Karyopharm Therapeutics Inc. Q1 FY2022 Earnings Call

Good morning, and welcome to the Karyopharm Therapeutics First Quarter 2022 Earnings Conference Call. I would now like to turn the conference over to Elhan Webb, Senior Vice President, Investor Relations. Please go ahead.

Thank you, operator. And thank you all for joining us on today's conference call to discuss Karyopharm's first quarter 2022 financial results and recent company progress. Today, I'm joined by Richard Paulson, President and CEO; Sohanya Cheng, Chief Commercial Officer; Dr. Reshma Rangwala, Chief Medical Officer; Dr. Pat Judson, SVP, Medical Strategy; and Mike Mason, Chief Financial Officer. This morning, we issued a press release detailing Karyopharm's financial results for the first quarter 2022. This release, along with the slide presentation that we will reference during this call, is available under the Events & Presentation section of our website at karyopharm.com. For today's call, as seen on Slide 2, Richard will provide some opening remarks. Sohanya will provide a commercial update for XPOVIO. Then Reshma and Patricia will provide an update on the clinical development program. Mike will then provide an overview of the financial highlights from the quarter, and Richard will provide some closing remarks before opening the call up 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 discussing the risk factors section of our most recent annual report on Form 10-K, 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 these forward-looking statements at some point in the future, we specifically claim 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 date subsequent to today. In addition, we will also be providing, on this call, outlook for non-GAAP R&D and SG&A expenses for 2022. 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 turn the call over to Richard. Please turn the slide...

Thank you, Elhan. And good morning to everyone joining us on the call and webcast today. Q1 was another strong quarter and I'm very excited to provide an update on our plan as we continue to execute on our growth strategy through our focused commercial execution and pipeline development that we are pursuing on behalf of patients in need. On Slide 5, we have an overview of the key pillars that drive our underlying value and provide opportunity for what we believe will be substantial future growth. First, we are successfully building upon our existing multiple myeloma franchise. This quarter, we generated strong revenues and expect to continue strong sales in 2022 through focused execution and proven commercial capabilities, creating value for both patients and shareholders. On the global regulatory front, we are expecting the European CHMP to complete its review of the selinexor application in the second line plus and issue an opinion during the first half of 2022. Together with our global commercialization partners, we are increasingly bringing XPOVIO to patients worldwide. Second, shifting from our multiple myeloma franchise to our pipeline, where we continue to make strong progress, we are advancing a clinical pipeline comprised of mid- and late-stage clinical development programs that is being purposefully built and strategically focused on targeting cancers with high unmet need where our science enables us to make the biggest difference in the lives of patients and in areas with high probability of success. To that end, we are pursuing approval opportunities in multiple myeloma, endometrial cancer, myelofibrosis, and myelodysplastic syndromes over the next 2 to 4 years. Our third pillar is our people and we strengthened the leadership team during the quarter. We believe we have the right people in place who have exceptional abilities to achieve both scientific and commercial excellence while executing on our key corporate objectives. Fourth and finally, to support our strategic and focused growth plan, we are well capitalized and expect to be able to fund our operations into early 2024. At Karyopharm, everything we do is driven by our mission to positively impact patient lives and defeat cancer. Our foundation is in our science and we are the global leader in the inhibition of nuclear export. Against this backdrop, we believe we have a strong organization which allows us to execute this year and beyond. The first quarter of 2022 was marked by several meaningful achievements, as outlined on Slide 6, including continued robust commercial performance and significant progress across our pipeline. To start, we achieved total revenues of $47.7 million, which included $19.4 million from certain license and milestone revenues, as our footprint expands globally. Second, XPOVIO delivered strong year-over-year growth in the US, during the first quarter achieving $28.3 million in net product revenue, representing year-over-year growth of 30%. We achieved these results through continued increasing uptake in the second through fourth line with strong growth in the third line, and despite COVID-related headwinds experienced during January and February. For global commercialization efforts, XPOVIO or NEXPOVIO is now approved in 37 countries, the most recent of which are Mainland China, Australia, and Singapore through our partner Antengene. In endometrial cancer, we recently reported top line results from the Phase III SIENDO study, where selinexor showed especially encouraging results in the exploratory subgroup of patients with p53 wild-type tumors, improving PFS by an impressive 10 months. And we are planning to initiate a registrational Phase III study in the second half of this year. We'll be presenting results at the upcoming ASCO 2022 annual meeting, including results from our subgroup and molecular analysis from this SIENDO study and the preliminary from our Phase I/II study investigating selinexor combined with ruxolitinib in patients with treatment-naive myelofibrosis. And last but not least on the corporate front, we recently strengthened the leadership team with Dr. Reshma Rangwala joining us as Chief Medical Officer. We are delighted to have her join the team, and we believe that her extensive experience developing and executing clinical strategies for novel oncology therapeutics, as well as engaging regulators and the medical community at all stages of development, will be of immeasurable value as we accelerate our 4 core programs in clinical development as shown on Slide 7. Our drive, vision, and innovations, along with the scope and range of data generated to date have led us to focus on our 4 core programs shown here: multiple myeloma, endometrial cancer, myelofibrosis, and myelodysplastic syndrome. Along with all of these being areas of high unmet need for patients, each has a significant addressable market. A key focus of today's call will be our endometrial cancer and myelofibrosis programs. As we turn now to Slide 8, I would like to turn the call over to Sohanya for her review of the commercial performance for the quarter. Sohanya?

Thank you, Richard, and good morning, everyone. Since our launch, we continue to focus on expanding the potential of XPOVIO and its benefit to patients in earlier line. Slide 9 shows how we have evolved from our original approval of Xd based on the STORM study to gaining FDA approval for the XVd regimen based on our BOSTON study, and now to initiating a Phase III study with selinexor, pomalidomide, and dexamethasone, an all-oral triple combination, which Reshma will expand on later. In this process, we have evolved from twice-weekly to once-weekly, from higher to lower doses, from a doublet to triplets, expanded into earlier lines with multiple combinations, and improved the overall patient experience. And we've achieved all of this during challenging times with the ebbs and flows of COVID. The team has done outstanding work to adapt quickly, focus on head-down execution, and continue to drive strong results. Turning now to Slide 10, on our commercial highlights for the first quarter of 2022, it's rewarding to continue to see patients being treated in earlier lines and staying on therapy longer. Despite the impact of COVID in the first quarter of this year, we grew net product revenue by 30% versus the same period last year, and continue to make excellent progress across key indicators since our second line plus launch at the beginning of 2021. In addition, inventory levels were consistent with the last quarter. The environment was particularly challenging with the surge of COVID in January and February, which impacted oncology patient visits and new starts, as well as our access to healthcare providers. We did see a recovery in March with patient visits starting to normalize, our new starts growing, and our access to physicians improving. We continue to make strong progress with our primary growth driver and what we believe is most important to patients, which is the positive shift in earlier lines. This shift into earlier lines, as well as continued education to improve tolerability, has resulted in more patients staying on therapy longer. We are also expanding in the breadth and depth of use of XPOVIO with strong growth in the community setting. While we continue to grow our breadth by adding more accounts every quarter and penetrating in more top myeloma accounts, as we progress through our launch phase, our focus is now on growing depth with our core customer base by increasing new patient starts and driving the shift into earlier lines where patients are more likely to stay on therapy longer, thus generating more refills in the future. We believe the beneficial impact to patients and growing confidence among our physicians in using the lower dose, once-weekly XPOVIO-based triplet regimen are seen in the data. Our intent-to-prescribe data continues to show sustained improvement in the efficacy and safety perception of the product in the third line. We remain confident about the guidance we provided for 2022 net product revenue of $135 million to $145 million. We see strong and consistent momentum across all our growth drivers, increasing confidence amongst physicians in using XPOVIO. And we have a field team that is laser-focused and committed to bringing XPOVIO to more patients in the second to fourth line. With regards to COVID, we continue to see the environment normalizing and will monitor and adapt as things evolve. The unmet need remains strong for new modalities like XPOVIO because in multiple myeloma, physicians' ability to class switch with multiple combinations has driven significantly better patient outcomes. A majority of treated patients in the first to second line are exposed to an anti-CD38 therapy. Many of these patients' disease will become refractory to or relapse from an anti-CD38 treatment. We believe this is where XPOVIO is a strong fit in the second to fourth line. It is a novel class of therapy with robust efficacy and with a breadth of data in the post anti-CD38 setting. It has a well-understood and manageable safety profile, and while we only promote FDA-approved regimens, physicians have the option to combine with several different backbones per the NCCN guidelines. Building on our momentum in 2021 and early this year, and with a rapidly advancing myeloma pipeline, we expect to continue to drive steady growth in the near, mid, and long term. With that, please advance to Slide 11 and I'll turn the call over to Reshma and Patricia to review our clinical pipeline progress.

Thank you, Sohanya. It's great to be here today, just under three weeks after I joined Karyopharm as Chief Medical Officer. Before discussing our pipeline, I'd like to take a moment to introduce myself. I'm a medical oncologist with more than a decade of experience in oncology drug development, both at large pharmaceutical companies and at smaller developmental stage companies. Prior to joining Karyopharm in mid-April, I spent ten years enrolled with increasing responsibility at three life science companies, including Aravive, Genmab, and Merck. During my career in industry, I've participated in the development of multiple oncology drugs with varying mechanisms of action, including immuno-oncology agents and antibody-drug conjugates across all phases of drug development from IND filings for Phase Is to designing and implementing registrational studies leading to successful first approvals, as well as additional major indications. In addition, I have participated in the development of companion diagnostics, including a PD-L1 IHC. I can see that both selinexor and eltanexor have significant potential for battling an array of cancer types and I'm thrilled to join the Karyopharm team at such an exciting and pivotal time in the company's growth. I'm impressed with both the team and the science of SPO1 inhibition and I am excited to realize that the potential of these therapies for patients that are being evaluated in our four core programs. Now turning to Slide 12, I will be reviewing our clinical developmental pipeline from our four core programs. As we look to the future on Slide 13, one of our top priorities is to expand our footprints in multiple myeloma, both in the US and across the globe. We have strategically partnered selinexor in key ex-US territories. Our partner Antengene recently obtained approvals, which include conditional and full approvals, for XPOVIO in Mainland China, Australia, and Singapore. For Europe, the application requesting approval for selinexor in patients with multiple myeloma, following at least one prior therapy, has been validated and is currently under review by the CHMP. The outcome of the CHMP review is expected by the end of the first half of 2022. There are also pending marketing approval applications for second line plus multiple myeloma submitted or on file in Canada and in other Asia-Pacific markets through our strategic partners.

Thank you, Reshma. So first, I'll provide an overview of the unmet need in endometrial cancer, and why we find our upcoming opportunity so exciting for patients. Endometrial cancer is the most common form of gynecologic cancer in the United States. Unlike other solid tumors, endometrial cancer mortality continues to increase. Of the 14,000 patients diagnosed with advanced or recurrent endometrial cancer each year in the US, approximately 50% have p53 wild-type tumors. The current landscape for advanced or recurrent endometrial cancer consists of first-line chemotherapy, where response rates are approximately 70%. However, following responses to chemotherapy, there are no effective treatments available and the NCCN guidelines recommend a watch-and-wait approach until disease progression. This approach clearly needs improvement because the five-year survival is only 17%. As selinexor is administered orally and maintenance therapy is well established with physicians that treat multiple types of solid tumors, including breast ovarian cancer, we believe selinexor has the potential to offer these patients a new maintenance option that could sustain the response from chemotherapy and help keep cancer from returning for longer. As you know, we recently reported results from the Phase III SIENDO study. A subset in this study, which is shown on Slide 16, demonstrated single-agent selinexor to have an impressive 10-month improvement in median PFS in a pre-specified exploratory subgroup of 103 patients who had p53 wild-type endometrial cancer. The patients in this study were diagnosed with advanced or recurrent endometrial cancer. They were treated with frontline chemotherapy and had either a partial or complete response to chemotherapy. In patients with p53 wild-type disease, the selinexor-treated patients achieved the median progression-free survival of 13.7 months compared to just 3.7 months in the placebo-treated patients. Based on these exciting data, we are partnering with opinion leaders, the Gynecologic Oncology Group, and the European Network for Gynecologic Oncology Trials, or ENGOT, to initiate a registration-enabling Phase III study, which we plan to initiate during the second half of 2022.

Thank you, Patricia. Since we issued a press release earlier today with the full financial results, I will just focus on the highlights, which began on Slide 22. Total revenue for the first quarter of 2022 was $47.7 million compared to $23.3 million for the first quarter of 2021. Net product revenue from US commercial sales of XPOVIO for the first quarter of 2022 was $28.3 million compared to $21.7 million for the first quarter of 2021, representing a 30% increase year-over-year. The estimated growth to net discount for XPOVIO in the first quarter was 19%. We expect growth to net discount to be in the 15% to 20% range for the full year 2022. We recognize $19.4 million of license and milestone revenue in the first quarter of 2022, which is inclusive of $8.6 million related to milestones earned in connection with our license agreements with Antengene and Promedico, and $7.1 million earned in reimbursement of development expenses from the Menarini Group. As a reminder, as part of the agreement that we announced in December, Menarini reimburses us for 25% of all expenses that we incur for the global development of selinexor, not to exceed $15 million per year. R&D expenses for the first quarter of 2022 were $42.1 million compared to $37.1 million for the first quarter of 2021. This increase was primarily attributable to higher clinical trial expenses, including startup costs for the Phase III SPD study. Cash, cash equivalents, restricted cash, and investments, as of March 31, 2022, totaled $207 million compared to $235.6 million as of December 31, 2021. Based on our current operating plans, we continue to expect net product revenue of $135 million to $145 million for 2022, reflecting approximately 40% growth compared to 2021. Non-GAAP R&D and SG&A expenses, which excludes stock-based compensation expense, to continue to be in the range of $265 million to $280 million for the full year of 2022. Certain previously expected launch preparation costs for endometrial cancer, which were included in our SG&A guidance, were shifted to R&D for the new SIENDO 2 study. Therefore, we expect non-GAAP R&D expenses to decrease by approximately 10%, including the cost of the SIENDO 2 trial, compared to 2021, with most of the decrease expected to occur in the second half of 2022. And finally that our existing cash, cash equivalents, and investments, as well as the revenue we expect to generate from XPOVIO product sales and other licensed revenues, will be sufficient to fund our planned operations into early 2024.

Thanks, Mike. We believe that we are well positioned for our strong 2022, both on the commercial front as well as with the advancement of our clinical programs. We continue to maintain strong momentum with a number of key near-term catalysts and corporate milestones for us to deliver on, as outlined on Slide 24, as we continue to strive each day for patients with high unmet needs. The key upcoming milestones we are focused on over the near-term, in addition to our continued focus on driving commercial performance, are to dose the first patient in our Phase III study, evaluating the all-oral SPD triplet in patients with relapse or refractory multiple myeloma by the end of the first half of 2022 and receive a decision from CHMP on our application requesting approval for selinexor, rituximab, and dexamethasone in patients with multiple myeloma following at least one prior therapy also during the first half of 2022. For the endometrial cancer program, we will be presenting subgroup and molecular analysis data from the SIENDO study in an oral presentation at ASCO '22. We are also planning to initiate a new registration-enabling Phase III study in p53 wild-type tumors during the second half of '22. For the myelofibrosis program, we look forward to presenting topline Phase I selinexor data in combination with JAK inhibition in treatment-naive myelofibrosis also at ASCO '22. And finally, for the MDS program, we expect to report preliminary Phase I eltanexor data in combination with a hypomethylating agent in frontline MDS during the second half of 2022. In closing, I would like to give a heartfelt thank you to all our teams at Karyopharm and our investigators as we work every day to positively impact the lives of patients with cancer. We would also like to thank our shareholders for your ongoing support and look forward to keeping you updated on our continued progress. It's an exciting time for the company and we are all diligently working to create value for all of our many stakeholders. With that, I would now like to ask the operator to open the call up to the question-and-answer portion of today's call. Operator?

The first question comes from Maury Raycroft with Jefferies.

First one is on myelofibrosis with the upcoming data at ASCO. Can you talk about how many patients or what kind of follow-up we might see at ASCO? Maybe talk more about how you are looking for selinexor plus rux for this combo to differentiate from some of the other rux combos in the clinic.

Yes, thanks, Maury. For the first part of that, I'll pass it over to Patricia to talk about what we expect to see at ASCO and also what we expect to see in combining rux with selinexor in the frontline myelofibrosis. So, Patricia?

Yes, thanks. So we're really excited about the preliminary data that we're going to be reporting at ASCO in about a month. So this is going to be the Phase I portion of the ongoing Phase I/II trial that obviously is looking at selinexor in combination with ruxolitinib in patients with treatment-naive myelofibrosis. So obviously we'll share more details when the ASCO abstracts are released on May 26. What we're hoping to see with this combination, so anytime you combine two agents with strong single-agent activity, we look to improve on the efficacy and still have a tolerable side effect profile. So as I reviewed during the presentation, in the ESSENTIAL trial with monotherapy selinexor, we saw really durable spleen responses. 40% of patients achieved SVR35 at 24 weeks or greater. In the ruxolitinib trial, 40% of patients achieved SVR35. Therefore, the combination should be higher than this.

Got it. That's really helpful. And also wanted to ask a question about myeloma too. So for proportion of patients being prescribed in early versus later lines, it seems like that's been at about 50-50 for a few quarters now. Are you seeing this start to shift more toward earlier lines? And can we learn more about that this year over the next couple of quarterly updates?

Yes, thanks, Maury. I'll turn to Sohanya to take you through that.

Thanks, Maury, for the question. So yes, we continue to see that steady shift into the second to fourth line. And we see now greater than 50% of our patients now in the second to fourth line versus the fifth line plus. And the good news is the patients are seeing the benefit here and are staying on therapy longer. So we are seeing an increasing proportion of patients, for example, staying on 4 cycles or greater. And you're seeing this benefit because of the earlier line shift, primarily.

And we'll continue to update on that as we move forward, Maury, during the year.

The next question is from Peter Lawson with Barclays.

I guess the first one's just around the impact of COVID. Is there any way, Richard or Mike, to kind of break out the impact of COVID in the first couple of months of the quarter?

Yes, thanks, Peter. I'll let Sohanya do that because it's pretty clear as you look at some of the numbers. Sohanya?

Yes, thanks, Peter. So overall, when you think about COVID impact, there's a couple of different facets, right? So particularly challenging environment in Q1, but when you look at January and February in particular, the data shows that COVID had up to approximately a 10% negative impact on oncology patient visits in Q1 of 2022. Now, that in turn impacted on new patient starts in that January to February period. The second component in terms of COVID impact is field activity and access to physicians. And this was impeded in that January to February period, including our proportion of live engagements. And as you know, in the initial stages of a launch, it's critical to have this time in front of customers. However, in March, we saw the trends improving both in the marketplace, we're seeing signs of patients returning back to the clinics; but more importantly, our access to physicians improved in March with over 60% of our engagements being live. Also, we grew our new starts in March as well. If you take a step back and look at our growth drivers holistically, we sustained improvement across all our growth drivers. So we continue to see that positive shift in earlier lines, which gives us that duration benefit. We continue to increase our breadth, but, more importantly, our depth of use of XPOVIO. And we also improved our perception per the intent-to-prescribe data.

And then it's encouraging to see the revenue guidance reiterated. What factors should we be thinking about that help re-accelerate quarter-over-quarter growth and also drive higher year-over-year growth? And what are the factors there and how should we think that kind of playing out through the year?

Yes, thank you, Peter. I'll turn that over to Sohanya in a minute, but as you know, there's obviously those dynamics that happen Q-over-Q. So focusing obviously on reiterating our guidance and achieving that range of about 40% growth over the year. I think Sohanya has talked about some of those headwinds we faced already in Q1, but I'll turn to Sohanya to kind of take you through why we have the confidence to deliver on that for the full year.

Great. Thanks, Peter. So, first of all, 30% year-over-year net product revenue growth, I feel extremely good about, given the backdrop of the significant COVID impact we experienced, particularly in the January/February phase. In terms of moving forward and the growth drivers, they remain the three key growth drivers where we've seen sustained improvement. So our focus for the rest of this year is to accelerate that earlier line shift. And we've seen our most rapid growth in the third line, and our focus is to continue to accelerate that third line growth. And as I mentioned earlier, you see, as a result, the benefit on duration when these patients move into earlier lines. I think the second area focuses, we talked about breadth and depth, but as we evolve through our launch phase, our focus becomes accelerating depth. So to give you an example of depth and increase in the use of XPOVIO with our core customer base, if you look at our top 20 XPOVIO accounts, which include a lot of the major community networks and they contribute to about a third of the business, we saw almost 50% revenue growth. So for the rest of this year with the access improving to our physicians, driving depth will be a critical success factor. And finally, improving the perception of the product. We've seen continued sustained improvement over the course of the year, and we plan to continue to do that in terms of proving perception of both the efficacy as well as the safety. And then in terms of, Richard pointed out, there can be quarter-over-quarter fluctuations. Typically, they are in Q4, Q1. You see some seasonality dynamics, some buying pattern dynamics in Q4, but when you think about Q2 and moving forward, we anticipate the marketplace normalizing in terms of patient flow, obviously excluding any potential future COVID impacts. So I feel confident about our annual guidance of $135 million to $145 million.

Are there any insights from the scripts or the access or patient flow for April? Did that improve compared to March? That's my final question.

Yes, well, I think we'll comment on that as we get into Q2. I think we just want to focus on Q1 now, because it takes a while obviously for that data to mature and see what it looks like.

The next question is from Mike Ulz with Morgan Stanley.

Just given that you're seeing some impact of COVID on the commercial side, I'm just curious if you're seeing any impact on the enrollment side, specifically for your Phase II MF and MDS studies.

Yes. Thanks, Michael. I'll hit that at a high level and then I'll turn it over to Reshma. But I think as we all experienced in the environment in January and February, a number of staff were out across our clinical trial sites, so that did affect some of our startups, did affect some of the access in different areas. And Reshma, maybe you want to expand on that a little bit?

Yes, thank you for the question. We are facing some challenges related to COVID in our clinical trials. We've encountered issues with resources, accessing sites, and opening our facilities. However, we are optimistic that we will see a turnaround and continue to increase enrollments across all of our studies.

Got it. That's helpful. I have one more question regarding the MF data you plan to present at ASCO next month. When considering the data, you mentioned that we can expect around 40% for rux, and in combination, it should be higher than that. As you look to advance this program in the future, what does significantly surpassing 40% mean? Is it an increase of 10 percentage points, or more than that? Any additional details you could provide would be appreciated.

Yes. Thanks, Mike. I'll turn to Patricia to talk to that, but I think there's a number of areas that Patricia will talk on. One is obviously the overall response rate. The other is also looking at the symptom burden across patients and looking to reduce, kind of, the other symptom burden as well as, kind of, some of the side effect profiles. So Patricia, maybe you can expand on that back to Mike?

Yes. Thanks, Mike, for the question. So when we talk to the KOLs, they believe that if we can see a response rate, anything better than 40%, that that would be a really good bar to reach. One of the things that we have noted with selinexor is that we improve on multiple fronts. So spleen volume reduction, symptom improvement, improvement in anemia and potential disease modification with the reduction in bone marrow fibrosis. And it's interesting, even though selinexor has a side effect of anemia, we note that with continued use in these myelofibrosis programs that the anemia actually decreases over time. So we're hoping that perhaps the combination of rux plus selinexor may actually decrease some of the anemia. But as you said, we're looking forward to the ASCO poster.

The next question is from Colleen Kusy with Baird.

So, in the Phase I study for myelofibrosis that you'll have at ASCO, is there anything that we should keep in mind in terms of the patient selection for that trial? Especially when comparing to other MF studies.

Yes, I'll turn to Patricia for that. Patricia?

Yes. In Phase I, the patients are new to JAK 1/2 inhibitors and are receiving frontline treatment. They must have platelet counts over 100,000, and aside from that, they are just frontline patients with myelofibrosis. Does that answer your question?

Yes, that's helpful. Could you clarify your approach to development in the frontline setting compared to the second line setting? Specifically, how are you determining the patient population for the second line setting, considering the differences between those who are really rux refractory versus those with just JAK experience? Please discuss the patient selection for the second line setting.

Yes, we'll turn to Patricia to expand on that.

All right. Thank you. So in the 035 study, which is the second line study, as you know, 40% of patients respond to frontline treatment with rux, leaving 60% of patients looking for options. There are no other classes of treatment other than the JAK inhibitors. And so there's a significant potential increased responses and improved survival in these patients. With a new class of drugs, we feel like this could really help the patients and give them more options.

And I think, Colleen, to add on that, we're truly looking for patients who are kind of rux refractory with at least 24 weeks or 6 months exposure to a JAK inhibitor.

Okay, great. And as a quick follow-on, as you've done more work on p53 wild type, are there any other tumor types that you think might make sense to pursue based on the signal that you're seeing in endometrial?

Yes, that's a great question. We're continuing to do work on that obviously with our development team. And maybe, do you want to expand on that, Reshma?

Yes, absolutely. The exploratory subgroup from the SIENDO trial showed impressive results for p53. Although these findings are preliminary, they are still noteworthy. We are continuing to investigate p53 across various tumors, including hematologic malignancies and other solid tumors. We aim to explore the potential of p53 wild type as a possible subgroup. Our focus is on p53 broadly to identify potential markers that we can pursue among different tumor types and patient populations.

The next question is from Brian Abrahams with RBC Capital Markets.

This is Joe on for Brian. Can you talk a little bit about the rux combo study in MF? So for the patient choice arm, can the physicians choose some of the newer JAK inhibitors that are recently approved or that may be approved? How do you see this impacting the potential responses across the arms? And for the monotherapy use for selinexor, how do you see the post-rux landscape evolving and where can seli fit in?

Sure. Maybe I'll turn to Patricia to talk to those two parts. Patricia?

Yes. So the frontline trial and treatment naive is looking at ruxolitinib plus Selinexor versus ruxolitinib single agent. So in that one, the physicians don't choose the JAK inhibitor. In the other trial 035, which is second line, that one is selinexor versus physician's choice, and the physicians can choose to either re-use ruxolitinib or they can choose any of the other treatments that are currently available. So chemotherapy, fedratinib, androgens, interferon, anything that is available for them. And then as far as the treatment landscape, obviously there's been a couple of approvals, pacritinib was approved for patients who have platelet counts less than 50. We know that there was just an acquisition of momolitinib, which is, of course, another JAK inhibitor. Again, we're pretty excited about selinexor as it gives patients a new mechanism of action outside of the JAK inhibitor population.

And I think, Joe, what's really important is to focus on the response rates and those refractory multiple myeloma patients. As Patricia just mentioned, if an agent from a different class can provide patients with more options across multiple classes, we've observed significant benefits, especially in multiple myeloma over the past decade.

The next question is from Eric Joseph with JPMorgan.

Just coming back to the COVID commercial impact, if it makes sense that COVID would impact new starts for the quarter. Is it also your sense that this impacted prescription refills as well? I'm just trying to reconcile, sort of, where the impact was experienced, given the steady 50:50 mix between earlier and late line. And to what extent, I guess, was there any shift in gross to net, given the cyclical coverage gap on the side of payers that we see in first quarter?

Yes. Thanks, Eric. I'll turn to Sohanya for that, to touch on the refill, and then I can have Mike talk to the shift Q-over-Q on the GTN.

Thanks, Eric, for the question. So overall, if you compare quarter-over-quarter demand units, we maintain demand units despite the COVID impact and the seasonality impact. So if we're breaking it down to new starts versus refills, the new starts were impacted particularly in January and February by COVID. However, we did see a growth in new starts again in March. But overall COVID did have an impact on new starts because oncology patient visits, from the data that we see, were impacted negatively by about 10% in January and February. Now, if you take a look at our refills, we have actually continued to improve our refill rate since the BOSTON launch, and the patients are showing signs of staying on therapy longer, particularly in the earlier lines. And as I mentioned before, for example, we see this increasing proportion of patients in 4 cycles or more. So we're making good progress overall, despite the COVID impact early this year.

Sure. Q1 GTN, as we mentioned on the call, was right around 19% versus Q4 GTN was around 15%. So, typical higher in Q1 versus in Q4 that you see every year. And we did guide in the call that we expect to be somewhere between 15% and 20% for the full year 2022.

Okay. That's very helpful. And maybe just a follow-up question on MM-031. As that study progresses this year, does patient enrollment there present any challenges to your commercial guidance for the full year? Additionally, regarding the costs related to that trial, considering the lifecycle opportunity for both you and your partners, Antengene and Menarini, to what extent might they be contributing to the costs associated with conducting that study?

Thank you, Eric. I believe that when we look at the study being conducted both in the US and Europe, it will not affect our commercial performance. As we anticipate the data in 2024 and seek approval in 2025, we have the chance to develop an all-oral treatment. The current study involves patients being exposed to anti-CD38 upfront. Considering the increasing number of patients being treated with anti-CD38 in the early lines, I am confident that this combination will create significant value for us, for patients, and for our partners as we progress.

The next question is from Ed White with H.C. Wainwright.

Can you give us your thoughts on off-label use right now with the other combinations, the ones that perhaps are in the NCCN guidelines? And then also you had mentioned that virtual versus in-person detailing is improving. In March, I believe you mentioned 60% were in person. Can you just give us some of the historical numbers for that? How low did it go in January and February, and what was the comparison to the fourth quarter of last year? And then, is there a noticeable difference in accounts that are virtual versus in detailing? Are you seeing a bigger penetration in prescriptions?

Thanks, Ed. Well, we'll add those three questions together and we'll get Sohanya to run through them. Sohanya?

Thanks for the questions, Ed. I'll address them in three parts. First, regarding the mix of treatment regimens and their usage, we don't have complete visibility into all XPOVIO data, and there may be fluctuations quarter-over-quarter. However, since the launch of BOSTON, we've observed an overall increase in the use of triplet therapies compared to doublets. The triplet usage is divided between XVd and other regimens. We're also seeing the use of other combinations, including XPOVIO with pomalidomide, daratumumab, and KYPROLIS. All four triplets are included in the NCCN guidelines, but we only promote the XVd regimen. Ultimately, it’s up to physicians to decide which regimen to use based on prior therapies. Regarding your second question on live versus virtual visits, approximately 60% of our interactions are currently in person. In January and February, this dropped to around 30% to 40% due to increased restrictions and the COVID surge. In Q4, those numbers were around mid-50s, reflecting a balance between virtual and in-person engagements. Overall, aside from the COVID surge, we're seeing a return to pre-COVID levels for live interactions. In terms of the effectiveness of live versus virtual meetings, I believe both are effective. While it's always beneficial to meet customers in person, our team has effectively adapted to digital methods. We've optimized our virtual channels alongside our in-person efforts. Although both approaches are quite effective, we still prefer in-person meetings, especially at this stage of our launch, and we aim to see improvement in live engagements.

The next question is from Jonathan Chang with SVB Securities.

This is Faisal on for Jonathan. I just wanted to ask, could you describe what the endometrial cancer, the new study design might look like and, sort of, how you think about this study relative to others ongoing in the landscape?

Yes, thanks. I think for that, I'll turn it over to Patricia to talk to the potential study design. As you know, we're still engaging with the FDA, so it's still high level. And then maybe what we're seeing in the environment overall, moving forward, Patricia?

Yes. Thanks for the question. So, as Richard said, we've really worked with ENGOT, GOG, and the Steering Committee to kind of design an appropriate clinical trial. We have a meeting scheduled with the FDA to discuss the study. We know that it will be a randomized placebo-controlled trial and it'll be maintenance therapy for patients with p53 wild-type endometrial cancer who've responded to chemotherapy. Obviously, we'll give more details on the study design when we initiate the study in the second half of this year. And then as far as the landscape, there's a lot of studies that are ongoing in endometrial cancer, and we're waiting for those to mature and see how they read out.

This concludes the question-and-answer session. I am sorry.

Thank you, operator. I'd like to thank everyone for joining today's call and have a great day, everyone.

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