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

Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome the Karyopharm team with us today. We're going to do a fireside chat to talk about Karyopharm. And with us, we've got Michael Kauffman, the CEO; Mike Mason, the CFO; and Ian Karp from Investor Relations. So thanks, everyone, for joining us today. And maybe to start off, Michael, if you want to provide an intro to Karyopharm for those who might not be familiar with the story.

Sure. Karyopharm was founded in 2009, focused on modulating nuclear export from the cell nucleus and treating diseases like cancer and other abnormalities, including autoimmune disease and certain viruses. We have our lead product, it's called XPOVIO. It's now marketed for 2 indications. It entered the clinic as selinexor, a first-in-class oral inhibitor of the nuclear export, protein exportin 1. And it is a drug that's now approved in relapsed/refractory myeloma and in relapsed/refractory diffuse large B-cell lymphoma. We have a third approval pending with the FDA right now for a sizable market in second-line myeloma. And we recently announced positive Phase III data in a difficult-to-treat disease called undifferentiated liposarcoma, where we showed a PFS benefit, and this is a randomized regulatory study. We hope to file on that early next year with approval in our first solid tumor indication. The mechanism of inhibiting XPO1 leading to tumor suppressor protein reactivation is a mechanism that is related or is generally applicable to essentially any type of cancer. And our goal for this compound is to move it ahead in a variety of different tumor types. It's a -- typically a once or twice a week oral compound that can combine well with other anticancer drugs and could be used in a great -- in a large majority of cancers or a large number of cancers going forward.

Great. Yes, I think that's a great overview and sets the stage. Maybe focusing on myeloma initially. If you can just talk about where you're at from a development standpoint in myeloma. And you recently had the publication in The Lancet, which is a great journal and a great accomplishment. So maybe if you want to talk about that as well.

Sure. Let me start with that. So the -- my history in myeloma goes back to Velcade days when we did the first accelerated approval ever in multiple myeloma, got Velcade approved first in last-line myeloma and then moved it up to second-line myeloma. I'm a bit stuck in a rut because I did the same thing with Kyprolis where we got it approved in late-line and then second-line. And now again, with XPOVIO, our hope is we have the approval in late-line myeloma and moving it to second-line. So same general idea. This -- the data in patients with one prior therapy was just published, as Maury said, in The Lancet, the full Lancet paper. It's quite a large paper. It's very long. They asked us to include a lot of data from the trial, and it's very comprehensive. Lancet's excitement with this particular regimen, although this is one of many Velcade-based combination, it is the first Velcade-based combination that was studied explicitly in Phase III with a once-a-week Velcade on the experimental arm. And the reason that's important is because the use of Velcade in the real world is almost exclusively a once-a-week therapy. And essentially, we're the first people to actually study it that way in what will hopefully be the study that leads to the approval. So physicians and patients will know exactly what to expect with the regimen as opposed to having to sort of guess what might happen in the real world when you cut the Velcade dose in half. The other beauty of this study is that although most people do a 3 versus 2, 3 drugs versus 2, and 3 drugs typically wins in myeloma, I know this was an investor concern going in. Because we've cut the dose of Velcade by 40% and we've cut the dose of steroids by 25%, our regimen represents really not a full 3 versus 2. You can think of it sort of 2.5 versus 2. So the single dose of selinexor weekly has to overcome not only the myeloma, but of course, the fact that you're using a lot less Velcade and steroid. This makes it very attractive for patients and physicians. This is the only once-a-week regimen where you can come in and get your Velcade subcutaneous injection, get a single dose of selinexor per week and take your steroid and essentially be done with the regimen. And that means compliance can be very good. The simplicity of this regimen is very good. Because Velcade is given subcutaneously as a shot and not as an infusion, it can be a relatively quick visit to the clinic. The only other simpler regimens, frankly, are all oral regimens, and we are exploring that with selinexor plus pom-dex, which leads me to the second part of where we're going with this in myeloma. So our plan in myeloma is to -- we recognize the big competitive landscape. We believe that XPOVIO, as the only nuclear export inhibitor which does have single-agent activity, is best used in combination with multiple different partners. And we believe that every patient in their myeloma journey should receive at least one, and possibly more than one regimen, with XPOVIO. Of course, these are at right now, off-label, but this is the way physicians are thinking about the use of most myeloma drugs, and it's pretty consistent across the board. So ultimately, XPOVIO, we believe, will get approved. We hope in the BOSTON regimen of Velcade, but we will provide data with Kyprolis and have already. We have updated data coming out at ASH with Kyprolis, with Darzalex, an oral presentation with Pomalyst and even an updated presentation with Revlimid, including in frontline myeloma with an all-oral selinexor-Revlimid-dex combination. So this, as a novel mechanism of single-agent activity, could be used ubiquitously in myeloma as physicians see most appropriate. And then we'll be exploring it, of course, in many other different tumor types, but that's the plan in myeloma.

Got it. And for the commercial setting, so you're approved in last-line myeloma and you've got a PDUFA set for the second-line opportunity. Maybe starting with the last-line opportunity. Can you talk about how that's going in terms of provider use and sales and also your growth expectations over the next 12 months?

Sure. I can take that one, Maury. So we just recently reported our third quarter sales, which were about 15% higher than the second quarter. And this was the second quarter in a row of sustained growth. So we grew at about 16% from the first quarter to the second quarter of this year. So nice growth so far this year, has been primarily driven by really a combination of patients staying on drug longer and us identifying new patients and new physicians who are using XPOVIO for the first time. So that's continued to go well. I would say that there's -- while we don't have an explicit breakdown, there's a nice distribution of usage between academic institutions and community-based physicians. This drug appeals to both settings really. The vast majority of the usage that we've seen is on-label penta-refractory patients, meaning, these are patients that have already seen the 5 major drugs or 3 classes of drugs with 5 specific drugs in their treatment journey so far. And then they're coming on to XPOVIO typically in the fourth, fifth, sixth or seventh line. Remember, most patients will receive multiple drugs in each line of therapy. So you can essentially become penta-refractory in some cases, even by the time you're in the third and fourth line. Many of our patients are, in fact, receiving XPOVIO already in combination with other myeloma drugs like Velcade as well as some of the other drugs like Pomalyst and Kyprolis, which Michael mentioned. But notably, these are -- the vast majority of these patients are still the labeled penta-refractory patients. In terms of -- now remember, this total population, sort of the fourth and later line of therapy, patients receiving myeloma drugs in the fourth and later lines, there's about 6,000 of these patients in the U.S. And that's primarily where we are gaining access, have reimbursement coverage, et cetera. We seek to continue to grow that business for the next few months to the first quarter of next year potentially. And then we would expect a significant inflection in sales opportunity once -- if and when we get approval in the second and third line. There are about 30,000 or more. Actually, some numbers put it even approaching 40,000, but at least 30,000 patients in the second- and third-line setting. And importantly, those patients from our studies, from our BOSTON study, the median time on -- or the average time on drug was 10 months in the BOSTON study compared to only 3 months in the late-line STORM study. So not only are there 5x as more patients, patients remain on drug for typically 3x, if not longer. And so that's where we believe the growth will significantly accelerate. So sort of modest growth between now and BOSTON approval and then more significant inflection following the BOSTON approval.

Got it. And you talked about the commercial use in some of the combo usage that you're seeing there. Is there a way to collect data from that? I guess, can you formally collect them, potentially present it at some point?

Well, we've already seen -- I mean we've already seen -- there was a recent publication actually by some of the folks at Mount Sinai Hospital in New York, who published a study of patients, highly refractory patients who were, in fact, getting XPOVIO plus Velcade in the late-line setting. So we have seen actually some of this data, in fact, published. Again, I think the greatest interest is in the second- and third-line setting. You're going to see a lot more data from the additional cuts of the BOSTON study will be presented at ASH. I think that's where you'll see more interest in earlier line settings, but there already has been quite a bit of data presented at least and published showing combinations in late-line settings. I don't know, Michael, if you'd add to that.

That's right.

Okay. And I guess for the 3 months on treatment based on the STORM study, it seems like you're seeing that commercially as well. Are you guys putting any numbers behind how that could change when you have the earlier line opportunity and you go to the 10 months based on BOSTON?

Yes. Well, I think the reality is it's -- like other myeloma drugs, we're likely to get a mixture of use depending on individual patient and individual physician. I think as you look out into the next year or two, there will be physicians who, I think, initially will be very quite comfortable using the BOSTON regimen in the second line. There'll be others that may reserve it for the third line, and still others that may reserve it for the fourth or fifth line. And as you might imagine, just on average, the earlier that you get this drug, the longer you'll stay on it -- the longer patients tend to benefit from a drug like this. And so I think ultimately, the real-world duration of therapy will likely be somewhere between 3 and 10 months, but it's very difficult for us to know exactly where that will land until we can see how good a job we are to move this into second line versus third line versus fourth line.

Got it. And for the last line, is there any other ways that you're exploring to potentially optimize and keep patients on treatment longer in that setting? And could that be -- could that change based on COVID clearing up and being able to engage with those patients more frequently?

Well, there's no question that the use of supportive care, optimal supportive care, which just keeps getting better. I think we've reached maybe near a plateau at least on proper use of antiemetics and potentially appetite stimulants with physicians who know how to balance this drug. And first of all, in the last-line setting, it's critically important to induce a response. What we know is if you don't have a response and stop this disease within the first couple of weeks, the patient's probably going to have an escaped myeloma, progressive myeloma and probably succumb to the disease. They just don't have a lot of options left. So use of higher doses of XPOVIO plus dex or XPOVIO in triplet is very important at the beginning of this. But that requires optimal supportive care, typically 2 anti-nausea agents to essentially eliminate nausea, properly administered Zofran for example, which is ondansetron plus either olanzapine, a low dose or an NK1 blocker like aprepitant can really mitigate the nausea down to grade 0, where it's gone, or grade 1. We prefer people get it before they start the drug so they can minimize any nausea at all. And then keep careful attention to that first couple of weeks when there's going to be potentially a lot of tumor cells that die, and it's important to stay hydrated and maintain your caloric intake while the drugs are doing their job. And if you can do that and get people through the first several weeks, you can start to pull back on some of the supportive care. But we think this is a really -- a relatively simple regimen to administer to patients and pretty effective.

And has that been useful during the COVID situation?

Well, the fact that patients don't have to come in and get infusions and spend any significant amount of time in health care facilities where there might be other people that are infected, especially given that patients with B-cell malignancies, in general, have a difficult time clearing this virus, the SARS coronavirus, and probably are -- are probably much more infectious for a lot longer than your average patient. So yes, people, I think, feel a lot better with an oral therapy.

I think the other piece, Maury, is from the data that we get from the specialty pharmacies that help distribute XPOVIO, that data suggests that right now, about 13% of patients in the real world, in the commercial setting, are discontinuing XPOVIO use due to its side effect profile, which is vastly different what we saw in the STORM study. So in a controlled clinical trial in penta-refractory patients, that number was 27%. And so I think that's a testament to as we've learned and physicians have learned and gotten much better at the supportive care and the preventive measures, to what Michael was talking about, particularly around nausea and fatigue and weight loss, that we've done a tremendous job in the real world helping patients stay on drug and do so comfortably and responsibly. And so I think that number kind of really supports that these tactics are working.

Got it. And maybe going back to the Lancet publication. So just wondering how that contributes strategically. Will it impact commercially in the near term? And could it factor into an NCCN guideline update at some point?

Well, it does a few things, and you alluded to the most important ones. The first one is that we've already submitted it to the NCCN Committee. Hopefully, they'll have a chance to review it sooner rather than later. There are insurance companies that accept NCCN guidelines as a basis for approving the use of drugs even before they might make it to the label. So that would be a potential upside. We don't know when the NCCN committee is meeting and -- but frankly, it's fairly black box. We do know that all the NCCN members are, of course, aware of this drug. It's already on the NCCN guidelines in the use -- in late line. The second thing is it gives physicians a lot more confidence in the data. This is -- these are peer-reviewed data. Obviously, Lancet is one of the top journals in the world. And we were privileged that they actually accepted more figures and more tables than are usually accepted to a typical Lancet paper in the main body of the paper, including extensive forest plots and so on and so forth. So there's a great deal of data here where you can examine specific situations. Some highlights would include the fact that our trial actually had the highest number of high-risk patients ever reported in a modern Phase III study, 50% as compared to 15% to 25%. That, of course, skews the overall results because high-risk myeloma patients unfortunately don't tend to stay on therapies as long as standard-risk patients. But when you dig into the data, you can see that we had a remarkable effect in most of the high-risk categories, particularly in the deletion of chromosome 17p, which is a most difficult-to-treat myeloma, those are patients who have lost at least one copy of the p53 tumor suppressor protein, and we had a remarkable -- a remarkably strong hazard ratio there. The corollary is though that when you look at the actual PFS in patients with standard-risk disease, it was quite a bit higher than the overall 13.9 months, closer to 20 and even as high as 23 months for some populations. So in a standard-risk patient, this simple regimen of XPOVIO-Vel-dex can be very effective. This is really the first time physicians will have the actual data sitting them -- in front of them as opposed to being flashed up on a screen at ASCO. And I think they're going to gain a lot of confidence in this.

Got it. And then you talked some already about the all-oral regimen. Maybe if you can talk about Ninlaro and Pomalyst some more and provide your latest thoughts on the best existing comps from a commercial perspective out there for XPOVIO.