Good morning. My name is Sheree, and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics COVID-19 Clinical Trial Initiation 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 call over to Mr. Ian Karp, Karyopharm's Vice President, Investor and Public Relations.
Thank you, Sheree, and thank you all for joining us on today's conference call to discuss the initiation of a new clinical trial to evaluate low-dose selinexor as a potential treatment for hospitalized patients with COVID-19. This is Ian Karp, and I'm joined today by Dr. Michael Kauffman, our Chief Executive Officer, Dr. Sharon Shacham, President and Chief Scientific Officer, and Dr. Jatin Shah, Chief Medical Officer. On the call today, Dr. Kauffman will provide a brief overview of the scientific rationale for our new clinical trial in patients with severe COVID-19, and then we will open up the call to help answer your questions. Earlier this morning, we issued a press release detailing Karyopharm's initiation of a new clinical trial in severe COVID-19 patients. This release is available on our website at karyopharm.com.
Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. These include statements about our future expectations and plans related to ongoing or potential clinical trials, clinical development, and regulatory matters and timelines, the potential success of our products and product candidates, including our expectations related to the commercialization of XPOVIO, financial projections and our plans and prospects.
Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including the risk that the COVID-19 pandemic could disrupt Karyopharm more severely than it currently anticipates, and those discussed in the Risk Factors section of our most recent annual report on Form 10-K, 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 as of today only. While we may elect to update these forward-looking 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.
In addition, please note that any references we make to clinical trial data during today's discussion refer to interim, unaudited site data, unless otherwise specified. I'll now turn the call over to Dr. Michael Kauffman, Chief Executive Officer.
Thank you, Ian, and good morning, everyone. It goes without saying that we are living in unprecedented times as we all grapple with the impact of the current COVID-19 pandemic. To all of our friends, colleagues, and those new to Karyopharm, we hope you are keeping safe, healthy, and navigating the current situation as best you can. Of course, the global healthcare community is playing a particularly important role during this ongoing crisis, which brings us to the reason for today's call. Whether it's the healthcare workers on the front line, the manufacturers of protective equipment and diagnostics, or those pharmaceutical companies like Karyopharm identifying and developing potentially effective treatment options for patients with COVID-19, the medical community is putting tremendous efforts behind alleviating and resolving this current pandemic.
It is therefore, with a great sense of optimism and pride that we announced earlier this morning that Karyopharm has decided to initiate a global randomized clinical trial evaluating low-dose selinexor to treat hospitalized patients with COVID-19. For those most familiar with Karyopharm, you are likely aware that our clinical development strategy until now has been focused on treating patients with various types of cancer. Our lead medicine, selinexor, marketed as XPOVIO in the U.S., is currently approved at higher doses than are going to be used in this current COVID-19 trial by the Food and Drug Administration as a therapy for patients with heavily pretreated, relapsed, or refractory multiple myeloma. selinexor is an oral selective inhibitor of nuclear export, or SINE compound, which blocks the cellular protein XPO1, or Exportin 1.
In addition to its roles in cancer, Exportin 1 may also be an important target in treating viral infections by impacting two distinct mechanisms: antiviral and anti-inflammatory pathways. Exportin 1 facilitates the transport of several viral proteins from the nucleus of the host cell to the cytoplasm, and it amplifies the activities of pro-inflammatory transcription factors. SINE compounds, which blocks Exportin 1, have been shown to disrupt the replication of multiple viruses in vitro and in vivo. They have also been shown to mediate anti-inflammatory and antiviral effects, including in respiratory infections in several animal models. In particular, SINE compounds have recently been identified as having the potential to interfere with key host protein interactions with the SARS-CoV-2 virus, the virus that causes COVID-19. In the past, the majority of pre-clinical work in viral infections was conducted with another one of our SINE compounds, or Exportin 1 inhibitors, called verdinexor.
Verdinexor is a closely related molecule to selinexor. They both have similar chemical, pharmacological, and pharmacokinetic properties, including similar oral bioavailability. Because time is clearly of the essence and we have already tested selinexor in over 3,000 patients with a variety of advanced cancers in clinical trials alone, we have decided to initiate a new clinical trial to evaluate low-dose selinexor in patients with severe COVID-19 infection. Additionally, because we already have sufficient supply of selinexor today, we can begin this trial immediately, and should it prove successful, we have the ability to ramp up production of selinexor much more quickly.
Importantly, Exportin 1 inhibitors have previously demonstrated activity against over 20 different viruses, including the RNA viruses influenza, respiratory syncytial virus, and other common causes of respiratory infection. Very recently, XPO1 inhibition has been identified in several assays as having potential activity against SARS-CoV-2, the virus that causes COVID-19, although specific animal models have not yet been available. One of the most important aspects of COVID-19 is the marked pulmonary inflammation with high levels of cytokines such as IL-6 and IL-1. Along these lines, selinexor and other SINE compounds have demonstrated potent anti-inflammatory activity through the inhibition of nuclear factor kappa B, also called NF-κB, leading to reductions in all of these cytokines in a variety of models, and this may be particularly beneficial to hospitalized patients with COVID-19.
The most common side effect of selinexor, particularly at the higher doses used in its currently approved indication in patients with relapsed or refractory multiple myeloma, are nausea, vomiting, anorexia, low sodium, and low platelets, which are generally dose-dependent and reversible. We do plan on studying a significantly lower dose of selinexor in this COVID-19 trial and anticipate selinexor to be well-tolerated based on two previous phase I clinical studies using this lower dose. There's already an expansive safety database of selinexor across all ages, including in the elderly and pediatric populations, at higher doses of selinexor used in oncology indications. There are also no known clinically significant drug-drug interactions with selinexor, which could prove to be important as a number of other experimental drugs are also being used and studied to treat patients with severe COVID-19.
Lastly, I do want to reassure our patients and healthcare partners within the cancer community that our announced clinical trial in COVID-19 is not expected to impact the timing or prioritization of other key Karyopharm goals, including the planned submission of an sNDA for XPOVIO in combination with once-weekly Velcade, also called bortezomib, and low-dose dexamethasone as a new second-line therapy for patients with previously treated multiple myeloma based on the BOSTON phase III trial. This planned sNDA submission remains on schedule for the second quarter of 2020. Additionally, we remain on track and are actively supporting the sNDA that we had previously submitted seeking accelerated approval for selinexor as a new treatment for patients with relapsed or refractory diffuse large B-cell lymphoma, also called DLBCL.
Finally, Karyopharm has sufficient supply of selinexor for current and expected commercial patients with multiple myeloma for ongoing clinical trials in patients with various cancers, as well as for this proposed study in patients with COVID-19. Before we open the call up for your questions, let me summarize what we've just announced earlier this morning. First, within the coming one to two weeks, we expect to dose the first patients in a new global randomized clinical trial to treat patients with COVID-19 with low-dose selinexor. There is a tremendous amount of existing, including some very recently published preclinical and new clinical data to support the evaluation of an XPO1 inhibitor in patients with severe COVID-19. Third, XPO1 inhibitors have been shown to disrupt the replication of multiple viruses in vitro and in vivo.
XPO1 inhibitors have demonstrated potent anti-inflammatory activity, which may be particularly useful in patients with severe COVID-19. Fourth, this new clinical program is not expected to impact the timing or execution of other critical Karyopharm objectives and milestones expected in 2020 related to our oncology pipeline. Lastly, Karyopharm is committed to working as quickly and as effectively as possible to help the world medical community address this ongoing COVID-19 pandemic. Our team is committed to making a difference in helping advance our understanding of how best to treat patients with severe COVID-19 disease, as well as with various cancers. We are all approaching this latest challenge with a great sense of urgency, and we are already collaborating with clinical sites across the globe, including in Europe, Asia, Israel, Australia, and here in the U.S., to begin this trial as quickly as possible in the days and weeks ahead.
With that, I'll now turn the call back over to the operator so we can answer your questions. Operator?
Thank you. As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question will come from Brian Abrahams with RBC Capital Markets. Please go ahead, sir.
Hey, guys. Thanks for taking my questions. Yeah, it's nice to see this moving into a COVID-19 study, given some of the emerging evidence for XPO1 as a potentially important target here. Just a few questions from me. I guess, first off, maybe bigger picture on trial design. Can you give us a sense of just the size of this study, the timelines, where you're planning to conduct it, and the endpoints you'll be looking at?
Sure. I'll start, and let Jatin add more information, specifically regarding time points. The study will include 230 patients. We will conduct it in eight to 10 countries in North America, in Europe, and Israel. We are planning to start this to hopefully dose the first patients within the next two weeks. Regarding time points, Jatin, do you want to elaborate?
Yeah, absolutely. Regarding the endpoints on the study, we'll be consistent with what's established by the WHO criteria as well as other large NIH studies in this space. The primary endpoint will be time to clinical improvement, looking at the WHO Ordinal Score, which is a really clinical relevant endpoint in terms of outcomes for patients. That's an eight-point score ranging from death all the way to discharge from hospitalization on the outcome of the patient. We'll be looking at a number of other secondary endpoints as well in the challenging, currently in the COVID-19 clinical trial design in terms of the optimal outcomes. There's going to be a number of secondary endpoints that we'll look at as well to identify clinical benefit.
Got it. That's really helpful. I guess on the mechanistic side, I guess you mentioned NF-κB. Is your view that this is primarily going to be anti-inflammatory through cytokine reductions via NF-κB, or whether or not this is acting more as a direct antiviral by preventing trafficking of some of the viral proteins like N and 3B?
We do assume that there will be a strong anti-inflammatory activity by reducing cytokines through inhibition of NF-κB and other related mechanisms. There is evidence, there is supporting evidence for antiviral activity for SINE compounds in many viruses. We tested over 20 of those, and it all falls within this concentration that we hope to achieve in humans. This includes RSV, influenza, and other viruses. The evaluation of selinexor directly in assays in vitro and in vivo for SARS-CoV is ongoing now, but there are several papers that were published in the last two to three weeks that suggest that XPO1 is an important host protein for the propagation of the SARS-CoV virus.
Specifically in one of these papers that was published about two weeks ago, they looked in a biochemical assay, looking at the interaction of the proteins from the SARS-CoV and the host protein, and in that assay, the SINE-related compound of selinexor was able to inhibit those interaction between the virus and the host protein. We hope that there is also a direct antiviral activity. We are testing it right now.
Got it. One last one from me, if I could. Just on the PK/PD side, can you talk about the doses you're going to be moving forward with and how you selected those, how you mapped those based on some of the in vitro and then prior phase I work? How much do we know about selinexor's distribution to the lung, to the target tissue here? Thanks.
The dose that we are looking at is 20 mg three times a week, a total dose of 60 mg weekly. When we are looking at the concentration, we have to remember first that this is a covalent inhibitor that binds to a cysteine residue on XPO1 and form a slowly reversible bond with a half-life in vitro of 24- 48 hours. This half-life, we confirmed it, looking at target occupancy through our pharmacodynamic assay and in other pharmacodynamic assays, such as increase in XPO1 mRNA, that really this biological half-life, we can demonstrate it in vitro, in vivo, and even in white blood cells from patients. Which leads us to believe that if we achieve the concentration that we need at 20 mg, we can sustain this effect for 48 hours, and therefore, we are going to dose 20 mg three times a week.
Thanks again.
I should also mention that at that dose, in patients from our phase I study, we did see clear anti-cancer activity. It is an active dose.
Thank you. Our next question comes from Maury Raycroft with Jefferies.
Hi, everyone. Good morning, and thanks for taking my questions. First question is just based around the drug-drug interactions. You mentioned that you don't see that with selinexor, and with antivirals, you typically see more success with combination regimens or antiviral cocktails. In one of the papers you mentioned you reference in the press release, it shows unique activity versus two of the viral subunits, NSP4 and then ORF6. Just wondering if there's rationale for a few optimal combo partners for selinexor in this setting, and does your protocol provide some sort of potential to expand into combination options?
Yeah. This is still early stages, obviously, of treating this disease, both in animal models and obviously humans. In some ways, the humans have outstripped the animal models, which are not great right now. We don't have a specific combination that we know or we think is going to be more effective. What we do know, at least from the cancer side, is that selinexor does combine very nicely with a multitude of different anti-cancer agents, both targeted therapies as well as chemotherapy. There's no specific restriction on what other therapies the patients can have. We intend to deal with concomitant antiviral and/or anti-inflammatory agents that are being used in these patients through our randomization procedure and stratification, and we're allowing other agents to be used.
Got it. That's helpful. The other question I had was just on verdinexor. If you can recap what happened with verdinexor development as an antiviral? Was there an efficacy or safety threshold that was not met, or was it just a matter of prioritization and Karyopharm's decision to focus on oncology?
It's essentially the latter. We did see a clear efficacy in all the animal models that we looked at in terms of influenza. We saw, by the way, the minimal efficacy dose in these models was five mg per kg, which fits very nicely with the 20 mg dose of selinexor that we are going to use in this study. Some of the other exciting things that we saw in that model in influenza is that we can dose as late as four days after the initiation of infection, which again, might be very relevant if this is also happening in this disease. We saw increase in overall survival and rescue of lung injury, which is again, relevant to the COVID-19. We did move into a phase I dose, phase I study in healthy volunteers. We have not reached the MTD in that study.
We dosed all the way up to 40 mg in the same dosing that we are planning now for selinexor. We saw that the PK was dose proportional and similar to what we expect based on the selinexor data, and that we show target engagement in terms of the pharmacodynamics assay, again, similar to what we expected based on the phase I with selinexor. At that point, we stopped the development to prioritize the development of selinexor in oncology. We were ready essentially to move into phase II in patients, phase I and II.
Got it. That's very helpful. Thank you for taking my questions.
Thank you. Our next question will come from Jonathan Chang with SVB Leerink.
Hi. Good morning, guys. This is David Ruch on for Jonathan. Congratulations on the update and thanks for taking our questions. First question is, will the timing of the treatment intervention impact the efficacy in COVID patients? The mouse data show activity given up to four days post-infection. I guess in your mind, what is the expected window where you think selinexor might be efficacious in humans post-infection?
Yeah. It's very difficult to know with all that's going on in these patients. The fact that it was active in that model, in the influenza model, that verdinexor was active four days after. You note from the figure that was in the press release that Tamiflu works in that model, but it has to be given immediately in that particular model when the high dose of influenza is given. We can delay verdinexor by four days, which is frankly pretty extraordinary in that kind of a model. Obviously, most of the patients coming into the hospital who are now hospitalized with COVID-19, given the situation and the lack of beds, et cetera, most likely will have had their infection for seven to 10 days, unfortunately, were not recovering. It's going to be a fair amount of time coming in.
That said, the problems that people get into that are mediated by inflammatory cytokines really start to erupt in this timeframe. Because our drug has a dual mechanism of action, potentially we'll have not only the antiviral effects, which may be important earlier in infection, but certainly later as the virus continues to propagate. Importantly, that we hit multiple cytokines at once. The multiple cytokine effects might be the most relevant in these later stage patients, where it seems like the immune response and the inflammatory response is perhaps worse than the infection itself.
Got it. Just to that point, a little bit further, how similar or different are verdinexor and selinexor in exporting the COVID proteins from the nucleus?
Well, in terms of the structure, they are very similar. They differ by one atom. In terms of their Exportin 1 inhibition, selinexor has an IC50 all the way between 20-40 nanomoles, and verdinexor is around 30 nanomoles. They're very similar. In all the other properties in terms of ADME and PK, they are very similar as well. In terms of inhibiting the interaction of the host protein with the cell's COVID protein, only verdinexor was evaluated. We are evaluating selinexor right now in several in vitro assays related to SARS-CoV.
Okay, great. Just last one from us. Given the selection of the low dose, you talked about this earlier, what do you expect the side effect profile can look like in non-cancer patients? Specifically, are there any comorbidities that might need to be excluded from the population? Thank you.
The study is going to be very liberal in terms of who's allowed into the study. As far as side effects, we know at this lower dose, both from our oncology studies during the dose escalation phase and Dr. Shacham mentioned that there was anticancer activity even at the 20 mg three times a week dose, including some partial responses in patients with lymphoma. We see very good tolerability. It's primarily very low grade, if present at all, nausea, some reduction in appetite, but no weight loss, and the occasional cytopenia, typically grade two, at those doses, even in patients with heavily pretreated cancers. We don't expect to see a lot in our patients here, and that was confirmed also in the verdinexor low dose study, that phase I study in normal volunteers that she mentioned, where the 20 mg three times a week dose was very well tolerated.
Thank you. Our next question will come from Eric Joseph with JPMorgan.
Hi, guys. Thanks for taking the questions. I guess just following up on dosing and the primary mechanism of action you think is at play here. I just want to just clarify that at the doses that you're testing in the clinic, do you expect an impactful antiviral effect with selinexor? Are you going to be assessing viral load in the trial? I'm just wondering also whether there might be a prep or prophylactic application with selinexor here at higher risk populations.
To answer your second question, we are going to test the viral load. The study will include patients that have severe COVID-19, and they will have to prove in a COVID-19 assay that they have the infection. We will monitor that throughout their treatment. We are still looking at the frequency of how many times we will evaluate that, but we will definitely monitor dose of selinexor given three times a week, assuming that this activity that we saw for other viruses with selinexor will translate also to SARS-CoV.
Thank you. Again, ladies and gentlemen, if you have a question at this time, please press the star, then one key on your touchtone telephone. Our next question will come from Ed White with H.C. Wainwright. Please go ahead.
Good morning. Thanks for taking my question. Just going back to a follow-up on Brian's question. Looking at the timeline, can you give us an idea as to, I know you haven't enrolled any patients yet, but when we'll see first data? Are you going to be taking an interim look at the data from these 230 patients? Are you thinking of this as a registrational type trial in the current market in trying to rush treatments in for COVID-19?
I'll answer related to the monitoring of safety. This is, of course, our first priority, like in every other study, is to make sure that the safety of our patients is conserved. We will have a DSMB that will be set from day one of the study. The DSMB, together with us and the investigator, will monitor the safety of our patients very carefully and probably on a more frequent basis than what you do in other studies.
In terms of the path after, one thing that's been remarkable about this is how the FDA, the Europeans, the Israelis, the Australians, frankly, across the world, the regulatory bodies in these places as well as the clinics and the physicians and other site staff have worked really on a timescale that I've never seen in my 20+ years in this business. People are moving, and it's been a very collaborative working relationship with all of these regulatory bodies. We're all looking for the best path forward here. You saw some emergency action taken on hydroxychloroquine. You see a lot of stuff going on. You see many trials. You see collaborative group studies, and we're in discussions with some of them. It's a long-winded way of saying let's get the data. We'll keep you posted on when we think we can have the data, and we'll see what happens.
I do believe that people are all working to try to get novel therapies to as many people as quickly as possible. I don't want to speak to when, whether it's registrational path or not. It is a randomized study.
Okay. Thanks, Michael. I know this is a COVID-19 call, but I'm just wondering if you can give us any update as far as has there been, due to the pandemic, any impact to XPOVIO sales? Also how you're thinking of launching in DLBCL, provided you get it with the pandemic procedures in place around the healthcare system.
Sure. In terms of current impact to the existing business from COVID-19, I would certainly say no company is unaffected by what's going on. I would say there's a number of factors that we certainly feel very fortunate about. Namely, some of them include, obviously XPOVIO was launched last year. We have ample supply of the drug. It's an oral drug that can be shipped to patients' homes. All of those things bode quite well for our existing business. As you know, the BOSTON data, the top-line data read out earlier in March, that is moving forward. We are on track to submit that data for an sNDA in the second quarter, and things are moving along quite well with the sNDA and DLBCL. We do feel quite fortunate in terms of the position that we're in relative terms.
That being said, from a commercial standpoint, it's obviously not ideal to have the current situation, to have patients not all going to their doctors as frequently as they really need to be. It's certainly not ideal having our sales organization not able to call on physicians. We are certainly making adjustments, and whether that's through virtual or detail, virtual ways, whether that's email, whether that's Zoom, et cetera, we are able to reach many of our physicians and patients through our KaryForward program as well. That's the sort of the current status of where we are in terms of the existing business. In terms of the upcoming potential, knock on wood, we hope, DLBCL launch.
We have a June 23rd PDUFA date. That was a priority review. I think we'll obviously see how things have progressed between now and June 23rd. Obviously, if we're fortunate enough to be approved, then we will be in a position to launch in DLBCL, and we'll obviously adjust our commercial plans to whatever type of access we have to clinicians and probably still be using the same kind of virtual detailing and Webex and Zooms, et cetera, until our sales organization has full access to the medical community.
Great. Thanks, Jatin.
Thank you. Our next question will come from Peter Lawson with Barclays.
Perfect. Thanks for taking my questions. Thanks for the update. Michael, just on the antiviral and anti-inflammatory activity you're seeing with selinexor against SARS-CoV-2, how does that compare to existing and other experimental agents?
It's really difficult to say. If you read some of the literature with some of the agents, we can tell you from some of our own assays, you can get very different answers depending very much on the assays that are done. I know there's several different IC50s published for things like hydroxychloroquine and even remdesivir. Remdesivir is certainly a direct antiviral. We just don't have great assays yet. As far as Sharon mentioned on the call, it's very difficult to get a good model now for cells for SARS-CoV for killing with our drug, because of course, we are very good at killing cancer cells. Most of the cell lines that are used in these viral assays are immortalized cancer cells, which we do a fine job.
Discerning whether we are actually having an antiviral effect whereas an anticancer effect is difficult, and that's one reason we haven't been able to give direct answer. That all said, as Dr. Shacham mentioned, there have been several publications recently where selinexor is clearly interfering with the normal viral program, meaning when a virus infects the cell, it changes the transcriptional profile of a cell in order to get that cell working for the virus, and we come in, we're one of the so-called hub proteins that comes in and actually interferes with that entire reprogramming of the cell, and we're hopeful that that'll have direct antiviral effects.
Thank you. Maybe I missed this, are you excluding any comorbidities in the trial?
We're only excluding comorbidities in the sense that it might affect the safety of the patient. In general, this is a very liberal protocol. We allow creatinine clearances down into the severe range to 20 cc per minute, much as we did in our cancer trials. We allow some mild hepatic dysfunction and so on. We're basically trying to allow real patients to come into the study to the extent possible.
Great. When should we think about initial data?
Yeah, we really can't say at this point, honestly. The trial should initiate the first patient in the next one to two weeks. We'll update you when we can. We'll give much more clarity once things get off the ground. Hopefully, this pandemic is starting to see some light at the end of its tunnel winding down, but there's still a lot of patients to treat, so we'll keep you posted, Peter. I just can't give you any better answer than that.
Gotcha. Thank you so much. Appreciate it.
Thank you. Our next question will come from Arlinda Lee with Canaccord. Please go ahead.
Hi, guys. Thanks for taking my question. I was curious about, you mentioned drug-drug interactions. I'm wondering if you're going to allow combinations with other COVID treatments and how flexible your protocol is. Everything is moving so quickly, as you said. Just curious about that.
Yeah, we are. I think I try to address this. We are allowing patients to come in on experimental, pretty much everything's experimental these days, anti-inflammatories and/or antiviral agents. We will try to take care of any potential imbalances through the randomization/stratification procedure. Our analyses, and we've discussed this with many people, our analyses will take into account what patients were on at baseline.
Thank you.
Thank you. Speakers, I'm showing no further questions in the queue at this time. I would now like to turn the call back over to CEO Michael Kauffman for any further remarks.
Thanks everybody for joining today's call. Go out there, be safe, and we look forward to updating you on our progress as soon as we can. Bye-bye.
Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may all disconnect and have a wonderful day.