Thank you so much. Good afternoon. Welcome to Barclays Healthcare Conference in Miami. My name is Peter Lawson. I'm one of the mid-cap biotech analysts at Barclays, focused around oncology. Do email me or send us Bloomberg if you need any questions addressed for this fireside chat. Really delighted to have with us, management team from Karyopharm. I do this slightly differently versus some of the others. I think management change, I mean, I guess it's been a couple of years now or so.
Almost two years now, Peter, yes.
Be great to get kind of the driving force behind the change and kind of where you came from and that experience you brought that kind of.
Sure.
Transform that direction.
Thanks, Peter. Thank you for hosting us at your conference. I've had the opportunity, it's almost been 2 years, as you mentioned, to be the CEO and president of Karyopharm. You know, from a broad background perspective, you know, I've spent a lot of time in oncology, leading businesses in the U.S. and around the world, and also in many other disease areas. Being fortunate, spent my first decade with Glaxo, working a number of different areas, in Canada. Spent a decade with Pfizer, working in Canada, the U.S., and started around the world in Europe, and Africa, running businesses. A decade with Amgen, running businesses in Europe, and then in the U.S., and running the Amgen oncology business.
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 a business in North America, setting up an innovation hub and an R&D and a kinda hub in Cambridge. Then had the exciting opportunity to actually join the Karyopharm board. I was on the board for a year before I took on the CEO role and really, you know, inspired by meeting our founders and the science behind XPO1 inhibition.
I think the opportunity to have a novel mechanism 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. It's been an exciting 2 years and really excited about the opportunities we have in front of us when we look at our core programs and 2 novel SINE compounds in selinexor and eltanexor.
Yeah. Reshma?
Yeah, thank you. Really appreciate the opportunity to present to everybody today. 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, you know, I've spent my entire career within the biopharma space. I am a medical oncologist by background. Started out at Merck, and, you know, really had a, you know, 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, you know, 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.
You know, as I mentioned, 11 months ago, joined Karyopharm largely because of the science. 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 the SINE compounds, both selinexor and eltanexor, in multiple additional tumor types, both solid as well as hematologic in nature.
Perfect. Thank you. One inbound question I got, for Richard, just on the idea of, kind of the confidence around the quarter-over-quarter growth in 2023. Kind of how should we think about that?
Well, we still have the first quarter in front of us.
Yeah.
Uh, still just finishing up. So, you know, when I look at, uh, uh, twenty twenty-three, you know, as, as you know, we've guided to a hundred and twenty-five to a hundred and forty million, uh, US revenue, which right in the midpoint is double-digit growth, and, uh, we feel very good and confident with that guidance. Uh, and I think when you look at our, our, our multiple myeloma business, uh, about seventy percent of our business is in the community and about thirty percent, uh, is in the institutions and academics. And, you know, it's a very competitive space, as we know, and continues to get more competitive as we're gonna see some more T-cell engaging therapies launch 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 2nd to 4th line, we feel very good about continuing to grow the breadth, in terms of prescribers and the depth, in terms of key accounts. I think in the institutions and academics, despite the increased competition last year, you know, we grew 7%.
I think as we continue to move forward, you know, in the institutions and academics, there's a lot of opportunity to really make sure that before many patients are going on to kinda these T-cell engaging therapies and more of the later line patients, that they're in a, you know, the T-cell environment is in a really positive space for patients to benefit from those therapies. I think we're working to generate data in that space, and given our mechanism action, we 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 a novel mechanism action before they may go to a T-cell engaging therapy.
Yeah. No, we've definitely heard that from KOLs using it ahead of BCMA therapies or cell therapies. What, what's the appeal there? Why is it being used?
I'll turn to Rashmi to that one because I think it's, you know, from a scientific perspective, it's quite interesting from a mechanism 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. Specifically, agents like Cytoxan can really have a negative impact on the ability to collect, you know, perform that apheresis and potentially on the efficacy that they achieve with those immunotherapies. It's really important for us to be able to look at the question, you know, 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 and, you know, therapy that a patient may subsequently receive.
Gotcha. Thank you. I know Blenrep's used in a later line, but just the removal of that from the treatment paradigm, has that changed in any way the use of selinexor?
Yeah. I mean, I think as you mentioned, Blenrep, you know, was really used in kinda your penta-refractory patients or kinda 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, you know, pockets of opportunity. As we mentioned, you know, the majority of our business and our focus has really been on that second to fourth line, where the majority of our business is in the community.
At the same time, you know, there's some, you know, nice pockets of opportunity, where having a novel mechanism 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, you know, a good opportunity in those institutions, academics, without that, you know, medicine being there.
Gotcha. Thank you. Just go back to sales kind of. What's the growth that you're seeing or expecting in 23? Is that gonna come from new accounts, increased revenues from existing accounts? Kind of how should we-
Yeah. Peter, I think it's a combination of both. Our focus will continue to be on that second to fourth line post anti-CD38. As we just mentioned, again, a pre CAR T, but really earlier lines. Our greatest growth last year was in the third line, and the majority of those patients are seen in the community. We're gonna continue to focus on the community, and continue to grow the breadth. We've continued to grow breadth of prescribers.
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, you know, 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 will really drive the depth in terms of key accounts prescribing more for patients 'cause 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. Combination of breadth, but I think more on the depth side, and more in the community than in the institutions and academics.
Perfect. Thank you. 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 action get kind of proven to benefit BCMA therapies, and so it remains? I'm just curious on how we should think about this.
Yeah. I think it continues. It doesn't disappear at all. I think it. Again, the great thing for patients and for clinicians is having access to novel mechanisms of action. IMiDs, PIs, anti-CD38s, XPO1 inhibition, T-cell engaging therapies, all of those are enabling patients to have better outcomes. You know, 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. You know, 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.
Gotcha. Thank you. Sorry to jump around. Duration of use, how does that change between later lines, earlier lines? How far can... how do you monitor that? Is there an average you're looking at or can you break it out by lines?
Yeah. Unfortunately, as we've talked to a lot and we know other companies have shared, it's difficult to really have that data with strong degree of accuracy over time. We do know as we're used in the earlier lines, we have greater duration of therapy. You know, continuing to be used in the earlier lines, we're seeing those patients with greater duration of therapy. We now have patients, you know, with the triplet who've actually been on selinexor for over a couple of years in multiple myeloma. Again, I think we're seeing that physicians and patients are increasingly having, you know, 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.
Gotcha. Thank you. I guess 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. You know, we don't know what therapy someone's gone on to after they're on selinexor for the next line of therapy. It's pretty hard to draw that out. I think broadly, you know, 70% in the community, 30% institutions and academics, and we know that the community is not using the BCMAs or CAR Ts. You know, you can kinda draw your analogies in there.
What was academia a year ago or two years ago? I'm trying to remember myself.
I forget offhand. I think it's moved about 5-10 points over the last couple of years, over the last year.
Okay. That's the, maybe the delta there that we should be thinking about.
Yeah.
Perfect. Thank you. 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. Kinda what should we expect to see?
Yeah. We just released a press release yesterday that we got accepted as a poster update for that phase I. 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 gonna have an opportunity to provide 24-plus, 24-week and beyond data on all patients. All 24 patients that were enrolled as part of the phase I. This update is gonna be including efficacy, SVR35, TSS50. We're gonna break it down by dose like we did at ASH, also provide, of course, that safety information again for all patients and then by dose as well.
What do you need to see to move it forwards? I mean, it's been a really impressive, the data we've seen so far.
Yeah.
During the KOLs , they've liked that data set. Internally, what's your bar to continue to move the drug forward?
You know, by and large, you know, we continue to remain extremely encouraged by the data, right? I mean, I think this is now gonna be our 5th opportunity to present updated data. You know, not, you know, 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. 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, you know, we can develop this combination in this treatment naive myelofibrosis population. We're looking forward to, you know, initiating a phase III trial in the first half of this year.
You know, all of Karyopharm is working behind that at this point.
Got you. I guess safety is an important metric.
Yeah, absolutely.
In these MF patients. Kind of what do you think the important bar is? You know, do you have the right dose for selinexor?
Yeah.
For protracted use?
I think similarly, right, you know, what this, what the datasets have also shown is that the safety is manageable, right? 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 dose reductions, dose modifications as needed with either one of the two drugs. The cytopenias are not causing bleeding, specifically the thrombocytopenia. By and large, patients are staying on therapy, that's really critical to drive ultimately that efficacy that the patient ultimately needs to see. You know, 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.
Got you. What's your timeframe around potential approval? I guess dovetailed into that is how does the treatment landscape change with, you know, potential BET inhibitors?
you know, I think, you know, as once the trial gets started, we're gonna be able to provide a little bit more color on the exact timing. You know, what we anticipate right now probably in the sort of approximately two-year timeframe. you know, we know that the first-line space is becoming more competitive. You know, with that said, right, I think it goes back to the clinical benefit that you see with any of these combinations. You know, which combination 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. I think, you know, selinexor in combination with ruxolitinib really checks that box for physicians as well as patients.
Good. What are you most worried about in that first-line competitive environment in MF?
I'm not worried. I'm not worried. You know, largely it's because, you know, 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. 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 1 of those 2 endpoints. The other key aspect is that not all patients benefit equally. If you look at some of the key subgroups, specifically male patients or patients who need to start on lower doses of ruxolitinib because of their platelet count, you see a substantially lower efficacy compared to their counterparts.
What we are looking forward to in our combination is really showing equal efficacy across all patients, again, who are treatment naive myelofibrosis. That's again what we want to show vis-à-vis ruxolitinib.
Got you. Thank you. 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 phase I, kind of how do we crosswalk between that phase I data and patient type in phase II?
Yeah, great question. We are evaluating eltanexor specifically in this MDS trial. Eltanexor is our second SINE compound. It also targets XPO1. 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 toxicities, 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 five days on, two days off. In preclinical models of AML, that more continuous dosing and therefore continuous inhibition of XPO1 drives antitumor activity.
It really makes eltenexor the perfect compound to evaluate in MDS. The patient population in the phase II is very similar to the phase I. This is a relapsed refractory MDS patient population. Unfortunately, it's very poor prognosis, with historical data suggesting median overall survival is really only 4-6 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. You know, 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 eltenexor.
Are there any differences in the phase I patient group versus the phase II patient group?
You know, by and large, again, they're very similar patient populations. Relapsed refractory, by and large, they are these primary refractory MDS patients, probably the sickest and have the poorest prognosis. Yeah, we're going to be looking at some of the, you know, the demographics a little bit more closely. You know, did they receive prior monos? Did they receive prior doublets? Really trying to understand how some of those key variables can ultimately impact outcome. I think again, the biggest driver is that these are these relapsed refractory, primary refractory HMA patients.
Got you. Thank you. What we see, 30 patients, is that right?
That's correct.
Are we gonna see what, interim PFS data or is that too early?
Yeah. Really, our focus is all about the overall survival, and it's going to be around ORR. Now, I will say, you know, 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. 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 controls.
Got you. Thank you. With a minute and a half on the clock, just endometrial cancer. I mean, it's really interesting data you had from the.
Yeah.
TP53 wild type population. I know it's sometime off, but kind of how has, or the readout from the, from the pivotal sometime off. How's receptivity like from physicians as well, and kind of this idea of creating a maintenance setting for endometrial cancer?
There's a lot of excitement, you know, 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. In addition to the fact that we see this impressive PFS, we have also identified a very important biomarker, right? Physicians, by and large, are looking for, you know, additional biomarkers, additional tools to help identify the best therapy for this patient population. So, you know, 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 for your time. Thanks for hosting us. Thank you so much, Dr. Reshma. Thank you.