And enrollment’s going so fast, Roger, that that’s not going to be — that should be well underway here after we reach the RP2D around midyear. The team is just crushing it in terms of enrollment. Did I answer your questions?
Roger Song: Yeah. I think you answered the first part. The second part really is just to clarify what is the Phase Ib expansion cohort because you mentioned the first line ven/aza combo, but how about the relapsed/refractory and the 7+3? Thank you.
Troy Wilson: I see. Okay. Got it. Yes. So the way to think about it is we will continue to evaluate the genotypes separately. So you have effectively seven arms. You have ven/aza, frontline ven/aza, NPM1 and KMT2A, you have relapsed/refractory, again, NPM1 and KMT2A. Same thing with 7+3 front line now no longer adverse risk. And then one cohort you might have picked up on, which is ziftomenib plus venetoclax, only venetoclax in the relapsed/refractory setting. And that’s one where we get a lot of interest from investigators asking the question, do you really need azacitidine? And you clearly need ven, but do you need azacitidine given that menin inhibitors are epigenetic. Their mechanism is an epigenetic modifier. We’ll test that in the clinic and see.
So when you consider each of two genotypes times those two essentially three plus the ven/zifto combo, that gives you seven arms. That’s what we’re describing, Roger, as the Phase Ib. We will not necessarily move forward with all of those into registrational. We’re gathering the safety data, the — we’ve activity data. We’re already working on what do — what is the first registration-enabling study look like, the second, etc. We’ll provide more color on that likely later this year.
Roger Song: Excellent. Okay. So that’s clear now. Actually, you already partially answered my last question, follow-up question is the registration path. Maybe can you give us a little bit in terms of time line guidance when you will start to think about the registration for either of those cohorts?
Troy Wilson: Yeah. So we’re already thinking about it. We’re already planning for it. Even though we’re learning — we’re continuing to learn about zifto as we dose escalate. And to some extent, what you’re waiting for is you need to be able to say to health authorities, this is the dose in the combination, and this is the data that supports that dose selection. That’s the point of this exercise. But you can leave that dose, Roger, in brackets and say this is what the design of the trial looks like. pending this dose. And our team is working quite intensely already to map out what do those registration trials look like? And obviously, you look at our emerging data, you look at the competitive landscape, you look at what are the regulators looking for in terms of endpoints, you do the commercial considerations all of that gets folded in.
What I can say to you is, so far, our belief is that ziftomenib has the potential to be the best-in-class menin inhibitor. And there’s nothing we’re seeing thus far that takes us off of that view in terms of safety, tolerability, combinability, absence of toxicities, QTc, drug-drug interactions, everything is looking good. So at this point, we have a wealth of options. We clearly won’t do them all or won’t do them all at the same time. We need to prioritize. And we’re doing that important work now, Roger. We’ll talk more about the design. We’ll probably give you a view on the design after we’ve gotten some input from the health authorities because we want to make sure that we bring them along as is appropriate when you’re considering registrational studies.
Roger Song: Excellent. Thank you, Troy for all the comments. That’s it from us.
Troy Wilson: Thank you.
Operator: Thank you. Your next question comes from Li Watsek, Cantor Fitzgerald. Li, please go ahead.
Li Watsek: Hey, good afternoon. Congrats on the progress. Just a couple of questions from me. Troy, I wonder if you can provide any color on whether the FDA has seen additional data for the breakthrough definition potentially from the ongoing pivotal study as well?
Troy Wilson: Yeah, Li. So you may find this answer unsatisfying. And for that, I apologize. We can’t really give you specifics on our engagement with the agency. Suffice it to say, they are very familiar with the benefit risk for ziftomenib. I mean they’ve been great partners with us from the beginning. As I say, we are in active discussions with them, already beginning to put the pieces in place to make sure that the modules of the NDA are lining up with their expectations. I can’t speak specifically to your question. I think they don’t frequently award a BTD unless they’re reasonably confident that the drug is actually going to deliver. Of the drugs that get Breakthrough Therapy designation, 90% of them go on to get approval.
The ones that don’t, it’s typically like a manufacturing issue or something else, which obviously won’t be the case of a small molecule. That gives you some guardrails. But we’re obviously thrilled by the BTD designation and particularly to be the first menin inhibitor and maybe the only ones to actually get it.
Li Watsek: Okay. Thanks. And then for the 400 mg dose, it sounds like it’s being cleared. So I wonder if you can share any maybe early indication whether you’re seeing a dose response here relative to the 200 mg. I understand the patient population is slightly different, but any color there would be helpful.
Troy Wilson: Yeah. I can’t really — so we cleared it for those of you who listen regularly, the last time we had — I had the microphone in a Reg FD-compliant setting, I said that one of the three cohorts was open at 600 mg. Here we are, I think it’s two weeks later or 10 days later, now three of the four are open. My point Li in telling you that is this data is evolving in real time. What is encouraging is, again, nothing really to be concerned about in terms of safety, tolerability, drug-drug interactions. I want to be careful not to get too far ahead of the data. The monotherapy data, Li, clearly says 600 mg is better than 200 mg. We didn’t test 400 mg, obviously, but 600 mg was clearly better than 200 mg. You would expect, Li, that same relationship to apply in the combination setting.
And so the real question is, can you actually — is the safety and tolerability manageable at 600 mg. If that’s the case, then you would expect improved activity to pull through in both populations. But I’ll answer you that — the question that way rather than sort of trying to give you an early peak at the 400 milligram cohort.
Li Watsek: Okay. Thank you.
Troy Wilson: Sure.
Operator: Thank you. Your next question comes from Brad Canino, Stifel. Brad, please go ahead.
Bradley Canino: Great. Thank you, and it’s nice to be able to focus on just your call this evening. I just wanted to check in on the BTD. Can you help me understand when you submitted for that designation? And why it ended up at that submission date?
Troy Wilson: Yeah. So, not really Brad. You — just to answer the question in a general sense, in our experience the way the BTD works is you have a pre-submission if the agency wants you to put in a full application, they’ll indicate it at that time, otherwise, they might indicate that they’d like to see you answer questions or provide additional data. If they invite you to submit the full application, they typically get back to you in about 60 days. That’s — again, that’s the general course. One of the questions that I think was out there in the community was what exactly is the unmet need in NPM1-mutant AML. And we — I think we were very successful in convincing the agency of the view of many of the docs, which is if particularly once you’re in the relapsed/refractory setting, there’s no difference in unmet need between KMT2A and NPM1.
So we’ve had a very constructive dialogue with the agency all the way back to — I hate to say it, but the agency was very helpful in terms of our navigating our partial clinical hold. They have been great partners ever since. I think they see the promise of menin inhibitors. I think they’re quite — I don’t want to speak for them, but they have been a great partner to work with.
Bradley Canino: Okay. And maybe if I can ask one more. As you’re progressing through the combo dose escalation, have the enrollment rate across the different cohort mutations come in line with your expectations headed into the trial? Thank you.
Troy Wilson: Yeah. So the enrollment has actually been pretty even across the cohorts. It ebbs and flows. As you go week to week, it — I’m not sure, Brad, we had really — I’m not sure what our expectations necessarily were going in. Certainly, we are seeing very, very strong engagement. I’ll just remind everybody that for each of these arms, if you will, it’s six patients per dose. Now some of these doses are actually over enrolling because sometimes you have patients who have cleared screening and — but you’re not yet ready to put them in the next highest dose. So there may be rather than six, we may have seven or eight or even more at a given dose. But at a minimum, when all is said and done and the escalation was at least 72 patients.
And I’m telling you now, it will be more than 72. Think about how fast that enrollment is gone. We started in July and look at it relative to other comparables out there, there’s just been incredibly strong engagement. The lag in the KMT2A frontline 7+3, Brad, is probably just reflective of the difference in the incidence. Again, NPM1 is 30% and KMT2A is probably 5% — it’s 10% if you include all of leukemia. It’s probably 3% to 5% in AML. That’s probably what you’re seeing. But it’s — again, it’s lagging behind only very, very briefly. We should — as we said, we should be clearing the 400-milligram cohort in the 7+3 KMT2A here imminently, and we expect that, that one will go to 600 mg as well.
