Karyopharm Therapeutics Inc (KPTI) 2024 Q1 法說會逐字稿

Good morning. My name is Liz, and I'll be your conference operator today. At this time, I'd like to welcome everyone to the Karyopharm Therapeutics first-quarter 2024, 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 Elhan Webb, Senior Vice President, Investor Relations.

Thank you, Liza, and thank you all for joining us on today's conference call to discuss Karyopharm's first -quarter 2024 financial results, and recent company progress. We issued a press release this morning detailing our financial results for the first quarter of 2024. This release, along with the 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'm joined by Richard, Reshma, Sohanya, and Mike, who will provide an update on our first quarter results and recent financing transactions that we announced this morning as well.

Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements or FLS for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995.

As outlined on slide 3, actual results may differ materially from those indicated by these SLS, as a result of various important factors, including those discussed in the Risk Factors section of our most recent Form 10-K which is on file with the SEC and in other filings that we may make with the SEC in the future. Any FLS represent our views as of today only. While we may elect to update these 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 call over to Richard. Please turn to slide 4.

Good morning. Thank you, Elhan, and thank you all for joining today for Karyopharm's Q1 2024 for earnings call. As you have seen this morning, we have shared important news from our financial perspective that strengthens our potential to deliver on our innovation and growth strategy. I'll touch more on this in a moment.

Turning to slide 5. We have had a strong start to the year as we work to deliver our next stage of growth and advance our late-stage pipeline with trials that have the potential to enhance and create new standards of care for patients while providing significant value creation opportunities in the near term. Resham will talk to our pipeline progress. Commercially, in the United States, we are pleased with our results this quarter in the highly competitive multi-myeloma market including XPOVIO's growing role pre and post T-cell therapies.

Additionally, with our partners, we continue to expand selinexor's presence, including recent reimbursement decisions in both China and the United Kingdom. Sohanya will talk to our commercial performance in the quarter. As we look to the future, the commercial infrastructure build provides us with the capability to support the rapid and smooth commercial launch of selinexor in new indications. If approved. We continue to believe that selinexor can generate up to $2 billion of annual peak sales in the United States alone, depending on the outcome of our three pivotal Phase 3 data readouts in 2025.

As seen on Slide 6. Importantly, from a financial perspective, we have taken a significant step that improves our capital structure, strengthening our opportunity to realize the full value of our late-stage pipeline. Our comprehensive refinancing and amended royalty agreement announced this morning extends the vast majority of our debt maturities into 2028 and 2029. Well beyond the expected data readouts and potential approvals of our 3 Phase III programs.

Finally, through continued disciplined execution and a concentrated pipeline we have and expect to runway into the end of 2025, providing us with the financial strength to deliver on our pivotal data readouts. Mike will discuss the details of the refinancing later on the call.

Moving to slide 7. I would now like to turn the call over to Reshma to expand further on our pipeline and the progress we have made. Reshma?

Thank you, Richard, and good morning, everyone. On slide 8, you can see our very promising late stage pipeline with selinexor in three Phase 3 studies, all of which incorporate selinexor doses at 40 or 60 milligrams once weekly.

Turning our attention to endometrial cancer on slide 10. Endometrial cancer is a key focus in our pipeline. Given the high unmet need and substantial benefit observed in patients whose tumors are p53 wild-type advanced and recurrent endometrial cancer is the most common form of gynecologic cancer in the United States with approximately 16,000 patients diagnosed each year.

The evolving treatment landscape is being driven by molecular classifications. Today for dMMR patients who represent approximately 20% of advanced recurrent endometrial cancer. The new FDA approved standard is just dostarlimab in combination with chemotherapy, followed by dostarlimab maintenance.

For pMMR, which represents the remaining 80% of patients the primary treatment option is chemotherapy followed by watch-and-wait despite the availability of the checkpoint inhibitors, given the limited efficacy achieved with these agents in this molecular subgroup. TP53 wild-type represents a potentially unique, but fundamental biomarker as it is found in the majority of all advanced recurrent endometrial cancer.

As seen on slide 11, patients whose tumors for both pMMR and p53 wild-type represents 40% to 55% of all advanced or recurrent endometrial cancer patients. For long-term follow-up data from the TP53 wild-type subgroup of the CMV trial, which evaluated selinexor as a maintenance therapy, has generated substantial enthusiasm from the medical community and highlight selinexor has potential to meaningfully improve outcomes for patients with TP53 wild-type endometrial cancer.

For the paradigm shift underway, opinion leaders confirmed there is a clear unmet need for patients whose tumors are p53 wild type and emphasize the opportunity for new agents.

On slide 12. You can see this long-term follow-up data with selinexor treatment after completion of approximately six months of chemotherapy showed a median PFS for selinexor for 27.4 months and 5.2 months for placebo, corresponding to a hazard ratio of 0.41. These robust subgroup data demonstrate the potential to provide substantial benefit to a unique and sizable population defined by p53 status, which directly ties to selinexor as mechanism of action, given that XPO1 inhibition retains p53 within the nucleus, thus enhancing cell kill.

As shown on slide 13, the benefit observed with selinexor and the pMMR. subpopulation is even more impressive with a hazard ratio of 0.32, and a median PFS that has not been reached as of our most recent data cutoff presented. These efficacy data, coupled with a generally manageable side effect profile, suggests that oral selinexor is uniquely positioned as an optimal maintenance therapy where convenience, tolerability, and meaningful efficacy, in a precise patient population are the hallmarks of the maintenance option.

We look forward to the oral presentation at the ASCO meeting in June where additional follow-up data new analyses from this important TP53 wild-type subgroup will be reported.

On slide 14, you can see the design of our EC-042, pivotal Phase 3 study, which will enroll approximately 220 women whose tumors are TP53 wild-type. We look forward to presenting top line results from this pivotal trial in the first half of 2025.

Let's now move to myelofibrosis. As you can see on slide 16, ruxolitinib remains the standard of care for the majority of JAK-naive patients. However, there's an opportunity to improve benefit given that the efficacy with ruxolitinib is limited with only about 35% of patients achieving an SVR 35 or less and half of those patients achieving a meaningful symptom improvement. XPO1 inhibition is a fundamental mechanism in myelofibrosis, given that it targets both JAK and non-JAK pathways, underscoring selinexor additive, If not potentially synergistic activity when dosed in combination.

As you can see on slide 17, we presented updated data last year from our trial evaluating selinexor 60 milligrams with ruxolitinib and JAK-inhibitor-naive patients. Amongst the 14 patients enrolled to the selinexor 60 milligram dose, a 78% SVR35 at week 24 was observed in the ITT population. Importantly, amongst the evaluable patients, 100% achieved an SVR35 at any time.

As we move to slide 18, when we look at SVR35 and TSS50 together, we see that 50% of patients experienced both of these responses at week 24% and 75% experienced both SVR35 and TSS50 response at any time.

On slide 19, both TSS50 absolute TSS should very meaningful improvements. At week 24, 58% of the ITT and 78% of the efficacy evaluable achieved a TSS50 response. For absolute TSS, an average 18.5 point improvement was observed in the efficacy evaluable population at the same time point. Compare these historical ruxolitinib data for TSS50 was observed in 42% to 46% of ruxolitinib treated patients and the average PFS improvement was 11 points to 14 points. All symptom domains were substantially improved with selinexor combination and showed that pro-inflammatory cytokine demonstrated rapid deep and sustained reductions relative to baseline. Taken together, these data validate that the novel combination of selinexor plus ruxolitinib has the potential to maximize symptom improvement relative to ruxolitinib alone in the ongoing Phase 3 study.

The subgroup analysis shown on slide 20, which depicts SVR35 and TSS50 responses despite treatment with suboptimal doses of ruxolitinib is suggestive of potential monotherapy activity. Further demonstrates selinexor's potential fundamental role in myelofibrosis and to build upon the growing data, demonstrating monotherapy activity in both treatment naive and JAK exposed myelofibrosis patients.

We have initiated CENTRIC 2 Phase 2 trial, as you see on slide 21. This trial will include treatment-naive myelofibrosis patients with moderate thrombocytopenia and has the potential to entrench selinexor as a foundational therapy in approximately 90% of treatment naive myelofibrosis patients. As the body of our data grow and positively evolve we see increasing interest from the medical community on the potential of selinexor in myelofibrosis.

We maintain a high level of confidence in our ongoing Phase 3 as shown on slide 22. Which evaluates the combination of selinexor 60 milligrams with ruxolitinib versus ruxolitinib alone in 306 JAK naive myelofibrosis patients. We remain on track to report top line results in the second half of 2025.

Turning now to multiple myeloma. There is a growing need being discussed amongst myeloma thought leaders to identify and incorporate therapies early into a patient's treatment journey that do not deteriorate a patient's T cell levels and which can be used pre and post T-cell redirecting therapies such as bispecifics and CAR-Ts. We have been building a body of evidence around selinexor as a role in preserving cytotoxic T cell function.

As seen on slide 24, we are further evaluating the effect of selinexor on the immune environment. Through preclinical translational and real world data as well as clinical trials. We have also been hearing encouraging feedback on the positive evolution of XPOVIO, its effectiveness and tolerability at the lower doses and real-world outcomes observed with patients in combination with the well-established backbone therapy of pomalidomide and dexamethasone.

Seen on slide 25, we are evaluating selinexor at the low dose of 40 milligrams. With this combination in our ongoing Phase 3 trial post anti -CD 38 antibodies, we expect to report top line data from this trial in the first half of 2025.

In summary, we have near-term late-stage opportunities supported by compelling data in our rapidly advancing pipeline that will potentially benefit multiple cancer patient populations of high unmet need building upon our approved indications.

With that, I will now hand it over to Sohanya to review our commercial highlights.

Thank you, Reshma. Turning now to slide 27, I will discuss our commercial highlights for the first quarter of 2024. In the first quarter, XPOVIO net product revenue was $26 million, minus 8% year- over- year and plus 4% quarter-over- quarter amid increased competition. Quarter over quarter growth was driven by an increase in new patient starts and partially offset by a softness in refills due to the impact of fewer new patient starts in the prior quarter.

Additionally, a higher gross-to-net discount. Typical of what we see in the first quarter of the year adversely impacted XPOVIO net product revenue this quarter. The community setting contributed to roughly 60% of exposure net revenues in the first quarter. There was increased breadth of use as we added new community prescribers to our customer base and growth in new patient starts offset by softness in refills. This is encouraging as new patient starts have the potential to positively impact exposure beyond net product revenue in upcoming quarters. In the academic setting, there was quarter-over-quarter growth in demand as exposure continues to fulfill patient needs in an evolving competitive multiple myeloma landscape.

As Reshma mentioned, XPO1 inhibition provides patients with a potentially T cell sparing treatment option before or after T cell therapies. This advantage places selinexor in a flexible position in the treatment paradigm as a novel mechanism of action. In the first quarter yields new patient mix in the second to fourth line, stayed stable quarter over quarter. As we look ahead, we expect to see continuation of selinexor treatment in second or fourth lines, primarily in the community setting and in later lines in the academic setting, typically pre or post T cell therapies.

In a highly competitive multiple myeloma landscape, our team is executing with resilience to drive an increasingly important role for Nexavar in the treatment paradigm as a novel effective treatment option for patients. We are reaffirming XPOVIO's 2024, net product revenue guidance of $100 million to $120 million.

Now turning to slide 28 and shifting to achievements in the ex U.S. as XPOVIO continues to expand its global footprint. We are pleased with the positive recommendation by NICE in the United Kingdom for reimbursement of selinexor in the earlier-line treatment setting.Inclusion in China's National Reimbursement Drug List as of January 1, 2024 and approval for reimbursement in Germany.

In conclusion, our multiple myeloma franchise continues to positively impact more patients every year, while being a key driver in funding our pipeline. Our strong commercialization team is focused on expanding our multiple myeloma business and rapidly launching in potential future indications.

Now I would like to turn the call over to Mike to discuss our recently announced transactions and give an update on our financials.

Good morning, everyone, and thank you, Sohanya. Before turning to our 1Q 2024 financial results. I'm incredibly pleased to announce we've extended the vast majority of our debt maturities into 2028 and 2029, well beyond expected data readouts from our three Phase 3 trials and potential launches, positioning Karyopharm for sustainable value creation.

Now I will walk you through the series of refinancing transactions announced this morning and as outlined on slide 30, you can see the impact on our balance sheet. First, we retired approximately $148 million for 86% of the $172.5 million existing convertible notes due in 2025, for approximately $111 million of newly issued secured convertible notes due in 2029. This exchange is at a 25% discount to par. We now have $24.5 million remaining of the existing convertible bond due in October 2025. In addition, Healthcare Royalty or HCRx purchased $5 million of the 2029 convertible notes. Second, we issued a new $100 million senior secured term loan due in 2028, with $85 million committed from certain existing convertible note holders and $15 million from HCRx. We used $49.5 million of the proceeds, along with $5 million in 2029 convertible notes and $15 million of the secured term loan to HCRx, to satisfy the remaining principal portion under our existing agreement with a HCRx.

Lastly, we amended our existing agreements, HCRx, eliminating any potential gross-up payments and reducing the royalty rate on net revenues to 7%, down from 12.5%. Overall, you can see the difference in our debt maturity profile on the right side of slide.

Net-net, our total liabilities are reduced slightly, an additional approximately $30 million of cash strengthens our balance sheet with cash runway into the end of 2025. The confidence and continued support of Karyopharm suture from healthcare royalty and our top convertible noteholders reflects their confidence in the potential of selinexor in our late-stage pipeline programs. These transactions represent a fundamental change and benefit to our capital structure and the financial health of the company, strengthening our opportunity to deliver the value of our late-stage pipeline as we provide benefit to patients in need of new treatment options.

Turning to our financials. Since we issued a press release earlier today, with the full financial results, I will just focus on the highlights, which are on slide 31. Total revenue for the first quarter of 2024, was $33.1 million compared to $38.7 million for the first quarter of 2023. Net product revenue from US commercial sales of XPOVIO for the first quarter of 2024 was $26 million compared to $28.3 million for the first quarter of 2023. Gross-to-net discount for XPOVIO in the first quarter of 2024 was 29%. As a reminder, gross-to-net is typically higher in the first quarter. We expect gross-to-net discount to be in the 25% to 30% range for the full year 2024. Our total expenses for the first quarter of 2024 were down year over year 4%, reflecting our ongoing cost reduction initiatives and focused investments in our late-stage pipeline.

R&D expenses for the first quarter of 2024, were $35.4 million compared to $32.3 million for the first quarter of 2023. The increase in R&D expenses is primarily attributable to higher clinical trial costs related to the advancement of our three pivotal Phase 3 programs. SG&A expenses for the first quarter of 2024 were $29.5 million compared to $35.9 million for the first quarter of 2023. The decrease in SG&A expenses was primarily due to our ongoing cost reduction initiatives, and lower headcount. Cash, cash equivalents, restricted cash and investments as of March 31st, 2024, for a total of $149.3 million compared to $192.4 million as of December 31st, 2023.

Based on our current operating plans, we are reaffirming revenue guidance for the full year of 2024 as follows. Total revenue expected to be in the range of $140 and $160 million. XPOVIO net U.S. product revenue expected to be in the range of $100 million to $120 million. We are also reaffirming our expense guidance for the full year of 2024 as follows. R&D and SG&A expenses are expected to be in the range of $260 million to $280 million, which includes approximately $20 million to $25 million of estimated non-cash stock-based compensation expense. And finally, we expect our existing cash, cash equivalents and investments, as well as the revenue we expect to generate from XPOVIO net product sales and other license revenues will be sufficient to fund our planned operations into the end of 2025.

In summary, we have taken significant steps to improve our capital structure. With our recent debt exchange, an amended agreement with HealthCare Royalty. We are rapidly advancing our three Phase 3 trials and driving commercial performance while continuing to be very diligent when allocating our resources.

I'll now flip to slide 32 and turn the call over to Richard for some final thoughts. Richard?

Thank you, Mike. As you can see on slide 33. We have several key milestones across '24 and '25 and are pleased to have extended the vast majority of our debt maturities into 2028 and 2029. Well beyond the data readouts and potential approvals of our three Phase 3 programs. With the substantial improvement in our capital structure, we have strengthened our opportunity to realize the full value of our late-stage pipeline with our Phase 3 clinical trials in multiple myeloma, endometrial cancer, and myelofibrosis. Each of which would be transformative for patients and our organization.

With data expected from each of these pivotal trials 2025 next year is going to be an incredibly exciting time for our organization as we believe the largest opportunities for selinexor are yet to come. We are focused on delivering on our next phase of growth, and our organization continues to be fueled by our belief in the extraordinary strength and courage of patients with cancer and the potential of our novel mechanism of action to positively impact their lives.

Thank you again for joining us today. And I would now like to ask the operator to open up the call to the Q&A portion of today's call. Operator?

(Operator instructions) Christopher Raymond, Piper Sandler Companies.

Hey, thanks for taking my question. Just a couple of quick ones here. Just on the refinancing and the amended royalty agreement. So there's a lot of moving parts here. And I don't think I saw and a description of this. you guys have been carrying a pretty consistent interest expense each quarter. Can you maybe just sort of boil this down to what the projected new quarterly interest expense might look like? That's first question.

And secondly, I know you guys have talked for quite awhile about the competitive environment between the for XPOVIO between the sort of academic and community settings. And I think in your prepared comments, you mentioned that gross-to-net spreads from this quarter were fairly consistent with what you'd expect in the first quarter. But is there any sort of difference in gross-to-net spreads between the two settings that you can describe? Thanks.

Yeah, thanks, Chris. As I mentioned, I think we have a lot of excitement around being able to fundamentally adapt our balance sheet really strengthen and strengthen as we move forward. So for the first part of your question. I'll turn to Mike to really talk about from a cash perspective and looking at our interest expense.

Thanks, Richard.

Yes, at a high level, these transactions certainly strengthen our cash balance and improve our cash runway into the end of 2025 beyond our expected data readouts in '25, based on our current operating plans and to your specific question on interest expense. So there's two components of interest expense for us. There's our interest on our debt, as well as our royalty, an agreement with HCR which is recorded through interest expense. So going forward, we expect interest expense this year to be around $18 million for the debt component. So that excludes HCR. And then as you saw as part of the refinancing, we amended our HCR agreement to reduce our royalty rate from 12% to 7%. So for the rest of this year, we expect that number based on our from the revenue guidance to be around $8 million. If you combine the two together, that's what you'll see.

Yeah. And for the second part, Chris, when you look at the GTN between the community and the academic, I mean, overall, I think as we've talked to the GTN is up to six points . And so when we look at it, I think it's quite difficult to break it out, really depends on source of business within each one of those areas versus kind of a general statement across academic and community.

Yes, I would just add the mix of business is really the key that drives GTN. And unusually in Q1, obviously, that starts higher in the year. So we think we'll still end up in that range of 25% or 30% with some volatility each quarter.

Thank you.

Thanks, Chris.

Peter Lawson, Barclays.

Hi, good morning. This is Alex on for Peter. Thank you for taking our questions. Just we have two questions on the endometrial program. I'm just wondering if you could what should what could we learn from the updated SIENDO data at ASCO? What do you think investors should focus on there? And then related, any differences in the patient population in SIENDO compared to the ongoing pivotal study that we should keep in mind. Thank you.

Yes, thanks, Alex, for that. I'm going to turn to Reshma to talk through that.

Yes.

Thanks, Alex, for the great question.

And so a couple of highlights around ASCO. So first off, and it's really an honor from ASCO, we were actually invited to present an update on the p53 wild-type subgroup. And this is a follow-on from the ASCO plenary last year. I think it resonated with a lot of KOLs, ASCO again, really wanted us to perform an update from that p53 wild-type subgroup. So at this upcoming ASCO, we're going to use this opportunity to really update both efficacy as well as safety and provide some new analysis that I think will further highlight the potential benefit risk that we see with selinexor in this novel population of p53 wild -type endometrial cancer. So can't go into more details, but really looking forward to this opportunity.

And I want to thank Vicky Makker at MSK for presenting on behalf of all of the investigators.

In terms of your second question, so really the units and the main differences in this trial relative to SEINDO, once again, it's going to be that patient population. So SEINDO enrolled an all comers population and that all patients with advanced or recurrent endometrial cancer were potentially eligible to be randomized in the current trial. We're just focusing on those patients who have p53 wild-type, which is evaluated by NGS testing with our partner Foundation Medicine. And the other key difference not necessarily related to the patient population, but an important differences to dose. So in SEINDO, we treated everybody with a dose of selinexor at 80 milligrams weekly. In this current trial, it's going to be 60 milligrams weekly. So those are the two main differences that I would highlight across the two trials.

Thanks, Alex.

Maury Raycroft, Jefferies.

Hi, good morning. Thanks for taking my question. I was going to ask a couple more specifics on the upcoming data at ASCO. So late last year, you guys presented some initial OS data at the IGCS conference. And also in your last cut, on the median PFS in the pMMR group was not amateur. For the data at ASCO in a couple of weeks on. Can you say if you're going to have an update on PFS ans the pMMR group and also on OS. for the study? And then you have a I'll start with that question.

Yeah. Thanks, Maury.

I really appreciate the question. So I can't at this point and just provide any additional details in terms of the exact analyses that we're going to present on. Just keep in mind, again, we are going to have an opportunity to present an update on efficacy for both PFS and then these new analysis, right? So that we'll provide additional color on the benefit risk. So more to come in the next few weeks, but really excited to be able to provide this update.

Got it.

That's helpful. And when you speak with doctors about ,what doctors want to see as on on OS ? what's the landmark OS that you want to achieve in this study done also, can you talk about some of the drivers of Alaska that you're focused on SIENDO?

Yes. So the trial is powered to detect a meaningful and statistical difference in terms of PFS. So progression-free survival, very similar to SIENDO trial and very similar to the endpoints in which the dostarlima was approved in combination with chemotherapy, followed by the dostarlima maintenance specifically in that the dMMR patient population. So the focus is very much going to be on PSS. With that said, OS is a key secondary endpoint and the goal is to really show no detriment at the time of the primary cutoff. And we define no detriment specifically by hazard ratio of less than one.

In terms of the full median overall survival. I think that's going to take some time for it to mature that these patients are living longer and longer, and we'll continue to follow that overall survival and as that data matures from this ongoing trial, we'll be able to provide those additional data at future with future updates.

Okay. And just to clarify, is there a benchmark or some sort of a landmark in SIENDO on OS that that you want to achieve that doctors would want to see for that study?

No notice not at this time, and I think it's very much of a holding. So, you know, at this point, I don't have a landmark to be able to provide. Again, I think the focus very much is the no detriment that I mentioned earlier.

Got it.

Okay.

And then maybe one last question and then I'll hop back in the queue. You said you could have myelofibrosis Phase 1 data update this year? What could that look like and what venue would make sense for for that update?

Yes. So I think the focus really is going to be on that Century 2 trials, the century to on a new acronym for the trial, but it is that 0.0 44 trial that we alluded to at JPMorgan. This is that selinexor arm monotherapy trial that we're evaluating in the JAK-naive patient population that is going to be our focus, you know, for this year and we anticipate being able to provide some initial preliminary data, both from an efficacy as well as the safety perspective on some time in 2024.

With that said, on the Phase 1 selinexor, ruxolitinib trial is still ongoing as well, and we'll be able to provide some additional updates both in efficacy and safety perspective later this year as well.

Okay, great. Thanks for taking my question.

Thanks very much.

Colleen Kusy, Baird,

Good morning. Thanks for taking our questions and congrats on refinancing one on it the endometrial Phase 3, how do you expect enrollment in the Phase 3 will be split among the pMMR. and dMMR. patients? And what are the characteristics are stratifying for? And would that include MMR status and then I have a follow-up.

Yeah, great question, and thank you on Colleen. So when we look at the endometrial cancer patient population and specifically MMR, the vast majority of patients are going to be that pMMR., that comprise approximately 80% of all patients. When we look at the remaining population of 20%, they're going to be in that the MMR patient population. When we look at the P53 subpopulation, that breakdown of 80/20 is going to be similar. And within that within that P53 wild-type subgroup, if I have to anticipate the proportion of patients who are dMMR to be enrolled in this trial, it would assume somewhere less than 10%, maybe between 10% and 20%, very similar to what we are seeing on the natural population.

And is that something you're stratifying for what are the items that you're shopping for in that Phase 3 enrollment?

We're not stratifying. Thank you for that follow up. So we're not stratifying based upon MMR status. So again because we assume that the majority of patients are going to be pMMR, we assume that there's going to be a similar split across the two arms, selinexor and placebo on. So again, not stratifying.

Understood. Helpful.

And then in myelofibrosis, your ongoing Phase 3 has the co-primary endpoint of both SVR35 and TSS50, Just curious if you've had any recent interactions with the FDA on kind of the role of TSS50 specifically and kind of how you're thinking about the approval endpoints of myelofibrosis.

Yeah, so we don't comment on the specifics with our FDA interactions. With that said, I think in the myelofibrosis space, the focus has always been and continues to be on two main endpoints. This is going to be SVR35 as well as TSS analysis and the precedent has always been 50%. And so we're very much focused on those endpoints and very encouraged by our Phase 1 data, which really suggests that the combination of selinexor plus ruxolitinib can maximize the benefit we see across these two endpoints. And it continues to remain that if you add additional DOR data, it really demonstrates that the patients once they achieve that SVR35 or TSS50 remain in those responses. So really encouraged by the compilation of data. And I think it just provides us further confidence in the potential outcomes for our Phase 3 trial.

Great. Thank you. And then one commercial question if I can. Sohanya in the pre and post T cell therapy setting. Can you speak to the type of duration of treatment you're seeing in that patient population versus what you see on average in the second to third line settings -- or second to fourth?

Yeah, absolutely. So there's several ways that selinexor can be used pre and post as well as per T cell therapies it can in the pre stage, it can be used as a shorter bridge, which could be one cycle or can be used as a unique line of therapy preceding a T cell therapy, which could be several months long. Now as you look at the different puts and takes of duration of therapy, there's a couple of key drivers. One is the new patient start volume, right. So no higher than new patient starts you higher refills. The good news in Q1, we saw really nice growth versus the prior quarter in new patient starts in the academic setting as well as the community setting.

The second area around duration of therapy is how long patients stay on therapy. That is really driven by a couple of different factors. One is what lines of therapy they are. They are on earlier lines. Patients stay on therapy longer. That's typically in the community as well as we've got the offset or balanced in the academic setting that we see with the bridge. So our goal in balancing out that shorter duration with the bridge and the academic setting is to continue to drive that new patient volume in the pre and post T cell therapy space.

Great. Thanks for taking our questions.

Thanks, Colin.

Brian Abrahams, RBC Capital Markets.

Hi there.

Good morning. Thanks for taking my questions. Two from me. I guess first on the endometrial Phase 3, I understand the majority of the patients are likely to be pMMR. But I guess I'm curious in light of the maturing data and the longer capital runway now whether you had any updated thoughts on whether you might consider focusing enrollment for the primary analysis on that pMMR population? Would there be any reason not to do that? And then secondarily, with regard to the updated agreements, any changes to the change in control provisions? I recall previously there were some gross-ups in that situation, and I'm just wondering if those are still in there are those have been eliminated as well. Thanks.

Thanks, Brian. Maybe I'll turn to Reshma going to talk to the first part, and then Mike to talk to the second part.

Thanks, Brian. Great question . One of the reasons that we're focusing on both the pMMR as well as the dMMR patient populations is because if you look at the hazard ratio across the two subgroups, they show very meaningful benefit. So that pMMR, p53 wild-type subgroup, are seeing a very impressive 0.43 hazard ratio. But when you look at the dMMR. patient population, you're also seeing a very strong approximately 0.4 hazard ratio. So the benefit is really seen regardless of MMR status and it really suggests to me at least that the key biomarker, that is thriving are predicting the benefit is all going to it's going to be about that p53 status. So right now, we really want to leverage that p53 status and determine the patient population based upon that unique biomarker and be able to ultimately drive use across this broad population.

For the second part when I look at the updated agreement, so I'll turn to Mike to touch on that point.

Sure, Brian and especially i think you are referring to the amended agreement with HCR.

So that's still stay consistent where in that case stake, they do get -- their return is capped at 1.95x. So that would stay the same. and as far as the convert, we have customary make-whole provisions in the agreement.

Thank you.

Thanks, Brian.

Edward White, H.C. Wainwright & Co., LLC.

Good morning. Thanks for taking my question. Just one for me, the SG&A it's trended lower. Was just wondering if you know with all your cost reductions, are they all in place now? Is the sales force rightsized now? And are you expecting to see further lower expenses in SG&A? Or are we sort of at a more stabilized level now?

Thanks.

Yeah. Thanks, Ed. And I think as you know, we've got a strong focus on really being very diligent with regards to our capital allocation, reducing headcount, and being very focused in our pipeline. And we've been able to obviously see those benefits come through over the last year. And overall, those benefits will continue and we don't see that beyond the focus right now is on our late stage pipeline, and we're going to continue that focus. At the same time, our commercialization capability and our commercial team as we've talked to is profitable with regard to our multi myeloma business. Now right now driving a 2-to-1, ROI and really helping to fund our pipeline. So I think we have the right resources in place.

And maybe, Mike, do you want to add some detail?

you have just a little more detail.

I mean, I think we've been running right around $30 million from Q3 last year, Q4 last year, Q1 this year, and we expect it to be consistent going forward.

Okay, great. Thanks for taking my questions.

(Operator instructions) Jonathan Chang, Leerink Partners.

Hi, guys, good morning and thanks for taking my questions. We're still working through the math on the refinancing agreements and amendments announced this morning.

So just a couple hard level questions for now. One, what are the key implications of these agreements for the equity holder?

And two, what is the impact of these agreements on your cash runway guidance?

It doesn't seem to have moved that much, but I might be missing something? Thank you.

Yeah, I think I'll turn to Mike, maybe make me start with number two first and then go to number one.

Sure, our cash runway guidance is now into the end of 2025. So it was between the $30 million of cash coming in from based on our current operating plan as well as the new interest payments offset by the lower royalty payments to take us into the end of 2025.

And then you want to touch on the first part.

I'm happy to. And I think overall, the important thing here for equity holders is a lot of excitement around our Phase 3 program. So we want to strengthen our balance sheet to unlock value by extending maturity of our debt obligations, well beyond our planned data readouts and potential approvals. So we took advantage of the convert trading at a discount, in exchange them at a 25% discount to par. And from a timing perspective, why now we wanted to address this some before it becomes current. So as we've said in the past, we really want to address this within 12 to 24 months maturity, and we're sort of right in the middle of that sweet spot. So overall, we're pleased to have the vast majority of our debt obligations well beyond our expected data readouts and potential approvals.

Got it.

Thanks for taking the questions.

Yes, thanks, Jonathan.

Then again, (Operator instructions) There are no further questions at this time, and I'd like to hand over the call to Richard Carsten for closing remarks.

Thank you, operator, and thank you again to everyone today for joining us.

As we've really highlighted on the call, we're very pleased with the substantial improvement in our capital structure. We've strengthened our opportunity to realize the full value of our late-stage pipeline and with our three Phase 3 clinical trials. And we've touched on the fact that each one of them would be transformative for patients, new and transformative organizations. Those will continue to be focused on delivering our next stage of growth. And once again, I want to thank you for joining us today.

Thank you.

Ladies and gentlemen, this concludes today's conference call. You may now disconnect.