Hi, everyone. My name is Maury Raycroft, and I'm one of the Biotech Analysts at Jefferies. Thanks so much for joining us today. I'd like to welcome our guests today, Richard Paulson, the CEO, and Reshma Rangwala, the CMO of Karyopharm. Thanks so much for joining us. We're going to do a fireside chat discussion. Maybe to start off, if you wanna provide a one-minute intro to Karyopharm.
Sure. Thanks. Thanks, Maury, and thanks for hosting us. Just a little housekeeping at first. Obviously, there's our forward-looking statement slide, but, you know, when you look at Karyopharm, as a little quick intro, you know, we are a commercial-stage oncology-focused company, which are kind of positioning ourself strongly for our next phase of growth. And that next phase of growth is building on our foundation, which is in Multiple Myeloma, with a very focused and rapidly advancing mid- and late-stage pipeline of our oral and innovative first-in-class selective inhibitors of nuclear export that target XPO1. And so when we look at our commercialization capability right now, we have a strong commercialization capability in the U.S. and also global partners, with approval in over 40 countries.
You know, together, we'll be delivering revenue of $145 million-$160 million this year, and that gives us the capabilities also, as we continue to move forward with our phase III trials, pending, you know, success and approvals, to really launch rapidly in these new areas. When we look at our phase III programs, we're very excited that across our phase III programs, we've been able to build a strong body of data and evidence to support moving forward with those programs, and the data just continues to get stronger, and Reshma can talk to that. Really, across our three phase IIIs, we're focused on endometrial cancer, myelofibrosis, and multiple myeloma.
We think in each of those areas, we have the opportunity to significantly improve outcomes for patients, but we also have the opportunity to significantly transform Karyopharm with any one of the opportunities and, of course, all three, together with our foundation in multiple myeloma, potentially U.S. peak revenue of $2 billion with success of those programs. We have a strong financial cash position to deliver. So we're seeing readouts across these programs over the next two years, and our current cash position enables us to run from a cash perspective to, you know, late 2025. So readouts for multiple myeloma in the second half of 2024, in endometrial cancer, the first half of 2025, and myelofibrosis, you know, through 2025.
So a real strong position to deliver on those, and I think, again, transform us as a company and really continue to deliver, you know, improvements in outcomes for patients.
Great. Yeah, I think that's a really good intro. Do you have more slides or-
That's it.
Okay.
You said one, you said one minute, so we're good.
Okay. Great. And so let's dive into endometrial first. A lot of interest in this program. You're running the phase III study for Selinexor as maintenance in first-line endometrial, and this is in patients who respond to chemo and are TP53 wild type. And you've recently shown initial survival data from your original SIENDO phase III in this patient population, but this is still immature, so still getting better over time. Maybe talk about the data that you've shown from this study and some of the durable efficacy that you're seeing there.
Yeah, absolutely. This, this is really a very exciting program for us at Karyopharm. You know, one of our first solid indications that we're exploring with Selinexor, this XPO1 inhibitor. So we originally conducted what's called the SIENDO trial. It was a phase III clinical trial that evaluated Selinexor versus placebo as a maintenance therapy in patients with advanced recurrent endometrial cancer. You know, unfortunately, the ITT didn't show clinically meaningful benefit. However, we observed a very meaningful subgroup, specifically patients whose tumors were p53 wild type. They represent about half of all patients who have endometrial cancer. And in this subgroup of p53 wild type, we observed a really remarkable benefit, right? With a hazard ratio of around 0.4, again, in that patient population, who was p53 wild type.
If you look at the benefit in those patients who are p53 mutant, you didn't see any benefit. It makes sense. This is our mechanism. XPO1 inhibition retains active tumor suppressors within the nucleus, therefore allowing apoptosis, decreased cell proliferation, so it ties again very nicely with the mechanism of XPO1 inhibition. That data for PFS has only continued to evolve very positively. The most recent data cut now shows that hazard ratio again in that 0.4 range, but when you look at the median PFS for Selinexor, it's 27.4 months. In placebo, it's only 5.2 months. And when you look at the patient population, who is now both p53 wild type and then MMR proficient, these are the patients who don't really benefit from the checkpoint inhibitors.
The data potentially are even more strong, with a hazard ratio of 0.32. The data that you were alluding to was just presented in South Korea at IGCS. We had an opportunity for the first time to present overall survival data. These are still immature, but continues to strengthen the profile. The overall survival is 0.76 in that p53 wild type subgroup. When you look at the p53 wild type pMMR, 0.56. So this profile for efficacy, again, really strong, and I think we have an opportunity to truly change the standard of care for patients with endometrial cancer, not only with the drug, but also by, by providing a new companion diagnostic for physicians.
Got it. Yeah, great overview of the endometrial data from SIENDO, and now you've started the XPORT phase III study in this population of patients. Talk about that trial design and why you chose the 60 mg weekly dose versus the 80 mg dose that you used in SIENDO.
... Yeah, very good. So the XPORT trial, very similar to SIENDO. Some of the key differences, though, the patient population is only p53 wild type. Again, you know, sort of based upon the data that we learned from SIENDO. So just p53 wild type. We have partnered with Foundation Medicine. They're using their NGS platform to identify the p53 status amongst all of the patients. The other key difference is that the dose is decreased from 80 mg to now 60 mg, and really the reason is because 60 mg truly is likely the optimal dose. It maintains benefit, potentially improves benefit by driving longer PFS and OS, but substantially decreases the toxicity. And a lot of these data are from our SIENDO trial, looking at both the clinical as well as the pharmacokinetic data. The study is enrolling really well.
We've partnered with both the GOG as well as ENGOT. These are two main cooperative groups within the gynecologic space in the U.S. as well as Europe. They include the top KOLs, and we look forward to reading out the data in the first half of 2025.
Got it. And, maybe talk about how enrollment is going for the study. And on your third quarter update, you updated the guidance for timeline for the study to first half 2025. Maybe talk, contextualize that.
Yeah, absolutely. So, so as I just mentioned, you know, sort of the study is actively enrolling. Again, we are, we have sites in the U.S., in Europe. We have a few sites in Asia Pac as well. You know, one of the delays that we have seen, and this is just in a couple of countries in the, in EU, is largely due to the IVDR process. It's a complicated process. It's relatively new, but it's a required process for any trial that has a biomarker-driven approach. So we have seen a couple of delays in some of the big countries in Europe, likely on track to get activated in the next couple of months. And again, you know, sort of strong enrollment will drive top-line results into 2025.
Got it. That makes sense. And there's been a good amount of progress recently with anti-PD-1s in the space, too, notably GSK's Jemperli and Merck's Keytruda. Although for the most part, it's been more in the MSI-high-
Yeah
... patient population in the front line in combo with chemo and then also as maintenance. Can you talk about how this patient population overlaps with the patient population you're pursuing?
Yeah, absolutely. Great question. So the checkpoint inhibitors have really become a game changer in endometrial cancer as well as many other tumors. But it's not surprising that the majority of the benefit really is seen in those patients who are MMR deficient. So unlike the proficient population that I just mentioned, this deficient population really comprises a very small minority of patients. Anywhere between 20%-30% are going to have patients that are deficient in their MMR. Again, the efficacy is really outstanding. The approval for Jemperli is, again, only in this dMMR patient population, which really means that that the vast majority of patients who are MMR proficient do not have a standard of care.
I think this is really where Selinexor fits in very nicely, largely because the benefit that we are seeing is really in that p53 wild type pMMR patient population. We have an opportunity to now provide a potential new standard of care in that patient population that right now really doesn't benefit from the checkpoint inhibitors.
Got it. Makes sense. There was a recent update from Jemperli that showed survival benefit in a broader patient population base, but we don't know the details-
Right.
-of that update. Just wondering what your thoughts are on that, and could they potentially have label expansion there at some point?
Hard to say. You know, I haven't seen the data, so I think it's, again, it's really gonna be important to see what was the benefit specifically observed in that pMMR patient population. You know, that press release did indicate overall survival was observed in that ITT patient population. But I think, again, for the regulators and certainly for the patients, it's really gonna be important to see what the benefit is in the pMMR, especially as we start to contrast it to the very meaningful benefit that we've seen with Selinexor in that pMMR-p53 wild type population.
Makes sense. And, just, from current practice right now, do you have an idea of how many patients are getting anti-PD-1 with combo upfront? And, how that's looking in your study as well. And do you see an imbalance between MSS, MSS and MSI-high patients, on your study?
It's still very small, right? You know, by and large, you know, when we look at the data, when we talk with the physicians, the large patient population that is receiving that checkpoint inhibitor is going to be that dMMR deficient patient population. As a result, even in our clinical trial, we see very few patients having received prior checkpoint inhibitors. And we expect, right, sort of when we look at the entire sample size, you know, the 220 patients, you know, I expect less than 10%-15% of the patients having received a prior checkpoint inhibitor. In terms of the MSS, MSI balance, so it's not a stratification factor. With that said, again, that MSS or pMMR patient population is gonna represent the vast majority at about 80% of the patients.
Just given, you know, sort of that very large prevalence, we do assume that there's gonna be equal balance across the two arms.
Got it. Okay, that's helpful. And, maybe talk about the market opportunity here and how they could look for endometrial maintenance for XPOVIO.
Yeah, absolutely. I mean, it's a very sizable patient population, about 16,000 women in the United States alone. Again, about half of those patients are gonna be p53 wild type, half or maybe even a little bit more, when you specifically look at that patient population who is p53 wild type pMMR, right? Again, that patient population that is not benefiting from the checkpoints, we assume they're anywhere between 40%-55% of that patient population. So again, very sizable. The other aspect that's important is the durability, right? So, you know, the fact that we are seeing these PFS data continue to evolve so positively is really based on the fact that patients are staying on therapy. So that durability, that ability to stay on treatment, is also gonna drive our market opportunities.
Got it. Makes sense. And let's shift gears to multiple myeloma. You recently reported around $30 million in sales, which is essentially flat from year-over-year. Can you talk first about the technical headwinds you've been facing in terms of higher use of patient assistance programs and gross to net discounts, and put specific numbers behind how much that has affected sales and maybe progress in alleviating these headwinds and when you could see them resolved?
Sure, Maury. So I think as we've talked to in end of Q1 and kind of through Q2 and Q3, you know, at the end of Q1, we saw a dramatic increase in the amount of patients that came onto patient assistance programs. Third-party foundations, you know, temporarily were out of funds. Now moving forward through kind of Q2 and Q3 and now into Q4, you know, two of the four main foundations are able to provide assistance, and this is for patients who are Part D Medicare patients who face a 5% beneficiary copay. So, you know, as we've evolved through the year, once those patients start, they need to continue to stay on therapy, and we continue to provide that therapy.
In Q3 of this year, you know, a free drug we gave out through the patient assistance program was 9%, and in Q3 of last year was only 4%. So obviously, that 5% delta negatively impacting us. And then also, when we look kind of Q3 this year versus Q3 last year, we see gross to net has gone up by about two points, so from 18%-20%, you know, driven primarily by increases in 340B, and Medicare, rebates.
Got it.
and kind of in your last part of the question, as we move forward into next year, there's IRA-related changes to the Medicare Part D design. Patients will not have the 5% beneficiary copay, so we expect to see significantly less patients, you know, accessing the patient assistance program, kind of moving back to a more normal state.
Okay, so more normal state in 2024-
Yeah.
-than for this. Makes sense. And then also, you've talked about competition in the later line setting and, and also making progress in the frontline setting. Maybe talk about how that has evolved over the past year, and how Selinexor is being used in earlier lines, which is where your focus.
Yeah, I think we've made really strong progress, kind of the later lines, kind of the fourth, fifth line plus, and then that second to fourth line being the earlier line, not the front line, but second to fourth line. So, you know, in Q3 of this year, new patient starts were at 60% in that second to fourth line, versus Q3 of last year was only 40%. So really strong progress in moving up, and primarily that's been because of our focus on the community. So the community setting sees the majority of patients in that second to fourth line, and I think with Selinexor being an oral, being a class change, I think it's enabled the community setting to really entrench ourselves into that community setting.
In the institutions and academics, as you mentioned, you know, in that setting, that's where we've seen, you know, a strong increase in competition with bispecifics, with CAR-Ts, et cetera. And as we evolve in that space, I think, and as we've talked to, you know, we're really creating, you know, significant amount of data to help establish Selinexor in terms of kind of being a T cell sparing agent that can be used kind of pre or post in the academic setting. So we're gonna continue, you know, focusing on the community and driving access in there, and at the same time, generating data and supporting institutions and academics with the evolution of what's happening in that space.
Got it. Makes sense. And any other specifics that you're seeing from either script refills or even doctor surveys or prescription data that you can comment on that gives you confidence in being able to access earlier line patients?
Yeah, I mean, again, I think moving up with 60% of our patients starts now being in that second to fourth line, I think the strategy is working, and we've got to continue to focus on it. In a very competitive space, I think we're making strong progress. When we look at patients in the earlier lines, yes, those patients are staying on therapy longer and having greater duration of therapy. So that's something we want to continue to build on. I think also, which is very positive, in the community setting and being recognized, you know, by physicians, we just got, you know, elevated in NCCN guidelines as a preferred Category 1.
And at the same time, in NCCN, they also put out guidance, you know, that physicians should make sure they're changing classes and not kind of recycling patients into Anti-CD38s. So again, positive for us as being an innovative medicine, only selective inhibitor nuclear export. And at the same time, you know, I think another tailwind for us is new data from a subset analysis. We did the BOSTON study, which looks at PI-naive patients. So increasingly, patients are getting DRd more up in the frontline. Right now, it's about 10%. And so in that PI-naive setting with XVd, we had a PFS of, you know, just over 29, 29.5 months and a hazard ratio of about 0.29. It's really positive data to continue supporting, you know, increased utilization in the community.
Got it. That's helpful. And you've also shown some data on using Selinexor pre- and post-T cell-directed therapy. Can that data be used to educate doctors on how to use the drug?
Yeah, absolutely. This whole concept of T cell fitness really is becoming very critical within multiple myeloma, just with the incorporation of now multiple T cell therapies within that space, whether it be CAR- T, BCMA, bispecifics, et cetera. You know, with that said, though, sort of sequencing all of these T cell therapies back-to-back is absolutely not efficacious, just given the negative impacts on that T cell environment. So physicians really are looking for therapies that they potentially could use pre-T cells to make sure that the immune environment is in that, you know, opportune position prior to giving a T cell, post-T cell therapies, and then, of course, in between each one of those T cell therapies.
This is where our preclinical data, our real-world evidence data, and now, you know, soon-to-come clinical data is going to be very informative, especially with some of the early data suggesting that Selinexor really has a positive impact on that T cell environment by really sort of decreasing the expression of checkpoint inhibitors, including PD-1s as well as LAGs. But also some preclinical data in Diffuse Large B-Cell, indicating that when you sequence Selinexor followed by a T cell therapy, your efficacy potentially can be optimized. Real-world evidence data as well. So when Selinexor is prescribed post-BCMA, you see an increase in your response rate and also an increase in your PFS. So that data is rapidly maturing.
Lastly, I'll mention is that we just announced a collaboration with BMS, looking at Selinexor in combination with Mezigdomide, which is a novel cereblon therapy, sort of a second-generation PI. Both of these therapies individually have shown positive impacts on this T cell environment. The hope is that this combination can actually reverse T cell resistance. So more to come from that clinical trial, but very encouraged by this collaboration.
Yeah, interesting. Last question on multiple myeloma, and then I want to shift gears to myelofibrosis. I think you've reported earnings early in the past. Wondering if you could do fourth quarter earnings early for next year and potentially issue guidance as well, beginning of next year.
Yeah, I think we're probably looking to keep the same kind of rhythm moving into next year.
Okay. Okay, got it. And, so for myelofibrosis, you're running the phase III study. Maybe talk about progress there and, maybe if you have line of sight to... I think you mentioned later in 2025, you could have the data for, for that study.
Yeah. So still relatively early days for this phase III trial. You know, just as a reminder, a relatively traditional phase III, looking at the combination of Selinexor with Ruxolitinib. The dose is 60 mg, and this is based upon data from the phase 1 study versus Ruxolitinib, double-blinded, co-primary endpoints of both SVR 35 and TSS 50 at week 24. This is going to be a global study, so in the U.S., EU, as well as Asia Pac, and really, sort of the team is doing a stellar job of activating countries, sites and, you know, as you mentioned, looking forward to top-line results, likely in the second half of 2025.
Got it. And you showed updated data recently at a medical conference and on your earnings call, where responders to Selinexor plus Rux seem to be durable, with median follow-up at 32 weeks for SVR 35 and then 51 weeks for TSS 50.
Mm.
Can you talk about the totality data and what gives you confidence going from this phase I study into a phase III, particularly on TSS 50, where we've seen other phase IIIs have issues?
Yeah, absolutely. So, you know, I thought the endometrial data are very encouraging. They still are, but these data are, you know, equally as encouraging. Specifically, because when you look at the main endpoints within myelofibrosis, again, SVR35, this is spleen volume reduction of at least 35%, and also the TSS50, which is a 50% or greater improvement in that baseline symptom score at week 24. We're seeing really remarkable numbers. Yeah, numbers are small from the phase I, but we're seeing an almost doubling in that SVR rate compared to Ruxolitinib, also very meaningful improvement in that TSS50. You know, with that said, this is just at a static time point. This was at 6 months. What physicians, what investigators really are looking for is how durable those SVR reductions and those TSS50 reductions.
These are the data that we just presented at the MPN conference in Brooklyn, which suggests that, which shows that for neither SVR or TSS50 are patients progressing. So, you know, it's a flat line, and this is with, you know, follow-up over a year. So in that SVR, that maximum follow-up is 78 weeks, and TSS50, 64 weeks. Again, none of the patients have progressed on either one of those two endpoints. But in addition to those, you know, very meaningful improvements in SVR, TSS50, obviously the durability, we're also encouraged by the fact, you know, that we have potential monotherapy activity, a big differentiator in, in myelofibrosis development, and all of this is in the context of a very safe and tolerable safety profile.
TSS50, yes, it is a hard endpoint, but just again, very encouraged by how the data are evolving with now the most recent, durability data.
Got it. And, we're looking out for Morphosys data for their BET inhibitor plus Rux. What are your thoughts on how that could impact your strategy? There's been a lot of interesting BD developments in myelofibrosis space. How do you think about that, and could you potentially partner this program if you wanted to?
Yeah. So I'll take the first part of the question. You know, looking forward to the data from, you know, sort of MorphoSys from that Pelabresib plus, you know, Ruxolitinib combination. You know, when I talk to physicians, when we talk to investigators, you know, combinations is going to be the new way forward in myelofibrosis, largely because Rux has been the standard of care for over a decade. You know, with that said, you know, efficacy is somewhat marginal, with less than 50% of the patients achieving SVR and TSS 50. These combinations, whether it be Selinexor plus Rux or even Pelabresib plus Rux, is really maximizing the benefits. So I think they're really doing a nice job of paving the way for a new paradigm in myelofibrosis.
Yeah, and then going to the second part, again, I think we're really focused on executing on the trial. You know, very open to the possibilities to make sure we maximize the potential of Selinoxor plus Rux as we execute on the trial. So I think a lot, a lot of opportunities are open for that, and there's a lot of value, I think, obviously, in the myelofibrosis franchise. When you look at the fact, as you engage with opinion leaders and physicians, you know, the majority want to be going to agents that are going to improve efficacy, improve outcomes, which we're seeing with the doublets. So excited about it, and I think it's a great opportunity.
Makes sense. Maybe to close out, if you could talk about cash runway and spend going forward, and just maybe recap the key catalysts ahead that investors should be focused on.
Sure. I think as we're guided to, you know, we believe we have strong cash position takes us through to late 2025. And our key catalysts really are continuing to deliver on our phase 3s with our multiple myeloma trial with XPOVIO all oral post anti-CD38 in the second half of 2024, endometrial cancer in the first half of 2025, and then myelofibrosis, as we talked about, through 2025. And obviously, you know, the completing the recruitment of those earlier, I think opportunity to share that with people, and then very confident as we continue to deliver on our guidance for the year and drive our multiple myeloma base revenue.
Great. Thanks so much for joining us today.
Thank you.