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

Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. I am happy to introduce our guests today, Richard Paulson, the President and CEO; and Reshma Rangwala, the CMO of Karyopharm Therapeutics. Thanks so much for joining us today.

Thanks for having us, Maury.

And we're going to do a fireside chat format. So maybe for those who are new to the story, if you can provide a 1-minute intro to Karyopharm.

Sure. I mean Karyopharm was founded in 2008 as an innovation and patient-focused company really driving a first-in-class focus on the selective inhibition of nuclear exports and developing an all-oral medicine, which inhibits XPO1. And from that start in 2008 to where we are today, we're a commercial-stage company with our foundation in multiple myeloma and our first selective inhibitor nuclear export, selinexor, now approved in over 40 countries around the world. We've guided revenue for between $145 million to $160 million this year. It's really building on that foundation of multiple myeloma and starting to see our global launches take place and continuing to drive our U.S. commercial presence. And from that foundation, I think we're really posed for strong growth moving forward with a very focused and a mid- and late-stage pipeline. We have 2 pivotal Phase III programs going. First, in our foundation of multiple myeloma with an all-oral selinexor combined with Pomalyst, kind of SPd. Second, pivotal Phase III program in endometrial cancer, which we're very excited about in terms of developing that with TP53 wild-type patients, endometrial cancer. And looking to initiate our third pivotal Phase III program very shortly in myelofibrosis with selinexor in combination with rux in treatment-naive myelofibrosis patients. And then our second novel SINE compound, eltanexor, some really interesting data in MDS in the mid-stage, which, again, we're looking to see how we can really benefit patients with MDS. So a very focused pipeline. As an organization, we've really been able to target our pipeline, be disciplined in terms of stopping noncore programs. And with that, we have a strong balance sheet, which enables us to have a cash runway into the end of '25. And as an organization, we believe we're really strongly poised to have multiple approvals over the next 2 to 4 years, which we believe have the opportunity to drive significant value for both patients and shareholders.

Got it. That's a great intro. And maybe starting with commercial and digging into multiple myeloma, specifically with XPOVIO, for 2023 guidance, you've adjusted that. Maybe talk a little bit about what went into the revised guidance and how much was technical such as with patient assistance programs versus gross to net versus competitive headwinds?

Yes. I think as we talked during our Q1 call, the significant amount was really driven by what you call -- what you would call technical in terms of we saw a significant increase in the utilization of our carryforward program, which is our patient assistance program. And traditionally, that's been about 5% of utilization when you look at our total utilization. That actually grew to 20% in April as we saw significant increase in patients needing access to patient assistance programs. So with that, that drove a large part of our guidance change. And then also with regards to gross to net, we saw a 5-point increase kind of year-over-year in gross to net, and we've guided between 20% to 25% in GTN. It's going to be at the high end of that. So really driven by those technical factors, which, again, as we look moving forward, I think in 2024, when you look at some of the evolution to IRA-related changes, patients who have Medicare Part D have a requirement for the kind of 5% co-pay or coinsurance when they hit the catastrophic coverage, and that goes away in '24. So we should see much less demand through foundations and again then much less demand for our carryforward program.

Got it. That makes sense. And for the amount impacted by the patient assistance program, are you saying what percent that was for first quarter? And how should that look for the rest of 2023 and even for 2024?

Yes. So again, the significant, significant portion was really driven by the carryforward and the patient assistance program. So with our revised guidance, we have to look at taking that into account because there's a large uncertainty with regards to that moving forward. So as we look at moving forward, I believe we've taken into account being conservative with regards to that into 2024. As you mentioned, we believe a large part of that demand should normalize back to what it's been traditionally, given the changes with regards to financial requirements for Medicare Part D patients.

Got it. And for competition, we've talked in the past about headwinds in the later-line setting with the approvals of CAR-T therapies and anti-BCMA bispecifics. Do you think late line selinexor use has stabilized? Or how do you see market share evolving there?

Yes. I think in Q1, as we talked to kind of year-over-year, selinexor, when you look at our total demand, which is obviously our sales plus our carryforward program, actually grew 6% year-over-year in a very competitive environment. In the institutions and academics, we actually maintained our sales in a very competitive environment, which I think is strong. And in the community setting, we grew our business. So I think when you look at moving forward, again, in the institutions and academics, yes, a number of new therapies coming in place. Again, not all patients are eligible for kind of the T-cell engaging therapies. So in the institutions and academics, as you know, we've done a lot of work, and we can talk to it with regards to ensuring -- looking at the T-cell environment and I think, again, given the mechanism of action of Seli and given data we've been working to generate, we're able to ensure we don't negatively impact the T-cell environment. So when you do need to go to that T-cell engaging therapy, you're able to maximize the benefit. And then also for patients who can access, again, I think in institutions and academics, we're being able to maintain our business, which is a strong sign in a very competitive environment. At the same time, our focus continues to be on the community where 60% to 70% of patients in general are treated. And with selinexor, we now have about 70% of our business in the community and about 60% in that second to fourth line. So we continue to move up into earlier lines, which is what our focus is and what we're going to continue to execute on.

Got it. And we'll dig into myelofibrosis a little bit more later. But just coming out of ASCO, wondering if you saw anything for multiple myeloma that's interesting. And there was some data there discussing XPOVIO as a bridging therapy to CAR-Ts. Maybe if you can just talk a little bit about that and what proportion of your late-line use would you say is attributable to this?

Yes. I mean, I'll start with the first part, and then I'll turn it over to Reshma to talk to some of the ASCO data. With regards to what proportion of our business currently in the late line is attributable to pre T-cell engaging therapy, it's still too early to really call that out, given the kind of limited utilization we're still seeing broadly in institutions and academics. But we're working to generate that data, and there's a lot of excitement, I think, around that given our preclinical data and given the importance of ensuring this T-cell environment is optimal before utilizing these therapies. But maybe, Reshma, do you want to expand on some of the data we just saw?

Yes, absolutely. I mean, ASCO did have an opportunity to present multiple new data sets for T-cell engager therapies, which is just a great opportunity for patients. With that said though, we know that these T-cell engager therapies do have an impact upon the immune environment. And so this ability to maintain efficacy once these therapies are sequenced back to back to back is still very much an unknown. Where we see selinexor potentially having an opportunity is really both pre and post T-cell engagers. And the reason I say is because we've got very compelling now translational data to suggest that selinexor positively modulates the immune environment by decreasing the checkpoint expressions, including PD-1s, LAGs, TIM3s. That modulation, that improvement of the immune environment potentially can then improve the outcomes with those T-cell engager therapy. So again, it positions selinexor in that pre T-cell engaging space, whether it's a bispecific or even CAR-T, more compelling is the data looking post T-cell engaging therapy. We put out some data at ASCO again that selinexor post T-cell engaging therapies may potentially improve the outcome. So it really suggests that selinexor has a very important role both pre and post T-cell-engaging therapies, which in this competitive, very rapidly evolving environment really suggests that selinexor is an important player, both in the community as well as in the academic settings.

Interesting. And so the benefit post-T-cell engager would be to basically preserve immune function for oncology patients or...

Yes, exactly right. I think it's to preserve the immune and function. But something that we are better -- we are looking at very closely is that can selinexor potentially improve the outcomes with that T-cell engaging therapy, whether it's a bispecific or even a CAR-T? So we are looking both from a real-world evidence perspective and potentially other clinical trials at that impact of sequence, right? Of T-cell engaging therapy followed by selinexor, what are the outcomes for those patients? Again, some of the initial data suggests that outcomes are positively improved once selinexor is administered post T-cell engaging therapy. So it's a rapidly evolving environment. But again, we are looking at our data very positively in this evolving sequence.

Got it. That's helpful. And maybe going back to commercial, Richard, you mentioned you're seeing more use in the early line setting for multiple myeloma. And I think you guys have said 65% of XPOVIO use is now in these early line patients. You no longer put out the refill rates, but can you say if you're seeing an increase in durability in these patients? And anything additional on refills at this point?

Sure. Yes. I think it's about 60% that we're seeing in that second to fourth line. That's evolved really nicely. So year-over-year, about a year ago, it was 45%. So really a positive improvement, I think, in the earlier lines in line with our strategy, which is really to say, when you look at that second to fourth line with data we've generated post anti-CD38, selinexor as a novel class with the ability to be used with many different agents is really positive for physicians and positive for patients. So that's been reflected well in the growth in our second to fourth line now at about 60%. And then also as we talked to in the commercial space, yes, we've seen growth in refills. Given the impact of the patient assistance program in terms of patients coming on to that overall, that's kind of modified the refills because we have to adjust for the patient assistance programs. But I think moving forward, as we continue to see positive evolution in growth in the second to fourth line, we continue to see growth in duration of therapy.

Got it. Makes sense. Currently, you can only market to the BOSTON regimen, but what can you tell us about real-world use, including the percent of patients that are on XPd triplet? And how that informs or derisks your ongoing Phase III?

Yes. There's -- as you know, XPd is what we promote to. On NCCN, we have selinexor with Pomalyst. We have selinexor with Kyprolis and selinexor with [indiscernible]. So SPd, SKd and SVd. And obviously, physicians can choose to use that, and I think it's the importance of having a novel class and having flexibility depending on what a patient has been treated with during the first two lines. Now as we have the opportunity to move forward with the SPd trial, a couple of important points on that. It's a lower dose. So at the 40 milligram, that will enable us to promote at the lower dose for starting. It will enable us to promote an all-oral regimen and also when you look at Pomalyst and Seli, both of them are T-cell sparing. So again, to be in that second to fourth line pre-T cell with SPd and to be able to promote following the successful outcome of data and getting registration, I think, it's an exciting kind of midterm growth opportunity for us.

Got it. And for the XPd trial, you mentioned you're using the 40 mg XPOVIO dose there. Given you saw a little bit of a dose response with our myelofibrosis study with 40 mg versus 60 mg, what's your level of confidence that 40 mg will be sufficient in the XPd study?

Yes. Great question. So these data too were published at ASCO. Specifically, we evaluated both the 40-milligram and the 60-milligram in two separate cohorts in patients with relapsed/refractory multiple myeloma. And in those two separate cohorts, what we observed is that the 40 milligrams absolutely improved the clinical benefit for these patients. Specifically, the efficacy was improved with the 40 milligrams when you look at PFS as well as OS and safety was a lot better. So that benefit risk was optimized with the 40-milligram cohort. As such, in this Phase III trial, we have included the 40 milligrams as the dose in combination with pom-dex. This arm will be compared to EloPd. A total of 222 patients will be randomized to this trial. All of the patients will also need to have an anti-CD38 in the most immediate therapies. So again, I think really is going to highlight the benefit that we see with SPd and looking forward to top line results in the near future.

Got it. And we talked about the T-cell fitness data that you have. How can you leverage that? What are next steps there? Maybe talk a little bit more about that?

Yes, absolutely. So to continue the conversation about the T-cell fitness, so again, we believe that selinexor has a really important role in maintaining and potentially even optimizing the immune environment, especially in this rapidly evolving field in which we see these T-cell engager therapies, whether it's a bispecific or CAR-T rapidly being embedded largely in the academic setting. Our focus is looking at multiple different data sets, whether it's translational data, whether it's preclinical data, and we've got multiple collaborators who are working on assessing specifically the immune profile with selinexor also looking at real-world evidence and potentially even looking at clinical trials. So looking across multiple modalities to better understand the impact of selinexor on this immune environment. The initial data really do suggest that selinexor has an opportunity to optimize the immune environment, specifically when patients are treated with selinexor, I should say, in preclinical studies, when animals are treated with selinexor, you see a decrease in the checkpoint expression. So PD-1s, LAGs, TIM3s are all decreasing in the presence of selinexor. We've also looked at experiments in which we sequenced selinexor followed by a CAR-T. And when we specifically look at that sequencing, we see that the outcomes are improved as compared to animals just treated with CAR-T alone or even seli alone. So it would, again, it suggests that selinexor followed by a T-cell engaging therapy optimizes the benefit that these animal models are seen. Separately, as I mentioned, at ASCO, we presented real-world evidence specifically looking at seli post T-cell engaging therapies. There too, you see a positive outcome. These are early days for us. We do expect over the course of the next 6 to 12 months being able to rapidly introduce additional data, again, looking at the role of selinexor on the immune environment and giving increasing confidence to investigators as well as physicians in being able to incorporate seli as part of the landscape for multiple myeloma patients.

Got it. And there's a lot of interest in your myelofibrosis program, where you're starting a Phase III study. Maybe just tell us what the latest status is there and you have line of sight into how long it would take the study to enroll and potentially get to data?

Yes, great question. So we're still up in the start-up aspect of the trial. We hope to initiate this trial shortly and especially in the first half of this year. And once we do, I think we'll be able to provide more details in terms of the time lines and give more color on the actual details of the trial.

Got it. And you showed updated data at ASCO for myelofibrosis. Could you quickly talk about that and in your confidence in the dosing strategy and moving into the Phase III?

Yes, absolutely. So the top line results, specifically the 24-week data, we had an opportunity to present earlier this year at AACR. So to recap, what we observed is a very compelling improvement in both SVR and TSS50 specifically with the selinexor 60-milligram dose in combination with standard of care ruxolitinib. When we look at the patients treated at 60 milligrams in the ITT population, we observed a very compelling 78% SVR. This is, again, at week 24 and a 58% TSS50. Again, really compares very nicely relative to historical rux data, in which only approximately 40% to 45% of patients achieve an SVR and TSS50 again, at that week 24 data. So these data compare very nicely. We have a lot of confidence with those Phase III -- with the Phase III study. What we had an opportunity to present at ASCO for subgroup data. And what we, again, are very intrigued by is when you look across all subgroups, specifically by gender, male, female as well as even by starting dose, what we find is a very consistent SVR rates, all in, again, that 70% to 80% range. I say this because you do not see this with rux alone. With rux alone, we find that the SVR rates in males is substantially lower than what females achieve at approximately 25% and you also see a very stark differential in terms of activity in those patients who have to start at lower doses of ruxolitinib. Again, when we see consistency across all subgroups, it really suggests that the combination maximizes the benefit that myelofibrosis patients can achieve. In addition to these efficacy data, we're also very encouraged by the data suggesting disease modification. And what I mean by disease modification, I'm specifically looking at what happens to the platelets and hemoglobin over time. What we see in our data set is that as patients stay on therapy over time, platelet levels increase, hemoglobin levels increase, really suggesting that the combination is modulating the underlying bone marrow and the potential regeneration of these important lineages in these patients. Again, you don't see this with rux alone. So we see very compelling efficacy results as well as disease modification results with this combination and really provides confidence going into the Phase III study.

Got it. That's helpful. And, going into the Phase III, maybe just talk about some of the steps you're taking to mitigate tolerability issues with hematological and GI tolerability and make sure that patients stay on the drug -- on the combo throughout the Phase III?

Yes. So it's important to note that the 60-milligram AE profile was very tolerable for these patients. Only two patients discontinued due to treatment-related AEs: One was due to thrombocytopenia; another patient was discontinued due to a neuropathy. So by and large, this is a very safe and tolerable side effect profile. Yes, we do see GI toxicity as well as cytopenias. This is no different than any of the other therapies currently being developed in myelofibrosis. We also see GI toxicity with other JAK inhibitors. And clearly, I think we're all aware of the cytopenias. We have an opportunity to further improve upon the toxicity profile though in this Phase III. So importantly, all patients are going to be required to take dual antiemetics for the first 2 cycles. That's going to substantially decrease the rates of nausea and vomiting that these patients experience. In terms of the cytopenias, so again, these are really lab-based. So physicians are very, I think, accustomed to being able to monitor these cytopenias. They're not discontinuing as a result of these cytopenias. We will incorporate and allow patients to take ESAs, erythro-stimulating agents, if necessary. But both of these maneuvers, I think, are going to, again, improve the toxicity profile, allow patients to stay on therapy longer. Ultimately, that's going to drive the outcomes for SVR and TSS50 and hopefully, overall survival.

Got it. Makes sense. And I wanted to ask a couple of questions about endometrial too. Your Phase III study is ongoing in p53 wild-type patients. It's supposed to read out in second half of '24. Can you talk about the mechanism in this setting, why you saw such a strong signal in these patients in your prior Phase III and the differences in design from SIENDO to the current study?

Yes, absolutely. So it's a really very simple mechanism. So selinexor is an XPO1 inhibitor, just blocks the export of proteins outside of the nucleus. And one of the most important proteins that is blocked is the tumor suppressor p53. What we're seeing is that selinexor, when administered to these patients, the p53, the wild-type or the normal functioning p53, is retained within the nucleus, which then promotes apoptosis and cell kill. And this is why you see all of the activity, specifically within the subgroup of patients who are p53 wild-type, and you really see no benefit in those patients who are p53 mutant, so a very simple mechanism. In the export -- the current trial, we're only enrolling patients who are p53 wild-type, and those patients are going to be identified because we have a strong collaboration with Foundation Medicine. They're using their NGS platform specifically to identify those patients who are p53 wild-type. Those patients will then be randomized to either of the selinexor arm or placebo. PFS or progression-free survival will be the primary objective in this study.

Got it. And for the new study, you're using a lower dose at 60 mg versus the prior study at 80 mg. Talk a little bit about that. And is this intended to keep patients on drug longer? Or how should we think about that?

Yes. This is really in our broader effort to optimize the dose of selinexor, so across our program. And if you all remember, the originally approved dose was 80 milligrams twice weekly, a total of 160 milligrams weekly, obviously, led to benefit, but there was a lot of toxicity challenges for that dose. In all of our current studies, the dose is 1/3 to 1/4 of that originally approved dose. So selinexor, the study also incorporates one of those lower doses at 60 milligrams. What we know about these lower doses is that it improves the safety profile, but it maintains, if not, enhances the efficacy by allowing patients to stay on therapy longer. So we really do believe that efficacy could be improved in this study compared to what we saw in the SIENDO trial, while also substantially improving the safety profile.

Got it. And I also wanted to ask just another endometrial question on the competitive landscape with PD-1s, which have been successful in MSI-high patients. Can you say what proportion of overlap there is between MSI-high and p53 wild-type patients? And if chemo PD-1 combo gets approved in frontline, do you think it will come down to which drugs showed the best clinical benefit? Or how should we think about that?

Yes, great question. So when you look at advanced recurrent endometrial cancer, about half of the patients are going to be p53 wild-type. Amongst those patients who are p53 wild-type, about 70% of those patients are going to be MSS or pMMR. The remaining 30 patients -- 30% of the patients are going to be MSI or dMMR. So the vast majority of these patients are going to be that MSS. If you compare the MSS or if you look at the MSS data from the checkpoint studies, whether it's GY018 which looked at pembrolizumab or the RUBY trial that looked at dostarlimab, the greatest benefit was seen in the MSI patients, that small fraction of patients who are p53. When you look at those trials, specifically in the MSS patient population, the benefit was extremely marginal. There was only an approximately 2-month improvement in that PFS. Compare that to the data that we have shown from the SIENDO subgroup in which the median PFS in the maintenance setting is already approximately 21 months. So there's clearly a benefit for p53 wild-type MSS patients. Ultimately, to your question, Maury, it is going to come down to a comparison. Again, just looking at our data, we already see a very clear improvement compared to what the checkpoints have seen in that MSS patient population.

Got it. And maybe to close out, we're pretty much out of time. If you can just talk about cash runway, strategy to potentially optimize cash runway and then key events ahead that investors should be focused on?

Sure, Maury. I think as we've guided, our cash runway is into the end of '25. A lot of work to really be disciplined and be focused in our spend and in our programs. We've stopped nonpriority programs. In Q1, our expense base was down 16%, so a 16% year-over-year reduction in our expense base. So I think a lot of work continues to go on to make sure we're disciplined and we're focused in terms of developing our programs and managing our spend. So we can see those programs through. As we get into key milestones over the near term, very excited. A lot of talk about endometrial cancer as the last few questions. So very excited over the near term in the second half of the year to be able to share updated progression-free survival data with regards to endometrial cancer. In the very near term, excited to be starting our pivotal Phase III program in myelofibrosis, and we'll talk to that soon. And then at the same time, continuing to drive our base in multiple myeloma and looking at the launches happening globally and driving our revenue here in the U.S. So a lot of exciting things in front of us, really working to deliver hard for patients and drive value for shareholders.

Great. Thanks so much for joining us today.

Thank you.