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

Thank you so much. Good afternoon. Welcome to Barclays Healthcare Conference in Miami. And my name is Peter Lawson. I'm one of the SMID Cap Biotech Analyst at Barclays, focused around oncology. And do e-mail me or send us Bloomberg's if you need any questions addressed for this fireside chat. Really delighted to have with us management team from Karyopharm. And I do this slightly differently versus some of the others. I think management changed, I mean, I guess it's been a couple of years now?

Almost 2 years now, Peter. Yes.

It would be great to get kind of the driving force behind the change and kind of where you came from and the experience you brought that kind of helped transform in this direction?

Sure. Thanks, Peter, and thank you for hosting at your conference. So I've had the opportunity. It's almost been 2 years, as you mentioned, to be the CEO and President of Karyopharm. And from a broad background perspective, I've spent a lot of time in oncology, leading businesses in U.S. and around the world and also in many other disease areas. Been fortunate, spent my first decade with Glaxo, working in a number of different areas in Canada and then spent a decade with Pfizer, working in Canada, the U.S. and started around the world in Europe and Africa running businesses. And then a decade with Amgen, running businesses in Europe and then in the U.S. and running the Amgen Oncology business. And made the move from the West Coast to the East Coast with Ipsen, and had the opportunity to really help further Ipsen's North American presence in running the business in North America, setting up an innovation hub and R&D and kind of hub in Cambridge. And then had the exciting opportunity to actually join the Karyopharm Board. So I was on the Board for a year before I took on the CEO role and really inspired by meeting our founders and the science behind XPO1 inhibition, then the opportunity to have a novel mechanism of action to take that into many multiple areas and really make a big opportunity for patients and drive home, I think, improved health with great science and great innovation is what excited me to move over to Karyopharm. And it's been exciting 2 years and really excited about the opportunities we have in front of us when we look at our core programs and two novel signed compounds in selinexor and eltanexor.

Reshma?

Yes, thank you, and really appreciate the opportunity to present to everybody today. So yes, my name is Reshma Rangwala. I'm the Chief Medical Officer at Karyopharm. I've been at the company for about 11 months. But by and large, spent my entire career within the biopharma space. I am a medical oncologist by background. I started out at Merck and really had a great opportunity working with their anti-PD-1 therapy, pembrolizumab or Keytruda in multiple solid tumors, including non-small cell lung cancer. From there, I went to Genmab. And there too, had an opportunity to work on multiple different agents, including one of their antibody drug conjugates, known as Tisotumab vedotin. Most recently, I was the Chief Medical Officer at a small biotech company known as Aravive. And as I mentioned, 11 months ago joined Karyopharm, largely because of the science. I'm very impressed by the data that was generated in a very hard-to-treat penta-refractory multiple myeloma population, but very intrigued by the mechanism and really saw an opportunity to develop defined compounds with selinexor and eltanexor in multiple additional tumor types, both solid as well as hematologic in nature.

Perfect. One question I got for Richard, just on the idea of kind of the confidence around the quarter-over-quarter growth in 2023. Kind of...

Well, we still have the first quarter in front of us. We're still just finishing up. So when I look at 2023, as you know, we've guided $225 million to $240 million U.S. revenue, which is right in the midpoint, is double-digit growth. And we feel very good and confident about that guidance. And I think when you look at our multiple myeloma business, about 70% of our business is in the community and about 30% is in the institutions and academics. And it's a very competitive space, as we know, and continues to get more competitive as we're going to see some more T-cell engaging therapies launched this year. In the community setting last year, we grew about 28%. And with the majority of our business being in that space and the majority of patients being in second to fourth line, we feel very good about continuing to grow the breadth in terms of prescribers and the depths in terms of key accounts. And then I think in the institutions and academics, despite the increased competition last year, we grew 7%. And I think as we continue to move forward in the institutions and academics, there's a lot of opportunity to really make sure that before many patients are going on to kind of these T-cell engaging therapies and more of the later line patients, that they're -- the T-cell environment is in a really positive space for patients to benefit from those therapies. So I think we're working to generate data in that space. And given our mechanism of action, I think we have an opportunity to help patients in what we call a runway. Definitely not a bridge, but a real runway to benefit from novel mechanism of action before they may go to a T-cell engaging therapy.

Yes. That would do. We've definitely heard that from KOLs using ahead of BCMA therapies or cell therapies. What's the appeal there? What's -- why is it being used?

I'll turn to Reshma for that. I think it's -- from a scientific perspective, it's quite interesting from a mechanism of action, and we're also working to help generate some data to support that.

One of the reasons that physicians are really interested in this topic is because they know that there are multiple agents within multiple myeloma that can have an adverse effect on that T-cell environment, so specifically agents like Cytoxan can really have a negative impact on the ability to collect and perform that apheresis and potentially on the efficacy that they achieve with those immunotherapies. So it's really important for us to be able to look at the question holistically, looking at real-world evidence, looking at preclinical as well as translational data to really understand that selinexor can maintain, potentially even improve that T-cell environment so that it gives physicians confidence to go ahead and use selinexor, regardless of backbone and therefore, not have a negative impact on a potential T-cell therapy that a patient may subsequently received.

Got you. And then I know some reps reusing a later line, but just the removal of that from the treatment paradigm. Does that change in any way the use of selinexor?

Yes, I mean I think as you mentioned, Blenrep was really used in kind of your penta-refractory patients or kind of fifth line, plus, to a large degree. In the short term, no, because many of those patients were just unable to continue with compassionate use and continued on therapy. I think there's pockets of opportunity. But as we mentioned, the majority of our business and our focus has really been on that second to fourth line where the majority of our business is and in the community. But at the same time, there's some nice pockets of opportunity, where having a novel mechanism of action, such as selinexor and again, linking to the opportunity to really use that novel mechanism, get the full benefit of it. Before someone may go on to other therapies, I think will enable us a good opportunity in those institutions academics without medicine being there.

Got you. Just going back to sales. Kind of what's the growth that you're seeing or expecting in '23? Is that going to come from new accounts, increased revenues from existing accounts? Kind of how should we...

Yes. Peter, I think it's a combination of both. So our focus will continue to be on that second to fourth line post-anti-CD38. And then as we just mentioned, kind of pre-CAR-T, but really earlier lines. Our greatest growth last year was in the third line and the majority of those patients are seeing the community. So we're going to continue to focus on the community and continue to grow the breadth. We've continued to grow breadth of prescribers. But also as we're a couple of years into the launch now and really, I think, had a really positive year last year with regards to physicians using the lower dose, understanding how to dose-adjust if they need to and also understanding how to use kind of dual antiemetics for the first couple of months. In the community setting, I think, we'll really drive the depth in terms of key accounts prescribing more for patients because they're comfortable with it. The nursing teams are very comfortable with it, and they're seeing good experiences with regards to the patients they've had on selinexor. So a combination of breadth, but I think more on the depth side and more in the community, but then in the institutions and academics.

Perfect. As the manufacturing delays for BCMA therapies kind of get resolved or hopefully get resolved, does that selinexor window kind of disappear? Or is there -- does that mechanism of action get kind of proven to benefit BCMA therapies, and so remains. I'm just curious on how we should think...

Yes, I think it continues. It doesn't disappear at all. I think, again, the great thing for patients and for clinicians is having access to novel mechanisms of action. And so IMiDs, PIs, anti-CD38s, XPO1 inhibition, T-cell engaging therapies, all of those are enabling patients to have better outcomes. And there's many patients with T-cell engaging therapies who may not be eligible, such as some of your older patients, which, the majority of multiple-myeloma patients are. Sometimes your more rural patients who may not be able to come to the institutions or academics. So for selinexor, I think we will continue to see a really good opportunity and having increased access to T-cell engaging therapies. I don't think we'll limit that opportunity.

Got you. And then -- sorry to jump around. The duration of use, how does that change between later lines, earlier lines, how far can -- and how do you monitor that? Is there an average you're looking at? Or can you break it out by lines?

Yes. Unfortunately, as we've talked to a lot, and we know other companies have shared, it's difficult to really have that data with a strong degree of accuracy, overtime. We do know as were used in the earlier lines, we have greater duration of therapy. And so continuing to be used in the earlier lines, we're seeing those patients with greater duration of therapy. And we now have patients with the triplet who've actually been on selinexor for over a couple of years in multiple myeloma. So again, I think we're seeing that physicians and patients are increasingly having positive experiences, increasingly able to dose-adjust with the data we've been able to share with them and manage and be on therapy for longer periods of time.

Got you. The other question is just around going back to the BCMA contribution. How big is that contribution do you think to revenues?

About 30% of our business is in the institutions and academics. So it's hard to -- we don't know what therapy someone has gone on to after they're on selinexor for the next line of therapy. So it's pretty hard to draw that out. But I think broadly, 70% in the community, 30% institutions and academics. And we know that the community is not using the BCMAs or RTs. So you can kind of draw your analogies in there.

What was academia a year ago or 2 years ago? I'm trying to remember myself.

I forget off hand -- I think it's moved about 5, 10 points over the last couple of years -- over the last year.

Okay. So that's the -- maybe the delta there that we should be thinking about?

Yes.

Perfect. And I'd love to talk about first-line MF, selinexor data in combination with ruxolitinib. Kind of what should we be expecting to see in the next update in first half? I think it's still the first half, right, that we see that data set. Kind of what should we expect to see?

Yes. So we just released a press release yesterday that we got accepted a poster update for that Phase I. So just as a background, right, this Phase I evaluated selinexor in combination with ruxolitinib in patients who are treatment-naive myelofibrosis. In total, we dosed 24 patients to either 40 milligrams or 60 milligrams. Next month at AACR, we're going to have an opportunity to provide plus 24 weeks and beyond data on all patients. So all 24 patients that were enrolled as part of the Phase I. I mean this update is going to be including efficacy, so SVR35, TSS50. We're going to break it down by dose, like we did at ASH. And then also provide, of course, that safety information, again, for all patients and then my dose as well.

What do you need to see to move forward? I mean it's been really impressive the data we've seen so far. Standard to care -- well, was -- if like that data set. But internally, what's your bar to continue to move the rock forward?

By and large, we continue to remain extremely encouraged by the data, right? I mean, I think this is now going to be our fifth opportunity to present updated data. Not -- the numbers aside, what really, I think, is quite encouraging is that the data, especially the efficacy, has just remained so stable. You don't necessarily see that erosion in efficacy like sometimes we see in a Phase I. So this stability that we're seeing in SVR35 and TSS50 that really suggests that the combination can substantially improve benefit compared to ruxolitinib alone, really suggests that we can develop this combination in this treatment-naive myelofibrosis population. We're looking forward to initiating a Phase III trial in the first half of this year. And all of Karyopharm is working behind that at this point.

Got You. And I guess, safety is an important metric for these MF patients.

Yes. Absolutely.

So kind of what do you think the important bar is? And do you have the right dose for selinexor or -- from attracted use?

I think similarly, right, what this -- what the data sets have also shown is that the safety is manageable, right? And this is regardless of whether we look at the 40% or 60%. What we are seeing is a manageable toxicity profile. By and large, the AEs can be managed with the dose reductions, dose modifications as needed with either one of the 2 drugs. The cytopenias are not causing bleeding, specifically the thrombocytopenia. And by and large, patients are staying on therapy, and that's really critical to drive ultimately that efficacy that the patient ultimately needs to see. So again, we're very encouraged by the efficacy data, but really, it's that clinical benefit. It's the efficacy in the context of a manageable safety profile that, again, really suggests that this combination could potentially be a best-in-class therapy for treatment-naive MF.

What's your timeframe around potential approval? And I guess, dovetailed into that is how does the treatment landscape change with potential Bev inhibitors?

I think once the trial gets started, we're going to be able to provide a little bit more color on the exact timing. We anticipate, right now, probably in the sort of approximately 2-year timeframe. We know that the first line space is becoming more competitive. With that said, right, I think it goes back to the clinical benefit that you see with any of these combinations, which combinations really can drive that efficacy and meaningful efficacy compared to rux alone and again, really do it in that context of a manageable safety profile. And I think selinexor, in combination with ruxolitinib really checks that box for physicians as well as patients.

Good. And what are you most worried about in that first-line competitive environment in MF?

I don't -- I'm not worried. I'm not worried. Largely, it's because regardless of what our competitors are doing right now, right? The only standard of care in first-line MF right now is ruxolitinib. That is the standard of care that I look to beat at this point. And unfortunately, right, the benefit isn't really there for the majority of patients. If you look specifically at SVR and TSS50 less than half of the patients who are treatment-naive myelofibrosis benefit from either one of those two points. The other key aspect is that not all patients benefit equally. So if you look at some of the key subgroups, specifically mel patients or patients who need to start on lower doses of ruxolitinib because of their platelet counts, you see a substantially lower efficacy compared to those -- compared to their counterparts. So what we are looking forward to in our combination is really showing equal efficacy across all patients, again, who are treatment-naive myelofibrosis. And that's, again, what we want to show vis-à-vis ruxolitinib.

Got you. And then for MDS and your kind of your second nuclear inhibitor, eltanexor, we got Phase II data. What should we expect to see from that Phase II data versus the Phase I kind of how do we crossbow between that Phase I data and patient type and Phase 2?

Yes. Great question. So we are evaluating eltanexor, specifically in this MDS trial. Eltanexor is our second signed compound. It also targets XPO1. But unlike selinexor, eltanexor crosses the blood brain barrier at a lower rate. One of the reasons this is so important is because some of the non-heme toxicity specifically the nausea, the vomiting, the fatigue that we can sometimes see with selinexor are likely going to be at a lower rate with eltanexor. The other key aspect is that eltanexor has a lower IC50. This is important because it allows us to dose the drug more frequently. In fact, we're dosing patients with MDS 5 days on, 2 days off in preclinical models of AML that more continuous dosing and therefore, continuous inhibition of XP01 drives antitumor activity. So it really makes eltanexor the perfect compound to evaluate in MDS. The patient population in the Phase II is very similar to the Phase I. So this is a relapsed/refractory MDS patient population. Unfortunately, very poor prognosis with historical data suggesting median overall survival is really only 4 to 6 months. We had an opportunity at ASH 2021 to provide efficacy data from the Phase I. And again, very encouraged by the benefit that we observed in that cohort, specifically OS, that was almost double what you normally see historically as well as very meaningful ORR rates. So our hope is that once we have an opportunity to perform this IA as part of the Phase II. Again, we can see that meaningful efficacy with eltanexor.

And are there any differences in the Phase I patient group versus Phase II patient group?

By and large, again, they're very similar patient population. So relapsed/refractory, by and large, they are these primary refractory MDS patients, probably the sickest to have the poorest prognosis. Yes, we're going to be looking at some of the demographics a little bit more closely. Did they receive prior monos? Did they receive prior doublets? And really trying to understand how some of those key variables can ultimately impact outcome. But I think, again, the biggest driver is that these are these relapsed/refractory, primary refractory HMA patients.

Good. So what we see, 30 patients, is that right?

That's correct.

And are we going to see interim PFS data? Or is that too early?

Yes, really, our focus is all about the overall survival, and it's going to be around ORR. Now I will say, within the MDS landscape, the definition of ORR as you probably know, is evolving, rapidly evolving with no true consensus in terms of how to define it. So our focus really is overall survival and really ensuring that we've got maturity of that overall survival data so we can compare it again to historical control.

And then 1.5 minutes on the clock, just endometrial cancer, I mean really interesting data you had from the TP53 wild-type population. And I know it's some time off, but kind of how has the readout from the pivotal some time off. How is enrollment going? What's receptivity like from physicians as well and kind of decider of creating a maintenance setting for endometrial cancer?

There's a lot of excitement with these data, especially because we have shown in this most recent data cut that we performed last November, that the PFS specifically in this p53 wild-type subgroup of the SIENDO has now increased from 13.7 months to now 21 months, really unprecedented data in this patient population. But in addition to the fact that we see this impressive PFS, it's really we have also identified a very important biomarker, right? And physicians, by and large, are looking for additional biomarkers, additional tools to help identify the best therapy for this patient population. So those two go hand in hand that we have an opportunity with this trial to not only develop maintenance therapy for this patient population, but to also develop a companion diagnostic.

Perfect. Great. Thank you so much.

Thank you.