Good morning. My name is Guru and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics Third Quarter 2023 Financial Results Conference Call. [Operator Instructions] I would now like to turn the call over to Elhan Webb, Senior Vice President of Investor Relations.

Thank you. And thank you all for joining us on today’s conference call to discuss Karyopharm’s third quarter 2023 financial results and recent company progress. We issued a press release this morning detailing our financial results for the third quarter 2023. This release, along with a Slide presentation that we will reference during our call today, are available on our website. For today’s call, as seen on Slide 2, I am joined by Richard, Reshma, Sohanya and Mike, who will provide an update on our results for the third quarter and recent clinical development. Before we begin our formal comments, I will remind you that various remarks we will make today constitute forward-looking statements, FLS for the purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995, as outlined on Slide 3. Actual results may differ materially from those indicated by these FLS, as a result of various important factors, including those discussed in the Risk Factors section of our most recent 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 FLS represent our views as of today only. While we may elect to update this FLS 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 FLS as representing our views as of any later date. I will now turn the Slide over to Richard. Please turn to Slide 4.

Thank you, Elhan. Good morning, everyone and thank you for joining Karyopharm’s 2023 earnings call. Turning to Slide five, we are strongly positioned for our next stage of growth driven by our focused and rapidly advancing mid and late-stage pipeline of innovative first in class, oral selective inhibitors and nuclear export, their target XPOVIO1, as well as a strong commercial organization that continues to positively impact the lives of multiple myeloma patients every day. Our U.S. and global commercial presence are on track to deliver $145 million to $160 million of annual total revenues in 2023. And provides us with the capabilities needed to launch in new indications. If approved. Following the outcome of our three pivotal Phase 3 clinical trials. We have the opportunity to significantly improve standard of care for patients across these indications. And we continue to generate compelling data, including impressive durability data observed with selinexor 60 milligrams in combination with ruxolitinib in patients with myelofibrosis, as well as the substantial progression free survival observed in patients with the TP53 wild-type endometrial cancer, which Reshma will expand upon shortly. We are committed to deliver on the opportunities ahead of us and believe selinexor could generate approximately $2 billion of peak annual revenues in the U.S. alone. With a cash runway through late 2025. We have the financial strength to deliver on key data readouts from our three Phase 3 studies. We will continue to be disciplined about our expense management, focusing our resources on our prioritized late-stage pipeline. As we move to Slide 6, presented here is an overview of the timing of the upcoming key data readouts, which we expect in 2024 and 2025. Each of our ongoing Phase 3 clinical trials, if successful represents an incredibly meaningful growth opportunity for our organization, with the potential to deliver at roughly $2 billion in annual peak revenues. Our proven and established commercialization and late stage development capabilities are focused on executing with our current label, and rapidly progressing these pivotal Phase 3 programs and approval and just one of these in three indications is a transformational opportunity for Karyopharm. And the clinical data that Reshma will review today continues to strengthen our confidence in each of these programs. With the potential for pivotal catalysts over the next two years, and with the cash runway to deliver on each of these top line readouts. We are well positioned for our next stage of growth. Moving to Slide 7, I would now like to turn the call over to Reshma to expand further on our clinical pipeline, progress, Reshma.

Thank you, Richard. Turning to Slide 8, we have a very promising late-stage pipeline with pivotal data readouts over the next two years, I will focus on our three Phase 3 trials where our confidence only grows given the positively evolving preclinical and clinical data that support each indication. Each of these trials could position selinexor to substantially change the treatment paradigms in each of these populations, if approved. Turning our attention first to myelofibrosis on Slide 10. Treatment of JAK naive myelofibrosis patients remains an area of high unmet need with more than 20,000 myelofibrosis patients in the U.S. alone. Ruxolitinib remains the standard of care for the majority of JAK naive patients. However, there is an opportunity to improve benefit given that the efficacy with Ruxolitinib is limited with less than 50% of patients achieving an SVR35 and TSS50. We are evaluating the potential for selinexor in combination with Ruxolitinib to provide benefit across all of the hallmarks of the disease including spleen reduction, symptom improvement, disease modification and stabilization if not improvement of cytopenias. On Slide 11, you see that XPOVIO1 inhibition is a fundamental mechanism in myelofibrosis, given that it targets both JAK and non-JAK pathways, underscoring selinexor’s additive or potentially synergistic activity when dosed in combination. Non-JAK mechanisms include inhibition of NF Kappa Beta, induction of cell cycle PH] arrest and P53 driven cell death. Together XPOVIO1 inhibition increases malignant cell death, decreases malignant cell proliferation and reduces inflammation. We presented updated Phase 1 data at the ASCO and EHA conferences in June, 2023 which can be seen on Slide 12. These data show meaningful SVR35 and TSS50 improvement with 60 milligrams selinexor including a 79% SVR35 and a 58% TSS50 at week 24 in the intent to treat populations. Importantly, amongst the valuable patients…

Thank you, Reshma. And good morning, everyone. On Slide 26. I'm pleased to present the progress we have made in our third quarter performance as we delivered sequential growth in net product revenues over three consecutive quarters in 2023. In an increasingly competitive landscape, and amidst high utilization of free drugs through our patient assistance program, XPOVIO delivered $30.2 million in net sales in Q3. And when compared to Q3 of last year. Net sales were adversely impacted by higher utilization of our patient assistance program due to the impact from myeloma foundation closures, as we have previously discussed. In the third quarter, two of the four main multiple myeloma foundations were open and continue to remain open. As a result, new patients entering PAP have largely normalized although we saw the refill impact of patients already in PAP earlier in the year. Total PAP utilization contributed to 9% of total demand in Q3, 2023 versus 4% in Q3, 2022. As we've mentioned before, in 2024, due to the IRA related changes in the design of Medicare Part D, which will eliminate the patient burden of the 5% beneficiary coinsurance requirement. We expect significantly less need for Medicare Part D patients to utilize PAP for copay assistance. Additionally, net revenue was impacted by two points higher year-over-year gross to net in the third quarter, driven by increased Medicaid rebates and 340B discounts. Total demand year-over-year declined 3% when compared to Q3 of last year, which was our strongest quarter thus far. Total demand growth year-over-year for Q3 was negatively impacted by increased competition in the late lines in the academic setting. In the earlier lines, we continue to make strong progress. In Q3, 2023 XPOVIO a new patient share mix was greater than 60% in the second to fourth line,…

Thank you, Sohanya. During 2023 we have further reduced our cost structure to focus resources on our pivotal Phase 3 trials. And in August, we reduced our workforce by approximately 20%, including contractors. These steps further strengthened our financial position to invest in our three ongoing Phase 3 studies with top line data readouts expected within our cash runway. Now on Slide 29, I will focus on the quarter’s financial highlights. Total revenue for the third quarter of 2023 was $36 million, compared to $36.1 million for the third quarter of 2022. Net product revenue from U.S. commercial sales of XPOVIO to the third quarter of 2023 was $30.2 million compared to $32 million for the third quarter of 2022. As Sohanya discussed, net product revenue continued to be adversely affected by more patients using our patient assistance program, as well as higher gross to net discounts. Growth connect discounts were 20% in the third quarter of 2023, as compared to 18% in the third quarter of 2022. Turning to costs with our continued focus on cost management, we are pleased to be delivering a combined 12% year-over-year reduction in our R&D and SG&A expenses for the nine months ended September 30th, 2023. R&D expenses for the third quarter of 2023 were $35.6 million, compared to $31.4 million for the third quarter of 2022. We expect fourth quarter 2023 R&D expenses to be relatively consistent to the third quarter as we continue to invest in our three ongoing Phase 3 studies, with each representing a large addressable market with unmet patient needs. We have reduced SG&A expenses in the third quarter of 2023 by 12% at $30.8 million, compared to $34.6 million for the third quarter of 2022. Cash and cash equivalents restricted cash in investments as of September 30th, 2023 totaled $209.2 million compared to $279.7 million as of December 31st, 2022. Based on our current operating plans, we are reaffirming revenue guidance for the full year of 2023 as follows, total revenue expected to be in the range of $145 million to $160 million. XPOVIO net U.S. product revenue is expected to be in the range of $110 million to $125 million. We're also reaffirming our expense guidance for the full year of 2023 as follows, non-GAAP R&D and SG&A expenses which exclude stock-based compensation expense is expected to be in the range of $240 million to $255 million. And importantly, coming to our cash guidance, our existing cash, cash equivalents and 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 through late 2025, excluding maturity of our convertible bonds in October of 2025. I'll now turn to Slide 30. And some final thoughts from Richard.

Thank you, Mike. Turning to Slide 31. As we have discussed today, we are rapidly advancing our pipeline, concentrating our investments in three Phase 3 programs that are expected to read out through ‘24 and ‘25. As we work to create near and long-term value for all our stakeholders. We are well prepared for the next stage of growth as we continue to expand on our foundation in multiple myeloma. With our proven commercialization and late-stage development capabilities. I would like to thank our teams who continue to execute in a disciplined manner, and who strive each day for patients with high unmet needs. Thank you again for joining us today. And I would now like to ask the operator to open the call up to the Q&A portion of today's call. Operator.

[Operator Instructions] The first question comes from Peter Lawson with Barclays. Please go ahead.

Hi, good morning. This is Shea [ph] on for Peter, thanks for taking our questions. Congratulations on the new IMF data. Today maybe they'll contextualize for us as we think about getting that top line data from Phase 3 in 2025. Maybe what the more appropriate bar is to be looking at rather than just JAK inhibitor monotherapy. And then secondly, just a quick add on question for [indiscernible], I believe we're potentially going to get an update on development plans here. Is that still on track or something we could learn about more in this quarter? Is it something we should be thinking of deprioritized for Karyopharm at this point? Thank you.

Thanks Shea, for your question. I will turn to Reshma for this, Reshma?

Yeah. Thank you. Shea, a lot of excitement around, the new MF data that we are presenting today at the NPN Congress in New York. It only builds upon the impressive efficacy that we see with the combination of selinexor and ruxolitinib in this JAK naive patient population. As you mentioned, we've already presented data at week 24, for both SVR as well as TSS50 79%, SVR rate as well as a 58% TSS50 rate. What patients and physicians really want to know is that how long are those SVR and TSS data or response is going to last. And that's the durability data that we're presenting today. And what you see is a very impressive durability for both of these endpoints. In fact, as of the data cut off of August 1st, none of the patients experienced a radiographic progression for either SVR or TSS50. This would again, just build upon the body of evidence that really suggest that this combination could be a game changer for patients who are JAK naive myelofibrosis. And we'll continue to evaluate this as part of our Phase 3 study right now. The focus is very much on SVR, TSS50 at week 24. But as you mentioned, we'll continue to look at durability as well as multiple other efficacy endpoints that are relevant to this patient population. In regards to your question about the appropriate comparator, it still remains ruxolitinib. So, ruxolitinib is the standard of care for patients who are JAK naive myelofibrosis who have platelet counts above 100. So, the study design is appropriate and evaluates again, the efficacy with this combination relative to the current standard of care. In terms of your question about eltanexor, great question. Very enthusiastic about those data as well specifically observed from the phase one phase two study. We have been evaluating eltanexor in a very hard to treat patient population specifically relapsed refractory higher risk MDS patients, overall survival is very poor in this patient population around four to six months. And as we've disclosed previously, the survival that we've seen as part of both the Phase 1 and Phase 2 are very encouraging, right, nine-to-10-month median overall survival. We are in the process of optimizing our next steps in this program, and look forward to updating everybody probably around the Q4 call.

Was there a follow up, ma’am?

Okay, thanks so much.

Thank you. The next question comes from Maury Raycroft with Jefferies. Please go ahead.

Hi, good morning. Congrats on the progress. And thanks for taking my questions. I was going to ask one on endometrial. So, for selinexor as maintenance and endometrial. When do you think you could show the initial overall survival data from the SIENDO Phase 3 study? And then also separately, how is the export Phase 3 in the TP53 wild-type patients enrolling? And do you have a sense of how many patients are getting anti-PD1 therapy with chemo upfront? If you can provide any perspective on that?

Yeah, great question. Maury. So, as you know, so we continue to follow overall survival. We are very excited; we are going to be presenting overall survival data for the first time from the SIENDO trials specifically from the P53 wild-type subgroup later this year. So, more to come in the next couple of months. Obviously, a key endpoint in addition to the progression free survival, some more to come over there. In terms of the question around the PD1 inhibitors in combination with chemotherapy. So there is a new standard as I mentioned on the call, it is Dostarlimab in combination with chemotherapy followed by Dostarlimab maintenance. Keep in mind that the approval is only for patients who are MMR deficient, so they represent the minority of patients and only 20%. The remaining patients who are PMMR are proficient in their MMR as well as TP53 do not have a new standard of care, continues to remain chemotherapy followed by watch and wait.

Got it. That's helpful. And any other perspective into enrollment and how that's going. And then also wanted to ask a separate question on multiple myeloma commercial. You said there were approximately 20%. There was 20%, year-over-year growth in second line to fourth line new starts. Can you give us some color on how repo rates have evolved, specifically in these early line patients, versus when you were just in the later line setting?

And maybe I'll turn to Reshma. Just to follow-up on the trial question, and Sohanya on the progress in multiple myeloma. Reshma?

Thank you. So, enrollment is going well, there's a lot and largely to do just from the enthusiasm around these data. And I think that was highlighted most recently at ESMO. A couple of weeks ago in Spain, a lot of enthusiasm largely because the benefit that we are demonstrating is again, in the high unmet need patient population that doesn't have a new standard of care. That is translating to activation insights, and enrollment onto our clinical trials, we in fact, have 70 plus sites that are already active and enrolling patients onto the study. So, the study is going -- it's proceeding quite nicely

And I can address the question around 20% year-over-year growth. So, when you look at our mix of XPOVIO new starts, over 60% of that is in the second or fourth line, which represents in Q3 year-over-year, a 20% growth. Now, the shift into earlier lines, as you pointed out is a huge growth driver for us, primarily because of the benefit of duration that we see. Now as we think about duration of therapy data. As we've discussed previously, the data can be choppy, takes time to mature. But as we triangulate multiple data sources, we are seeing a nice upward trend in our duration of therapy and refills. And this is largely driven by this increasing patient on the earlier lines. And also better management of patients on the lower dose and supportive care.

Got it. That's helpful. Thanks for taking my questions.

[Operator Instructions]. The next question comes from Colleen Kusy with Baird. Please go ahead.

Great. Thanks. Good morning. And thanks for taking our questions. First one on a multiple myeloma with the elevation of the NCCN guideline recommendation for XVd to category one. Can you help us understand how much of a tailwind that could be through the end of the year? And then I have a follow-up?

Yeah, thanks Colleen. So, as we think about the evolving competitive landscape and multiple myeloma, XPOVIO has become established as a foundational mechanism. Now this elevation from of XPOVIO from category one, which used to be other recommended regimens to now category one and preferred regimens is meaningful, particularly in the community setting where it's a large driver of treatment decisions. So, notably, the NCCN guidelines made two updates that were favorable for XPOVIO, as I mentioned, one was recommending class switching against supports a novel class of therapy like XPOVIO as well as the elevation of XPOVIO Velcade, dex into the category one and preferred status. In terms of impact. We are not going to see an impact overnight. However, with multiple myeloma, it is an area that is highly promotionally sensitive. And we see steady growth over time. So, we are excited that our field team is now able to actively promote this update today and moving forward. And we believe this strengthens our position in the community and in the earlier lines.

That's helpful, thank you. And then for endometrial given the evolution of the treatment landscape with Dostarlimab and BMMR and you're really encouraging results in PMMR. Have used pre specified, any sort of analysis and this PMMR P53 wild-type patient population for the ongoing Phase 3 study?

Yeah, great question Colleen. So similar to SIENDO, in which we had endpoints, looking specifically at the DMMR versus PMMR we'll continue to do that in our ongoing Phase 3 as well. It’s not a stratification factor, we assume that the vast majority of patients are going to be MMR proficient given the fact that they represent 80% that'll ensure balance likely. But again, we will be looking specifically at the efficacy across these two MMR subgroups.

Great, thanks for taking our questions.

The next question comes from Eric Joseph of JP Morgan. Please go ahead.

Hi, thanks for taking the question. This is [indiscernible] on for Eric. Quick one from us just on the combination with the BMS drug could be [indiscernible]. Just overall thoughts on what the rationale there is, in terms of the combination with [indiscernible]?

Absolutely a great question. We're really, really excited about this novel combination. Just to give you a little bit of insight, right, this combination was pushed by some of our key KOLs coming out of Dana Farber Cancer Institute PH], specifically Paul Richardson, he just thought that this builds upon the number of combinations, selinexor has already shown remarkable efficacy in patients with multiple myeloma. The other aspect that is intriguing to him, but also BMS, and of course, us is the fact that both of these drugs XPOVIO1 inhibition with selinexor, as well as this novel cell mod in mezigdomide has individually and potentially in combination, shown that it can reverse T-cell resistance. And this concept of T-cell resistance is of course, becoming more and more important for multiple myeloma traders. Given the fact that they are now introducing T-cell therapies into the multiple myeloma arsenal, this novel combination potentially gives them a really important tool to help with sequencing of these therapies for their multiple myeloma patients.

That's helpful, thank you. And then just wanted to mind quickly on the Patient Assistant Program and how kind of see the impact of the foundation closures going forward? And then kind of a Medicare D design might be effective in 2024?

Yeah, thank you for the question. I can take that. So, in terms of -- as we know, we saw an increase utilization of PAP free drug this year due to foundation closures. Now year-to-date through Q3, the impact of PAP has been roughly $5 million to $6 million, which includes about a $1 million to $2 million PAP impact in Q3. Now in Q3, there were two of the foundations that were open and we -- as a result saw new patient starts in PAP, normalized, but the refill impact remained now in Q4 these two of the four foundations remain open to date. And we anticipate the PAP impact being very similar in Q4 as it was in Q3, assuming the foundation dynamic does not change. Now as we move forward into 2024, where we are encouraged by the IRA related change to the design of the Medicare Part D which eliminates the patient burden of the 5% beneficiary coinsurance requirements. And we expect therefore, significantly less need for these patients to utilize our patient assistance program for copay assistance.

Great, thanks for taking my question.

[Operator Instructions] This concludes our question-and-answer session. I would like to turn the conference back over to Richard Paulson for any closing remarks.

Thank you, operator. And thank you, everyone for joining us today. As we mentioned, we are well prepared for the next stage of growth as we continue to expand on our foundation of multiple myeloma with our proven commercialization of late-stage development capabilities. And as we continue to rapidly advance our pipeline, concentrating investments in our three Phase 3 programs that are expected to read out through ‘24 and ‘25 as we work to create near and long-term value for all stakeholders. Thank you for joining. And have a wonderful day.

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