Good morning, everyone, and thank you for joining the H.C. Wainwright 26th Annual Global Investment Conference. My name's Arabella, and I'm an analyst on the corporate access team at H.C. Wainwright. H.C. Wainwright is a full-service investment bank dedicated to providing corporate finance, strategic advisory, and related services to public and private companies across multiple sectors. We have a total of 24 publishing senior analysts and over 636 companies covered across all sectors. Please visit hcwco.com for more information. We're grateful you're able to join us for what will hopefully be a productive day of one-on-one meetings, corporate presentations, and panels. With that being said, I'd like to introduce Richard Paulson, the CEO, and Reshma Rangwala, the Chief Medical Officer and Head of Research of Karyopharm Therapeutics.
Thank you, Arabella, and thanks to H.C. Wainwright for hosting us today. Please refer to our forward-looking statements here. So, you know, at Karyopharm, our mission is to positively impact patients' lives and defeat cancer, and we're very focused on advancing our innovation and growth strategy, which is foundational to our growth, and our evolution as a company, building on our novel XPO1 inhibition science, where we're the global leader, in XPO1 inhibition. And when you look at our pipeline, we wanna build on our foundation in multiple myeloma, with the opportunity to create new standards of care in myelofibrosis and endometrial cancer. And if you look first at myelofibrosis, in myelofibrosis, you know, we have an opportunity to combine with ruxolitinib in treatment-naive frontline patients and really transform the frontline treatment opportunity in myelofibrosis.
And that opportunity just continues to grow, and to strengthen as we see strong interest in our clinical trial, which is advancing very strongly. Great interest from clinicians looking at our program and a competitive environment which continues to evolve positively for us from a Karyopharm perspective. And Reshma will talk to our program and how it continues to advance and how we see that moving forward rapidly. In endometrial cancer, we have the opportunity to really benefit a significant amount of patients, building on the molecular classification in endometrial cancer, where about half of women with endometrial cancer have tumors who are p53 wild-type pMMR. And that opportunity, really with transformative outcomes for patients, as we've seen in our phase III SIENDO trial, we continue to advance our EC-042 trial.
And again, in this area, Reshma will talk to our opportunities and how we see the opportunity to transform outcomes for patients in endometrial cancer. You know, as we build on our foundation in multiple myeloma, we have a strong financial position. Our multiple myeloma franchise already is profitable to us and continuing to fund our pipeline. We have cash runway into Q1 of 2026 . And as we look at our global presence, you know, we continue to advance globally with Selinexor now being available in over 40 countries, with reimbursement growing across our key markets as our reimbursement processes follow through in key markets around the world.
And when we bring it all together, you know, as we advance Selinexor with the opportunity in myelofibrosis and endometrial cancer, building on multiple myeloma, we see Selinexor alone in the U.S. as a potential for in excess of $2 billion in peak. If you look at our financial results and kind of overview of financials, again, in Q2, we lowered the bottom end of our guidance in the U.S. to $105-$120 million for revenue, and our total revenue $145-$160 million.
And we also lowered our expense guidance, where now we see our expense guidance at $250-$265 million, and a cash runway that's sufficient into Q1 of 2026, excluding our remaining sub on our convert, and our minimum cash covenant of $25 million under our new debt and convert agreements. So strong financial position to really deliver for patients, strong financial position to deliver our pipeline. And again, if we look at what that is as an opportunity, seeing here, the bubbles kind of represent the size of the opportunity. So building on our multiple myeloma franchise, you know, we see significant opportunity in myelofibrosis and endometrial cancer, again, with the potential to transform outcomes for patients. And with that, I want Reshma to talk to our opportunities and kind of kick it off from a myelofibrosis perspective.
Resh?
Yeah. Thank you so much, Richard. So before I go into some of the myelofibrosis data, you know, let's talk at a high level about how Selinexor leads to, you know, these substantial improvements in patients with myelofibrosis. When we look from a mechanism standpoint, what we are seeing is that Selinexor specifically, which is an XPO1 inhibitor, targets both JAK and non-JAK pathways. This is relevant given the fact that we know that the mainstay of therapies available for these patients with myelofibrosis still do not lead to optimum results in the majority of patients. If you look at ruxolitinib, which was approved over a decade ago, unfortunately, patients who are still JAK-naïve, less than half, right, maybe even 1/3 , achieve that optimal spleen volume reduction of at least 35%.
And from a symptom improvement, still there, too, less than half of all patients are achieving a meaningful symptom improvement. So from a mechanistic standpoint, the field really is looking at what are the other pathways that are relevant in myelofibrosis? Targeting these pathways, including NF-kappa Beta, looking at tumor suppressors, specifically P53, as well as cell cycle arrest, apoptosis, are important complementary pathways that can lead to additive, if not synergistic, effects, especially when you combine with other agents like a JAK inhibitor, including ruxolitinib. Now, there's been extensive preclinical data, non-clinical data, that have been generated with XPO1. We have clinical data specifically in that intolerant refractory population that shows a very meaningful SVR and TSS improvement in that hard-to-treat population. We also conducted a phase I study, specifically in that JAK-naïve myelofibrosis population.
Again, a high unmet need, given the fact that less than 50% of all patients are achieving a response. When we combine Selinexor in combination with standard of care or ruxolitinib, what we see is very meaningful outcomes. You can see on the table on the left, when you look at that ITT population, or the 14 patients treated at the recommended phase 2 dose of 60 milligrams of Selinexor, you see a 79% SVR35. Again, compare that to that approximately 35, low 40s, that you see with ruxolitinib alone, really suggesting meaningful additive, if not synergistic, effects when you combine these two agents alone. On the right is an important waterfall plot. When you look at any time, all patients are treated with Selinexor 60 milligram achieve that SVR35. Symptom improvement is also key, critical in treatment with these myelofibrosis patients.
Unfortunately, part of the disease manifestation of myelofibrosis are intractable symptoms, both stemming from a very large spleen, right? As well as non-spleen-related symptoms. What we see in our combination trial, this phase I trial, is again, a very meaningful improvement. In that intent-to-treat population of fourteen patients, we see a 58% TSS50, or a 50% reduction in that symptom score relative to baseline at week 24. Another way of looking at symptom improvement is something called absolute TSS, or the mean change over time. What we see with the combination is an 18.5 improvement relative to baseline, compared to approximately 11-point improvement with ruxolitinib alone. So when you look at TSS50 as well as absolute, two different ways of assessing symptom improvement, both showing very meaningful outcomes from that endpoint.
Another point that we interrogated was looking at the improvement again across all of the relevant domains or symptoms that you see within myelofibrosis. As I mentioned before, you see primarily two classes of symptoms, those that are deriving from the spleen, this is gonna be your abdominal fullness, early satiety, as well as non-spleen-related symptoms, the night sweats, the bone pain. What you see on this graph here is that regardless of where the symptoms are stemming, you see a very meaningful improvement across those domains. In fact, greater than 50% in the vast majority of cases, further suggesting that the combination of Selinexor plus ruxolitinib is very meaningfully improving symptom outcome with this combination.
Now, what we know is that interrogation across the entire myelofibrosis landscape, you know, discussions with investigators, of course, looking at the other combinations that have been evaluated in this JAK-naïve, is that symptom score or symptom outcome is impacted by multiple variables, right? These include the domains that are included in the symptom analysis, the patient's symptom burden at baseline, how you analyze symptoms, as well as your compliance or completion rate of these symptom evaluation forms. We are cognizant of every single one of these and incorporated, by and large, almost all of them into our phase III trial, again, increasing the confidence of the outcome from this important phase III trial. What are some of the other aspects that are very important, both from a regulatory perspective as well as from a patient perspective?
We know that when we look at SVR35 as well as TSS50, that's a fixed moment in time, specifically evaluated at week 24. From this JAK-naïve patient population, it's important to understand the durability, right, and what you can see from these two graphs here, which are Kaplan-Meier curves, is that none of the patients actually had progressed at the time of the data cutoff. 100% durability, and this is again, both for SVR35 as well as TSS50, so not only are we seeing meaningful reductions in the percentage of patients who are achieving these thresholds, but these patients, once they reach response, they stay in response. Another important and differentiating aspect that we see with Selinexor is potentially monotherapy activity. I already alluded to a trial that was conducted in that intolerant refractory patient population.
Again, a very meaningful SVR35 observed in that hard-to-treat patient population. This analysis was specifically done among the cohort of patients enrolled in our phase I, whose ruxolitinib doses were reduced to very low doses. In fact, they were reduced to five milligrams. If you look at the literature, these are suboptimal doses of ruxolitinib. Patients treated with rux five milligrams, unfortunately, do not achieve SVR35. They do not achieve TSS50. In fact, if you look at the data, unfortunately, spleens are growing on these doses. Among this subgroup of patients, their ruxolitinib doses were reduced down to five milligrams as early as cycle one, largely due to the cytopenias that they were experiencing while they were on ruxolitinib. Despite these very low doses of ruxolitinib, what we saw is exactly the opposite. In fact, all of these patients achieved that SVR35, and three out of four achieved that TSS50.
Small numbers, but again, it demonstrates Selinexor's fundamental mechanism within myelofibrosis, and, you know, in addition to that monotherapy study in that intolerant population, further suggests that Selinexor has monotherapy activity within myelofibrosis. Lastly, let's touch upon, you know, the percentage of patients who achieved both SVR and TSS50. Here, too, again, you see a very sizable population, 50% at week 24 achieve both endpoints, and when you look at any time, that number climbs to 75%. That's the efficacy side of it. Obviously, some very unique and differentiating aspects that we see with this very novel combination. When you look from a side effect profile too, this is an extremely manageable side effect profile.... Right?
The reason I say this is because largely, and we have a very, very vast experience with Selinexor, over 30,000 patients have been treated with Selinexor to date, so we understand this profile very well. When you specifically look at the profile in combination with Ruxolitinib, we do not see any new AEs. Primarily, we are seeing cytopenias and GI toxicities, nausea. Not only is that consistent with what we see with Selinexor in other tumors, but this is very consistent with the profile that physicians are used to in the myelofibrosis space. They know how to monitor, they know how to treat it. Importantly, despite these AEs, patients stayed on therapy. We only had two patients who discontinued therapy due to treatment-related AEs. One was due to a thrombocytopenia, another due to a neuropathy.
That ability to stay on therapy is ultimately what has driven the very promising efficacy that we see in our phase I. This is the phase III trial design. So this is specifically a JAK-naïve population, very similar to that enrolled as part of our phase I. Approximately 300 patients randomized in a 2-to-1 ratio to either the combination of ruxolitinib selinexor or ruxolitinib alone. Two co-primary endpoints, so SVR35, TSS50, and these are tested hierarchically. Enrollment is going very well in this myelofibrosis space, and right now, we expect top-line data in the H2 of 2025. With that said, let me transition to endometrial cancer, and let me start again with that mechanism slide. So in endometrial cancer, what we are harnessing is XPO1's ability to retain a very important tumor suppressor relevant in endometrial cancer. This is gonna be p53, right?
The guardian of the genome. It's a very simple mechanism. XPO1 inhibits the efflux of p53 from the nucleus into that cytoplasm. The retention of p53 is what's driving cell death through multiple mechanisms. Very simple. What we know is that Selinexor obviously is a novel oral maintenance therapy in TP53 wild-type endometrial cancer. So this is the target population, patients whose tumors are p53 wild-type, are being enrolled in the ongoing phase III trial. When you look at the prevalence of p53, we know that more than half of all patients who have advanced recurrent endometrial cancer have tumors that are p53 wild-type. When you further segment that into the percentage of patients who are both p53 wild-type, as well as MMR proficient, another important emerging biomarker within endometrial cancer, we know that population is very sizable at approximately 50%.
We had an opportunity, I should say, Dr. Vicky Makker from Memorial Sloan Kettering, to present updated data from the SIENDO subgroup at ASCO earlier this year. What she presented was a very, meaningful long-term follow-up, a median PFS of about 28 months in all of the patients who are P53 wild-type. This Kaplan-Meier is specifically the efficacy in that subgroup of patients who are both P53 wild-type and pMMR. Again, represents approximately 50% of all advanced recurrent endometrial cancer. What you see in this long-term follow-up is truly unprecedented. A median PFS for selinexor of, 40 months, right? 40 months. That median PFS already exceeds the overall survival that was achieved with the checkpoint inhibitors in that pMMR subgroup. Compare that to the placebo arm that had an approximately 5-month PFS, that equates to a hazard ratio of 0.36.
Very extensive follow-up, with a median follow-up of about 39 months. These are the treatment-emergent adverse events that were observed as part of that p53 wild-type subgroup of the SIENDO. Again, very consistent with what I presented as part of myelofibrosis. Two flavors of AEs: you're gonna have your GI toxicity, you're gonna have your cytopenias. Just like myelofibrosis, this is something that physicians are very used to treating. They know how to dose modify. Ultimately, they're able to maintain their patients on therapy, which is what drives that long-term efficacy. This is the trial design for the phase III trial. Again, this study is ongoing. It is a maintenance trial, specifically evaluating Selinexor as a maintenance therapy in advanced recurrent endometrial cancer, whose tumors are p53 wild-type. These patients are randomized 1:1 to either selinexor 60 milligrams, dosed weekly, or placebo.
Primary endpoint is progression-free survival, and we project top-line results in early 2026. Lastly, let me segue into multiple myeloma, another exciting program for us. This trial that I will touch upon momentarily is specifically evaluating a very important novel, all-oral combination in multiple myeloma. So this is Selinexor in combination with Pom-dex at the low dose of 40 milligrams. We had an opportunity to present, publish updated data, specifically from an SPD cohort earlier this year in Frontiers of Oncology, and what we saw from this cohort was that the PFS is positively evolving. That median PFS in all of the patients is now 18.4 months, and 11.2 months specifically in that cohort of 16 patients who received a prior anti-CD38.
This is the trial design of our ongoing phase III trial, comparing SPD to EPD in patients with relapsed refractory multiple myeloma. This trial is ongoing with the primary endpoint of progression-free survival. Top-line data expected in the H1 of 2025. That said...
Yeah, thanks, Reshma. So just to wrap it up, as we touched on at the beginning, you know, the next 12 -18 months is truly transformative for Karyopharm, and we think transformative, with the potential to dramatically improve outcomes for patients, especially in endometrial cancer and myelofibrosis. We're very focused, as you see, on our top-line results in multiple myeloma in the H1 of 2025 , in myelofibrosis in the H2 of 2025 , and endometrial cancer in early 2026 . And with that, we'll wrap it up, and thank you for joining, and, looking forward to having further conversations with all of you.
Reshma, Richard, thank you so much for the great presentation. We really appreciate the time and effort that goes into preparing it, and we're so grateful you were able to attend the conference. So from the whole team at H.C. Wainwright, thank you so much. And if-