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

Good afternoon, everyone. I'm Brian Abrahams, one of the senior biotech analysts at RBC Capital Markets. Our last session on day 1 of our health care conference is going to be featuring Karyopharm. Really happy to have with us their CEO, Richard Paulson; and their new Chief Medical Officer, Reshma Rangwala. So Richard and Reshma, thanks again for joining us, and it's great to see you guys in person.

Absolutely.

Thank you for having us. It's wonderful to see people in person again.

Indeed. So maybe just to start things off on the commercial side with XPOVIO, you've -- you successfully launched the drug into a crowded space in the midst of a pandemic, and you've continued to see nice uptake. Can you talk a little bit more about like the market dynamics that you're seeing overall? Where are you seeing the drug deployed? How that's been evolving over the past several quarters? And what do you see as the biggest medium-term growth driver for the drug overall?

Sure. Sure, Brian. So I mean maybe to start kind of right in the middle. As you know, we just kind of finished our first year of our second-line plus approval. And what we've been focused on is really in that second to fourth line, where, as you know, there's a number of agents where patients can benefit and the importance of a novel class. And so as we launched and as we came to market in the second-line plus last year, what we did is we put in place a positioning, which is targeting a class switch post anti-CD38. And so when you look at through the first couple of lines of treatment, you tend to have the majority of patients treated with a PI, with an IMiD and anti-CD38. And so what we wanted to do is make sure that we were able to share some data, which we did last year, looking at our drug post anti-CD38, be able to get out and share that information with physicians. And as we've done that, I think, increasingly, we've seen a shift into the earlier lines in that second to fourth line. I think we've seen with that kind of greatest growth in the third line, which makes a lot of sense. And I think also over time, we're going to continue to see the anti-CD38 even move up into the front line, which will enable us, I think, even more opportunity in that second-line setting. And as we've done that, I think we've also been able to see nice evolution in terms of duration of therapy, or patients in the earlier lines are having a longer duration of therapy. And then the third component has been, as we've done that, we've ultimately share a lot of information about the evolution of our dose. So obviously, initially, as we launched, we launched in the penta-refractory setting at 160 and at twice weekly, now once weekly, helping physicians understand the way to best manage patients, helping them understand the side effect profile at a much lower dose. And as we've done that, we've seen physicians' kind of intent to prescribe and their view on how to utilize the drug continue to grow quarter-over-quarter. So I think those 3 drivers within a market that really values novel classes and the multitude of classes that have been there are giving, I think, patients great outcomes in multi myeloma.

Excellent. How much were the dynamics that you observed in first quarter impacted by factors like additional discounting, channel changes and the Omicron wave? And what kind of dynamics are you seeing now exiting the first quarter as we get into the spring? Are you -- I guess what's your level of confidence you're going to start to see reacceleration in demand growth?

Yes. I think when you look year-over-year in Q1, we had 30% growth. And definitely, as we all experienced in Q1, especially in January and February with the resurgence of COVID, we saw about a 9% to 10% impact in patient flow. That impacted us, obviously, in terms of new patients. As we kind of saw March, and I think as all of us evolved positively with regards to less impact of COVID, we're able to get patient starts -- new patients, especially back up to a more normal level. And I think for us also through the quarter, given that we're still a new agent, given that we're still in very much of a dynamic launch phase, what's critically important also is our field force and their ability to engage with customers. And through January and Feb, customers and our field force, many of them were impacted through COVID as well. And so we were able to see kind of in March, again, getting back to a pretty high level of engagement, about 60% actually in person. And that also has had a nice positive impact for us in terms of uptake. So overall, COVID definitely in January and February had an impact. We saw it coming back to a more normal phase in March. And then when you look at the kind of quarter-over-quarter dynamics, you have some evolution, obviously, in terms of gross to net and the first quarter of the year always being higher in the fourth quarter. But that works itself out through the year, and we tend to end up with an average between 15% to 20% GTN through the year.

Got it. You mentioned increasing durations of use as you move up in lines on -- into earlier lines. Can you elaborate that a little bit more? And just maybe provide some granularity on how long penta-refractory myeloma patients were on average are staying on XPOVIO versus what you're seeing with the earlier line patients and how you expect that to continue to change?

Yes. I mean as we've talked about before, I think it's a really difficult metric to share details on with very much accuracy because of all the different kind of data sources and lack of continuity in following patients. So what we have seen and what we talk to is definitely as you move up in the second to fourth line, you have a longer duration of therapy. And what we have been seeing is in terms of patients who are on 4 cycles or more, that's been increasing nicely in terms of the percentage. So I think we expect to continue to see as we're moving up into earlier lines, continued increase in terms of duration. Not sharing a specific number, unfortunately, the data just doesn't bode well in terms of sharing it with any degree of confidence.

Okay. Fair enough. How has reimbursement and access been, especially as you've kind of moved into the earlier lines? Are there any bottlenecks or anything that you expect will ease? Or are you kind of already there with respect to lives covered?

Yes. I mean our reimbursement access has been very positive through the whole launch, so we have 97% plus kind of reimbursement and coverage. So that hasn't been a bottleneck at all. And I think also we have strong support programs in place where needed to work with physicians and patients to make sure they have access and can work through the access kind of challenges. But overall, our access is very strong.

Okay. And where are physicians now with respect to understanding how to identify and manage some of the side effects associated with selinexor, which may be some similar and some different than side effects that they typically have seen with other cancer medications?

Yes. And I think we touched on it a little bit earlier. I think it's evolved really nicely since we launched. So moving from a twice-weekly higher dose into the once-weekly lower dose. With physicians, we wanted to share the data also that if you do need to dose reduce, you can dose reduce without negatively impacting the efficacy. So we've shared that data as we mined some of the BOSTON data. Also, what we've been able to share with physicians is looking at proactively managing with a couple of antiemetics early on over the first couple of months. And as they do that, patients are able to work through and really have -- I think, have a much different experience, a much more positive experience with the once-weekly versus the twice-weekly. The other part with the majority of patients with multiple myeloma in the second to fourth line, the majority of those patients are treated in the community. And a lot of those community physicians are pretty used to managing with antiemetics, whether it be in solid tumors versus kind of in the institutions and academic centers on the heme side not managing as aggressively. So I think we've seen a really good evolution with that. And I think physicians, nurses really understanding how to manage patients and/or seeing it evolve very positively.

That's great. Myeloma space has always captured a lot of interest, and there's a lot of marketed therapies, and there's a lot more sort of coming down the pike. Where do you foresee XPOVIO fitting in over the -- maybe the medium to longer term with some of the newer therapies like CAR-T, BCMA bispecifics, the recently marketed ADC? How does this all fit together? And what -- given that the paradigm is often using combo treatments, what additional studies do you think are going to be most important to really entrench XPOVIO in the future treatment paradigm?

Yes, great question. I mean, I think the positive thing for patients is this innovation. With more and more innovation, we're seeing patients with multiple myeloma live longer. And that's what we're all focused on, is how do we help bring this innovation to life to benefit patients. I do see us really continuing to focus on that second to fourth line. I think a number of the agents you mentioned, whether the [ bispecifics ] or the CAR-Ts are in that fourth-line plus or even fifth-line plus, right now focused on institutions versus the community. For us with 70% plus patients in that second to fourth line in the community. I think being an oral is a positive. I think the patients being in the community setting is a positive. So I do see us continuing to focus on that area, again, creating more data post anti-CD38 to help physicians best understand where to use this and how to use this. And as you know, we're moving forward with a registration-enabling study with SPd with Pomalyst, which would give us the opportunity for an all-oral combination, and that trial will be for patients who have been post anti-CD38. So I think even if you think about whatever the evolution of therapy is going to be, whether it's quads or other aggressive therapies upfront, some more intensive therapies later line, to have the opportunity for all-oral regimens right in the middle, if not even earlier, which is efficacious, I think is going to allow us kind of that medium and longer-term growth as we continue to grow. And as you know, multiple myeloma, it is an area where you grow steadily and consistently over time because there are a lot of agents, so you have to kind of come in and really establish yourself and then continue to expand with new indications.

Makes sense. I'd love to talk a little bit more about some of the new indications beyond myeloma, and I'd love to hear more about the rationale behind exploring selinexor in combination with rux in early line myelofibrosis and the potential synergistic effect it can have. And I guess, in particular, we saw an EHA abstract just, I think, last week where 5 out of 6 patients had the spleen response at week 12. I guess curious like how indicative is that of the efficacy we expect to see with more patients? And how confident are you in the potential durability there? Because that's, of course, an impressive number, but it's a relatively small number of patients. So how should we think about that? And what should we expect to see at EHA in terms of patient numbers?

Yes. That's a great question. I'm going to step back here and just when I look at myelofibrosis, really the JAK inhibitors and specifically ruxolitinib was a game changer for these patients' lives. It was introduced 10 years ago and really has shown meaningful improvements in these patients' lives by decreasing the spleen size and also improving on symptoms. With that said, there is still room to improve. The SVR35 at 24 weeks was only 40%. TSS50 scores still are below 50%. What this field needs, what these patients need are a novel class of therapies. The SINE compounds are a very unique mechanism, as you know, right? They inhibit this nuclear transport, and this inhibition of this nuclear transport is critical for the survival of these JAK mutant cells. If you look at the preclinical data, I think it's very intriguing. So it induces -- selinexor induces very potent cell kill in JAK mutant cells. More importantly, when you combine it with ruxolitinib in MPN [ minus ] mice, you see a synergistic activity when you compare the combination with either seli alone or rux alone. So very strong and convincing preclinical data. Then take that to some of the initial clinical data, and that was first presented at ASH last year. This was a refractory patient population, and now you see that monotherapy activity. This is a very difficult-to-treat patient population. There is no standard of care for this patient population. When we administer selinexor to this refractory patient population, you see an SVR35 at 24 weeks and beyond 40%. You also see some very meaningful improvements in their anemia by increasing hemoglobin and also conversion from transfusion dependence to now independence. So that sets the foundation of strong monotherapy activity. When we go into the treatment naive, this suggests that when we combine it with, again, a very potent JAK inhibitor with ruxolitinib, it suggests that you too are going to see additive, if not synergistic activity. The data that you're citing is now those first pieces of data. That's the first evidence that this is suggestive of that activity. Five out of six patients at week 12 with an 83% SVR35. It's just week 12. And the reason I'm intrigued by those data is that if, again, you look at the essential data, we too look at week 12, 24 and beyond. And what you saw over the course of that time period is not only an increase in the rate of the SVR35, you saw a deepening of response too. So again, I think these are very encouraging data, especially as you translate and move forward into a first-line population.

What -- I know the abstract indicated you had sort of a mix of low, intermediate 1, intermediate 2 risk patients. I guess what's your level of confidence that this first cohort is representative of the typical mix of frontline MF patients versus maybe -- I don't know if there was anything in the trial design such that you have started off with the lowest risk patients first. And I guess we're all kind of wondering how indicative this 83% might be over the longer term and with more patients or if there's anything we should be kind of keeping in mind as a caveat that this is maybe -- that the larger population might have different characteristics and different responses.

This really is a very traditional treatment-naive patient population, so there really is a mix of patients across all of the risk score categories that you just mentioned. But with that said, we know that there are multiple variables that can influence response, not only including risks for baseline anemia, baseline platelet counts based on symptom score 2. So we'll be continuing to monitor those as the data which are...

And how many patients' worth of data might we expect at EHA roughly? Or how much more data should we look for?

There's going to be more data. We haven't guided on that yet in the EHA abstract. 10 patients, of which 6 are evaluable for SVR35. Again, what we're saying is that there will be more patients included in that data cut.

Will we have any SVR24 data by that point?

We haven't guided on that either.

Okay. And then what's the right way to think about the safety profile of selinexor in an MF population? I think the abstract mentioned about 1/3 of the patients had -- got prophylaxed for -- with antiemetic still experienced nausea, but it was generally low grade. But in the MF population, of course, spleen responses and symptoms or both -- symptomatic improvements are both important endpoints. So I guess what do you think are the most important factors to consider with respect to the side effect profile as it relates to an MF population relative to, say, myeloma or some of the other indications you've looked at?

I look at the safety profile as tolerable and then -- a profile that the investigators can treat through, right? And I say that because with the nausea, we know that they have multiple tools that they can give. They can give single antiemetic. They can get dual antiemetics, and we've actually done that neuro myeloma. So that should not be dose-limiting for that patient population. We're also looking at the cytopenias the same way. We know these patients unfortunately suffer from cytopenias. Rux also has a lot of cytopenias. Again, what we want to help these physicians is to just be able to treat those cytopenias while not having to discontinue the therapy.

Got it. Will -- are you looking at TSS in this initial combo study?

That's right. So we're looking at multiple different efficacy endpoints. Of course, there's SVR35 at multiple time points again. But we're going to be looking at TSS50, but also anemia response, overall survival, ORR. So really looking at -- across the gamut.

Got it. Maybe shifting gears to endometrial cancer. I guess in light of the patient enrollment for the p53 wild-type endometrial cancer study starting later this year. What are some of the lessons from the SIENDO study and key study design parameters that are -- you're going to be considering as you move forward here to maximize the probability of success and replication of what you observed in that population in SIENDO?

I think the most striking learning from that trial was the p53 subgroup. The benefit, especially when you compare it to the ITT population, the benefit that was observed in that very sizable patient population of over 100 patients, demonstrated that you can improve median PFS by 10 months, right, 3.7 to now 13.7 which, again, for this patient population, extremely meaningful. So this just gives us a very robust dataset that we have a lot of confidence that we can move forward in another randomized Phase III trial.

What do you see as the bar in that study? What do you want to see out of the Phase III? I mean, obviously, you showed a huge delta in that subpopulation in SIENDO. Does it need to be quite as big? Or is there a certain -- what do you hear from physicians where the benefit/risk in a maintenance population would be really clear and robust in terms of PFS?

I think what we hear from physicians that 10-month improvement is like to knock out of the park. I mean that is a true game changer for this patient population. So I think if we can see something within that range, again, we've dramatically changed the lives of those women.

Okay. Got it. What are your current thoughts on exploring selinexor in other tumor types where there might -- patients might also be likely to be p53 wild-type. Is that something that's on your radar? I know that, obviously, you need to kind of focus on the highest probability indications where you already have validation. But it seems like mechanistically and based on some of the initial clinical data, there's a lot of other places you could go and other solid tumors you could potentially go in. I guess how much of a priority is exploring that further?

Yes, you're absolutely right. I mean I cannot believe that endometrial is the only place in which we're going to see such effect with p53, so we are doing a broad interrogation across solid as well as hematologic malignancies in order to identify the next set of tumors, next set of patients that we can bring forth and develop in that subgroup.

Great. Well, maybe just in the last minute or 2, and I know you guys have to catch a flight. There's been some recent changes overall in the leadership team and leadership structure at Karyopharm. I'm just curious to learn a little bit more about how you're thinking about any changes or evolution to the overall strategy? How you guys view the business and what you think are kind of the most important things that you're going to be focusing on and the changes that we might expect to continue to evolve?

Yes. I mean, I think we're at a real turning point or an inflection point where we're building on more of a decade of great research and development in terms of how we're discovering. And as you know, we're the leader in our platform, the selective inhibition nuclear export. So through that, the focus that we've laid out is really to focus on our 4 core programs. Multiple myeloma is the lead, endometrial cancer, myelofibrosis and MDS. And in each one of those, we continue to see high unmet need. We see their science has shown it can have a big impact for patients and then a high probability of success. And so as we move forward, we're really going to be focused on how do we execute successfully on these, how do we kind of take the proven capabilities we have from the clinical development, apply them across these areas and really move forward pretty rapidly. So that's going to continue to be our focus, and I think it's just a natural evolution of the company, and we're bringing in. Now Reshma comes in with a lot of solid tumor experience, and so she's -- when you talk about the p53 data, she's excited, she jumps. Let's continue to move forward. So I think continuing the evolution, continuing, again, executing on what we have in front of us and then finding the next generation of opportunities as well. It's exciting, and those are all opportunities we have. So it's wonderful to have a platform that works across so many different types of cancer, but better focus and deliver and then continue to build.

Great. Well, no, it's great to see you've already started to take all the work that's been done in the clinical development side and really now focused that into the key areas and look forward to seeing that continue. So thanks again. I really appreciate it. Great to see you.

Thank you. Thanks for having us.

Thanks, everybody.

Thank you.