And in fact as you know it’s a $10 billion to $15 billion market today ibrutinib, itself is $10 billion of that the AbbVie, J&J drug. What we’re looking to do in lymphoma is hit NF-kappaB as hard as we can. There are now five big pharma companies that are chasing after BTK inhibitors of various flavors covalent or non-covalent, all of them working effectively the same way, all of them blocking that, BCR pathway driving NF-kappaB. The second pathway, the toll-like receptor pathway is currently unaddressed. Curis is the only company that has a drug that blocks that path, that’s emavusertib. It binds to MYD88 Myddosome and without that binding in the absence of IRAK4 Myddosome and the toll-like receptor path more broadly shut down. So it stands to reason when you step back, if you have lymphoma that’s effectively treated by BTK, you’ll always want to block the NF-kappaB or down regulate NF-kappaB as strongly as you can.
So hit the BCR path with BTK, hit the toll-like receptor path with IRAK4. The combination not monotherapy, the combination should always be better than either one alone. And that’s what we found in the lab. And, of course, that’s what we’re finding so far in the clinic. So that’s the logic for the combination with emavusertib. In terms of going to front-line eventually, of course, we would like to suggest that the long-term possibility that we’re going to explore is, is this an opportunity to have a companion front-line standard of care with BTK across non-Hodgkin’s lymphoma? Now it’s a little premature for that. We’ve chosen primary CNS lymphoma as our proof-of-concept indication to prove it out. And we’ve been able to show that we can generate data pretty quickly.
But long-term, I think of course we’re going to want to go frontline in combination with BTK inhibitors. For now having an ultra-orphan indication where we can go into the relapsed/refractory setting where there are no drugs approved that should offer a pretty compelling regulatory opportunity. So that’s why we’re going down that path. I hope it was helpful.
Soumit Roy: No we got it. And speaking of companion, since you’re moving into the solid tumor, I’m curious if you’re going to push forward the companion diagnostic for IRAK4 mutation assay, and if that would be helpful in carving the market both for — inside the solid tumor space and also eventually in the leukemia setting?
James Dentzer: Yeah. So the short answer is yes. The long answer is it’s a little more complicated. So in the short answer, are we pursuing the identification and the regulatory path for a companion diagnostic for IRAK4 expression? The answer is yes, absolutely. The more complicated answer is we don’t want that to slow down our path to development and making this drug available for patients. So the way we’re ensuring that fastest path is in monotherapy in the leukemia side where we’re looking to go into patients that have either a FLT3 mutation or an IRAK4 overexpression. We’re going to focus the IRAK4 population using spliceosome mutations. Now spliceosome mutations are a subset of patients that over-express IRAK4. The reason why you’d go after spliceosome mutations, is those mutations are already identified in existing gene panels.
So a companion diagnostic is much easier. We don’t need to have a new assay identifying IRAK4. We can just lean into the existing panels, the Illumina panel, the FoundationOne panel, places like MD Anderson that have a proprietary gene panels. These panels are already run on their existing patients. And we can lean into that and say if you have one of these specific mutations by definition, you have IRAK-4 expression and use that as our mechanism. But longer term, of course, we’re going to want a diagnostic. It’s the logic for going frontline in combination. We’re going to go all comers where we won’t need a companion diagnostic.
Soumit Roy: Thank you again, for taking all the questions and congrats on the progress.
Jim Dentzer: Sure. Thank you.
Operator: The next question comes from Li Watsek of Cantor Fitzgerald. Please go ahead.
Li Watsek: Hey. Good morning. Thanks for taking my questions. Jim, I guess, for the data that you’re going to present from the Leukemia study around midyear, maybe just set the expectations for us a little bit with data set that we are going to see, what the bar is for the three as well as for spliceosome mutations? And then for the combo data that’s going to come second half of this year, maybe tell us a little bit about, the bar here. Because is [indiscernible], as we know, the bar is fairly high, pretty effective. And also, as you alluded to earlier about toxicities and do you expect any overlapping talks with this regimen?
Jim Dentzer: Yeah. Thank you, Li. I appreciate you dialing in. So on those questions, first, in terms of the number of patients, we’ve consistently said what we’d like to have is a data set of 10 to 20 patients. We now have a data set of three patients, in spliceosome, three patients in FLT3 at our target dose and five patients, of course, in primary CNS. We’d like to increase that data set to — equals 20 to 50, somewhere in that range. I hope that we’re going to be in a position, where we’ve got data collected. Of course, you enroll the patients, treat them, follow them for a period of time and then assess the responses. My hope is that we would be in a position to have that level of and that level of data in Leukemia, Spliceosome and FLT3 by midyear and in Lymphoma by year-end.
In terms of the benchmark, what we think we need to do to be effective in the monotherapy side is, we’re targeting a CR/CRh rate of 20%, lower bound in the low-teens, 12%, 13% kind of lower bound. But a 20% CR/CRh rate in salvage-line therapy, for either FLT3 or spliceosome in leukemia, we think is very compelling. Of course, our first three patients look better than that. But let’s not get ahead of ourselves. It’s only three patients. As we get to 10 to 20 patients, what we’d really hope is that we can clear that CR/CRh rate of 20% and be [indiscernible]. On the Lymphoma side, because there are no existing treatments, that bar is probably lower. What we do know is that the largest data set available for BTK as a monotherapy in primary CNS lymphoma was a study of 52 patients, the CR rate was 19.
So you’d expect one out of five patients or again, roughly a 20% CR rate in that population. And that’s in BTKi-naïve patients. Once they’ve failed BTK, you’d expect that re-challenging them with BTK yet again, probably wouldn’t work at all. You might expect zero out of 5. That we’re getting three out of five so far is obviously highly encouraging. I don’t think we need to maintain quite that rate. But if we can maintain in BTK experience patients, a 20% or higher CR rate in lymphoma, I think that we’ve got a very compelling data set to have a discussion with FDA. So 10 to 15 — I’m sorry, 10 to 20 patients in all indications, is what we’re hoping for. We look to be in a position to have data in that range for leukemia by midyear and for lymphoma by year-end.
Was that helpful?
Li Watsek: And overlapping toxicities with antiretroviral.
Jim Dentzer: Yes. Yeah. Yeah. So that’s the number one thing to look for in the triplet. Of course, it makes sense that — if you looked at our preclinical data and we’ve got a really nice outline of the preclinical data in our corporate deck, it’s very clear that from an efficacy perspective, in the lab we were able to add efficacy to aza to aza-ven. And it looks like if the consistency that we saw from mechanism to lab to clinic works the same way in the leukemia triplet, that it’s worked everywhere else we’ve tested we would expect to see that. The part that I’d say really merit some exploration is making sure knowing that the toxis is high in aza-ven, that we don’t add to it. We don’t have any reason to believe that it would be – that adding emavusertib would make it less tolerable based on what we know.
There is no overlapping safety profile. However, as we said, half of all patients that go on to aza-ven have difficulty tolerating it. We – first thing we’re going to look for as we add our drugs to aza-ven is to make sure we’re not exacerbating those toxicities. I think with efficacy you always look for but first things first, let’s make sure that we’ve got a drug that’s tolerable in combination.
Li Watsek: And what are your thoughts on the maintenance setting in AML? Are you collecting any data points that could potentially maybe support off-label use?
Jim Dentzer: Well, obviously, off-label use is something that happens but companies don’t target that. What we do look for is do we have a drug that first and foremost is safe. Second has a compelling and unique efficacy profile, so that we can provide a measure of efficacy that you can’t get from other drugs. And then third to your point, you want to make sure you’ve got a drug that can be taken chronically for long periods of time. Some of the indications we’re going after like AML are fairly aggressive but others like Waldenstrom’s are quite indolent. We have a patient that’s been on drug for I believe over four years now. So we’ve got a great track record. These are still early days of drug development for emavusertib but I think so far we’ve been able to check all three boxes.
The drug looks in almost 200 patients tested to have a really good safety profile. It looks as though it does provide in humans the same kind of clinical efficacy that we were seeing in the lab. And it looks as though you can take this drug over a long period of time in a maintenance setting. And that’s of course, that’s the trifecta that you hope for as a drug developer.
Li Watsek: Thank you.
Jim Dentzer: Yes.
Operator: Next question comes from Yale Jen of Laidlaw & Company. Please go ahead.
Yale Jen: Good morning and thanks for taking the question. Jim you have talked about that you will be interested to move to MDS, high-risk MDS, the second line but your waiting for the VERONA study readout. Just to your best knowledge, when do you think that might happen and what – and if that takes place sometime in the future? And what’s your plan at this point?
