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

All right. Good afternoon, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here, and it's my pleasure to introduce the team from Karyopharm Therapeutics, including Richard Paulson, CEO, on my far left; and Reshma Rangwala, CMO, on my near left. Just a reminder, the format for today is a fireside chat. But before we get started, I just need to read a quick disclaimer. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative. And with that, we can start the Q&A.

So I thought maybe, obviously, XPOVIO is an important part of the story here. It's been on the market several years now in the U.S. And the key focus area for you guys is commercial execution. So maybe just remind us how things have evolved over the past few years? And what are some of the key hurdles you're facing today?

Sure. Thank you, Mike, and thanks for having us. When you look at XPOVIO and our launch in multiple myeloma, we're just over 1.5 years into our second-line plus launch. And so what we've focused on a lot over the last 1.5 years is really how do we evolve XPOVIO from its initial approval, which was in the fifth line plus at a high dose kind of twice weekly 160 into that second-line plus low dose once weekly. So a lot of our work has been very focused on that. And I think as we're in there, fortunately, for patients, there's a lot of choices in multiple myeloma. And as we've always said, it's an area where it grows steadily over time. We continue to grow steadily over time, really entrenching ourselves as a novel new class, which is really important in that second to fourth line, an agent which is growing not only in the U.S. but globally. As you know, we're getting approvals around the world as well as in the U.S. with our Q2 revenue being about $40 million, $39.7 million. So then continue to make strong progress in that second to fourth line, establishing ourselves as a standard of care and really growing kind of significantly in the community. So right now, from a triplet perspective, over 50% of our business is now in that second to fourth line and actually over 65% of our business is in the community, which is really important because the majority of those second to fourth line patients are in the community setting.

Yes. Can you talk about, just over time, how you expect that breakdown between community setting to sort of expand further here? And where can the peak sort of go?

Yes. So I think we have a lot of room to continue to grow, right? So in the community setting, a large majority of the patients are treated in the first or second line usually with an IMiD, a PI and an anti-CD38. And so what we have focused on is really positioning ourselves post anti-CD38. And community setting probably sees about 60% to 70% of the patients in those earlier lines. So even though there's a lot of competition coming in the later lines, kind of fourth, fifth line plus. I think there continues to be a real unmet need, and I think in the community setting for us being in oral. And now the physicians are understanding it's okay to dose reduce us, also here is the right kind of supportive care to use upfront, that there's significant growth for us in that setting.

Makes sense. Maybe you can talk a little bit about just off-label use. Obviously, the label is in the combination with Velcade in the second-line plus setting. You're moving forward with SPd as well sort of in a Phase III, but just beyond Velcade, how much use are you getting in other combinations?

Yes. I mean as you know, we only promote obviously to the XVd label indication. Fortunately, I think for physicians and patients also, there's a lot of data, which has supported us to be in the NCCN guidelines with Velcade, of course, but with Pomalyst, with DARA and with Kyprolis, so XPd, XDd and XKd. And it's difficult to break out all the different regimens, but definitely, XVd is the one we promote to. And for patients which may not have seen V in the first line, having the opportunity to get exposed to V in the second-line plus is obviously a good opportunity, but also a lot of patients who may have been exposed, but they haven't really been refractory to V can also get reexposed to V. So for us, having the opportunity to grow patients in that area, plus at the same time, obviously, the NCCN listing and the different options there for patients are important. And as you mentioned, we're moving forward with the trial with Pomalyst, which would be an all-oral combination. And again, I think that's important because as we get a chance to promote it, obviously, that will allow us to grow share more as our sales force can talk to it.

Can you maybe just talk about timing of that in terms of where you are in the study, maybe timing of the data? And how soon after that can you get into a label?

Yes. So we started that study in Q2, our first patient in, and we see that data coming out through 2024. So fortunately, for patients, there's some good opportunity for some strong PFS. So as we engage in that trial and we'll see that data come out, and then obviously, we'll have to engage with the agency and move forward to get into the label.

Got you. Maybe you can just make a comment on product perception because I know that's been an area of focus, and you've made some progress there and maybe just talk about how you've done that and sort of how that's evolved?

Yes. So I think we kind of started with that upfront where I think the product perception as many agents that have come in oncology, especially if they've come in those later lines -- later line, high-dose patients that are more sick. And so we've done a lot of work to really, again, help physicians understand the lower dose and also even help physicians understand 2 things really with selinexor. One is you can dose reduce and actually continue to get the kind of efficacy that we saw in our trials. And also kind of through the first couple of months with proactive engagement with antiemetics, patients were able to move through those first couple of months and have a very tolerable treatment regimen with selinexor. So I think that's something that we've had to address because when it was first launched, the high dose kind of 160, selinexor had a stronger toxicity profile. And so in the community setting, many of the physicians probably didn't try it, but they heard from others that tried it. So we've had to go through that to make sure we educate people well on it. And as we're doing that, you can see consistently the intention to prescribe, has continued to move up quarter after quarter, which shows that we're making strong progress in those areas. And also even kind of 1.5 years into the second-line launch, we continue to grow breadth. So the number of new accounts, especially in the community, kind of continue to keep coming on board. So that's -- as physicians are seeing and hearing from others, critically important. At the same time, for those who are using it, we're growing the depth. So in those accounts, especially in the larger community accounts, which are now experienced, know how to use it are not kind of thinking about 2 years ago in the fifth line plus setting, but we're looking at using it today. We're seeing the depth really grow in those community accounts.

Maybe just to round out the commercial discussion here. And if you could comment just on the opportunity in Europe and your partnership with Menarini.

Yes. I mean Menarini, excited to have them as a partner, a really strong organization in Europe and around the world, we're in Europe, U.K., Latin America and a few other select countries, but focusing on their -- obviously, with our full approval in July. They're moving forward into the launch sequence in Europe with the first launch will be occurring kind of in Q3, Q4 in Germany. And then as they work and kind of drive the pricing reimbursement discussions in the different countries. I think for us, the Menarini partnership is a strong partnership. And when you look at it, as those launches start to come to life, we have kind of strong tiered nice teens royalty that will start to come into play. At the same time, we have just over $200 million -- I think about $202.5 million in additional milestones that we can earn as we continue to get different milestones across the markets with Menarini. And the Menarini partnership is important because it also contributes to R&D. So from a development perspective, they contribute from 2022 through 2025. 25% of R&D up to $15 million per year. So a number of areas, which I think the partnership is really important. But as we move forward, very excited to see them launch it in Europe and start to see the royalty come in as we get that access in Europe.

Okay. Great. You mentioned R&D, so that's a good sort of transition into looking at some of the other programs in development. Maybe we can start just with endometrial cancer. And if you can describe sort of the current treatment landscape and sort of where you see the opportunity?

Absolutely. So -- and thank you for having us. I really appreciate it. So endometrial cancer remains one of the highest unmet need. It's the most prevalent gynecologic cancers that affect women, not only in the U.S., around the world, about 14,000 women unfortunately are diagnosed with endometrial cancer this year. And we know that amongst those 14,000, approximately 50% of those patients are going to be p53 wild-type. And the reason I mentioned that statistic is because from our SIENDO trial that we conducted and read out earlier this year, we noticed a really robust subgroup analysis when we looked at the intention to treat and amongst the intention to treat just those patients who are p53 wild-type, we identified a very robust signal with selinexor. 13.7 median PFS in those patients who were treated with selinexor as compared to just 3.7 months treated with placebo. So really shows a very sizable and robust, meaningful benefit in those patients who are p53 wild-type, Contrast that to the patients who are P53 mutant, and you essentially saw no benefit. 5.6 months versus 3.7 months. So it really suggests that this is a patient population who can derive meaningful benefit from selinexor in the maintenance therapy. Maintenance is not a current treatment paradigm in endometrial cancer. By and large, patients are treated with standard of care chemotherapy and are just treated with then a watch-and-wait approach. And unfortunately, once you get to that watch-and-wait approach, survivals are very low with a 5-year overall survival of about 17%.

Maybe you can touch a little bit on what you saw in terms of safety and remind us what dose you use sort of in the SIENDO study?

In the SIENDO study, we use 80 milligrams weekly. And this was, by and large, it is a manageable safety and tolerability profile. Again, as Richard mentioned, it is about the mitigation, so treating patients with antiemetics and telling the investigators about dose reductions by and large, we can keep the safety profile manageable for these patients.

And maybe you can talk about next steps here. I think you're in the process of trying to design a pivotal study, specifically in that subset of patients with wild-type p53. Maybe you can talk about the remaining hurdles there and how you currently think about the trial design?

Absolutely. So we've heard -- you're absolutely correct. So this next trial is going to be focused specifically in patients who are p53 wild-type. We've had some very good discussions with the FDA and are looking to initiate this trial later this year. We are working with some very strong partners. So similar to SIENDO, we're working with the GOG who's the gynecology-oncology group, a very large and established cooperative group in the U.S. and also ENGOT, which is a European cooperative group in Europe. So we're going to have 2 very strong partners in both of those regions. In addition, we are going to have a companion diagnostic partner, probably one of the foremost leaders in NGS testing, who is going to facilitate the p53 wild-type. So we feel very confident that amongst this group of 4 of us, right, that we can initiate and stand up a really important trial for these women with endometrial cancer.

Maybe you can talk a little bit about your sort of -- you're in the process of finalizing a partnership for your companion diagnostic, maybe just -- is that something we should expect near term later this year, by the end of the year? How should we think about that?

We're on track to start the trial this year. So everything is going very well from that initiation standpoint.

Can you maybe talk about how you're thinking about the number of patients you need to enroll in this study? And is it hard to find the patients? Or is that pretty easy?

So we'll have an opportunity to disclose the trial results once we initiate the trial later this year. In terms of the trial enrollment, again, we have the strength of our SIENDO subgroup. There is a lot of enthusiasm again both in the U.S. and ENGOT around the degree of benefit that we observed there. So with our partnerships and again, with the enthusiasm, our opportunities to be able to present the data at SGO and ASCO, we're really confident about the interest in this study.

And I know you haven't started the study yet, but just -- when you're thinking about potential time line for readout, is that 2024...

2024, yes.

All right. Maybe we can just switch to myelofibrosis. This is another area of focus. You've shown some nice early data there, but maybe just talk about the current treatment landscape there and where you're seeing some opportunity for select -- selinexor to fit in?

Yes, absolutely. So by and large, for the past 10 years, myelofibrosis patients have been treated with JAK inhibitors and primarily ruxolitinib. The JAK inhibitor, ruxolitinib, specifically has an SVR rate. So this is a spleen volume reduction rate of approximately 35% or 35% at week 24 of around 40%. So it's a good rate, but relatively modest. We also know that ruxolitinib has issues with myelosuppression from anemia to neutropenia and thrombocytopenia, and that myelosuppression really can inhibit a patient to stay on ruxolitinib and some of the other JAK inhibitors for a long term. So there really is a high unmet need to identify new therapies with novel mechanisms of action. Selinexor as an inhibitor of nuclear export is one of those new novel classes. We know that JAK relies very heavily on this Nucleocytoplasmic shuttle. And by inhibiting that transport, you retain JAK and potentially reactivate that tumor suppressive activity. We see that as a monotherapy in cell culture as well as also in mouse models. We also see a very additive, if not synergistic effect when we combine these 2 agents, again, in those nonclinical models. That lends itself to being able to develop selinexor not only as a monotherapy, which we are doing as part of the relapsed/refractory trial, but in combination as well and really have an opportunity to embed selinexor amongst the broadest patient population within myelofibrosis.

Got you. Maybe we can just focus on combo with RUX sort of in the frontline setting. You provided some data maybe earlier this year at EHA. Maybe you can highlight some of the key data points there and put that data into context for us?

Yes, absolutely. So as I mentioned, ruxolitinib has an SVR35 rate of approximately 40% at week 24. In this trial, trial 34, we've designed it as a full Phase I all the way to a registrational Phase II or potentially registrational Phase II. In the Phase I portion, we are evaluating 2 different dose levels of selinexor, 40 milligrams and 60 milligrams. Again, this is dosed weekly in combination with standard of care ruxolitinib. So one of the key things for us to keep in mind is that these are the low doses of selinexor that we're evaluating in our multiple myeloma trials as well. We completed the Phase Ia. There were no DLTs or dose-limiting toxicities. We then had an opportunity to then enroll as part of our Phase Ib in order to further evaluate the efficacy and safety of the combination at those 2 dose levels. What we presented at EHA was a subgroup of that Phase I portion. And amongst that subgroup, we identified 6 out of 8 evaluable patients met that SVR35 threshold at week 24 or 75%. In addition, we noticed that all patients, again, as early as week 12 had symptom improvement with 3 out of the 7 patients, meaning that TSS50 or that 50% reduction in their baseline symptom score at week 12. And lastly, we noticed a very nice anemia response with half of the patients either stable or improved in their anemia scores.

Got you. And I think you're planning to give another update sort of later this year, sometime in the second half. Should we be thinking just more patients, longer follow-up?

Yes, absolutely. So because this is an open-label trial, and we enrolled up to 21 patients in that Phase I portion, we have an opportunity to, again, to your point, increase the number of patients as well as their follow-up as well.

Just in terms of deciding, you mentioned early on, there's opportunity in the front line in the second line and just in the frontline setting, is there anything specific you're looking for or a particular bar that you need to see to decide to move forward in frontline at this point?

We're looking at that rux bar of 40%. We also know that it's very meaningful to improve upon multiple different efficacy endpoints, including the SVR rate, the TSS50 as well as the anemia. So we're continuously observing the efficacy and, of course, the safety, we'll have an opportunity. The FDA, of course, is a close partner of ours to engage with them and then discuss opportunities for that registrational portion.

Got you. And maybe in the relapsed/refractory setting, maybe you can talk about what data you've seen there so far and just -- how that compares?

Yes, absolutely. So I mentioned the preclinical and the nonclinical data that supports selinexor as a potential agent within myelofibrosis. In addition to those data, we have a clinical trial known as the ESSENTIAL trial that was evaluating selinexor as a monotherapy in patients who have been previously treated with selinexor. In that ESSENTIAL trial, we observed 20% of the patients who had an SVR35 as early as week 12 at week 24 and beyond, 40% of those patients had an SVR35. So those data really suggest that more patients not only increase their SVR35 thresholds, but they continuously deepen their responses as well. In addition to that SVR rate, we also saw some very meaningful improvements in their anemia scores with 2 out of 3 or 67 patients having a frank improvement in their hemoglobin levels.

Got you. And the ESSENTIAL study sort of supported your decision to move into a Phase II potentially registrational study in this refractory setting. Maybe just I think you're planning to give an update, is it later this year or...

Next year.

Okay, later next year, but maybe you can chat discuss enrollment how that's tracking versus your expectations?

It's on track. It is on track to -- for us to report out data in the first half of 2023 for 035 -- that trial, just as a reminder, is a randomized Phase II in which we're comparing selinexor as a monotherapy to physician's choice chemotherapy. So there's multiple different options in that physician's choice arm, including retreatment with the JAK inhibitors to other therapies, including hydroxyurea and anagrelide, even corticosteroids for the treatment.

[indiscernible] Reshma is getting lots of patients, so the data will be second half '23, not first half '23.

Second half, sorry about that. Thank you.

Can you just maybe comment on what we should expect for the physician's choice in terms of the control arm and maybe SVR?

Yes, absolutely. So we know with the physicians choice, given the multiple different therapies that are options, the response rate can be very modest to less than 5% to potentially up to 30%. And that 30% is probably more in line with what we can maybe expect with the JAK inhibitor use, either fedratinib or even rux retreatment. So again, there is a spectrum. But by and large, we expect it to be quite modest, again, given the fact that this is a refractory patient population.

Makes sense. Maybe we can just shift to myelodysplastic syndrome, that's another area of focus for you. You're using eltanexor instead of selinexor here. So maybe to start, you can just comment on the differences there?

Yes, absolutely. So eltanexor is another sign inhibitor, but there are some major differences from selinexor. The first one being around the IC50 or the inhibitory concentration. So we know that the doses of eltanexor require about 30% to 50% lower drugs to reach that IC50 as compared to selinexor. The other key difference is the ability of eltanexor to cross the blood brain barrier. It is limited, and therefore, much of the central toxicity, including nausea, fatigue, are limited with that compound as compared to selinexor. Those 2 main differences allow us to dose eltanexor differently. We can dose at lower doses more chronically. So in the MDS trial [ 801 ], we are treating patients 5 days on, 2 days off in this refractory myelodysplastic patient population.

Maybe you can just talk about the current treatment landscape for MDS and kind of where is the opportunity?

Yes. It's really unfortunate. There's really not anything. Once patients -- so again, these patients are refractory to standard of care HMAs. Once they progress on those HMAs and/or become refractory to those agents, by and large, it is best supportive care therapy, including transfusion support, maybe some low-dose chemotherapy. But by and large, again, these are not effective therapies. To put it into context, this refractory patient population, the median overall survival are less than 4 months. So again, a very high unmet need patient population. Eltanexor being, again, another fine inhibitor really serves as an opportunity to bring a very novel class of agents to them.

Yes. And you've got a Phase II expansion study ongoing right now in the relapsed refractory setting, and I think you're going to provide some interim update maybe in the second half of this year. Can you maybe give us a little bit more color on what you're thinking there?

It's going to be. So we had an opportunity to present initial data at ASH 2021. This was from our Phase I portion. Again, a very similar patient population in a refractory MDS setting. We provided some ORR data, but more importantly, it's that OS data, right? Again, median overall survival of only 4 months. So we'll have an opportunity with this next update to provide similar efficacy parameters for a larger patient population.

As we think about the OS you mentioned, I think, or is it 9.9 months? I got that right?

Yes, absolutely. Yes.

Is there any difference in baseline characteristics? Or how should we think about 9.9. Should we expect that to be duplicated? Or as you go up in patient numbers and maybe that comes down a little bit?

Yes. It's -- these are refractory patients. So that's what we presented in our Phase I. And again, 9.9 very meaningful. So we hope to present data around that OS for this updated population as well.

Got you. Got you.

Will you present at ASH this December?

We will be opportunistic in when we present updated data for MDS.

Certainly, you're aware of [indiscernible] myeloma patients, I think that around [indiscernible] was also approved for line three or line four for [indiscernible]

Correct. Second-line plus DLBCL. Yes.

[indiscernible]

Sorry to hear that.

Sorry.

I have my own [indiscernible] and a different type of lymphoma [indiscernible]

Maybe we can just wrap this up since we're just out of time, and I'd just like to thank Richard and Reshma for your time today. Really appreciate it.

Thank you.

Thank you very much. Thanks, Mike.

Thank you.