Good morning. My name is Sherry and I will be your conference operator today. At this time, I would like to walk to the Karyopharm Therapeutics COVID-nineteen Clinical Trial Initiative 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, Sherry, 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 COVID19. This is Ian Karp, and I'm joined today by Doctor. Michael Kauffman, our Chief Executive Officer Doctor. Sharon Schackam, President and Chief Scientific Officer and Doctor.
Jaden Shah, Chief Medical Officer. On the call today, Doctor. Coleman will provide a brief overview of the scientific rationale for our new clinical trial in patients with severe COVID-nineteen 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 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 come 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 Xpobio, 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 risks that the COVID-nineteen pandemic could disrupt Carrie from the more severely than incorrectly anticipates and those discussed in the Risk Factor section of our most recent annual report on Form 10 K, which 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. 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 Doctor. Michael Kaufman, 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-nineteen pandemic. To all of our friends, colleagues in those new to carry a farm, 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 and manufacturers of protective equipment and diagnostics or those pharmaceutical companies like Carrier Farm, identifying and developing potentially effective treatment options for patients with COVID-nineteen.
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 Cariopharm has decided to a global randomized 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 United States is currently approved at higher doses than are going to be used in this current COVID-nineteen 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 sign compound, which blocks the cellular protein XPO1 or EXORTIN1. In addition to its roles in cancer, EXORTANT 1 may also be important target in treating viral infections by impacting 2 distinct mechanisms.
Antiviral and anti inflammatory pathways. Exporting 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. Signed compounds, which blocks export in 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, sign compounds have recently been identified as having the potential to interfere with key host protein interactions with the SARS CoV-two virus, the virus that caused it COVID-nineteen.
In the past, the majority of preclinical work and viral infections was conducted with another one of our sign compounds or exporting 1 inhibitors called verdenexor. Verdenexor 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, we have already tested selinexert over 3000 patients with a variety of advanced cancers in clinical trials alone. We decided to initiate a new clinical 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, export and 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, EXporting 1 inhibition has been identified in several assays as having potential activity against SARS CoV-two, the virus that causes COVID-nineteen, although specific animal models have not yet been available. One of the most important aspects of COVID-nineteen is the mark pulmonary inflammation with high levels of cytokines such as IL-six and IL-one. Along the lines selinexor and other sign compounds have demonstrated potent anti inflammatory activity through the inhibition of nuclear factor Kappa B also called NF Kappa B leading to reductions in all of these cytokines in a variety of models and this may be particularly beneficial to hospitalized patients. With COVID-nineteen.
The most common side effector selinexor, particularly at the higher doses used in its currently approved indication in patients with relapsed to multiple myeloma, our nausea, vomiting, anorexia, low sodium and low platelets, which are generally dose dependent and reversible. However, We do plan on setting a significantly lower dose of selinexor in this COVID-nineteen trial and anticipate selinexor to be well tolerated based on 2 previous phase 1 clinical studies using this lower dose. Additionally, there's already an expansive safety database of selinexor across all ages including in the elderly and pediatric populations at higher doses of selinex are used in oncology indications. Finally, there are also no known clinically significant drug interactions with selinexor, which could prove to be important a number of other experimental drugs I do want to reassure our patients and healthcare partners within the cancer community that our announced clinical trial in COVID19 is not expected to impact the timing or prioritization of other key carrier farm goals, including the planned submission of an sNDA for Expobio in combination with once weekly Velcade also called Bortezimin 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. And 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-nineteen. Now, before we open the call up for your questions, let me summarize what we've just announced earlier this morning. First, within the coming 1 to 2 weeks, we expect to dose the first patients in a new global randomized clinical trial to treat patients with COVID-nineteen 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 Xp01 inhibitor in patients with severe COVID-nineteen. 3rd, Xp01 inhibitors have been shown to disrupt the replication of multiple viruses in vitro and in vivo. Xp01 inhibitors have in the timing or execution of other critical karyopharm objectives and milestones expected in 2020 related to our oncology pipeline. And lastly, Karyopharm is committed to working as quickly and as effectively as possible to help the World Medical Community address this ongoing COVID-nineteen pandemic. Our team is committed to making a difference in helping advance our understanding of how best to treat patients with severe COVID-nineteen 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 United States to begin this trial as quickly as possible in the days weeks ahead. With that, I'll
Our first question will come from Brian Abrahams with RBC Capital Markets. Please go ahead, sir.
Hey guys. Thanks for taking my questions. And yeah, it's nice to see this moving into a COVID-nineteen study given some of the emerging evidence for XPO-one is a potentially important target here. Just a few questions for me. I guess first off, maybe bigger picture on trial design.
Can you give us a sense of just the size of the study, the timelines where you're planning to conduct it and the endpoints? Sure.
So I'll start and let Jatin add more information, specifically regarding time points. So the study will include that 230 patients We will conduct it in 8 to 10 patient 8 to 10 countries, in North America, in Europe and Israel. And, we are planning to sell this to hopefully those the first patients within the next 2 weeks. Regarding time points, Jason, do you want to elaborate?
Yes, absolutely. So regarding the endpoints on the study, so we'll be consistent with was established by the WHO criteria, as well as other large NCI studies, sorry, NIH studies in this space. So the primary endpoint will be a time to clinical improvement, looking at the, who or no score, which is a really clinical relevant endpoints in terms of for patients. And that's an 8 point score ranging from death all the way to discharge from hospitalization on the of 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.
And so there's going to be a number of secondary endpoints that we'll look as well to identify clinical benefit.
Got it. That's really helpful. And then I guess on the mechanistic side, I guess, you mentioned NF Kappa B. Is your view that this is primarily going to be anti inflammatory through cytokine reductions via NF B or whether or not this is acting more as a direct antiviral by preventing trafficking of some of the viral proteins like N3B?
So we we do assume that there will be an strong anti inflammatory activity by reduced cytokines through inhibition of NF Kappa B and other related mechanism. There is evidence. There is supportive evidence for anti viral activity, both sign compounds in many, many viruses. We tested over 20 of those, and it all falls with this concentration that we hope to achieve in human. This includes, our 3 influenza and other viruses.
The evaluation of selinexor directly in assays in vitro and in vivo for, cell scope is ongoing now, but there are several papers that were published in the last 2 to 3 weeks suggest that EXPARONE is an important protein, important host protein for the propagation of the SARS CoV virus. And in specifically in one of these papers that was published, about 2 weeks ago, they looked at in a biochemical assay looking at the interaction of the proteins from the South Globe and the host protein. And in that assay, Well, the Nexo related compounds, so the Nexo was able to inhibit those, interactions between the virus and the host protein. So we hope that there is also a direct antiviral activity. We are testing it right now.
Got it. One last one for me, if I could. Just on the PKPD 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 1 work? And how much do we know about selinexor's distribution to the lung to the target tissue here? Thanks.
So the dose that we are looking at is 20 mg three times a week. So a total dose of 60 mg weekly. When we are looking at the the constipation we have to remember first that this is a covalent inhibitor, that binds to assist in Resideo and X-four-1 and form a, we reversed a slowly reversible bond with a half life, in vitro of 20 48 hours. Now this half life, we confirmed it, looking at target occupancy through our pharmacodynamic assay and others for macroeconomic essays such as, increase in XFOR-one MRna. That's really this biological health 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 needed for any MIG, we can, we can sustain this effect for 48 hours. And therefore, we are going to dose 20 mgs 3 times a week.
Thanks again.
And she also mentioned that at that dose, in patients from our Phase I study, we did see a clear anticancer activity. So it is an active dose.
Thank you. Our next question comes from Maury Roycroft 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 referenced in the press release, it shows unique activity versus 2 of the viral subunits NSP 4 and then OR 6. 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?
Yes. This is still early stages, obviously, of treating this disease both in animal models and obviously humans and 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 anticancer agents, both targeted therapies as well as chemotherapy. And so 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 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. And then the other question I had was just on Vergenxor. If you can recap what happened with for the next sort of development as an antiviral? Was there an efficacy or safety threshold that was not met or was it just a matter prioritization and Karyburn's decision to focus on oncology?
So it's essentially the last one. We did see a clear efficacy in all the animal models that we looked in terms of influenza. We saw, by the way, the minimal application stores in these models was a 5 mgkg with 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 we saw in that model in influenza is that we can dose as late as 4 days after the initiation after the infection, which again might be very relevant in this is also happening in this disease. And 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 1 dose, a Phase 1 study in healthy volunteers. We have not reached the MTD in that study with those all the way up to 40 mg in the same dosing that we are planning now for Selinexor. We saw that the PK was dosed proportional and similar to what we expect based on the selinexor data and that we show target engagement in terms of the pharmacodynamic assay against similar to what we expected based on the Phase 1 with selinexor. And at that point, we stopped the development to prioritize the development of selinexor in oncology, but we've already essentially to move into a phase 2 in patients. Phase 1
and 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 4 days post infection So I guess in your mind, what is the expected window where you think selinexor might be applications in humans post infection?
Yes, it's very difficult to know with the with all that's going on in these patients. The fact that it was active in that model the influenza model that Verde Nexo was active 4 days after. You note from the figure that was in the press release that Tammy Flu 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 verdenexor by 4 days, which is frankly pretty pretty extraordinary in that kind of a model. Obviously, we most of the patients coming into the hospitals who are now hospitalized with COVID-nineteen, given the situation and the lack of beds, etcetera, most likely we'll have had their infection 7 to 10 days.
And then unfortunately, we're not recovering. So 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 time frame. And because our drug is a dual mechanism of action, potentially will have not only the antiviral effects, which may be important earlier in infection, but certainly later as the virus continues to propagate, but importantly that we hit multiple cytokines at once. And that seems to be the the those the multiple cytokine effect might be the most relevant in these later stage patients where it seems like the immune response and the inflammatory responses is perhaps worse than the infection itself.
Got it. And then just to that point, a little bit further, how similar or different are for Dinexor and selinexor in exporting the COVID proteins from the nucleus?
Well, in terms of the structure, they are very similar. They are different by one Awesome. In terms of their EXFO 1 inhibition, the Nexstar has an IC50 all the way between 20 to 40 nanomolar cells and about the Nexos around Circular. So 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 this host, the interaction of the protein with the South cold protein only for the nexor was evaluated. We are evaluating Selinex right now instead of all invigorated sales related to South Coast.
Okay, great. And then just last one from us. Given the selection of the low dose, you talked about this earlier, but what do you expect the side effect profile could look like in non cancer and specifically, are there any comorbidities that might need to be excluded from the population? Thank you.
The study was going to be very liberal in terms of who's allowed in to the study. As far as side effects, we know at this lower dose, both from our oncology studies during the dose escalation phase. And Doctor. Schacken mentioned that they're there was anticancer activity even at the 20 milligram 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 2, in those doses, even in patients with heavily pretreated cancers. So we don't expect to see a lot in our patients here. And that was confirmed also in the Verde and Exeter low dose study, that Phase 1 study in normal volunteers you mentioned where the 20 mg3 times a week dose was very well tolerated.
Thank you. Our next question will come from Eric Joseph with JP Morgan.
Hi guys. Thanks for taking the questions.
I guess just following up on dosing in the primary mechanism of action you think of at play here. Do you I just want to just clarify that At the doses that you're testing in the clinic, you expect an impactful antiviral effect for selinexor and 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?
So to answer your second question, we are going to test the viral load. And the The study will include patients to have severe COVID-nineteen and they will have to proof in a COVID-nineteen in a COVID-nineteen assay that they have infection. And we will monitor in that throughout the through adult treatment. We are still, looking at the frequency of how many times we will evaluate that, but we'll definitely monitor dose of Selinex are giving three times a week. Assuming that this activity that we sold for other viruses with selinexor will translate also to South Coast.
Our next question will come from Ed White with H. C. Wainwright. Please go ahead.
Good morning. Thanks for taking my questions.
So 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? And also, are you thinking of this as a registrational type trial in the current market in trying to rush treatments in for COVID-nineteen.
So I'll answer related to the monitoring of safety. This is, of course, our first priority, like in every other study to make sure that the safety of our patients is conserved. And we will have a DSMB that will be set on day 1 of the study and the DSMB together with us And the investigator will monitor all the safety of our patients very, very carefully. And probably in a more equipment based on what you do in other studies.
Mike? Yes. In terms of the path after, I mean, one thing that's been remarkable about this is how the FDA, the Europeans, the Israelis, the Australians, frankly across the world have worked the regulatory bodies in these foot places as well as the clinics and the physicians and other site staff have worked really on a timescale that hasn't I've never seen in my 20 plus years in this business. People are moving. And it's been a very collaborative working relationship with all of these regulatory bodies.
So 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, 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 see what and we'll see what happens. And I do believe that people are all working to try get novel therapies, to as many people as quickly as possible. And I don't want to speak to when traditional path or not. It is a randomized study.
Okay. Thanks, Michael. And then I know that the COVID-nineteen fall, but I'm just wondering if you can give us any update as far as has there been due to the pandemic and the impact to Xplovio sales? And 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-nineteen, 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 shifted to patients' homes.
So 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 with the SND and DLBCL. So we do feel quite fortunate in terms of the position that we're in, in relative terms.
And that being said, from a commercial standpoint, it's obviously not ideal to have the current situation, to have patients I'm 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 But we are certainly, making adjustments and whether that's through virtual or detail virtual ways, whether that's email, whether that's zoom etcetera, we are able to, to reach many of our physicians and patients through our carry forward program as well. So 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 what we hope DLBCL launch, We're on we have a June 23 PDUFA date. That was a priority review.
I think we'll obviously see how things have progressed between now June 23rd. But 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 Webexes and Zooms, etcetera, until our sales organization has full access to the medical community.
Great. Thanks, Ian.
Thank you. Our next question will come from Peter Lawson with Barclays.
Perfect. Thanks for taking our questions. Thanks for the update. Michael, just on the antiviral and anti inflammatory actives you're seeing with selinexor, against SARS CoV-two. How does that compare to existing and other experimental agents?
Yes, it's really difficult to say. I mean, if you read some of the literature, with some of the agents. And 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. So I know there's several different IC50s published for things like hydroxychloroquine and even remdesivir.
These are and 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 sales for SARS CoV for killing with, with our drug because of course we are very good at killing cancer cells. And most of the cell lines that are used in these viral as our immortalized cancer cells, which we do a fine job. So discerning whether we are actually having in any viral effect, whereas the anticancer effect is difficult. And that's one reason we haven't been able to give direct answer.
That all said, as, as Doctor. Shaka mentioned, there have been several publications recently where selinex area 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, that entire reprogramming of the cell. And we're hopeful that that'll have direct antiviral effects.
Thank you. And then maybe I missed this, but are you excluding any co morbidities in the trial?
We're only excluding comorbidities, in the sense that it might affect the safety of the patient. I mean, 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, but we're basically trying to allow patients real patients to come in to the study to the extent possible.
Great. And then where should we think about initial data?
Yes, we really can't say at this point honestly. The trial should initiate the 1st patient in the next 1 to 2 weeks. And then we'll update you when we can and we'll give much more clarity once things get off the ground. And 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.
Got you. Thank you so much. Appreciate it.
Thank you. And our next question will come from Arlinda Lee with Canaccord. Please go ahead.
Hi, Ari. Thanks for taking my questions. 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, I mean, everything is moving so quickly, as you said, I'm just curious.
Yes, we are, we are, I think, I try to address this So we are allowing patients to come in on experimental, I mean, 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. And our analyses And we've discussed this with many people. Our analyses will take into account what patients were on at baseline.
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 Kaufman for any further remarks.
Well, 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.