Okay, good morning. My name is Peter Lawson. Welcome to Barclays Healthcare Conference in Miami. I'm really pleased to have with me up on stage, management from Karyopharm. So we've got, Richard Paulson, President, CEO, and Reshma Rangwala, Chief Medical Officer. And Richard's gonna start off with a brief introduction.
Thanks, Peter, and thanks to Barclays for having us. You know, before we get started, maybe just a little housekeeping. I'd like to remind you that various remarks we make today will constitute forward-looking statements, you know, as you see on the slide, and also please refer to our most recent 10-K. Karyopharm is an innovation-driven commercial-stage oncology company, and we're the leader in the oral selective inhibition of nuclear export, which was developed to address the fundamental mechanism of oncogenesis. We're intently focused and have positioned ourselves for our next stage of transformative growth, with three late-stage trials supported by a growing body of unprecedented data in both solid and hematological malignancies that are expected to read out next year.
The data we are seeing in endometrial cancer and myelofibrosis are highly encouraging, and we believe the largest opportunities for selinexor are yet to come, as we potentially enhance and create new standards of care for patients. We have a cash runway through to late 2025, providing us with the financial strength to deliver on the key data readouts from our three phase III programs. And we're concentrating our investments in these programs and leveraging our profitable commercial multiple myeloma franchise, with XPOVIO now approved in over 40 countries. We're committed to delivering on these opportunities ahead of us and believe selinexor could generate $2 billion of annual peak revenue in the U.S. alone.
So as we accelerate our innovation and growth strategy over the next two years, you know, this year, we expect to generate total revenue of $140 million-$160 million. And in multiple myeloma, we're gonna continue to advance our data with regards to T-cell fitness. We're gonna continue to advance our program in multiple myeloma SPd, with a data readout in the first half of 2025. In endometrial cancer, we're gonna continue to look and track the progress and look for continued data from our SIENDO trial, advance our ECO42 program, as we look to have the data readout again in the first half of 2025.
In a myelofibrosis, again, we're gonna continue to look at our data evolution as it positively evolves, and we're gonna continue to advance recruitment and look to have the data readout in the second half of 2025 from our pivotal myelofibrosis program. So as you can hear, it's an exciting time at Karyopharm. We're focused on the transformative opportunities in front of us, and believe in the opportunity to deliver and transform outcomes for patients, for our organization, and for shareholders. And with that, Peter, let's jump into some Q&A.
Great. Thank you so much. I guess first question, as you return to your seat, is just running around product guidance. It was kind of flat year-over-year, essentially. Kind of, what do you need to do to kind of grow to the top end of that guidance, and should we view as revenues going forward as essentially flat until new products come online? Just trying to work through the positives, as we kind of work through 2024 and into 2025.
Mm-hmm. Yeah, I'll break the two parts out. I think as we look, you know, over our multiple myeloma franchise, we're gonna continue to work to grow XPOVIO in multiple myeloma. And I think when we put the guidance in place this year, you know, some different tailwinds and headwinds from a tailwinds perspective, we continue to make a really positive evolution in the community, and our focus is on that community setting, where the majority of multiple myeloma patients are treated.
I think we've made a really nice evolution in that space, where in the community setting, you know, in our targeted key accounts, which have the majority of multiple myeloma business, and I would say we're about 80% penetrated, but we want to drive depth in those accounts and continue to get those accounts prescribing selinexor more. I think that's strongly supported by the enhanced positioning we have in NCCN, you know, as well as the continued positive data we've generated for PI-naive patients, which again, when you look at the treatment paradigm early in the community setting, with daratumumab being used much earlier, I think, again, with our positioning and with our, you know, ongoing data, we'll be able to see increased penetration in the community.
Secondly, in the community, our focus is really on those patients second to fourth line. So we've been able to grow our, our new patient starts. Last year, second to fourth line was around 55% of our new patient starts. This year, it's around... Or in 2023, it was about 70%. So as we continue to focus on that, I think again, we'll see, you know, positive evolution in terms of duration of therapy, 'cause as patients are treated earlier, we see longer duration of therapy.
And then third, I think in the academic setting, you know, that's some of the headwinds where, you know, last year was really the eye of the storm, so to speak, as we saw, you know, a number of new bispecifics come to market, a couple of them at the second half of last year. We see kinda continued evolution of the CAR-Ts. So that impacted the academic setting, really impacted our new patient starts. I think as we look at this year, we're looking at one more, you know, bispecific to be approved, potentially. So, you know, the treatment paradigm in the institutions or academics, you know, is pretty fluid....
We're continuing to make sure we position selinexor with our data kind of pre and post-CAR T, enabling a pretty flexible approach for physicians in that setting. And also, you know, in that setting, they really value having an innovative and novel mechanism of action. So I think in the institutions and academics kind of playing through that, that's kind of the headwind we're gonna face, but I think we're also making really good progress there. So, you know, over the near term, I feel very comfortable and confident in delivering on our guidance this year. And I think as we continue to move forward, you know, in multiple myeloma, XPO data we just talked to, I think that will continue to drive nice revenue growth.
But for sure, the greatest growth opportunities over the mid to long term are potentially in endometrial cancer and myelofibrosis.
Gotcha. Thank you. The bispecific headwind, does that continue through 2024? You kind of talked about 2023 as the eye of the storm, but is there a kind of a lingering effect through 2024?
Yeah, I think with a couple of them coming to market at the same time, that was probably the most intense competition you can face. We're obviously gonna continue to see, you know, good, strong uptake from those. But I think, you know, we've kind of faced the worst, you know, impact in terms of near-term impacts. I think as we move forward, you know, again, looking at our positioning in that space, I think we'll be able to, you know, evolve positively.
Gotcha. Thank you. And just the duration of treatment, how is that kind of changing in the real-world setting as you've kind of... whether it's moving from academic to community or later line to earlier line?
Yeah. It's evolving really positively for us. So with, you know, 70% of our, our new patient starts in that second to fourth line, we're seeing positive evolution in the, in the duration of therapy. At the same time, you know, still with about a third of our business in institutions and academics, you know, selinexor is used in, in multiple places. So sometimes it may be used for bridging, you know, for, in, into CAR Ts, which can have a pretty short duration. Sometimes it may be pre or, or post, a CAR T. So the duration, you know, in institutions and academics is pretty variable, whereas, you know, in that second to fourth line, I think we're seeing really positive evolution on duration of therapy.
Gotcha. Thank you. And you mentioned on the earnings call, I don't know if it was the first time, but the commercial infrastructure was profitable. Just if you could kind of elaborate upon that. I think that got missed by many.
Yeah. No, it's a great point, and, you know, our commercial business is really resilient. I think the team is doing a great job in a very competitive environment. And if you just look at the commercial business by itself, it's profitable with a 2-to-1 ROI. So it's also allowing us to have the capabilities and the infrastructure built and ready to launch the new indications. So, you know, potentially following positive data and approval, we don't have to build a commercial infrastructure. We can rapidly engage, and the majority of patients treated in myelofibrosis and in endometrial cancer are also in the community. So I think not only is our business profitable now from a commercial perspective, but we also have the infrastructure and the capabilities to launch quickly.
Gotcha. And would that profitability continue as you add new products or?
It'll just grow. Yeah, 'cause again we really, we really have a great opportunity to leverage the capabilities we have. We don't need to add around the edges. And I think, you know, to be able to have new indications will just enhance our profitability.
Gotcha. Thank you. And then, as we think about the pipeline and endometrial cancer, what are we gonna learn from the updates for p53 wild-type patients? Reshma?
Yeah, absolutely. So the SIENDO trial, from which this p53 wild-type subgroup was observed, is still very much ongoing. So we had an opportunity at the end of last year at a conference in South Korea, known as IGCS, to present our initial overall survival data. Very encouraging, by and large, you know, tracking with some very impressive PFS data that we've seen from that p53 wild-type subgroup. So again, as we see more events, we'll have more opportunities to update that overall survival data, not only in the overall p53 wild-type subgroup, but that important p53 wild-type pMMR subgroup, for which there really is no standard of care. The other aspect that we're really looking closely at is, again, the PFS in that p53 wild-type pMMR subgroup. That hazard ratio, very impressive, at about 0.32.
The median PFS for the selinexor arm still has not been reached. So as we see more events, we'll have an opportunity to update those data and potentially observe what that overall median PFS will be. Hopefully, we'll see something, you know, northwards of 30 months. And that's... I just wanna highlight, that's just in the maintenance setting, so those patients have already received prior chemotherapy of around six months. So, you know, the overall benefit that those patients are achieving really is quite meaningful.
Gotcha. Okay. As that data matures, is there risk around the hazard ratio? Just if you could walk through kind of the dynamics there, we should be thinking about.
The risk around the hazard ratio as the data mature? No, I don't think so, largely because, you know, we just continue to see it strengthen, right? You know, sort of we see more events. You know, that hazard ratio, we're not really seeing any changes within that placebo arm. It's really staying, you know, very close to that four to five months. We do see some improvement in the hazard ratio over time, again, both for PFS and I assume for overall survival too. The medians, though, are just getting longer as well.
Gotcha. Okay, and then the differences between that phase III SIENDO and the phase III XPORT-EC-042.
Yeah. So let me start first with some of the commonalities. So we're still evaluating selinexor in that maintenance setting. So again, all of the patients must have received prior chemotherapy of approximately four to six months. Some of the key differences, though, is one, gonna be the patient population. So SIENDO was an all-comers population. Any patient who was an advanced, recurrent endometrial cancer, who was in response, potentially could be eligible. In contrast, this current study is only enrolling patients whose tumors are p53 wild type, and we're assessing that p53 status using an NGS platform through Foundation Medicine. So again, that patient population is going to be a key difference. The second difference is the dose. So in the SIENDO trial, every patient was treated with 80 mg of selinexor weekly.
Through some pretty extensive dose optimization, we've been able to lower the dose to now 60 mg in the current trial. We really do believe that that 60 mg is likely that minimally effective dose that is only going to enhance that overall benefit risk. That efficacy should be the same, potentially even longer in our current trial, but the safety profile, hopefully substantially improved.
Gotcha.
The last point I will say as a differential is, patients can receive a prior IO therapy. So whether it's a PD-1 therapy, PD-L1, another kind of IO, we excluded that in SIENDO. That's allowed in this current trial.
Perfect. Thank you. And then frontline treatment for endometrial cancer seems to be evolving with-
Yeah
Chemo plus IO. How does that impact the trial and potential results?
Yeah. It's really minimal impact. So the checkpoint inhibitors, especially in that population that we're evaluating selinexor, it's only approved in that dMMR patient population. So MMR deficient, they represent approximately 20% of all advanced recurrent endometrial cancers patients, so relatively small, and that approval is in combination with chemotherapy and then continuing on into the maintenance. Unfortunately, that pMMR, which again represents about 80% of all patients, there is no, there is no standard of care, no new standard of care. Those patients are still gonna be treated with carboplatin, followed by a watch-and-wait paradigm. So really no, impact, right, with the checkpoint inhibitors. I think we're also very encouraged, and the investigators are very encouraged by the data that we are seeing from the SIENDO trial.
Again, I'll you know, go back to that pMMR p53 wild-type subgroup, where that hazard ratio is 0.32 and median is still not reached. So there's a lot of enthusiasm about the potential benefit that is being observed in this very novel patient population.
Gotcha. Thank you. Will you have patients enrolled that have exposed to chemo and IO?
We-
Proportion.
We do, but we're still seeing a very small subgroup that has been exposed to a prior checkpoint inhibitor. I will say some of the patients had received checkpoint inhibitor in the adjuvant setting, and then they received chemotherapy. We have a far fewer patients that had received the triplet in that treatment setting, i.e., the carboplatin plus checkpoint inhibitor. But again, it's still a very small group of patients.
Gotcha. Thank you. And, what's the bar you wanna see for this-
Yeah
Maintenance setting? What's, what's the appropriate bar, you think?
Yeah, it's a great question. So, you know, for the placebo arm, that PFS is sort of sitting around that four to five months. So I think anywhere between a, you know, a five- to six-month improvement in PFS, that delta, I think, would constitute a very meaningful benefit for this patient population.
Gotcha. Thank you. And, I guess, how's enrollment going? What's the feedback been like from physicians?
It's going really well. The feedback is tremendous. You know, we just got back from Barcelona, from the European Society of Gynecology Oncology. I think we're really seeing a solidification of the potential role of selinexor in endometrial cancer. Again, it's all about molecular entities. In endometrial cancer, I think they see the benefit, the value of identifying that p53 wild-type status, and hopefully, this drug, or this trial, I should say, will ultimately enable both the approval as well of the drug, as well as the companion diagnostic. So lots of enthusiasm, largely because the data really are so impressive.
Gotcha. Are there any issues or benefits for identifying patients?
No issues. You know, and largely it's because endometrial has largely become a molecularly based tumor type, right? So patients and physicians, you know, they are ready to test that tumor, if at diagnosis, but then at the time of recurrence, too. So it's part of the system. Being able to send the tumor off to Foundation Medicine really is not any kind of obstacle for this population. Yeah, we don't see any barriers.
Gotcha. When do you think you could see approval?
So right now, top-line results are gonna be in the first half of 2025. You know, ultimately, approval timelines are up to the FDA and usually span anywhere between six and 10 months. So, you know, hard to say, but hopefully relatively soon.
Gotcha. Thank you. And then I'd love to pivot to myeloid, myelofibrosis, just kind of the timeline of data we should be thinking about. What do we see in 2024 versus 2025?
In 2024, it's really gonna be continued data from our phase I study, which is evaluating selinexor in combination with ruxolitinib. This is a JAK-naïve patient population. In 2023, we had multiple opportunities to really present those top-line results of SVR35 as well as TSS50 at week 24. We then had an opportunity to complement those data with those durability data, and that durability data really suggests that if a patient achieves that SVR35 or TSS50 at week 24, they're gonna be maintained within that response, which is ultimately what those patients need to see. Patients are still on therapy, the study is still ongoing. We'll have an opportunity to update those durability data. We're also doing a lot of work from a translational perspective, as well as preclinical work, too.
So lots of data coming from multiple different fronts, you know, from that study. We also have another trial known as the O44 trial, which is specifically evaluating selinexor as a monotherapy. This is also a JAK-naïve patient population. All patients have that moderate thrombocytopenia, so their baseline platelet count is anywhere between 50-100. I'd say this, too, is a very high unmet need patient population. Benefit achieved from currently available JAK inhibitors is quite minimal. So this is really an opportunity to demonstrate the benefit, both efficacy and safety, with selinexor as a monotherapy, and we'll have an opportunity to present some initial data from that study later this year as well.
Gotcha. Thank you. And then just number of patients we should expect to see for MF this year, and kind of what do you want us to kind of hone in on that, those datasets?
It's really gonna be... So I, I don't have numbers yet, right? I mean, we're gonna have to just see how, you know, the trial evolves and how many patients achieve that SVR, you know, reach that 12-week and 24-week time point. But I think the main focus is really gonna be about that spleen volume reduction. What we observed from the phase I study is that we saw a very rapid but durable spleen volume reduction and also a TSS50 response, too. So I think, you know, to be able to see that rapidity in spleen shrinkage is gonna be a key focus, but also the tolerability data as well.
Gotcha. And then on the competitive front for MorphoSys BET inhibitor plus JAK inhibitor, how does that change the bar from that data that we saw in ASH last year?
Yeah. I think it just goes back to our data set. You know, sort of when I look at our phase I data set in those 14 patients that were treated with that 60 mg selinexor, numerically, those SVR rates are probably some of the highest out there at around 78%-79%. More than a doubling with what you achieve with ruxolitinib alone. Similar is the TSS50 data, and then most recently at our earnings call on March 1st, we had an opportunity to then complement those data with some absolutes. Whether you look at TSS50 and now absolute, numerically, those data are also suggesting an optimal TSS response. So, you know, I think this combination potentially could be very much best in class, right? It's maximizing the efficacy, both from a spleen shrinkage, symptom improvement.
We clearly have signs of disease modification and controlling the cytopenias. So looking across all four areas, this is a combination that I think really can, you know, maximize benefit across all four domains.
Gotcha. Thank you. And then, does the BET inhibitor in any way, you know, if approved, does that affect enrollment rates? Do you kind of have to factor in for that?
Likely not, right? You know, we anticipate, you know, an approval, if they ultimately get approved, probably, you know, sometime in 2025 when we're close to or already completed enrollment. So no, I don't think that there's gonna be any impact.
Gotcha. Then the BET inhibitor combo, what they had at SVR35 of 68%, is that the bar to beat, you think? Can you beat that in the phase 3?
I think the bar is still very much gonna be ruxolitinib, right? I mean, that's our control. So we clearly wanna show that significant improvement compared to rux, but I go back to our data. Like, even if, you know, people are gonna compare across the two trials, you know, numerically, our data are much better, too, on that front.
Gotcha. Final question, just safety, how does that compare, BET inhibitor pluses versus yours?
You know, I go back to our tolerability profile. I mean, by and large, this is a very tolerable combination, right? We see a very similar profile as multiple other agents in myelofibrosis. We see the GI toxicities, we see heme toxicities. These are very classic toxicities in myelofibrosis and ones that physicians are very used to modifying. Ultimately, patients are not discontinuing therapy as a result of these AEs, and ultimately, that's what's driving that SVR and TSS50 response. One last thing before we leave, I just wanna highlight, you know, we have patients who are on selinexor therapy, and this is from our monotherapy study that is now exceeding five+ years, right? So five+ years in the myelofibrosis space. Going back to endometrial cancer, we have patients that are on selinexor for four+ years at this point.
Really a testament to just how tolerable this drug is.
Perfect. Thank you so much. Thank you, Reshma. Thank you, Richard.
Thank you, Peter.
Thank you.