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

Great. Thank you. Good morning, everyone. Welcome to Barclays Global Healthcare Conference. My name is Peter Lawson. I'm one of the biotech equity analysts at Barclays. I just want to thank everyone for taking the time out of the day. I've got a series of questions, but do ping me by e-mail, so it's [email protected] or ping me on Bloomberg. It gives me a great pleasure to introduce the management team from Karyopharm today. I've got Michael Kauffman and various other members of management team as well on the line.

And so maybe it's just an opening question as kind of a 2- to 3-minute kind of overview kind of the company's differentiation in the oncology space, what would you kind of define as Karyopharm's core competencies?

Yes. Well, we're a unique company because we have a completely unique discovery platform and now marketed product called XPOVIO, which is a first and currently the only nuclear export inhibitor that's approved in both myeloma and second-line myeloma and then third line or later diffuse large B-cell lymphoma. This is a completely new approach to treating cancer, and it relies on reactivation of a set of guardian proteins called tumor suppressor proteins that exist in all of our cells. Normally, these proteins prevent the development of cancer. The cancer cells are very good at exporting them out of the nucleus and therefore, inactivating them. We block that export, we reactivate the tumor suppressor proteins, and we, therefore, have potential for broad activity. We do expect the drug to have activity beyond hematologic malignancies, and we're currently engaged in Phase III trials. Recently, we had a positive trial in liposarcoma, and we have upcoming data, Phase III trial in uterine cancer. So this is a potentially very broad foundational platform for the treatment of cancer.

Perfect. And then maybe we could dive into selinexor kind of revenues. Kind of what factor do you think drives an uptick in scripts in 2021? And what do you think are the primary drivers there for script uptick?

Sure. I think the main driver is going to be and is, and we're already seeing it, is the recent approval of XPOVIO in the second-line setting in multiple myeloma. This is based on the Phase III BOSTON study, which was published last year in Lancet. FDA came in with an approval -- a full approval now in second or later line myeloma for patients after at least one prior therapy and that came in 3 months early in late December last year. And we've seen now that we're getting more new patients on the drug, and we're getting patients and physicians using the kind of dosing regimen that we utilized in the BOSTON study as opposed to the much higher dosing and intensive dosing regimen that we were using for XPOVIO in the previous approval, which was in patients with penta-refractory myeloma. So we have arguably one of the, if not the, simplest regimen for the treatment of relapsed myeloma. This is a once-weekly regimen consisting of 3 drugs, 2 of them oral, the dexamethasone and the XPOVIO, and 1 of them a short injection, which literally requires a patient to come in, sit down, check their vitals and then take a needle, place it under the skin and squirt and you're done. It's a very rapid clinical turnaround. Again, this is one of the simplest regimens, and this is done weekly 4 out of 5 weeks, which makes it really convenient regimen. The efficacy here was on par with a lot of the other more complicated regimens used in the second line. It was particularly appealing in patients over 65-years old, where the tolerability was quite good and in patients with high-risk cytogenetics, and it was, as expected, more effective in second line as opposed to fourth-line disease. So we have a really unique regimen. We have a simple regimen. It's very important now, especially in this pandemic setting, but it's also important for patients who are elderly and who don't want to spend a lot of time in the clinic.

And maybe we can walk through that kind of the subsets of patients that are -- whether it's in the second line, third line or fourth line that you're kind of seeing great traction around.

We don't have definitive evidence that we're in second, third or our fourth line based on the data that we see, but what we do know is that the once-weekly dosing regimen, which is what was employed in BOSTON, is -- has really taken over as the vast majority of the new prescriptions being written, which is great news, because this is a very potent regimen. It's far better tolerated than the twice-weekly regimen. As you'd expect, given the lower dose and the lower frequency. And it's quite an effective regimen. And the other point to make is that there is no cumulative toxicity that is clinically significant, meaning people don't build up clinical toxicity. So you can really continue this regimen indefinitely until disease progression. We also note that we had 2 additional NCCN listings besides the BOSTON approval, that is to say XPOVIO plus Pomalyst plus dexamethasone, which is a once-weekly all-oral regimen, and XPOVIO plus Darzalex plus dexamethasone, which employs the subcutaneous or IV Darzalex weekly again with XPOVIO and dex. So again, very simple regimens. The use of the drug is optimal, as I mentioned, in a couple or many different subsets of patients. And we've talked a lot about that in our Lancet paper and our presentation at ASCO. But just to review quickly, for any patient who gets Darzalex, Revlimid, dex regimen in frontline, which is an increasingly used regimen, because it's quite effective, has minimal long-term toxicity pretty much coming from the Revlimid. It makes sense to switch both the Darzalex to a new mechanism and the IMiD -- the Revlimid to a new mechanism. And the mechanisms that come to mind are proteasome inhibitors and selective inhibitors of nuclear export, namely XPOVIO. So DRD -- patients receiving DRD in frontline would be a very key patient to come in second line to get the XVD BOSTON regimen. The second group of patients was we had really nice data in the over 65-year olds, and this is because the once-weekly Velcade regimen that we employ, along with once-weekly selinexor or XPOVIO when given with proper anti-nausea agents, is really quite well tolerated. And the hazard ratios were very nice for that group of patients, tolerability was good. And again, it's a very convenient regimen for older folks, who want to spend as little time in the hospital as possible. And then the last group of patients, 2 groups I want to mention, are the patients who might normally be switched to a second IMiDs right after Revlimid and that's probably not the best kind of strategy because, generally, we like to switch mechanisms. So anyone who might be considering a Pomalyst-based regimen right after Revlimid might consider an XPOVIO-based regimen. And finally, high risk -- patients with high-risk set of genetics, particularly the del(17p), which is the worst outcome in myeloma. These are patients whose myeloma has lost one of the p53 tumor suppressor protein genes. And this myeloma tends to be responsive, but for a very short period of time with the currently available drugs. What we showed in the BOSTON study was that if you add XPOVIO to Velcade, you can really overcome a lot of that, not only in the 17p, but in several of the other high-risk markers. So we recommend for the approximately 50% of patients in BOSTON, who got the -- who had high-risk cytogenetics, this would be a very effective regimen. There's lots of places to use XVd.

Great. That's a lot to kind of unpack this. Maybe if we could talk through the side effect profile. I mean it's gone through quite a journey. It's kind of an interesting point now. Kind of how have doctors managed? How have patients manage their side effects? How doctors got more comfortable with using the drug? What if you kind of talk through how that's morphed over the last year or so? And where you see it headed?

Yes. So let's remember that all myeloma drugs and all cancer drugs, in general, require prophylaxis. People often forget that antibodies -- when you give any antibody to any patient regardless of their type of tumor, you use a cocktail of between 4 and 6 prophylactic medicines to reduce infusion reactions. And we don't often discuss those because it's pretty standard. Similarly, when you give an IMiD, you have to put people on an anticlotting agent because there is a reasonable risk of venous thromboembolism, which can include DVT and pulmonary embolism. And when you put somebody on a proteasome inhibitor, you have to put them on herpes zoster prophylaxis, because there's a high risk of reactivation of zoster and other viral infections. Our drug is similar in the sense that we do need to put people on prophylaxis. But the good news is it's pretty standard for oncology drugs. And that is to say that our main side effect is nausea and in some people anorexia, which is actually a bit separate from the nausea. You can prevent the nausea. You can almost eliminate the nausea with 2 standard anti-nausea agents given for about 36 hours around the drug dosing. And this means that people coming in to get their BOSTON regimen, for example, would be given a 5-HT3, a standard Zofran, antinausea agent with a second drug typically either olanzapine or an NK1 antagonist. These are very standard practices all over the NCCN guidelines, and we have several supportive care papers, and we really see very good results. The second point I'll make is that it's important to remember that the overall nausea rate in BOSTON was 50%, 5-0 percent, 30% -- 33% or so of the patients had nausea in the first cycle. So only 1 in 3 patients getting a single antinausea agent is going to have nausea in the first cycle, and it's going to get better over time. We know that the nausea rates -- new nausea rates go down substantially. It's about 33%, then about 10%, then about 3% and so on. By the time a patient reaches the third cycle, there's really very little risk of nausea with only a single agent. Now we are recommending that doctors start patients on 2 anti-nausea agents, and we believe that, that's likely to result in the vast majority of patients having little to no nausea, meaning grade 1 or grade 0 nausea. Once the nausea is treated, you need -- you just need to do the standard kind of multiple myeloma monitoring. And that's regular blood counts and regular serum electrolytes, just to make sure the patient is doing okay. But the beauty of the BOSTON regimen is, and frankly, the other once-weekly regimens, is that once you treat the nausea and make sure that people are eating properly and drinking properly, you really don't have to worry about long-term toxicities.

What point do you -- is it like within 6 weeks that most of the side effects just dissipate or managed sufficiently well?

Yes. Most patients are off their second nausea agent between 4 and 6 weeks. They do take a single -- they will take Zofran, for example, before their XPOVIO. Just like they'll be taking an aspirin or even Coumadin or a Factor X inhibitor with their IMiDs continuously, but we can wean people off. There are a growing number of patients who are labeled in late cycles, meaning 6-plus cycles. 6 months on the drug, they can come off of all the anti-nausea medicine or just get a single dose in the clinic. And this is really kind of an extraordinary backdrop for myeloma drugs, because although we do have the nausea, it does dissipate over time, which is different than other drugs. We don't have cumulative toxicities. And we've had patients on, I think, now the longest is 5 years on XPOVIO with no clinically significant cumulative toxicities and a handful of patients over 3 years and tens of patients that are over 2 and 2.5 years now on the drug.

Is there a defining feature of those patients that are on [indiscernible] for a long period of time?

Yes. We are looking at our sort of extraordinary responders, if you will, and patients with long-term disease control. We noted, for example, in our approval for diffuse large B-cell lymphoma, we are the only single-agent oral therapy that's approved in DLBCL, and about 1 in 8 patients or about 13% will have a complete remission. The average duration of those complete remissions is 2 years, which for a single-agent oral therapy is pretty interesting. When you think about R-CHOP, which cures patients in the frontline, that's a mixture of 5 different drugs with significant potential long-term toxicities. It can be curative in about half the patients. But when a patient reaches our drug after 2 prior therapies, to have single-agent activity with 1 in 8 CRs is pretty interesting. And for those patients, we do see this long-term tolerability, most of those patients are on for once a week now. We don't yet have, Peter, a marker for the extraordinary responders, if you will, and we're looking very hard using all sorts of genomic technologies and artificial intelligence now, and we are looking into that. Similarly, we have patients with myeloma that are on the drug for 3 years, 4 years with relapsed/refractory myeloma. We've had other patients with other diseases with solid tumors and things that go into a complete remission that can be quite long. So we are trying to define those extraordinary responders and on the patients with extraordinary tolerability. But I would say that almost all patients on the drug for more than 4 to 5 months really tolerate the drug extremely well with minimal toxicities.

The -- you mentioned kind of 3 groups that you'll see an increased interaction [indiscernible] kind of patients that should swap mechanism of action in these kind of higher-risk patients. Do you need further clinical studies there? Or is -- do you have enough from the BOSTON study or other things going on to kind of heighten that awareness in those 3 groups?

Yes. Well, we're continuing to dig into the BOSTON data as are typical of Phase III studies. These are very robust data sets with lots of interesting information. Most of these -- many of these subsets were prespecified in the study, and many of them reached statistical significance. And generally, in those cases, doctors will take the data and face value and not require additional data to feel comfortable. There are some very intriguing subsets. We'll be showing some new analyses that we hope at upcoming medical meetings. And we're trying to dig into some of the pathways even in myeloma, we don't, for example, think much of RAS pathway. There are 10% to 20% of patients that do have -- with myeloma that do have RAS or RAS pathway mutations, and they turn out to be an extraordinarily poorly treated subset. Based on some data, actually, we had in solid tumors preclinically published in nature and in solid tumors in clinic now, we thought that RAS might be interesting. So that will be something to keep an eye on. And we do have some other additional analyses that are in preparation, have been accepted to journals, in some cases, in manuscripts in preparation. But we think it's a pretty robust data set that probably doesn't need a separate trial for approval. What we are going to be doing, though, is to move to a XPOVIO-pomalidomide-dex Phase III trial, XPD, versus a control arm, which will be elotuzumab -- XPOVIO -- elotuzumab-pom-dex in patients who've already seen the typical first- and second-line therapies, which, of course, mean Revlimid, Velcade and a CD38 monoclonal, typically Darzalex. So this study will start in the second half of the year. What's beautiful about the XPD regimen, it's already on the NCCN guidelines, but it's the -- it's probably one of the most potent oral -- all-oral regimens, all-oral triplets, and had 60% response rates in recent medical meetings. And that's pretty remarkable for an all-oral triplet in patients with double or triple refractory disease. And we think this is a regimen that we're aware of is being used now, but we want to solidify that and generate Phase III data.

Could we talk about, I guess, the the effect of COVID on the launch? I mean as you talk about like oral therapies and you've got oral triplet therapies, they should be kind of a natural uptick. But was it the side effect profile that kind of worry doctors from prescribing it for the first time? We should kind of maybe talk through those dynamics.

Sure. Well, look, sales forces are always optimal in-person. That's why we have sales forces, and they go meet people in-person. There's body language. There's the communication. There's the in and out -- we've converted -- our sales force is doing a lot of Zoom calls and other virtual calls as well as telephone calls and so on, but it's never as optimal. You have to remember that myeloma is a busy market. Physicians generate their own preferred regimens, and they do what they're used to and changing behavior, which is what we're very hard at work doing, and we're seeing that. Changing behavior is not easy, especially in a market that has many other drugs. We do believe that the attributes of the BOSTON regimen, in particular, and some of the other triplets that have given -- been on NCCN guidelines as well as like Kyprolis triplet, which has been presented at multiple medical meetings, make this a really attractive regimen, but you have to change behavior, and that's always more optimal in-person. Things are starting to open up again. As you know, things started to open up in mid-summer to late summer, and then they shut down again at the end of the year and through the winter months. Things are starting to open up again. Doctors are accepting in-person meetings, but it's still only 15% or so of our interactions. So we have to get in there and convince docs. I think once they understand that they just need to use their standard anti-nausea medicines, that's pretty much it with the BOSTON regimen, they will try this on a patient. And physicians are typical humans that like to do with what they work -- with what has worked. So we just got to get that first script. And once people try it, they're usually pretty excited.

I'd love to switch gears completely just over to like solid tumors and kind of which ones are you getting most excited about? What readout should we expect to see in 2021? So there's melanoma we can see, et cetera.

Sure. I think the first point is, there are a few drugs, very few drugs actually, other than chemotherapy itself that can cross between hematologic and solid tumors in a major kind of way. Because we attack a foundation of cancer, that is to say all cancers inactivate their tumor suppressor proteins, and we reactivate the tumor suppressor proteins. This drug should have activity across both hematologic and solid tumors. What we see in the heme tumors, as you know, is about a 25% to 30% response rate in myeloma, DLBCL, we get responses in AML and so on. But we see about a 10% response rate in certain solid tumors as a single oral therapy in patients with refractory disease. If I can take one step back, though, the other big issue with these -- with drugs is always can they really penetrate solid tumors. Because depending on the molecule, you can have better or worse penetration. And many drugs for myeloma just don't penetrate solid tissues very well. And I'll just say as an aside, one of the places we see XPOVIO used in myeloma is for plasmacytomas, which are masses of myeloma tissue where many drugs cannot penetrate well, and we do. So if you move over now to solid tumors, what we showed was that in liposarcoma, in patients whose disease had already become relapsed or refractory to 2 chemotherapy regimens, we saw bona fide responses about 3% RECIST responses, and these are huge tumors as opposed to 0% on the placebo control arm. And we saw patients with tumor shrinkage of at least 15% in about 5% to 6% of patients versus 0% on the placebo. And that tells you the drug does penetrate. But some of the little-known data that people are aware of are the Phase II data in gynecologic malignancies. So we conducted a fairly substantial Phase II study where -- and which has been published now, showing a 9% bona fide-confirmed RECIST response rates in both platinum refractory ovarian and heavily pretreated uterine cancers separately. Both had 9% response rates, including PRs and CRs in both diseases as a single oral therapy after at least 5 or -- median of 5 regimens in ovarian and a median of 2 regimens in uterine cancer. And we saw additionally about 30% or 35% patients with good disease control, meaning at least 4 months of stable disease. All patients coming into that trial had come in with progressive disease and needed to have therapy, but had exhausted available therapies. This Phase II study is published. Vergote, V-E-R-G-O-T-E, is the first of them. Based on those data, it is clear that we have single-agent activity in both uterine and ovarian cancer. When we look around at the unmet medical need, particularly in uterine cancer, which is substantially underserved as opposed to ovarian where there are multiple options, we know that there is no maintenance therapy in -- after treatment for advanced uterine cancer. In ovarian cancer, maintenance therapy with PARP inhibitors is pretty standard. But in uterine cancer, there is nothing. So patients with uterine cancer are typically treated with a platinum-taxol doublet for 6 cycles. These are 3-week cycles, so for 18 weeks. And about 80% to 90% of them will have some sort of a response, meaning a PR or a CR. So it is a responsive disease. Unfortunately, all of those patients will progress. The average progressive time on -- in the PR is about 3 months, and it's about 5 to 6 months with a CR. And this is an unmet medical need. So we looked into this, and we have initiated the SIENDO study some years ago, which is selinexor in endometrial cancer as a maintenance therapy after the chemotherapy frontline, and we passed our first interim analysis in this study. The primary endpoint of the study is PFS. The goal hazard ratio is at least 0.6, meaning we can reduce progression or death by at least 40% as compared to the placebo control arm, and we believe that this would be sufficient for an approval and an important medical advance for patients with refractory -- sorry, for frontline uterine cancer. We expect data from this study by the end of this year. And should the data be positive, we will quickly submit to the FDA for approval. And this is a big potential population. There are about 16,000 of these patients in the United States alone. There is currently no therapy indicated for them. The average duration of treatment will be estimated at 5 to 6 months. And we think we could have a real impact if we can hit that hazard ratio goal. Again, we passed the first interim analysis. This is the only interim analysis, and final data or top line data will be available end of the year. We have additional solid tumors. I'll just go on for a little bit more, because very important work going on in glioblastoma multiforme. The main nausea side effect and anorexia are from blood brain barrier penetration and that is essentially mediated. We've seen a 10% bona fide response rate in patients with relapsed or refractory GBM as a single agent. And I think our longest patient over 5 years now has GBM and has been treated for over 5 years with single-agent oral XPOVIO once a week. So we're looking into frontline treatment with temozolomide radiation, and we're also looking at recurrence treatment in combination with lomustine in that. I'll just mention briefly that we have ongoing studies in lung cancer with -- in combination with docetaxel in patients with RAS mutant as well as RAS wild type non-small cell lung cancer following failure of both an immunotherapy agent, such as Keytruda or Opdivo, and failure of a chemotherapy regimen. It can be given together or it can be apart. So it's typically third-line lung cancer with no standard of care. Docetaxel is indicated in this regimen but it's -- in this line, but it tends to be palliative. It has a 0% to about 5% single-agent response rate and a very poor progression-free survival. So we'll have data I'm hoping later this year in lung cancer, in combination with docetaxel as a single-arm study. And if that looks positive, we'll move into a randomized study for approval in combination with docetaxel following progression after an immunological agent plus chemotherapy. And we have studies going on in colorectal and we'll shortly in melanoma as well.

Great. So it's like an exciting year. Michael and team, thank you so much. Always a pleasure to speak to you. I know we could speak for much longer. I know also, you've got a busy day. So l'll kind of cut things off now. And I just wanted to thank you for joining us, and I'll hand the line back to the operator. Thank you so much.

Thank you very much, Peter. Great to be here.