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

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 is going to start off with a brief introduction.

Thanks, Peter and thanks to Barclays for having us. 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, as you see on the slide and also please refer to our most recent 10-K. Now 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 3 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. And 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 3 Phase III programs. And we're concentrating our investments in these programs and leveraging our profitable commercial multi 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. And so as we accelerate our innovation and growth strategy over the next 2 years, this year, we expect to generate total revenue of $140 million to $160 million. And in multi myeloma, we're going to continue to advance our data with regards to T cell fitness. We're going to continue to advance our program in multi myeloma XPd with a data readout in the first half of 2025. In endometrial cancer, we're going to continue to look and track the progress and look for continued data from our SIENDO trial and advance our EC-042 program as we look to have the data readout again in the first half of 2025. In myelofibrosis, again, we're going to continue to look at our data evolution as it positively evolves and we're going to 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 and I guess first question, as you return to your seat is, is 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 is essentially flat until new products come online? Just trying to work through the positives and as we kind of work through '24 and into '25?

Yes. I'll break it into 2 parts out. So I think as we look over our multi myeloma franchise, we're going to continue to work to grow XPOVIO in multi myeloma. And I think when we put the guidance in place this year, 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 multi myeloma patients are treated. I think we've made a really nice evolution in that space, where in the community setting, in our targeted key accounts, which have the majority of multi myeloma business and I would say we're about 80% penetrated, where we want to drive depth in those accounts and continue to get those accounts prescribing selinexor more. And I think that's strongly supported by the enhanced positioning we have in NCCN as well as the continued positive data we've generated for PN [ 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 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 new patient starts last year, second to fourth line was around 55% of our new patient starts. This year, it's around -- or in '23, it was about 70%. So as we continue to focus on that, I think, again, we'll see positive evolution in terms of duration of therapy because as patients are treated earlier, we see some longer duration of therapy. And then third, I think in the academic setting, that's some of the headwinds, where last year was really the eye of the storm, so to speak, as we saw a number of new bispecifics come to market, a couple of them at the second half of last year. We see kind of continued evolution of the CAR Ts. So that impacted in the academic setting, really impacted our new patient starts. I think as we look at this year, we're looking at one more bispecific to be approved potentially. So the treatment paradigm in the institutions or academics 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 in that setting, they really value having an innovative and novel mechanism of action. So I think in the institutes and academics kind of playing through that, that's kind of the headwind we're going to face but I think we're also making really good progress there. So 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, in multi myeloma XPd 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.

Got you. The by specific headwind, does that continue through '24? Or you kind of talked about 23% as the eye of the storm but is there kind of a lingering effect through '24?

Yes. 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 going to continue to see good strong uptake from those. But I think we've kind of faced the worst impact in terms of near-term impact. So I think as we move forward, again, looking at our positioning in that space, I think we'll be able to evolve positively.

Got 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?

Yes. It's evolving really positively for us. So with 70% of our new patient starts in that second to fourth line, we're seeing positive evolution in the duration of therapy. At the same time, still with about 1/3 of our business in institutions and academics, selinexor is used in multiple places. So sometimes it may be used for bridging into CAR Ts, which can have a pretty short duration. Sometimes, it may be pre or post a CAR-T. So the duration, institutions and academics is pretty variable, whereas in that second to fourth line, I think we're seeing really positive evolution on duration of therapy.

Got you. And you mentioned on the earnings call, I don't know if it was for the first time but the commercial infrastructure was profitable because if you could kind of elaborate upon that. I think that got missed by many.

Yes. No, it's great point. And 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 2:1 ROI. So it's also allowing us to have the capabilities and the infrastructure built and ready to launch the new indications. So potentially following positive data and approval, we don't have to build the 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.

Got you. And would that profitability continue as you add new products or just grow?

Yes, because we -- 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 to be able to have new indications, we'll just enhance our profitability.

Got you. And then as we think about the pipeline and endometrial cancer, what are we going to learn from the updates for TP53 wild-type patients?

Go ahead.

Yes, 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 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 isn't a 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 a 0.3. 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 and hopefully, we'll see something in the northwards of 30 months. And that's -- I just want to highlight, that's just in the maintenance setting. So those patients have already received prior chemotherapy of around 6 months. So the overall benefit that those patients achieving really is quite meaningful.

Got you. Okay. Does -- as that data matures, is there a risk around the hazard ratio? Just if you can 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 we just continue to see it strengthen, right, sort of we see more events. That hazard ratio, we're not really seeing any changes within that placebo arm. It's really staying very close to that 4 to 5 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.

Got you. Okay. And then the differences between that Phase III SIENDO and the Phase III XPO EC trial?

Yes. 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 4 to 6 months. Some of the key differences, though is, one is going to be the patient population. So SIENDO was an all-comers population, any patient who has 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 milligrams of selinexor weekly. Through some pretty extensive dose optimization, we've been able to lower the dose to now 60 milligrams in the current trial. And we really do believe that, that 60 milligrams is likely that minimally effective dose that is only going to enhance that overall benefit risk. So that efficacy should be the same, potentially even longer in our current trial with the safety profile hopefully substantially improved. 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. And then frontline treatment for endometrial cancer seems to be evolving with [indiscernible] plus IO, how does that impact the trial and potential results?

Yes. 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 cancer 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 standard of care, no new standard of care. Those patients are still going to be treated with Carbo/Taxol 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 go back to that pMMR p53 wild-type subgroup where that hazard ratio is 0.32 and median still not reached. So there's a lot of enthusiasm about the potential benefit that is being observed in this very novel patient population.

Got you. And will you have patients enrolled that have exposed to chemo or IO, proportion?

We do but we're still seeing a very small subgroup that has been exposed to a prior checkpoint inhibitor. I would 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 Carbo/Taxol plus checkpoint inhibitor. But again, it's still a very small group of patients.

Got you. And what's the bar you want to see for all this maintenance setting? What's the appropriate bar you think.

It's a great question. So for the placebo arm, that PFS is sort of sitting around that 4 to 5 months. So I think anywhere between a 5- to 6-month improvement in PFS delta, I think would constitute a very meaningful benefit for this patient population.

And I guess, how is enrollment going? What's the feedback been like from physicians?

It's going really well. The feedback is tremendous. 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. And endometrial cancer, I think they see the benefit and value of identifying that p53 wild-type status. And hopefully, this drug or this trial, I should say, will ultimately enable both the approval of the drug as well as the companion diagnostics. So lots of enthusiasm, largely because the data really are so impressive.

Got you. Is -- are there any issues or benefits for identifying patients?

No issues. And largely, it's because endometrial has largely become a molecularly based tumor type, right? So patients and physicians, they are ready to test that tumor diagnosis but then at the time of recurrence, too. So it's part of the system being able to send the tumor off the Foundation Medicine, really is not any kind of obstacle for this population. Yes, we don't see any barriers.

Got you. When do you think you could see approval?

So right now, top line results are going to be in the first half of 2025. Ultimately, approval time lines are up to the FDA and usually span anywhere between 6 and 10 months. So hard to say but hopefully, relatively soon.

Got you. And then I'd love to pivot to myelofibrosis, just kind of the time line of data we should be thinking about, what do we see in '24 versus '25?

So in 2024, it's really going to be continued data from our Phase I study, which is evaluating selinexor in combination with ruxolitinib. This is a JAK naive patient population. In '23, we had multiple opportunities to really present this top line results of SVR35 as well as TSS50 at week 24. We then had an opportunity to complement this date with this durability data. And that durability data really suggests that if a patient achieved that SVR35 or TSS50 at week 24, they're going to 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 this 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 from that study. We also have another trial known as the 044 trial, which is specifically evaluating selinexor as a monotherapy. This is also a JAK-naive patient population. All patients have that moderate thrombocytopenia. So their baseline platelet count is anywhere between 50 to 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.

Got you. And then just a number of patients, which you expect to see for MF this year. And I kind of, what we should -- what do you want to start kind of hone in on those data sets?

It's really going to be -- so I don't have numbers yet, right? I mean, we're going to have to just see how the trial evolves. And how many patients achieve that sCR -- reach that 12-week and 24-week time point. But I think the main focus is really going to 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 to be able to see that rapidity in spleen shrinkage is going to be a key focus but also the tolerability data as well.

Got you. And then on the competitive front from MorphoSys is BET inhibitor plus and JAK inhibitor. How does that change the bar from that data that we saw in [indiscernible] last year?

Yes. If we can just go back to our data set and this is, when I look at our Phase I data set in those 14 patients that were treated with that 60-milligram selinexor, numerically, those SVR rates are probably some of the highest out there at around 78% to 79%, more than a doubling with what you achieved with ruxolitinib alone. Similar is the TSS50 data. And then most recently at our earnings call on March 1, we had an opportunity to then complement those data with some absolute -- so whether you look at TSS50 and now absolute numerically those data are also suggesting an optimal TSS response. So 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 4 areas, this is a combination that I think really can maximize benefit across all 4 domains.

Got you. And then does the BET inhibitor in any way, if approved, does that affect enrollment rates? Do you kind of have to factor in for that?

Likely not, right? We anticipate an approval, if they ultimately get approved probably sometime in 2025, when we're close to or already completed enrollment. So no, I don't think that there's going to be any impact.

Got you. And then the BET inhibitor combo what they had SVR35 of [ 58% ]. Is that the bar to beat you think, can you beat that in the Phase III?

I think the bar still is very much going to be ruxolitnib, right? I mean that's our control. So we clearly want to show that significant improvement compared to rux but I go back to our data, like even if people are going to compare across the 2 trials, numerically our data are much better too, on that front.

Got you. And then final question, just safety, how does that compare BET inhibitor pluses versus yours?

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 one that positions a very use 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 want to highlight, we have patients who are on selinexor therapy. And this is from our monotherapy study that is now exceeding 5-plus years. right? So 5-plus years in the myelofibrosis space, going back to endometrial cancer, we have patients that are on selinexor for 4-plus years at this point, really a testament to just how tolerable this drug is.

Perfect. Thank you so much. Thank you, Reshma and thank you, Richard.

Thank you Peter.

Thank you.