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spk16: My name is Andrea, and I will be your conference operator today. At this time, I would like to welcome everyone to the Carrier Farm Therapeutics Fourth Quarter and Full Year 2022 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 of Investor Relations. Please go ahead.
spk11: Thank you, Andrea. And thank you all for joining us on today's conference call to discuss the Carrier Farms fourth quarter and full year 2022 financial results and recent company progress. We issued a press release this morning detailing our financial results for the fourth quarter and full year 2022. 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, Sohania, Reshma, and Mike. Richard will start the call with some opening remarks, Sohania will provide a commercial update, and Reshma will provide an update on our clinical development programs. Mike will then present an overview of financial highlights from the quarter and full year 2022 and provide guidance for 2023. Richard will end with some closing remarks before we open up the call for questions. 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 3. 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 10Q form, which is on file with the SEC, and in other filings that we may make with the SEC in the future. Any forward-looking statements represent our views as of today only. While we may elect to update them 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. In addition, we will also be providing on this call an outlook for our non-GAAP R&D and SG&A expenses for 2023. We are not providing reconciliations of these forward-looking non-GAAP measures because projections of stock compensation expense which is required for such reconciliations are not available without unreasonable efforts. I will now turn the call over to Richard. Please turn to slide four.
spk04: Good morning. Thank you, Alhan, and thank you everyone for joining us today for CarioFarm's Q4 and full year 2022 earnings call. My name is Richard Paulson, President and Chief Executive Officer of CarioFarm. As you can see on slide five, Keriopharm was founded in 2008 as an innovation and patient-focused company developing first-in-class oral selective inhibitors and nuclear export, which target XPO1 to improve patient outcomes in cancer. Fast-forwarding to Keriopharm today, where we are successfully leveraging this fundamental mechanism of action to build upon our existing multi-myeloma franchise, anchored around our commercial drug Expovio, which is now approved in 40 countries and continues to move into earlier lines of therapy in multiple myeloma. With our U.S. Expovio revenue, milestone and royalty payments from our ex-U.S. partners, we have generated 157 million total revenues in 2022, meeting our guidance range for the year. For 2023, we are well positioned for our next phase of growth, where we expect to further grow our total revenue and U.S. Expovio sales, which Sohanya and Mike will go into more detail later on. We have a focused pipeline comprised of mid- and late-stage clinical development programs that can help patients who suffer from cancers with high unmet need demonstrate efficacy at lower doses with improved tolerability, and where we believe we will have the highest probability of success. We are conducting pivotal phase three studies in both multiple myeloma and endometrial cancer with a third pivotal phase three study in myelofibrosis, which we expect to start in the first half of 2023, pending regulatory feedback. Through continuing a disciplined and focused approach in advancing our pipeline and a strengthened balance sheet from our recent financing, which included participation by both existing stockholders and new investors, we have extended our cash runway through late 2025. 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 mid to late stage development capabilities as we work to generate value for patients and shareholders. Turning now to slide six, let's review some key accomplishments from our four core programs in 2022 as we have made considerable progress across all programs. In multiple myeloma, despite increased competition, we grew Expovio U.S. net sales by 22% in 22 compared to 21. So Hanya will go into more details on our U.S. sales performance in multiple myeloma in a moment. In endometrial cancer, we are excited to be moving forward with a novel biomarker-driven Phase III study by leveraging the potential substantial benefit of Selenexor that we've observed in patients that are TP53 wild type. Our partnership with Foundation Medicine will enable us to develop a companion diagnostic. In myelofibrosis, we are very encouraged by the preliminary results observed from our phase one study across three relevant domains, including SVR35, TSS50, and hemoglobin stabilization. Finally, in high-risk relapsed refractory MDS, a population with a very high unmet need, we completed recruitment for the interim analysis and are looking forward to seeing the overall survival data mature in our phase two study. As we turn now to slide seven, I would like to turn the call over to Suhanya for her review of the commercial performance for the quarter and full year 2022. Suhanya?
spk12: Thank you, Richard, and good morning, everyone. On slide eight, I am pleased to talk about the role of Expovio within an evolving multiple myeloma landscape. It is clear there continues to be an unmet need despite the advancements in treatment options. The disease remains incurable. If we look at the first and second lines of therapy, we typically see utilization of three major classes with increasing proportion of patients being treated with an anti-CD38 antibody. Following this, there is a need for a class switch to a novel mechanism of action. In this second to fourth line setting, there is no clear standard of care. If we now move forward to the late line setting, we see rapid advancements with the emergence of T cell redirecting therapies. However, these medicines can be complex in terms of patient management and infrastructure needed for administration, and therefore are typically localized to the academic setting. Thus, for patients in the second to fourth line setting who are largely treated by community prescribers, Expovio continues to have a strong value proposition as an effective, manageable, easily combinable, convenient oral therapy. In addition, we have data to strongly support the rationale and efficacy of Expovio use following an anti-CD38 regimen. Furthermore, with the emergence of T-cell-mediated therapies, the concept of T-cell fitness is becoming increasingly critical for physicians, particularly in the academic setting. PerioPharm is playing a leading role in exploring this topic and building a body of evidence around the effectiveness of Expobio pre- and post-T-cell redirecting therapies. And we expect to see more data generated in this area through the course of the year to further bolster our positioning in the multiple myeloma treatment landscape. Turning now to slide nine and our commercial highlights for the fourth quarter and full year 2022. In 2022, we grew Expovio net revenues by 22% versus 2021, meeting our guidance. This was primarily driven by demand growth. which included a year-over-year increase in both new starts and refills as we continue to treat more patients with Expobio and extend their time on therapy. Our team executed with strength, delivering 28% sales growth in the community in 22 versus prior year. The community setting remains a primary area of focus, contributing to about 70% of sales in Q4. In the academic setting, which was impacted by new competitive entrants, including one novel class of therapy becoming commercially available in December, expansion of CAR T sites, and ongoing clinical trials, we grew 7% in sales in 2022 versus 2021. In addition, we continue to make progress across our growth drivers, including shifting into earlier lines and increasing our duration of therapy. We also continue to improve the perception of the product with clear support and advocacy for Expobio at the podium from KOL scene and medical congresses. As we turn to slide 10, let's walk through the details of the progress we have made across our key growth drivers. We have grown the proportion of patients in earlier lines with now roughly 55% of Expovio patients in the second to fourth line, driven by rapid growth in the third line. With this shift into earlier lines, we continue to see an increase in duration year over year. Finally, we continue to expand our breadth of use as we increase the number of prescribing accounts across the US, with roughly 70% of accounts being in the community. On slide 11, as we look to 2023, we remain focused on further expanding these growth drivers. We're guiding to a US net product revenue range of 125 to 140 million, which at the midpoint represents 10% year-over-year growth. We believe this guidance range reflects solid growth in a competitive landscape that is expected to further intensify in 2023 with four potential new competitor approvals. We anticipate Q1 sales in line with the prior quarter, given ongoing pressure from increased adoption of Tech Bailey in the academic setting and a higher GTN driven by the Medicare Donut Hole Reset and IRA rebate. We will continue to execute with a well-established and entrenched field team, leveraging our broad base of prescribers in the community building upon their positive experiences, and further expanding their use. We also plan to continue messaging and positioning Expovio in the second to fourth line post-anti-CD38. In 2022, we saw the most rapid growth in the third line. Our focus remains on continuing to accelerate our growth in this line of therapy. In addition, in 2023, we plan to engage with key academic institutions to generate data pre and post T cell mediated therapies, further potentially strengthening our position in the second to fourth line. Finally, as we look to the mid and long term, we expect that the all oral phase three study of Selinexor in combination with pomalidomide and dexamethasone with a focus on targeting the community setting will be a key driver of future growth if approved. We look forward to continuing to grow Expovio and build our myeloma franchise, benefiting more patients in this challenging and incurable disease. Now I would like to turn the call over to Reshma to give an update on our clinical pipeline progress. Thank you, Sohania. As you can see the overview of our clinical pipeline on slide 13, we have two differentiated complementary novel sign compounds, Selinexor and Eltenexor, which are being evaluated across multiple cancers of high unmet need, including myelofibrosis, myelodysplastic neoplasms, endometrial cancer, and multiple myeloma. Selinexor, brand name Expogio, is our first novel XPO1 inhibitor. It is FDA-approved in multiple myeloma and in diffuse large B-cell lymphoma. It is currently being investigated in both solid tumors and hematologic malignancies. Eltenexor is our second XPO1 inhibitor and is currently being investigated in relapsed refractory MDS. Compared to Selenexor, a lower blood-brain barrier penetration is observed with Eltenexor. In addition, its IC50, a measure of potency, is lower than Selinexor's, which enables more continuous dosing. In fact, in select animal models evaluating MDS, continuous XPO1 inhibition has been shown to lead to enhanced anti-tumor activity. Turning now to slide 14, we are working to optimize the dose of Selinexor across our clinical programs. Since Expovio's first approval in 2019, we have utilized real-world experience coupled with observations from our own clinical trials to demonstrate that lower doses of Selinexor can optimize the patient benefit by improving its tolerability, which ultimately allows patients to stay on therapy longer and therefore improve their overall benefit. As a result, all of our ongoing clinical trials incorporate salinexor doses at 40 or 60 milligrams once weekly, which is a quarter to less than half of the original approved doses of 80 milligrams twice weekly. Let's now turn our attention to endometrial cancer. On slide 16, I would like to discuss the unmet need in endometrial cancer and why we find this opportunity so exciting for women. First, endometrial cancer is the most common form of gynecologic cancer in the United States with approximately 50% of advanced or recurrent tumors classified as TP53 wild type. Second, the current treatment landscape for advanced or recurrent endometrial cancer consists of first-line chemotherapy. Upon completion of chemotherapy, the NCCN guidelines recommends a watch and wait approach 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 improve the overall clinical benefit for these patients. At ASCO 2022, we presented the subgroup analyses and molecular classification data from the Ciendo study, evaluating Selinexor in endometrial cancer as a maintenance therapy. A previously disclosed subgroup analysis showed that patients whose tumors were TP53 wild type and treated with Selinexor demonstrated a median progression-free survival of 13.7 months compared to 3.7 months for patients treated with placebo. On slide 17 are the updated PSS results in this p53 wild-type subgroup from a data cut as of November 2022. This update now shows that the median PSS for Selinexor has increased to 20.8 months compared to 5.2 months for placebo with no observed change in the safety profile. This improvement in the progression-free survival highlights the potential benefit that can be achieved with Selinexor in patients whose tumors are p53 wild-type, supports the evaluation of sign compounds in this molecular subtype, and underscores the rationale for evaluating Selinexor as a maintenance therapy in p53 wild-type endometrial cancer in our ongoing pivotal EC042 study as seen on slide 18. This study will utilize Foundation Medicine's tissue-based next-generation sequencing test to identify patients whose tumors are p53 wild-type. A total of 220 patients will be randomized in a one-to-one manner to receive either once-weekly Selinexor at a dose of 60 milligrams or placebo. 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 NGOT, the European Network for Gynecological Oncological Trials Group, and GOG, the Gynecology Oncology Group. Top-line results are expected in the second half of 2024 and could represent a paradigm shift for women with TP53 wild-type endometrial cancer. Let's now take a closer look at myelofibrosis. As you can see on slide 20, there is a high unmet need for new therapies and novel mechanisms of action, given that the efficacy with the current standard of care, JACIFI, is limited to patients with JAK-naive myelofibrosis. Approximately 45% of patients achieve an SPR35 or TSS50 at week 24. Overall survival is limited, and key patient populations do not benefit The rates are substantially lower for male patients as well as patients who start on ruxolitinib 15 milligrams twice a day. The SVR35 for both of these key patient populations is only approximately 25%. These are both critically important given that the males comprise approximately half of myelofibrosis patients. And real-world evidence data suggests that the majority of patients are treated with ruxolitinib at 15 milligrams twice a day or less. And about a third of patients are treated with five milligrams twice a day. Selinexor has the potential to enhance multiple factors important to all patients, including decreasing spleen size, improving patient symptoms, stabilization of hemoglobin levels, increasing overall survival, disease modification, all in the context of a manageable safety profile. As seen on slide 21, targeting XPO1 can potentially be very effective as it inhibits multiple pathways downstream of JAK, including AKT, FAT, and ERK. This may lead to potent monotherapy activity as well as potential synergism in combination with JAK inhibitors and other targets. Turning now to slide 22, you can see the design of our frontline myelofibrosis study, a phase one study evaluating the combination of Selinexor and Ruxolitinib in patients with treatment-naive myelofibrosis. In this study, we completed enrollment of the phase one portion and dosed 24 patients. Our objectives for this study are to explore the combination of Selinexor and Ruxolitinib, building on the single-agent activity of both compounds. Turning to slide 23, we recently shared updated results at ASH 2022. Based on an October data cut, 92% of the valuable patients achieved a 35% or greater spleen volume reduction at week 24. In addition, 67% of evaluable patients, which included those patients who completed their symptom evaluation forms, achieved a 50% or greater reduction of their total symptom score at week 24. And finally, 57% of transfusion-independent patients who had at least eight weeks of treatment maintained a stable hemoglobin or improved their hemoglobin levels at their last follow-up. The combination of Selinexor and Ruxolitinib was generally well tolerated and had a manageable safety profile with the most common reported grade 3-4 treatment emergent adverse events being anemia and thrombocytopenia. The grade 3-4 anemia rates observed with the combination were 38%, less than the 45% observed with Ruxolitinib alone. We plan to present updated results from this study in the first half of 2023, including a TSS50 analysis that will incorporate symptom scores collected from patients' medical charts. This will enable a robust assessment of the symptom improvement observed with the combination of selenoxor and ruxolitinib from the majority of patients enrolled in this phase one study. As you can see on slide 24, 92% of evaluable patients at week 24 achieved an SVR 35% or greater, and 100% of evaluable patients achieved any degree of spleen volume reduction. The data on slide 25 are new subgroup analyses from the phase one portion of the 034 study. Specifically, we identified seven patients whose ruxolitinib was reduced to five milligrams due to cytopenias at cycle one or two and who remained on this dose for the duration of their treatment. We are interested in this subgroup given that, quote, long-term maintenance at five milligrams twice daily has not shown responses, end quote, as noted in the ruxolitinib prescribing information. Despite this reduction to sub-therapeutic doses of ruxolitinib, all patients dosed with Selinexor in combination with ruxolitinib experienced reductions in their spleen and improvements in their symptoms, with all five patients who were assessed at week 24 experience a greater or equal to 35% reduction in spleen volume. These data suggest that Selinexor may potentially have monotherapy activity in treatment-naive patients and underscores the potential of XPO1 as a fundamental mechanism in myelofibrosis that could be leveraged both as monotherapy and in combination. Turning to slide 26, based on the observations from the 03-04 study, coupled with the need to develop effective therapies in the broadest population of JAK-naive myelofibrosis, we are optimizing our development plan to maximize the benefit observed in this population. We anticipate having defined this plan by the first half of 2023. Now turning to L-Connexor and MDF. As you can see on slide 28, approximately 15,000 people in the United States are expected to have been diagnosed with intermediate to high-risk MDS in 2022. HMAs are the current standard of care for newly diagnosed higher-risk MDS patients. Prognosis in HMA refractory disease is poor, with the median overall survival of four to six months And there are currently no approved therapies for HMA refractory MDS. On slide 29, you can see the design of our phase two study of Eltenexor in relapsed refractory high-risk MDS. In this phase one portion of this study, single agent Eltenexor demonstrated promising activity among patients with HMA refractory MDS. Specifically, a median overall survival of approximately 10 months was observed. We have completed enrollment of a planned interim analysis in our phase two study and expect to report efficacy and safety results in the first half of 2023. With that, I will now hand it over to Mike.
spk06: I hope everyone is having a lovely morning, and thank you, Reshma. 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 began on slide 31. Total revenue for the fourth quarter of 2022 was $33.6 million compared to $126.3 million for the fourth quarter of 2021. In line with our guidance for the year, total revenue for the full year of 2022 was $157.1 million compared to $209.8 million for the full year of 2021. As a reminder, in the fourth quarter of 2021, we recognized $96.5 million of license and other revenue including the upfront payment of $75 million from Manarini. Net product revenue from U.S. commercial sales of Expovio for the fourth quarter of 2022 was $31.1 million compared to $29.8 million for the fourth quarter of 2021. Net product revenue from U.S. commercial sales of Expovio for the full year 2022 was $120.4 million, meeting our guidance for the year compared to $98.4 million for the full year 2021, representing a 22% increase year over year. The gross to net discount for Expovio in the fourth quarter of 2022 was 21%, and for the full year 2022 was 19%. We expect the gross to net discount to be in the 20% to 25% range for the full year 2023. R&D expenses for the fourth quarter of 2022 were $30.9 million compared to $44 million for the fourth quarter of 2021 and $148.7 million for the full year 2022 compared to $160.8 million for the full year 2021. The decrease in R&D expenses was primarily attributable to decreased clinical trial and related costs due to the prioritization of our core programs in our clinical pipeline during 2022. In 2023, as we continue to make progress with our clinical pipeline, we expect our R&D expense to remain relatively consistent, including the cost from three pivotal clinical studies, two of which are ongoing, and one additional plan to initiate in the first half of 2023. The increased costs from advancing these pivotal programs will be mostly offset by the cost-saving measures we initiated in 2022, which included an overall headcount reduction and continued focus on our prioritized pipeline. SG&A expenses for the fourth quarter of 2022 were $34.6 million, consistent with the fourth quarter of 2021. SG&A expenses for the full year of 2022 were $145.4 million, compared to $143.8 million for the full year of 2021. In 2023, we expect our SG&A expenses to slightly increase in line with increased inflation and cost of living. On a non-GAAP basis, which excludes stock-based compensation, our total R&D and SG&A expenses in 2022 were $259 million, in line with our guidance for the year. Cash, cash equivalents, restricted cash and investments as of December 31, 2022, totaled $279.7 million, following successful completion of $165 million private placement in December. compared to $235.6 million as of December 31, 2021. As a reminder, we expect to receive $22 million in cash payments from Antigene this quarter related to previously earned and recognized milestones. Based on our current operating plans, we are expecting total revenue of $160 to $175 million for 2023 consisting of U.S. Expovio net product revenue and licensed royalty and milestone revenue expected to be earned from our partners, primarily Menorini and Antigee. We expect U.S. Expovio net product revenue of 125 to 140 million, non-GAAP R&D and SG&A expenses, which excludes stock-based compensation expense, to be in the range of 260 to 280 million for the full year of 2023. And finally, that our existing cash, cash equivalents and investments as well as the revenue we expect to generate from Expovio product sales and other license revenues will be sufficient to fund our planned operations into late 2025. I'll now flip to slide 32 and turn the call over to Richard for some final thoughts. Richard?
spk04: Thank you, Mike. We are focused on maintaining momentum as we deliver on our next phase of growth. with a number of key near-term catalysts and corporate milestones as you see on slide 33. Our people continue to strive each day for patients with high unmet needs as we work to generate value for patients and shareholders. Thank you again for joining us today and I would now like to ask the operator to open the call up to the question and answer portion of today's call.
spk13: Operator?
spk14: We will now begin the question and answer session.
spk16: To ask a question, you may press star then 1 on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then 2.
spk14: At this time, we will pause momentarily to assemble the roster. And our first question will come from Peter Lawson of Barclays.
spk16: Please go ahead.
spk07: Great. Thanks so much. Thanks for taking the questions. Just on potential data readout, the Phase 2 MDS for data for Elton X, so that looks like it's now first half versus 1Q, kind of where should we expect to see the data and how much do we expect to see?
spk05: Yeah, thanks, Peter. I'll turn to to talk to that.
spk12: Yeah, thank you. Thank you, Peter. Great question. So, you know, the timing of the MDS interim analysis is very much dependent upon the overall survival data. And I say that partly because very high admit need patient population in this very hard to treat relapse refractory patient population. We know from the published literature that overall survival for these patients is less than a year at only four to six months. So being able to identify a robust overall survival signal allows us to identify the best path forward. So, you know, at this point, you know, we're still following the OS data. It looks like it is going to occur in the first half of this year. But again, hard to project, you know, as we continue following these patients' survival. We'll be opportunistic in terms of how we present those data, whether it's at a medical congress or through some kind of company forum. But, you know, the way I look at it, this is only a good thing for our patients.
spk07: Gotcha. Thank you. And then just as we think about Selinex or use with BCMA therapists or head of BCMA therapists, just if you kind of walk through kind of the potential impact or benefit you had from GSK's blend back in, withdrawn, and then if you're seeing Selinex or being used ahead of cell-based BCMA therapies.
spk05: Yeah, Peter, maybe I'll turn to Sonia to touch on the first part of that, and then I'll have Reshma kind of close it with some interesting data looking at T-cell fitness.
spk04: Sonia?
spk12: Great. Thanks, Peter, for the question. So let me tackle the BlendRep question first. BlendRep was used primarily in late line patients. And as you know, with Expobia, we are focused in that second to fourth line setting. Secondly, GSK continued their compassionate use program so that current patients on Blend Rep could continue on. Having said that, now we're starting to see pockets of opportunity around the country where some of the Blend Rep opportunities in the late line academic setting are starting to materialize as new starts on Expovio. Switching gears into kind of overall competitive landscape and the T-cell mediated therapies and the BCMA class and the role of Expovio. So taking a step back and when you look at this class, primarily all the entrants in the class have been coming into the late line setting in the academic center. When you look at our performance in 2022, we grew over 20% year-over-year for the full year. But in the academic setting, despite increased competition with a new BCMA as well as a CAR T, we grew 7% year-over-year. Now, this is an important space because Expobio continues to have a strong value proposition in the academic space. We already see physicians using it in certain accounts, primarily as a runway leading up to a T cell therapy. And secondarily, we also see some Expobio use post T cell therapy in the academic setting. Now, as we generate more T cell fitness data, this should further strengthen our positioning in the academic setting. My final point is that, as we know, these complex therapies can be very difficult for certain types of patients to access. For example, the elderly patients and rural patients, which constitute a majority of multiple myeloma patients. So that will be a target population for us in the academic setting. Now, as we continue to generate more data on this T-cell fitness story, I'd love to call on Reshma to elaborate on some of the exciting work that we've got planned ahead for this year. Yeah, thank you, Sohania. So, you know, we are looking at the T-cell fitness story largely because physicians are very interested in the T-cell fitness story. They really want to know what agents that they can prescribe to their patients They're not going to negatively impact their ability to get some kind of immunotherapy later in line, including CAR Ts. This is very important for them because they know from experience that certain class of drugs, including the alkylating agents like Cytoxan and Melphalan, kill dividing cells, including T cells, which ultimately cause damage and negatively impact a patient's apheresis collection. You know, given the minimal slots, given that, you know, getting a slot for these patients on CAR-T, again, is so difficult. Again, they want to have confidence that if they can prescribe Selinexor to their patients, it is not going to, again, negatively impact their ability to get one of those therapies. What we are doing is looking across multiple different data sets, including preclinical data, leveraging our own translational data, as well as looking at real-world evidence to really assess whether Selinexor can maintain that immune environment and therefore maximize the benefit that they can achieve with one of those newer immunotherapies.
spk07: Great. Thank you. And then just finally, Mike, is there anything you can say around the 2023 revenue growth? Is that, so in terms of volume and pricing, would be great. Thank you.
spk05: And maybe I'll turn to Sohanya on that. Sohanya?
spk12: Thanks for the question. So different components kind of going into the guidance. First of all, we feel confidence in delivering within our guidance range. As we look at the different levers going into the guidance, it's really a balance between demand growth from expansion in the community and shift into earlier lines. And that's balanced with increased pressure in the academic setting from new competition coming in 2023. I think a few points on the tailwinds, just increased use in the community setting. We grew 28% year over year last year. This continues to remain our primary area of focus. I think the interesting thing as we mature with this drug is we have now built a very strong base of prescribers and will continue to drive depth there. We also continue to shift into earlier lines. So these factors will help to drive demand here.
spk06: The only thing I would add to that, Peter, is we did guide that growth to net will be higher in 2023 versus 2022. So we expect the range to be somewhere in the 20% to 25%, where in 2022 we were around 19%. Thanks so much.
spk13: Thanks, Peter.
spk14: The next question comes from Laurie Raycroft of Jeffery.
spk16: Please go ahead.
spk17: Hi, good morning and congrats on the progress and thanks for taking my questions. I was going to ask about multiple myeloma with some of the data that you're seeing in the third line setting. I guess, are you breaking out that percentage from the 55% total? And can you talk about what exactly the treatment paradigm is that you're seeing prior to third line? I guess how well defined is that front line and second line treatment in the paradigm? Yeah, thanks, Mario. I'll get Sonia to talk to that.
spk05: Sonia?
spk12: Yeah, thanks, Mario, for the question. So our most rapid area of growth within that second to fourth line bucket is in the third line. That is a large contributing factor to that nice upward trend that we're seeing in the second to fourth line. And as you know, we now see 55% of our patients in that bucket. Little hard given the data that we see to break down exact numbers by line of therapy, but we know that third line is a contributing factor. And in 2023, our focus will remain on accelerating our growth in the third line. Now switching to the dynamics in the first and second lines, we see the use of the major three classes upfront, but primarily the trend that we're seeing is an increase in the use of the anti-CD38 antibody in the first and the second line. As a result, that unmet need is growing for an effective, manageable treatment following an anti-CD38. And that is where we have actively generated data to demonstrate the rationale and efficacy of Expobio immediately following an anti-CD38. Got it.
spk17: That's helpful. And is this third line setting, is this aligning with your community uptake data? And do you expect this to be a key driver behind your future growth expectations in the community setting?
spk12: Absolutely. We see, again, the most rapid growth in the third line. The community, as you know, when they start off prescribing a drug, these community physicians see a variety of patients across tumor types. So when they start off any new therapy, they can come across a couple of initial hurdles. With Expovio, given the time into the launch that we are, they've crossed a lot of these initial hurdles. And now it's really about moving them into earlier lines and continuing to build the confidence that they already have from some of those initial experiences.
spk17: Got it. Makes sense. And I was going to ask one question on myelofibrosis too. Just wondering if you can give any granularity on timing for the additional data, the recommended phase two dose and the phase three start updates in the first half of 23, and what do you need to see from the 40-meg data to go forward with that dose, or what are your latest thoughts on dosing strategy for that study?
spk05: Hey, Reshma, do you want to capture that one?
spk12: Yeah, absolutely, and thanks for the question. So their next update is going to occur sometime in the first half of 2023. The update, again, is just going to include the patients, the 24 patients that were enrolled as part of the phase one. So all of these patients, again, were treated with a combination of Selinexor and Ruxolitinib, and they're all treatment-naive patient populations. We're following all of them for maturity. So the key time point that we want to assess their SVR, TSS50, hemoglobin, and safety is specifically going to be at that 24-week and beyond. So as we continue to follow these patients, it's going to help guide the optimal timing of when we can provide that update, again, across those key efficacy as well as safety endpoints, as well as additional data, including translational data and important subgroup data as well. In terms of how we identify the recommended phase two dose, we're going to look across multiple parameters. So, it's going to be about the efficacy, again, that we specifically see at the week 24. Of course, that important safety profile. but we also need to incorporate pharmacodynamic data too. So, you know, stay tuned for the update. Again, it'll occur in the first half of this year.
spk13: Okay. Thanks for taking my questions. Thanks, Maury.
spk14: The next question comes from Chris Raymond of Piper Sandler. Please go ahead.
spk10: Good morning. This is Nicole Gabreski on for Chris. Thanks for taking the questions. Maybe just two for us. The first, just for the pivotal phase three frontline study and myelofibrosis, I guess, can you just provide some more color around the regulatory feedback you're waiting for in order to initiate that study? And then, I guess, second, just with endometrial cancer, I know that you guys have indicated that you'll present updated subgroup results from Siendo this year. Maybe can you just help frame what updated data we should expect to see and if there's a particular venue or venues that we should maybe think about as a good fit for the update?
spk05: Thanks, Nicole. I'll turn to .
spk12: I'm sorry about that. Jumped the gun there. But great question. So in terms of the next steps for the myelofibrosis program, again, it's going to be that data that I just mentioned in the previous question, the efficacy, the safety, the pharmacodynamics, the dose, and then of course, you know, just getting alignment from the FDA on the design and statistical analysis plan for the phase three. So that meeting is going to occur sometime in the first half of this year. And then we look forward to presenting the trial design, along with the updated data, again, in the first half of this year. But, you know, I will say, you know, we've got a lot of other precedents out there in terms of this first-line space. So looking at a combination versus ruxolitinib is likely something that we are going to pursue as well. And we're going to focus on the endpoints that are relevant to the patient population, specifically SVR35, as well as the TSS50 at week 24, but also look at important aspects, including hemoglobin, stabilization, and then, of course, the safety profile as well. In terms of endometrial cancer, so, you know, an important update that we presented on this earnings call was a recent update on the PSS results from the Ciendo subgroup. So, based upon a November 2022 cut, we reanalyzed the progression-free survival, specifically in those P53 wild-type patients, which comprise approximately 50% of all endometrial cancer, and very encouraged by the updated results. What we've now seen is that median progression-free survival for the Selinexor arm has increased from 13.7 months to now 20.8 months. The placebo arm, by and large, has stayed the same, and the most recent update shows a median PFS of 5.2 for placebo. So very, very, very encouraged by the now quadrupling in that median PFS observed for the Selinexor-treated patients. We continue to follow all of these patients, and we'll update PFS. also looking at overall survival, too. As those events accrue, we'll look to present those updated data.
spk14: Great. Thank you.
spk13: Thanks, Nicole.
spk14: The next question comes from Mike Oles of Morgan Stanley.
spk16: Please go ahead.
spk08: Good morning, and thanks for taking the question. Maybe just one on the myelofibrosis strategy. Just based on some of the data you highlighted in your prepared remarks, are you thinking about potentially moving monotherapy in frontline myelofibrosis? And then maybe secondly, can you just give us your current thinking on the strategy and second line at this point? Thanks.
spk15: Thank you. Thank you, Mike.
spk12: I was going to wait for Richard, but I'm going to go ahead and get in there. Great question. So, our focus right now is absolutely the combination of Selinexor and Ruxolitinib, you know, largely based upon the very compelling results that we continue to see from the phase one portion of the 034 study. So, looking forward to interacting with the FDA and then initiating that trial in the first half of this year. You know, with that said, though, there are some very important learnings from the phase one portion that suggest that Selinexor really is a fundamental mechanism within myelofibrosis across the patient populations. And it affords us an opportunity to really maximize the development of Selinexor in this important patient population. whether it's looking at monotherapy, novel combinations, et cetera. But that is something that we want to define in the future. Our focus right now is absolutely the combination of Selenaxor and Ruxolitinib.
spk13: Great. Thank you. Thanks, Mike.
spk14: The next question comes from Brian Abrahams of RBC.
spk16: Please go ahead.
spk00: Hi, this is Joe. I'm for Brian. Thank you for taking my question. I have two. So first one on the L-tenoxor, what you would like to demonstrate from the interim data. And also, if you could tell us a little more about sort of like the latest data cut you saw in the endometrial cancer and how that shapes your expectation in the new phase three data in terms of both the PFS and the OS. Thank you.
spk05: Yeah, thanks, Joe. I'll turn to Reshma for both of those.
spk12: Absolutely. So, you know, as I mentioned earlier, right, I mean, this relapsed refractory, and I will actually say the patients that were enrolled as part of the phase one and also in the phase two are the hardest to treat patient population. I mean, in fact, these are these primary HMA refractory patient populations. Survival is extremely short, unfortunately, in this patient population with published data indicating median survivals of only four to six months. We're very highly encouraged by the phase one data that we presented at ASH22. Specifically, the median overall survival of those patients treated with L-tenexor was approximately 10 months. With that improvement in overall survival that, again, we hope to see as part of this phase two, It'll allow us to best determine the registration path with L-tenoxor in this patient population. In terms of the endometrial cancer, again, very encouraged by the updated PFS results that we've observed from the November 22 cut. Median PFS for the selenoxor patient population has increased from 13.7 months to now 20.8 months. Overall survival is still immature, and so we're continuing to follow those survival data, but these data have very much informed our current Phase III trial, EC042, and are encouraged by the benefit that these patients can achieve in this EC042 trial.
spk13: Super helpful. Thank you.
spk14: The next question comes from Eric Joseph of JPMorgan.
spk16: Please go ahead.
spk02: Hi, good morning. Thanks for taking the questions. Just a couple on endometrial cancer. One around this PFS update. Can you just talk about how closely duration on treatment lines up with the extended benefit on PFS? And then secondly, I'd be interested to get a sense of how site participation or the regional mix of patient enrollment will kind of line up between the EC042 study and the experience in Siendo. Thanks.
spk12: Thank you. Thank you, Eric. Great questions. So, as we look at the updated PFS, you know, we see an increase going from 13.7 to 20.8. We also see a proportional increase in that duration of therapy too. So, that duration is driving progression-free survival benefit in that patient population. We're going to continue to follow not only the duration, but the PFS and OS in this trial. In terms of site activation, There's a lot of activity that is happening within EC042. One of the benefits that we can leverage is actually our experience with the Siendo. We had approximately 100 sites as part of the Siendo trial that included sites, you know, from the GOG and NGOT. With EC042, we can identify those highest performing sites and incorporate them into the EC042 trial as well as add additional sites. I say that because in this ECO4-2 trial, we're actually looking to activate approximately 140 sites in the U.S. and Europe.
spk02: Okay, got it. And maybe just a follow-up, if I could, on myofibrosis. I know that starting the Phase III trial is, you know, depending, is pending, but regulatory feedback. I guess I'm wondering if there's any reason to think that the phase three trial design, you know, should, may not, I guess is the manifest two trial a good proxy for how the phase three design with SEL and XR should look? Thanks.
spk12: Yeah, good question. I mean, yeah, right. I think we know in first line SVR and TSS50 are the key endpoints both the physicians are interested in, but also the regulatory agencies are interested in. So, we know those are going to be the endpoints in which we design our trial. And it's going to be, you know, a relatively simple comparison, right? Just comparing the efficacy and safety of the combination of SALI plus RUX to RUX alone. So, you know, this is going to be a very traditional trial. but optimizes our ability to demonstrate the benefit that patients can achieve with the combination compared to ruxolone.
spk13: Great. Thanks for taking the questions. Thank you, Eric.
spk14: The next question comes from Ed White of HC Wainwright.
spk16: Please go ahead.
spk03: Good morning. Thanks for taking my questions. You had mentioned several times that you're seeing an increase in the duration on therapy in the second to fourth line patients. I'm just wondering if perhaps you can quantify that and perhaps give us an indication of what you're seeing in the fourth quarter of this year versus the fourth quarter of last year.
spk05: Yeah, so, Anya, do you want to take that one?
spk12: Yeah, thanks, Ed, for the question. So, on duration, When we look at it year over year and it takes time for this data to mature, we do see an upward trend in our duration year over year. And this is really driven by two factors, the increase in the proportion of patients in earlier lines who are staying on therapy longer, but also it's driven by effective management of these patients with dose adjustments and supportive care. Now, as the data matures, we see an increase in proportion of patients reaching cycles three, four, and five in 2022 versus 2021. In the outer end of the range, as you know, patients, you know, there's a broad range of patients staying on therapy. On the outer end of the range, we do see patients on Expobio over two years of therapy. And over time, physicians are getting increasingly confident
spk15: in managing these patients.
spk13: Okay, great. Thank you for taking my question. Thanks, Ed.
spk14: The next question comes from Jonathan Chang of CVV Securities.
spk16: Please go ahead.
spk01: Hey, guys. This is Matt Calper on for Jonathan. Thanks for taking my question. Just a couple initially on the myelofibrosis update in the first half. Can we expect to see any week 48 SVR35 data there? And then also for the TSS50 by chart review, I was wondering if you could elaborate on how that may or may not differ from how that data is typically collected. And then second question, I was just wondering how do the late-stage combination trials in treatment naive myelofibrosis influence your trial design or your thinking on that opportunity? Thanks.
spk05: Yeah, thanks, Matt. I'll turn to Reshma for those.
spk12: Yes. So, you know, let me talk about the TSS50 data. So, you know, we'll have an opportunity to present, you know, additional TSS50 data at the next update, largely because patients filled out forms from a symptom perspective. Physicians also collected the same symptom data in their medical charts. So we can use these two platforms, i.e., the forms as well as the medical chart data to really provide a comprehensive overview of the TSS50 that has been achieved in the combination. So look forward to presenting that additional data in the first half of this year. In terms of the week 48 data, yeah, absolutely. So we've got multiple patients that are staying on therapy. Some patients are coming in, they've been dosed for approximately a year. So being able to provide this durability data is going to be an opportunity again for us in the first half of this year. In terms of the other competitor trials within the first-line space, Um, by and large, I mean, look forward to seeing those data, but I don't think that they're necessarily influencing our decision about the design. You know, as I mentioned previously, this is really a very traditional phase three. We want to be able to demonstrate the benefit that can be achieved with the combination as compared to Rux alone. So it is really going to be a very traditional phase three of combination versus Rux alone, focusing on that SVR and TSS 50.
spk01: Thanks for taking my questions.
spk13: Thanks, Matt.
spk16: This concludes our question and answer session. I would like to turn the conference back over to Richard Paulson for any closing remarks.
spk05: Thank you, operator, and thank you, everyone, for joining us on today's call.
spk04: And once again, a huge thank you to all of our teams and our people across the organization as each and every person at CarioFarm is working every day to say how can we improve the lives for patients suffering from cancer. And we look forward to sharing an update with you here in the near future.
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