Good morning. My name is , and I will be your conference operator today. At this time, I’d like to welcome everyone to the Karyopharm Therapeutics' Third 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 Jason Finkelstein of Argot Partners.

Thank you, Cladia and thank you all for joining us on today's conference call to discuss Karyopharm's third 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; Mr. Stephen Mitchener, Chief Business Officer, and Dr. Sharon Shacham, Chief Scientific Officer. During today's call as 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 investments and then Mike will discuss the third quarter financial results, highlights and guidance. 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 third quarter of 2021. This release along with the slide presentation that we plan to reference on today's call are 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 quarterly report on form 10-Q which is on file with the SEC and in other filings that we may make with the SEC in the future. Any 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, Jason and good morning everyone. Now please turn to slide 5. After joining as President and CEO in May and now having been in this position for a full fiscal quarter, I valued the opportunity to meet and speak to many of our shareholders, customers and investigators. From our insightful conversations I have enjoyed the enthusiasm and the commitment to our science. With the ability to positively impact patients and work across many different types of cancers. I look forward to continuing these interactions in the future as our future outlook for Karyopharm is rooted in three key fundamentals. First is our execution XPOVIO launch. Currently, XPOVIO is approved and three indications in the U.S. in multiple myeloma and diffuse large B-cell lymphoma. We have a tremendous opportunity in front of us to continue expanding XPOVIO's breadth and depth through continued head down execution and the approved indications and advancement of key late stage myeloma studies. We delivered strong commercial results in the third quarter with a significant increase in net product revenues compared to the second quarter of 2021 driven by an acceleration demand growth for XPOVIO. XPOVIO continues to move into earlier lines of therapy and multiple myeloma as a new effective modality that can become the standard of care and second line plus which Sohanya will discuss later in the call. In parallel, we will continue to build our foundation globally. We are anticipating that the European medicine agencies committee for medicinal products for human use will complete the review of our XPOVIO marketing application as a second line plus treatment for multiple myeloma, which is expected during the first half of 2022. Second is our pipeline. As we advance our pipeline, we are actively working to prioritize our clinical development plan and hematological malignancies…

Thank you, Richard. And good morning, everyone. We have accelerated growth in the third quarter and continue to make strong progress across key indicators since our second line plus launch at the beginning of this year. Please now turn to slide 7. Total XPOVIO net product sales for the quarter were $26.7 million, a 32% increase quarter-over-quarter and a 25% increase year-over-year. These increases were driven by strong execution with over 9000 prescriptions filled as at the end of the third quarter. We continue to see a positive shift from the Penta refractory setting towards earlier lines with the most rapid growth this year in the third line as we continue to focus our messaging on the whitespace in myeloma between second and fourth line where using a new class of therapy could be vital for the success of patients outcomes. We are expanding in breadth and depth of use of XPOVIO with strong growth in the community setting. We continue to add more accounts every quarter and increase penetration at top myeloma accounts. In addition, our intent to prescribe data continues to show sustained improvement in the efficacy and safety perception of the product and growing confidence in utilization in early aligns. As physicians have an increasingly positive experience with the lower dose once weekly XPOVIO base triplet regimen. While patient visits and field activity improved in the third quarter, they have not returned to pre-COVID levels. We will continue to monitor any further COVID impact and remain focused on strong execution and positioning XPOVIO as a standard of care in second line plus. With the foundation we are laying now and with a rapidly advancing myeloma pipeline, we hope to continue to drive a steady growth in the near mid and long term. If you will now advance to slide 8, I will turn the call to Jatin to highlight our clinical development efforts to further build our position in multiple myeloma, other hematological and solid tumor indications. Jatin.

Thank you, Sohanya. If you'll now please turn a slide 9. I'd first like to touch on a key regulatory advancements. As you know, our marketing authorization application in the EU has invalidated is currently under review by the CHMP and as Richard mentioned earlier we expect this review to be complete in the first half of 2022. We are seeing progress with bringing selinexor to patient in need across the globe by ex-U.S. partners, including a new drug submission that was recently submitted by force therapeutics and accepted for review by Health Canada. In addition, we saw the approval of Selinexor for the treatment of patients with multiple myeloma and DLBCL in South Korea, and several new drug applications in multiple Asia-Pacific markets including China, Hong Kong, Australia, Singapore and Taiwan; all with our partner antigen. Turning now to slide 10, for clinical stage programs. We are advancing our pipeline across multiple oncologic indications with a high unmet need. This is a snapshot of our clinical pipeline including key new clinical studies that were recently initiated including the MF-34 Study evaluating Selinexor in combination with ruxolitinib in treatment, naive myelofibrosis. The MEL-33 Study evaluating Selinexor in combination with pembrolizumab in patients with locally advanced or metastatic melanoma, and finally the 801 study evaluating eltanexor in myelodysplastic syndromes. We'll provide more details on these studies in just a moment. We're actively prioritizing our pipeline and look forward to communicating our refined corporate vision and objectives on our virtual investor day that's planned for December 8. 2021. At this time, the Phase 3 SIENDO study represents the next major milestone and we remain highly encouraged by the opportunity for Selinexor in patients with endometrial cancer in the maintenance study, which is outlined on slide 11. Endometrial cancer is the most common…

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 21. Total revenue for the third quarter of 2021 was $37.7 million compared to $21.3 million for the third quarter of 2020. Net product revenue for the third quarter of 2021 was $26.7 million, compared to $21.3 million for the third quarter of 2020 from U.S. commercial sales of XPOVIO. The estimated growth the net discount for XPOVIO in the third quarter was 15%, which was on the lower end of our expected range of 15% to 20% and we continue to expect to be in that 15% to 20% range for the full year 2021. We recognized $11 million of license and other revenue for three months ended September 30, 2021 including $9.8 million in milestone payments for managing following the July, 2021 approval of Selinexor for the treatment of patients with multiple myeloma and DLBCL in South Korea, and 1.2 million of revenue associated with named patient programs. R&D expenses for the third quarter of 2021 were $45.8 million compared to $37 million for the third quarter of 2020. The increase in R&D expenses as previously stated, on our Q2 call, was primarily attributable to the $7.4 million asset purchase of new medicines in the third quarter of 2021. SG&A expenses for the third quarter of 2021 were $35.1 million compared to $31 million for the third quarter of 2020. The increase in SG&A expenses compared to the third quarter of 2020 due primarily to an increase in personnel costs primarily related to an increase in headcount and compensation costs. Cash, cash equivalents, restricted cash investments, as of September 30, 2021, totaled $209.3 million compared to $276.7 million as of December 31, 2020. 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 that our existing cash, cash equivalents, 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 the middle of 2023. I'll now flip to slide 22. And turn the call over to Richard for some final thoughts. Richard?

Thank you, Mike. We are building off a very strong first nine months of the year. And as we move into the fourth quarter and beyond, there are a number of key near term catalysts and milestones for us to deliver on as we continue to strengthen our organization and deliver for patients with high unmet needs, as outlined on slide 23. In multiple myeloma, our focus remains on the continued enhancement and strong execution for our commercial organization to secure increased XPOVIO sales in the second line plus treatment setting. We are awaiting the completion of the review of the MA package in the EU based on the data from the phase three Boston study. We plan to initiate our phase three study of XPD in multiple myeloma later this year and all oral combination that would 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 or early next year, a market opportunity where there are no approved drugs in the maintenance setting, following chemotherapy in any line of treatment. We have additional Selinexor data in various hematological indications submitted to ASH 2021 and we look forward to announcing our selected abstracts tomorrow, Thursday, November 4. Lastly, we plan to host a virtual investor day on December 8 to review our strategic imperatives and pipeline priorities to support our continued evolution as a company. To close we're excited to continue delivering for patients who are fighting cancer across the world. 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 the call up to the question and answer portion of today's call. Operator?

Thank you very much. The first question comes from Mauri Raycroft from Jeffries, please go ahead.

Good morning everyone and congrats on the update today. Thanks for taking my question. So I was just wondering if you can talk more about what you're seeing in third line setting? What are the most common treatments that patients are coming off of before getting XPOVIO? And in that third line setting is it the Boston regimen that's being used? Or what else can you say about the combo preferences?

Thanks Mauri, maybe I will turn this to Sohanya to answer that.

Yes. Thanks, Richard. As you heard earlier, we're seeing an acceleration in that shift from later lines into earlier lines and our syndicated data indicates the strongest growth this year is in the third line setting. In terms of patient proportions, we see an approaching 50/50 split between patients in the second to fourth line and patients in the fifth line class setting. In terms of the overall treatment paradigm, most patients are treated with an image of proteasome inhibitor or an anti-CD 38 in the first or second line. In the later lines, we see several new competitors or classes in the mix. We believe we are strongly positioned in that middle section of second to fourth line where a class switch to an XPOVIO base regimen could be vital for the success of the patient. We're also highly effective in subgroups of patient types, such as high risk elderly and renal dysfunction. As we continue to look into the future we expect to see the sustained shift in the line of therapy from the later lines from the original Penta refractory indications to earlier lines in line with our Boston data, which launched at the beginning of this year.

That addressed your question Mauri?

Yes. That helpful. Maybe one quick follow up. In the last couple quarters you guys have reported metrics on refill rate, just in I'm not seeing in this update. Just wondering if you can comment a little bit on what you're seeing with refill rate?

Yes. Absolutely Mauri. So we are still in the early stages of the launch of the second line plus indication since the beginning of this year and this data is still maturing. We do have preliminary data that shows that more patients are staying on therapy longer. And this is driven by two factors, the shift into earlier lines, as well as better side effect management. As we evolve into earlier lines, we expect to see the duration increase driven by that shift into earlier lines and in line with our targeting positioning. However, we cannot definitively guide to a specific duration number at this time since we're in a dynamic phase of our transition into earlier lines of use and in an early stage of the launch. So we need to let that data mature.

Okay Makes sense. Congratulate and thanks for taking my questions.

Thanks Maury.

Thank you. The next question comes from Peter Lawson from Barclays. Please go ahead, Peter. Peter sorry to interrupt, if you don't mind just speaking up a bit because we cannot hear you. Your line is quite low.

Yes. Picked up my handset. Congratulations on the quarter and the drivers in 3Q kind of what we're continuing to 4Q? How should we think about that and to kind of what's left to accelerate revenue growth in 4Q and into 2022? Thank you.

Thanks, Peter. I will turn this to Sohanya on that.

Yes, thanks for the question, Peter. So we saw significant demand growth this quarter contributing to 32% quarter-over-quarter revenue growth and we feel very confident in our sustained growth. This was driven by strong execution and the new positioning we introduced in the second quarter in that whitespace of second to fourth line. Now in terms of drivers, there's these three key indicators. Number one is the acceleration of that shift into earlier lines. And as I mentioned, our syndicated data is indicating that strongest growth this year in the third line as well as that shift from the XPOVIO based doublet regimen to the once weekly triplet based regimen in line with our Boston indication and we expect to continue to see a shift in that line of therapy. The second driver is that expansion in the breadth and depth of use of XPOVIO. We're adding more accounts every quarter. And we're increasing our penetration at the top myeloma accounts. The most significant growth that we saw within the community setting and we expect to continue to see that in the future as well. Lastly, in terms of the qualitative market research as well as customer feedback that we're getting, we see a sustained improvement in the overall product perception and a growing confidence amongst physicians in managing this product with our new lower dose once weekly XPOVIO based triplet regimen. So as I mentioned, we are still in the early stages of the second line plus launch and we won't be giving sequential growth guidance but we remain confident in our ongoing efforts to drive increasing use in early aligns growth, position, confidence and XPOVIO and remain focused on very strong execution.

Great, thank you just with one time as in the quarter that we should be thinking about as we kind of grow revenues off of Q3.

No, no one time impact in the quarter.

Perfect. Thanks so much. Thanks for taking the questions.

Thanks, Peter.

Thank you. The next question comes from David Lebowitz from Morgan Stanley. Please go ahead, David.

Thank you very much for taking my question. Given that there's so much shift in the treatment paradigm for multiple myeloma, where does Velcade combination actually end up, I guess being most predominant will be in the second line or the third line, given that where Darzalex has been increasing its use. And beyond that, was there any inventory shifts or anything in the quarter on the wholesaler side?

Maybe I'll just start with – with Mike to talk on the inventory side. And then I can turn to Sohanya to talk about the utilization in that second to fourth line data.

Sure. On the inventory side, there was a minor drawdown in inventory in the quarter. But as you remember from last quarter weighed about a $2 million shift through the minor impact on the quarter. So we expect inventory to not have a meaningful impact on quarterly revenue going forward.

Yes. And as far as your treatment paradigm question, most patients, as you mentioned, are treated with an anti-CD-38 or PI in the first and second line. So following that and prior to the later line therapies, there is that significant unmet need where we have seen the most rapid growth in both second and third line for XPOVIO. Now, our sales and marketing teams will of course only promote to the FDA approved XPOVIO combination with Bortezomib and Dexamethasone, and we're continuing to see a rise in that triplet regimens in the third line and second line setting. However, NCCN also has other regimens onboard, XPOVIO in combination with pomalidomide and Dexamethasone and XPOVIO in combination with Daratumumab and Dexamethasone. And as I mentioned, we only promote to the XPOVIO combination in our FDA label. But we're seeing that that positive shift from the doublet late line setting towards that triplet setting in earlier lines in line with our Boston indication.

And Jason maybe just want to expand on that from your perspective.

Yes, absolutely. I think from the treatment paradigm perspective, we're seeing increased using a CD-38 based therapy in that first and second line as Sohanya mentioned. And so as these patients are either getting intimidated, plus the CD-38 Or a PI plus a CD-38 as they progress on that those therapies then come into third line, it starts really leveraging two principles that were very comfortable within myeloma, which is class switching. And so if they're on an image based therapy, then switching to PI based therapies such as Velcade becomes attractive and is based on kind of sound reasoning for the last 20 years of class switching. So I think that there's a strong degree of comfort around Velcade based therapies in the community for many years. And so as Sohanya mentioned, there's multiple options now for XPOVIO based therapy for what the physicians want to do. And they have that optionality.

Thank you for that. And shifting over to Eltanexor has selinexor been studied previously in MDS if you could remind us and what was the experience? And how would Eltanexor differ?

Great question. So selinexor has been evaluated in MDS previously. There was a phase 1 study – phase 1, 2 study done with Dr. of Memorial Sloan Kettering. There, they showed a proof of concept with activity with single agent selinexor in that setting and relapsed MDS with a response rate greater than 30%. So there is a proof of concept now with both selinexor and Eltanexor in MDs that provides that body of data and the confidence around compounds in MDS.

And the decision I guess to move with Eltanexor exogenous population was based on the tolerability?

Yes. So as we looked at the totality of the data, there are differences with Eltanexor were with the ability to give low dose continuous Eltanexor for five days in a row, we saw better activity in our early data with Eltanexor when you look at totality of data with selinexor and Eltanexor we made the decision to really develop Eltanexor in MDS in myeloid malignancies.

Got it. Thank you very much for taking my questions. And congrats on the quarter.

Thank you.

Thank you. The next question comes from Brian Abrams from RBC Capital Markets. Please go ahead Brian.

Hello, this is Leonid on for Brian, thanks for taking our question. Actually I wanted to stay with Eltanexor for a moment. So I'm curious what you guys are thinking about in terms of the regulatory and clinical MDS for Eltanexor kind of what you're hoping to see and how you're seeing this landscape evolve right now? I mean, is there potential for this to be a registrational trial given the unmet need? I'm just curious on your thoughts there. Thanks.

Yes. Great question. And so you as you know, this field of MDS is rapidly evolving. But what's clear is this right HMA therapies are the standard of care in first line. All the other drugs in development and there are no other drugs other than HMA based -- HMAs right now that are approved in MDS. Number two, when you look at all the other kind of study drugs that are being evaluated in MDS, those are all being evaluated in newly diagnosed MDS. So the field is actually not evolving in the relapsed refractory space. There are no drugs approved in the relapsed refractory space and there's really limited to no therapies being developed in that relapse space. So we look at the other most of the other studies, they're all in newly diagnosed. So that really leaves a very clear unmet need and an opportunity in the relapse space. And that's where we see a clear signal without Eltanexor in that setting. And so, as you look at the field in the relapsed refractory space, the field is not evolving as quickly as you would anticipate. And then I think maybe Jason, just expand on look at the evolution of the data. And with the study, how we would look at, positively engaging with regards to the FDA based on the outcomes or any of our data continues to hold off that's obviously a big impact for patients and positive for them.

Yes. Absolutely. There's a clear unmet medical need there. And when we look at the response rates that we see with Eltanexor, I think if we continue to see response rates in this range then these will be positive and we'll have discussions with the agency at that point in time.

Got it. Thank you.

Thanks.

Thank you. The next question comes from Eric Joseph from JPMorgan. Please go ahead Eric.

Hi, good morning. This is Hanna on for Eric, thanks for taking the questions. Just a few from us. So first, looking more closely at the new patient starts, are you able to see if there's any physician stickiness? Meaning like, are you seeing any formerly prescribing physician now prescribing Eltanexor for their patients in their earlier lines or are the majority of earlier line scripts coming from new prescribers?

Yes, thanks for the question. We're seeing a continued growth in new patient starts and that's driven by an expansion in both the breadth and depth of use. So there's new prescribers coming on board and trying XPOVIO for the first time as well as we're growing in depth. So there's prescribers that had used XPOVIO in the original later line indications and we're now seeing them growing in confidence in using it in earlier line. So we're seeing that shift into second and third line.

That address your question Hanna?

Yes, that addresses and then moving towards your recently initiated phase 2 trial on in combination with pembrolizumab for melanoma, just where and how do you see this combination fitting into the indication in the current treatment mostly?

Sure. I'll turn to Jatin on that.

Yes, no, absolutely. So great question around that. So we've seen some activity now as presented by the MD Anderson group looking at selinexor and pembrolizumab in patients with disease that's refractory to checkpoints. And based on early promising signals that we're continuing to really confirm the signal there for what the activity that we see with this combination specifically and checkpoint refractory disease in the field is evolving there, especially in checkpoint naive patients. I think there's still a clear unmet need and opportunity in patients who checkpoint refractory disease. And we're evaluating both those patients who have primary refractory disease or those who have a response and then become refractory as those who have two different biologies. And based on the data that will inform or guide us in terms of the next steps.

Great, thanks for taking the questions.

Thanks Hanna.

Thank you. The next question comes from Jonathan Chang from SVB Leerink. Please go ahead Jonathan.

Good morning and thanks for taking my questions. First question, can you remind me what data you have available that gives you color into what lines of treatment and combinations XPOVIO is being utilized?

Yes, as you know, it's very difficult to get an accurate picture of lines of therapy. But we do have syndicated data from payer claims data that gives us good coverage on our patients that indicates that shift in line of therapy.

Got it. And second question and this is a higher level question. Can you talk about how you're thinking about moving towards being a cash flow positive company in the future both on the revenue and expense side and how we should be thinking about your strategy in relation to your cash runway?

I think maybe I will just start off and obviously, as we look moving forward a number of catalysts, first is just continuing to drive our breadth and depth of multiple myeloma, and continuing to grow in multiple myeloma. And obviously moving forward I think, with our SIENDO study as we're talking to that being very near term and I think also, as you've heard from Jatin in that opportunity right now, that's an opportunity, which has a very different uptake, than you see in multiple myeloma, a much more rapid uptake, because there is no approved therapy for patients in this setting. And obviously, there's a big incidence population which would benefit pretty rapidly from, from having an improvement in the setting of actually having more time to extend in remission when you're looking endometrial cancer patients. And then continuing to build on that obviously was bringing other new indications forward. So driving our revenue growth is key. And I think also making sure that as we talk to you that we're very focused in terms of where we invest in terms of having the highest impact for patients, and the highest probability of success. And then on top of that Mike, talk to it. But you've heard some of the talk about our partner revenue and different areas that we're adding in terms of evolving our cash runway. Mike?

Sure. Yes. That's a good summary. Just to add I think, obviously on the inflow side our goal, with Europe, with potential approval in the first half of 2022, is to be commercially ready there, potentially with a partner. So that's certainly one source of capital coming in outside of traditional revenues or financing. We also have $40 million remaining on our healthcare royalty financing agreement as another tool in our belt. And as Richard said, and we'll give a lot more color that's in our R&D day and about a month on how we really focus on prior to prioritizing our investments in our pipeline.

Got it. Thank you.

Thank you. The next question comes from Colleen Kusy from Baird. Please go ahead Colleen.

Great, thanks so much for taking our questions. And congrats on the quarter. For the top line growth that you saw in 3Q, are you able to comment on between longer duration and new patients? What was more of a driver in 3Q and looking forward where you see the bigger opportunity for growth, whether it's adding new patients or prolonging the duration?

No, thanks Colleen. I'll just start at a high level but then turn it to Sohanya but again, I think it's a combination of both. As you heard Sohanya talk to you, we're going to continue to drive the breadth and depth as we move into earlier lines of therapy, which we've done very well in this quarter with the greatest growth being in through the year and that third line setting. And as we move up into earlier lines, patients have a greater duration of therapy. So it's both in terms of bringing new patients on board and earlier lines and having a greater duration of therapy through that the patient obviously benefiting in the earlier lines. Sohanya anything you want to add to that?

Well, I think that's a great summary, Richard. Yes.

Does that address your question Colleen?

Yes, it does. Thank you. And on the impact from COVID that you saw in 3Q, can you put that into context versus what you saw in 2Q and what your expectations after that in the coming quarters?

So I'll turn this to Sohanya on this.

Yes. So we saw an increase in 3Q field activity and an increasing proportion of our visits being in person versus virtual. But we have not returned to pre-COVID levels. Similar trend on patient visits while there's a gradual increase over time in patient visits that also has not returned to pre-COVID levels. At Karyopharm we have a nimble, dedicated, very patient centric team that is able to reach our prescribers to ensure they have the right education. We've also strengthened our digital capabilities to complement field efforts. So we are entirely focused on strong execution. We have to actively monitor the COVID impact and adjust our engagements as needed, but we remain focused on strong execution.

Great, thanks so much for taking our questions.

Thanks Colleen.

Thank you. We have no further questions at this time. I would like to hand back to Richard to complete. Thank you.

Thank you, operator and thank you again to everyone for joining our call today. Looking forward to continue to update you on our success as we continue to bring XPOVIO to more patients not only in multiple myeloma, but also in other key hematological indications and solid tumors with a high unmet need or we can make a significant impact to positively impact the lives of cancer patients. Thank you for joining us today and have a great day.

Thank you very much sir. You may now disconnect your lines.