Selinexor, primarily functions by blocking the export of P 53 from the nucleus to the cytoplasm when pieces do three accumulates in the nucleus. It leads to disrupt the DNA repair processes cell cycle arrest and increased a park, Texas. This mechanism is underscored by the anti tumor effects in P 53 depend.
Speaker Change: Tumors, specifically in endometrial cancer.
Speaker Change: As seen on slide 25 patients with both P. MMR and P 53, wild type tumors make up approximately 50% of all advanced or recurrent endometrial cancer cases, representing a very sizeable group of patients on slide 26 from the long term follow up of the <unk> exploratory subgroup.
Speaker Change: Data Selinexor has the potential to provide promising outcomes for example, recurrent endometrial cancer patients with P. 53 of Wild type PNM are tumors with a median PFS benefit of 39.5 months observed with Selinexor are compared to the $4 nine months observed with placebo corresponding to a hazard ratio.
Speaker Change: 0.36.
Speaker Change: 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 P. M. Omar patients emphasizing selinexor is substantial efficacy for these individuals.
Speaker Change: The safety data in endometrial cancer patients from the <unk> trial is displayed on slide 27, it's important to note that the adverse events associated with Selinexor were generally manageable and well tolerated nausea, vomiting, and diarrhea were the most frequently observed adverse events regardless of grade.
Speaker Change: Notably prophylactic dual anti emetic were not incorporated into the Sandoz trial, whereas dual anti emetic for the first two cycles are required in E. C 042, and all of our phase III trials, including century.
Speaker Change: We anticipate the safety profile from our phase III trials will be improved given the incorporation of these anti emetic as well as the lower starting doses of Selinexor IRA.
Speaker Change: I remain encouraged with the potential of selinexor to achieve clinically meaningful outcomes in the maintenance setting for patients with P. 53, Wild type endometrial cancer on slide 28, we outlined the updated Stat study design for our export E. C 042 trial consistent with the key changes that I highlighted earlier.
Speaker Change: Given these changes and the increased number of patients we plan to recruit we expect to report topline data in mid 2026.
Speaker Change: Lastly, our phase III E M. N S. P. D 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.
Hernia: <unk> 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 so hernia.
Speaker Change: Thank you Rachel and good morning on Slide 32, I will discuss our commercial highlights for 2024 <unk>.
Speaker Change: <unk> net product revenue was $29 3 million for the fourth quarter similar to what we delivered in the third quarter and up 16% compared to the fourth quarter of last year.
Speaker Change: I'm very pleased with how our organization responded to increased competition that pressured revenue last year.
Speaker Change: For the year, we delivered within our guidance range for <unk> with net product revenue of $112 8 million up from 112 million in 2023.
Speaker Change: This gain was achieved despite the introduction of new medications in the second half of 2023 into what was already a highly competitive multiple myeloma market and also a substantial increase in our gross to net.
Speaker Change: Even with the increased competition and demand for <unk> was consistent in 2024 versus 2023 with 60% of our sales coming from the community setting.
Speaker Change: Physicians continue to find value in <unk> with 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.
Speaker Change: In the academic setting we continue to see exposure being used pre and post T cell therapy.
Speaker Change: And in January the International Myeloma working group a globally recognized myeloma expert committee published updated recommendations with sequencing immunotherapies.
Speaker Change: This includes recommendations of ex <unk> as a bridging option prior to car T and also as a treatment for patients who have disease progression. Following an anti D. C. I mean your treatment.
Speaker Change: These recommendations are built upon a growing body of evidence we have generated exploring the potential role for <unk> in promoting an anti tumor immune microenvironment.
Speaker Change: Moving now to slide 33, we received a number of reimbursement approvals internationally throughout 2024 that triggered additional regulatory milestone payments.
Speaker Change: 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.
Speaker Change: As Richard and raised my both mentioned our organization biggest area of focus in 2025 is a phase III readout in myelofibrosis and our commercial team is preparing for this opportunity.
Speaker Change: As outlined on slide 34, we continue to believe that our peak revenue opportunity in the U S alone is approximately a billion annually if approved with additional royalty and milestone revenue globally.
Speaker Change: On slide 35, we outline why we believe we're still well positioned for a rapid launch in myelofibrosis.
Speaker Change: As we've shared previously 75% of the physicians that we surveyed stated that they intend to adopt a combination therapy in myelofibrosis, if one becomes available.
Speaker Change: <unk> is approved in combination with rux, a lesson that we could be the first combination therapy on the market.
Speaker Change: We would be an all oral therapy, which makes adoption much easier, especially in the community setting.
Speaker Change: On this point, we believe there is an 80% overlap between the physician, but we would targeted myelofibrosis and the group of physicians that our organization is already calling on in multiple myeloma.
Speaker Change: And the same overlap apply for our patient support programs and medical Affairs organization. This.
Speaker Change: This means two things first we should be able to launch rapidly because we have already trusted relationships with many physicians.
Speaker Change: Second the upfront investment required for us to launch in myelofibrosis would be minimal since we can launch with our existing organization.
Speaker Change: Finally in endometrial cancer as shown on slide 36, we continue to believe that we have a significant opportunity in the P 53, while site in P. MMR patient population, which represents approximately 50% of advanced or recurrent endometrial cancer patients.
Speaker Change: Well listen what I outlined for myelofibrosis.
Speaker Change: As a large overlap between the potential community based oncologists caring for endometrial cancer patients and those that we are already engaging with.
Speaker Change: Now, bringing it back to our commercial focus for 2025. It will remain strongly on driving exposure revenue growth in 2025. Following the success, we delivered in the second half of 2024 as well as planning for a successful launch in myelofibrosis.
Speaker Change: Route.
Speaker Change: Now I'm delighted to turn the call over to Laurie for the first time to give an update on our financial results and guidance.
Laurie: Good morning, everyone and thank you Sonya it is a pleasure to be participating in my first carrier firm earnings call I look forward to getting to know many of you personally.
Speaker Change: Turning to our financials.
Speaker Change: Since we issued a press release earlier today with the full financial results I will focus on the highlights and review our guidance for 2025.
Speaker Change: Starting on slide 38.
Speaker Change: Total revenue for the fourth quarter of 2024 was $30 5 million compared to $33 7 million for the fourth quarter of 2023.
Speaker Change: This decrease was primarily due to lower milestone related revenue from our licensing agreement.
Speaker Change: Total revenue for the year was $145 2 million compared to $146 million in 2023.
Speaker Change: U S ex fovea net product revenue for the fourth quarter of 2024 was $29 3 million compared to $25 1 million for the fourth quarter of 2023 for.
Speaker Change: For the full year U S exposure net product revenue of $112 8 million compared to $112 million in 'twenty two 'twenty three.
The gross to net discount for <unk> in the fourth quarter and full year 2024 was 33, 3% and 39% compared to 23, 5% and 22, 3% in the same periods in 2020 three.
Speaker Change: The increase in both periods was primarily driven by 340 b utilization in Medicare rebates.
Speaker Change: We expect the gross to net discount to be similar in 2020 five to 'twenty 'twenty four.
And as seen in previous years. It is expected to be higher in the first quarter than our average for 2025.
Speaker Change: R&D expenses for the fourth quarter 2024 were $33 3 million compared to $39 4 million for the fourth quarter of 2023.
Speaker Change: And $143 2 million for the year ended December 31, 2024 compared to $138.8 million for the year ended December 31 2023.
Speaker Change: The increase in R&D expenditure in both periods was attributable to the advancement of our pivotal phase III study.
Speaker Change: Partially offset by a reduction in head count and contractors related to ongoing cost optimization initiatives.
Speaker Change: SG&A expenses for the fourth quarter of 'twenty 'twenty four for $27 2 million compared to $30 7 million for the fourth quarter of 2023.
Speaker Change: SG&A expenses for the year ended December 31, 'twenty, 'twenty, four or $115 4 million compared to $131 9 million for the year ended December 31 2023.
Speaker Change: The decrease in both periods was due to a reduction in head count and contractors in connection with cost optimization efforts.
Speaker Change: On a combined basis, R&D and SG&A for $258 7 million for the year.
It's the lower end of our guidance of $2 55 to 65 million.
Speaker Change: As a result, we delivered $12 million of annual savings compared to 2023, while advancing three phase III clinical trials.
Speaker Change: We continue to be very diligent in allocating our resources and pipeline prioritization.
Speaker Change: Additional cost savings in 2025, while continuing to advance our phase III clinical trials and driving our commercial performance.
We exited the year with cash cash equivalents restricted cash and investments of $109 1 million compared to $192 4 million as of December 31, 2023.
Speaker Change: Based upon our current operating plans, we are introducing guidance for the full year of 'twenty to 'twenty five as follows.
Speaker Change: Total revenue of 140 to 155 million consisting of U S. <unk> net product revenue and license royalty and milestone revenue expected to be earned from our partners, primarily met Irene and antigen.
Speaker Change: We are projecting U S exposure net product revenue to be in the range of $115 million to $130 million.
Speaker Change: R&D and SG&A expenses will be in the range of $2 40 to $2 55 million.
Speaker Change: And finally, our guidance for cash runway remains unchanged we.
Speaker Change: We expect our existing cash cash equivalents and investments.
Speaker Change: The revenue, we expect to generate from X fovea net product sales and other license revenues.
Speaker Change: And ongoing disciplined expense management and cost saving measures will be sufficient to fund our planned operations into Q1 'twenty 'twenty six.
Speaker Change: This guidance does not include payment for the remaining 2025 convertible notes and our $25 million minimum liquidity covenant under our term loan.
Speaker Change: 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 our operations into the fourth quarter of 2025.
Speaker Change: In summary, we are focused on the advancement of our phase III clinical trials and driving commercial performance, while continuing to be very diligent when allocating our resources.
Speaker Change: We expect our 2025 operating expenses to be lower than 2024.
Speaker Change: We recognized a full year benefit of our ongoing cost saving initiatives.
Speaker Change: 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.
Richard Rosemont: I will now I'll turn the call back to Richard for some final thoughts.
Speaker Change: Turning to slide 40, and 2025, we expect to grow exposure net product revenue and advance our transformative programs in myelofibrosis and endometrial cancer working hard to unlock our innovation and growth strategy.
Speaker Change: Myelofibrosis in endometrial cancer, depending on the outcome of the data are both game changing opportunities for patients our organization and our shareholders alike.
Speaker Change: As Lori just stated as we deliver on 2025, we will also be working to explore various financing or business development activities to strengthen our financial resources and extend our cash runway and.
Speaker Change: In 2025, our number one priority is to deliver on myelofibrosis.
Speaker Change: 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.
Speaker Change: Pending positive data, we were excited by the opportunity to meaningfully improve clinical outcomes for myelofibrosis patients.
Speaker Change: With the support of leading physicians and patient advocacy organizations and rapidly, bringing the combination of Selinexor plus rux.
Speaker Change: Two patients.
Speaker Change: You again for joining us today, and I would now like to ask the operator to open the call up for the Q&A portion of today's call operator.
Speaker Change: Thank you ladies and gentlemen, we will now begin the question and answer session should you have a question. Please press star followed by the one on your Touchtone phone, you'll hear a prompt on your hand husband raised should you wish to decline from the polling process. Please press star followed by the U S.
Speaker Change: We are using a speaker phone handset before pressing any cheese one moment. Please for your first question.
Speaker Change: Your first question comes from Choline Cousy with Baird. Your line is now open.
Choline Cousy: Great. Thanks, Good morning, and thanks for taking our questions. So for myelofibrosis phase III you ought to see the data again to turn 18.5 point reduction in TSS for the combo versus 11 of 14 for Rux alone. So what production. She is asking the phase III would help would make you reach that say just trying to figure out how much of a buffer your starts off.
Speaker Change: Are you getting the phase III and then I have a follow up please.
Speaker Change: Yes, Hello, and thank you for the first part of that Yeah, I think I'll turn to Richmond to talk to that and then a follow up on your second question.
Colin: Yes, Thanks Colin.
Colin: Great question. So you know 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 T. S sauce and the data suggests right and you alluded to that you know with our 18.5 improvement relative to the 11 points.
Colin: 11 to 14 point improvement that we see with Brookfield at Nab and contemporary phase III trials.
Colin: We really could see a delta of three four plus points.
Colin: 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 III trials and I'll allude to the manifest trial that stat Sig was actually demonstrated with something far more.
Speaker Change: I'm, sorry far more narrow in fact that they saw stat Sig, where it's really only about a two point difference. So that gives you. Some context in terms of the data that we can provide from our phase three as well as the delta that would need to be seen to tissue and Scott said we had.
Speaker Change: Haven't provided any of the details specifically from our phase III trials. 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 III sentry trial.
Speaker Change: Okay.
Speaker Change: Super helpful. Thank you and then can you give a little more color 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 P. M. EMR data that Jim made the F. D. A direct you towards just the DMR population.
Speaker Change: Yeah.
Speaker Change: Yeah, absolutely. So you know as we announced back in December of 2024, we were engaged with the F D. A spin.
Speaker Change: Typically are evolving.
Speaker Change: 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 carbo taxol for a fixed number of cycles, followed by watching weight, hence the incorporation of that the placebo.
Speaker Change: In that control arm, you know fast forward to 'twenty three 'twenty four we've now got introduction of multiple new therapies, including checkpoint inhibitors, whether its pember lives a mab to starlet Mab Dorval, a mab available in combination followed by checkpoint inhibitor maintenance really for all patients with advanced recurrent endometrial.
Speaker Change: Cancer, regardless of their MMR status. It was this evolving standard of care I E. The incorporation of the checkpoint inhibitors that loved the F. D. A to have a discussion with them about how this trial right fit into this evolving treatment landscape, we really had some very.
Speaker Change: 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 and this is that P. M Omar patient population P.
Speaker Change: TMR patients with P. M M R tumors represent.
Speaker Change: Majority of endometrial cancer patients at 80% with that said and this is very consistent with the biology of the checkpoint inhibitors, the efficacy or the benefit that those Ah patients achieved with the checkpoint inhibitors is a very very modest so they recommended that we focus our pay.
Speaker Change: <unk> population on that on that group of patients and.
Speaker Change: And conduct our phase three as we currently our.
We currently are they are very well of our data right. So they appreciate from the <unk> subgroup specifically in that P. M. M. R. P 53, wild type population hazard ratios of approximately you know 0.36 can be achieved with selinexor. So it really provides a potential new.
Speaker Change: <unk> option for patients who are specifically P 53, wild type P. M. EMR that benefit can now rival what the checkpoint inhibitors are now specifically providing to DMR patients.
Speaker Change: Great. Thank you and Disney inclusion.
Speaker Change: The MMR status will that impact the rate of enrollment you think or will these patients already has kind of known there mark MLR status.
Speaker Change: Yeah really the ladder. They they are you know it is very much standard of care to tests that MMR status. So this is really not an obstacle at all.
Speaker Change: Great. Thanks for taking my questions.
Richard Rosemont: Thanks Colin.
Speaker Change: Your next question comes from Maury Raycroft with Jefferies. Your line is now open.
Maury Raycroft: Hi, good morning, and thanks for taking my questions I'm wondering for the century study can you talk more about whether patient baseline baseline profiles are tracking with your expectations and is there any perspective, you can share on baseline TSS and SPR 35, and what youre seeing for discontinuation rates and potentially dose reductions for rux or selinexor.
Maury Raycroft: 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 you know recent contemporary phase III trials include.
Maury Raycroft: [laughter] manifest as well as transform.
Maury Raycroft: So again right. These are all JAK naive patients every single patient has to have a baseline platelet count of 100 or Baas again. This is very consistent with the enrollment criteria in our phase one beyond that when we look at the breakdown between depths status intermediate one intermediate to high risk.
Maury Raycroft: 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.
Maury Raycroft: In terms of your other questions in regards to discontinuation both treatment as well as study as well as dose modifications.
Speaker Change: So this is a blinded study so we're not privy to any of that information by treatment arm and we haven't provided any additional blinded data.
Maury Raycroft: And you know the demographics that I've provided earlier.
Speaker Change: Okay, I guess for the for those rates or are you seeing are they tracking with your expectations for discontinuation with what you would expect yes.
Maury Raycroft: Yes, yes.
Maury Raycroft: They are.
Speaker Change: And then maybe one other quick question just for absolute TSS endpoint for the <unk> study.
Speaker Change: I believe fatigue is not included but youre still measuring it just wondering if you could talk more about that how FDA will assess.
Speaker Change: And way fatigue and factored this into the approval.
Speaker Change: The decision process.
Speaker Change: Yeah, So you're correct. So the M. S. I say a version for collects information on seven different domains fatigue being one of those domains. So we are collecting that information.
Speaker Change: However for the primary analysis of absolute TSS.
Speaker Change: Fatigue is going to be excluded.
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 you know when the topline data report out in the second half of <unk>.
Speaker Change: Thousand 25, we will always have that option right to incorporate fatigue at a later date. If that's an analysis that we want to conduct but again the primary analysis will not will not include fatigue.
Speaker Change: Lastly, I'll just remind everybody that this is the same way that the original comfort trials.
Speaker Change: All were performed so when <unk> was approved based upon comfort one comfort to boutique was also excluded this was very similar to house. The dry NEP also evaluated their symptoms too. So there is multiple precedent in the domains included four overall symptom analysis.
Got it okay. Thanks for taking my questions.
Martin: Thank you Martin.
Speaker Change: Your next question comes from Peter Lawson with Barclays. Your line is now open.
Alex: Hey, Good morning. This is Alex on for Peter Thank you for taking our questions.
Speaker Change: So I have two questions one on endometrial.
I guess you noted depending on the strength of the data you would pursue regulatory approval.
Speaker Change: Can you walk us through your thinking here with respect to the bar for success.
Speaker Change: What would be a scenario, where you seek approval works versus a scenario, where maybe you don't take approval.
Speaker Change: And then my second question is on the century to study and JAK naive.
Speaker Change: Patients with moderate thrombocytopenia.
Speaker Change: I guess have you submitted an abstract already for a medical meeting for this data and then how much data could we expect to see thank you.
Speaker Change: Yeah. Thanks for the question, Alex I mean, I'll just address the second one first and then I'll turn to a duration meant to address the first one on <unk>.
Speaker Change: Overall with regards to the Sentry two trial as we've shared.
Speaker Change: We will be sharing some data in the first half of this year on.
Speaker Change: An initial set of patients.
Speaker Change: And we don't comment on whether or not we've submitted that yet for an abstract but we walk in to share that data here in the first half of the year and maybe a rich maybe you can answer the second question with regards to <unk> and kind of the strength of the data and what we're looking to see.
Speaker Change: Yeah, absolutely. So you know just stepping back to the <unk> subgroup.
Speaker Change: In which we evaluated the benefit and the rest with Selinexor specifically in that piece of it to three wild type subgroup. We saw very very meaningful benefit you know at the time of the topline results. We saw a more than 10 months adulthood, and approximately 10 months Delta when you compare the median P.
Speaker Change: So absorbed with the in the Selinexor arm as compared to the placebo arm that in the context of a very safe and tolerable.
Speaker Change: Safety profile really suggests that the overall benefit risk of selinexor could be substantial for this patient population and.
That was a robot subgroup and we do expect that similar kind of profile to translate to our ongoing E. C. O. Four too you know with that said I will remind everybody that in E. C 042, the starting dose of Selinexor is lower and we've incorporated dual anti emetic for the first two cycles. So what we.
Speaker Change: Could actually observe is very meaningful benefit I E. A median PFS of delta of greater than six months or potentially even turn as we saw before in the context of now even a better safety profile I think that that again would be a very meaningful outcome for this patient population.
Speaker Change: Thank you Alex.
Speaker Change: Your next question comes from Jonathan Chang with Leerink Partners. Your line is now open.
Jonathan Chang: Hi, guys. Good morning, and thanks for taking my questions.
First question can you provide any color on how enrollment in the phase III endometrial cancer study had progressed to date.
Jonathan Chang: And then second question.
Jonathan Chang: How should we be thinking about your cash runway guidance relative to the timelines of the phase III studies and data Readouts. Thank you.
Speaker Change: Sure. Thanks, Jonathan maybe for the first I'll turn to our Richmond, and we'll come back with Oreo in the second part.
Speaker Change: Yeah sure Jonathan and thanks for the question enrollment is going well and our endometrial cancer trial, we are now tracking to approximately 276 patients.
Speaker Change: It is a global trial, where there is a lot of interests right and selinexor in specifically in this novel population defined by their P. 53 status. So that interest is translating to robust enrollment and we're now looking at topline results in the middle of 2026.
Speaker Change: No worries you want vendor second part, yes, hi, Jonathan and thank you for the question.
Speaker Change: And it's an important one that I know and understanding how we're going to extend our cash runway and to ensure that we can see that the the data readouts from these phase III trials.
Speaker Change: The first thing I just wanted to make sure that I emphasize we do understand the importance of being well capitalized in the first thing that I want to make sure that I emphasize is we do have a profitable revenue generating business in Luxembourg myeloma. So that starts our foundation and as you mentioned we have these two big data readouts coming in front of US we have a lot of her loyalty.
Speaker Change: Process and then also for E. C. So we are very well thinking through how are we going to be well capitalized going into these readouts 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 are.
Speaker Change: Strategic alliances, particularly on our early stage programs.
Speaker Change: For example, with ultra in Ecuador, where we can look at for K P. T $3 50, or K P. T 90, 274, which has a rare pediatric disease, an 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 will continue to evaluate all of them.
Speaker Change: Options, we just want to make sure that we maximize the value for shareholders.
Speaker Change: Proper path forward.
Yeah.
Speaker Change: Understood. Thanks, John for taking the questions.
Speaker Change: Your next question comes from Brian <unk> with RBC capital markets. Your line is now open.
Speaker Change: 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 DMR population that is not eligible for checkpoint inhibitors and any reason to expect any different efficacy is there and just to add onto that did you have any such patients in the sandal studying just curious.
Speaker Change: How they did on that study thank you.
Speaker Change: Sure Great Great question. So these DMR patients who are medically ineligible.
Speaker Change: No there are not any unique characteristics about this patient population again is that patient population, whose tumors are P. M. M. R of course, they're gonna be pizza 53 Wild type. This is again one of the key criteria.
Speaker Change: That medical and eligibility 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 a checkpoint inhibitor and then they unfortunately develop.
Speaker Change: Some kind of toxicity that requires them to permanently discontinue that checkpoint inhibitor. So it's really nothing about their underlying endometrial cancer tumor type.
Speaker Change: That would make them eligible for this trial, it's really more about the comorbidity is that again doesn't prevent them from receiving or continuing with that checkpoint inhibitor therapy in terms of data from the <unk> trial, no I I can't comment we.
Speaker Change: Haven't gone back and taken a look at the C&I data.
With that said, we don't expect there to be any difference to I go back to the <unk> subgroup, which really suggested that P. 53 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.
Speaker Change: Ratio by MMR status the P MMR as well as D. MMR really demonstrated very robust improvement with hazard ratios in that 0.45 0.35 range.
Speaker Change: Thanks, Kevin.
Speaker Change: Yeah.
Ladies and gentlemen, as a reminder, should you have a question. Please press star one.
Speaker Change: Your next question comes from Ed White with H C. Wainwright. Your line is now open.
Ed White: Good morning, Thanks for taking my questions.
Ed White: Just wanted to dive in a little bit more on your revenue guidance for 2025.
Ed White: Can you break it down in how you're thinking about growth in volume versus growth in price.
Ed White: Okay.
Speaker Change: Yeah, Thanks, Ed I'll turn to so on who you talk to that.
Speaker Change: Thanks for the question.
Speaker Change: Still confident about the guidance range, we put out there of 115 to around 30 million, which where the midpoint represents approximately 11% revenue growth year over year.
Speaker Change: We think about the drivers on the headwinds are.
Speaker Change: 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 2024, where we grew demand in both the community and academic setting and our plan is to.
Speaker Change: Okay and grow in 2025 versus 2024.
Speaker Change: 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 exposure. It is distinctly positioned in the community setting.
Speaker Change: Second to fourth line is 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.
Speaker Change: The second key headwind really is gross to net we expect it to be similar in 2025 to 2020 or as Lorie mentioned.
Speaker Change: Q1, having a higher gross to net than the average for 2025.
Speaker Change: With our historical results.
Speaker Change: And in terms of sort of quarterly variability, we expect to see similar seasonal patterns that we've seen in the past and so all of these components are captured in the revenue guidance that we put out and we feel confident in delivering within that range.
Speaker Change: Okay. Thank you and just a question on your R&D and SG&A guidance.
Speaker Change: Should we expect to see you know what we saw in 2024 as you are investing more in your phase III studies that R&D should move a bit higher well youre still seeing SG&A cuts.
Speaker Change: Yes, Thanks, Ed for that I'll turn it over to talk to a broadly yeah hi.
Speaker Change: Hi, Ed for R&D to be honest, there's going to be fairly comparable to 2024. As you know we have the phase III clinical trials that were heavily investing in where we are seeing the reductions is on the SG&A due to the cost optimization initiatives that we've put in place over the last two years and that's where we were.
Speaker Change: The significant decline in our operating expenses.
Speaker Change: Okay, great. Thank you for taking my questions.
Ed White: Thank you Ed.
Speaker Change: There are no further questions at this time I will now turn the call over to Richard Thompson for closing remarks.
Speaker Change: Thank you operator, and thank you everyone for joining US today, you know as I shared earlier.
Speaker Change: Focus and in 2025, our number one priority is to deliver on myelofibrosis.
Speaker Change: 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 bringing this combination of selinexor plus rux wouldn't have to patients.
Speaker Change: Once again, thank you for joining us for today's call and hope everyone has a great day.
Speaker Change: 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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