Curis, Inc. (CRIS) Earnings Call Transcript & Summary

Okay. Perfect. Yes. So I'll just kick off. Thank you all for joining, and welcome to the Credit Suisse Healthcare Conference. I'm Ryan Silva, VP and our Equity Capital Markets team here at Credit Suisse. And it's my pleasure to present to you here today the team from Curis that well be presenting to you. At the conclusion of this presentation feel free to send through any questions through the appropriate -- the appropriate moderator e-mail channel. And with that, I will turn it over to James Dentzer from the company to introduce the opportunity.

And I'm just going to verify before I get started, you can see my screen?

I can, yes.

Excellent. Thank you. Thank you very much for having us, and thank you, everyone who's watching the webcast today. So I would not go through every slide in our corporate deck, but there are a number of slides here that I think are critically important. A number of the things that Curis is doing, I think, are unique in the biotech industry. What we look to do at Curis is develop novel, first-in-class cancer drugs. There are no me-too programs, and they need to be in areas where we believe there is significant unmet patient need. By that, I mean, it's got to be a program that merits a $1 billion market or greater. If it's not a program that we don't think can make a significant difference to a specific therapeutic area, it's not the right thing for Curis. So novel, first-in-class, really important. There are 2 drugs in our pipeline, 4948 and 8993 that really fit that test, and that's where I'm going to focus most of our attention today. As you can see, 4948 is our IRAK4 program. We believe this drug is positioned to become the cornerstone agent in heme malignancies. We're looking in NHL, CLL and Waldenström's and B-cell cancers today. We're also looking at AML and MDS. I'm going to talk a little bit more about the mechanism of action and why we think this is such a unique drug. But with its unique mechanism of action, as an oral small molecule with a great safety profile, we think it's going to be applicable, in certain settings, as a monotherapy, and in every other setting as a really strong component of a combination therapy regimen. And VISTA, the second program in our pipeline that I'll talk about today, and I'll touch on it just briefly. It's earlier stage development, but incredibly exciting in the world of immune-oncology. So this is a relatively new area of focus of harnessing your immune system to fight cancer for you. VISTA is the last of what most people consider the big 3 immune checkpoints. The other 2, of course, being CTLA-4 and PD-1. We'll talk about that when we get there. But the early data from the lab, very compelling. And of course, we've got the lead program in VISTA, and I look really forward to see what those those patient data look like in the clinic. So now let's focus a little bit more on a deep dive on IRAK4 and the biology. Curis is the company that first identified that IRAK4 was a terrific target in oncology. Other companies in the past had looked at IRAK4 and had gone after its anti-inflammatory properties. So it is used in things like RA, lupus and those sorts of areas. What Curis identified, and you can see it clearly in the graphic on the right, is that IRAK4 is also a great target in oncology because it's a key component of the myddosome. We were looking at B-cell cancers. And as you can clearly see in that diagram, B-cell cancers are driven by NF-kappaB overactivity and NF-kappaB itself has 2 main drivers that push it. The first is the BCR pathway. That's been addressed over the last decade with BTK inhibitors. Ibrutinib is the lead product among that competitive class. And then there's the toll-like receptor pathway. That's the second pathway known to drive NF-kappaB. What Curis scientists learned is that nobody was addressing that pathway. And as we started to dig deeper and try to figure out the best way to block that pathway, we found that the oncogene that most people had focused on, it's the gene that when mutated is driving cancer in these patients is the MYD88 gene myddosome. That's a very difficult gene and protein to target. In fact, if you google it, oftentimes you find the word undruggable. We found that you didn't have to. That IRAK4, which is also a component to the myddosome, is functionally required by the myddosome for its activity. That if you block IRAK4, the myddosome ceases to ceases to function. And in fact, as a happy circumstance in the application of this drug, the myddosome is a chokepoint in the TLR pathway. So if you block the myddosome, not only are you blocking any oncogenic activity that comes in the myddosome, but you get the benefit of locking any oncogenic activity that came from upstream through any of the individual TLR receptors. So bottom line is, Curis first identified this application, and we went fast and furious down to B-cell cancer route. In the last 18 months, new research has come to light that highlighted a second family of cancers that are driven by IRAK4. And that you see on the left-hand side of the screen. That's AML and MDS. The original publication that garnered all the attention was in Nature 2019, and then in ASH of that year, so not quite 2 years ago. In ASH of that year, a presentation was made by two doctors, Dr. Verma at Einstein and Dr. Dan Starczynowski at Children's. And what they showed, they were looking at very specific genetic mutations that were known to occur with some frequency in the AML and MDS patient population, but nobody really knew why. It wasn't clear was this a correlation or was it a causal relationship. And what these two doctors discovered was, in fact, the reason why these spliceosome mutations show up so frequently in the AML and MDS population is precisely because they're causing disease. As you can see in that diagram on the left, in a normal process, so when there is no spliceosome mutation, you get the normal form, the short form of IRAK4. That IRAK4 kinase interacts primarily with MAP kinase, and it's an important normal functioning part of the cell process. If, on the other hand, you have one of these mutations, and there are 2 mutations specifically that were referenced in this paper, the U2AF1 mutation and the SF3B1 mutation. If you have 1 of these 2, what happens in the splicing process is that additional material gets spliced into the IRAK4 kinase, making it a physically longer kinase. When that happens, it changes the properties of its behavior, and it now starts to interact primarily, not with MAP kinase, but with NF-kappaB. And as you remember in the B-cell cancer side, of course, as it's driving NF-kappaB into overactivity that causes disease and it does in AML and MBS as well. So this was a novel finding at less than 2 years ago now. Of course, everyone in the industry started focusing on that. Curis having an IRAK4 drug ready to hand already in the clinic for B-cell cancers, we were thrilled to take this new application and get patients dosed. Maybe let's talk a little bit about the fingerprint of the drug. So this drug was designed by Curis and our partners at Aurigene. Aurigene's a wholly owned subsidiary of DocReady. We were working with our partners at Aurigene to specifically design a molecule that would block IRAK4 and block it really hard, as you can see in the data on the right-hand side in the binding affinity. But also hit several other targets of interest. Now not all of those targets were going to be of interest in every single cancer indication, but we knew that IRAK4 was going to be a very important target across multiple cancer types. So we wanted to make sure that we could hit as many really important contact points as we could, and we did. In the case of AML and MDS, you'll find that FLT3 is going to, of course, turn out to have been a very important secondary hit of this molecule. When we look at the preclinical data supplemented by the clinical samples that we've taken from patients as part of our clinical trial process, one of the things that we've learned is that, in the lab, that fingerprint design that we built to hit IRAK4 really hard is in fact hitting IRAK4 really hard in these patients. We're finding that, as you look on the left-hand side, perfect PK profile from what we were hoping for, half-life of about 6 hours, which supports, of course, our twice daily dosing regimen. At the trough level of exposure, so the lowest level of exposure that our patients are seeing, we're finding that's correlating with 98% inhibition. Not only do we have the very first IRAK4 program going into the clinic to be tested in human patients in these diseases, but we have a drug that's getting 98% inhibition at trough levels, at lowest level of exposure. We know there are a number of other companies looking to follow us and copy our approach with IRAK4 coming into the clinic, none of those companies have a drug with this kind of performance. And none of those companies have a drug that, in addition to IRAK4, is hitting FLT3. And as you'll see as we move forward with the data, that turns out to be very important. So this slide is Slide 9. Slide 9 focuses on the preclinical data. The preclinical data, of course, informed our clinical design. On the left-hand side, you see monotherapy at AML and MDS. The logic here is that the patients in AML and MDS, who should benefit in monotherapy, are going to be the patients who have either lots of IRAK4 or a lots IRAK4-Long to be specific, or a mutation in the FLT3 gene. And as you can see in the lab data on the left, this is IRAK4-Long over expression in that model, if you have lots of IRAK4-Long in the lab, treatment with 4948 shows a dramatic reduction in leukemic blasts. For everybody else, for those patients who are, in this case, preclinical models, they don't have tons of IRAK4-Long, but they do have some. It stands to reason you would expect there would be some benefit, maybe not as powerful a benefit as you saw with monotherapy, but certainly an important benefit and a benefit that if it could be combined with other treatments, and the two most commonly used treatments in this setting are venetoclax and azacitidine, that if you combine 4948, you would expect that it would be an extra bump that would be really helpful. And you can see that's true. In this model, whether you're in the green, whether you're in venetoclax or you're treated in the blue with azacitidine or in the sort of amber color of aza-venetoclax in combination, all 3 cases, you're better off if you add 4948 to it. So it's exactly what would have been predicted in the scientific theory given the mechanism of action, but of course, the preclinical experiments bear that out. Some patients, if you have lots of IRAK4-Long, monotherapy is going to be the right choice. For everybody else going to combo therapy, adding 4948 to your existing regimen should provide benefit and it does in the lab. And then on the right-hand side, of course, in the original indications we looked at in B-cell cancers, what you find is whether you're on ibrutinib or BTK inhibitor or whether you're on an IRAK4 inhibitor, so you're blocking either the BCR path or the TLR path, either one in monotherapy, Red line or blue line in that graph, either one in monotherapy, it provides benefit. But the best answer is, of course, we turn off both. You've got 2 pathways. You don't want to shut down one or the other, you want to show down both, and that's what you see in the bottom graph. So as you look to our clinical design, that's exactly what we've done. On the right-hand side in B-cell cancers, monotherapy is not the right answer. You're not going to choose one or the other. You want to do both. We've got 4 buckets of patients that we believe will be the patients who should show the highest probability and the fastest study to prove that this combination is beneficial. On the opposite side, on the left, in monotherapy for AML and MDS, those patients who have lots of IRAK4-L or a FLT3 mutation should benefit from combo therapy. And again, the spliceosome mutations are known to cause lots of IRAK4-L. So if you have lots of IRAK4-L or FLT3, monotherapy is the right answer. And then in the middle, all the rest of the patients, whether you're on an HNA, like aza -- like azacitidine, or whether you're on venetclox, adding 4948 to it should be beneficial. As we look into the clinical data, again, one of the things to start with is the 2 targets of this molecule, IRAK4-L and FLT3 happen to be the #1 and #2 disease drivers genetic to these disease drivers in this population. Our safety data, which I'm going to pass over, I don't need to go through everything, but bottom line is, as you might imagine, in the relapsed/refractory setting, these patients are very sick. The disease is very serious. The prognosis is frankly quite grim when untreated. Our safety profile is terrific. We have seen that there was no overlapping dose-limiting toxicity with the existing therapies, which was really important because while half the population we expect will want monotherapy, the other half of the population is going to want to combine with aza or ven or both. We know that aza and ven then both have pretty toxic side effect profiles. Both of them have a dose-limiting toxicity of myelosuppression. We wanted to make sure that we didn't make that worse, that we didn't add to it. And of course, in the safety data we have so far, it looks like this is a safe combination to add, that we do not exacerbate their toxicity profiles. And of course, in efficacy data, this is the answer that's the most exciting to patients so far. A small number of patients, that's the obvious caveat. But in every case so far that we have been able to test in this patient population, you can see the 3 spliceosome patients. Again, those are high IRAK4-L expressers, in the 3 spliceosome patients, you're seeing a very dramatic reduction in the cancer blasts in all 3 of these cases. The percentage of marrow blast fall -- the marrow blasts that are causing cancer, so these are the cancer cells and the bone marrow, are going from elevated levels as high as 23% in 1 of these patients and falling down into the normal range in all 3 responses. In the FLT3 patient, that's the green line, it's potentially even more exciting. There was recent literature, not written by Curis, but recent literature that describes FLT3 patients and FLT3 inhibition. And what that paper suggests is that the reason why conventional FLT3 inhibitors don't work very well is that the body's response, the compensatory reaction to FLT3 inhibition is IRAK4 signal. And so the paper recommended that patients shouldn't be on only a FLT3 inhibitor, they should go on a FLT3 inhibitor and an IRAK4 inhibitor to treat their disease. Of course, that's exactly what 4948 does. It hits both. In this specific patient, this patient was on gilteritinib, which is the leading FLT3 inhibitor, and flew right through it did not get a response to that drug. When this patient joined our study, just 2 cycles into treatment, not only is that patient now a responder, but by genetic analysis, that patient's FLT3 mutation has been completely eradicated, incredibly encouraging, obviously, only one patient, we need more data, of course. But to see this kind of result, which is exactly what was predicted by literature outside of Curis was tremendously exciting. And then the bottom part, you can see in the swimmer plots of charts, how long patients have remained on therapy? Of course, that's also really exciting. The prognosis for this population once you relapsed/refractory to azacitidine is unfortunately pretty grand. The median survival in studies to date outside of Curis is that somewhere between 4 and 5 months survival once you're relapsed/refractory to aza on median. And to see that all 3 of our spliceosome patients are past that point already is, of course, highly encouraging. I'm going to bypass this. This is the combination data of patients that would be, of course, eligible for combination therapy. They're not on combo yet. They will be. We just announced, of course, this week that we've got our first patient dosed in our combination study. So we don't have efficacy data yet. All we really have is data that show that we can make a contribution to those patients as well. We'll find out whether or not we can combine well with aza and ven in that study. So the summary here in AML and MDS is our preliminary clinical data, they are early, but we're getting clear activity. We're gaining deepening durable responses. It's only 4 patients so far in our target population will get monotherapy, 3 spliceosomes and one FLT3, but all 4 of these patients are showing response, which is, of course, outstanding. We think there might be multiple paths to regulatory approval. What we have said externally is that we are hoping -- we had 3 patients -- spliceosome patients on drug at June. That was in the first year of the study. We think excitement has really built. We hope to have a minimum of 10 patients, somewhere between 10 and 20 patients on drug by December 31. If we can hit that goal, we think we're in a position to have a very interesting conversation with the FDA, and we hope to have an agreement with what our next step, what our pivotal design might be and what those clinical end points might be. In B-cell cancers, maybe just in the interest of time I'm going to move quickly forward through this and talk about some of the underlying data. As a reminder, of course, what we're doing in B-cell cancers is we're blocking IRAK4 in the myddosome, and that's shutting down TLR pathway. What we found in the data to date is that in these patients, at our recommended Phase II dose, which is 300 milligrams twice daily, you can see it in the graph on the left, the majority of patients that are on this drug in monotherapy are showing clear activity of the drug, which is fantastic. And this is monotherapy. We don't expect patients who are going to use this in monotherapy, they're going to be using it in combination with a BTK inhibitor. But just shutting down the TLR pathway is having these kind of effects on patients. Obviously, very encouraging. On the right-hand side is just a classic dose response curve. So this is a patient that's been on drug over 2 years now. And we're seeing that, over time, the patient just gets better and better as the patient has remained on drug and increased dose up to the recommended base of 300 milligrams of BID. Maybe just -- again, just to make sure I'm conscious of our time, I want to talk through VISTA. There are only a few VISTA slides. So this is the second drug in our pipeline that I wanted to mention today. It's very early stage, but it's incredibly important. As I mentioned at the outset, there are 3 that are considered the big 3 checkpoints in immune-oncology, and this isn't our view. We've taken this graphic actually from an issue of Science last year. So VISTA, CTLA-4 and PD-1, in that order, are the big 3 checkpoints. Of those 3, this is the only one that governs the activation of T-cells. The next step, of course, would be any T-cells that are activated would get primed and that priming function is governed by CTLA-4, and then PD-1 governs the effector function for those T-cells. But the first step of those 3 is, of course, activation. VISTA controls quiescent. It keeps T-cells quiet and also controls how many of them, therefore, become activated and leave that quiescent state. There's a graphic I've got on here or 4 graphics that have gone in this slide, Slide 27, where we talk to the specifics of what happens in the tumor microenvironment. In the first graphic, as you can see, this is what the world looked like 10 years ago. This is illustrating PD-1 and PDL1, but CTLA-4 would have a similar story. What's happening is that PD-1 is expressing on the tumor -- I'm sorry, on the T-cell. And it's binding to its ligand on the tumor, PDL1. When that happens, the tumor is passing a signal through to put the T-cell into an exhausted state. When it does, of course, the T-cell no longer recognizes or fight the tumor cell, the tumor cells, of course, can grow unabated. The second graphic is what won Jim Allison the Nobel Prize last year. And that is, once you've identified one of these checkpoints, and you know what's happening, you want to block that connection. And whether you block it on the PD-1 side or you block it on the PDL1 side, either way you're preventing that signal from getting through, you're keeping the T-cell in its activated state so that your own T-cells are now seeing and fighting your tumor cells. It sounds like a really exciting idea and it is, it's groundbreaking. PD-1 is now a $50 billion industry. But there are 2 major questions that have been plaguing everyone in this industry about PD-1, in fact, about checkpoints in general. And that is, while it is really exciting and it is, I said it's a $50 billion space, it's a Nobel prize winning idea. The response rates for these drugs are really shockingly low. Outside of Hodgkin's lymphoma, which is not [indiscernible], the ORR for PD-1 drugs is somewhere between 10% and 20%. 80% to 90% of patients who go on a PD-1 do not respond to that therapy. Why is that? The second question that everyone's been struggling with is, if you happen to be one of the lucky 10% to 28% that does get a response, you typically and very quickly develop some sort of competitive response. The drug stops working for you. Well, what is driving that reaction? What -- why are you losing that efficacy so quickly after starting? What happens, and this is in that third graphic, and this has been detailed by Jim Allison and Pam Sharma at Texas in their lab, but by many others now, looking at CTLA-4, looking at PD-1 and looking at PDL1. The problem appears to be, or at least one of the key issues on driving these 2 problems that everyone is looking to is VISTA. The body's natural response to blocking a PD-1 or a CTLA-4 checkpoint is you get an explosion of this expression. It increases up to fivefold. It increases in expression on T-cells, on tumor cells and critically on the myeloid cells. When that happens, again, think back to the primary function of VISTA, VISTA controls quiescents of T-cells. It controls whether T-cells are active or go quiet. So by getting this explosion of VISTA as a reaction to getting another checkpoint therapy, it's your body's way of putting the T-cell back to sleep. Well, if you have that as a problem, of course, now you get to the fourth graphic, and this is from -- directly from Randy Noelle and his lab. Randy Noelle, of course at Dartmouth is the one who discovered VISTA. And what you find is the next logical step is, of course, if VISTA is the problem, why don't you just block it? And what you find, if you do block Vista is this next slide, Slide 28. These are lab data, but they're incredibly compelling. On the left-hand side, this is what happens if you have a cancer type that is believed to be driven by VISTA. So if you looked at the cancer genome atlas, these would be tumor types like melanoma, mesothelioma, gynecological cancers. In these settings, using this anti-VISTA as a monotherapy appears to be very effective. And of course, in the lab, as you can see, it is. For other cancers, these are cancers like colorectal, for example. This is a CT26 model, a very aggressive colorectal model. These are cancers that are not driven by VISTA from the get-go. They only become driven by VISTA because you take an autoimmune inhibitor. You take a CTLA-4 or an anti-PD-1. In those cases, as you can see in this experiment, they dosed mice with a PD-1, CTLA-4 combination, and they found that at day 14, all of the mice were dead. Again, it's a very aggressive model. But if you give VISTA or an anti-VISTA, to be specific, in addition to PD-1 and CTLA-4, and it's the only thing you do differently, just adding VISTA in anti-VISTA drug to that regimen meant that 60%, 6-0, of those mice were still alive at day 14. And in fact, if you go out to the end of that experiment, you can see on the far right at day 60, 40% of those mice are still alive, again, in an incredibly aggressive model. So it appears to transform the effect or the efficacy of PD-1 and CTLA-4 therapy in these mice. It hasn't been duplicated in humans, of course, yet. But these data are really groundbreaking and really exciting. And it's, of course, why Curis is chasing after this checkpoint. This is the last slide on VISTA, and the part I would just mention about this drug that's really important is that Curis did not invent this specific molecule. This specific molecule has in fact been in the clinic before. And it was withdrawn from the clinic after it had shown that, at lower doses, doses below the therapeutic window or doses that were believed to be below the therapeutic window, started causing a cytokine response. So at 0.15 and at 0.3 mg per kg, this on-target toxicity of cytokine response became quite problematic. This is back in 2016. And you may recall that in the early days of CAR-T therapy, Kite and Juno specifically had programs going forward. Cytokine release syndrome was a problem with CAR-T therapy, and many people thought at the time that it was going to prevent CAR-T therapy for being used. Well, of course, this VISTA finding then CRS was on target talks for VISTA as well, was obviously unsettling to the folks running this study. They decided to stop this study and they gave all of their rights back to Dartmouth. We come in 5 years later with our own experience in VISTA, knowing want to look for. And frankly, having the benefit of 5 years of the industry's work in CAR-T, where CAR-T became, of course, a standard care. Physicians, oncologists everywhere are quite accustomed to managing cytokine release syndrome. You administer steroids, or if IL-6 is an issue, tocilizumab. And we also have the benefit of an additional 5 years of work at Dartmouth how to titrate dosing to desensitize patients to cytokine release. Well, with all of these different new tools for how to manage this process, Curis came in. We struck a deal, of course, to get rights to this drug from Dartmouth. We wrote the protocol and took to it the FDA last year. The FDA agreed that, that protocol made sense, that there was a chance that we could manage this drug effectively and manage CRS effectively and hopefully get into that therapeutic range. We started this study last year. And our goal for this calendar year is to try and dose everywhere that Janssen did. So we are going to try and dose at 0.15 and 0.3, and see if we can have success where they failed. We hope to be in a position to answer that question definitively by year-end of this year. We're getting pretty close, of course, it's early November. So obviously, our optimism is pretty high that we can do that. We're not quite there, but we're close. We want to make sure that we've got enough patients at enough of these dose levels to be able to say for sure that we can manage that on-target tox. And if we can, then I think the focus changes very quickly to 2022 being the hunt for efficacy. If we can get past that 0.3 mg per kg range, now, of course, we're going to be looking to see if we can see anything in humans that approximates the kind of success that we've seen in the mice models in the lab. And if we can, I think, there are a lot of folks who believe VISTA could become a transformative therapy in the IO checkpoint space. We certainly agree, and we're very excited about the process so far. So 2 big programs in our pipeline, one being 4948 and IRAK4, the second one, 8993 blocking VISTA. Both of them are novel. This is new ground. Nobody has had success in these areas before. We have really compelling data, early data, to be fair, but really compelling data so far, and we're looking very forward to providing updates as we go. Tomorrow night, we've got our earnings call. We'll be talking a little bit more about these drugs in detail. I would encourage everyone who's listening to this webcast to go through our materials and through the materials at the SEC that -- in which we've disclosed much more information about these drugs. And of course, on our website where we've got a host of posters and publications that we find a great interest. We think these are very compelling, novel, first-in-class drugs that, if successful, we think, are going to offer groundbreaking therapy alternatives for cancer patients. So with that, I would say thank you. Really appreciate your attention and your time, and thank you, Ryan and the Credit Suisse team for inviting us. It's terrific to be part of this platform, and we're grateful for the opportunity. Thank you.

Thank you very much, Jim. Much appreciate it. We've now opened up the forum for questions, and so some of those are starting to begin to be sent through. So to start with the first one. Could you please summarize once more of the primary points of differentiation of 4948 from the other IRAK4 inhibitors in your view?

Sure. In fact, one of the things I may do as I answer these questions, and I'll go back to a couple of slides as a reminder. So I'll start with the obvious. This is the very first drug to be used in the oncology setting, targeting IRAK4. That's huge. We've got a 2- to 3-year head start on all of our competitors period. We think the IRAK4 space is going to evolve to look a lot like the BTK space did 10 years ago. There was 1 small company, Pharmacyclics, that nobody had paid attention to. They saw this opportunity with ibrutinib first. Ibrutinib gone into the clinic, got a 2-, 3-year head start and a decade later, that's now a $10 billion industry, 95% market share is ibrutinib because they got there first. So I'd say the first thing that differentiates us is, we took all the scientific risk, and we fully expect to see the benefit as being the first mover in this space. The second thing that differentiates us is that we have an advantage that Pharmacyclics and ibrutinib never had and that's on this slide. We not only have the first molecule in this space, we have the best molecule in this space. No one has been able to match these data. We are showing trough level, the lowest level of exposure or lowest level of inhibition that we're getting at these drug exposures is 98%. And only one of our competitors has been brave enough to even mention their data. They're getting median exposure, median inhibition of 85%. So we're getting, by far, the most effective inhibition of IRAK4, period, of anyone that we're aware of in the space. And on top of that, even if someone were to be able to match this and that they could get this kind of inhibition, none of them, to our knowledge, also hit FLT3. The hitting FLT3 in wild-type patients, in patients without a FLT3 mutation, that's not a huge difference maker. Other FLT3 inhibitors have been tested in non-FLT3 patients, single-digit response rates. My point is, it doesn't need to be huge. It's non-zero. So even if somebody we were able to get the near complete inhibition of IRAK4 that we're getting, those competitors don't also hit FLT3, so we will always be superior. So our 2 big advantages that differentiate us are we are clearly first to market. We are the ones who took all the scientific risk. We are going to get the benefit, the first mover benefit of that by being 2 to 3 years first. But on top of it, I think all of those fast follower molecules, and there will be fast follower molecules, they're all going to have inferior molecules. So I like where we sit.

Great. Moving to the second question here. Could you please expand on why it is you chose these particular patient populations for 4948 in AML/MDS?

Yes. It's based on, as I mentioned earlier -- so thank you, Ryan. This question is really looking at the graph on the left here on this slide. So we're building on that finding that was published in Nature. And by the way, we were thrilled to read it. But that work was not our work. That work came from the lab of Amit Verma at Einstein and Dan Starczynowski at Cincinnati Children and others, who are focused in on these spliceosome mutations. But they were focused in on spliceosome mutations that were known to be correlated with disease. No one knew why they were correlated with disease. The key finding of that Nature paper, and they presented their findings at ASH 1.5 years ago, almost 2 years ago now. What they found was not just that the spliceosome mutations were causing disease, but they were able to elucidate exactly why these mutations were causing disease. And the reason they're causing the disease is because they're causing a mutation in the IRAK4 splicing process. So when this kinase is being created, and you can see this clearly in the graphic here, in a normal process for a patient who doesn't have 1 of these 2 spliceosome mutations, you get a very short form of the IRAK4 kinase. That short form is normal. It's wild-type. And in most people, that's what you get, and it's good. It interacts primarily with MAP kinase, does not cause a problem. If you have one of these spliceosome mutations, however, you get the path on the right. What happens is incremental and aberrant splicing happens and additional material gets added into the kinase. Critically, the death domain gets retained. That causes this long isoform, IRAK4-L to become oncogenic. It's driving constitutive activation of the myddosome, meaning it's on and on all the time. And when myddosome is on and on all the time, it drives over activity of NF-kappaB, which disrupts the normal process for apoptosis and, of course, drives cancer. So the reason why we got so excited about AML/MDS was this mechanism of action, again, it came from this article in Nature, not from our internal lab, we were just fortunate enough to have the ideal drug to take advantage of it. And it was IRAK4, as a target, becomes important in the context of patients with spliceosome mutation. Not every patient with IRAK4-Long has a mutation. There are other causes of IRAK4-Long, but the single biggest cause is a spliceosome mutation. 30% of the population of patients, for example, with MDS have a spliceosome mutation. And every single one of those should have an overexpression of IRAK4-Long and therefore, be amenable to therapy. And of course, that's exactly what we're seeing so far. All 3 of our patients that have been on drug with this therapy with a spliceosome mutation have seen a response.

Moving to our next question. Could you please remind us of the status and anticipated timing of the collaboration programs with Aurigene and ImmuNext and further -- are there any other partnering ambitions on the horizon?

Sure, we've got lots of ambitions right, Ryan. So IRAK4 is a product of our collaboration with Aurigene. They're a terrific partner for us. We had originally -- let me stop for a second. And ImmuNext is our partner on VISTA. Let me talk about IRAK4 first. As you saw on the graphic on the right, we originally got interested in IRAK4 because of its role in B-cell cancers. We knew that it was the best target to disable myddosomal activity and therefore, to block the entire toll-like receptor pathway. But we came to that realization before we had an IRAK4. We didn't have a program in house. Based on that finding, we were led by the science. And in learning that inhibiting IRAK4 was going to become a critical new opportunity for cancer patients, we started canvassing the world to see who had an IRAK4 library? Who had the best intellectual property of patent portfolio supporting that IRAK4 platform? And what we found was it was Aurigene, this wholly owned sub of DocReady. So this is a new product discovery company. And, as I said, a subsidiary of DocReady, they had been looking at IRAK4, but none of their programs were in the clinic. This was all preclinical work and all theoretical design, but they had some really terrific intellectual properties supporting it. As we looked at all the different people in the world that had an IRAK4 portfolio, this was clearly superior, and the only downside was that it was early. And we did something that most companies would never dream of doing, and that is, we signed a licensing deal with Aurigene 2 years before having a drug that could enter the clinic. So we signed the deal with them. We spent 2 years doing the medicinal chemistry tweaks to specifically design the IRAK4 molecule. As I said, it was a very specific fingerprint that we were going for. We worked with them on that process, and they were terrific partners. And of course, now that we're seeing it in the clinic, all that early work is paying off, but it was a long string of early work and Aurigene, world-class leaders in this research, they're terrific partners for us. Something else on this slide, you'll note in the upper right-hand corner. The NCI, just recently, in the last year, has also started focusing on IRAK4 as a very new and important driver in cancer. And when they looked through the world of IRAK4 inhibitors, they came to the same conclusion that we did. That this was the single best platform and IRAK4 as a drug, in our case, meaning was the single best drug. And we were the company and that drug was the drug that they chose to sign a credit with for future studies to find the next indications in cancer where IRAK4's an important target. So Aurigene on the IRAK4 side, a critical partner for us. On the VISTA side, in many ways, a very similar story. At ImmuNext, which is the company that's been set up by Randy Noelle to hold his IP and work in concert with his lab on the academic side of Dartmouth, they did, of course, all of the early work in VISTA. They discovered VISTA as a target. So VISTA as an immune checkpoint was first discovered and outlined by Randy Noelle. Now a lot of people look into VISTA, but Randy is the Pioneer. He licensed that IP portfolio to Janssen back in 2012, so that they could develop the monoclonal antibody, which they did. And as I mentioned, after an early setback with on-target tox, they abandoned that programming gave the IP back to Dartmouth, thankfully, for us. Randy's team at -- with Dartmouth and ImmuNext then spent another 5 years developing the process for how to optimize therapy with an anti-VISTA monoclonal antibody. And when we had had an internal program, there are only 2 companies on the planet that have ever had a clinical study in VISTA, targeting this new immune checkpoint. One was Janssen with the monoclonal antibody. The other was Curis, and we did it with a pill, with a small molecule. What we learned was the small molecule didn't hit VISTA as hard as we needed it to in humans in patients. that it was a good target. But in order to really inhibit VISTA as a checkpoint we needed to do what you do with PD-1 and CTLA-4, and that is cover it completely as you can with a large molecule and monoclonal antibodies stick like velcro. We needed that kind of complete coverage of the receptor. When we started looking around and see who had IP in VISTA, and there are other people who had looked at VISTA, of course, the one who discovered it has the best. So we were pleased that in meeting with Randy he appreciated our work in VISTA and was very eager to work with us. And in bringing that in-house to Curis just over a year ago, and in working with him and his team to design the protocol to help us manage this profiling and really optimize treatment of cancer with this drug. ImmuNext and Dartmouth have been terrific partners for us. We're very grateful for their work. And our hope is that we are very close to being able to show how this could be a transformational product, offer a new paradigm of treatment. It could transform IO checkpoint therapy, and I don't say that lightly.

Thank you, Jim. I think we have time for one final question in our queue here, which is, any comments on the current cash runway? And any guidance you may have on that?

Yes. So we are in a very fortunate position that we have a very sizable cash position. We do not need to go to the market and raise cash anytime soon. We've got over 2 years of cash in the bank, which is fantastic. We went last year at this time, a very different position. We were just sort of inching our way into the AML and MDS story. VISTA was just on the brink of getting through the FDA. With our initial success in AML and MDS, we were able to go out and do a very large and significant financing. And that allowed us, as we saw that AML and MDS, that the data were going to be even better than we had hoped that we could hit the accelerator across the board. And we went very quickly from effectively having one iron in the fire to we've now got 10 different studies or core populations that we were studying between IRAK4 and VISTA in the clinic in humans right now. All 10 are going fast in furious, and that's as a direct result of being able to do the significant financing at the tail end of last year that we did. So right now, little over 2 years of cash in the bank, 10 different catalysts that we've got coming, various timing across the board, but lots of opportunities for news over the coming 12 months. And I think we're in a very strong position. And I think our balance sheet strengthening that we did at the last year is a major part of ensuring that we had that uninterrupted operational focus to execute the way we've been executing this year and that the data has come out even better than we thought has been icing on the cake. So very strong balance sheet, looking really forward to an exciting year to come.

Wonderful. Well, thanks so much, Jim, for your time and everyone for your questions. We appreciate you all joining and this is the conclusion of the presentation. So we're available for any further inquiries post the call.

Yes, thank you, Ryan. Really appreciate the opportunity.

Thank you so much. Bye-bye.