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spk13: Good morning. My name is Jason, and I will be your conference operator today. At this time, I would like to welcome everyone to the CarioPharm Therapeutics second quarter 2023 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 Ellen Webb, Senior Vice President of Investor Relations.
spk02: Thank you, operator. And thank you all for joining us on today's conference call to discuss Carefarm's second quarter 2023 financial results and recent company progress. We issued a press release this morning detailing our financial results for the second quarter 2023. This release, along with a slide presentation that we will reference during our call today, are available on our website. For today's call, as seen on slide two, I'm joined by Richard, Reshma, Sohani, and Mike, who will provide an update on our results for the second quarter and recent clinical developments. Before we begin our formal comments, I'll remind you that various remarks we'll make today constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995, as outlined on slide three. Actual results may differ materially from those indicated by these forward-looking statements, FLS, as a result of various important factors, including those discussed in the risk factors section of our most recent form 10Q, which is on file with the SEC, and in other filings that we may make with the SEC in the future. Any FLS represent our views as of today only. While we may elect to update these FLS at some point in the future, we specifically disclaim any obligations to do so, even if our views change. Therefore, you should not rely on these FLS as representing our views as of any later date. I will now turn the call over to Richard. Please turn to slide four.
spk07: Thank you, Elhan. Good morning, everyone, and thank you for joining CarioFarm's second quarter 2023 earnings call. Turning to slide five, we had a strong second quarter as we accelerate KaryoPharm to its next stage of growth with our novel sign compounds, Selinexor and Eltenexor. As Raishma will discuss further, we are advancing a focused clinical pipeline with three ongoing phase three pivotal studies based upon a strong foundation of supportive data, a recently obtained fast track designation of myelofibrosis, and a set of pivotal catalysts over the next two years. With our current approved multiple myeloma indication in the U.S. with Selinexor, we continue to expand and shift into earlier lines. As Sohanya will discuss further, year-over-year total demand for Expovio continues to grow in a competitive multiple myeloma marketplace. Selinexor is also expanding its global footprint with approvals in various indications in approximately 40 countries outside of the US, providing us with a growing stream of payments from royalties and milestones from our partners as launches move forward globally. As part of our continued prioritization of our late stage clinical pipeline, we have taken additional actions to streamline our operations and optimize our cost structure. As a result, We have reduced our workforce by approximately 20%, which is expected to enhance our financial strength, provide us with the capital needed to deliver on our three phase three studies, and maximize value for our shareholders. This was an extremely difficult decision given the direct impact this has on our employees. However, after careful consideration, this action was imperative in order to further focus the organization on the near-term opportunities ahead of us. I am sincerely grateful for the tireless work and commitment of all colleagues who are being impacted and to the colleagues that will enable CarioFarm's success moving forward. As we move to slide six, presented here is an overview of the timing of the upcoming key data readouts, which we expect in 2024 and 2025. Each of our ongoing phase three clinical trials, if successful, represents an incredibly meaningful growth opportunity for our organization with the potential to deliver roughly $2 billion in annual peak revenues. Starting with multiple myeloma, a successful phase three trial with SPD anticipated in the second half of next year would accelerate Selinexort into the second line treatment and enable continued growth in multiple myeloma. In endometrial cancer, we believe Selinexor has the potential to transform the treatment paradigm for TP53 wild-type endometrial cancer patients, given the unprecedented data, which was presented at the virtual ASCO plenary series last week, of which Reshma will speak to momentarily. Finally, in myelofibrosis, we recently announced the initiation of our pivotal phase three with the potential to transform the frontline treatment for patients with myelofibrosis as we build upon the rapid, deep, and sustained responses we have seen thus far. Collectively, we believe we have the potential to achieve multiple product approvals over the next two to four years as we deliver our next phase of growth. leveraging our proven and established commercialization and late stage development capabilities. Shifting to Cell and XOR's position internationally on slide seven, our continued global expansion with our partners provides further opportunities to treat patients in need with Cell and XOR as our partners continue to commercialize and launch in additional global territories. Our license agreements with our partners provides us with a steady stream of revenues through growing double digit future royalties and potential development and sales milestone payments of up to 400 million. Moving to slide eight, I would now like to turn the call over to Reshma to expand further on our clinical pipeline progress. Reshma.
spk04: Thank you, Richard. I want to start off by highlighting our rapidly advancing pipeline on slide nine, which includes three pivotal phase three trials with Selinexor that are enrolling in multiple indications of high unmet need. In addition, we are evaluating our second sign compound, Elkinexor, in myelodysplastic neoplasms. As seen on slide 11, we are expanding our multiple myeloma franchise with an important ongoing phase 3 trial that is evaluating selenexor at the low dose of 40 milligrams in combination with the well-established backbone therapy of pomalidomide and dexamethasone. Patients with relapsed refractory multiple myeloma who have received an anti-CD38 antibody as their most recent therapy are are randomized one-to-one to the oral regimen of selenoxor, pomalidomide, and dexamethasone, or elotuzumab, pomalidomide, and dexamethasone. The primary endpoint is progression-free survival. The potential approval of this combination could lead to the only all-oral, potentially T-cell-spurring regimen for patients with relapsed refractory multiple myeloma. On slide 13, advanced and recurrent endometrial cancer is the most common form of gynecologic cancer in the United States, with the current treatment landscape primarily consisting of first-line chemotherapy with the platinum and taxane. Upon completion of chemotherapy, patients are observed until disease progression. This approach clearly needs improvement given that the five-year survival rate in this patient population is only 17% As Selinexor is administered orally and maintenance therapy is well established in other cancer types, we believe Selinexor has the potential to offer a maintenance option in TP53 wild type patients and meaningfully improve the overall clinical benefit for these patients. As seen on slide 14, endometrial cancer treatment will ultimately be based upon patient's individual molecular classification, including assessment of their microsatellite instability and P53 status. Of the approximately 16,000 patients diagnosed with advanced or recurrent endometrial cancer in the United States, roughly 50% of advanced or recurrent tumors are classified as TP53 wild type. Within this subgroup, 70% of patients are microsatellite stable, or MSS, and 30% are microsatellite instable, or MSI-high. The long-term follow-up data observed from the pre-specified exploratory TP53 wild-type subgroup analysis from the SIANDO trial, which evaluated Selinexor as a maintenance therapy, reinforces our rationale and ongoing confidence in the current phase 3 EC042 trial. Long-term follow-up data from the SIANDO trial recently presented at the virtual ASCO plenary series on July 25th is seen on slide 15. With a median follow-up of 25 months for the TP53 wild-type exploratory subgroup, the median PFS for the Selenexor arm is now 27.4 months compared to 5.2 months in those patients receiving placebo. The hazard ratio for the subgroup is 0.42, representing a 58% decrease in the risk of disease progression or death. Patients whose tumors are either TP53 mutant or aberrant and treated with Selinexor demonstrated the median PFS of only 4.2 months. These data show that the potential clinical benefit achieved with Selinexor is isolated to women whose tumors are TP53 wild type and demonstrate that TP53 wild type has the potential to be a robust biomarker. As we turn to slide 16, patients with TP53 wild-type endometrial cancer were further classified by microsatellite instability status given the growing importance of this diagnostic marker in endometrial cancer. While potential PFS improvements were seen regardless of microsatellite instability status, most notable is the signal of a 68% decrease in the risk of disease progression or death corresponding to a hazard ratio of 0.32, and a median PFS that has not been reached in those patients whose disease is P53 wild type and MSS. These data are important given the evolving data observed in the checkpoint inhibitors, which continue to show that the greatest clinical benefit is observed in the minority of patients whose disease is MSI high. As seen on slide 17, we believe that the AE profile of Selinexor is generally manageable as a maintenance therapy. The most common treatment emergent adverse events seen in the TP53 wild type exploratory subgroup were nausea, vomiting, and diarrhea. And overall grade three, four treatment emergent adverse events were rare, with the most common being neutropenia, nausea, and thrombocytopenia. No grade five treatment emergent adverse events were observed. Treatment emergent adverse events incidents and severity were generally similar in the subgroup of patients whose tumors were either TP53 mutant or aberrant. Turning to slide 18, given the data we observed in the exploratory subgroup of TP53 wild type endometrial cancer, we see an opportunity to transform the treatment paradigm for endometrial cancer given the signal of approximately five-fold increase in the time to disease progression or death compared to placebo. The data in the P53 wild type MSS is especially notable in light of first-line endometrial cancer trials evaluating the efficacy of checkpoint inhibitors. While some of those trials evaluated the efficacy of checkpoint inhibitors in both the treatment and maintenance settings, they demonstrate that the overwhelming benefit is largely observed in those patients whose disease is MSI high. Given that 70% of patients whose disease is MSS do not achieve the same degree of benefit with these immunotherapies, and in light of the recent approval of disarlimab in combination with chemotherapy in first-line endometrial cancer whose disease is MSI high, we anticipate that the majority of solanexor will be administered to patients classified as P53 wild-type MSS, pending the successful approval of Selinexor. This highlights the importance of molecular testing early in a woman's endometrial cancer diagnosis as novel therapies transform treatment opportunities for these women. On slide 19 are details that are actively enrolling EC042 pivotal phase 3 study. Evaluating Selenexor as a monotherapy for patients with TP53 wild type, advanced or recurrent endometrial cancer. The study utilizes Foundation Medicine's tissue-based next generation sequence test to identify patients and enroll approximately 220 women whose tumors are TP53 wild type. Patients are randomized in a one-to-one manner to receive either once-weekly Selenexor at a dose of 60 milligrams or placebo. Ultimately, this trial will enable the development of a companion diagnostic, and we anticipate the approval of a companion diagnostic would occur at the same time as Selinexor, if approved. The study's primary endpoint is progression-free survival, with a key secondary endpoint of overall survival. The study is a collaboration between Keriopharm and ENGOT, the European Network for Gynecological Oncological Trial Group, and GOG, the gynecology oncology group. Given that this is an event driven trial, we currently anticipate top line data readout in late 24 to early 2025. Turning our attention now to myelofibrosis on slide 21. We are excited to announce that the FDA has recently granted fast track designation to Selinexor for the treatment of patients with myelofibrosis. This designation emphasizes the high need for new therapies and novel mechanisms of action given that the efficacy with the current standard of care is limited with less than 50% of patients achieving SVR35 and TSS50. Furthermore, in subgroups such as men and those who start on a low dose of ruxolitinib, efficacy is even lower with only approximately 25% of patients achieving an SVR35 at week 24. On slide 22, you can see the phase one trial design of our frontline myelofibrosis study, evaluating the combination of selenexor and ruxolitinib in patients with treatment-naive myelofibrosis. We presented updated phase one data at the ASCO and EHA conferences in June 2023, which can be seen on slide 23. In the table, you can see that the SVR35 and TSS50 results in 60 mg selenexor. In the ITT population, the SVR35 rate at week 24 achieved with the low dose of Selinexor was 79%. Furthermore, these reductions occurred rapidly with the 71% SVR35 rate observed at week 12. At week 24, TSS50 was observed in 58% of patients. Here as well, you see rapid improvement in symptoms with approximately 67% of patients achieving a TSS50 as early as week 12. The rapid, deep, and sustained efficacy observed with Selinexor in combination with Ruxolitinib substantially improved the potential benefit that JAK-naive myelofibrosis patients may achieve. These data underscore our conviction on our ongoing phase three study as seen on slide 24 that was initiated in June. The trial will enroll 306 symptomatic, intermediate, and high-risk JAK-naive myelofibrosis patients. Patients will be randomized two-to-one to ruxolitinib plus selenexor or ruxolitinib plus placebo. We anticipate top-line results in 2025. Given the important subgroup data in patients who received suboptimal doses of ruxolitinib as presented at ASCO and EHAH, We are planning to initiate a phase two trial evaluating Selinexor as a monotherapy in JAK-naive patients with a baseline platelet count between 50 to 100,000. This is a uniquely high met need patient population with limited treatment options available. This trial will allow investigators to add on Ruxolitinib or Procritinib at either week 12 or week 24 in the event suboptimal responses to Selinexor are observed. This trial, coupled with the ongoing phase three, has the potential to transform treatment of myelofibrosis patients and embed Selinexor as a backbone therapy for treatment-naive myelofibrosis. With that, please turn to slide 25, and I will now hand it over to Sohania for a review of our commercial performance for the quarter. Thank you, Reshma, and good morning, everyone. On slide 26, I am pleased to present the progress we have made in our second quarter performance, where Expovio continued to show growth year over year in total demand of 9% in a competitive marketplace. In line with our strategy to expand use of Expovio in the community setting, total demand grew by 11% year over year in this setting, contributing to about two-thirds of Expovio's revenues in the second quarter. We also achieved total demand growth of 6% year-over-year in the academic setting, driven by use of Expovio pre- and post-T-cell therapies. Net revenue continued to be adversely impacted by higher utilization of Carry Forward, our patient assistance program, or PAP, which provides free medicine to qualified patients unable to get financial support elsewhere. This was a result of continued closures beginning late Q1 of many of the third-party multiple myeloma foundations that provide financial support to Medicare patients. In the second quarter, one of the four main multiple myeloma foundations was open for a period of time and continues to remain open. This allowed for a reduction of new patients entering our patient's assistance program, although we continue to see the cumulative refill impact of patients who are already in PAPP earlier in the year. PAPP contributed to 14% of total demand in Q2 2023, which amounted to a roughly $3 million revenue impact. In comparison, PAPP contribution to total demand was 9% in Q1 2023 and 5% in Q2 2022. Moving forward in 2024, IRA related changes in the design of Medicare Part D will eliminate the patient burden of the 5% beneficiary coinsurance requirement, and we expect significantly less need for Medicare Part D patients to utilize carry forward for copay assistance. Additionally, net revenue was impacted by 5% higher year over year gross to net in the second quarter, driven by increased Medicare and Medicaid rebates, as well as 340B discounts. Despite headwinds in the marketplace, we are pleased to see the progress we have made not only in growing total demand for Exposio, but also in shifting into earlier lines. In Q2 2023, Exposio new patient share surpassed 60% in the second to fourth line, compared to 49% in Q2 of last year. Our intent to prescribe data showed an improvement in third line use, which continues to support the potential for patients to have a more optimal experience in earlier lines and extend time on therapy. We reaffirm our US Expovio net revenue guidance of 110 to 125 million in 2023. Let's now turn to slide 27. Amidst an evolving landscape, we believe we're strongly positioned to treat multiple myeloma as a novel class of therapy in the second to fourth line in three distinct patient populations. In the community setting where earlier line patients tend to be treated, we believe Expobio is an optimal therapy in the second to fourth line post-anti-CD38 treatments as a novel class of therapy that is an effective, manageable, easily combinable, and a convenient oral therapy. It also has the advantage of decreasing the logistical burden of accessing a hospital for elderly or rurally-based patients. In the academic setting, Expobio may be used as an optimal therapy with a novel mechanism of action pre- or post-T cell therapies. As we turn to slide 28, We're encouraged by the future growth potential of our myeloma franchise. In our SPD study, the triple combination of Selinexor at the lower dose of 40 milligrams with pomalidomide and dexamethasone could lead to the only all oral regimen following an anti-CD38 therapy in the marketplace if approved. The partner backbone of pomalidomide is a commonly used therapy in the second to fourth line generating over $2 billion in revenues in the U.S. Given these characteristics that make up the SPD combination, we are encouraged by the potential of unlocking significant value to patients with multiple myeloma if approved. Shifting to the opportunity in endometrial cancer. On slide 29, we are encouraged by the potential for Selinexor to address a significant unmet need in key molecular subgroups. As we engage with key opinion leaders in this space, it is clear that they see the unmet need for a targeted treatment in unique molecular subgroups including TP53 wild type tumors. While frontline treatment options are emerging rapidly, a clear unmet need remains in the P53 wild type and specifically MSS subgroup. As we look at the potential opportunity in this large market, endometrial cancer is the most common gynecological cancer in the U.S. with over 8,000 patients in the U.S. and over 50,000 globally that have P53 wild-type advanced or recurrent endometrial cancer, of which about 70% are P53 wild-type MSS patients. We are very encouraged by Selinexor's opportunity to help women who need a more effective, targeted, and safe treatment option. Given that Selinexor is being evaluated as a maintenance therapy, convenience is a critical factor. As an oral therapy, we maximize treatment duration by eliminating the need for frequent clinic visits. Turning now to slide 30, as you heard from Reshma, XPO1 inhibition has the opportunity to transform the frontline treatment paradigm in myelofibrosis. There are no other drug classes other than JAK inhibitors approved in the frontline. As we look at the potential opportunity in the myelofibrosis market, there are over 4,000 patients in the U.S. and over 26,000 patients globally that are intermediate to high-risk myelofibrosis. We are very encouraged by Selinexor's opportunity to transform myelofibrosis treatment paradigm. Based on third-party market research, about 75% of healthcare providers were willing to adopt combination therapies as frontline standard of care, replacing ruxolitinib monotherapy due to the potential of better efficacy. Additionally, there is a strong perception around Selinexor in combination with ruxolitinib, with approximately 50% of healthcare providers indicating that they would select Selinexor plus ruxolitinib as their preferred frontline combination therapy if approved, based on promising initial SBR35 and TSS50 efficacy rates and a manageable safety profile. As Richard discussed in his opening remarks, Terrier Farm has a tremendous opportunity for growth by leveraging our strong commercial team and continuing to build on our base multiple myeloma business with three potential launches ahead of us. Please advance now to slide 31, and I'll turn the call over to Mike.
spk06: Thank you, Sohanya. Looking at slide 32, we have further optimized our cost structure to focus resources on our pivotal phase three trials and reduced our workforce by approximately 20%, including contractors. These steps further strengthen our financial position to invest in our three ongoing phase three studies, with each representing a large addressable market with unmet patient needs. finally as richard mentioned mentioned we have the capital needed to deliver on our three phase three studies and maximize value for shareholders now on slide 33 i will focus on the quarter's financial highlights total revenue for the second quarter of 2023 was 37.6 million compared to 39.7 million for the second quarter of 2022. net product revenue from u.s commercial sales of expobio for the second quarter of 2023 was $28.5 million compared to $29 million for the second quarter of 2022. As Sohanya discussed, net product revenue continued to be adversely affected by more patients using our patient-assisted program as well as higher growth-to-net discounts. Growth-to-net discounts were 22% in the second quarter of 2023 as compared to 17% in the second quarter of 2022. Turning to costs, With our continued focus on cost management, we are pleased to be delivering a combined 12% year-over-year reduction in our R&D and SG&A expenses in the first half of 2023. As we recognize the cost benefits from our previous efforts to focus our pipeline, our R&D expenses for the second quarter of 2023 were $31.5 million, down 28% compared to $44.3 million for the second quarter of 2022. Likewise, we have reduced SG&A expenses in the second quarter of 2023 by 7% at $34.5 million compared to $37.3 million for the second quarter of 2022. Cash, cash equivalents, restricted cash and investments as of June 30th, 2023 totaled $237.7 million compared to $279.7 million as of December 31st, 2022. Based on our current operating plans, we are reaffirming revenue guidance for the full year of 2023 as follows total revenue in the range of 145 to 160 million expovio net us product revenue of 110 to 125 million with our cost reduction initiatives we are lowering our expense guidance for 2023 we now anticipate non-gap r d and sgna expenses which exclude stock-based compensation expense to be in the range of $240 to $255 million for the full year of 2023, down from our initial guidance of $260 to $280 million in February. And finally, coming to our cash guidance, we have entered into an amendment to our Revenue Interest Financing Agreement with affiliates of healthcare royalty partners, extending our aggregate payment amount date by six months from December 31, 2024 to June 30, 2025, in increasing the payment cap amount from 1.85 to 1.95. Taken together, our existing cash, cash equivalents and investments, as well as the revenue we expect to generate from Expovio product sales and other licensed revenues, will be sufficient to fund our planned operations through the end of 2025, excluding the maturity of our convertible bonds in October 2025. I'll now turn to slide 34 and Richard for some final thoughts. Richard?
spk07: Thank you, Mike. Turning to slide 35, as we have discussed today, we are rapidly advancing our pipeline, concentrating our investments in three phase three programs that are expected to read out through 2024 and 2025 as we work to create near and long-term value for all our stakeholders. I would like to thank our teams who continue to execute in a disciplined manner and who strive each day for patients with high unmet needs. Thank you again for joining us today, and I would now like to ask the operator to open the call up to the Q&A portion of today's call. Operator?
spk13: Thank you. We will now begin the question and answer session. To ask a question, you may press star, then 1 on your touch-tone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then 2. At this time, we'll pause momentarily to assemble our roster. Our first question comes from Peter Lawson from Barclays. Please go ahead.
spk01: Good morning. This is Cheyenne for Peter. Thanks for taking our question. So first, I just wanted to get maybe a little more color around free drug through the PAP program. I believe this is also an impact in 1Q. So just any color you could provide around how this is compared to 1Q and how you see this dynamic playing out for the remainder of 2023. Thank you.
spk07: Thanks, Shea. Maybe for that, I'll turn to Sohania to kind of lay out how the patient assistance program and free drug has evolved from Q1 to Q2. Sohania?
spk04: Hey, thanks for the question. So in terms of the foundations in Q2, one of the four main multiple myeloma foundations was open for a period of time in Q2, which helped to allow for a reduction in patient new starts entering PATH. but we saw continued refill impact in PAP. So PAP contribution in Q2 to total demand was 14% compared with in Q1 was 9%. If you compare it with Q2 of last year at historic normals, it was 5%. So the total net revenue impact from PAP loss alone due to foundation closures in Q2 was roughly 3 million. As we think about Q3 and Q4, currently the one foundation that was partly open in Q2 continues to remain open to date. We have no line of sight or control into how these funds are disseminated, but our guidance range does incorporate several factors like GT and impact, but also largely this uncertainty around the PAC impact due to foundation closures.
spk01: Great. Thank you. And maybe just a final quick question is around some of the cost refinements. So I know there's a workforce reduction this quarter. Is there anything the team has been thinking about in terms of whether there may be program refinements kind of later in the year, any other kinds of cost cuttings that we should be thinking about?
spk07: Yeah, thanks, Shay. I think as we've highlighted, you know, we continue on an ongoing basis to make sure we're kind of optimizing and focusing our cost structure. So we've continued to do that with the, you know, approximately 20% reduction in our workforce this quarter to really ensure we're focused on being able to deliver our three phase three programs with our investments, obviously, in multiple myeloma. endometrial cancer and myelofibrosis. And on an ongoing basis, obviously, we continue to evaluate our costs to ensure we're really being diligent in how we're allocating our capital.
spk01: Great. Thank you.
spk13: Our next question comes from Mari Raycroft from Jefferies. Please go ahead.
spk08: Hi. This is Kevin on for Morrie. Thanks for taking my questions. Just for endometrial, could you say whether the shift in timeline there for the readout, was that due to competition with PD-1s? And then also, could you talk about the powering for this study and whether you will look at the MSS and MSI-high patients as pre-specified subgroups within that P53 wall-type patient population? Thanks.
spk07: Yeah, thanks, Kevin. I'll turn to Reshma to kind of put all that together and talk about the focus and the progress in endometrial cancer as we advance our EC042 trial.
spk04: Hi, Kevin. This is Reshma. So, thanks for the question. You know, in terms of the timelines, there's a slight modification from, you know, end of late 2024, beginning of 2025. Of course, this is an event-driven trial, so when we see the events actually occur, you know, that'll trigger our ability to perform the analysis for progression-free survival. You know, with that said, we're closely looking at how the data is positively evolving. In this most recent update that Brian Flomovitz presented at the ASCO Plenary, we now see the median PFS in those TP53 wild-type patients evolve from the 13.7 months that we initially disclosed back in the beginning of last year to now 27.4 months, so more than a doubling in that median PFS that is going to have a slight impact on how fast those events accrue. Taking that into account, we reprojected and anticipate, again, those PFS events to occur either late 2024 or beginning of 2025. We're probably looking at approximately, you know, a couple-month spread. In terms of Looking at the P53 wild-type MSS, it's a great question. Obviously, the data are very encouraging in that subgroup, which does comprise the vast majority of all patients. The way that the ECO42 trial, the phase three, is designed, it's specifically focused on that P53 wild-type subgroup, regardless of whether MSS, MSI. And largely because this is a novel subgroup, And again, we believe that the data specifically observed in that P53 wild-type subgroup truly is unprecedented. Of course, we will be looking at the subgroup of patients who are P53 wild-type MSS and separately P53 wild-type MSI. But right now, our focus truly is on that large P53 wild-type subgroup or patient population, I should say.
spk08: Great. Thanks, Rich, but that makes a lot of sense. And then just to follow up on myelofibrosis, you know, we saw that one of your competitors recently top-lined data, phase three data, showing they hit STAT-SIG on spleen size but not symptom score. There's also another update expected this fall. Could you just talk about how you view the evolving treatment landscape here, and then what gives you confidence that you'll be able to succeed on the symptom score co-primary in your phase three? Thanks.
spk04: Yeah, yeah. So I saw that press release too. I'm not privy to any additional data beyond what you saw as well. You know, what I found very intriguing is actually how that ruxolitinib arm performed. It was actually an SVR rate of approximately 30%, right, which is a little surprising to me, lower than what the data that was presented in the COMFORT trial, you know, analyzed more than 10 years ago. It really suggests to me that, the benefit that ruxolitinib is having on that important spleen volume reduction, probably lower than what we expected. When I look at our data from the phase one trial, specifically assessing selenoxor at 60 milligrams in combination with ruxolitinib, my confidence goes up given the fact that we saw 78%. So that 78% compared to that 30-ish percent really suggests that we can have a very meaningful benefit on-screen volume reduction in our ongoing Phase 3 study. In terms of the TSS50, so to a certain degree, I'm not that surprised. So, you know, my understanding from the earlier TRANSFORM Phase 2 trials is that their TSS50 was marginal at best. Now, why is it marginal? Hard to say, right? We know that a lot of aspects can contribute to TSS50 scores, including toxicity, as well as you know, patients not completing out their form, so missingness in that data. Obviously, AbbVie is going to continue to analyze their data and hopefully, you know, report on more mature data later this year, maybe even beginning of next year. I go back to our data in which we had an opportunity to look at the TSS50 data obtained from the patients enrolled as part of that phase one. And I'm, again, very encouraged by the 58% TSS data that we saw. Again, compared to Ruxalone, which TSS 50s are in the low 40s, it really does suggest that the combination of selenexor plus ruxolitinib can meaningfully improve both SVR and TSS50, both important endpoints that we need to hit as part of our phase three trial.
spk12: Great. Thank you very much, Reshma.
spk13: Our next question comes from Colleen Cussey from Bayard. Please go ahead.
spk03: Great. Thanks. Good morning, and thanks for taking your questions. So in the Ciendo presentation from the ASCO plenary, you continue to see an increase in PFS versus placebo. Can you share what the average time on therapy has been? Just trying to think about that in context of the market opportunity for duration in endometrial cancer.
spk04: Yeah, I appreciate the question, Colleen. So we haven't reported on that median duration of treatment yet, and it's only because those data are still maturing. We actually still have patients on treatment. And as the data continue to mature, we'll have an opportunity to present that median duration of treatment, likely at an upcoming presentation in the next six to 12 months. Now, we do know that median duration of treatment and PFS don't track one-to-one. However, we are seeing an interesting trend. So as median PSS gets longer, we're also seeing that median duration of treatment also get longer. So I think that is a very meaningful evolution, both from a progression-free survival, but time on therapy as well.
spk03: That's helpful. Thank you. And then congrats on getting the phase three myelofibrosis study up and running and the fast track status there. I know it's early, but how challenging is it to find naive myelofibrosis patients? And how many centers do you think you'd target for this study?
spk04: Yeah. So, yeah, very important milestone to get that phase three initiated. You know, we've got a lot of momentum behind this trial, right? I think, again, you know, many of our investigators are very encouraged to by the aggregate data that we've been able to present from that phase one trial evaluating selenexor in combination with ruxolitinib. Again, not only the spleen volume reduction and TSS50, but those key aspects that really suggest that the combination is having a positive disease modification and this potential monotherapy. So it's this holistic profile that really suggests that this combination can be a game changer. for patients who are treatment-naive myelofibrosis. In terms of competition, well, there is none, right? So there's no other large phase three trials. By and large, this is going to be a global trial. We are activating sites in the US, Europe, as well as Asia. We're looking at approximately 150 sites. And again, there's really no competition for those treatment-naive myelofibrosis patients that are diagnosed throughout the globe. So we're encouraged by the enthusiasm, the lack of competitive headwinds, and just really strong support from all of our investigators.
spk03: That's great. Thanks. And last one from us. On the monotherapy myelofibrosis study you talked about on the call, can you just talk about the rationale and why you picked that patient population to look at?
spk04: Yeah, so this is a really innovative trial design for us, and it's largely based upon this really intriguing finding we've seen from the phase one study, specifically in that subgroup of patients who were treated with suboptimal doses of ruxolitinib. We're finding that patients are still achieving that important SVR35 and TSS50. Again, you don't see that with ruxolitinib alone. It really suggests that XPO1 is a fundamental mechanism, and selenexor potentially has monotherapy activity. So this trial allows us to better investigate that hypothesis. How this trial is going to be conducted is that patients who are treatment-naive myelofibrosis, and specifically who have baseline platelet counts of 50,000 to 100,000, are going to be treated with Selinexor monotherapy at either the 60 milligram or 40 milligram doses, and that in the event they achieve a suboptimal response to Selinexor, they have an opportunity to add on either pacritinib or ruxolitinib. Why are we looking at this patient population? Because we know that patients whose baseline platelet counts are between 50 and 100 are really has very limited treatment options. By and large, the only therapies available to them are going to be picritinib and ruxolitinib. Despite these therapies, their SVR and TSS50 with these therapies are still quite marginal. So it's an opportunity to assess selenexor monotherapy and potential these novel combinations too.
spk11: Great. Thanks for taking our questions.
spk12: All right, in the interest of time, please limit yourself to one question.
spk13: And our next question comes from Chris Raymond from Piper Sandler. Please go ahead.
spk05: Hi, good morning. This is Nicole Gabreski on for Chris. Thanks for taking the question. So maybe just around overall survival and endometrial. So I know that was a secondary endpoint in the SIANDO trial and kind of came up as a topic of discussion during the ASCO plenary session. I was just wondering if we should expect you to disclose any OS data from the trial in the future. And then just quickly for LTN XOR, I know you guys are focused on your late-stage programs, but just wondering how you're thinking about the path forward for LTN XOR and MDS at this point, and maybe just how we should think about the prioritization of that program.
spk07: Yeah, thanks, Nicole. Yeah, no, thanks, Nicole. I think, you know, as Reshma has indicated, you know, over the next six to 12 months as we continue to see, you know, the maturity of the data in the endometrial cancer CNDL trial, you know, we'll report out on the OS. And maybe I'll turn to Reshma to kind of talk about Eltenexor, which obviously is very important for us as we continue to move forward in looking at potential benefit we can bring patients. Reshma?
spk04: Yeah, thanks, Nicole. You know, L-tenexor is one of our four core programs. We're specifically evaluating myelodysplastic syndromes, neoplasms, specifically relapsed refractory MDS with L-tenexor. Very encouraged by the data that we reported from the phase two. We'll have an opportunity in the next few months to really define that optimal development plan specifically with L-tenexor in this high-risk patient population.
spk11: Great. Thank you.
spk13: The next question comes from Brian Abrams from RBC Capital Market. Please go ahead.
spk00: Good morning. This is Joanne from Bryan. Thank you for taking our question. With the fall of data at ASCO, just going back to the endometrial cancer, the fall of data continued to seem very encouraging and I know you just mentioned that some patients continue to remain on therapy and continue to show PFS benefits there too. So just wondering if there's any expedited pathway for approval. and before the top line reads out in late 24 or early 25? Or is this something that you have discussed with the FDA so far?
spk11: Thank you.
spk04: Yeah, thanks, Joe. So we don't comment on our interactions with the FDA. You know, with that said, ECO42, remains our opportunity to get both Selinex or the drug as well as the companion diagnostic in the form of the NGS platform in which we assess P53 as our approval opportunity in the U.S. as well as ex-U.S. too. You know, ECO42 is a well-designed trial in that we are prospectively evaluating patients who are P53 wild type. It's a well-powered study. that would specifically allow us to assess that important progression-free survival and overall survival compared to placebo. So we remain focused on that ECO42 trial that is really evolving quite nicely. Fiendo, though, and the data that we've observed from Fiendo very much is informing our, informed our design of that trial. We remain encouraged. Those data only increase our confidence in the likely outcome from ECO42.
spk12: Our next question comes from Eric Joseph from JP Morgan.
spk13: Please go ahead.
spk09: Hi, this is Noah on for Eric. Thanks for taking our question. In regards to the EEC042 study, what median TFS in the placebo arm is anticipated for your powering assumptions in your guidance for the readout? And is it similar or more generous than that of the P53 wild type group in the C&O study?
spk04: Yeah, so great question. So we haven't disclosed on those kinds of details. You know, with that said, we are assuming a median PFS for selenexor exceeding that 13.7 months, right? So those were the data. that we observed at the time of the initial data cut, again, in the beginning of 2022. Given the fact that median PFS continues to increase quite nicely, again, we're quite confident that that median PFS is going to be in the excess of 13.7 months. It is, you know, all of our phase three trials are well powered, you know, well above that 80%. So again, very confident that at the time, that we're able to read out the PSS anticipated end of 24, beginning of 25, we're going to see a very meaningful improvement in that PSS with the Selinex or treated patients compared to placebo.
spk12: Got it. Thank you. And the next question comes from Jonathan Chang from Lear Inc.
spk13: Partners. Please go ahead.
spk10: Hey guys, this is Matt Calperon for Jonathan. Thanks for taking my question. You mentioned there's some enthusiasm around the ex-OVO Rux-Pombo and treatment of malified venesis, and the data are certainly impressive. I was just wondering, you know, with the upcoming, you know, combination readouts and potential approvals there, how does that impact the development and regulatory interactions for your trial, given it's only against Rux monotherapy? Thanks.
spk04: Yeah, we don't really anticipate any kind of impact with either the data readouts, right? You know, data readouts are just the top line results. Obviously, the companies need to go through the extensive regulatory process. We anticipate, you know, our trial to be enrolled or almost close to enrollment, completion of enrollment by the time that regulatory approval is obtained, again, assuming that those data are positive for both SVR and TSS50. So, again, we're very confident, not only in the data, but in the design of our phase three trial.
spk12: Got it. Thank you so much for taking my question.
spk13: This concludes our question and answer session. I would like to turn the conference back over to Richard Paulson for any closing remarks.
spk07: Thank you, operator, and thank you, everyone, for joining our call today. You know, as I indicated at the beginning of the call, we had a very strong second quarter, you know, as we continue to accelerate KarioPharm to its next stage of growth with our novel sign compounds, both Selinexor and Eltenexor. And once again, I'd like to thank our teams who execute in a very disciplined manner, striving each day for patients with high unmet needs. And thank you, everyone, for joining the call today.
spk13: The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.
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