Welcome to our BioConnect Conference. I'm Robert Burns, a Senior Biotech Analyst and Managing Director at H.C. Wainwright, and I'm joined today by Richard Paulson, the CEO of Karyopharm, and , the CMO of Karyopharm. Gentlemen, lady, thank you for joining us today. Why don't we just jump right in? For those who may be unfamiliar with Karyopharm, could you provide a brief high-level overview of the company and its pipeline?
Sure. I mean, I'll start. Thank you for having us, Robert, you and the team. Just a little housekeeping before I begin, you know, various comments we make today may constitute forward-looking statements, so please refer to our latest 10-Q on file. You know, it's a super exciting time at Karyopharm, I think we're gonna cover some of those areas this morning. Karyopharm is a commercial stage pharmaceutical company pioneering the science of nuclear export inhibition to develop, you know, breakthrough therapies for patients suffering from cancer. As a company, our lead asset is selinexor or XPOVIO, which is currently approved in multiple myeloma and in the U.S. and in over 50 countries around the world with our partners.
We're guiding to around $130 million- $150 million in revenue this year in multiple myeloma. What's really exciting, I think, and truly transformative is really building on that base in two areas of very high unmet need. The first is myelofibrosis, where we just read out our phase III SENTRY trial in March, just the top line data. I'm sure we're gonna jump into that more. We have an oral, late breaking presentation at ASCO coming soon. Endometrial cancer, where we just completed enrollment into our phase III XPORT-EC-042 trial. That trial is on track to read out in the middle of this year. I'm sure we're gonna jump into that. Exciting times, busy times, really advancing the science to make a meaningful impact for patients.
Yeah, thank you for that overview. You know, you just mentioned the phase III SENTRY trial top line data. You know, for those who might have missed that, those results, can you talk a little bit and go a little bit more into detail as to, you know, what that trial was, how it was designed, as well as the endpoints and what the results were from that top line release?
Yeah, I can take that one. SENTRY was, you know, as Richard alluded to, a randomized phase III trial. It was specifically focused on evaluating the efficacy and safety of selinexor in combination with ruxolitinib versus ruxolitinib alone in these front-line patients or JAK-naïve patients, right? Essentially think of them as newly diagnosed myelofibrosis patients. All of the patients had to have baseline platelet counts of greater than 100. It was a double-blind study, 2:1 randomization, with the primary endpoints of SVR35.
which is spleen volume reduction of at least 35%, as well as absolute TSS, which is just a measure of symptom improvement. Both of those endpoints were evaluated specifically at week 24 at six months. We had multiple secondary endpoints including overall survival, as well as exploratory endpoints looking at multiple translational endpoints, including variant allele frequency. Which is just a measure of clonal burden. When we read out the data, what we found was something very meaningful, at least I think very meaningful for the patients. We saw an approximate doubling of that SVR35 for the combination relative to ruxolitinib. We also saw this SVR kinetics that is very important, again, for the patient, very rapid. This SVR35 occurred as early as week 12 and sustained, right?
Beyond week 24 into week 36. This rapid, deep, sustained SVR35. Symptoms was not statistically significant relative to . We did see a very meaningful improvement at week 24 relative to baseline, and I would argue that's what's most relevant for the patient.
In terms of overall survival, this is where I think the data really shine. We saw this very promising, but preliminary signal in overall survival, and what that demonstrated, again, as of a median follow-up. 12 months, is a hazard ratio of 0.43, this is again for overall survival, equating to a nominal P value of 0.0222.
Yeah.
From a patient perspective, you can imagine this is what they wanna see is can I potentially live longer with a new treatment that may be developed in myelofibrosis? Of course, we saw something very interesting in terms of VAF or this clonal burden measure, a very deep reduction in that VAF as early as week 24 relative to ruxolitinib.
Really, I think that's a measure of why we see this.
Overall survival
SVR as well as overall survival.
Yeah. You know, it's interesting to see that overall survival so early on in this trial.
Yes.
I don't think we've really seen that with some of the you know, historical agents, as well as some of the ones that have been in development as well.
Yes.
You know, I know you're gonna be presenting data at ASCO. Help frame the expectations here. I know abstracts are gonna drop relatively soon.
Yeah. Don't break the embargo.
Don't break the embargo. Talk a little bit about, you know, what investors can expect here and how they should be thinking about the dataset that's going to be presented.
Yeah. Really, really exciting. ASCO chose SENTRY to be presented as one of the late breaking abstracts—
Okay.
—at ASCO. We're gearing up for it. It's less than a few weeks away. I'm really excited that John Mascarenhas, he is one of the leading KOLs, expert globally, you know, within the myelofibrosis field, and he's gonna be presenting the totality of data.
on behalf of all of the SENTRY investigators. What we're gonna be presenting, this is again, the first time the data will be presented as part of a congress. Is again that totality of data from the efficacy endpoints in which we've included multiple, but also secondary endpoints, disease modification data, the mechanism, and why the mechanism, which is so important for selinexor, why does that drive this rapid SVR, this overall survival improvement, and then other markers of improvement for this patient population, and then of course contextualize it in the context—
Yeah.
—of the safety.
Okay. how much additional follow-up or more specifically, will there be additional follow-up relative to when you top line these results?
I can't comment.
Okay.
Right?
I'll be waiting for those abstracts release.
ASCO's gonna send me a nasty email.
Okay.
So.
You know, one of the things that, you know, investors have spoken to me about, obviously they'll cite historical precedents of pelabresib and navitoclax where, you know, they hit SVR35 but didn't hit it on absolute TSS. Obviously, you know, they discontinued navitoclax for development in MF, but pelabresib, they're gonna have to run another phase III trial. Do you think that there might be the possibility of that here?
I can't comment on Novartis and their programs.
You know, sort of any of the interactions between the company as well as the FDA. Again, where I look at it is our differentiated profile with the combination where we see this rapid, deep, sustained improvement with SVR35, no change in TSS, and then this early promising signal in overall survival, all in the context of a very safe and tolerable safety profile.
Right.
Selinexor is approved. We've treated tens of thousands of patients, right? We have a lot of confidence around that safety profile. No new safety signals identified, especially issues like leukemic transformation. We know that the confirmed rates of leukemic transformation are exactly the same across the two arms.
Okay.
I think this really identifies a very novel treatment approach and one that potentially could maximize the benefit risk for this patient population. The last thing that I'll mention is that, you know, this trial was designed to follow OS all the way into maturity.
Okay.
Right? It's again, it's a double-blind trial. Patients as well as physicians are not aware of the arm to which they were randomized. We continue to follow these patients. You know, as data mature, we'll continue to show the strength of that benefit profile.
Okay. you know, can you provide some historical context, regulatory context that supports the possibility of selinexor being approved, you know, despite missing on TSS?
Hitting on SVR35?
Yeah. Really great question, and I think this is where there are multiple precedents that, you know, I can identify. Pacritinib is a great example. Pacritinib is another JAK inhibitor. It received accelerated approval specifically for those patients that have very low platelet counts.
They got accelerated approval on SVR35 only.
Okay.
Right? This is a great example in which it obviously shows that the FDA values SVR35. They believe it's an important potential surrogate endpoint for long-term outcomes. Of course, it's on the market in the U.S. Another great example is momelotinib. Momelotinib is also another JAK inhibitor. They had multiple clinical trials, and just like ours, they were focused on SVR35 as well as TSS. Similar to our trial as well as multiple other trials in the space, they showed this beautiful SVR35. TSS is again where it was a little wobbly. Interestingly enough, this is where the FDA showed flexibility right, in their approval. Ultimately, they got approved on anemia benefit.
A endpoint that was not even included in their statistical analysis plan or at least in the primary endpoints, and yet it demonstrated something very meaningful for a key patient population in myelofibrosis. It shows again that the FDA is flexible. They're willing to be creative, and looking at, you know, again, the totality of data to identify new treatments for this patient population.
It's interesting that you mentioned the anemia benefit. Did momelotinib actually show an OS benefit? 'Cause obviously, OS is king—
Yeah.
—when we're thinking about oncology.
That is it.
Right?
From my knowledge in their prospectively, no.
Okay.
I'm not aware of any OS benefit.
Well, it seems like you have this really good possibility—
Yes.
—of still being FDA approved. I mean, if the FDA were to not even consider OS, I, you know, it doesn't sound like that would be something that they would do, considering that's the gold standard relatively.
That's right.
Right? I know you're planning on engaging with the FDA on selinexor trial results and the potential for an sNDA. We do note the near-term potential inclusion of compendia, a compendia listing. When we think about the potential market opportunity for just a compendia inclusion, help frame that expectation because obviously compendia is a much more near-term event. Talk to me a little bit about that market opportunity with just a compendia listing.
Yeah, Robert, I think you've framed it well. We're still working very much towards, you know, an FDA approval and listing. In the near term, you know, from a compendia perspective, obviously that's NCCN.
You know, NCCN really looks at the data that's there.
Important that we have our presentation coming up at ASCO, also working to have a publication very soon. From an NCCN perspective, you know, the committee can meet, can put selinexor and rux on the guidelines.
Obviously, that's important from a reimbursement perspective, enables insurers to reimburse us, which we feel very comfortable with, to have good coverage. When you look at a number of different analogs out there in similar situations where there's a high unmet need, you know, as you've, as you've heard from Reshma, you know, less than a third of patients actually achieve a spleen volume reduction of 35% or more at week 24 with rux. The opportunity we have to, you know, nearly double that benefit, with benefit across all the areas we're showing and obviously the OS signal, I think there's a high level of excitement. In other areas where products have already been approved and some more unmet need, you know, you'll see that products can achieve about 50% of what their peak revenue potential may be with a label.
If you look at myelofibrosis, you know, it's a multi-billion dollar market, and we think, you know, the peak potential for selinexor is up to about $1 billion in the myelofibrosis market. Obviously meaningful revenue opportunity.
Again, most importantly, a real meaningful opportunity to improve outcome for patients.
Okay. You know, when we consider potential regulatory approval not in the U.S., how are you thinking about the EU, right? Obviously, I would assume that they're a little less stringent than the FDA, even though the FDA has shown flexibility. Talk to me a little bit about your ex-U.S. plan here for selinexor in MF.
Yeah, there's a high degree of excitement with our partners, you know, to engage the regulatory agencies in EU, and they've, I think, shown different levels of flexibility. I think we're working hard on that path and looking forward to give some updates in the future.
Why don't we shift gears now to the endometrial cancer program? Obviously, I'm very excited about this near-term data readout. Given, you know, the imminence of that readout, remind us of the SIENDO trial results, because I really think that that's de-risking for the XPORT-EC-042 trial, and why it gives you confidence for that top line release.
Yeah. you know, I can take this one on. ECO42 is really exciting for us, and I think the first obvious, you know, aspect is this is endometrial—
Yeah.
—from myelofibrosis. The reason we've got this opportunity to be looking at the efficacy in such disparate patient populations and tumor types is because of the mechanism of selinexor. It's really leveraging that p53 tumor suppressor, which we know is really relevant in both myelofibrosis as well as endometrial cancer. The reason I say that is because SIENDO, which is a prior phase III, specifically evaluated selinexor as a maintenance therapy in all advanced recurrent endometrial cancer patients. When we read out the PFS results at the time of the top line in early 2022, you know, in that all-comers population, we didn't really see a clinically meaningful outcome in terms of PFS. With that said, we saw something very intriguing specifically in that subgroup of patients, which comprises about half of all endometrial patients in p53.
Those patients who had a wild-type p53, what we saw is a median PFS of 13.7 months versus only 3.7 months seen in placebo arm. That was equating to about a hazard ratio of 0.44, a delta median PFS of about 10 months. Very intriguing. We used those data to then initiate our ongoing phase III, which is now known as ECO42. The obvious difference again is the patient population.
Yeah.
We didn't go for an all-comers. ECO42 is specifically focused on those patients whose tumors are p53 wild type. We enrolled 253 patients. We announced completion of enrollment about a week and a half ago. Patients are randomized 1: 1. Again, we look to aim to show meaningful benefit in terms of PFS, which is the primary endpoint in that patient population, which is p53, as well as in p53 wild type pMMR.
Again, this is where the data really shines. Even in long-term follow-up, right, we see a very profound signal in that p53 wild type pMMR subgroup where hazard ratios are really in that 0.36-0.4 range.
That's phenomenal.
Really phenomenal, meaningful benefit in this patient population, which we know from historical data really do not benefit from, current therapies including the checkpoint inhibitors.
When I look at the trial design of 042, obviously you're looking at a few different patient populations.
Yeah
You've got a modified intention entry, and then you go to ITT.
Yeah.
Talk to me a little bit about the statistical design of this trial and, you know, how you're evaluating, like the sequence of evaluation here?
Sure. It's relatively easy. We've got a modified intention-to-treat population and an intention-to-treat population T hat modified intent to treat population is approximately 220 patients, right? Think of them as your patients who are going to be p53 wild type and MMR proficient. Again, this patient population or subgroup comprises about 50% of all advanced recurrent endometrial patients. The reason we're focused on this patient population is, again, because this patient population doesn't benefit from the checkpoint inhibitors. If you go back to the RUBY data, which RUBY evaluated dostarlimab, so this is GSK's PD-1 inhibitor, they specifically evaluated the efficacy in this similar patient population. What they observed is a hazard ratio of 0.77. Marginal, right?
Yeah.
Especially compared to the benefit we've seen in SIENDO.
Yeah.
We're focused on that patient population. If that patient population is positive for PFS. The full alpha one-sided 0.025 is going to then be rolled down to the larger ITT population, which just comprises all patients who are p53 wild type.
Okay. Now, you know, when we think about the potential market opportunity here, if you hit on mITT, obviously that's roughly 50% of the endometrial cancer patients. What about the ITT population? How do, how does that incrementally change from a market opportunity perspective?
Yeah, I think as you touched on and Reshma touched on, you know, first, you know, it's really that personalized biomarker of p53 wild type, which is slightly more than 50% of patients.
Okay.
Within, you know, p53 wild type patients, about 80% are pMMR.
Okay
About 20% are dMMR. I think as Reshma touched on, you know, the mITT is really that p53 wild type pMMR, and then dMMR patients that are ineligible for checkpoint inhibitors. That's gonna be a pretty small group.
Okay.
The overall ITT population then, yeah, would encompass the 80/20 when you look at pMMR and dMMR.
Yeah. You know, obviously, this is a different sort of beast than what you've typically played in with XPOVIO. Obviously, it's solid tumor. It's completely different indications. Talk to me a little bit about the commercialization strategy that you have for endometrial cancer and what progress you've made thus far, as you sort of prep to, you know, potentially launch this in this indication.
Yeah, we've been doing a lot of work, Robert. It's exciting. You know, there's a lot of excitement for the reasons Reshma mentioned, from opinion leaders from the community to get more treatment options for these patients.
The positive thing is we have the capabilities already. You know, we have a strong commercial footprint. We have a strong medical and scientific affairs capability. That enables us to build really rapidly to be able to launch in endometrial cancer. You know, even though it's, you know, a different cancer than multiple myeloma or myelofibrosis, the good thing is majority of patients are actually still treated in the community.
In that community setting, we have the coverage, you know, it's gonna be highly synergistic to the capabilities we have in place, in terms of also our payer capabilities, our access capabilities, patient support. All that's in place. The team's been working hard already to get kind of the messaging, the tools, the material in place. Our global medical scientific affairs team has really strong relationships. They've been well engaged as we've been working to bring the trial forward.
We're doing a lot of work with opinion leaders. Just about a month ago or so, we were at a major congress actually in SGO, and the amount of excitement for new treatment options and really, you know, already all these physicians are testing patients for p53 status.
To have, hopefully, the opportunity to then bring a treatment which is designed specifically for patients p53 wild type, there's a big level of excitement, and we're looking forward to hopefully bringing it to patients soon.
Yeah. You know, you mentioned, Reshma, before that, you know, the checkpoints don't really serve much of a benefit in this patient population. What exactly is the standard of care here? You know, like, what are you really coming up against?
It's really just chemotherapy, right?
You know, these patients are getting treated with fixed number of cycles. Usually, it's gonna be a taxane plus a platinum doublet chemotherapy. They're treated for about four to six cycles. Usually it's like a watch and wait, right?
Okay.
Until, unfortunately, their tumors progress. You know, there really is a very urgent need to identify new therapies for this patient population.
Yeah, no, I completely agree with you. Well, I'm super excited to see this top-line data in the middle of this year. Well, that's really all the questions I had. Are there any questions from the audience as of right now? No? All right. Richard, Reshma, thank you so much for joining us today.
Thank you.
Thanks for having us, Robert.
No problem.