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

Good day. My name is Chad, and I will be your conference operator today. At this time, I would like to welcome everyone to Karyopharm Therapeutics Phase III SEAL study results conference call. There will be a question and answer session to follow. Please be advised that this call is being recorded at the company's request. I would now like to turn the conference over to Mr. Ian Karp, Karyopharm's Senior Vice President, Investor and Public Relations. Please go ahead.

Thanks so much, Chad, and thank you all for joining us on today's conference call to discuss the results from the Phase III SEAL study presented this morning at the Connective Tissue Oncology Society 2020 Annual Meeting. This is Ian Karp, and I'm joined today by Dr. Michael Kauffman, Chief Executive Officer; Dr. Jatin Shah, Chief Medical Officer; and Dr. Sant Chawla, Director of the Sarcoma Oncology Center in Santa Monica, California. On the call today, Dr. Kauffman will provide some opening remarks about the Phase III SEAL study and results; and then Dr. Chawla will review the key findings from the study, which were presented for the first time this morning at the CTOS 2020 Virtual Annual Meeting. We will then open up the call for Q&A, for which we'll also be joined by Dr. Mrinal Gounder, Sarcoma Service and Developmental Therapeutic Service at the Memorial Sloan Cancer Kettering -- Memorial Sloan Kettering Cancer Center, who is also a lead investigator in the SEAL study. Please note that Dr. Chawla and Dr. Gounder are not employees of Karyopharm and have been invited to participate on today's call as they were both investigators in the study and experts in the field of sarcoma. Their comments and opinions shared today are completely their own and do not reflect official statements from Karyopharm or their institutions. Earlier today, we issued a press release detailing the results from the Phase III study. This release as well as an accompanying slide presentation are available on our website at karyopharm.com. Before we begin our formal comments, and for those following on, on the slide presentation, you'll see on Slide 3. I'll remind you the various remarks we'll make today constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Act of 1995. These include statements about future expectations, clinical developments, regulatory manners, time lines, potential success of products and product candidates, including our expectations relating to the commercialization of XPOVIO. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent quarterly report, which is on file with the SEC and in other filings that we may make with the SEC in the future. Any forward-looking statements represent our views of today. While we may elect to update these statements at some point in the future, we specifically disclaim any obligation to do so even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today. With that, I'll now turn the call over to Dr. Michael Kauffman, Chief Executive Officer.

Thank you, Ian, and good afternoon, everyone. We are delighted today to discuss the positive pivotal results from the Phase III SEAL study, which met its primary endpoint with a significant increase in progression-free survival in patients with unresectable dedifferentiated liposarcoma. This is Karyopharm's first positive pivotal study in a solid tumor indication, and we believe represents a major advance to the development and commercial potential of XPOVIO in oncology. We are tremendously excited about the results presented virtually this morning in an oral presentation at the CTOS Annual Meeting and believe they are particularly encouraging because advanced dedifferentiated liposarcoma remains very difficult-to-treat cancer with no established standard of care and limited treatment options available to patients with heavily pretreated disease. Importantly, XPOVIO is the first oral therapy to show activity in a randomized trial in patients with previously treated liposarcoma. Before we discuss the SEAL study in more detail, I'd like to take a moment to briefly provide some perspective on the foundational and unique approach we are taking toward innovating cancer drug therapy. On Slide 4, we have highlighted 5 core pillars of cancer drug therapy, which are all foundational and used across tumor and patient types, often in combination to give each patient the best chance of clinical improvement. XPOVIO is the first approved anticancer drug whose primary activity is the activation broadly of tumor suppressor proteins. There are about 20 of these proteins, including p53, BRCA1 and 2, retinoblastoma protein and the inhibitor of NF-kB called IkB, which are a critical part of each cell's own natural defense mechanism to prevent the generation of cancer cells and to direct the cell which has become cancerous to commit suicide. This broad anticancer mechanism is potentially relevant to any malignancy. Our goal is to continue to demonstrate the impact that XPOVIO can have in combination with drugs from all of the other pillars in order to maximize the impact that XPOVIO can have on improving outcomes for a large variety of patients. Turning now to Slide 5. Our clinical strategy for XPOVIO continues to be to innovate with a purpose. Specifically, our approach has been to demonstrate meaningful activity in difficult-to-treat patient populations, and then to expand dramatically into earlier lines of treatment and additional tumor types, particularly in combination with other anti-cancer drugs. This strategy has been evident in our approach in both multiple myeloma and DLBCL, where we began our successful STORM and SADAL studies and has led to subsequent development in earlier line in combination settings. Similarly, now that we have seen the positive Phase III SEAL data, we plan to follow the same path and continue and expand our clinical development approach in a number of important and much larger solid tumor indications, including endometrial cancer with the ongoing Phase III SIENDO study, lung cancer, glioblastoma multiforme and melanoma, which have been selected based on encouraging clinical data and commercial potential. If you'll please now turn to Slide 6. Here we have an overview of soft tissue sarcomas, which are a diverse group of rare malignant tumors that originate from the mesenchymal cells within the soft tissues, including fat, muscle, nerves and others. As outlined in the left pie chart, liposarcoma, which occurs in the body's fat cells is the most common subtype and accounts for approximately 20% of all sarcomas. According to the National Cancer Institute, in 2020, about 13,000 new cases of soft tissue sarcoma will be diagnosed in the U.S. and over 5,000 Americans will die from this disease. Common first-line treatments for sarcomas include radiation, surgery and chemotherapy. Advancing now to Slide 7. We have a deeper -- we'll have a deeper dive into the current treatment paradigm for dedifferentiated liposarcoma, which is a high-grade type of liposarcoma that grows more aggressively than a low-grade well-differentiated liposarcoma. Dedifferentiated high-grade liposarcoma is associated with a poor prognosis. The median overall survival in these patients is unfortunately just 2.5 to 5 years. For patients whose disease is not fully resectable with surgery, first-line treatment is typically chemotherapy regimens, including doxorubicin, alone or in combination with ifosfamide. Our response rates are typically low and essentially all patients will need additional treatment options. In patients whose disease progresses following frontline therapy, typical treatments include trabectedin, where previous studies have shown a 2.2-month median PFS, and eribulin, which has been shown to have a 2.0-month median PFS in patients with DDLS. On Slide 8, we highlight that most sarcoma patients in the U.S. are treated at centers of excellence that have particular expertise in treating patients with these types of tumors. There are about 90 sarcoma alliance-affiliated centers in the U.S. and the SEAL study included patients at 26 of these sites throughout the country. In fact, the SEAL study was the largest trial ever conducted in patients with dedifferentiated liposarcoma. Should XPOVIO ultimately receive FDA marketing approval in DDLS, we believe we could effectively commercialize in this setting with a very small, tailored sales and marketing effort, primarily leveraging our existing infrastructure. I'd now like to ask you to move to Slide 9, where Dr. Chawla will detail the results from the SEAL study. Dr. Chawla?

Good day, everybody. I hope this COVID crisis is soon over and we have a good, better political climate, but we are very excited to hear the presentation for our patients who suffer from sarcomas. So dedifferentiated liposarcoma, sarcoma or all cancers are like criminals in the body and the low-grade tumors, which is like a well-differentiated liposarcoma, is like a low-grade criminal like pickpocketing, home robbery and other things, while dedifferentiated part is like a gangster. Not only it damages the organ where it is, but it's metastasized as it goes all over the body. So this drug is the first drug, we did a very rigorous randomized study in multicenter, largest number of patients and a unique drug which is not chemotherapy, which we have only used. Just to declare that I'm not employee of the company, as stated before, I don't have any conflict, and I devoted 25 years of my life in taking care of the sarcoma patients. I'm participant to this study as well as I have played a pivotal role in approval and a study of the previous drugs approved in liposarcoma such as trabectedin and eribulin. Now I'm on Slide 10. Selinexor, as stated by Dr. Kauffman, demonstrated antitumor activity in these cell lines preclinical studies. And in Phase I study, it showed impressive response of 40% as shown in the graph on your right side with the multiple patients. Now I'm moving to Slide 11. This was the largest study in 285, which is almost 300. 2:1 randomization, that means almost 200 patients received the actual drug and 97, which is almost 100 patients, received the placebo. Patient had to show that the tumor was increasing by the radiological means, which was confirmed by the blinded radiologists, that means they didn't know they were not blinded. They were obviously blinded from the results. And then the scans were performed on progress and confirmed progress and then the label was opened. And if the patients were on placebo, were crossed over to actual drug. The drug was oral, given 60 milligrams twice a week. Now I'm moving to the next slide, which is Slide 12. And inclusion criterias were standard that come from diagnosis, progressive disease within 6 months, and patients must have received at least 2 prior treatments, the standard treatment or doxorubicin and other chemotherapy, but maximum over 5 and standard lab criterias to be enrolled in the study. Patient were allowed even some mild renal insufficiency and creatinine clearance up to 30 ml per minute because this drug does not cause any nephrotoxicity. As Slide 13 shows the characteristics of both patients who are in selinexor group and placebo group. And as you see, they are reasonably well matched for age, sex, race, geographical area, performance status and site of disease. And majority, as you see, 80% were in retroperitoneum or in abdomen. And as you see in both groups there, about 70% had metastatic disease. Next slide, which is Slide 14. And again, continuing the characteristics of the patients, which were both matched both in selexinor (sic) [ selinexor ] group as well as in placebo group. Coming to the Slide 15 shows the randomization, the 285 patients, 187 to the actual drug. And it -- the patients -- the drug was well tolerated in majority of the patients but was discontinued in 57% in the -- because of disease progression, while in 69%, which is about 12% more because of the disease progression in the placebo group. Rest of the things are similar as shown here. Currently, 18 patients are continuing on the active drug on the selexinor. Next. This is the Kaplan-Meier curve, which shows the slight separation of the curve and showing there was significant PFS in selexinor, 2.83, which we expected 2.7 prior to the study start, and it made the criteria, while the placebo PFS was 2.07 with a 2-sided p-value of 0.02, hazard ratio of 0.7, that means 30% risk reduction in the relapse. This is significant, met the criteria, and it is similar PFS in the previously approved drug like trabectedin and eribulin. And next on the Slide 17, it shows the overall survival, which is similar and these cross at multiple places, although numerically, selexinor survival was 10 months and placebo was 12 months. And as we have said, they did cross those patients who are on placebo, did get selexinor. So it's not an appropriate comparison, but this is also not statistically significant. We are on the Slide 18, which shows overall survival, again, in the patients who were initially only received selexinor whether to start with or on the placebo. And as you see, selexinor group had a survival of about 10 months versus placebo, which is 9 months. Again, it is not statistically significant. Overall response is shown in the Slide 19. And as you see, the RECIST criteria showed that 2.7% of the patient in selexinor achieved partial remission, which is in definition more than 30% reduction in the tumor. But if you took the overall group, which is more than 15% reduction in the tumor was in 7.5%. While those 97 patients in placebo, there was no patient showed either more than 15% reduction or no more -- or no patient showed more than 30% reduction. So there was no RECIST criteria response in placebo group. This slide of 20 shows the overall response who did not cross over during open label. And finally, the 5.3% patients who achieved the response more than 50 -- let me say again. More than 15% reduction in the -- was seen about 5.3% of the patients who received selexinor after crossing over and 3.5%, which is similar, showed partial remission, more than 30% reduction in the tumor size. Overall, side effects were well tolerated, substantially less than any of the chemotherapy. There were no drug-related death. And if you see the Grade 3 and 4 in the right-hand column were in less than 10% and predominantly contained nausea and vomiting. Other mild side effects noted included fatigue and dysgeusia, which is the change in the test. Next slide. Serious side effects like anemia, thrombocytopenia was rare and anemia was in 8.2% which we do not -- which is very mild as compared to any chemotherapy -- I'm sorry, in 18% in selexinor group and 8.2% in the placebo group, and it's mostly related to the disease rather than the drug. But of course, mild anemia and thrombocytopenia or neutropenia can occur with the drug in less than 10% to 20%. Next slide. So in conclusion, this is the first novel drug, which is an XPO1 inhibitor-targeted drug, which has shown effective in dedifferentiated liposarcoma. We do not have any other drug specifically approved for this disease, although for liposarcoma, we use doxorubicin, trabectedin and eribulin. Overall [ effectivity ] of this drug was similar to them, and it is an oral drug. Future of the drug, this drug can be combined with other drugs. And as stated earlier, this drug has a unique mechanism of action so can be combined with chemotherapy, immunotherapy and is already approved in myeloma and Non-Hodgkin's lymphoma. So if you have any questions, I'll be happy to answer. And thank you for your participation in this call.

Thank you, Dr. Chawla. With the positive SEAL data now in hand, we look forward to submitting a new drug application to the U.S. Food and Drug Administration during the first quarter of 2021, requesting approval of XPOVIO to treat the patient population studied in SEAL. If approved, XPOVIO would represent the first oral nonchemotherapy agent available for patients with dedifferentiated liposarcoma. Beyond liposarcoma, as we think about other solid tumor indications on Slide 25, we show areas that we plan to explore. As I mentioned earlier, we are already collecting data from our non-small cell lung cancer, glioblastoma multiforme and colorectal cancer studies and have begun to explore additional settings where we'd like to initiate new studies. We plan to explore XPOVIO, either alone or in combinations in a wide variety of lines of therapy in clinical settings in the future, including an ovarian, endometrial, GBM, non-small cell lung cancer, colorectal cancer and melanoma. Ultimately, we view XPOVIO as a novel tumor suppressor activator and a potential pan-cancer drug that could become an important option for patients across both blood cancers and solid tumors. We see XPOVIO's greatest utility as a combination partner with other anticancer drugs and dosed only once per week in these combination settings. With that, I'll now turn the call back over to the operator for questions. Operator?

[Operator Instructions] And the first question will come from Brian Abrahams with RBC.

This is David Szeto on for Brian. Congrats again on the data and initial success in solid tumor. I guess just to start, you mentioned development in several solid tumors planned eminently perhaps next year. I guess I'm just looking for more color here. And maybe could you provide some color on where and how you might prioritize across these solid tumors, as you think about factors such as mitigating trial performance in this current environment with increasing COVID lockdowns? Or any regulatory considerations as you engage the FDA with liposarcoma data?

I think for the COVID lockdowns, hopefully, the vaccine will get out relatively quickly, and we'll be able to relieve some of the stress going on. But the fact is that these tumor cells keep dividing even in the pandemic, and these patients are in dire need of additional therapy and pretty much all of the solid tumor lines in the areas that we spoke about. The current ongoing studies are well supported by Phase I data from the company and/or investigator-sponsored trials that have been going on and where we're privy to some of the early data from those studies. And that's what led to the initial trials that we're carrying out right now in non-small cell lung cancer in combination with docetaxel and the combination with pembrolizumab in CRC and the ongoing studies that we have in glioblastoma multiforme now move from second and third line into first and second line. For additional tumors, we have demonstrated in Phase II study, single-agent activity in ovarian cancer. And we've also demonstrated single-agent activity in melanoma, and this melanoma activity was further strengthened by the investigator-sponsored trial results presented this year at ESMO from MD Anderson showing what appears to be at least additive activity of selinexor plus Keytruda in frontline melanoma. So basically, we're looking at the clinical data that are available to us and additional data that are not public, and we will be making decisions on -- going forward for the company-sponsored trials, including on the size of these markets and the overall unmet medical need. I don't know of any particular regulatory-specific hurdles that are in place at this time as essentially all of these tumors remain uncurable.

And the next question will come from Maury Raycroft with Jefferies.

Congrats on the updated data. First one is just on dosing strategy. So in HemOnc, I think part of the strategy there is to get patients to respond, and then you can optimize dosing for the patient and manage tolerability. Do you think the dosing used in SEAL is in line with what will be used in the real world in liposarcoma? Or is there some optionality possible in the real-world setting? And then for Dr. Chawla, I was wondering if you can talk more about combo dosing strategy that doctors might use in the real-world setting and what data from SEAL can potentially help guide how to combine other drugs.

Okay. Sure.

Let's start with Dr. Chawla because he may have to get off.

Yes. Dr. Chawla, are you still able to be on? I'm not sure? If not...

Yes. This drug is an oral drug, long half-life, given twice a week. So this is very easy to combine with all other drugs. Since the side effects are minimal of this drug, systemic toxicity of myelosuppression or immunotoxicity is minimal, I think it will be a very well combination effort and can be easily combined. And the real question will be the efficacy of this drug could be more efficacious and more synergistic, although our hope it will be because this is a unique mechanism of action.

Great. And briefly, Dr. Shah -- Jatin, maybe you can speak to our -- the MD Anderson study. I think we're doing combination work with eribulin there?

Yes, exactly. So we're developing combination data. I mean we're studying preclinically, there's data in combination with various agents. In the clinical setting, there's ongoing kind of investigator-sponsored studies, both looking at selinexor within than that, maybe in GIST sort of sarcoma subtype as well as with eribulin ongoing ISTs, and we're exploring other options as well.

And the next question will come from Peter Lawson with Barclays.

Just maybe for Michael initially, just your thoughts on the PFS that kind of dropped from Phase II to Phase III. Is there anything we should be concerned about? Is that just kind of a larger end number? Or is there anything else we should be thinking through?

Yes. I think our assessment -- a couple of points are very important. And the first one is that the PFS of trabectedin was reported at 2.2 months in an earlier population. The PFS of eribulin in an earlier population was reported at 2.0 months. So here now with the first nonchemotherapy, oral therapy, we're talking about a 2.8-month PFS, which doesn't sound like a lot, perhaps. But when you have this devastating disease and you're in third line with no options, this is pretty interesting that you could have a PFS that's in the range or higher than what's been reported in earlier therapy. And then I'll turn it over to Dr. Gounder in just 1 minute. I think the move from Phase II to III is just the numbers of patients and the more robust data set that we have now. Dr. Gounder, do you want to add anything?

Yes, absolutely. I'd like to echo a lot of the comments you just made. If you just look at -- this is really heavily pretreated patients who mostly -- they've all had doxorubicin, they've had eribulin or trabectedin now coming in, in the third line to the fifth-line setting. When we look at the retrospective data from many, many institutions, Sloan Kettering, MD Anderson, Europe for just the dedifferentiated liposarcoma patients, in the first-line setting with doxorubicin, the PFS is 1.5 to 2 to 2.5 months. These are all like in that ballpark. Even with combinations like, say, doxorubicin plus ifosfamide, the PFS gets a little better. But the vast majority of the median PFS in the first-line setting with doxorubicin-based agents is somewhere between 2 to 4 months at most. So in context of that, it's really surprising and very promising that in the third-line setting in patients who failed all these drugs, selinexor is performing just as well as doxorubicin, which frankly is really -- came to me as a big surprise, and I'm -- it is very encouraging, to say the least.

I would like to add the comment to Dr. Gounder's comment. When we talk about the improvement in the PFS about a month or a little less, it doesn't mean that everybody gets that much benefit only. There's obviously big range, and we have to decide some parameters as a PFS for improvement. If this was in the financial world, where everybody gets -- I mean, some people get rich, some people lose money, and that's how cannot be decided, but there are -- I treat the patients. So there are patients who can get long-term benefit for months and some patients even on trabectedin, eribulin and even this drug go for a year or 2 years. Of course, those are the minority of the patients. We just can't define at this stage, but that's what we are looking. And so the average improvement in a -- for about 4 weeks does not mean everybody only gets improvement in 4 weeks.

Yes. And if I just reiterate that, I think the other point -- another way to look at it is that the tail of these curves is that we're approximately doubling the people with the long-term benefits, which is quite important to those folks. And it's reminiscent, frankly, of other novel therapies, where the medians are perhaps less affected than an important minority of patients who have a real, real benefit that otherwise would be left without therapy.

Great. And then a follow-up for the doctors on the line. Just whether you could potentially use this, I guess, either in earlier line or outside of dedifferentiated liposarcoma, just your thoughts there based on the strength of the data you've seen.

Yes. Now if I could jump on that question. I mean, yes, the study was designed in the third line and beyond setting. But when you look at the totality of the PFS benefit, it's in line -- similar to drugs in the second line and even the first-line setting. So personally, when -- if I were to see a patient, there are many patients. I mean you can see here that many of these patients were 65 years of age, the median entry is 65, and 10% of patients were 75 years of age. These are patients who are -- have other comorbidities that could preclude drugs like doxorubicin, and we can only give 6 cycles of doxorubicin, then we have to stop for cardiotoxicity and then switch to something else. So I think in a case-by-case basis, one can make the argument to use this in an off-label setting for an individual patient. And of course, having that conversation with patients. I personally think patients would prefer a drug like this, given that it had no neutropenic fever, had an oral dosing convenience compared to a classic cytotoxic chemotherapy. Patients are always asking, are there oral pills for convenience or are there drugs that can -- that are targeted. I mean here, we don't know the exact precise target, but I think a lot of that work will -- hopefully, future work will show that even within this study itself. So in summary, I do think that we're not losing -- we don't have to wait till the third, fourth, fifth line before we think about this drug. I don't think I will be thinking about it in the event that this gets approved by the FDA.