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

Good morning, everyone. I'm Brian Abrahams, senior biotech analyst at RBC Capital Markets. Thanks, again, for joining us. Our next featured company is Karyopharm, represented by their CEO, Michael Kauffman; their CFO, Mike Mason; as well as Ian Karp, their VP of Investor and Public Relations. Thanks very much, guys, for joining us.

Great to be here. Thanks, Brian.

So maybe just kicking off on the clinical side. We're going to be seeing some data upcoming from your positive Phase III BOSTON study at ASCO in just a few weeks. You tell us a little bit about what we should be looking for out of XPOVIO in this data? And what you think is going to be most useful for physicians to determine how to best use the agent coming out of the presentation?

Sure. Thanks, Brian. As many of you are aware, the study was positive. We released top line data couple of months ago. And recently, the abstract came out. We had a statistically significant and very clinically meaningful delta between the progression-free survival for the triplet selinexor-Velcade-dex versus Velcade-dex. We also had a significant improvement in the overall response rate in deep responses and time to next therapy and a trend in a favorable direction for overall survival. Couple of points on the study, which I think doctors will be looking for, especially. First of all, the progression-free survival of the once-weekly SPd triplet will differentiate itself from the Vd, and they'll be looking at the graph because they'll be looking to see if this is a late effect and early effect for both. They will remember, and you'll all recall that this regimen is the first ever regimen to be tested in a large Phase III study for patients with relapsed myeloma that utilizes once-weekly Velcade in the experimental arm. The reason that's so important is because the actual use of Velcade in most places in patients with relapsed myeloma is once weekly. But all of the Phase III studies that either led to approval or major publications have been done with twice-weekly Velcade. So no one's ever sure what you're really going to get when you're using a modified regimen. We're the first people to do that to actually give the real regimen. And we show this remarkable benefit with a very simple regimen. The other thing that doctors will be looking for besides all of these important efficacy parameters is they'll be looking at the overall survival graph, which we think is even more meaningful because this is also the first trial to ever have crossover built into the study. So patients who progressed whose disease progressed on Velcade-dex were able to cross over to a selinexor-based regimen. And the fact that we're seeing a favorable trend in the overall survival even with the crossover suggests that the early use of selinexor is beneficial. And they'll also look at the subset analyses to see what kinds of subgroups patients are most likely to benefit from this regimen. On the side effect profile, we've said this is in line with what's been reported recently. And in the past, with selinexor, they'll want us to have some interest there, and they'll be looking at the dropout rates as well.

Got it. That's really helpful. And looking forward to seeing that data for sure. Maybe shifting to the commercial side. Can you talk about, in general, some of the different pushes and pulls of the -- in the launch and really of the pandemic that you're seeing on the commercial dynamics? And how significant have the headwinds been to overall access, reimbursement, monitoring and physician engagement?

Yes, this is Ian. Maybe I'll start, and Michael can comment on some of the physician monitoring aspects. But certainly, from a commercial standpoint, we continue to be quite pleased and encouraged by much of the data that we continue to see, particularly from our specialty pharmacy providers that are providing XPOVIO to patients. Specifically, the refill rates continue to be strong. The dropout rates, specifically due to side effects, continue to improve and are much lower in the real world than what we had seen in the STORM study itself. So what we're seeing is that patients that are on therapy or that have been on therapy are doing particularly well, and the average number of cycles or the average number of prescriptions continues to grow each quarter since we launched in July of last year. I think the dynamic that we saw in the first quarter not so much that there was a drop-off in usage because end patient demand or the number of prescriptions generated was essentially flat quarter-over-quarter from the fourth quarter of last year to the first quarter of this year. Where we did see the biggest impact from COVID-19 was really just in new patient starts. And what we were expecting was a lot greater number of new patient starts in the month of March. And to be honest, that was lower than we had expected, primarily due to a combination of fewer patients going in to see their oncologists or initiating new therapies or delaying treatment or delaying visits to their oncologists as the COVID-19 pandemic was kind of really getting kicked off in earnest in March. And we also know that our sales force was out of the field beginning in March. And we have a new drug with a new mechanism of action, and that requires discussion and education with physicians. Now we were encouraged. So we think those 2 factors impacted the number of new patient starts in March, particularly, again, not that we saw this dramatic decrease but just we didn't see the significant increase that we were expecting. We have said publicly on our earnings call, we were certainly encouraged by the trends we've seen in the month of April. So we do think perhaps the worst is behind us in terms of these access issues. But again, we'll follow, obviously, additional months of data, but we feel very good about ASCO coming off and additional data to be disseminated and the benefits that XPOVIO presents to patients and physicians.

Got it. And can you maybe talk a little bit more about sort of what you're seeing in terms of lingering or kind of ability to manage through these COVID-19 effects? I guess, are you -- are you continuing to see -- are you seeing a continuation of some of these encouraging demand trends that you saw in April? And I guess, what are you learning overall about the penta refractory market based on what you're seeing with respect to durability of treatment and overall, new patient starts?

Yes. We think that people are getting more comfortable with the drug. Certainly, we feel like some of this advice that's been given by many of the different cancer councils regarding the use of oral therapies when a patient could have a choice and may be starting to catch on. I think what Ian said is really important, though, is that to remember that when someone's given a choice -- doctors given a choice between starting a drug, they barely ever or never used versus something they're comfortable with. Even under the current circumstances, they generally will take the more well-known course. But I think we're starting to see some -- make some headway in that regard. As Ian mentioned, the patients that are already on the drug have been staying on the drug. We're very encouraged by the refill rates, et cetera, et cetera. So we don't think that's a problem. And we also believe that the fact that we're testing lower doses of this drug against the SARS coronavirus gives people some confidence that they're probably not going to be harming their patients. If they're exposing them to XPOVIO during this pandemic and possibly might even have some benefit, but that remains to be seen in the trial. I think some of those headwinds are starting to go away, but our biggest challenge is still to get the new prescriptions up. We were in the 6 months of launch when this -- during the quarter when things started to go south with the pandemic, and that's what really, I think, hit us. But we're starting -- we feel like we're starting to see some improvement.

Got it. Can we talk about safety and tolerability a little bit, if you look at the adverse events database by the FDA, it looks like there's a relatively recent decline in the number of entries, which seems consistent with the feedback you've described from physicians and patients. So I would love to hear a little bit more about maybe just reminding folks how the -- what the tolerability looks like in the real world? How it's being dosed in BOSTON relative to the penta refractory population? And I guess, how you're able to best help physicians manage through some of the side effects in light of some of the limitations and challenges of the pandemic and the limited ability to have face-to-face interactions?

Yes. So maybe I'll start sort of in the middle, Brian. And I think the most important point about the side effects with XPOVIO is while there are a lot of side effects, they really are side effects rather than sort of toxicities. And when I say toxicities, I mean things that can leave you impaired for a long time or even permanently, we see nausea, anorexia, fatigue and low platelets that can recover. Those are our main side effects. All of those side effects, maybe except for fatigue, which is also part and parcel in myeloma are preventable and treatable and reversible. So for example, if -- we don't really talk about, for example, treating nausea due to platinum therapy because we're all -- we all know that you have to use 3 drugs or 4 drugs, and you can completely prevent nausea from platinum therapy. But our drug is nowhere near as emetogenic as platinum, and the trick is really to get doctors who are not -- myeloma doctors are not used to treating patients with anti-nausea agents because the current myeloma drugs, except for the alkylating agents do not cause nausea. And so really, it's just getting people comfortable and to remind them that everybody should be started on standard HT3 antagonist like Zofran and that Zofran needs to be continued to the second day. This is an oral drug. You take it 3 times on day 1 and twice on day 2, and you're done. If a patient still has nausea, there's no reason for that patient to continue to suffer. You can add a second drug like an NK1 blocker or olanzapine. Olanzapine has a very nice added side effect in -- especially in myeloma, that it seems to help with some of the steroid-induced psychosis. And we all remember that every regimen in myeloma utilizes high-dose steroids, relatively high-dose steroids. So olanzapine turns out to work nicely for that. It's also part of the treatment for anorexia, which is one of our side effects. So we recommend that every patient we started on a 5-HT3 blocker as well as for any patient who has any anorexia or is at risk for it that they start low-dose olanzapine as well at night. And that can really essentially eliminate nausea. That also can eliminate -- the olanzapine can eliminate anorexia and as you might imagine, if people are eating better, their fatigue starts to decline, and you're back to sort of baseline myeloma fatigue, which unfortunately is prevalent in patients with especially penta refractory disease. The platelet counts, lastly, again, are both reversible and preventable. Although off-label, we have learned and we have published, and we are continuing to publish evidence that the use of mid to high doses of thrombopoietin receptor agonists, such as romiplostim or Nplate, can help mitigate thrombocytopenia due to selinexor. This is an on-mechanism inhibition by selinexor of STAT3 signaling and megakaryocytes. And it's well-known that the TPO agonist can bypass that mechanism and lead to continued platelet production even during continued therapy. So these are really preventable, just like we use GCSF to prevent neutropenia with chemotherapy and with lenalidomide, Pomalyst, et cetera, we can use TPO agonist again off-label, but more evidence is accumulating, and there are numerous publications now across the board for chemotherapy and targeted therapy induced cytopenias with the use of these agents. The BOSTON regimen is an entirely different story. The STORM regimen, the patients penta refractory are current label, utilizes 80 milligrams of XPOVIO plus dexamethasone twice a week. That's the highest dose we ever use. In BOSTON, we're dosing once a week. We're dosing 100-milligram starting dose with once a week Velcade and 40 milligrams of dexamethasone, which can be given either once a week or 20-milligram split day 1, 2, which is generally tolerated better by patients, but it's oral, so it doesn't matter. And that once a week regimen with selinexor is very well tolerated relative to the higher doses in patients that are more beaten up. Unfortunately, penta refractory patients have gone through an awful lot in a study, there were about 8 prior regimens. What you're seeing, I think, in the field, FDA websites and our reports through our pharmacovigilance is that doctors are getting better at preventing the relatively simple side effects of XPOVIO. They also can dose modify. And lastly, in some cases, doctors do choose to use XPOVIO once a week, often in combination with other agents, allow the BOSTON regimen with Velcade or other regimens we've focused on. So in the end, the side effects are dose and schedule dependent. They're preventable, they're modifiable and they're reversible. And we really can have patients on for a while, as long as they continue to take the drug and have the appropriate supportive care.

Great. And then maybe moving on to the DLBCL indication, another late-stage indication for XPOVIO. Can you talk a little bit more about the ongoing regulatory process there? And how you guys are thinking about the launch strategy, assuming accelerated approval? And I know it's a very different market from myeloma. So I'm curious how you're planning to tackle that.

Yes. I'll start, and then Ian will talk about the launch a little bit. This is another big unmet medical need. There's about 25,000 new cases a year of DLBCL. About 60% of them overall are cured. Or at least have long-term disease remissions to the tune of about 15,000 of those 25,000 patients are going to be out of danger from the disease, at least initially. So you're left with about 10,000 patients per year. And unfortunately, unless you can have CAR-T and have a durable complete remission or the small number of patients who have a durable complete remission after a high-dose chemotherapy and stem cell transplant, you're unfortunately going to die from DLBCL. So that leaves you about 10,000 patients per year who are in trouble. Of those, those patients tend to live about 2 years on average. So it gives you about 20,000 patients overall who can -- who need additional therapy, and there's a bunch of different second-line therapy as well as what I mentioned, CAR-T and then high-dose chemotherapy and transplant. We believe that we're hopeful to get a third-line indication that is after 2 prior therapies in patients who are not eligible for transplant or CAR-T therapy. We're hopeful just to get both transformed and de novo DLBCL, which would be a unique aspect. This was part of our protocol. So we're hopeful to see that. And importantly, we had about a 28% response rate that we've disclosed, and we had about an 11%, 12% complete remission rate. And the durability overall of the responses was 9 months with the CRs about 23 months. So this is a very different kind of a therapy. If we do get approved, this will be the first and only oral therapy ever approved for relapsed DLBCL. This will be the first single agent ever approved for DLBCL. And whereas it's not the right therapy for everybody, it's certainly a welcome, we believe, would be a welcome addition to an armamentarium, which is currently all parenteral therapies, plus or minus some orals, and requiring prophylaxis for chemotherapy and so on and so forth and clinic visits, et cetera, and this is particularly relevant during this pandemic. Let me turn it to Ian now.

Yes. I think in terms of the commercial launch, we're really excited about the prospects here. As you may know, there's a significant overlap in the treater -- in the base of treaters particularly out in the community setting, where myeloma treaters are also lymphoma treaters. And so we think we are starting already with a base of particularly out in the community physicians who have used or are aware of XPOVIO for myeloma. We think that the proposition and the benefits in lymphoma patients will be clear, again, especially for those kinds of patients, older patients, who have been out through multiple rounds of Rituxan chemotherapy-based regimens or now what some have gotten is a bendamustine-Polivy regimen, that many of these patients are looking for a novel mechanism, are looking for an oral mechanism you may recall that the regimen for SADAL for DLBCL is a lower dose. It's 60 milligrams twice a week. There's no dexamethasone. It's relative to the data that we've seen in STORM. It's much better tolerated. And the patients who respond well tend to respond really well, which is why you've seen 11%, 12% CR rates. And durability of those responses for the complete responders is out 23 months. So we think this will be a really welcome drug, again, particularly in the community setting, we'll do a confirmatory Phase III study, which we've talked about, which will be a combination study with Rituxan chemotherapy, which will be a more aggressive therapy. So ultimately, we think that, that will be needed, and there'll be many patients to who'll want that kind of regimen. But we think in the initial launch, there is certainly a sizable patient population that will fit quite nicely with the product profile of single-agent XPOVIO for DLBCL.

Got it. You're also looking at XPOVIO for COVID-19, as Michael, I think, you alluded to earlier in our discussion. Can you talk a little bit more about the progress with that study? And how you guys are thinking about that from a prioritization and capital use standpoint? Is that something you might expect to monetize down the line? How is that study going overall? When might we see the results?

So the study was initiated very urgently following both internal analyses as well as external laboratory data that showed direct antiviral effect as well as data that we had that we had specific anti-inflammatory effect on reductions of IL6, IL1, TNF-alpha and other cytokines. That we already knew. And this -- we had a number of programs ongoing preclinically with influenza and other respiratory viruses. And a marked activity in those situations. And there's a lot of overlap in terms of, at least in the serious end-stage disease in patients with severe influenza versus severe COVID-19 because at the end, you end up with severe disease with respiratory failure. And a lot of it's due to the overexuberant inflammation that you get with both of these viruses. So anti-inflammatory effects plus anti direct antiviral effects. Those antiviral effects have now been confirmed by several laboratories. Another paper just literally came out last day showing, again, very high potency in the 100 nanomolar range. And what we know is that low doses of selinexor, that is 20 milligrams can deliver about 300 to 350 nanomolar in the blood, so well above that 100 nanomolar target. We opened up the trial several weeks ago. We've enrolled a good number of patients where we have multiple tens of patients. We passed our first safety review. So we're not seeing any major or significant safety issues with this low dose. It's very well tolerated. It is a blinded, randomized study. But the DSMB has reviewed all the data and there are no issues. And we're going to continue to enroll. We do have a couple of interim analyses, which we're not going to go into today. And if we see efficacy, as measured by a change in the so-called ordinal score, then 2-point change in the ordinal score, then we'll be able to disclose this and hopefully bring this drug out for patients suffering from -- hospitalized patients suffering from severe COVID-19. I'll turn it to Mike now to talk a little bit about steps after that, if we do have positive data.

Yes. I think it's a little too early to comment on the commercialization side of it. We're certainly working behind the scenes. But I think from a capital allocation perspective, as we said in our Q1 call, we're going to -- we're able to fit this spend into the previous spend guidance we gave and still come out on the lower end of the range. We have ample supply of selinexor to use for the study. So it's really just about running the clinical trial.

Great. And then just wrapping up in the last minute or 2, what do you think is going to be the biggest surprise for physicians or even for investors out of the BOSTON data at ASCO?

I suspect there'll be a lot of interest around the subgroup analysis. The drug has a reputation for being difficult, maybe less well tolerated in people that are older or frail. I think those will be interesting data. I think there'll be some interesting data around patients who have high-risk chromosomal abnormalities and how we perform against standard twice-weekly Velcade. In the end, we feel the data are extremely consistent. This was a remarkable study conducted across essentially the entire world, except for the Far East. I mean we have patients from India, Australia as well as North America, Western and Eastern Europe and Israel. And it was really a remarkable study for a company of our size to conduct. And the consistency of the data will be, I think, well appreciated.

Great. Well, that takes us to the top of the hour. So thank you guys so much. Congrats on all the progress. Obviously, a lot to look towards over the next couple of quarters. So looking forward to that. And thanks again, everyone, for listening. This ends the session. Thank you.

Thanks, Brian.

Thank you.