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

Everyone, my name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. I'm happy to introduce the CEO of Karyopharm, Richard Paulson; and the CMO of Karyopharm, Reshma Rangwala; and also the CFO is joining us too, Mike Mason. Thanks so much for joining us today for the fireside discussion.

Thank you, Maury. Thanks for having us.

Maybe to start off, for those who are new to the story, can you provide a 1-minute intro to Karyopharm and talk about key catalysts ahead in the next 6 to 12 months?

Sure. I mean when you look at Karyopharm, we're a global company and a fully integrated commercial-stage company with a foundation in a mechanism, which is the inhibition of nuclear export. And our mission is to positively impact patient lives and defeat cancer. Our foundation in nuclear export has been driven first by approvals in multi myeloma. And we have penta-refractory and second-line plus approval as well as DLBCL. And we have 4 core areas that we're focused on, and that's multi myeloma, endometrial cancer, myelofibrosis and MDS. And currently, our medicine -- our lead medicine, selinexor, is now approved in 38 countries around the world with Canada just coming online last week.

Got it. Yes, it's a great intro. And you just recently presented some data at ASCO from your myelofibrosis program. Can you recap those data and explain why selinexor mechanism would work in this disease, particularly in combination with ruxolitinib? And then maybe talk about anemia in particular as well.

Yes. Absolutely. So we were very excited at ASCO. This was our first opportunity to present data in that first-line trial. So it's the 034 study in which we are combining ruxolitinib -- standard of care ruxolitinib with selinexor in -- again in a treatment-naive population. These data build upon very important data in which we evaluated selinexor as a monotherapy in a refractory patient population. So when that refractory patient population, we were -- we already demonstrated proof of concept with an SVR rate of 40% and again in a very hard-to-treat population, which available therapies are very limited for this patient population. So building upon those data, we then take it into the 034 study again, combination setting, treatment-naive. And at the data -- in the data that we presented at ASCO, we presented a subset of patients treated in the Phase Ia as well as a portion of the Phase Ib. 15 patients were included in the safety. From an efficacy standpoint, and we're looking at multiple different efficacy end points, what we demonstrated from an SVR rate, which is a very important assessment, was that 6 out of 8 patients achieved that SVR35 at week 12. And I will note that there was an additional patient who's right at the cusp of 34%. So very close of, again, hitting that 35% mark. But those data start to demonstrate this kinetics, this rapid reduction in the spleen response that, again, we're seeing as early as week 12. In addition to that, we also demonstrated symptom scores with all patients improving in their symptoms, 3 out of 7 hitting that 50% mark. And then to your question, also had an opportunity to present anemia data, which we know is a very important parameter in this patient population. At this week 12 time point, which I frame that because it's at that week 12 that you would expect accounts to actually nadir or bottom out with rux alone, what we found is that in -- in half of the patients, we actually saw stabilization or improvement in the anemia. So when I look across and when we look across all 3 of these different efficacy end points, including SVR, symptom score and week 12 as -- and anemia, as early as week 12, you really do see some very exciting rapid disease modification that is now being amplified across all of these different efficacy end points.

Got it. Yes, I think that's a good summary of the data. For this study, are you continuing to enroll patients and treat patients? And then could we get another update with more follow-up later this year?

Yes. Absolutely. So we're currently enrolling in the Phase Ib portion. And once we complete the Phase Ib, we'll identify the recommended Phase II dose and then have an opportunity to then segue into the randomized Phase II portion of the study. These data and the study is open label, so we'll be opportunistic. And hopefully, we'll have an opportunity to present additional data later this year.

Got it. And how do you view this combination versus other combinations that are being developed in the space? How does the selinexor plus rux differentiate?

Again, I just -- I want to emphasize the enthusiasm that I at least have for this data, partly because this is such a unique mechanism through the XPO1 mechanism. We've got very strong preclinical data that is then, I think, further manifested by monotherapy data, and now we go into combination. So again, it's the combination of a very unique mechanism of XPO1 inhibition in combination with rux that suggests this additive is not synergistic therapy. Hard to compare with the other agents out there. We are very much focused on developing this combination treatment in first-line MF patients.

Got it. And for safety, can you go talk about cytopenias and how they were reversed with dose modifications?

Sure. So we do see cytopenia. So in the ASCO presentation, we did note that 27% of the -- we saw Grade 3-4 thrombocytopenia rates, 20% Grade 3-4 anemia rate and Grade -- and a 20% Grade 3-4 neutropenia rate. With that said, all of these AEs, especially these cytopenias, are managed just with dose modifications, dose reductions. And once that occurs -- and this is primarily with the rux. Once that occurs, these counts do come up. It's important that none of these cytopenias led to infections or bleeding and all patients continue to stay on therapy. So while they are occurring, they're very easily managed, and most importantly, not dislimiting.

Got it. And for the dose reductions, is that primarily rux or is it both rux and selinexor or...

What we are primarily seeing is with the rux that they were limiting or just holding the therapy, and in some cases, decreasing as necessary.

Got it. Okay. And for hemoglobin levels, are you seeing something that is better than the profile of rux alone so far? And how do you think selinexor mechanism is contributing to hemoglobin levels, either positively or negatively?

Yes. We are seeing something very interesting. And I go back to the data that we presented at ASCO. As early as week 8, week 12, we start to see stabilization or improvement. And I look at those data, and we get the same feedback from investigators that this is quite remarkable because this is the opposite trend that you would expect with rux alone. So it really does suggest that this combination is modifying the underlying disease, decreasing spleen responses, and therefore, improving the anemia. So this is quite unique and quite differentiated.

Got it. And what are your current time lines and potential regulatory plans in myelofibrosis in both monotherapy and combination?

So as we continue to obtain more data, we'll absolutely engage with the FDA and discuss with them very closely about our registrational plans, especially for that 034 study, we'll do that with the 035 study as well.

Got it. Could that be some sort of an update this year on that or...

We haven't guided towards that.

Yes. I think we can share more data towards the end of the year with the 034 in the front line. And then I think as we've shared, continuing to recruit in the second line in the monotherapy. And that data, we're looking to have in the second half of next year.

Got it. Okay. And maybe moving on to endometrial. You recently presented more detailed data from your SIENDO trial at ASCO, and endometrial showed strong signal, particularly in the p53 wild-type patients. Can you recap the data, what the mechanism is for selinexor and p53 and what are next steps with starting the next Phase III?

Yes. Absolutely. So the SIENDO Part 1 study, just very briefly, so this was an advanced recurrent endometrial population. All patients were treated with at least 12 cycles, 12 weeks of Carbo/Taxol, which is standard of care first-line treatment for this patient population. For patients who had a PR or CR after completion of at least those 12 weeks were potentially eligible to be randomized on to this trial, and they were randomized to either selinexor or placebo, again, in the monotherapy setting. And what we identified in a explored -- prespecified exploratory subgroup was that patients who were p53 wild-type, which is approximately 50% of this patient population, had a very sizable improvement in their PFS, 13.7 with selinexor as compared to 3.7 months with placebo. So this is, again, for a patient population that has no maintenance opportunities, no maintenance therapies available to them, to observe a 10-month improvement in their median PFS really is very encouraging to us but also with the investigators who have to treat this, again, hard-to-treat patient population. What we additionally presented at ASCO were data in the p53 mutant population, so approximately the other 50%. In the mutant population, we saw no benefit. Those data together really do confirm that p53 wild-type is a very appropriate predictive biomarker in this patient population. So of course, very encouraged by these data, and we'll utilize these data in planning our next Phase III study.

And maybe just talk through our mechanism of action and how that makes a lot of sense for p53 wild-type.

Right. Absolutely. So as Richard mentioned, the -- selinexor is an XPO1 inhibitor. An XPO1, by inhibiting it, it retains p53 within the nucleus. We know that p53 is a very important tumor suppressor. And by retaining it in the nucleus, again, exerts its -- potentiates anti-tumor activity. So from a mechanistic standpoint as well as the clinical data really does suggest a very important biomarker with p53 when we're looking at XPO1 inhibition.

Got it. And for the selinexor benefit working against -- is it primarily when p53 is just inactivated versus mutated? Or how should we think about that?

We are specifically looking at the wild-type. So not just inactivated, but we are specifically looking at p53 wild-type. There are multiple different alterations that we can see in p53, including mutations, missense, et cetera. But the platform we are looking in the mechanism by which we are identifying p53, again, is just the wild-type, yes.

Got it. Okay. And how do you view the potential change landscape for endometrial maintenance therapy when this trial reads out?

There is -- so I think the way we look at it is that maintenance option is not available for this patient population. And again, what we are seeing is a very substantial and meaningful improvement with this maintenance option. So I think the way we look at it is that once these data read out and we can further confirm the benefit in a maintenance population, I think it's going to be a very reasonable therapy for investigators and physicians to use, couple that with the fact that we have a biomarker that they're going to be able to use to best identify the patients who benefit.

And maybe just expand, Reshma, on MSS and MSI-high and the different groups when you look at other therapies potentially in the future.

A lot of the therapies that are currently being developed are the checkpoint inhibitors. And the checkpoint inhibitors, what we've seen, whether it's in the recurrent setting or even in the first line, really demonstrates its largest benefit in that MSI-high population. MSI-high is -- I don't want to say mutually exclusive, but they are very different patient populations as p53 wild-type. So p53 wild-type and MSS correlate very well together. MSI-high tends to be a very distinct patient population. So yes, we do anticipate that the checkpoint inhibitors, either alone or in combination, may be available therapies for this patient population. But it's -- again, it's going to be a very different patient population that will benefit from selinexor.

Got it. Makes sense. And can you talk about other indications where the XPO1 mechanism with p53 would be beneficial? And are there some areas where it may not make the most sense? I guess what sort of effect would you expect in myeloma or myelofibrosis?

So interestingly enough, when you look at the myeloma and myelofibrosis data in the context of p53, those tumor types already have very high levels, greater than 90%, of p53 wild-type. So it doesn't make sense to look at it as a biomarker. What it does underscore is that the benefit that we are seeing with selinexor is partly driven by the fact that there are such high levels of p53 wild-type. So those, I think, are covered and there's no need to again pursue a biomarker-driven approach. What we are doing is a very broad interrogation across other solid as well as hematologic malignancies in which looking at p53 wild-type as a potential biomarker makes sense. And we're looking at it from a frequency standpoint but also looking at it in the context of where is the highest unmet need for this patient population. So we're currently in the midst of doing that interrogation. But because we know that p53 is such an important -- it's the guardian of the genome, right, that we do believe that there's going to be multiple opportunities across different tumors as well as different patient populations within those tumors.

Got it. Makes sense. And maybe moving on to your commercial myeloma opportunity. For myeloma, you've recently -- or you've adjusted your messaging and strategy over the last couple of quarters in order to reach earlier lines of patients and maximize selinexor's potential. Can you talk about what led to some of the changes and how you view your implementation of that strategy so far?

Sure. Thanks, Maury. I think as we touched on at the beginning, originally, our multi myeloma indication was in that penta-refractory population. And then as we moved just over a year ago in the second-line plus with our BOSTON approval, I think what's been really important, first, is identifying the importance of adapting the dose. And we first moved from a 160 twice weekly to 100 or even down to 80 once weekly. And with that, with selinexor, we know that our side effect profile really is dose- and schedule-dependent. So the evolution of that dose, I think that's been core to our positioning in helping physicians understand that at 100 or 80 in the second-line plus setting, it's a very manageable product and also giving them the kind of tools and data to help support how they manage the patients. And then within that evolution, the second-line plus, what's important also and as we recognized in multi myeloma for patients, it's the opportunity to have access to multiple classes of therapy. And as we know through the first 2 lines, the large majority of patients have access to kind of an IMiD, a PI and an anti-CD38. And so again, being a novel new class, what we wanted to do is make sure we have the right kind of data to support our positioning. So we introduced positioning in line with post anti-CD38. So as patients have had access to those 3 classes through the first couple of lines, having access to a novel new class which is efficacious was critical. And so that's the positioning we put in place is in that second- to fourth-line post anti-CD38. And with that, I think we've really continued to see really positive feedback from physicians. We've shared the data with them. And as we've done that, we've seen -- in the evolution of our prescribing, we've seen a nice evolution into the second to fourth line; last year, being the fastest-growing agent in the third line. And with the evolution, we now see that greater than 50% of patients are being treated in that kind of second to fourth line versus the later lines. And that evolution takes time in multiple myeloma as it evolves. We also see that greater than 90% of patients are being dosed at 100 micrograms or less with regards to selinexor. So I think the evolution of the second to fourth line has been very well received. We're helping to educate physicians on the appropriate dose modification with the right kind of data. And also, when you look at our kind of intent-to-prescribe metrics, that continues to evolve very positively as physicians get that experience. And really, that positioning in the second to fourth line has resonated very strongly in the community. And the community is where about 70% of those second- to fourth-line patients are actually treated versus the penta-refractory, which is treated much more in the institutions and the academics.

Makes sense. And for additional metrics, I guess, are you seeing anything on durability in refills and the breakdown of prescriptions by -- I guess, how some of the metrics have changed over the last couple of quarters?

Yes. I think as we've shared, unfortunately, there's a lot of noise in the data, and you can't really talk to it with any consistency with regards to duration of therapy. But what we have shared is as we're moving into the earlier lines, we're seeing increasing percentage of patients, what you're on kind of getting greater than 4 repeats and then beyond. And I think that's going to continue to grow as we have patients in that second to fourth line.

Got it. And you recently reported your first quarter sales of approximately $28 million, which came in a little bit under consensus, but you kept your guidance for the year at $135 million to $145 million. Can you talk about what gives you confidence in these numbers?

Yes. And I think when we look at our guidance, we still have confidence in $135 million to $145 million is our guidance, which represents about 40% year-over-year growth. And I think when we look at the first quarter, as we talked to, we delivered 30% growth, and that was really in the face of a strong COVID surge. In January and February, we did see in the marketplace about a 10% decrease in terms of patient flow in multi myeloma. We also associated with that. We saw a pullback in new patient starts as not as many patients were able to access physicians. And at the same time, unfortunately, in January and February, we also saw a number of clinics were impacted with staff, just not being as available. So I think as we move, we saw January-February impact. We saw March moving back to a more normal flow. We saw that kind of increase in new patient starts. And also for our staff and their ability to access physicians and engage in conversations is critically important for us as a new product and very much kind of in our launch phase. So again, in January and February, that kind of was impacted significantly. It came back to a nice level again in March and has continued well through Q2. So we feel confident in our guidance of about 40% growth, $135 million and $145 million for the year.

Got it. And also, how do you view physicians' perception of selinexor as having changed over time? And are there any metrics on that you can share?

Yes. As we talked to, we continue to see strong improvement in physicians' intent to prescribe, the perception with regards to our safety, efficacy. And that evolves over time, and it really goes back to what I talked about earlier. It goes back to helping physicians understand the shift from the penta-refractory kind of twice-weekly higher dose to the once-weekly lower dose. It also goes back to helping physicians understand that it's okay to dose-reduce. And again, as you dose-reduce and patients are on therapy, you're able to see strong benefit in terms of efficacy and also giving physicians the kind of tools and confidence that it's a very kind of repeatable antiemetic approach they can take upfront. And as they do that, patients will get used to the XPO1 inhibition, and the evolution and the ability to stay on therapy progresses very well. So I think we've made that kind of progress, and it happens again as physicians get that confidence and you get the experience, and we're seeing it move forward well.

Got it. And you've shown some data in the past on how selinexor can be combined with a lot of other drugs in the myeloma space. And you recently started dosing your all-oral XPd Phase III trial. How do you view this trial as impacting your myeloma opportunity? And also, it's interesting because this combo is already in the NCCN guidelines. So how does this study make a difference?

Yes. We have -- with selinexor, we have a number of combinations which are in NCCN guidelines. But I think it's also critically important to be able to move forward with a all-oral combination and able to kind of continue the ability for physicians to get access to an oral combo in that second to fourth line. We know that a majority of patients get access to an oral in the second to fourth line. So if we can show an efficacious opportunity which is well tolerated in an all-oral combination, I think it's important for us. And we do know, obviously, we only promote to XVd. And so to have the opportunity to have XPd read out positive and added to our label, it allows us to promote to that. And that's going to allow us to kind of drive continued growth in the years beyond as we wait for that data to read out.

Got it. And for eltanexor in MDS, how would you define the unmet need as well as the market opportunity there?

So I'll first start out with eltanexor. It's a very unique mechanism. It's a SIGN inhibitor, but it differentiates from selinexor in that there's minimal blood-brain barrier central nervous penetration. This is very important because we do believe that the nausea that the patients are experienced with selinexor is centrally mediated. So given this lack of penetration, we may have a better safety profile that allows us to continuously dose 5 out of 7 days with eltanexor, causes sort of continuous suppression of that XPO1 inhibition. So given this profile and this ability to dose more chronically, we are evaluating eltanexor in myelodysplastic syndrome, which again is a high unmet need population. And we're doing something very similar to what we're doing with myelofibrosis, looking both at a relapsed/refractory patient population as a monotherapy but also because of the encouraging data including what we presented at ASH last year, also using it as an opportunity to look at it in combination with the HMA inhibitors as part of our first-line opportunity as well.

Got it. Makes sense. And also I just wanted to check on ex U.S. partners, if there's any status update there you want to highlight.

Yes. I think we're making great evolution. We just got approval in Canada for our post first-line therapy with our partners there. So now 37...

38.

38 countries. As a Canadian, I happen to [ forget ] adding the numbers. So 38 countries around the world with multiple approvals. I think our partner's moving forward really well with Antengene in Asia Pac with the China launch. Also, obviously, in Europe given the positive opinion, waiting for the final approval and the Menarini team moving forward in Europe, excited about that. And then with FORUS in Canada, looking forward to them moving forward to that. Evolution is happening really positively and excited to see -- continue the launches as we bring selinexor to patients around the world.

Great. Well, Reshma and Richard, thanks so much for joining us today.

Thank you, Maury. Thanks for having us.

Appreciate it.