Karyopharm Therapeutics (NASDAQ: NASDAQ:KPTI) has provided updates on its clinical trials and financial status during the Third Quarter 2024 Financial Results Conference Call on November 8, 2024.
The company discussed significant developments in its Phase 3 trials, particularly the SENTRY trial for myelofibrosis and the ECO-042 trial for endometrial cancer, both of which show promise and target annual U.S. peak revenues of $1 billion each.
Financially, Karyopharm reported Q3 2024 revenues of $38.8 million, with a narrowed 2024 revenue guidance of $145 million to $155 million, and expects to maintain operations into Q1 2026 with its current financial resources.
Key Takeaways
- Phase 3 SENTRY trial for myelofibrosis has a favorable regulatory update, with top-line data expected in the second half of 2025.
- Selinexor shows potential in endometrial cancer as a novel maintenance therapy, with top-line data from the ECO-042 trial expected in early 2026.
- Q3 2024 revenues reached $38.8 million, with a slight decrease in XPOVIO net product revenue from the previous year.
- The company has sufficient cash to continue operations through Q1 2026 and has narrowed its 2024 revenue guidance to $145 million to $155 million.
- Karyopharm is preparing for rapid launches of selinexor, pending approval, in both myelofibrosis and endometrial cancer markets.
Company Outlook
- Karyopharm is optimistic about its late-stage pipeline and market potential for selinexor in myelofibrosis and endometrial cancer.
- The company is focused on advancing its Phase 3 trials and enhancing its commercial performance, with significant milestones anticipated in the near future.
Bearish Highlights
- XPOVIO net product revenue saw a marginal decrease from Q3 2023, with a gross-to-net discount increase due to higher 340B utilization and Medicare rebates.
- Cash and equivalents have decreased from the end of 2023, totaling $133.9 million as of September 30, 2024.
Bullish Highlights
- Total (EPA:TTEF) revenue is up from Q3 2023, with the company maintaining consistent growth in net product revenue.
- Strong connections with treating physicians and market research support selinexor's potential success upon approval.
Misses
- Despite overall revenue growth, there was a slight decline in net U.S. XPOVIO revenue compared to the previous year.
Q&A Highlights
- Reshma Rangwala addressed the SPd Phase 3 study for multiple myeloma, noting a reduced patient target and fewer PFS events needed for primary analysis, thanks to positive data.
- The company is awaiting FDA feedback on an amendment to the SPd study, which will clarify the timeline for top-line results.
Karyopharm Therapeutics has shown resilience and strategic focus in the face of challenges, with a clear path towards potential product launches that could significantly impact the treatment landscape for myelofibrosis and endometrial cancer. As the company continues to navigate the regulatory environment and refine its commercial strategies, investors and stakeholders will be watching closely for the outcomes of the pivotal trials and the potential market entry of selinexor in the coming years.
InvestingPro Insights
Karyopharm Therapeutics' (NASDAQ: KPTI) recent financial results and clinical trial updates paint a picture of a company at a critical juncture. While the company's pipeline shows promise, particularly with its Phase 3 trials for myelofibrosis and endometrial cancer, investors should be aware of some key financial metrics and expert insights provided by InvestingPro.
As of the latest data, Karyopharm's market capitalization stands at $110.22 million, reflecting the market's current valuation of the company's potential. Despite the optimism surrounding its clinical trials, InvestingPro Tips highlight that Karyopharm is "quickly burning through cash" and is "not profitable over the last twelve months." This aligns with the company's reported financial status, where they expect current resources to sustain operations only through Q1 2026.
The revenue growth of 1.77% over the last twelve months, as reported by InvestingPro, corroborates the company's slight increase in total revenue mentioned in the Q3 2024 results. However, with an operating income margin of -84.86%, Karyopharm faces significant challenges in achieving profitability, a point emphasized by another InvestingPro Tip stating that "analysts do not anticipate the company will be profitable this year."
These financial metrics provide context to the company's narrowed 2024 revenue guidance and its focus on advancing late-stage clinical trials. The potential market success of selinexor in myelofibrosis and endometrial cancer becomes even more crucial given the current financial landscape.
For investors seeking a more comprehensive analysis, InvestingPro offers additional tips and insights that could further illuminate Karyopharm's financial health and market position. With 6 more tips available on the InvestingPro platform, subscribers can gain a deeper understanding of the company's valuation, liquidity, and growth prospects.
Full transcript - Karyopharm Therapeutics Inc (KPTI) Q3 2024:
Operator: Good morning. My name is Jenny, and I will be your conference operator today. At this time, I would like to welcome everyone to Karyopharm Therapeutics Third Quarter 2024 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 Elhan Webb, Senior Vice President, Investor Relations.
Elhan Webb: Thank you. And thank you all for joining us on today's conference call to discuss Karyopharm's third quarter Q2 2024 financial results and recent company progress. We issued a press release this morning detailing our financial results for third quarter 2024. This release, along with a slide presentation that I will reference during our call today are available on our website. For today's call, as seen on slide two, I'm joined by Richard, Reshma, Sohanya and Mike who will provide an update on our results for the third quarter 2024 and recent clinical developments. Before we begin our formal comments, I'll remind you that various remarks will make today constitute forward-looking statements, FLS for 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 this FLS as a result of various important factors, including those discussed in the Risk Factors section of our most recent Form 10-Q, 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 obligation 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.
Richard Paulson: Good morning. Thank you, Elhan, and thank you all for joining us today for Karyopharm’s Q3 2024 earnings call. Turning to slide five, I want to begin with the exciting news that we shared last week regarding our Phase 3 SENTRY trial in myelofibrosis. We announced a very favorable regulatory update as we are changing the co-primary endpoint of SENTRY to absolute TSS following productive discussions with the FDA. Absolute TSS is supported by leading investigators and patient advocacy organization and increases our overall confidence in our trial. We remain on track to report top-line data from SENTRY in the second-half of next year. SELINEXOR's unique mechanism of action, compelling data, our targeted approach to clinical development, and ongoing discipline cost management position us well to advance our prioritized late-stage pipeline, which may enable two transformative opportunities as we build on our multiple myeloma foundation. With our existing commercialization capabilities, we are pleased to deliver our third consecutive quarter of net product revenue growth in the U.S. and are on track to deliver revenue in the upper half of the guidance outlined at the start of the year. Our established commercial organization is well set up to potentially drive successful and rapid launches in myelofibrosis and endometrial cancer. Turning to slide six, in myelofibrosis, if the data from our Phase 3 SENTRY trial is supportive, we believe we will have the opportunity to transform the treatment paradigm by providing the first combination therapy in Jack-naive myelofibrosis. While ruxolitinib alone has remained the standard-of-care for over a decade, less than half of all patients achieve meaningful spleen reduction. We believe that combination therapy with a novel mechanism of action like XPO1, inhibition holds the key for driving rapid, deep, and durable responses for the vast majority of myelofibrosis patients. We continue to estimate that our annual U.S. peak revenue opportunity of myelofibrosis is approximately $1 billion in the multi-billion dollar myelofibrosis market. In endometrial cancer, the opportunity remains substantial given the evolution in the molecularly driven therapies. Our data in TP53 wild-type endometrial cancer offers the potential of a meaningful and unique mechanism in maintenance therapy for approximately half of all endometrial cancer patients. This represents approximately $1 billion annual U.S. Peak revenue opportunity as well. Sohanya and Reshma will expand in detail on both these near-term transformative opportunities. Now, I'd like to turn the call over to Reshma, who will give an update on our clinical programs. Reshma?
Reshma Rangwala: Thank you, Richard. Turning to slide eight, I want to highlight the unique potential of our promising late-stage pipeline led by our three ongoing Phase 3 studies. Karyopharm has the potential to establish new standards-of-care in solid and hematologic malignancies, building on our foundation in multiple myeloma, while also optimizing the patient experience by incorporating substantially lower doses of selinexor in these studies. Beginning with myelofibrosis on slide 10, selinexor is a novel inhibitor of XPO1 that prevents the new export of various proteins and messenger RNA molecules. By doing so, it promotes the nuclear localization and activation of important tumor suppressor pathways, such as TP53, while concurrently inhibiting the cytoplasmic activation of various proliferative and profibrotic pathways linked to myelofibrosis pathobiology. In addition of these multiple pathways, position selinexor’s a unique potential therapeutic option in myelofibrosis. Before highlighting our important update to the co-primary endpoint relating to total symptom score, I will recap efficacy and safety data observed from the Phase 1 trial evaluating selinexor plus ruxolitinib in JAKi inhibitor naive myelofibrosis patients as outlined on slide 11. Amongst the 14 patients, who received selinexor 60 milligrams plus ruxolitinib, all evaluable patients achieved an SVR35 at any time, and 79% of patients achieved SVR35 at week 24 in the ITT (NYSE:ITT) population. As you've heard from some of the leading physicians in this space on our call last week, clean volume reduction is viewed as one of the most important factors by treating physicians, given its correlation to overall survival. Having nearly 80% of patients achieve SVR35 is viewed as very positive. Durability of response is also a key efficacy measure relevant to JAK-naive patients. Our Phase 1 data demonstrates a 100% probability of continuing response for both SVR35 and TSS50 as shown on slide 12 over a median duration of follow-up of 32 weeks and 51 weeks respectively. This is particularly meaningful as it suggests that once patients experience a response, they remain in response. On our call last week, one of the KOLs indicated that this is why he believes treatment Selinexor should be added to ruxolitinib early on in the treatment journey, given the view that deep responses early on are important and can improve outcomes for patients. Turning to slide 13, we were very pleased to announce last week that absolute total symptom score will replace TSS50 as a co-primary endpoint in our SENTRY Phase 3 trial in myelofibrosis. Assessing the average improvement in symptoms over 24-weeks has gained support from the FDA, investigators, and patient advocacy groups, and is a more sensitive method to assess symptom improvement in myelofibrosis. The combination of Selinexor and ruxolitinib has demonstrated promising evidence of improvement in absolute total symptom scores in our Phase 1 trial, and we look forward to utilizing this more comprehensive assessment of symptom improvement moving forward. Building on our impressive SVR35 results from our Phase 1 trial, changing our co-primary endpoint to absolute TSS further increases our overall confidence in the SENTRY Phase 3 trials. And we look forward to potentially addressing a tremendous unmet need in myelofibrosis with this combination. On slide 14, the seep symptom improvement with 60 milligrams of selinexor plus ruxolitinib in our Phase 1 trial can be seen in comparison to historical data for ruxolitinib monotherapy. The average reduction, which signifies improvement, an absolute TSS of 18.5 points with our combination, compared favorably to the average 11 point to 14 point reduction that has been observed with ruxolitinib alone in prior Phase 3 clinical trials conducted by others. The rapid, deep, and durable findings observed with SVR35 is also observed with average TSS, as seen on slide 15. These are new data we are presenting for the first time today. Specifically, in our Phase 1 trial, selinexor plus ruxolitinib demonstrated rapid, deep, and sustained improvements in average TSS. These rapid improvements in symptoms are seen as early as week four, despite any side effects that the patients may experience from the treatment. These symptom improvements continue through week 24, demonstrating meaningful sustained symptom improvement for the entire six-month duration evaluated. For the adverse events experienced, the most common were GI side effects such as nausea, anemia, thrombocytopenia, and fatigue. And I think it is worth considering what we heard from our KOLs and GI side effects last week. These GI side effects are most common at the start of treatment, only last approximately two cycles and can be effectively managed with anti-emetics. Given this well-documented profile, we believe patients and physicians can easily be educated around this profile, enabling patients to stay on treatment long-term, which ultimately is what drives meaningful spleen reduction and symptom improvement. In summary, slide 16 highlights why the combination of selinexor and ruxolitinib has the potential to become the new standard-of-care if the combination is approved. And as we have heard at our recent call with myelofibrosis physicians, the myelofibrosis community wants to adopt combination therapies, which quickly lead to deep and durable spleen reduction symptom improvement. Selinexor’s potential in myelofibrosis is strengthened by its well-established safety profile as it has been administered to approximately 30,000 patients across multiple cancer indications. The low dose of 60 milligrams that is currently incorporated in the Phase 3 trial suggest that selinexor has the potential to be a tolerable convenient once weekly oral treatment, especially with the use of anti-emetics during the first two cycles of treatment. Turning to slide 17, we have increased confidence with the favorable changes made to the SENTRY trial. We've proactively increased the total sample size to approximately 350 patients to further increase the statistical powering. Given the strong enrollment, our expectations of top line data remain in the second-half of 2025. Furthermore, the co-primary endpoint will change from TSS50 to absolute TSS. The two co-primary endpoints, SVR35 and absolute TSS will be tested sequentially. SVR35 will be evaluated first, and if positive, the alpha will then be rolled down to absolute TSS. Just in focus to endometrial cancer on slide 19, selinexor primarily functions by blocking the export of TP53 from the nucleus to the cytoplasm. When TP53 accumulates in the nucleus, it leads to disrupted DNA repair processes, cell cycle arrest, and increased apoptosis. This mechanism is underscored by the anti-tumor effects in TP53 dependent tumors, specifically in endometrial cancer, and has the potential to be the first novel oral maintenance therapy for patients with TP53 wild type endometrial cancer. As seen on slide 20, the TP53 wild type status continues to increase in relevance throughout the treatment landscape for advanced and recurrent endometrial cancer. Recently, the FDA approved checkpoint inhibitors in combination with chemotherapy, followed by maintenance therapy with checkpoint inhibitors for advanced recurrent endometrial cancer patients, regardless of MMR status. However, the efficacy in patients with MMR proficient tumors is notably lower, compared to those with MMR deficient tumors, aligning with the mechanistic rationale for the effectiveness of checkpoint inhibitors in MMR deficient solid tumors. Notably, patients with both MMR proficient and TP53 wild-type tumors make up approximately 50% of all advanced or recurrent endometrial cancer cases. On slide 21 in the SIENDO trial, exploratory subgroup data presented at ASCO revealed that selinexor has the potential to provide promising outcomes for patients with TP53 wild-type endometrial cancer, achieving a median TSS of 28.4 months, compared to just 5.2 months for placebo, translating to a hazard ratio of 0.44. Looking more closely at the MMR proficient subgroup on slide 22, our ASCO data on SIENDO showed selinexor demonstrates an encouraging signal of long-term median PFS benefit of 39.5 months. This was substantially higher than the 4.9 months observed with placebo, corresponding to a hazard ratio of 0.36. Although we acknowledge the limitations of cross-trial comparison, it's important to note that the PFS improvement with selinexor in this subgroup exceeds the median overall survival achieved by checkpoint inhibitors in MMR proficient patients, emphasizing selinexor substantial efficacy for these individuals. The updated safety data in endometrial cancer patients from the SIENDO trial is displayed on slide 23. 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. Grade 3 plus treatment emergent events were infrequent with neutropenia, thrombocytopenia, and nausea being the most common. Notably, the prophylactic dual anti-emetics were not required during the SIENDO trial, whereas dual anti-emetics are not only required in ECO42, but all of our Phase 3 trials, including SENTRYs, which is why we anticipate the safety profile from our Phase 3 trials will be substantially improved. On slide 24, we remain on track for top line data readout for our pivotal export EC-042 Phase 3 trial in early 2026. I remain encouraged with the potential of selinexor to achieve clinically meaningful outcomes in the maintenance setting for patients with p53 wild-type endometrial cancer, especially those with MMR proficient tumors. Lastly, our Phase 3 EMN29 SPd trial is outlined on slide 26. This trial aims to address the unmet needs of patients with multiple myeloma by offering an all-oral treatment option that could also benefit those undergoing free and post T-cell engaging therapy, and built on the positive progression-free survival data previously observed with SPd 40. As we noted on our second quarter earnings call, we have worked with the sponsor of the trial, the European myeloma network to amend the statistical analysis plan. We have completed screening for the planned approximately 120 patients, who will provide an updated time line for top line data following regulatory feedback. We are very excited for what the future holds for Karyopharm, working swiftly to progress our three pivotal Phase 3 programs, fueled by increasingly compelling data selinexor could significantly benefit various patient populations facing substantial unmet needs and also enhance our currently improved indications in multiple myeloma. I will now turn the call to Sohanya, to provide updates on our commercial results from this quarter.
Sohanya Cheng: Thank you, Reshma, and good morning. On slide 28, I'll discuss our commercial highlights for the third quarter of 2024. XPOVIO net product revenue was $29.5 million, up 5% compared to our results in the second quarter. We are very pleased with our third consecutive quarter-over-quarter growth of XPOVIO U.S. revenues amid a highly competitive marketplace and are well on track to deliver in the upper half of the guidance that we outlined at the start of the year. In Q3, XPOVIO revenues were driven by double-digit demand growth versus the prior quarter, powered by an increase in refills and partially offset by an increase in gross to net, largely due to a higher 340B book of business. We achieved strong demand growth quarter over quarter in the community where XPOVIO tends to be used as a convenient oral and manageable option for patients as an earlier line of therapy or if the patients are unable to access a T-cell therapy. We also delivered growth in demand in our academic setting as our use as a novel mechanism of action pre and post T-cell therapies continue to increase. With our team's strong execution driving demand growth for XPOVIO year to date, we are confident in our ability to deliver on our revised full-year 2024 U.S. XPOVIO net product revenue guidance range of $110 million to $115 million. Now I'd like to turn to slide 29 and shift our focus toward milestones accomplished outside of the U.S. I am pleased with our momentum as we expand our global footprint with continued reimbursement and regulatory approvals for selinexor across the world. In the third quarter, XPOVIO received reimbursement approvals in Italy and France and continue to expand its global footprint with additional regulatory approvals globally. Our commercial franchise continues to benefit an increasing number of multiple myeloma patients globally and as a profitable business serves as a critical driver in funding our pipeline. With our dedicated commercialization team and partners, we have the capabilities for strong launches in potential future indications. I'd like to now present in detail the potential market opportunity that we see for selinexor in myelofibrosis and endometrial cancer, each amounting to approximately $1 billion in potential annual U.S. peak revenues. Turning to slide 30 starting with myelofibrosis. As discussed by Reshma and on our call last week, selinexor has the opportunity to transform the frontline treatment paradigm in myelofibrosis. There are no drug classes other than JAK inhibitors approved in the front line, which presents a unique opportunity for an efficacious and tolerable new drug with a novel mechanism of action to improve current standard of care. As we look at the myelofibrosis market in detail, there are roughly 7000 estimated incidences in the U.S., about 6000 of which are patients with intermediate to high-risk myelofibrosis. Approximately three quarters of these patients with baseline platelet counts of 100 or above make up the target patient population for selinexor combination therapy. Third-party market research conducted last year showed that 75% of physicians indicated their intent to adopt combination therapies as a front-line standard of care, replacing ruxolitinib monotherapy due to the potential of better efficacy with the combination. The survey results also showed a strong perception from physicians on the product profile of selinexor in combination with ruxolitinib. We would anticipate strong demand at launch, if approved, given our data to date showing selinexor ability to meaningfully improve spleen volume and symptom management when added to the current standard of care. Furthermore, we have an established commercial infrastructure in the hematology space and about 80% overlap in community based physicians who treat multiple myeloma and myelofibrosis. This gives us a tremendous opportunity to build a strong presence for selinexor in the multi-billion myelofibrosis market with a potential annual U.S. peak revenue opportunity of approximately $1 billion. Now I'd like to shift your attention to endometrial cancer on slide 31, which is an equally attractive opportunity for us. We are very 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 pMMR subgroup. Looking now at the potential market in more detail, endometrial cancer is the most common gynecologic cancer in the US with about 17,000 expected incidences in 2032, approximately 80% of which is expected to be pMMR, and 20% dMMR. About 10,000 advanced or recurrent endometrial cancer patients are expected to have p53 wild-type status. With about two-thirds of patients expected to respond to their front-line chemotherapy, roughly over 6000 patients would be eligible for selinexor, a potential novel and biomarker-specific oral maintenance therapy. In third-party market research, when U.S. physicians were shown multiple product profiles, selinexor was the preferred regimen for 75% of patients with Tp53 wild type and pMMR status. With our strong commercial presence in community accounts with Xpovio, we expect to have roughly 80% overlap in community-based oncologists who treat multiple myeloma and endometrial cancer. As a result, we expect a rapid potential launch of selinexor in endometrial cancer, if approved, with a potential annual U.S. peak revenue opportunity of approximately $1 billion. Now I'd like to turn the call over to Mike to give an update on our Q3 financial results.
Michael Mason: Good morning, everyone, and thank you Sohanya. Turning to our financials. Since we issued a press release earlier today with the full financial results, I will just focus on the highlights which are on slide 33. Total revenue for the third quarter of 2024 was $38.8 million, compared to $36 million for the third quarter of 2023. Net U.S. XPOVIO revenue for the third quarter of 2024 was $29.5 million, compared to $30.2 million for the third quarter of 2023. The gross-to-net discount for XPOVIO in the third quarter of 2024 was 31%, as compared to 21 % in the third quarter of 2023 and 29% in the second quarter of 2024. This increase was driven by increased 340B utilization and Medicare rebates. We expect GTN for the full year of 2024 to be approximately 30%. Our total expenses for the third quarter of 2024 were down year over year by 3% due to ongoing headcount reductions and other cost-saving measures, partially offset by our continued investment in our three ongoing Phase 3 clinical trials. R&D expenses for the third quarter of 2024 were $36.1 million compared to $35.6 million for the third quarter of 2023. The increase in R&D expenses was primarily attributable to higher clinical trial costs related to our ongoing pivotal Phase 3 trial in myelofibrosis. SG&A expenses for the third quarter of 2024 were $27.6 million, compared to $30.8 million for the third quarter of 2023. The decrease in SG&A expenses was primarily due to ongoing cost reduction initiatives and lower headcount. Cash, cash equivalents, restricted cash, and investments as of September 30, 2024 totaled $133.9 million, compared to $192.4 million as of December 31, 2023. Based on our current operating plans, we are narrowing our guidance for the full year of 2024 as follows. Total revenue expected to be in the range of $145 million to $155 million as compared to previous guidance of $145 million to $160 million. U.S. XPOVIO net product revenue expected to be in the range of $110 million to $115 million as compared to previous guidance of $105 million to $120 million. R&D and SG&A expenses are expected to be in the range of $255 million to $265 million, which includes approximately $20 million of estimated non-cash stock based compensation expense, as compared to previous guidance of $250 million to $265 million. And finally, we expect our existing cash, cash equivalents, and investments, the revenue we expect to generate from XPOVIO net product sales and other license revenues and ongoing disciplined expense management and cost-saving measures will be sufficient to fund our planned operations into Q1 2026. Note that our cash runway does not include paying off the remaining 2025 convertible notes in our $25 million liquidity covenant under the new term loan. Taking into account the repayment of the 2025 convertible notes and the minimum liquidity covenant carry from expected cash, cash equivalents, and investments will be sufficient to fund its operations into the fourth quarter of 2025. We expect our 2025 operating expenses to be lower than 2024 as we recognize the full-year benefits of our ongoing cost-saving initiatives. In summary, we are focused on the advancement of our three Phase 3 trials and driving commercial performance while continuing to be very diligent when allocating our resources. Before turning the call back to Richard, I'd like to extend my gratitude to everyone here at Karyopharm, our shareholders and everyone that I've had the opportunity to interact with in this role. I'm proud of helping to bring XPOVIO to the market and offering people with multiple myeloma a new therapeutic option. And I continue to believe the company has a very meaningful opportunities ahead, particularly in myelofibrosis and endometrial cancer. I'll now flip to slide 34 and turn the call over to Richard for some final thoughts. Richard?
Richard Paulson: Thank you, Mike. It goes without saying that we are so grateful for your leadership and service to Karyopharm over the last five and a half years. You've played a very important role in Xpovio's launch in the U.S., our partnership with Menarini, and the debt refinancing that we announced earlier this year. We wish you the best of luck in your new professional endeavors. Now as depicted on slide 35, several significant milestones are approaching for Karyopharm in the near future. We are excited about our innovation and growth strategy, which offers transformative opportunities with our Phase 3 clinical trials in myelofibrosis and endometrial cancer, while building on our Multiple Myeloma Foundation. These trials have the potential to deliver new standards of care for patients and significantly advance our company as we work to deliver value for our shareholders. As we move forward, we will continue to work diligently toward unlocking the full potential of selinexor and driving our next phase of growth. 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?
Operator: Ladies and gentlemen, we will now begin the question-and-answer session. [Operator instructions] Your first question is from Brian Abrahams from RBC Capital Markets. Your line is now open.
Brian Abrahams: Hi, good morning. Thanks for taking my questions, and best wishes to Mike as well and his future endeavors. Two quick ones from me, I guess first on the average total symptom score on slide 15 that you've shown. Obviously, pretty meaningful or pretty notable reduction over that 24-week period. But I'm just wondering how the magnitude of that change is influencing your powering assumptions? And the reason I ask is I believe Pelabresib and its original open label Phase 2 study on top of rocks showed at least a median absolute TSS improvement in that same 60% or so ballpark and then ended up just being on the cusp of statistical significance in a 400 plus patient Phase 3? And then I guess secondarily on TSS50, is that still going to be a secondary endpoint in the phase 3 study? And is that something that you think the FDA will still be looking at least to even see some -- observe some trends there as potentially supportive of approval? Or have the regulators completely shifted to really only focusing on absolute? Thanks.
Reshma Rangwala: Thanks, Brian, for the question. This is Reshma. So in terms of average TSS as you noted on slide 15, yes, I think those are very meaningful data. I'll just reiterate as I did on our prepared remarks, what those data show over time is that the average TSS substantially improves starting as early as week 24. And then you can see as the patients progress from week four to 24, you continue to see this decrement all the way to that average 18.5 reduction that we've reported as part of the absolute TSS. So it really reinforces this meaningful improvement, which again is signified by a reduction in that TSS score. When we look at our powering assumptions, what we're looking at is the delta across the two arms. So the average or the absolute TSS is an average assessment of the change in TSS from baseline to week 24. In the manifest data, they observed an approximately two-point difference across the two arms. It was not statistically significant. Our data suggests that we could observe something that is far higher well above two, if not double to four or above. So again, I think the data are strong, really shows a very meaningful improvement. When you translate the likelihood to a Phase 3, it really suggests that you cannot only see statistical significance in that absolute TSS, but a clinically meaningful result as well. In terms of your second question for TSS50, we are in a very enviable position to replace TSS50 with absolute TSS. So the co-primary endpoints again will be SVR35 followed by absolute TSS. We will not be evaluating TSS50. I think we are really seeing an evolution in terms of how we assess symptoms within a JAK naive space. I think everybody is in alignment, and when I say everybody, I'm really talking about our KOLs, patient advocacy groups, certainly the regulatory agencies that absolute TSS, which again looks at the average over time, is probably the more sensitive in their comprehensive way to analyze these symptoms.
Brian Abrahams: Really helpful. Thank you.
Richard Paulson: Thanks, Brian.
Operator: Thank you. Your next question is from Ed White from H.C. Wainwright. Your line is now open.
Ed White: Good morning. Thanks for taking my questions. Congratulations on the new regulatory approvals outside of the U.S. I'm just wondering if you can give us an update of where you stand in the countries where you've already launched, how the launches are going, and an outlook outside the U.S. for 2025.
Richard Paulson: Thanks, and I'll turn to Sohanya for that.
Sohanya Cheng: Hi, Ed. We continue to see approvals for reimbursement, as well as regulatory approvals in the past quarter. And we're very pleased with the global expansion of selinexor. As you compare to some of the U.S. launch experiences, they're starting in largely earlier lines of therapy versus pent-refractory and that obviously -- they have some of the learnings in terms of anti-emetic side effect management. And so as we look at 2025, we'll obviously provide guidance on total revenues on the Q4 2024 call. But with the ongoing reimbursement approval and launches this year, we anticipate royalties from U.S. selinexor revenues to increase in 2025. Now in 2024, we achieved a majority of the major market reimbursement approvals. Therefore, we don't expect those to reoccur next year. Again, we'll provide more color on total revenue guidance on our Q4 '24 call.
Ed White: Okay, thanks. And just to dig down into the endometrial market, I just wanted to get your thoughts on some of the challenges of entering a maintenance therapy market versus a treatment market and how the company is addressing that particular market on maintenance and getting patients to take the drug in a maintenance setting.
Sohanya Cheng: Yes, we are thrilled about the opportunity to launch in endometrial cancer as a potential novel and biomarker-specific oral maintenance only therapy for a couple of different reasons. I think as you've seen, the marketplace evolve rapidly, particularly in the past year. There continues to be a significant unmet need in specific molecular subgroups, and in our case, particularly focused on the p53 wild type and pMMR subgroup. And this is where our data, as Reshma has discussed, is most compelling. Now as we look at our product profile as a maintenance therapy, it is a highly compelling profile as supported by our market research. As I mentioned, when U.S. physicians were shown multiple product profiles, selinexor was the preferred regimen for a majority 75% of patients with p53 wild type and pMMR status. So my belief is we have a potentially groundbreaking therapy in this maintenance space in a highly targeted subgroup with a compelling profile and a convenient oral therapy. Important to also reinforce that as a commercial team, we have very strong overlap with treating physicians both in the multiple myeloma space and the endometrial space in the community, which enables us to hit the ground running with our messaging on the day of approval. So we're very excited about the potential opportunity to launch in this maintenance setting.
Ed White: Okay, thanks for taking my questions.
Richard Paulson: Thanks, Ed.
Operator: [Operator instructions] And your next question is from Peter Lawson from Barclays (LON:BARC). Your line is now open.
Peter Lawson: Great, thanks so much. Thanks for taking the questions. I guess just initially on the quarter, Sohanya, you've seen three quarters of quarter-over-quarter growth. And if you can make any comments about any underlying trends there or anything that was different from the last couple of quarters for that quarter-over-quarter growth and the mix between price and volume and then academic versus community settings. Thank you.
Sohanya Cheng: Thanks, Peter, for the question. We're very pleased with our three consecutive quarters of net revenue growth. Very proud of the team for the resilience and success they have demonstrated, particularly in Q3 in driving double-digit demand growth quarter over quarter. As we look at some of the dynamics here in terms of settings of care in the community setting, we achieved strong growth quarter over quarter. This remains the majority of our business. About 60% of our business came from the community setting. Now importantly in Q3 as well, we did see an uptick in demand in our academic setting as well quarter over quarter. And this is really driven by the body of evidence that we have worked hard to build in the past year around this concept of T-cell fitness and selinexor as potential ability to preserve the immune environment with respect to T-cell therapy. So as we look at this current year to date and our performance, our team is working hard to continue to drive demand and position XPOVIO as a flexible, combinable, manageable drug that allows for a class switch. Even though the marketplace is highly competitive, it's clear that we are in a space where a multi-mechanistic approach is increasingly needed for successful patient outcomes, and that's exactly where selinexor comes in as a differentiated mechanism of action. So, again, very pleased with our performance this quarter. We've narrowed our guidance for the full year and feel confident in meeting that range.
Peter Lawson: Thank you. And then just on the MMR proficient patients, do you need any kind of alignment with the FDA around calling that out as a marker, and how's enrollment going there?
Reshma Rangwala: Yes, thanks, Peter. So no, we don't, largely because the patient population that we're targeting is p53 wild type. And that p53 wild type, I think the regulatory agencies and the FDA particularly really appreciate is going to include multiple molecular subgroups including MMR proficient. So there's no need to specifically call them out. With that said, will we be looking at potential subgroups by MMR status? Yes, that's something that we will be considering. In terms of enrollment, enrollment is going well. We're certainly on track to report top-line results in the early part of 2026. A lot of that is fueled by, again, just I think strong enthusiasm for the data. As we presented at ASCO and then again had an opportunity to present very recently at IGCSE in Dublin, those data, specifically the benefit that selinexor provides to p53 wild types, is almost unprecedented. We are seeing in that p53 wild type subgroup a 28.4-month median PFS. If you specifically look in that subgroup who are both p53 wild type and MMR proficient, again, that PFS now climbs to 40 months, which you know I mentioned earlier on the prepared remarks, cross-trial limitations aside, exceeds the overall survival that you see with the checkpoint inhibitors. So strong enthusiasm about the trial largely due to the benefit that we are seeing with selinexor and the strong anticipation that these results are going to translate in our ongoing Phase 3.
Peter Lawson: Great. Thank you so much.
Richard Paulson: Thanks, Peter.
Operator: Thank you. Your next question is from Maury Raycroft from Jefferies. Your line is now open.
Maury Raycroft: Hi, Good morning. Thanks for taking the question and all of our best wishes to Mike as well for the next steps. I was going to ask one on the ongoing multiple myeloma SPd Phase 3 study. Just if you could talk about the powering assumptions of the new trial design, what else do you need to align with regulatory agencies to get the go ahead there? And when do you anticipate you'll be able to clarify the timeline to data for this study?
Reshma Rangwala: Yes, thanks so much, Maury, for the question. So what we were able to do is to really leverage the positively evolving data that we specifically observed with SPd40. The median PFS, as I mentioned previously, is substantially larger, longer than what we previously assumed. So that ability allows us to target not only a smaller number of total patients. And as you can see from earlier prepared remarks, we're now going to be targeting 120 patients as part of the ongoing trial. But it also allows us to reduce the total number of PFS events that's going to trigger that primary analysis for PFS without compromising any of the power that had already been built into the trial. So we don't specifically comment on our exact powering assumptions. With that said, in all of our phase 3 with power above 80%, this trial is no different. So again, that ability is just based upon our ability to leverage the positively evolving efficacy. In terms of alignment with the FDA, so the updated enrollments, as well as the updated statistical assumptions were incorporated to an amendment. And that has been sent to the FDA. We expect any kind of feedback to be coming in the next few weeks. At that time, we will update our top-line results milestones accordingly.
Maury Raycroft: Got it, Okay. And maybe one follow-up just for the myelofibrosis study. Study goes out to 24 weeks. Do patients continue on treatment, and what's the likelihood that you'll have to have a longer-term follow-up potentially going out to 48 weeks?
Reshma Rangwala: Yes. So patients are going to continue on therapy well beyond 24 weeks. So the 24-week mark just indicates when that SVR and the absolute TSS are going to be analyzed. Patients are going to be continuing. We have multiple longitudinal endpoints that we are going to evaluate, including PFS overall survival. In terms of long-term endpoints, right now based upon our discussions with the regulatory agencies, the key endpoints that are going to drive regulatory decisions are again week 24. We'll have the opportunity to provide longer-term data. But right now, we're really focused on that 24-week data for again regulatory decision-making.
Maury Raycroft: Got it. Okay. Thanks for taking my questions.
Richard Paulson: Thanks, Maury.
Operator: Thank you. There are no further questions at this time. Please proceed.
Richard Paulson: Thank you, operator, and thank you everyone for joining us today. As we mentioned, as an organization, we are focused and excited about delivering our innovation and growth strategy, which offers transformative opportunities with our Phase 3 clinical trials in myelofibrosis and endometrial cancer as we build on our Multiple Myeloma Foundation. These trials, we've heard the potential for them to really deliver new standards of care and significantly advance our company as we work to deliver value for shareholders. Once again, thank you for joining us today.
Operator: Thank you. Ladies and gentlemen, the conference has now ended. Thank you all for joining me. I'll disconnect your lines. Goodbye.
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