Karyopharm Therapeutics Inc. Q2 FY2021 Earnings Call

Good morning. My name is Karen, and I will be your conference operator today. At this time, I’d like to welcome everyone to Karyopharm Therapeutics' Second Quarter 2021 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 Joe Rayne from Argot Partners. Please go ahead, sir.

Thank you, Karen. And thank you all for joining us on today's conference call, to discuss Karyopharm's second quarter financial results and business update. Today, I'm joined by Mr. Richard Paulson, President and Chief Executive Officer, Ms. Sohanya Cheng, Senior Vice President, Sales and Commercial Operations, Dr. Jatin Shah, Chief Medical Officer, Mr. Mike Mason, Chief Financial Officer; Dr. Sharon Shacham, Chief Scientific Officer; and Mr. Stephen Mitchener, Chief Business Officer. During today's call, which is outlined on slide 2, Richard will provide some introductory remarks, Sohanya will provide an update on our XPOVIO commercial progress, Jatin will highlight recent pipeline advancements, and then Mike will discuss the second quarter financial results highlights. We will conclude with some thoughts from Richard on upcoming milestones, and then we will move to the Q&A portion of the call. Earlier this morning, we issued a press release detailing Karyopharm's results for the second quarter of 2021. This release, along with the slide presentation that we plan to reference on today's call, is available on our website at karyopharm.com. 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. These include statements about our future expectations, clinical developments and regulatory matters and timelines, the potential success of our products and product candidates, including our expectations related to the commercialization of XPOVIO and NEXPOVIO, financial projections, and our plans and prospects. 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 Factor 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 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 date subsequent to today. I'll now turn the call over to Richard Paulson. Please turn to slide 4.

Thank you, Joe, and good morning, everyone. Please turn to slide 5. Since joining as President and CEO in May, my focus has been on execution to ensure we are providing the highest quality customer engagement and are operating effectively to achieve our milestones. Karyopharm was founded on the innovative science of selective inhibition of nuclear export as a mechanism to treat a broad range of cancers with significant unmet need. The foundation in oncology was established with the regulatory approvals and commercial launches of XPOVIO in three immunological oncology indications. We are proud of the commercial progress seen thus far. But we know we still have work to do in order to best serve our patients and drive continued steady growth. Specifically, in multiple myeloma, I believe we have a great opportunity to continue expanding our breadth and depth of XPOVIO through our execution in the approved indications and advancing our wastage combination studies, which Jatin will cover later in the call. While in parallel, we will continue to build our foundation globally. With the completion of the European Medicines Agency's Committee for Medicinal Products for Human Use review of our application for NEXPOVIO as a second-line plus treatment for multiple myeloma expected in the first half of 2022. As we look toward greater pipeline, we are actively working to prioritize our clinical development plan and hematological malignancies and in solid tumor indications to focus our efforts on programs with the highest unmet need, probability of success, and attractive market opportunities. This includes our Phase 3 SIENDO study evaluating XPOVIO in endometrial cancer, where there are no approved treatments for maintenance therapy following chemotherapy in any line of treatment. Top line results for this study are expected by the end of this year. And if positive, it further reinforces the therapeutic potential of XPOVIO in solid tumor indications. We're also advancing several targeted late-stage clinical studies across multiple solid tumor indications with high unmet needs that Jatin will review later on our call. To support our focus growth plan, we're well capitalized to fund our operations with a cash runway into the middle of 2023. I believe the important efforts we're undertaking today are further building on our foundation and position us well for continued growth. We're actively completing a full strategic review of our pipeline to fine-tune our future objectives and priorities as part of our evolution. And we look forward to hosting an Investor Day during the fourth quarter to outline strategy and pipeline focus to lead Karyopharm through the near-term multiple myeloma growth opportunity and the next chapter of expanding approvals in both solid tumors and additional hematological malignancies. As we turn now to slide 6, I would like to take this opportunity to introduce Sohanya Cheng, our new Senior Vice President of Sales and Commercial Operations. Sohanya brings nearly two decades of biopharmaceutical commercialization and research experience, predominantly in the oncology space. Sohanya has spent over 10 years of her career in the commercial organization at Amgen, where she held various sales and marketing leadership roles, supporting the commercialization of key oncology brands, including serving as Executive Director and Head of Marketing and Sales for multiple myeloma and overseeing Kyprolis. We are extremely excited to have Sohanya join the team at this critical time, as XPOVIO is rapidly evolving into a Standard of Care in multiple myeloma. I will now turn the call over to her to review the commercial results for the quarter.

Thank you, Richard, and good morning everyone. I share Richard's excitement regarding the potential of XPOVIO in multiple myeloma. I know firsthand about the intricacies of commercializing a product in the multiple myeloma market. And I firmly believe that XPOVIO provides a differentiated approach to treating this disease. Please now turn to slide 7. Total XPOVIO net product sales for the quarter were $20.2 million, an 8% increase compared to the second quarter of 2020. Year-to-date sales for the first half of 2021 were up 21% compared to the first half of 2020. Several key indicators continue to show progress, including growth in prescription demand quarter-over-quarter, and over 7,600 prescriptions filled as of the end of the second quarter. XPOVIO unit demand was at 28% compared to the second quarter of 2020, up year-to-date 33% compared to the first half of 2020 and up 4% from the first quarter of 2021. According to our market research data, we see a rising confidence in treating physicians and an overall perception of the XPOVIO product profiles across lines, with an evolution from penta-refractory to early lines with strong growth in the third line. This is a result of our strong field execution and our proactive education plan that we believe is helping prescribers gain confidence in improving the patient experience with dose reduction and proactive side effect management. We're also reaching more customers and seeing the number of prescribing accounts continue to sequentially increase quarter-over-quarter, with an 11% growth compared to the first quarter of this year. Patients continue to average 2.9 treatment cycles of XPOVIO, consistent with the previous quarter. We're still early in the rollout of XPOVIO in the second line plus setting and expect the average duration of treatment to increase over time as more and more patients are treated in early lines with a once-weekly XPOVIO dose and as part of a combination triplet regimen. Importantly, approximately 97% of U.S. lives have confirmed access to XPOVIO if prescribed. In June, we launched three new strength tablets for XPOVIO at 40, 50, and 60 milligrams to help healthcare providers individualize the dosing and administration of XPOVIO based on patient needs. These tablet options may also increase patient compliance by simplifying their treatment regimen, and reducing the pill burden experienced by some patients. Please now turn to slide 8. Overall, the quarter showed promising growth across several indicators and we continue to believe there is more work to be done to further increase our position in the market and better expand the reach of XPOVIO. We have recently implemented key initiatives designed to achieve just that. We have de-layered and strengthened our commercial team with key additions in marketing and the creation of a launch excellence capability to enhance our execution. Our team is investing in transforming our data capabilities and partnerships with our customers to help identify the right patient for XPOVIO at the right time. Our positioning has adapted to meet a critical unmet need in the treatment paradigm in second line plus therapy. Most patients get treated with IMiDs, PIs, and anti-CD38 in the first and second lines. Several different options are approved in the fourth line plus, but there is a wide space in the middle section of the treatment journey between the second and the fourth line where using a different mechanistic approach, also known as a class switch, could be vital for the success of the patients’ outcomes. XPOVIO is the first new class of multiple myeloma treatment approved in five years, with the ability to combine with different regimens as recognized by the NCCN guidelines. As we look at the myeloma marketplace as a whole, two themes emerge. Firstly, the innovation in this space is outstanding and is resulting in patients living longer lives, allowing the market to grow long term. Secondly, given the competitive nature in this space, several new entrants from the past few years have shown steady uptakes that are sustained over six years. With the foundation we are laying now, and with a rapidly advancing myeloma pipeline, we believe we will continue to drive steady growth in the near, medium, and long term.

Thanks, Sohanya. I'd first like to touch on our exciting pipeline updates and key regulatory advancements. We're making progress on bringing XPOVIO to patients in need across the globe, with the recent approvals in the United Kingdom and South Korea that are further outlined in slide 10. Turning now to slide 11. Our priority Phase 3 study is the SIENDO study, evaluating XPOVIO in patients with endometrial cancer in the maintenance setting. SIENDO is enrolling approximately 248 patients, randomized 2:1, to receive either 80 milligrams of XPOVIO once weekly or placebo. Eligible patients include those with stage IV or recurrent disease who have completed a course of taxane-platinum combination chemotherapy and achieved either a partial or complete response. The primary endpoint of the trial is an improvement in progression-free survival, or PFS, defined as the time from randomization until death or disease progression. In November of 2020, we announced the trial had passed its planned interim futility analysis. And so the study continues as planned and we expect the top-line data by the end of this year. We remain highly encouraged by the study and the opportunity for exposure in this disease area as a maintenance therapy, which is outlined on slide 12. Endometrial cancer is the most common gynecologic cancer in the U.S., with over 65,000 new cases. Now while most women are diagnosed with early stage disease and have a good prognosis after surgery alone, approximately 14,000 patients each year in the frontline will have advanced or metastatic disease and are treated with chemotherapy. When their disease progresses, these patients are typically treated with additional chemotherapy, immunotherapy, and/or targeted agents. However, currently there are no approved drugs in the maintenance setting for patients who had a response to chemotherapy in any setting. This is the setting in which we're studying XPOVIO in the SIENDO study. A similar approach was taken with PARP inhibitors for patients with ovarian cancers, and they're used in a maintenance setting, and that disease is now the standard of care and widely adopted. To put our potential opportunity in endometrial cancer in perspective, assuming about two-thirds of frontline patients respond to chemotherapy, approximately 4,000 patients could be treated each year in the maintenance setting. We look forward to presenting these results later this year, which has the potential to benefit additional patients and has a significant opportunity to expand confidence in XPOVIO’s ability to work in both solid and hematologic tumors. Turning now to slide 13. I'd like to review some of the key data presentations from this year's ASCO and EHA annual meetings. First off is the data from a STORM study, which analyzed XPOVIO containing regimens in patients who had previously been treated with an anti-CD38 monoclonal antibody. This is an important setting to explore because at least 70% of patients will be treated with an IMiD, a PI, and a CD38 in the first two treatment lines. Beyond that, there's a lack of data to guide physicians on what will be the next best treatment. As you can see on slide 14, we have observed strong response rates for the XPOVIO-containing triplet combinations of XPd and XKD for 58% and 67% respectively, along with prolonged PFS with both XPd and XKD. On slide 15, we look specifically at the response rates for XPD, where we see that the response rate of the recommended Phase two dose is 65%. Patients who had previously been treated with an anti-CD38 monoclonal antibody had an overall response rate of 58%. Both of these response rates compare favorably to the less than 30% response rate expected for pomalyst dexamethasone. Advancing now to slide 16, we also present the updated data from all patients in the XPd arm of the Storm study, which continues to show higher response rates and the favorable PFS and duration of response. Collectively, these data support a new randomized Phase 3 study we expect to initiate by the end of this year. This new study is designed to evaluate XPOVIO in combination with Pomalyst and dexamethasone versus elotuzumab plus pomalidomide and dexamethasone in patients with previously treated myeloma. If the results of these trials are positive, this regimen could represent a prudent oral drug option for patients with early relapse myeloma. The safety profile continues to be manageable with supportive care and those modifications. Next on slide 17, we look specifically at the response rates for XKd which appears to be highly active in the post anti-CD38 setting. Here we see the response rates ranging from 73% to 87% for these various subgroups, including patients in first relapse and patients with high-risk cytogenetics. Then on slide 18, we showed the equally impressive PFS data. PFS for all patients, patients with high-risk cytogenetics, and patients who received anti-CD38 are 15 months and 23.7 months, respectively. On slide 19, we showed data presented from all patients in the XKd arm of the Storm study, which continued to show high response rates and favorable PFS with no new safety signals identified. Next, on slide 20, we have an overview of some of the important data to come out of the Phase 3 Boston study in patients with multiple myeloma following at least one prior line of therapy. This analysis looked at older patients who are 65 years of age and older. In this group, exposures were associated with a significant overall survival benefit, in addition to prolonged PFS, better response rates, and lower rates of peripheral neuropathy versus the comparator arm. On slide 21, we show the recommended supportive care which is very simple and only requires two antiemetics which can be tapered and no other prophylactic medications. On slide 22, we show that the incidence of patients experiencing nausea decreased after the first month of treatment with appropriate dose reduction and antiemetic measures. These results are consistent with physician feedback that we've experienced, as there's a continued gain in confidence in prescribing XPOVIO. Moving on to slide 23, we are encouraged by the new selinexor data at ASCO in patients with hypomethylating-agent refractory myelodysplastic syndrome, an indication with no approved therapies. In this study, single-agent selinexor achieved an overall response rate of 53% and a median overall survival of 9.9 months, with the expected overall survival being three to four months, providing strong rationale for continued development for this attractive market opportunity and unmet medical need. Turning now to slide 24, you can see a snapshot of a robust clinical pipeline, including two new clinical studies that were recently initiated in melanoma and myelofibrosis. As Richard mentioned, we're actively prioritizing our pipeline and focusing our development efforts within hematologic malignancies and solid tumors. This includes building on our breadth and depth in multiple myeloma with emerging clinical data that continues to show the potential of XPOVIO in combination with other anti-cancer therapies and expanding into other hematologic malignancies such as myelofibrosis and MDS with selinexor. We're also working to demonstrate activity and safety in other high unmet need solid tumor indications in the years ahead, such as endometrial cancer in the SIENDO study. With that, we’ll now advance to slide 25 and turn the call over to Mike Mason to review the quarterly financials.

Thank you, Jatin. Since we issued a press release earlier today with the full financial results, I will just focus on the highlights, which began on slide 26. Net product revenue for the second quarter of 2021 was $20.2 million, compared to $18.6 million for the second quarter of 2020. Following the launch of our additional strength tablets in June, we saw an approximate $2 million reduction in channel inventory to allow for purchasing of the new tablets, which we expect to be a one-time occurrence. The estimated gross-to-net discount for XPOVIO in the second quarter was 21%, which is slightly higher than our expected range of 15% to 20%. But we continue to expect to be in the 15% to 20% range for the full year 2021. License and other revenue for the second quarter of 2021 was $2.4 million, compared to $14.9 million for the second quarter of 2020. This difference between periods is driven by increased recognition of revenue from our license agreements with Antengene and Ono Pharmaceuticals in 2012. We expect to recognize $10 million in the third quarter of 2021 for achieving two regulatory milestones from our Antengene collaboration. R&D expenses for the second quarter of 2021 were $34 million, compared to $42.6 million in the second quarter of 2020. The decrease in R&D expenses in the second quarter of 2021, compared to the second quarter of 2020 was primarily attributable to the COVID-19 trial activity in the second quarter of 2020 that did not occur in 2021. SG&A expenses for the second quarter of 2021 totaled $36.5 million, compared to $38.8 million for the second quarter of 2020. The increase in SG&A expenses compared to the second quarter of 2020 was due primarily to activities to support the U.S. commercialization of XPOVIO, including the launch of XPOVIO in a second line plus setting. Cash, cash equivalents, restricted cash, and investments as of June 30, 2021, totaled $239.3 million compared to $276.7 million as of December 31, 2020. On slide 27, you can see that based on our current operating plans, we expect our non-GAAP R&D and SG&A expenses, which exclude stock-based compensation expense for the full year 2021 to be in the range of $270 million to $290 million. We expect those existing cash, cash equivalents, investments, as well as the revenue we expect to generate from XPOVIO product sales and other license revenues will be sufficient to fund our planned operations into the middle of 2023.

Thank you, Mike. We've already made strong steps forward in the first half of the year, including the expansion of XPOVIO in the second line plus treatment setting, enhancement of our commercial capabilities to promote future growth, securing an additional $60 million in funding from healthcare royalties, conditional marketing approval in Europe and the UK, and numerous other clinical development events. As we look ahead, we are focused on execution to drive our evolution and have several key milestones to look forward to as listed on slide 29. In multiple myeloma, our focus is on the continued enhancement and effectiveness of our commercial organization to promote increased XPOVIO sales in the second line plus treatment setting. We plan to initiate our Phase 3 study of XVd in multiple myeloma later this year, an oral combination that could allow us to further build in the multiple myeloma landscape. From our solid tumor programs, we expect top-line data from the Phase 3 SIENDO study in endometrial cancer later this year. A market opportunity where there are no approved drugs in the maintenance setting following chemotherapy in any line of treatment. We also plan to initiate multiple late-stage clinical studies in Myelodysplastic syndrome, Myelofibrosis, and colorectal cancer. We expect to present combination data from both our hematologic malignancies and solid tumor programs at medical meetings in the coming months, including ESMO in September. Lastly, we plan to hold an investor day during the fourth quarter to review our strategic imperatives and pipeline priorities to support our evolution as a company. To close, I would like to recognize and thank our employees for the hard work thus far this year and their dedication to serving our patients. I look forward to updating the investment community on our continued progress in the months and quarters ahead. And with that, I would now like to ask the Operator to open up the call to the question-and-answer portion of today's presentation.

The floor is now open for questions. We'll take our first question from Maury Raycroft with Jefferies. Please go ahead.

Good morning. This is Kevin Strang in for Maury. Thank you for taking my questions. So just wanted to ask if you could potentially book and what your average prescription renewal numbers could look like. They are in terms of increase in treatment duration versus increase in new providers or new patient starts?

Sure, Kevin, yeah. Let me turn to Sohanya to expand on that. Sohanya?

Yes. Great. Kevin, thank you for the question. First, I just want to underscore the demand growth that we've seen in the first six months of our launch in the second line, again, 28% year-over-year for the quarter and 33% for the first half of this year versus last year, and I feel very good about this growth. Regarding some of the drivers that you mentioned around new patient starts and the prescriber base, we're seeing very positive growth on new patient starts, as well as on expanding our customer base as we're adding new accounts quarter-over-quarter. Furthermore, we're also seeing a gain in confidence based on our intent to prescribe data of physicians and their overall perception of the product.

Great, thank you. And then just another question on the rationale and strategy for Eltanexor and MDS, maybe a single agent and then combo. And then also the same question for Myelofibrosis and maybe what your expected positioning is in these indications?

Sure, Kevin. Let me turn to Jatin to talk to those two. Jatin?

Yes, absolutely. Thanks so much. So I think the rationale for exploring Eltanexor and MDS is really based on two things. One is strong preclinical rationale. We have early data from selinexor and MDS and now additional data with Eltanexor and MDS as well. And keep in mind two things. One, there's no approved therapies in the relapsed MDS space. Other therapies, including those that are effective drugs, have a response rate of less than 10% in relapsed MDS, especially primary refractory MDS. So in that setting, we're looking at the overall response rate of 53% with Eltanexor as a single agent, the overall survival greater than nine months, while the expected overall survival is three to four months. It's in that setting that we see a strong rationale to develop Eltanexor as a single agent in refractory MDS as well as looking at combinations in the future and earlier lines of therapy. Similar thoughts for Myelofibrosis also apply.

Hey, Jatin. If you can just talk to Myelofibrosis as well?

Yes. That's actually the same thought in Myelofibrosis. There's really outside of JAK inhibitors limited therapeutic options for patients in the relapsed Myelofibrosis space. There's a now new JAK inhibitor in that space, but really the same class of drugs. And so you'll see data coming out of ASH again, the strong preclinical rationale, and you'll see data coming out of ASH, where we see an IST single-agent activity with selinexor, given once weekly at a low dose in myelofibrosis, and based on that, we're moving forward with the studies that were planned. We're also exploring a combination with other agents in the newly diagnosed setting. Again, keeping in mind that there're limited therapeutic options for patients with Myelofibrosis and only one class of drugs right now that are approved, and Myelofibrosis JAK inhibitors are seeing some single-agent activity that's promising.

Great, thank you very much.

We’ll take our next question from Brian Abrams with RBC Capital Markets. Please go ahead.

Hey guys, Thank you so much for taking my questions. Good morning. A few for me. As first off, I was hoping to reconcile some of the metrics that you provided a little bit more. So sounds like prescription demand is steady. Gross to net was flat quarter-over-quarter and you took a 5% or so price increase at the beginning of the quarter. So I guess I'm wondering why that's not pulling through to sales numbers more. Is this all just because of that negative inventory effect? Are you seeing any, I guess, extended spacing of doses for patients who might be titrating down? And I guess to that end, why do you think gross to net wasn't more improved quarter-over-quarter? And do you think the new strengths that you're launching could potentially mitigate some of that individualized lower frequency spacing of prescriptions, or spacing of doses?

Thanks, Brian, you had a few questions in there. So maybe I'll start, Mike, to talk on the gross-to-net and the impact of inventory. And then, we'll turn to Sohanya to talk about the metrics with regards to demand, Mike?

Sure. Hi, Brian. Yeah, so just to help with the reconciliation with the rollout of the alternate sizes, the three new alternate size tablets, as Sohanya mentioned earlier in the call. We did see our customers and specialty pharmacies and especially distributors sort of reset their channel. We do expect it to be a bit of a one-time occurrence. So the focus really is on demand, which is up about 4% from Q1 to Q2. And with that, when they switch over to growth set, I'll go back to Sohanya who is facing. So growth was 21% for the quarter, like we said slightly higher than the range of 15% and 20%. But you're right. It is also a reset on pricing something like 3% to 4%, et cetera, so we do expect that to come down in Q3 and Q4. And we'll be well within a range of 15% to 20% for the year.

Great, thanks. So let me touch on some of the demand drivers, and specifically your question around duration. Again, going back to the demand growth that we saw in the first half of the year is 33%, in the first half of this year versus the first half of last year. So very good demand growth here. Some of the drivers I touched on earlier. New patient starts, prescriber base, increasing. We are gaining confidence, and then the movement towards earlier lines. Now let me touch on duration of therapy and the tight earlier lines. When we think about the duration of therapy, you have to look at the reasons for discontinuation of treatment. There are two primary drivers of that, first, side effect management and second, disease progression. Now as we progress and shift from later line to earlier lines, which is a primary focus of our strategy and execution, and as we proactively educate on side effect management, we will see progress here in terms of the duration of therapy. Again, we're still early in the rollout of the second line plus launch, and it takes time for the real-world data to mature.

Can you provide an update on your outlook for XPOVIO for the second half of this year? Are you noticing any improvements in duration, refill rates, and demand as we moved out of June and July compared to earlier in the year? What should we anticipate concerning growth in the latter half of this year? I understand that it takes time for pull-through as you transition to earlier treatment lines. Do you expect to see an inflection point this year or in the coming years? Thank you.

Thanks, Brian. Let me start with that. And then I'll turn it to Sohanya. We are seeing, as we said, really good progress and moving up into earlier lines of treatment. And then, it's a difficult area to measure; there's only qualitative market research, not quantitative data on that with regards to the lines of therapy. But I do think one of the key indicators is really looking at how patients are being prescribed either the 160 starting dose or the 100 starting dose. So last year in the first half of the year, about 50% of patients were getting the 160 starting dose, whereas this year, now in the first half of the year, only about 15%, or just 15%, are getting that 160, so about 85% that are getting the 100 or the 80 kind of starting dose. So I think that's a real good leading indicator of how we're moving forward into the triplets and how we're moving forward into earlier lines of therapy. And maybe I'll turn to Sohanya to talk about some of our qualitative research, which helps to strengthen that and is a leading indicator going into the rest of the year.

Thanks, Richard. Yes, as I mentioned earlier, in intent to prescribe data, we see a couple of things. One is that increasing confidence among the physicians about the overall perception of the product. And this is a key leading indicator because the perception on both the efficacy and tolerability profile of the product is improving. Also, on the intent to prescribe data, we see a shift from the later lines to earlier lines. So, I feel very good about the momentum that we've seen in the first half of the year. I am also very excited by the team that we have in place, which is excited, passionate, and highly patient-focused. We are 100% focused on execution and growth in the second half of this year. We've initiated a couple of key initiatives to enhance our commercial and data capabilities, that I touched on earlier, delayering the sales and marketing team, reporting directly to Richard. We've identified new data partnerships to get to the right patient at the right time. We're enhancing our digital capabilities to better target our customers. So, lots of good initiatives in place. And I'm confident about the growth that will continue, not just through the end of this year, but that will sustain in the medium and long-term as well.

Great. Thanks so much. I'll hop back in the queue.

Our next question comes from Peter Lawson with Barclays. Please go ahead, sir.

Thank you for your insights. As we consider the dynamics, did you experience any challenges or impacts from COVID, particularly regarding trends in oncology visits, and did this affect your underlying growth?

Yes, thanks, Peter. I think as we hear from everybody, and we're all experiencing every day, we continue to work through the challenges of COVID. But I'll turn to Sohanya to go through some of the specifics on it. Sohanya?

Great. Thank you, Peter for the question. So, we continue to see recovery from the impacts of COVID, both on patient visits as well as field activity, but we have not returned to the pre-COVID level baseline. To kind of double-click on the U.S. field activity, we've improved quarter-over-quarter reaching 90% of pre-COVID levels, and our face-to-face customer interactions are increasing and are about 60% of the activity during the second quarter. The education happening both in-person and virtually, we've really optimized and it is having an impact, as I spoke to earlier, on how we're moving the needle on some of the intent to prescribe data. So, we are seeing good momentum. We haven't returned to pre-COVID levels, but we're seeing good momentum this year.

Thank you. And then were there any disruptions or departures on the sales front in the quarter? Just from the transitions we've seen at the management level?

Sorry, Peter, can you just repeat that?

Just listing, have you seen any disruptions or departures on the sales front in the quarter from the transitions and changes that have been implemented from the management side?

Yeah, so Peter, I think with regards to our staff and our team, we have really good momentum. We've been able to bring a number of people on board over the last 12 months. And as we're implementing the changes, we're getting very positive feedback on them is it really is enabling the sales organization and the marketing organization, both to report directly to me, they are very streamlined to make sure we're focused on execution.

Thank you. And is there anything you can say around, I guess, either repeat prescriptions of physicians that are kind of re-prescribing the kind of, the most likely the same store growth number?

Yes, I think we have some real good data on that and I'll turn to Sohanya on it. When you look at the multiple myeloma market, it is a market which is relatively concentrated in that you have about 80% of your business in about 1,000 accounts across the country. So maybe with that Sohanya, you can talk to some of our prescribing metrics and the impact we're having.

We have seen approximately 1,000 unique accounts that have placed orders to date. This growth is mainly in community clinics, but we are also observing it in academic settings. As Richard mentioned earlier, our business is notably concentrated among these top accounts, and we are expanding our presence in them.

We'll take our next question from David Lebowitz from Morgan Stanley. Please go ahead, sir.

Sorry, I was muted. When looking at the quarterly performance, how is performance in the original approved indication going at this point, assuming that you're getting some concrete share from Boston? Is there a kind of a max steady state for the original penta-refractory? Or how is usage changing in that particular area?

Thank you, David. I think as I mentioned before, it is hard. And there are no quantitative metrics to look at what line of therapy specifically. But I think again, it goes back to what I talked about with regards to the amount of new patients we're seeing initiated on XVd, which is our triplet store and triplets at the once-weekly 100 starting dose. Again, in the first half of last year, about 50% of patients were started on the 160 and about 50% were started on the twice-weekly 160. Whereas now, in the first half of this year, we have 85% starting on the once-weekly dose, and only 15% on the 160 twice weekly. So I think that is seeing a strong shift into the triplet and into our once-weekly business.

I guess, my question is, is what would then be the driver, I guess, the decline in the original population as opposed to just maintaining a steady state?

I think, David, our focus is really on moving up into earlier lines. So that's where we're focused with regards to our promotional efforts and our education efforts. So that's an active strategy. And I think as Sohanya talked about, that's really where we also see a significant opportunity with regards to that second line plus setting. So in between the second and fourth lines, patients 80% plus of patients through the first two lines you can have immediate PI and anti-CD38. Physicians really want to be able to bring in down board a class switch, which is why they're using all those agents upfront. And we have the ability as the first new agent in the last five years in that second and fourth line for a class switch with great efficacy. So our focus is in the earlier lines.

Thanks for taking my questions.

We'll take our next question from Eric Joseph from JPMorgan. Please go ahead.

Good morning. Thanks for the questions. Maybe, just picking up on that last question. Your breakdown of use between the once weekly in combination versus with dexamethasone, I guess, just how does that square with a pretty consistent duration therapeutic to the entity point 2.9 cycles? I would think sort of kind of moving to that combination regimen might extend a little bit further. What are you seeing in terms of discontinuation rates and tolerability? And then I have a follow-up.

Sure. Thanks. So I'll start and I'll turn to Sohanya. Again, I think as we highlighted in part two, as we move into earlier lines, you will see the length of therapy will evolve. And that takes time, and there are a few factors that weigh into that. Sohanya can talk to the factors that drive duration.

Yes. Absolutely. So as I mentioned, there are really two drivers of discontinuation, and our discontinuation rates have been maintaining at 12% to 13%, consistent with the prior quarter. Now the two drivers here are side effect management and disease progression. As we are moving into the earlier line, as you mentioned, with the once-weekly triplet regimen, and we're proactively educating on side effect management and appropriate dose reduction to optimize the side effect management, as well as movement into earlier lines, we're going to see movement over time in the duration of therapy. We are still early in the launch and it takes time for that data to mature.

Okay. I guess in unpacking your comments about steady growth expectations, steady expansion into earlier lines, I guess, how should we interpret that kind of in line with this kind of mid-single-digit quarterly growth expectation? Is that fair? I guess, is there any selective growth expectation in several quarters out? And I guess as also as a relief to the endometrial cancer opportunity and SIENDO. Can you just talk a little bit about sort of tolerability expectations there as a comparison with the myeloma experience, as we expect either better or worse or in line tolerability to be intended compared to as active treatment?. Thanks.

Thanks, Eric. I’ll just start on the first part and then I’ll turn to Jatin to talk to endometrial. We're not going to give guidance kind of moving forward. It’s still very early in our second-line launch. Going back to Sohanya’s point, I think our 33% demand growth year-to-date versus the same period last year shows very strong demand growth. And we're moving up into earlier lines and feel very confident on our continued progress and into earlier lines. And Jatin can you talk to the endometrial?

Yes, I'm sorry. I cut out for a quick second. What was the question again regarding endometrial?

Just endometrial and tolerability, and you can talk to the dosing that we're seeing that we're putting in place?

Yes, absolutely. Good question. It's important to really highlight where we're going with XPOVIO and the schedule on dose; we really transition from high dose twice weekly to once weekly low dose. And that's what we're doing with the SIENDO study where we're dosing patients with 80 milligrams once weekly in the maintenance setting. And so we find that dosing schedule is well tolerated, and many of our oncology line, oncologists are comfortable with XPOVIO management of side effects, and supporting care there. And so many of our solid tumor I think are very comfortable managing nausea and vomiting. And with these low doses, we see a lower incidence of nausea and vomiting.

Okay. Great. Thanks for taking the questions.

We'll take our next question from Jonathan Chang with SVB Leerink. Please go ahead, sir.

Hi, thanks for taking my questions. First question. In the past comments have been made regarding seeing the benefits of a longer duration of treatment associated with earlier lines in the second-half sales numbers. Is that something that investors should still be expected?

Yeah. Thanks, John. I think as we've said, as we move up into the earlier lines, we will see that progress, and we're seeing that, so we expect to start seeing that come through into the second half of the year, and it continues to move forward. Again, earlier lines with longer duration of therapy. The overall duration of therapy across the whole portfolio of patients takes longer to shift as you balance innovations from later lines and earlier lines.

Got it. On the second question for endometrial cancer, I understand we don't have the SIENDO results yet, but can you discuss the reasons for confidence that XPOVIO could achieve commercial success in that setting? If the study is indeed positive, and the drug is approved?

Yeah. So I think, you know, I'll kick it off. Then I'll turn to Jatin to talk about kind of the current impact of patients in that area and what we would expect to see looking at how we power the study with their hazard ratio. So again, in the maintenance setting, there are no approved therapies. So to have the ability to benefit patients in that setting was a positive study, I think you would see a very rapid uptake, just as we've seen in ovarian cancer with the PARP inhibitors. And so Jatin, maybe you can talk to kind of the current expectations for patients and what we powered to and what we would love to see if the study was positive?

Yeah. Absolutely. So, I mean, the powers phase the hazard ratio of 0.6. And we had our first interim analysis in November of 2020, as we mentioned. We passed and continue the trial as designed and expect top line results by the end of this year. If we have a positive study, with a hazard ratio of 0.6 or less, that will be both statistically as well as clinically significant for patients. Mind you, that's in the setting where there is no other approved maintenance therapies in endometrial cancer and a place that people are looking for maintenance. And the GYN oncologists are comfortable using maintenance therapy, as Richard alluded to.

We'll move on to our next question from Colleen Kusy with Baird. Please go ahead.

Hi, good morning. Thanks so much for taking our questions. You talked about increasing confidence from physicians, I guess, can you talk a little bit more specifically about what you think is driving that increase in confidence? And then you also mentioned fine-tuning the messaging and positioning? Can you provide a little more color on how do that shift that you're putting out there?

Hey, Colleen. Yeah, I'll turn to Sohanya for that.

Thank you, Richard. So let me tackle your question in two parts. The first is around the intent to prescribe data and the improvement in the perception. When we assess the improvement or the change in perception among a broad range of physicians, both in the community and academic setting, on their perception of both efficacy attributes, the variety of efficacy attributes, as well as tolerability attributes, including GI toxicity, as well as the patient's impact on quality of life. Across all these metrics, across all lines over time in the first half of this year, we have seen an improvement in the perception of the overall product profile. Regarding your second question on messaging and positioning, we are moving steadily from the penta-refractory original label to now the once-weekly label in the earlier line setting. As I mentioned earlier, it's quite a crowded marketplace in the fourth line plus with many options there. And in the first and second lines, we've got also several classes there including the anti-CD38 PIs. However, there is this unmet need, this gap, this white space in between the second line and fourth line, where there is a need for a class switch or a new class of therapy, where it can have an impact on patients' outcomes. And this is where we are positioning XPOVIO with its efficacy and strong tolerability profiles, as well as the convenient once-weekly dosing options; we’re positioning it in that white space.

Sure, I'll address that. The impact for the quarter is approximately $2 million. As Sohanya mentioned earlier, we introduced three New Strengths in June, which was essentially a reset for our customers. We anticipate that this will be a one-time occurrence for this quarter and should not affect Q3 or Q4 of this year. Regarding the net cost to patients, we experienced a 21% gross to net in Q2, but we expect this to decrease in the second half of the year, aiming for an annualized range of 15% to 20%.

And there are no further questions at this time. We'll turn the floor back over to Mr. Paulson for closing remarks. Please go ahead.

Thank you very much, operator. I’d like to thank everyone for joining us for the Q2 call today. Again, as an organization and team at Karyopharm, we’re very excited about the progress we continue to make in order to expand our breadth and depth in multiple myeloma to continue to expand our pipeline, both in hematological and solid tumor indications. And we're looking forward to coming back and sharing at our investor day in Q4 with regards to our strategic priorities and our prioritized pipeline. With that, thank you, operator and thank you for joining the call.

Thank you, again for joining today's call. We look forward to updating you on our progress as soon as we can. This does conclude today's teleconference. You may disconnect your lines at this time and have a great day.