Good afternoon. My name is Kate, and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics Third Quarter 2020 Financial Results Conference Call. [Operator Instructions] Please be advised that the call is being recorded by the company's request..

I would now like to turn the call over to Mr. Ian Karp, Karyopharm Therapeutics Senior Vice President, Investor of Public Relations. .

Thank you, Kate, and thank you all for joining us on today's conference call to discuss Karyopharm's Third Quarter 2020 Financial Results and Business Update. This is Ian Karp, and I'm joined today by Dr. Michael Kauffman, Chief Executive Officer; Dr. Sharon Shacham, President and Chief Scientific Officer; Mr. Mike Mason, Chief Financial Officer; Mr.

John Demaree, Chief Commercial Officer; Mr. Christopher Primiano, Chief Business Officer and General Counsel; and Dr. Jatin Shah, Chief Medical Officer..

On the call today, Michael and John will provide an overview of key recent corporate developments and an update on our commercial progress, and then Mike Mason will provide an overview of the third quarter 2020 financial results. We will conclude with the Q&A portion of our call..

Earlier this afternoon, we issued a press release detailing Karyopharm's results for the third quarter of 2020. This release, along with the slide presentation that we plan to reference, 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 provision under the Private Securities Litigation Reform Act of 1995.

These include statements about future expectations, clinical developments and regulatory matters and time lines, the potential success of our products and product candidates, including our expectations relating to the commercialization of XPOVIO, financial projections and our plans and prospects.

Actual results may differ materially from these indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent 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 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. In addition, please note any references we make to clinical trial data during today's discussion refer to interim unaudited site data, unless otherwise specified..

I'll now turn the call over to Dr. Michael Kauffman, Chief Executive Officer. .

Thank you, Ian, and good afternoon, everyone. I'm pleased to report that Karyopharm has continued to make tremendous progress so far in 2020 with the achievement of numerous commercial pipeline and operational accomplishments, positioning us well for what we believe to be continued and sustained future growth.

As we get closer to the end of 2020 and hopefully closer to an end of the COVID-19 pandemic, we are already preparing for numerous significant opportunities for our company and the patients we serve in 2021 and beyond. .

Before I begin, I'd like to take a moment to briefly put into some perspective a foundational and unique approach that we are taking towards innovating cancer drug therapies.

On Slide 4, we've highlighted 5 core pillars of cancer drug therapy, which are all foundational and used across tumor types often in combination to give each patient the best chance at clinical improvement..

XPOVIO is the first approved anti-cancer drug whose primary activity is the activation of tumor suppressor proteins.

There are about 20 of these proteins, including p53, BRCA1 and 2, Rb in the inhibitor of NF-kB, which are critical parts of each cell's own natural defense mechanism to prevent the generation of cancer cells and to direct the cell which has become cancerous to commit suicide..

This broad anticancer mechanism is potentially relevant to any malignancy. Our goal is to continue to demonstrate the impact that XPOVIO can have in combination with drugs from all of the other pillars in order to maximize the impact that XPOVIO could have on improving outcomes for a large variety of cancers..

Moving to Slide 5. I'll focus on our near-term and medium-term goals. First and foremost, we remain committed to increasing the positive impact we are having in the lives of patients battling cancer, and this is a core principle that guides everything we do at Karyopharm.

And as you may have seen in press release we issued this afternoon, we have just achieved another very important milestone with our announcement that the top line results from the Phase III SEAL study met its primary endpoint with a significant increase in progression-free survival in patients with unresectable dedifferentiated liposarcoma..

Additionally, over the next 1 to 2 years, there are a number of key goals that will be critical for us, including, first, securing the U.S.

approval for XPOVIO in second-line multiple myeloma, which we believe will help significantly drive total XPOVIO sales higher; second, receiving the initial approval for XPOVIO in Europe for patients with relapsed/refractory multiple myeloma; third, launching our first solid tumor indication in the U.S.

based on the data just announced; and fourth, continuing to generate supportive clinical data for our growing clinical portfolio, which includes XPOVIO, eltanexor and KPT-9274..

Looking a bit further out to the next 3 to 5 years, we anticipate that XPOVIO could be approved in multiple oncology indications across the globe with substantial revenue contributions from ex U.S. royalties and sales milestones.

This next chapter is also anticipated to bring continued expansion of our pipeline across multiple assets and, finally, the broad establishment of XPO1 inhibition as a core therapeutic approach in cancer treatment..

Please now turn to Slide 6, where I'll highlight the exciting news we announced earlier this afternoon regarding our randomized Phase III SEAL study. As a reminder, SEAL evaluated the efficacy and safety of single-agent XPOVIO in patients with advanced, unresectable dedifferentiated liposarcoma following 2 or more prior therapies.

Unfortunately, there is no standard of care for patients with advanced disease, and we are thrilled to announce that the study met its primary endpoint with a significant increase in progression-free survival and a hazard ratio of 0.7 with a p-value of 0.023..

We believe that these results not only represent a significant advance in the treatment of patients with dedifferentiated liposarcoma, but we believe these data further support XPOVIO's substantial potential across multiple solid tumors, representing a major advance for the development and commercial potential of XPOVIO in oncology more generally.

This is also consistent with other earlier-stage positive results from ongoing XPOVIO studies in diseases such as endometrial cancer, GBM, melanoma, lung cancer and others.

Liposarcoma also represents an important entry point for XPOVIO into the solid tumor treatment landscape where 9 of the top 10 most common and fatal forms of cancer are solid tumors..

We look forward to presenting the detailed results of SEAL at the upcoming Connective Tissue Oncology Society, or CTOS annual meeting. We plan to submit a new drug application, NDA, in the first quarter of 2021, requesting the FDA approval of XPOVIO to treat the patient population study in the SEAL Phase III trial..

Please now turn to Slide 7. Our clinical strategy for XPOVIO continues to be innovative -- to be innovating with a purpose.

Specifically, our approach has been to demonstrate meaningful activity in difficult-to-treat patient populations and then to expand dramatically into earlier lines of treatment and additional tumor types, particularly in combination with other anticancer drugs.

This strategy has been evident in our approach in both myeloma and DLBCL where we began with our successful STORM and SADAL studies and has led to subsequent development in earlier lines in combination settings..

Similarly, now that we have seen a positive Phase III SEAL data, we plan to follow the same path and continue with expansion our clinical development approach in a number of important and much larger solid tumor indications, including endometrial cancer with the SIENDO study, lung cancer, GBM, melanoma and others, which have been selected based on encouraging earlier clinical data and commercial potential..

Turning to Slide 8. I'll focus on other recent highlights. During the third quarter, we achieved record quarterly XPOVIO net sales of $21.3 million, the strongest quarter since our July 2019 launch in penta-refractory multiple myeloma. These results reflect a 15% increase compared to the second quarter of this year.

These strong results were driven by demand for XPOVIO in both new multiple myeloma patient starts and initial prescriptions in patients with relapsed or refractory diffuse large B-cell lymphoma..

For our pipeline progress, I'll remind you that the FDA recently accepted our supplemental new drug application seeking approval for XPOVIO for the treatment of myeloma after at least one prior line of therapy and has signed a PDUFA action date of March 19, 2021.

In addition to a decision by the FDA, we are awaiting a decision in Europe from the EMA on our MAA, seeking approval of XPOVIO for the STORM population..

In addition to the SEAL study, we also made important progress with our development programs in other solid tumors.

This includes several presentations of data at ESMO in September, which showed promising results for XPOVIO in combination with Keytruda for the treatment of melanoma and XPOVIO in combination with carboplatin and paclitaxel for the treatment of advanced or metastatic solid tumors..

Finally, on the financial front, we ended the quarter with a strong cash position of approximately $304 million that we expect will be sufficient to fund our plant operations into the second half of 2022..

I'll now ask John Demaree, our Chief Commercial Officer, to provide some additional details on XPOVIO sales performance during the third quarter.

John?.

Thank you, Michael, and good afternoon, everyone.

As Michael noted earlier, I am proud of the commercial momentum seen during the quarter, a direct result of the dedicated Karyopharm commercial organization that continues to drive our educational initiatives forward virtually and in person, where appropriate, in support of our greater multiple myeloma and diffuse large B-cell lymphoma communities of patients, families and caregivers..

On Slide 9, we outlined results for market research that highlight the key features of XPOVIO treatment that are resonating most with health care providers in helping to drive the increased usage of XPOVIO that we've now seen over the past few quarters.

Specifically cited are XPOVIO's rapid response data with some responses reported as early as 1 week as well as the positive STORM data that showed a strong objective response rate in very difficult-to-treat patient populations, which included 100% of patients being refractory to daratumumab and 57% having high-risk cytogenetics..

Next, physicians noted that XPOVIO is the first-and-only FDA-approved oral XPO1 inhibitor that selectively binds to and blocks XPO1 whose over-expression in cancer cells is increasingly being recognized as a core driver of tumor growth.

And finally, there is increasing recognition and experience that XPOVIO's side effect profile can typically be manageable and reversible with dose modifications in prophylactic treatments..

Slide 10 shows the positive and increasing quarterly sales and prescription trends for XPOVIO so far in 2020. The third quarter saw a 15% increase in both net sales and patient demand compared to the second quarter. Importantly, we saw a robust increase in new myeloma patient starts in the third quarter compared to the second quarter.

The majority of prescriptions for the quarter continue to come from multiple myeloma patients, but we did see important initial contributions from DLBCL patients as we continue to introduce XPOVIO to this segment of the market and build momentum in this new indication..

Slide 11 highlights the increase in new account growth for the third quarter, which jumped to 202 new accounts prescribing XPOVIO, bringing the total to 543 new accounts for the year. New accounts secured this quarter reflect multiple myeloma and DLBCL treating physicians.

These results are particularly promising as physician education in many geographies continues to be conducted via virtual and web-based tools due to ongoing restrictions related to the COVID-19 pandemic..

The graph on Slide 12 shows the prescription refill rate for XPOVIO over time for both the first and second refill for those patients eligible for these refills. These numbers remain stable for the third quarter but are significantly higher as compared to our initial launch period.

For instance, in September of 2019, which marked the first -- which marked the end of the first quarter that XPOVIO became commercially available, roughly 42% of patients were going on to get a second prescription. One year later, that number stands at 60%, a substantial increase..

These promising and increasing refill rates, coupled with an average of 2.9 treatment cycles per patient as of the end of September, further reinforced the positive feedback we've received from patients and physicians regarding their experience and usage of XPOVIO.

Importantly, the patient discontinuation rate due to side effects remains relatively low at 13%, which we believe is a testament to more and more physicians gaining comfort in helping their patients manage the side effect profile of XPOVIO with proper prophylactic therapies and dose modifications..

The third quarter of 2020 represented the first full quarter of our launch in relapsed/refractory DLBCL following approval in late June. On Slide 13, we're pleased to share preliminary launch metrics for this period, which showed 2/3 of prescriptions have come from community-based physicians.

Early retail trends have been strong as well at 60%, which matches what we've seen in the multiple myeloma space, and we were able to secure Category 2A NCCN compendia listing within 2 weeks of approval..

These efforts have translated into positive initial feedback from treating physicians and their patients. Based on our market research, target physicians are most attracted to XPOVIO's response rate as a single agent, oral option and the ability to treat DLBCL patients in a completely new way.

Additionally, we've seen positive payer dynamics with no on-label patient denials seen to date..

And finally, the feedback we are hearing regarding XPOVIO's side effect profile has also been positive with most physicians reporting the 60-milligram twice-weekly dose, the approved dose, being manageable for patients.

We will continue to fully leverage the newly approved indication in DLBCL to access our key stakeholders, educate on this new indication and also generate increasing excitement in multiple myeloma to help more patients impacted by these diseases..

Now I'd like to turn the call back over to Michael to discuss our regulatory updates and clinical development priorities.

Michael?.

Thank you, John. On Slide 14, I'll provide a brief update on our key upcoming regulatory activities. The positive results from the BOSTON study served as the basis for our sNDA submitted to the FDA for the treatment of patients with multiple myeloma after at least one prior line of therapy.

Our sNDA was accepted for filing in July with the decision expected by March 19, 2021..

In Europe, we've submitted the final additional remonitoring data from the STORM study requested by the EMA in September of 2019.

And in October 2020, Karyopharm received a further updated list of outstanding issues from the CHMP, summarizing the remaining topics for Karyopharm to address and indicating the CHMP intends to consult its scientific advisory group for additional advice. We continue to expect the decision from CHMP by the end of this year..

In addition, continuing upon and following receipt of CHMP's opinion, we expect to submit an MAA based on the data from the BOSTON study before the end of 2020. For DLBCL, we're still in the process of evaluating the optimal approach and timing of future regulatory submissions, and we look forward to providing you with an update in the future..

Please now turn to Slide 15. The potential expansion of our XPOVIO label based on the promising BOSTON data results represent an important turning point in the multiple myeloma treatment paradigm.

XPOVIO's current penta-refractory multi-myeloma indication is largely applicable to the approximately 6,000 patients in the United States who are treated in the fourth and later lines of therapy annually.

If approved, an expanded label based on the population studied in the BOSTON trial would expand XPOVIO's potential impact to over 30,000 patients annually in the U.S. treated in the second and third-line settings..

This slide highlights some of the key differences between the STORM and BOSTON population study and data generated from these trials.

As you can see, the patient studies in the BOSTON trial have been previously treated with far fewer therapies than the patients in STORM and had disease that was far less refractory to treatment, i.e., a median of 8 prior therapies in STORM as compared to 2 in the BOSTON study..

Subsequently, the response rate in median PFS in the BOSTON study was substantially higher than in the STORM study.

This was also driven by the mechanistic approach of combining 2 drugs with different and additive or synergistic mechanisms of action in the BOSTON study as XPOVIO, an XPO1 inhibitor was given in combination with once-weekly Velcade, a proteasome inhibitor, along with standard low-dose dexamethasone.

Importantly, the mean duration of treatment was 10 months in the BOSTON study as compared to 3 months in the STORM study..

This comparison of studies is key to why we believe XPOVIO has just begun to make an impact on the treatment paradigm in multiple myeloma.

We believe the greatest utility for XPOVIO in the future will be as combination therapy with other potent anti-myeloma drugs, such as Velcade and taken only once per week instead of the currently approved dose of twice per week..

And finally, I'd be remiss if I didn't mention some updates for a number of other exciting pipeline opportunities we're pursuing for selinexor, which can be seen on Slide 16.

In the hematologic malignancy space, we expect to dose our first patient by the end of the year in our confirmatory Phase III DLBCL trial, which will study selinexor in combination with rituximab and a chemotherapy regimen of gemcitabine, dexamethasone and platinum-based therapy..

We have also recently initiated 2 new trials in myelofibrosis where we have been encouraged by some smaller investigator-initiated studies, and we expect to begin enrollment in these new studies in 2021.

And as I mentioned earlier, we have a number of important ongoing studies in the solid tumor setting, both as a single agent and in combination, which followed nicely from the positive SEAL results we announced today..

With that, I'll turn the call over to Mike Mason to review the quarterly financials.

Mike?.

Thank you, Michael. Since we issued a press release earlier today with the full financial results, I will just focus on the highlights, which begin on Slide 18..

Net product revenue for the third quarter of 2020 was $21.3 million. Third quarter sales were driven by patient demand from academic and community-based physicians with channel inventory sales growing in line with actual prescription growth. The estimated gross-to-net discount for XPOVIO in the third quarter was approximately 16%.

We continue to expect the gross-to-net discount to fall between 15% and 20% through the remainder of the year..

Research and development expense for the third quarter of 2020 was $37 million compared to $26.3 million for the third quarter of 2019. The increase in R&D expenses compared to the third quarter of 2019 was mainly attributable to COVID-19 trial activity and continued activity in our other ongoing clinical trials..

SG&A expense for the third quarter of 2020 was $30.9 million compared to $25.3 million for the third quarter of 2019. The increase in SG&A expenses compared to the prior year was primarily due to activities to support the U.S.

commercialization of XPOVIO, including expenses related to the launch of XPOVIO as a treatment for patients with relapsed or refractory DLBCL..

As noted on Slide 19, cash, cash equivalents, restricted cash investments as of September totaled $304.2 million compared to $265.8 million as of December 31, 2019.

We currently project XPOVIO sales to grow modestly through the remainder of 2020 based on expected catalysts with more significant growth expected following the potential expanded approval of XPOVIO based on the results from the BOSTON study..

Based on our current operating plans, we expect our non-GAAP R&D and SG&A expenses for the full year 2020 to be in the previously projected range of $240 million to $260 million.

In addition, we currently expect that our existing cash, cash equivalents and investments and the revenue we expect to generate from XPOVIO product sales will be sufficient to fund our planned operations in the second half of 2022..

I'll now turn the call back over to Michael for some concluding remarks.

Michael?.

Thank you, Mike. Before moving to the Q&A, let me highlight some of the key clinical and regulatory milestones that we expect for the remainder of 2020, as shown on Slide 20..

As you can see, we have achieved many key milestones throughout the year but still have important goals to accomplish by the end of this year. First, we expect a decision from the EMA on the STORM MAA.

Next, we plan to submit the full BOSTON data to the EMA before the end of the year, continuing upon and following receipt of CHMP's decision on the STORM MAA. And finally, we anticipate initiating our confirmatory Phase III study of XPOVIO and DLBCL in support of our recent accelerated approval.

And of course, we'll continue to support the FDA through the review of our sNDA based on the BOSTON study where we expect a decision from the FDA on or before the PDUFA date of March 19, 2021..

We appreciate your ongoing support, and look forward to keeping you updated on our future progress. I'll now turn the call over to the operator for questions.

Operator?.

[Operator Instructions] Our first question is from Jonathan Chang from SVB Leerink. .

Congrats on the positive SEAL readout.

First question, can you talk about the dedifferentiated liposarcoma treatment landscape? How you see this commercial opportunity? And what, if any, read-through this has on your broader thinking regarding the solid tumor opportunity for XPOVIO?.

Sure. Let me dive in, and it'll be brief because we don't -- can't give a lecture on this. Unfortunately, the dedifferentiated liposarcoma landscape is only populated by parenteral chemotherapy cytotoxic agents.

Pretty much every patient will get anthracycline like Adriamycin in combination with gemcitabine or some other cytotoxic, and most patients will receive eribulin and/or trabectedin during their treatment course. Beyond that, there are really no other treatments that have clear documented activity and are routinely used..

XPOVIO potentially could be the first oral therapy approved in this indication. And furthermore, this is the largest study of liposarcoma ever performed. And I believe it's the largest dedicated liposarcoma study ever performed.

So we think we can really become one of the important drugs after chemotherapy is used and could provide a real -- better tolerated, we believe, oral option for these patients who are heavily pretreated. .

Got it. Just one follow-up question then on a different topic.

Can you provide additional color on the outstanding questions from the CHMP that you received in October, I think, you said?.

Yes, I'll turn that over to Dr. Shacham to comment. .

I'm sorry, Michael, can you start and I will follow up?.

Sure. So I believe the question was can we provide additional color on some of the questions from the EMA that they continue to ask us.

And I think as we've described previously, the EMA has requested additional information regarding some of the laboratory analyses in patients who are in the study, in particular some of the responding patients, and we've provided those to the EMA.

In addition, we provided -- as the EMA has asked us to continue to justify the benefit risk, we provided the BOSTON data in support of the STORM MAA application. .

Our next question is from Peter Lawson from Barclays. .

This is Mitchell on for Peter. Congratulations on the positive data. So the first question I have is for SEAL. The hazard rate came in like 0.7, or just wondering did the FDA say what would qualify as meaningful.

And how much do you beat those expectations by?.

The FDA doesn't say that. What they do, the -- both the FDA and EMA have provided advice, in particular, scientific advice from EMA and post-meeting advice from the FDA, considering that this trial could potentially serve as the basis for an approval.

And generally, that means that you have to hit the statistical boundary of 0.05, which we did, and that the trial has to be well conducted and internally consistent, which we also believe it has been. So we believe we've hit the appropriate goalpost..

I should also mention that the hazard ratio in the Phase II portion of this study was essentially identical to that in the Phase III. So the FDA was aware of that as was EMA. And they went into this Phase III expecting a hazard ratio of about 0.7, which is what it was designed for. .

Great. And then if you could just comment on discontinuation rate for the SEAL study.

Is that consistent with the 13% you've seen in the real world for myeloma? And then, what additional data should we expect at CTOS beyond PFS?.

Yes. I can't speak to the exact discontinuation rate, but I can say that it was -- these patients are not as heavily pretreated as patients with last-line myeloma. They also have much less systemic comorbidities that late-stage myeloma patients have. And one would expect the dropout rate, therefore, would be lower..

In addition, the dose here was lower. So you might look at the dose being used in the SEAL study was more similar to the DLBCL SADAL study. You'll see a complete presentation that as far as time permits at the CTOS. This will be given by our lead investigator, and it should be a full data set. .

Our next question is from Maury Raycroft from Jefferies. .

I'll offer my congrats on the liposarcoma data as well. I'll ask a question about myeloma. So for XPOVIO in 3Q and also DLBCL too, can you talk about the COVID impact? And for new myeloma patients, what line of treatment are you seeing with some of the new patients? And if you can break out combo preferences as well..

And then you mentioned the average treatment cycles per patient at 2.9. Just wondering if you expect that to continue to increase in the current market opportunity in the last-line setting. Or do you see it leveling off around 2.9? And then when you get into the expansion with the earlier-line patients, that number could potentially go up. .

Wow, Maury, that was quite an encyclopedia. So I'll ask John Demaree, our Chief Commercial Officer, to begin to address that, and we'll keep our -- we'll keep it a little bit short. But go ahead, John. .

If I miss any of those, keep me honest. But let me answer the one about BOSTON first. And are we seeing XPOVIO use with Velcade in earlier lines of therapy. Currently, the majority of use for XPOVIO is in fourth-line plus, as indicated. We obviously do expect that to move earlier once the BOSTON indication in combination with Velcade is approved.

We do know from our market research that many of the academic and community-based physicians are prescribing XPOVIO in combination with other drugs. So it's not just XPOVIO plus dexamethasone, but they're using it primarily in that fourth-line-plus setting now currently where it's indicating.

Again, we do expect significant acceleration in earlier lines of usage once we get the new indication for patients with approval, one prior line of therapy..

In terms of second question around the impact of the pandemic. We do think the pandemic does still continue to have multiple effects. In-person visits by our sales force, nurse liaisons and payer teams to our key stakeholders continue to be impacted. Our data and research suggests about 15% to 20% of HCPs can be seen via in-person visits..

We do continue to believe it's harder to appropriately educate changed behavior in a virtual environment as compared to maintaining prescribing habits like the goal of more established brands.

We have done and are doing a number of initiatives to offset the impact of being virtual, including increasing peer-to-peer education, increasing other nonpersonal promotion and digital content, training our field teams on how to be more effective in the virtual environment and, finally, targeting some large physician networks and their EMR systems to better identify patients in the penta-refractory setting..

So it's 2 of the questions.

What were the other questions?.

I think one was about the average duration of treatment with a number of cycles. And maybe what I would just say there is, yes, I mean, we're close -- we're at 2.9 through the end of September, which we're excited to be at that level, a little bit over a year into the launch.

I think to some extent, as we get closer and then into the launch in the BOSTON population, that number will hopefully go significantly higher because, as Michael mentioned earlier, the average duration of treatment on BOSTON or the mean duration of treatment in BOSTON was 10 months versus 3 months in STORM..

So potentially it could go a little bit higher, but I think the reality is we're going to come up pretty soon to hopefully at BOSTON approval. And then I think patients who will be getting treatment much earlier with XPOVIO, hopefully will stay on drug and be treated for longer. .

Our next question is from Brian Abrams from RBC Capital Markets. .

Congrats on the SEAL data. I'm curious how frequently physicians are looking to use XPOVIO in earlier-line myeloma post the BOSTON presentation, but maybe can't do to access. And the degree to which inclusion in NCCN guidelines might open up earlier-line access even prior to label expansion.

Any update on timing there or timing for the BOSTON publication?.

Yes. Well, we do expect the Boston publication to come out soon, hopefully, before the end of the year, but maybe sooner. We don't know exactly, but they will be published in a good peer-reviewed journal. And that will hopefully facilitate an NCCN guideline addition. Again, the speed of that addition, we don't know..

There -- our expectation is that there are not insignificant number of places where you can use the NCCN guidelines as a basis for insurance coverage, which is the major impediment right now to earlier-line adoption.

We believe that this combination of selinexor, XPOVIO plus Velcade dex once a week is actually the simplest of all of the regimens for relapsed/refractory myeloma patients with one prior therapy and, therefore, could be really beneficial to folks.

So we're hopeful that we can facilitate access once the NCCN guidelines come out and then, of course, ultimately through the FDA approval. .

Got it. And then just as a follow-up, you mentioned some of the continued multiple effects that the pandemic is having. Looking forward, I guess, in the near to medium term, I'm curious your expectations for the second or even third wave of COVID that we're seeing may impact near-term use and uptake.

I guess I'm wondering if you'd expect continued challenges to physician and patient engagement. Or conversely, if you might be able to take advantage of some of the benefits of oral administration and perhaps fewer facilities available for administration of CAR-T and DLBCL. .

So I think the answer to your question is, yes, there are opportunities and there are challenges in the current COVID situation. Obviously, for many patients, an oral therapy is preferred, particularly with less visits during the time of peak pandemic impact. I think it is also, as you mentioned, more difficult to engage physicians in person.

We have tried to offset that and are continuing to do more and more to offset in terms of some of the digital nonpersonal promotion initiatives that I Just mentioned earlier. .

Our next question is from Eric Joseph from JPMorgan. .

First, in relation to the SEAL and the liposarcoma opportunity, I'm curious to get a sense of whether you see an opportunity to advance selinexor earlier up in the treatment paradigm for liposarcoma, either as an alternative to chemo or as maintenance and whether that's strategically of interest. And then I have a follow-up on XPOVIO. .

Well, liposarcoma is a relatively small population in the dedifferentiated type in around 2,000 patients per year. It's obviously an important disease and needs addressable therapy.

There's been a good bit of interest from various groups given the SEAL data, which, of course, they just heard about, and we expect to continue additional studies in earlier lines probably with outside groups, if you will. Part of that is because we want to focus our internal resources in some of the larger tumor groups that were showing activity..

Our SIENDO study is ongoing. For those who don't recall, this is a Phase III randomized blinded study of once-weekly selinexor versus matching placebo in patients with endothelial cancer who received frontline chemotherapy, typically a platinum-taxol caplet and then have at least a partial response, which is approximately 80% of these patients.

And then right now, there's no maintenance therapy for those folks, unfortunately. And we know that essentially, all of them will relapse. So we're conducting SIENDO study in the maintenance setting after first-line chemotherapy in that group..

And that's a big focus. That study is ongoing. We expect data within -- before the end of next year, and that's a fairly substantial-sized population with the big unmet medical need. So that will be our next big focus in solid tumors.

And then, of course, you heard about some of the earlier data at ESMO that we mentioned and some of the other places in GBM where we've shown clear single-agent activity, which we intend to pursue..

So we're going to try to move in all fronts, but we'll take advantage of our CRADA with the NCI and other external groups that have shown interest to move in the sarcoma area. .

Got it. That's helpful. And maybe just a question on XPOVIO commercial, if I could. It sounds like you had pretty good visibility on where demand is coming from between myeloma and DLBCL. I'm wondering if you could just unpack how much demand -- how much strip demand is actually coming from DLBCL..

And I'm also just trying to just square some of the conservative expectation in terms of growth for the balance of the year.

Do you -- I guess, how much of a growth opportunity do you see in third-line DLBCL? Are you seeing kind of competition from other agents in the community setting? How much of a growth opportunity does third-line DLBCL sort of represent near term?.

So to address the first question, for competitive reasons, we don't break out sales separately between multiple myeloma and DLBCL, but we can tell you is that the majority of prescriptions in the third quarter came from multiple myeloma. The DLBCL patients were an important contributor that we believe will continue to grow over time. .

Yes. And just in terms of the competitive landscape and growth moving forward. I mean, I think we've mentioned a few -- I think we've been as transparent as we possibly can be, which is we're certainly quite pleased that we grew 15% quarter-over-quarter this quarter. The myeloma metrics continue to look good.

And obviously, we're starting to get contribution from DLBCL, and we balance that with -- we're still in the midst of a COVID pandemic, which does create some challenges. And as you mentioned, obviously, there are some new competitive entrants, particularly in the DLBCL space..

But we also have a number of catalysts that we're expecting, and we'll see when those come in, including publication of BOSTON data we talked about, NCCN guidelines we talked about and the actual DLBCL launch gaining momentum. So all of those create sort of pushes and pulls..

I think, ultimately, we continue to keep our eye on the BOSTON submission and working with the FDA in that piece as well as in Europe because we know that clearly, the biggest driver of growth in the near term is going to be upon a BOSTON approval and our ability to sell into second-line multiple myeloma.

So those are really the things that we think drive growth over the next 3 to 6 to 9 months, and we look forward to keeping abreast of all those things. .

Our next question is from David Lebowitz from Morgan Stanley. .

Given that prescription demand increased from 12% to 15% from second quarter to third quarter, sales growth ultimately stayed pretty similar between the 2 quarters, how is the cadence of those prescriptions relative to sales over the quarter? And what dynamics, I guess, are at play causing the conversions?.

Yes. I think if the cadence is on a quarter -- I mean, on a monthly basis, yes, that's not something that we typically disclose on a monthly basis.

I think in terms of where the scripts are coming from, certainly in DLBCL, they're largely coming from the community-based physicians, which is a little bit different than I think some of the early uptake we saw in multiple myeloma, which was coming from both large academic sites as well as with some community-based sites as well..

I think that was your question. If I missed it, John, I don't know if you want to add anything to that. .

I thought that was the question as well. .

And with respect to the liposarcoma data, given, I guess, specifics regarding that tumor type, how does that, I guess, give you confidence going forward with respect to other solid tumors?.

Well, I think I've said before, there are similarities and differences. And every tumor type is different. The fact that virtually, there are really no very effective drugs in liposarcoma. And thankfully, we have eribulin approved, Anthracyclines are generally approved, and trabectedin..

But these are chemotherapies that are essentially all cytotoxic agents. It's -- these are large tumors. They're difficult for drugs to access. And the fact that we could show a real benefit was, in the third line, a very difficult population following at least 2 chemotherapies, we think is very important for -- leading to other solid tumors..

These data show that XPOVIO clearly penetrates large masses. It can go in. It can slow tumor growth. We'll see about some responses, perhaps, which are quite unusual in this tumor, particularly in the second and third-line setting, especially for an noncytotoxic agent. And hopefully, this gives those patients an oral option.

But it does speak to the fact that this drug can penetrate into solid tumors, particularly connective tissue, which tends to be more difficult..

So its -- positive results are always beneficial in cancer. This represents our third disease type and quite different from the hematologic disorders that we've talked about before. We think this provides a great foundation.

It also helps solidify some of the early data we've seen in combination that's been reported from the ESMO place and in other studies. .

Our next question is from Mike Ulz from Baird. .

Congrats on all the progress as well. I just had a follow-up on an earlier question related to the SEAL data. Just wondering if you could maybe comment a little bit further on the safety profile you're seeing there beyond discontinuation rate and maybe how that compares to the label.

Just trying to get a sense if there's anything notably different there that we should be looking for. And then I have a quick follow-up. .

Sure. What we can say is kind of what we said in our press is that we see a safety profile that's consistent with what you've seen before qualitatively. Quantitatively, it tends to be substantially less, particularly on the cytopenias. Remember, these patients are coming in with only 2 prior cytotoxic therapy. So not a lot of marrow suppression.

They don't have disease in their bone marrow..

Bottom line is they have a much healthier marrow than the kinds of myeloma patients that we've treated, even on BOSTON, even as compared to BOSTON. So you expect a lot less cytopenias, which is what we saw..

And frankly, unfortunately, because these tumors are in the abdomen and can often compress GI structures and the like, these patients often come in with baseline nausea and fullness and abdominal pain, which may or may not get better or worse on XPOVIO. So expect higher baseline levels of nausea.

But basically, this looks like selinexor without cytopenia. .

Got you. That's helpful. And then just a quick follow-up. You mentioned a couple of other opportunities in solid tumors, and this liposarcoma kind of gives you more confidence there.

Maybe you could just talk a little bit about time lines for some of these other tumor types or your strategy in some of these tumor types?.

Yes. I think in 2021, we're going to be elaborating some additional studies. We already have ongoing a Phase I combination study of selinexor plus docetaxel Phase I/II, I should say, was seli plus docetaxel based on some not-yet-public data from an investigator-sponsored trial by the atomic group.

This is in patients non-small cell lung, both KRAS mutant and KRAS wild-type previously treated non-small cell lung cancer where we were seeing some interesting things, and we want to recapitulate that in the company's hands..

We have studies ongoing in GBM, where we have announced and we'll continue to update on a single agent, approximately 10% bonafied response rate in temozolomide radiation relapsed or refractory GBM patients that have a dire prognosis..

We have data with a bunch of different solid tumors with -- in combination with platinum taxol, including in patients who've already seen platinum and/or taxol. And we'll be moving on some of these, both internally and again through our NCI collaboration going forward, more in 2021 on those..

Lastly, we got very exciting data, and our investigators are quite excited about the potential combination with Keytruda. Amongst 9 patients with untreated melanoma, we saw a 55% response rate, including 2 CRs, in that initial study.

And importantly, there were no major autoinflammatory side effects recorded, which is quite distinct from similar multi-immune modifier combinations. And if we're able to combine with Keytruda in melanoma, that opens up possibilities in other tumors.

But importantly, it may open up those possibilities in melanoma and other tumors without the major auto-inflammatory side effects that some of the sort of Opdivo plus urivoid types of combinations can deliver. .

Our next question is from Ed White from H.C. Wainwright. .

Congratulations on the SEAL data and just a couple of questions on solid tumors. So you had mentioned the GBM study and the Phase I/II trial. The first patient was enrolled in June with this large 400-patient trial. I'm just wondering how the enrollment is going in that.

Has it been impacted by the pandemic? When can we see data?.

And then second question is just what are your thoughts on the launch strategy in solid tumors? So liposarcoma is small.

What is your strategy for hiring a sales force? How many people? And how do you build up in solid tumors?.

Sure. So I'm going to ask Dr. Shacham to take the first question about the corona on the GBM study.

Sharon?.

The study has 3 arms, including 2 arms in patients with GBM that are newly diagnosed and then another arm looking at patients with a relapsed-refractory disease.

And enrollment is going well in all arms with a 3-plus-3 design, and we don't see any impact from the corona study and enrollment for this study, the sites engaged, and the study is moving forward. .

And then, yes, maybe just quickly on the solid tumor side of things. I think certainly, within the liposarcoma space, the vast majority of patients in the U.S. will be treated. And first, with all sarcomas are treated at centers of excellence across the U.S. There's probably about 90 or so of them total.

And then you can narrow that down to probably 30 or so that are seeing the lion's share of patients here in the U.S..

That's something we could certainly do from a commercial standpoint with a handful of folks, whether those are medical science liaisons or sales reps or a combination. But that's certainly a fairly straightforward call point at the centers of excellence..

As you start to get out to the endometrial cancer study, the SIENDO study, knock on wood, should that study be positive, that's obviously a much larger solid tumor indication. These patients are seeing that vastly a significant number of sites. So we'd have to take a look at what that commercial model looks like and make a decision.

But certainly, that would be a terrific issue to have to think about how we would commercialize in endometrial cancer. .

And we have a follow-up from Peter Lawson from Barclays. .

Just congrats on the sarcoma data.

And will you be able to submit that to the EU? Or would you need a different trial? And how should we think about the patient that you can initially treat with that -- using that data as a label?.

Well, this trial did receive positive expert advice from the EU scientific -- from their scientific advice group. So it's been -- it was discussed with them. It was approved with them. And we do believe it could serve for approval in the EU.

The on-label indication there would be patients with dedifferentiated liposarcoma that have received 2 prior systemic therapies, at least 2 prior systemic therapies. .

And what number of patients -- because there's around 2,000 patients.

what's [indiscernible] we'd be thinking about?.

That's the way -- yes. .

Okay. And then on the endometrial, is that the next data after sarcoma? Or what should we think about as the next solid tumor data... .

Well, in terms of randomized Phase III data, yes, I can say with a little tongue and cheek, it's hard to -- these are huge trials. It's hard to conduct a lot of them, especially the company our size, but yes, that is the next one, and that should be out by the end of next year.

We have updates during the year with other combinations, including in both hematologic and solid tumors as well as potentially data within the next year, say, in myelofibrosis and other areas. .

Got you. And then just on multiple myeloma DLBCL.

Do you get a sense of the duration of treatment in multiple myeloma or DLBCL?.

Well, I mean, we're at about -- I mean, across our specialty pharmacy network, it's about 3 months on average per patient. Now again, DLBCL just started. So those patients are not at 3 yet. And you'll have patients out for 10, 12 months, some longer, and you'll have patients that don't get a response after 1 or 2 months..

But the average right now is about 3 months. And it's been climbing.

Someone asked an earlier question, how much higher can it go? We think it's probably going to go a little bit higher, but it probably can go substantially higher once we -- if and when we get the BOSTON indication because those patients in the second and third line, obviously, stay on drug for much longer periods of time. .

Great. And just a final question, just around guideline changes.

When do you think that happens?.

I assume you mean for myeloma. The way it works procedurally is you have to have a publication. We believe that publication will be out before the end of the year. There will be a publication in a peer-reviewed journal coming out.

That will be submitted to the NCCN committee, and they will determine the timing of when -- if and when they add the regimen to their recommendations. .

Could that be year-end? Or do you think that kind of is more of a 2020... .

Naturally. It really depends on the publication. It could be. It depends on the publication timing and the timing of the NCCN committee..

In addition to BOSTON publication, we will be submitting the other single-arm study results, particularly with daratumumab, Kyprolis and Pomalyst, and those could potentially follow. But all of this is dependent upon, of course, publication and NCCN adjudication..

Well, thank you, everybody. I appreciate your following with us, and we look forward to talking to you again in the near future as fast. .

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect..