Jim Dentzer: Yes. Thank you. Appreciate it, Bill. Thanks for joining us. So let me try and knock off those three questions in a row. So first, the split on FLT3 patients versus spliceosome patients. So this one is really, really interesting. And I think it reflects the unmet need in AML. Both of these studies are recruiting quickly, as you may recall, we came off our partial clinical hold midyear last year, got our sites up and running. And we are seeing really strong enrollment rates across the board at our sites. There’s a real pent-up demand in AML for a novel target. In particular, as you note the pace of spliceosome has been really interesting. So FLT3 constitutes roughly one-third of AML, one-third of AML patients have a FLT3 mutation.
Patients with a splicing factor mutation make up a much smaller portion of that community, maybe 10% of AML patients have a splicing factor mutation. And yet — that has outpaced enrollment in FLT3. And I think, it is precisely what we said. There are no drugs available. Not only is nothing approved, nothing works for these patients. This is the first time people are seeing activity. And to see that kind of activity with a single agent is really compelling. So we look forward to sharing our results with you next week in those two populations. And we look forward in having the discussions with FDA as well. We — we’ve got to our data set in 20 patients with spliceosome. We are going to add another couple in FLT3 and follow these patients and take those data to the FDA and begin the discussions on registrational design, and we’re looking forward to that.
The second question was about triplet safety. So the design of this study, as you may remember, I think is really interesting, and it’s all about, as I mentioned to Yale, ensuring that our leukemia program is partner ready. So we will have, by year-end, mature data sets in two distinct genetically driven populations in FLT3 and splicing factor mutation. The study we just started in triplet is a study that enrolls patients who are currently on aza-ven in the frontline setting who have achieved CR but are still MRD positive. We’re going to then take those patients into the study and add emavusertib to their therapy, turning the doublet into a triplet. Of course, what we are hoping is that we can see efficacy and get those patients to MRD negativity.
But the key is that we will have been able to isolate the safety effect of adding emavusertib to that aza-ven doublet to the current standard-of-care. So that by the time we get to year-end, obviously we are always hoping to see signs of efficacy. But what we really want to be able to say is we have got a drug that’s hitting a novel target in IRAK4. That novel target clearly matters because we are seeing single-agent activity. We know that the existing standard-of-care of aza-ven doesn’t hit it. And then we hope to add to the discussion by year-end, we can add a drug emavusertib to that doublet that allows the current standard-of-care to address this new novel target of IRAK4, and we would hope of course, that we would then see in the clinic in that setting, what we saw in the preclinical data, which is we have the potential to establish a new benchmark and establish a new standard-of-care in frontline therapy and AML across the board, all comers, FLT3 mutation or not.
Then your third one was on BTK-naive patients in the study in lymphoma. So just as a reminder we have tested the combination of emavusertib with gilteritinib in multiple indications within NHL, and specifically with primary CNS lymphoma in BTK naive patients, as well as BTK experienced patients. The underlying logic of the drug is that patients who are on ibrutinib or NHL patients who are on ibrutinib are on it precisely because it allows them to down-regulate NF-kappaB over activity by blocking the BCR pathway. There are 2 pathways that are driving NF-kappaB over activity in these patients. There are a lot of BTK-inhibitors today. There’s only one drug that blocks TLR pathway, that second pathway driving NF-kappaB over activity, and that’s emavusertib.
Our view would be blocking both of those pathways that are driving NF-kappaB, which is driving disease in NHL. Blocking both pathways is always going to be better than blocking either one alone. So if we can then take that mechanistic logic into the preclinical setting and see the hypothesis is supported, which we’ve already done. And now go into the clinic and compare and contrast, as you say, BTK naive and BTK experienced patients, being able to show both as good and we already have. But we think it’s even more powerful. If all we had were BTK naive patients, someone might wonder whether the efficacy was coming from the BTK inhibitor. But because we know these patients are on a BTK and then fail, either relapsed or refractory, you would, of course, expect that to immediately rechallenge them with ibrutinib yet again, the response rate is probably going to be 0.
So if we can show that we can get activity in those patients, even though they’ve just failed BTK, then it’s obviously either the performance of emavusertib alone or emavusertib’s synergistic combination with BTK and its ability to resensitize patients to BTK, that is driving that. And so we think that’s a really powerful thing to do. Thank you for asking that question. I guess that was pretty long. I hope it answered your question thoroughly.
Billal Jahangiri: It did. It did. I just one more on the comparison front, but back in the triplet I know it’s meant to be safety, but I guess, just for those of us who is our job, right? So how would we – again I think all of you to not give a [milestone] (ph) to some of these patients for the sake of comparison, right? So are there any historical benchmarks that you can point to get as aza-ven and then have MRD positivity and how they fare off, just so that we have something to compare to when that time comes.
Jim Dentzer: Yes. Actually, within the leukemia setting, Bob, maybe you’re a better person to talk to that.
Robert Martell: Yes. I don’t have the details right in front of me, but clearly, it’s a major problem for AML induction because if a patient continues to have molecular evidence of disease, that implies that the disease has not been taken care of. So a significant portion of patients are able to get to MRD negative, but there’s also, I’d say, a significant majority of patients who can’t achieve that, who maybe they achieve a CR or a CRh but when we do a molecular analysis, it is not MRD negative, and that correlates very strongly with relapse. And so that’s what we’re ultimately would be looking to achieve. In this early study, like Jim said, we are looking mainly for safety. And so we don’t have that as a goal for this particular study, but ultimately, that would be the long-term goal ultimately in earlier sort of upfront situation where we would start out the study in combination with aza-ven from the beginning.
