All right, let's go ahead and get started. My name is Nicole Gabreski. I'm a biotech research analyst here at Piper Sandler. It's my pleasure to introduce Karyopharm Therapeutics. Joining us today, we have President and CEO Richard Paulson, and CMO Reshma Rangwala. Welcome.
Thank you.
Just to go over the format really quickly, we'll have a couple minutes of introduction from the company, and then we'll go into a fireside chat format with some more detailed Q&A. Without further delay, Richard, I'll turn it over to you.
Yeah, thanks, Nicole, and obviously, a little housekeeping. I mean, please refer to our FFLs or our most recently filed 10-Q. You know, Karyopharm is a commercial stage, innovation-focused oncology company. And I think we are well positioned for our next stage of growth as we're building on our foundation in multiple myeloma with a rapidly advancing and focused pipeline and a mid- and late-stage areas of opportunity. And those are in endometrial cancer, myelofibrosis, and building on our foundation of multiple myeloma. And we look at our opportunities in these three areas. We have an opportunity, I think, to significantly improve patient outcomes, and each opportunity by itself, you know, if positive, I think is a significant opportunity for Karyopharm.
Together, the opportunity for selinexor, I think, is, is potentially, if all of them were successful, to, to reach a, a peak of about $2 billion in, in revenue. We, are in the strong kind of financial position to be able to see the readouts, of this data across all three areas, with multiple myeloma, you know, second half of 2024, endometrial cancer first half of 2025, and myelofibrosis through 2025. You know, as we have a cash position through to late 2025. So we're excited to be working on this, I think, to really deliver value, obviously, in the near and long term for, for shareholders and for patients.
Perfect. All right. So we have just a little over 20 minutes to dive into Q&A. So this will be kind of an open format, so we look for participation from the audience, so feel free to speak up and raise your hand if you have any questions. But maybe with that, I'll go ahead and dive into some to some Q&A. So just to start, so let's dive into ongoing developments for selinexor and endometrial cancer. So you guys are currently evaluating selinexor as a maintenance therapy following systemic therapy in patients with TP53 wild-type, advanced or recurrent endometrial cancer. So maybe just around some of the survival data. You guys had recently presented some updated data at the IGCS Annual Global Meeting from the phase III SIENDO study.
Maybe just walk us through those updated analyses and help frame their meaningfulness.
Yeah, absolutely. Well, thanks so much for highlighting. I mean, really just, I think, very encouraging data from that p53 wild-type subgroup. We have already presented multiple times very encouraging progression-free survival data, right? And just to recap, right, when we look at the progression-free survival from these long-term updates, we're really looking at encouraging hazard ratios in the, in the range of 0.46 for that p53 wild-type group as an entirety. When we look specifically in that p53 wild-type pMMR patient population, hazard ratio improves even further, down to the 0.32 range, medians not even reached for selinexor. These overall survival data that you referenced, we just presented in South Korea at IGCS. First time we've presented those data. Now, with that said, they're still immature, right? So we're still following this event.
With that said, the data are really tracking with that PFS. So we see a hazard ratio of 0.76 when we look at all p53 wild-type patients. And here too, when you just look at those patients who are p53 wild-type pMMR, hazard ratios improve even further, now in that 0.57 range. This is again, survival data. So the two endpoints together really do suggest very compelling benefit for patients who are p53 wild-type and treated with selinexor in the maintenance setting.
Great. So then, just from the subgroup analyses from SIENDO, you know, they have been quite impressive so far. I guess, has that affected enrollment dynamics at all in your ongoing phase III EC-042 study?
Yes. I mean, I think there's just a very obvious enthusiasm, as you can imagine, from KOLs, both in the U.S. as well as in the ex-U.S., you know, specifically in Europe and Asia as well. Why is that? It's really because as we look at the checkpoint inhibitor data, especially with just dostarlimab, where we know it's approved, both the treatment and in maintenance, the benefit and the approval really is seen in that small dMMR patient population, represents about 20% of all endometrial cancer patients who are advanced or recurrent. Which really leaves you know, open that large patient population who is pMMR, right, at 80%.
That group, you could argue, still does not have a standard of care and really why our data are so relevant, because again, when you see PFS improvements with hazard ratios of 0.32, overall survival data of 0.57, really suggests that we can provide a benefit on the same range as the checkpoint inhibitors. So lots of enthusiasm. I think investigators really appreciate that these data from the phase III SIENDO positive really can define a new standard of care. That's driving enrollment, right? So a lot of enthusiasm. We're seeing good, robust enrollment both in the US and the ex-US, and looking forward to top-line results, probably in the first half of 2025.
Perfect. And maybe just touching on the top line results.
Yeah.
for first half of 2025. So I think that timing has shifted just a little bit over time, but maybe can you just walk us through the rationale for that?
Yeah. So I, I don't want to bog down into the technicalities, but unfortunately, I have to get into the technicalities just a little bit. But one of the nuances about this trial, again, it's only enrolling patients who are p53 wild-type. So this is a biomarker-selected patient population. We are partnering with Foundation Medicine. They're using their NGS platform to identify the p53 status from the patient's tumors. This requires an extra step, an extra approval step, specifically in Europe. It's something called the IVDR process. It's relatively new, again, an additional approval that we need to get. It has caused a delay in a couple of the big countries in Europe.
You know, that delay is probably in the order of one to two months, and so that, yes, unfortunately, has slightly impacted our enrollment, and which is why we have now updated top-line results to first half.
Got it. Okay. And I know I keep referencing the EC-042 study-
Yeah.
without digging in, but maybe just walk through the design of that trial. And then just on dosing, I know you've been looking at utilizing lower doses of selinexor.
Yeah.
But maybe just talk about the rationale to move to a 60 mg, once-weekly dose versus the 80 mg once-weekly dose that, you studied in SIENDO. And just given us maybe help frame your confidence around maintaining efficacy, in the 042 study, that you've witnessed so far, from the SIENDO, subgroup analyses.
So the current phase III trial is very, very similar to SIENDO in that it's evaluating selinexor as a maintenance therapy in these patients who are advanced recurrent endometrial cancer. With that said, an important difference from SIENDO is that we're only enrolling patients who are p53 wild-type, right? So this is p53 wild-type, represents a little over half of all patients. They'll be randomized to either selinexor 60 mg versus placebo. We're looking at approximately 220 patients. Primary endpoint is going to be progression-free survival, as assessed by the investigator. Key secondary endpoint is going to be overall survival. You highlighted another important difference. So again, it's the patient population, just p53 wild-type. The other aspect that does differ is the dose, the 60 mg.
And as you highlighted, right, this is part of a sort of general sort of aspect that we're looking about selinexor, right? We are looking to optimize the dose, whether it's an endometrial cancer in myelofibrosis, certainly in multiple myeloma. Toxicity was aggressive, right, at the initially approved dose of 80 mg twice weekly. But looking at clinical data, certainly talking with our physicians, understanding real-world experience, looking at our, pharmacokinetic data, it really suggests that we can optimize the dose by lowering it almost by a third to a quarter. So all of our trials, whether it's endometrial, myelofibrosis, or other Phase III, which is evaluating selinexor in combination with Pom dex versus Elo-Pom dex, all incorporate these doses of either 40 or 60 mg dosed weekly. That 60 mg, you know, again, it too, was based upon robust clinical data.
So looking at the efficacy, safety data from SIENDO and incorporating that pharmacokinetic data, really strongly suggested that 60 mg can maximize that benefit risk. Not only do I think it's going to maintain that efficacy, there's a really good possibility it's actually going to improve that efficacy. Only because safety is going to get better, patients are going to be able to stay on therapy. That ability to stay on therapy is only going to drive efficacy. So I think we can really see some positive aspects, both from an efficacy as well as a tolerability coming out of this phase III.
Great. And then I think you're also developing a companion diagnostic-
Yeah.
-to evaluate the p53 wild-type status. So maybe just provide a little bit of background around the test, talk about docs' willingness to use a companion diagnostic, and maybe just where in the patient journey or the treatment process you would potentially see this test being utilized.
Yeah, absolutely. Great question. So as I mentioned before, so we are partnered with Foundation Medicine. They already have a commercially available NGS platform. So in that platform, they're already reporting approximately 300 different molecular entities. p53 status is one of those entities. So that, again, that test is already available. Physicians are already using this NGS. You know, with that said, there's never been an actionable drug for p53 status. So now, with the results of this trial, again, if positive, they will certainly be able to utilize a drug in selinexor, you know, with that patient's p53 status. This is not a new paradigm for endometrial physicians, whether they're a gyn-onc or a medonc. In fact, if you look at the NCCN guidelines, very early on, it's all about molecular testing, right?
So looking at the patient's MMR status, p53 status, POLE status is something that they are looking at through a variety of methods, whether it's IHC or NGS. So this is already routine practice. What you can really see is that they're really evolving how they're testing. So a lot of physicians are testing at the time, you know, even with an early-stage tumor, at the time that they completely remove it, they'll assess their molecular status. For some of these women whose tumors unfortunately recur, they will test again. So this is, again, you know, not a new obstacle, not a new challenge.
... Okay. And then maybe just, given the data from SIENDO, you've refined kind of the addressable market, or the addressable patient population over time. Maybe just, walk through your current thinking around the market opportunity, for selinexor in this setting.
Yeah, absolutely. So in the United States, you know, there's approximately 16,400 women who are in that advanced recurrent stage. Of that 16,400, a little over half are going to be p53 wild-type. And of those, you know, sort of like about 80% are actually going to have a response to their prior chemo. So we're looking at a very robust market that ultimately can be treated with selinexor.
Perfect. Okay. Let's go ahead and transition to myelofibrosis. So you've presented some interesting data from your phase I study so far, but maybe just remind us about the most recent data cut that you guys have presented and maybe how that compares to ruxolitinib, and maybe some of the other major competitors in the space.
Yeah, absolutely. So you're referring to the durability data that we presented at MPN. Just to highlight, we also have an oral at ASH coming up. So, you know, there's going to be both clinical as well as translational data that we're going to be able to highlight again from that phase I study. You know, with that said, right, you know, when you look at a JAK-naive patient population, I think we all appreciate that there's some pretty standard endpoints. We're looking at SVR, which is spleen volume reduction of at least 35%. There's also symptom assessment, right? These are very clear drivers and important endpoints along with cytopenias. You know, with that said, when we report these data out, we're always looking at week 24 data, six months.
But for a JAK-naive patient, right, they really want to assess how long is that response going to last, whether it's an SVR response or whether it's a symptom response. So this is, this is the analysis that we performed and we updated at the MPN Congress. Very, very encouraging. You know, in addition to that 78% SVR35 rate, 58% TSS50 rate, you know, at week 24, what we presented is that none of the patients actually progressed. So none of the patients, you know, progressed radiographically, and none of the responders actually had worsening symptom improvement. So really very impressive durability data to, I think, really complement those nice rates that we're already seeing.
Perfect. And then, you know, given the results from your phase I study, you guys have moved directly into a registrational-
Yeah
... phase III study, known as XPORT-MF-034, which is evaluating selinexor in combo with RUX and treatment-naive myelofibrosis. Maybe just, walk us through the trial design and maybe, some expectations around, data release.
Yeah, absolutely. So, you're absolutely correct. So this is a JAK-naive patient population, so they can never have received a prior JAK inhibitor. Patients must have a baseline platelet count of 100 above, right? And so this is a very similar patient population that was enrolled as part of our phase I. These patients are randomized in a double-blind fashion to either the combination of selinexor 60 mg in combination with standard of care, ruxolitinib, or ruxolitinib plus placebo. There are two primary endpoints, so SVR 35 is going to be evaluated first at week 24. If positive, we're then going to be looking at symptom assessment. A total of 306 patients will be randomized.
Perfect. And then maybe just some questions maybe around the endpoint. You know, we saw MorphoSys their top-line data release from phase III MANIFEST-2 for pelabresib in treatment-naive myelofibrosis with what we'll call mixed study results.
Yeah.
In a way, it's been kind of frustrating watching the space. It seems like consistently these studies hit on SVR 35, but then fall short kind of on the symptom scoring side. At least on our team, we've had a lot of-
Yeah.
internal debate about maybe, kind of like what's going on and the rationale behind that. But I guess, I'd kind of love to get your thoughts, just, you know, as you think about the total symptom scores changing as you go from an open label study to a blinded study, maybe how do you think about incorporating, you know, some of those potential differences into a trial design?
It's really interesting. I mean, what I find remarkable is actually the data are translating pretty well. So if you look at the phase II results, you know, and now you look at the phase III data, they're very similar, right? For both SVR as well as TSS. So I think, you know, that bodes really well for us, too. You know, although we have a small patient population enrolled as part of our phase I, it really suggests that, again, those phase I, phase II data are robust and really can translate to that phase III. I think some other key takeaways that I really appreciated now, looking at both TRANSFORM as well as MANIFEST, is that unfortunately, you know, sort of the performance of RUX, especially on spleen, is really not as robust as what I think we had all anticipated, right?
So in the COMFORT trials, SVR35 were in that 40% range. I think we've really seen it's really only positively impacting about a third of patients. So really suggest, right, you know, sort of this desperate need to identify new therapies. SVR35 is still going to be such a critical endpoint because there are growing data that really suggest SVR35 correlates really well with overall survival, too. So again, it really suggests that, you know, sort of a small fraction of patients are benefiting. You know, Manifest, right, has been looking at symptoms multiple different ways. We've been doing that as well, right? And we'll continue to evolve and adapt our trial to incorporate the best method to analyze symptom score, both from an absolute standpoint as well as a percent standpoint, too.
Okay, and then maybe another endpoint question. You guys are utilizing co-primary endpoints of SVR35 and the TSS50 at week 24 in your study. But I guess most other study designs have been set up to have, sorry, SVR35 as the primary endpoint, and then TSS50 as a key secondary endpoint. I guess based on kind of that design, you know, or thinking about that, does it matter which way you kind of frame these as being co-primary endpoints or having, you know, a primary and a key secondary like that?
So we test SVR35 first, right? So all the alpha is going to be allocated to that SVR35, and if it's positive, we're then going to roll it down to that symptom score. You know, this is very similar to how these other trials have been analyzed as well. I think the key takeaway, though, is that both of these endpoints need to be positive, right? I mean, I think the FDA has been very adamant that, you know, symptoms are relevant to these patients, as our spleens both need to show clinical improvement, right? I completely agree. I think we are evolving beyond TSS50, but one way or another, we do need to demonstrate relevance around symptom improvement.
Perfect. Then, maybe just thinking about real-world uptake, I guess, you know, assuming a positive outcome from your phase III study and approval, maybe just how do you think about real-world utilization of a therapy like selinexor? And part of the reason I ask is because we've gotten some mixed feedback-
Mm-hmm.
-from KOLs. Some have been, you know, very positive about using a combo approach upfront in their patients, and others have kind of framed it as, you know, they would use selinexor most likely as, like, an add-on therapy.
Mm-hmm.
Maybe how do you guys think about that?
I'll frame it from the perspective of, like, what is most relevant to the patient. So we know that a patient who has myelofibrosis, right, is seeking treatment, it's because they have these very enlarged spleens, they have these intractable symptoms, and most likely, they have some very debilitating cytopenias, right? Furthermore, their treatments also cause further cytopenias that are going to cause them to discontinue. So when we talk to investigators, they're really looking at therapies, whether it's monotherapy, combination therapies, that can radically manage every single one of those aspects. And that's where the combinations, I really do think, is going to be the new standard of care.
Because what we are seeing by and large from these combinations, not all, but by and large, is that you are seeing meaningful improvement in that SVR35, meaningful improvement in that TSS50, and maybe improvement, at least not worsening of that cytopenias. So you're able to manage that patient holistically. I think the one aspect that is very unique about our combination is the fact that it likely has monotherapy activity, even in that JAK-naive patient population. Why do I say that? Because again, we know that ruxolitinib can exacerbate cytopenias, thrombocytopenia, anemia, causing that patient to have to discontinue from drug. Monotherapy activity allows an investigator or a physician to discontinue the RUX, maintain the selinexor, but know that they're not going to compromise that efficacy.
So it really puts together, I think, a profile that maximizes the benefit, but still gives physicians flexibility in terms of how they treat.
Perfect. Okay, in the time remaining, maybe just I'll sneak in some commercial questions. So, just on commercial performance for XPOVIO this year, I know you had lowered guidance earlier in the year, in part due to increased utilization of free drug. And there's also been increased competition in the fifth-line plus setting. But maybe just can you talk a little bit more in depth about the headwinds you've experienced? And then just for 2024, I'm not asking for guidance, but just how do we think about kind of the commercial setup, generally as we move into next year?
Yeah, thanks, Nicole. As you mentioned, yeah, this year, some of our headwinds in multiple myeloma, definitely the increased utilization of patient assistance or free goods, as we saw early on in late Q1, early Q2 of the foundations, you know, not having appropriate funding. So that, you know, caused an increase in our patient assistance programs. And once those patients come on a free drug, you know, it's our commitment to keep them on through the year. So in Q3, you know, we saw the patient assistance representing about 9% of our demand this year. Last year, 4%. And on top of that, you know, we've also seen some increase in GTN.
So, you know, from those headwinds, as you mentioned, we've also seen, especially in the institutions and academics, which probably represent about 30%-40% of multiple myeloma patients, typically the later line, as you mentioned. You know, three new competitors coming in, the bispecifics, you know, increased utilization of the CAR Ts. So yeah, a very competitive space, especially in the institutions and academics. You know, it's something that we've been getting ready for and continuing to generate data with selinexor, doing a lot of work to generate data. Really, I think in an area that's going to become, you know, increasingly important pretty quick, because none of these therapies are cures, is what's the right, what's the right therapy to be using pre-T cell engaging therapy? What do you use post T cell engaging therapy?
And with selinexor, I think we're generating a really good body of evidence and continuing to do that. And in fact, you know, even if you look at, at Pomalyst and you look at selinexor by themself, together, the two of them are, are really seen as probably T cell sparing individual actions. So obviously, that's an area that as we move forward with our, our XPD phase III trial, I think we'll get an interesting opportunity. So, you know, those headwinds, very competitive in, in that space. At the same time, you know, 60%-70% of patients are in the community, earlier line patients, second to fourth line.
I think we've been very focused on that area, and we're seeing that the strategy, you know, really paying off, where we've grown the second to fourth line patients, new patients, from about 40% of our new patient starts to now 60%. In that space, you know, what's been working well for us in terms of tailwinds are, you know, some evolution in the NCCN guidelines and also some new data that we've generated for PI-naive patients, and we're going to continue to focus on that and bring that to life as we go forward into 2024.
Great. Well, we will stop there, since we're out of time, but thank you both so much for joining us today.
Thank you.
Thanks, Nicole.
Thanks.