All right, good afternoon, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ultz, one of the Biotech Analysts here, and it's my pleasure to introduce the team from Karyopharm, including Richard Paulson; CEO, as well as Reshma Rangwala; CMO. Just a reminder, the format for today is a fireside chat. Before we get started, I just need to read a quick disclosure statement. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, maybe I'll turn it over to you, Richard, just for some introductory comments for people that may not be familiar with Karyopharm, and then we can get into the Q&A.
Sure. Thanks, Mike, and thanks to Morgan Stanley for having us and hosting us here today. You know, Karyopharm is an innovation-driven commercial-stage company, where our mission is to, you know, positively impact lives and defeat cancer. Our foundation is in multiple myeloma, with our first approved drug, pomalidomide, which goes by the trade name of Xtampiza. And right now, we're focused in multiple myeloma. Second- to fourth-line is where the majority of our patients are treated, a kind of a second-line plus multiple myeloma indication. We're approved in over 40 countries around the world with our partners around the world. And we're really focused on advancing rapidly to our next stage of growth, which is moving forward with three phase III trials, one in multiple myeloma, one in endometrial cancer, and one in myelofibrosis.
As you're looking to where we are today, it's to build on that foundation, and it's to really move forward and execute in the trials with the opportunity, I think, in areas of high unmet need, to bring some great new potential therapies to patients.
Yep. Great. That was a perfect introduction, and maybe we can start with some questions on the foundation, so XPOVIO in multiple myeloma. Maybe talk about some of the commercial trends you're seeing and what the levers of growth are as you're looking forward.
Sure. I mean, our primary focus has been in that earlier line setting, and it's been to focus on the community. So, you know, as we talked about in Q2, you know, from a demand perspective, we grew demand by 9% in Q2. In the first half of the year, we've grown demand by about 8%, 6% Q1, 9% Q2. And what we're seeing now is about two-thirds of our utilization is in the community, where the majority of multiple myeloma patients are treated, and that shows our strategy is working, 'cause that's been our focus, is to focus on the community. At the same time, about 60% of our patient utilization is in the second to fourth line. Again, very much in line with our strategy.
That's moved up year-over-year, where a year ago it was about 49%, to now over 60%. So focus on the community, focus on the earlier lines, and our strategy, I think, is moving forward really well.
Yep. Maybe just on the two-thirds, use in the community setting, do you think you can keep driving that higher, or where do you ultimately sort of expect to end up?
Yeah, I think we're gonna probably see that higher. You know, in the earlier lines, you probably have 65%-70% of patients in general, which are treated in the community. So I think we can see ourselves continuing to grow there. You know, in Q2, we grew in the community by around 11%, and we grew in institutions and academics by around 6%, so almost double the growth rate in the community than in institutions and academics. But I think importantly, you know, growth in both of those segments.
So it sounds like underlying trends here are definitely positive, but you're having some headwinds on the revenue side a little bit this year. So maybe just walk us through that. What's been the challenge, and then, you know, how do you address that, or when can we move past that?
Yeah. You know, our net revenue is being adversely impacted, you know, year to date by an increase in what's called our carry forward program or our patient assistance program. And that's really where, you know, patients who can't afford co-pays and especially on the Medicare/Medicaid side or the uninsured, you know, we would provide free drug to them. Usually, that's at about 5% for us and many other companies in this space. In Q2, that went up to about 14%. In Q1, it was about 9%. So what happened in that space, kind of, is the end of Q1, early Q2, some of the major foundations which provide support for these Medicare/Medicaid patients ran out of funds and weren't able to provide funding.
Now, since then, you know, the major foundation, which does provide support, has been open, you know, and continues to be open, so we see less utilization of new patients coming into that space. But at the same time, you know, as we start patients on, we also have to maintain them. So that's kind of been a carryover effect. You know, we do see moving forward, if foundations continue to be open, that we'll, you know, move more to a normalization of that. And also, as we move into next year with some redesign, the benefits program on the Part D side, this 5%, you know, beneficiary co-pay goes away with some redesign under the IRA. So we expect to see, you know, that kind of normalize as we move into next year.
Yep. I guess, how confident are you that that will be the case? It sounds like pretty confident there's a set deadline for that to happen.
Yeah. I mean, pretty confident that'll be put in place January one.
Gotcha. Okay, maybe sticking with multiple myeloma, we can maybe touch on your phase III study, ESPD, maybe talk about some of the advantages of that combination, and how you see that sort of changing, or fitting with your current strategy to drive use sort of in the second-line plus setting.
Yeah. I can take that one. So it's one of our phase III trials that we're currently conducting. Specifically, we're evaluating selinexor, XPOVIO, in combination with pomalidomide Dex. One of the key attributes of that combination, it's an all-oral, you know, regimen, so perfect for that community-based physician and for patients who may be in the rural setting, in which, you know, coming, you know, going back and forth to centers is gonna be difficult. We're evaluating ESPD, specifically at the 40 mg dose, one of the lower doses, versus Elotuzumab Pom Dex. Patient population must have received one-four prior lines of therapy, and all patients must have received a prior anti-CD38 in its most immediate prior line. It's a 1:1 randomization.
Approximately 220 patients will be enrolled, and the primary endpoint is progression-free survival, with key secondary endpoints of overall survival, as well as objective response rate. Tracking really well, and right now, we anticipate top-line data from that study in the second half of 2024.
I think that's really important because it, you know, enables us to kind of continue growth in the next few years with an all-oral combination. You know, when you look at Pomalyst, you know, it's about a $2 billion backbone to be partnering with. And I think also, when you look at the evolution of having an all-oral option through the treatment continuum that many patients engage in, I think it, you know, that gives us a really strong probability of continued growth as we move forward.
Yep. In the community setting, you mentioned oral, all oral is attractive, and I think it makes sense why. I guess, what's the current preferred regimen in the community setting, and is there an all-oral regimen available today?
I mean, I think there's a lot of different options that physicians can obviously choose. So I think, you know, when you look at selinexor and what it's combined with, you know, obviously, what we promote to is with XVd, with Velcade. But also on NCCN, we do already have listing with Pomalyst, and so that utilization already is occurring in the community. And we also obviously have listing with Kyprolis and with daratumumab, but we don't promote to those. So in the community, you know, physicians are using a lot of different agents. I think there's a need for more oral options, so, you know, we view it as a pretty positive option moving forward.
Yep. So definitely. Reshma, you mentioned going with 40 milligram dose. I guess, what are the advantage, advantages there? And maybe on the other hand, are there any risks to going, you know, lower in the dose?
Yeah. You know, so over the last year and a half, you know, we've aggressively looked to optimize the dose of Selinexor. You know, as many of you remember, the initial approved dose was 80 milligram twice weekly, or 160 milligrams total weekly. Obviously, there was benefit, but aggressive, meaning that the toxicity profile was aggressive. I think looking at real-world evidence and talking with physicians, looking at our own clinical trial data, as well as looking at pharmacokinetic data, it was clear that we could optimize the dose and substantially reduce the dose by a third to a quarter. And you can see that within this trial specifically, in which, again, the dose is 40 milligrams. Now, to further elaborate, we have multiple cohorts of patients who were treated either in... with ESPD at the 40 milligram dose, separately at the 60 milligram starting dose.
Looking at those data, both the efficacy is optimized at that 40 mg dose. Tolerability is also improved, again, at that 40 mg dose. That data set clearly shows that that clinical benefit is optimized at that 40 mg, really providing confidence around the success in that phase III.
Makes sense. Maybe we can shift to just endometrial cancer.
Mm-hmm.
You've got a phase III ongoing there.
Absolutely.
Maybe just talk about the unmet need, and where selinexor could fit in there.
Yeah. So, so clear unmet need in endometrial cancer. You know, by and large, patients are gonna be treated with standard carboplatin. So this is chemotherapy, been around for decades. Unfortunately, though, once patients complete that four-six cycles, they progress very quickly. In fact, the PFS on that carboplatin is very limited at around four-five months. There has been no maintenance options for these patients, unlike ovarian cancer, unlike breast cancer, which really have prolonged that progression-free survival. What we've identified with the SIENDO data is that patients who are specifically p53 wild type, treated with selinexor, really have a very substantially prolonged PFS. At the time of the initial data cut that we performed last year, you know, that median PFS in that selinexor arm was 13.1 months.
We had an opportunity to present long-term PFS data at the ASCO plenary in July of just this past year, 2023. What we see is now that PFS, that median PFS, has more than doubled, so it's gone from 13.1 months to now 27 months. That is, as Gini Fleming described, unprecedented data
in the field of endometrial cancer, and it highlights the importance of this biomarker selection. Obviously, precision medicine is at the frontier in oncology. Being able to identify now a unique molecular subgroup that can benefit patients who are endometrial is clearly gonna drive that benefit, you know. What we also further did was we looked at specifically the benefit in those patients who are P53 wild type in MSS and P53 wild type MSI. Why is that important? Because that classification of MSS versus MSI is now evolving, given the emergence of the checkpoint inhibitors. Dostarlimab was recently approved, specifically in those MSI high patients, but from that data set, it was also clear that MSS patients just clearly do not benefit. I say that because in our analysis, what we found is that the benefit was overwhelmingly identified, specifically in patients who are P53 wild type and MSS. They represent 70% of all P53. In that subgroup, median hasn't been reached.
Hazard ratio is now 0.32, and clearly sort of sets the foundation of selinexor becoming a clear standard of care within this subpopulation.
Maybe you can talk about mechanistically, why it makes sense that selinexor would work in, specifically in the wild type population?
Yeah, such a great question. So selinexor is an XPO1 inhibitor. XPO1 controls the shuttling of proteins between the nucleus and the cytoplasm. Part of these proteins are going to include tumor suppressors and also oncoproteins. Probably one of the most important tumor suppressors is P53. By able to retaining or that retention of P53 within the nucleus, only increases, apoptosis and, you know, decreases cellular proliferation. So the fact that we see the benefit, specifically in that wild type subgroup, again, just underpins the basic mechanism of selinexor itself.
Yep. Part of the strategy is selecting those patients.
Yes.
So maybe you can talk about, I think you have some agreements, with Foundation, maybe. Maybe just talk about that and-
Yes.
How you kind of move that forward as well.
So the ongoing phase III trial, EC-042, is another maintenance trial, so we're evaluating selinexor versus placebo. However, we're only enrolling patients who are P53 wild type. So we've collaborated with Foundation Medicine, and they're using their proprietary NGS platform to assess the P53 status within patients' tumors. What we anticipate is that at the time we get approval, hopeful approval for the drug, we'll also get that approval for the companion diagnostic. So selinexor will be approved specifically in patients who are P53 wild type.
Got you. Maybe just talk about the progress of the Phase Three study, timing of data-
Yes.
and how to think about that.
Yes. Enrolling well, you know, we have strong collaborators, not only with Foundation Medicine, but also the GOG, as well as ENGOT, the two key cooperative groups, both in the U.S. as well as in the E.U., respectively, and they've partnered us as early as Siendo. So, you know, we've had years of collaboration with these, with these important groups. You know, we still anticipate, you know, top-line data at the end of 2024, beginning of 2025.
Okay. Maybe we can shift to myelofibrosis. Maybe talk about your strategy there, and maybe touch on some of the data we've seen so far, which has been pretty encouraging.
Yeah, absolutely. So we had an opportunity earlier this year at AACR to present the top line 24-week data, both for SVR as well as TSS 50, specifically from our phase I e xperience, in which we evaluated selinexor in combination with standard of care, ruxolitinib, specifically in patients who are treatment naive or JAK-naive myelofibrosis patients. All of these patients had to have platelet counts of 100 or above. What we identified and presented at AACR were really impressive SVR and TSS 50 data. These are the two main endpoints, specifically in myelofibrosis. What we observed in the intention to treat population was a 79% SVR 35 rate, specifically within the 60-mg group, and a corresponding 58% TSS 50, again at week 24, it was that 60 mg selinexor dose.
These data are unprecedented, that SVR is more than doubling what you would see with Rux alone. Even that TSS 50 is a very meaningful and sizable increase compared to Rux alone. So based upon those data, we've initiated a phase III trial, again, in that JAK-naive myelofibrosis patient population, in which we're evaluating selinexor 60 mg in combination with Rux versus Rux alone. Key primary endpoints are going to be SVR 35 and TSS 50, evaluated at week 24, and we anticipate data sometime in 2025.
Maybe you can talk a little bit about what you saw on the safety side?
Yeah.
and, and how that's trending.
Yes, great question. So we evaluated two different doses of selinexor as part of the phase 1. We evaluated 40 milligrams, 60 milligrams, both dosed weekly. Again, these are the third to a quarter of the dose of the originally approved, so these lower doses of selinexor. In terms of efficacy, we saw a very interesting dose response in that 60 milligrams meaningfully improved the efficacy compared to the 40 milligrams. In fact, that SVR35 in the 60 milligram subgroup is double what we saw in the 40 milligrams. But interestingly, when we looked at the toxicity profile, the AE profile was very similar between the 40 and the 60 milligram group. Yes, numerically, it was a little bit higher in the 60 milligram group, but importantly, despite these AEs, patients were able to stay on therapy.
Only two patients discontinued therapy due to AEs, one due to a thrombocytopenia, another due to a neuropathy. But that ability to stay on therapy is what drove that SVR and TSS50. So again, a very meaningful efficacy without compromising the safety.
Yep. Maybe just quickly back to the AACR update-
Yeah.
In terms of, you know, the 24-week data, are there patients that haven't hit the 24-week time, time point yet, or is everyone past it? And then when is the next update we could get from that study?
At that time point, everybody had been followed for at least 24 weeks. So, you know, at this point, you know, patients are still on therapy. We're still continuing to follow patients. So we'll have an opportunity to update over the course of the next 3-18 months, you know, sort of that long-term durability of response-
Yeah.
potentially progression-free survival, maybe even overall survival data.
Yep. Yep. Maybe you can just touch on the competitive landscape in myelofibrosis. I know there's several other competitors out there.
Yeah.
Maybe just talk about your, your positioning.
Yes, absolutely. So there was a couple of other combinations that are currently in development. So one is the BCL-2 inhibitor, navitoclax, in combination with ruxolitinib. Some of you may know, they released a press release that indicating they saw a very meaningful improvement on their SVR endpoint. However, TSS50, they need to continue to follow. It's important to emphasize again, both SVR and TSS50 need to show that meaningful improvement. So hard to say how those data evolve, how that combination is gonna be able to provide benefit across both of those endpoints with that combination. In terms of the others that we're following very closely is the BET inhibitor, pelabresib. They, too, are combining in combination with ruxolitinib in a patient population very similar to what's enrolling in our own 0034 selinexor-ruxolitinib combination. Those data, you know, time will tell.
You know, hopefully, they will be able to present, you know, top-line data later this year. But again, you know, I just want to emphasize, we're very confident in our profile. Again, both SVR and TSS50, numerically, are probably the best-
Mm-hmm
-reported out there in the context of a very meaningful safety profile. I also want to mention that beyond the SVR and TSS50, we also differentiate in that we have potential monotherapy activity that's been seen in the SENTRY trial in a relapsed refractory MF patient population. We also have very intriguing subgroup data from the phase I, suggesting monotherapy activity, specifically, patients were dose-reduced with their ruxolitinib. Despite that very low dose, ineffective dose of Rux that they were on, they still saw very meaningful SVR and TSS50 data. That ability to treat as a monotherapy and maintain that activity is paramount in that it gives physicians flexibility-
Mm-hmm.
around the dosing in that combination setting, but also allows us to pursue additional populations who are treatment naive-
Mm-hmm.
that are currently not benefiting from standard of care therapy. We announced earlier this year at our earnings call that we are going to initiate a separate phase II trial, specifically looking at selinexor as a monotherapy in patients whose platelet counts are 50-100. This is an especially high unmet need patient population. We'll have an opportunity, hopefully, to expand selinexor as a backbone in the largest treatment-naive population in myelofibrosis.
Maybe just back to your point about the monotherapy activity-
Yeah.
with low doses of Rux. Could there be a situation where you start with the combo, sort of full-strength Rux, and kind of Rux sort of falls out of the regimen over time? Is that potential?
I think that could happen, right?
Yeah.
We know that patients start on ruxolitinib because of thrombocytopenia and anemia, known toxicities due to ruxolitinib.
Mm-hmm.
They need to dose reduce and then potentially, you know, even long-term dose discontinue. So that paradigm is still going to exist even in combination. You know, what these data suggest is that they can discontinue the ruxolitinib, but maintain patients on selinexor without compromising their efficacy.
You mentioned sort of the phase III data, sometime 2025.
Right.
I guess, any risk to enrolling the study? It seems like there shouldn't be because most patients are getting a JAK already, so.
Yeah, I mean, the JAK-naive space is, from a clinical trial perspective, open.
Yeah.
There are really no other competitors. You know, we don't have the challenges around COVID that-
Yeah
-some of our other competitors had. So we really look at it as very open space, you know. You know, and I will say the third point that is, that is critical is that, again, our KOLs, physicians in general, again, are very bullish on our data-
Right
really do believe that this combination could be best in class.
Yeah.
In terms of barriers, no, none that we see right now.
Gotcha. Maybe in the last few minutes here, just, just maybe quickly touch on eltanexor...
Yeah.
MDS, maybe just how it's different from selinexor and kind of your current thinking in MDS.
Absolutely. So eltanexor is our second-generation SINE compound. Just like selinexor, it too inhibits XPO1, but it differentiates in that it doesn't penetrate the blood-brain barrier as effectively as selinexor. One of the reasons this is critical is that some of the AEs that we see with selinexor, specifically the GI, the nausea, some of the fatigue, some of the vomiting, we believe is centrally mediated. So eltanexor safety profile potentially could be better from this non-heme tox profile. The other key issue is that the IC50, and therefore the potency for eltanexor, is lower than selinexor. One of the reasons this is critical is that there are multiple cancers, such as AML and MDS, in which preclinical models suggest that more chronic dosing of eltanexor actually leads to greater antitumor activity.
Based upon those data, we of course embarked on a phase 1 and a subsequent phase II, evaluating eltanexor in probably the most difficult-to-treat MDS patient population, specifically this higher risk relapse refractory MDS. What we observed across both phase 1 and separately the phase II is very encouraging median overall survival data in that 9-10-month range. Currently, best supportive care and few available therapies only afford an OS around four-six months. So really meaningfully pro-- you know, increasing that overall survival time for that patient population. It gives us an opportunity to further optimize the development plan that we want to embark with eltanexor, and we'll do that before the end of the year.
Good. Okay, great. Why don't we just wrap it up there? Thanks, Richard. Thanks, Reshma.
Thank you.
Appreciate your time.
Thank you, Mike. Appreciate it. Thanks.