Karyopharm Therapeutics Inc. (KPTI) Earnings Call Transcript & Summary

All right. Good afternoon, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Michael Ulz, 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. And just a reminder, the format for today is a fireside chat. And before we get started, I just need to read a quick disclosure statement. So 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. And 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. Karyopharm is an innovation-driven commercial stage company. Our mission is to positively impact lives and defeat cancer. Our foundation is in multiple myeloma with our first approved drug, selinexor, which goes by the trade name of XPOVIO. And right now, we're focused in multiple myeloma, second to fourth line is where the majority of our patients are treated, the 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 3 Phase III trials, 1 in multiple myeloma, 1 in endometrial cancer and 1 in myelofibrosis. So as we're looking to where we are today is to build on that foundation to really move forward and execute on the trials with the opportunity, I think, in areas of high unmet need to bring some great new potential therapies to patients.

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 as we talked about in Q2, 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% in Q1, 9% in Q2. And what we're seeing now is about 2/3 of our utilization is in the community where the majority of multiple myeloma patients are treated, and that shows our strategy is working because 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.

Yes. Maybe just on 2/3 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?

Yes. I think we're going to probably see that higher. In the earlier lines, you probably have 65% to 70% of patients in general, which are treated in the community. So I think we can see ourselves continuing to grow there. In Q2, we grew in the community by around 11% and we grew in institutions and academics by about 6%, so almost double the growth rate in the community than in institutions and academics. But I think importantly, 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 how do you address that? Or when can we move past that?

Yes. Our net revenue is being adversely impacted year-to-date by an increase in what's called our carryforward program or our patient assistance program. And that's really where patients who can't afford copays and especially on the Medicare and Medicaid side, or uninsured, we will 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 at the end of Q1 or early Q2, some of the major foundations which provide support for these Medicare/Medicaid patients ran out of funds, and we're unable to provide funding. Now since then, the other major foundation, which does provide support has been open and continues to be open. So we see less utilization of new patients coming into that space. But at the same time, as we start patients on, we also have to maintain them. So that's kind of been a carryover effect. We do see moving forward if foundations continue to be open, that will move more to a normalization of that. And also, as we move into next year with some redesign of the benefits program in the Part D side is 5% beneficiary co-pay goes away with some redesign under the IRA. So we expect to see that kind of normalize as we move into next year.

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.

Yes. I mean I'm pretty confident that will be put in place January 1.

Got you. Okay. Maybe sticking with multiple myeloma. We can maybe touch on your Phase III study, XPd. 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?

Yes. I can take that one. So it's one of our Phase -- 3 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 regimen. So perfect for that community-based physician and for patients who may be in the rural setting in which coming -- going back and forth to centers is going to be difficult. We're evaluating SPd, specifically at the 40-milligram dose, one of the lower doses versus elotuzumab pom-dex. Patient population must have received 1 to 4 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.

And I think that's really important because it enables us to kind of continue growth in the next few years with an all-oral combination. When you look at Pomalyst, 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, that gives us a really strong probability of continued growth as we move forward.

In the community setting, you mentioned all-oral is as 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?

Yes. I mean I think there's a lot of different options that physicians can obviously choose. So I think when you look at selinexor and what its combined with, obviously, what we promote to is with XVd with Velcade. But also on NCCN, we do already have a 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, physicians are using a lot of different agents. I think there's a need for more oral options. So we view it as a pretty positive option to move forward.

Definitely. Reshma, you mentioned going with the sort of lower 40-milligram dose, I guess. What are the advantages there? And maybe on the other hand, are there any risks to going lowering the dose?

Yes. So over the last 1.5 years, we've aggressively looked to optimize the dose of selinexor. As many of you remember, the initial approved dose was 80-milligram twice weekly or 160 milligrams total weekly. Obviously, there was a benefit, but aggressive -- being at 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 1/3 to 1/4. 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 with SPd at the 40-milligram dose separately at the 60-milligram starting dose. And looking at those data, both the efficacy is optimized at that 40-milligram dose, tolerability has also improved again at that 40-milligram dose. So that data set clearly shows that, that clinical benefit is optimized at that 40 milligrams, really providing confidence around the success in that Phase III.

Makes sense. Maybe we can shift to just endometrial cancer. You've got a Phase III ongoing there.

Absolutely.

Maybe just talk about the unmet need and where selinexor could fit in there?

Yes. So clear unmet need in endometrial cancer, by and large, patients are going to be treated with standard Carbo/Taxol. This is chemotherapy. Have been around for decades. Unfortunately, though, once patients complete that 4 to 6 cycles, they progress very quickly. In fact, the PFS on that Carbo/Taxol is very limited at around 4 to 5 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, 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 June -- July of 2020 -- just this past year 2023. And what we see is now that, 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 going to drive that benefit. 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 side, it was also clear that MSS patients just clearly do not benefit. I'd say that because in our analysis, what we found is that the benefit was overwhelmingly identified, specifically in patients who are p53 wild-type in 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?

Yes. 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 decrease the 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.

And part of the strategy is selecting those patients. So maybe you can talk about -- I think you have some agreements with Foundation. Maybe just talk about that and how you kind of move that forward as well?

Yes. 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 will 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 III study, timing of data and how to think about that?

Yes. Enrolling well. We have strong collaborators, not only with Foundation Medicine, but also the GOG as well as ENGOT. The 2 key cooperative groups, both in the U.S. as well as in the EU, respectively. And they've partnered us as early as SIENDO. So we've had years of collaboration with these important groups. We still anticipate 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.

Yes, 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 TSS50, specifically from our Phase I experience 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 TSS50 data. These are the 2 main endpoints, specifically in myelofibrosis. What we observed in the intention-to-treat population was a 79% SVR35 rate specifically within the 60-milligram group and a corresponding 58% TSS50 again at week 24 with that 60-milligram selinexor dose. These data are unprecedented that SVR is more than doubling what you would see with rux alone, even that TSS50 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 milligrams in combination with rux versus rux alone. Key primary endpoints are going to be SVR35 and TSS50 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 and how that's trending?

Yes. Great question. So we evaluated 2 different doses of selinexor as part of the Phase I. We evaluated 40 milligrams, 60 milligrams, both dosed weekly. Again, these are the 1/3 to 1/4 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 2 patients discontinued therapy due to AE is one due to 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.

Maybe just quickly back to the AACR update in terms of the 24-week data. Are there patients that haven't hit the 24-week time point yet? Or has everyone passed 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 at this point, 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 to 18 months, sort of that long-term durability of response, potentially progression-free survival, maybe even overall survival data.

Yes. Maybe you can just touch on the competitive landscape in myelofibrosis. I know there's several other competitors out there. Maybe just talk about your positioning.

Yes, absolutely. So there was a couple of other combinations that are currently in development. So one is the BCL-2 inhibitor venetoclax 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 going to 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 034 selinexor ruxolitinib combination. Those data, time will tell. Hopefully, they will be able to present top line data later this year. But again, I just want to emphasize, we're very confident in our profile, again, both SVR and TSS50 numerically are probably the best we 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 ESSENTIAL 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 a very meaningful SVR and TSS50 data. That ability to treat as a monotherapy and maintain that activity is paramount and that it gives physicians flexibility around the dosing in that combination setting, but also allows us to pursue additional populations who are treatment naive 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 to 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 with low doses of rux, is it -- 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? So one of -- we know that patients start on ruxolitinib because of thrombocytopenia and anemia known toxicities due to ruxolitinib, they need to dose reduce and then potentially even long-term dose discontinue. So that paradigm is still going to exist even in combination. What these data suggest is that they can discontinue the ruxolitinib, but maintain patients on selinexor without compromising their efficacy.

And 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...

Yes. I mean the JAK-naive space is -- from a clinical trial perspective is open. There are really no other competitors. We don't have the challenges around COVID that some of our other competitors had. So we really look at it as very open space. And I will say the third point that is critical is that, again, our KOLs, physicians in general, again, are very bullish on our data and really do believe that this combination could be best-in-class. So in terms of barriers, none that we see right now.

Got you. Maybe in the last few minutes here, just maybe quickly touch on eltanexor, 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's 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 model suggest that more chronic dosing of eltanexor actually leads to greater antitumor activity. Based upon those data, we, of course, embarked on a Phase I in a subsequent Phase II evaluating eltanexor and probably the most difficult to treat MDS patient population, specifically this higher risk relapsed/refractory MDS. And what we observed across both Phase I and separately, the Phase II, very encouraging median overall survival data in that 9- to 10-month range. Currently best supportive care and few available therapies only afforded OS around 4 to 6 months. So really meaningfully 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.

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.