Good afternoon, everyone. Thank you for joining us at the 23rd Annual Needham & Company Healthcare Conference. My name is Gil Blum. I'm a Senior Biotech Analyst here at Needham, and it is my pleasure to have with me today Jim Dentzer, the CEO of Curis. He will walk us through the story, and we will have some time for Q&A at the end. With that, Jim, you have the stage.
Thank you, Gil. Thank you for having us today. Really appreciate the opportunity. Welcome, everyone. I'm not going to walk through every slide in our deck. I'm just going to try and hit the high points. Happy to take questions as we get to the end.
So, Curis, we have a pretty broad pipeline, but we've been focusing our attention and our funds on our lead program. It's a first-in-class IRAK4 inhibitor. IRAK4 is a really interesting target in the context of oncology, and as we'll see, it plays a major role in leukemia, lymphoma. And stay tuned. It looks like it may also have broad application in solid tumors as well. Today we're going to focus on the hem-onc leukemia and lymphoma. Our near-term milestones are going to be at ASCO and EHA for leukemia, and then in December at ASH for lymphoma. So as I mentioned, IRAK4 is a really exciting target in oncology. And it plays a major role in both the lymphoma and the leukemia space. In lymphoma, there are two biologic pathways driving disease: the BCR pathway and the TLR pathway.
The BCR pathway is blocked by ibrutinib or by BTK inhibitors. The TLR pathway is blocked by our drug and IRAK4. In leukemia, it's the TLR pathway and the FLT3 pathways that are driving disease. In our case, our drug actually blocks both. As we'll see when we go through the biology of the molecule and the mechanism of action, you'll see that we block both IRAK4 and FLT3. It's almost like combination in one molecule. I'm going to bypass this one very quickly. You can find it on our website. Our corporate presentation deck is at curis.com on the main page. Bottom line is that we're going to look at proof of concept subsets or subpopulations within leukemia and lymphoma first to prove out the molecule and try to get to a label as quickly as we can.
But even these populations, while they're small, these are still very large commercial applications. Of course, it gets only broader if it turns out the hypothesis pans out across leukemia and lymphoma in front line. But the original data sets, while they are subpopulations which are attractive from a regulatory perspective, they also have very attractive commercial potential as well. So this is the data set in lymphoma that we published at ASH just a couple of months back. There are a couple of things of note. When we walk through the mechanism, we'll see that blocking both the BCR pathway and Toll-like receptor pathway is really important in this space. And it makes sense, and the hypothesis is that blocking both is better than blocking either alone, as we saw in that first slide.
When we look at these initial data, a couple of things really stuck out for us and really encouraged us. First, these are very sick patients, very heavily pretreated, up to 10 prior lines. The second is, as you can see, we've bifurcated the data to show patients who are naive to BTK, as well as those who have been on BTK and failed and then come onto our study. This is really important because, of course, in combining with BTK, we want to be able to show that the combination matters, and that, in fact, if you've already failed BTK, it clearly raises the import of having our drug as part of that combination. This is why it's so important to show the BTK failures on the right-hand side.
Another thing that we point out is, of course, across the space of non-Hodgkin's lymphoma, you can get a pretty nice response rate with monotherapy and BTK, but you typically get PRs, not typically CRs. We're seeing CRs in combination. And again, it makes sense, given the mechanism. This data set in primary CNS lymphoma is what we're looking at as our proof of concept. So within the landscape of non-Hodgkin's lymphoma, we're going to go here first to prove that the molecule works and look for a potential path to first label. You can read it faster than I can talk to it. But what makes this so attractive is, obviously, it's an orphan indication, which should make it very attractive to regulators. But it is an indication where there are no drugs approved in relapsed refractory disease. All of these patients are relapsed refractory.
In this chart, all of these patients had failed BTK. We also appreciate that in this population, front line is methotrexate and chemo. Typically, the relapsed refractory patients then will go on a BTK. We know what the efficacy looks like for patients in relapsed refractory PCNSL who go on BTK. The standard is ibrutinib, and the CR rate is 19%. Now, what happens after those patients fail ibrutinib? You would have expected, of course, if they were naive, 1 of 5 would get a CR. Well, presumably, when you rechallenge them with the same drug, you might get 0. We don't know that. But of course, it stands to reason it's not going to get better. What we're seeing here is, of course, all the more encouraging. These have failed ibrutinib, and it's not 0 of 5. We're getting 3 of 5, small n.
We need to prove it out with more patients, and we'll do that when we get to ASH. But it appears as though the original theory underlying the mechanism of action that played out so well in the lab looks like it's holding up in the clinic. On the leukemia side, again, when we go through the mechanism, we'll see hitting IRAK4 really matters. We followed a really nice progression to date. So on the far left, this is all-comers, all-doses, classic phase 1 study. We're seeing a really nice signal. There appears to be single-agent activity here. When we start parsing through the data to look at specific genetic populations where we would anticipate the drug would have an outsized effect, in our case, it's either FLT3 or IRAK4 patients, FLT3 or splicing factor patients. We're seeing that, of course, the waterfall gets even better, as we would hope.
And then on the last, on the far right, what happens when you optimize for dose? We know that our dose in monotherapy is 300 milligrams b.i.d. And when we do, of course, the data get even better. So nice signal in all-comers, all-doses. Signal gets stronger when you focus on the subpopulations where you'd expect, and stronger still when you go to the right dose. So nice progress so far. At EHA in a couple of weeks, we expect to be showing an update of these data where, instead of n equals 3 for each data set, we're going to be looking at n to 10- 15 patients in each of these data sets. Let's talk a little bit about the design. So, as I mentioned, this is an IRAK4 drug. It was the very first IRAK4 drug to come down the pike for oncology. We pioneered it.
But we had the opportunity to design a molecule that wouldn't just be first-in-class, but had the potential to sustain a best-in-class performance. That was with all the other hits that we designed in. So FLT3, which in the context of leukemia is going to be very important as a second target hit, was added in. But also, you'll see we hit DYRK. We hit the CLKs. We hit another of other targets of interest in oncology that we think help make this molecule differentiated from anybody else that might come down the path in IRAK4. Within leukemia, there are two broad pathways. The FLT3, for the interest of time, I'll bypass for now. There are three leading FLT3 drugs: gilteritinib, the market leader, quizartinib, and midostaurin. All of them hit exclusively FLT3. They do not hit IRAK4. We, on the left-hand side, also hit IRAK4.
This really matters in the context of patients with FLT3 mutation, but also all-comers. IRAK4 is overexpressed in nearly all AML patients, if you look at The Cancer Genome Atlas . The reason why it matters is that IRAK4, especially in its oncogenic long isoform, binds very tightly, directly and tightly, to MYD88. And when it does, it forces constitutive activation of the myddosome, that driving overactivity of NF-κB, and that drives disease. So when we look at the preclinical data to try and identify where should this drug work and why, on the left-hand side, we just address the hypothesis of IRAK4 in general. Is hitting IRAK4 the target helpful in AML? And the answer is, of course, in this experiment, we've shown that the answer is yes. On the top, you see the vehicle. This is an IRAK4 expressing model. Lots of leukemic blasts.
When you treat that model with immunosuppressive with our drug, we, of course, knock down or inhibit IRAK4. And that leads to a dramatic reduction in leukemic blasts. So a lot of different variations of this experiment, but addressing IRAK4 in the context of AML appears to be beneficial, and we have a strong drug targeting IRAK4. In the middle graph, this is highlighting the importance of adding FLT3 to our molecule. So we think IRAK4 has the potential to go front line in combination with Aza-Ven. But because we also hit FLT3, there may be the ability to go after a label in relapsed refractory disease in monotherapy. So this publication, the Melgar paper, it's well known to FLT3 KOLs. It was originally written to try and understand why is it that FLT3 drugs as a class don't work all that well.
What they found was that the reason they don't work all that well is there's an escape path for FLT3 inhibition, and it's IRAK4 signaling through the Toll-like receptor path. They tested this out. You can see the graph here that we've reproduced. When you treat with a FLT3 inhibitor or an IRAK inhibitor, you get a really quick reduction in tumor burden in these patients or in these models. But the disease, of course, comes roaring back. If you block both FLT3 and IRAK, you get the bottom. You get the bottom chart. You get the much deeper response, and you can hold that response. That's what we would be looking to replicate in the clinic. There are three big players in the FLT3 space today, but none of them hit IRAK4 as well. We're the only one that does.
Our early data suggest that this looks to be a valid approach and that we've got the potential. We'll need more patients to prove it out, of course, but we've got the potential to not just be a first-in-class dual inhibitor, but best-in-class among the FLT3 population. Now, on the right-hand side, again, this is mirroring what you see on the far left. Hitting IRAK4 seems to have great effect in the AML population broadly. The two leading drugs, standard of care or Ven-Aza, neither of them hit IRAK4. As long as there's no safety overlap, and we'll find out this year as we initiate our triple combination study. Adding IRAK4 to standard of care from a mechanistic perspective looks like it could provide benefit. So in this chart, what you see is what happens when you treat with AZA.
Of course, AZA on its own nicely leads to good tumor reduction. When you add our drug to it, it gets even better. Then you look at the doublet of Aza-Ven. Aza-Ven, it stands to reason, is better than AZA alone. When you add Ema to it, make it a triplet, better still. So this supports the idea. This experiment, of course, is an all-comers model. It's not a specific mutation. It supports the idea that going front line with Aza-Ven should be an effective approach for this drug and an opportunity for this drug in the front line setting. It does add a unique degree of efficacy by hitting IRAK4, and it does not appear to have any overlapping dose limiting toxins. So we're excited about that prospect as well.
So moving forward at EHA, we're going to see data in the IRAK4 population and the FLT3 population in monotherapy. So we've got n=3 in each, as we've seen so far. We're going to have 10 or 15 in each of these buckets at EHA at Madrid in June. And then in the triplet study front line, we've got an ongoing study that we're just initiating now. We'll have a handful of patients by year-end. And once we've proven out safety, once we make sure that there's no toxins associated with the triplet, of course, we'll be looking to go full bore into that setting as well. With that, let me switch over to the lymphoma side. So leukemia, again, very powerful story for IRAK4. The additional hit of FLT3 may afford an opportunity as a monotherapy. We'll explore that at EHA.
In lymphoma, this story, we just announced the data at ASH, which I reviewed earlier. We're going to have another bolus of patients at ASH this calendar year in December. The logic or mechanism is very similar in that, just as in leukemia, it's NF-κB is the problem, and downregulating NF-κB is how you want to treat the disease. As you can see on the left-hand side, in lymphoma, there are two pathways driving disease. Two pathways are driving NF-κB overactivity. The first is the BCR pathway. That's addressed with a BTK inhibitor. The second is the Toll-like receptor path. That's addressed with our drug blocking IRAK4, which blocks the myddosome. We would suggest that blocking either pathway should provide benefit. But the scientific rationale is that blocking both pathways ought to be better than blocking either one alone. The preclinical data proving that out are on the right-hand side.
So it shows a model what happens when you block ibrutinib alone and what happens when you block emavusertib alone, when you block IRAK4 alone. Both drugs lead to reduction in tumor volume. But the combination, blocking both paths, blocking the BCR path and the Toll-like receptor path, blocking with ibrutinib and emavusertib, respectively, leads to a deeper, more sustainable response. So it's nice that we see a good consistency between mechanism and preclinical findings. Now, of course, let's talk about clinical data. And this is the slide that we saw in the beginning. When we look at relapsed refractory primary CNS lymphoma within the landscape of NHL, this is one of those diseases that it's an ultra-orphan disease, but we know that it's got an association with a MYD88 mutation, which means it is especially sensitive to reductions in Toll-like receptor pathway activity.
It's a great lead proof of concept data set for us. It means in a relatively small number of patients, we should be able to see the role of our drug in providing benefit. And as I said before, front line is methotrexate and chemo. Second line treatment of BTK, we know what that does. It's been published that the CR rate for ibrutinib is 19% in these patients. We would expect that if they had not seen a BTK before and we put 5 patients on the combination, ibrutinib alone should be able to provide a 1 out of 5 CR rate. These are patients who have all failed BTK. Presumably, if you put them all on BTK again, you'd get 0 out of 5. What we're seeing here is 3 out of 5.
I'm not suggesting we're going to have a 66, I mean, a 60% CR rate going forward. What I am suggesting is that we're very encouraged by what we're seeing, that it is consistent, that the theory that blocking down both pathways should be better than either alone, that panned out when we got to the lab appears to be panning out in the clinic as well. And that's reassuring. So moving forward to ASH of this year, what we're going to look to do is expand this data set, go from 5 patients to 10- 15 patients. And if we can see a consistent signal at that point with a larger N, of course, we pivot to having a discussion with the regulatory authorities about how do we get this drug approved and what does that pivotal design need to look like.
And of course, with more money, we would expand across NHL. We'll look to mantle cell, to DLBCL, CLL, anywhere where knocking down the Toll-like receptor path or downregulating the NF-kappaB complex as heavily as we can, wherever that matters, this is where we're going to want to test out and explore the use of the combination of immunosuppressive with BTK. The last bit that I always get questions on, so I'll just kind of throw that out there. It has been a tough year, Gil, as you know, or last couple of years in the market. As the market started to retreat, we focused our pipeline to conserve our cash and very effectively so. We finished out December with $56 million in the bank.
We have emerged over the last 2 years from a partial clinical hold that was originally focused on a safety issue that the FDA had some concerns about. We came through, obviously, very positively, addressed any concerns that they had, and at the same time, we established our dose. In the last 6 months of the year last year, coming out of that hold in early July, got all our sites up and running, got new patients enrolled into the study, and thankfully finished the year with cash in a good position. All the bad news is behind us, and we're looking forward to having the conversation at EHA with our first new data post-clinical hold.
Hopefully, as I say, the data will remain consistent and beat the benchmarks that we've got in front of us. We'll be looking at an exciting future both in leukemia and lymphoma over the course of 2024.
All right, Jim. Thank you very much for that. The floor is actually open now for questions. But in the meanwhile, maybe a couple from me. Just as a clarification to help me understand, your target molecule is sufficiently potent to target the FLT3 patients all by itself?
Oh, yeah. All by itself. So it's one of the things we intentionally designed. In fact, I'll go to that slide while we talk about it. So I mentioned that Curis is the company that first identified the utility of IRAK4 in oncology. So we found this out before anybody else did. That was a huge luxury in taking the time to design the molecule. We had our eyes set on Pharmacyclics as an example, right? They developed ibrutinib. And they got to market first. But they didn't have any competitive position due to their design. They were vulnerable to fast followers, which they now have. So they've got acalabrutinib. They've got zanubrutinib. They've got pirtobrutinib. They've got a bunch of competitors hot on their heels looking to become best-in-class. What we did was design a molecule, first and foremost, that hit IRAK4 really hard.
We wanted 100% inhibition, and we got it. But then we wanted to know, what else can we design into this molecule so that we can resolve this before we get started, not just be first-in-class, but sustain it as best-in-class? And so we hit FLT3. And as you can see in the binding affinity, the CA-4948 is very powerful. We're getting 100% inhibition there at our dose concentration. But also, we're hitting DYRK. We're hitting CLKs. We're hitting a number of other targets that will establish this not just as a first-in-class molecule, but we hope is a best-in-class. And in this last year, we saw the benefit of that because we had a fast follower in Kymera who came out of us with a protein degrader.
We spent 2 years explaining what I just walked you through, that we were not just first-in-class, but they were never going to match our efficacy. Sure enough, 2 years later, they figured that same thing out, and they just announced in Q4 they are out of oncology.
I'm actually going to get back to that in a minute. But there's one thing I really want to understand for investors and then for myself as well. So some of the pushback on the AML space is this kind of slicing and dicing to smaller and smaller subpopulation because of mutation rate IDH1 and 2 and FLT3. And you'll hear that a lot from investors. This is not a good value prop. How do you counter that argument?
Yeah. I would say two things. We look at AML, first and foremost, as an opportunity in front line from a commercial perspective. I'll pull up a slide while I'm talking. One thing that is known about IRAK4 that's different than all of those others, IDHs, FLT3, everything else, IRAK4 is expressed and overexpressed in nearly all patients with AML. It is an unaddressed target that is ubiquitous. This is coming from the Smith-Choudhary paper from Nature Cell Biology in 2019. The largest market or the largest genetic target is IRAK4. The second largest is FLT3. We hit both. Our view would be standard of care today is Aza-Ven. If the data hold, standard of care tomorrow is going to be Aza-Ven-Ema. That's what the preclinical data, as we saw earlier, support. We're going to be chasing after that as our long-term commercial opportunity.
We do think because we hit FLT3, we might also have an ability to go first-in-class in a relapsed refractory setting to outperform all the FLT3s because they don't hit IRAK4 as well. But the long term is the value of IRAK4 in AML is an add-on to Aza-Ven. Hit Aza-Ven, add this to it. And I think we're hearing a lot from our investors, anybody that's interested in, say, Syndax or the menin inhibitors, they see the value of this. Show us a drug that is safe, that adds unique efficacy to as wide a group as possible, that can be included in a drug cocktail because front line combination is where the market is headed.
We think we're making a pretty strong case, and we're going to make it stronger, that adding this drug to a combination regimen has the potential to be the best thing for patients in a front line setting.
Okay. That makes sense. May I have a quick question from the audience here? We're asked to remind us what was the clinical hold about and kind of how that was the result.
That's a very painful question, Gil. Looking back in time, I'm not quite at the point where I can look back and laugh just yet. It was a painful period. The FDA asked this question because we had a patient death. What we said was that in relapsed refractory AML, median survival is 2.3 months. It's really a grim prognosis. The patient in question died in month 9. In our view, the question shouldn't be, "Why did the patient die in month 9?" It should be, "My gosh, how did the patient make it all the way to month 9?" So what I said publicly at the time and what we said to the FDA was, "Look, we've got lots of data on this case. We're happy to share it with you." And you're quickly going to come to the same conclusion we did.
The patient died from cancer, not from any concern about the drug. They reviewed the data and very quickly came to that conclusion. Said, "Yep, absolutely. The patient died from cancer, not from underlying concern about safety or the drug." What kept us on hold for a longer period of time was when they pivoted the conversation. Project Optimus isn't something they can put you on hold for. But once you're on hold, they can ask you questions. And we were right in the crosshairs. It's the ideal drug to flex Project Optimus. We dosed in 200, 300, and 400 milligrams b.i.d. in leukemia. All three doses were safe. All three doses led to responses. From the FDA's perspective, great place for them to have a discussion.
They looked at our data, and what we told them was, in our view, of those 3 doses, 300 milligrams led to a higher probability of response than 200. So 300's better. When we looked at 400 versus 300, we didn't see a difference in the probability of response, which means we're probably saturating the target in most patients at 300. So again, 300's the right choice. The FDA's view was they looked at 300 versus 400 and said, "We like that logic. That makes sense. The data support that." Between 200 and 300, they didn't think we had enough patients at 200 to make that case. And we pointed to our lymphoma data where we had lots of patients that had been dosed at 200 and 300 as well. And their view is that's a different division.
So they asked us to put more patients at the low dose, follow those patients, recapitulate all of our reports, send them off to them, and then they'd help us with that decision. And so that's what we did. We enrolled a bunch more patients at 200, redid all the exposure analyses, sent it off to them, and they called us and said, "Oh, looks like as we review all the data, you're right. 300 milligrams is the right dose." A year and three months later.
Yeah. That is painful.
Yeah. I mean, the FDA, of course, they can't worry about the commercial concerns. But from a biotech company's concern, damn near killed the company. I mean, we were at one point a $1.5 billion market cap. At our depths, we went down $25 million. We lost almost every single investor we had. And you can understand it, right? If we can't enroll patients, we can't generate data. There's no catalyst. The good news is that's now behind us. We now have not just the safety having been evaluated by FDA, but the good news is they've already been through Project Optimus with us. So we're all aligned on dose. And as of last July, we can enroll patients. So we spent the back half of last year getting all our sites up and running again. We're now enrolling patients again.
Our very first data coming post-hold in leukemia is going to be at EHA in a couple of weeks. We're really looking forward to getting that data out there and having a discussion about the future of this drug.
I mentioned I would come back to Kymera. So kind of the reverse analogy for what you were saying. What about autoimmunity? I mean, everyone who has an IRAK4 is now, especially the degrader companies, seem to be interested as a program now.
Yeah. So we certainly see the utility of IRAK4 in the inflammation space and autoimmune space. That's originally where IRAK4 was targeted. So there are a lot of big pharma programs that have an IRAK4 small molecule. And of course, Kymera is proceeding there with its degrader as well. I'm not saying never, but we're an oncology company. We're focused on the utility in AML and leukemia. And as we just announced in Q4, we now have this study going on in metastatic melanoma with Merck that Merck's picking up the tab for, thankfully. Thank you, Merck. And we've got a really nice preclinical data set that shows how we potentiate both pembro and chemo. With luck, by the end of the year, we'll be able to see that there's some human data as well.
Between leukemia, lymphoma, and potentially solid tumors, I think we've got our hands full as a small company, and that's where we're going to focus.
Yeah. I mean, the other angle that I wanted to kind of address here is actually the CNS lymphoma, the fact that you're getting what appears to be brain penetrance, right?
Yeah.
That's notable. Maybe remind us what the value proposition is in CNS lymphoma. Most CNS lymphoma patients are excluded from studies.
Yeah. So the prognosis is pretty bad in this population. As I mentioned, there is nothing approved in the relapsed refractory setting. So these patients, typically, the patient journey, they start with chemo or methotrexate. And then from that point, once they progress, they're typically going to go on ibrutinib. ONO just has a study going with their BTK inhibitor as well. But they typically go on ibrutinib. And we know what the response rate is. The response rate's roughly 20%. It's 19%. Roughly 20%, 1 out of 5, you're going to get a response. But it's not approved. It's just the guideline. It's just the standard. The opportunity that we see in this space is, first and foremost, there is a very clear unmet need. Because it's ultra-orphan, we think we'll get a very friendly reception, not just from regulators, but from payers as well.
We know that Primary CNS Lymphoma is associated with MYD88 mutation, which means it should be sensitive to a drug that can block the TLR pathway as we can. And because we know the hurdle is so clear, we can establish as a proof of concept the idea that blocking both pathways is better than blocking just one. If we can beat that 19%, and I would argue beating 19% among naive patients is really what you'd want to be able to do, that we can beat 19% in patients that have already failed BTK, I think makes a very strong case for proof of concept. So that's where we're headed. And then commercially, because nothing's approved, you've already seen these data, this is a very meaningful market. This has the potential all by itself to be a company maker.
That's before we talk about any other indication in lymphoma or certainly anything in AML.
Maybe a little bit of leap of imagination here. You probably are well aware of this, but multiple sclerosis, right? Brain penetrance and multiple sclerosis as being the failure from Merck KGaA and doesn't name any other. Interesting.
Yeah. And as you can imagine, given my past advisory, that's a forefront of my thinking as well. Yeah. IRAK4 as a target looks to be really important in many different spaces. As I said, right now, our published focus is going to be in leukemia and lymphoma. But there are a number of areas that we're going to be pursuing that we see where this might make sense. Obviously, MS is one of those places where it makes sense for a small molecule that can cross the blood-brain barrier and address inflammation. But I would say first things first. We're off hold. We're enrolling patients. We've got near-term data in leukemia. Presuming that those data are consistent and that we could beat the benchmarks that are out there, 21% in the case of FLT3, sadly, 0 in the case of splicing factor patients.
We need to be able to show that this drug is going to make a meaningful advance in that space. And then coming up with lymphoma at year-end and then hot on the heels, we're going to expand everywhere where we can with this opportunity.
Excellent. All right, Jim. With that, I think we're out of questions from the audience as well.
Excellent. Well, thank you very much, Gil. Really appreciate the opportunity. Thank you, everyone, for joining us today.