All righty. Welcome, everyone, to Jefferies London Healthcare Conference 2025. My name is Roger Song, one of the senior analysts covering SMID-cap biotech in the U.S. It is my great pleasure to have the fireside chat with Kura Oncology CEO, Troy Wilson. Welcome, Troy.
Thank you, Roger. Thank you to you and Jefferies for the invitation.
Absolutely. I have to say, in the very beginning, it's an exciting time for oncology, for Kura Oncology, and then for the AML menin and the AML population, patient population. So maybe we just kick this off right away. You just got an FDA approval, which is a fantastic milestone for Kura Oncology. So how do you see the label for this R/R population, AML with the NPM1 mutation? And then how do you think about the potential launch with this label?
Yeah. Thank you for the congratulations. I think menin inhibitors are the most important thing to come along in AML, probably in two decades. And they will do tremendous good for patients. In terms of the label in the relapsed/refractory setting, we think about four pillars: efficacy, safety, combinability, convenience. And we've tested this with KOLs. We've tested it with payers. We've tested it with strategics. And so let's take them in turn. There are two approved agents now in NPM1 mutant AML. Both of them have good activity, right? We're seeing, which is why the agency gave full approval. You're seeing good CRH rates. You're seeing durable responses. You're seeing the cases if the men have good transfusion independence. I would say it's probably a draw between the two compounds there on an efficacy basis. They have slightly better CR/CRh rates. We have slightly better duration of response.
Let's call it a draw. Safety. There, I think there's a pretty stark difference. Both drugs have a black box warning for differentiation syndrome. That's part of the mechanism of action. We have QTC prolongation in the warnings and precautions. They have a black box warning for QTC and torsades. That's significant, right? The agency, and in case people aren't familiar, you can go and read the FDA's regulations. The FDA doesn't have any discretion. If you have greater than a 10-ms elongation of QT, you can draw a warning and precaution. Just means watch out. If you're greater than 20 seconds, that's life-threatening. Ours is 7.7 ms, a mean of 7.7 ms. The upper bound of the confidence interval is 12 ms. That's why we have a warning and precaution. Our competitor is 23 ms. The upper bound of the confidence interval is 25 ms. That's a significant signal.
They have one nearly fatal event, one fatal event in 100 patients, 100 in NPM1. That's one in 100 risk of sudden cardiac death. There's nothing to sneeze at. So I think they are, I think zifto stands tall. Combinability. We do not have any clinically meaningful drug-drug interactions. There is, people have asked in the label, it does say there's a moderate interaction with CYP3A4, but there's no dose adjustment required. What that tells you is it's not clinically meaningful. The significance of that we'll talk about in a second, but those two relate to one another. The fact that our competitor has a drug-drug interaction and they have a risk of sudden cardiac death, that makes that very challenging. We have neither. Finally, on convenience. Ours is once a day. Theirs is twice a day. You might say, why does that matter? This is oncology.
The issue is the average patient in NPM1 is 65 and older. They're often on a lot of other medications. They may have other comorbidities. If you're BID and you have to fast twice a day, that can be rather inconvenient for an elderly patient. So I think as we go down from efficacy, safety, combinability, convenience, ziftomenib looks very good. Now, at Kura, those who have followed us know we are always conservative, whether it's enrollment, whether it's revenue, whether it's timing. We like to underpromise and overdeliver. The total addressable market, in our view, in NPM1 relapsed/refractory is $350 million-$ 400 million, the TAM. And that is between one and 2,000 patients, an average duration of treatment of six months. I would love that we outperform that number. That's what we're seeing.
And the difference between that and the launch with our competitor that has happened to date is in the KMT2A rearranged setting, there really isn't any other competition. Nothing works well. So kudos to our competitor for getting approval because that gives KMT2A patients hope. In NPM1, there are co-mutations. So not only do you have in-class competition between two SMID-cap biotech companies, but you have venetoclax, IDH inhibitors, and importantly, gilteritinib. Half of your NPM1 mutant patients are FLT3 mutant. So you got to worry. You worry about sequencing. Are patients going to get venetoclax, gilt, and then a menin inhibitor? We're being conservative. And we know that you can overcome that with data. What do I mean by that? So we have two presentations, two orals coming at ASH, one in frontline ven/aza combo with zifto, one in relapsed/ refractory. Look forward to that data.
Where you want to go is you want to educate physicians that they should think about giving the triplet right up front. Don't wait. If you wait, the patients are going to do suboptimally. If you can give ven/aza a menin inhibitor right up front, do that. You will see our gilteritinib combo data next year. Same thing. Again, don't wait. Don't put them on gilt. Let them progress and then try to rescue them. Ideally, give those in combo. Let me come all the way back to the end. We're just talking about relapsed/refractory. Our competitor in their abstract at ASH has data combining gilteritinib and their compound, and you can see they have dose-limiting QT, right? The end of the abstract says effectively, we need to evaluate this combination in a non-ASOL population. Why is that? Because of the DDI and the risk.
You're not going to see that with zifto. So I think we're assuming 50% share, a TAM of $350 million - $400 million. If we're wrong to the upside, that's great. Everybody will be pleased. I think that's a good place to start. You know I've said it before. You will see the numbers go up as we see off-label usage, longer durations. That will come with data. And we're generating that data, and others are as well. The frontline, 10 times larger, at least 10 times larger, possibly 20 times larger.
Excellent. Great. That's a good.
And so we're done.
We have first line and then also the launch as well. So just to drill down a couple of specifics, you mentioned the QT prolongation, and then obviously it's very clear you don't have the black box warning. That's a stark difference. I totally agree. You do have the monitoring requirement, very similar to [Hughes] index. So how should we think about that? Because people say this is common sense. I think you said that as well. But what's the difference between with the black box warning, with this monitoring requirement versus not?
So very simply, don't confuse convenience and risk, right? Monitoring is a question of convenience. And ours is in warning and precautions, which we had a KOL on our call last week. In her view, if it's warning and precautions, you need to think about it. If it's black box, you need to do it. The difference, Roger, is the FDA could have put a black box warning on zifto. They put a black box for differentiation syndrome. Zifto did not draw a black box. The data didn't support a black box. You have to ask yourself, why is that? Why did the FDA go to short of a REMS, the most significant kind of risk reduction algorithm with the competitor? And it goes to the magnitude of the QT prolongation. That's the whole ballgame.
We have said, and I think this is right, we have data that says ziftomenib doesn't have clinically meaningful QT. We could have tried to share that with the agency. I think that would have extended our PDUFA. I felt like that was an IQ test. Do you accept the warning and precaution and work with them to get it out of the label, or do you extend the PDUFA? I think if you extend the PDUFA, the bottom falls out. To be fair to the agency, their goal is patient safety, right? And their argument to us is it's a single-arm trial. You can't exclude relatedness. So bring us randomized data. We have randomized trials underway, both in the frontline and in the relapsed/refractory setting. We're doing a study where we have Holter monitoring. So we can go to them with data.
And the reality is you don't see clinically meaningful QT in any other of our trials, whereas you do for the competitor. That kind of tells you everything you need to know. I would say this. You have two drugs. Let's just assume they are otherwise equivalent. You treat 100 patients. You have a one in 100 chance of sudden cardiac death for which you have no biomarker. You don't know who it's going to be. Which one are you going to use?
That's totally fair. If they don't have an alternative, yeah, they can choose to do whichever. But if you do as a comparison side by side, it's a pretty clear difference.
And to your point, so that's the reality of gilteritinib, the FLT3 inhibitors approved in the relapsed/refractory setting. Quizartinib is approved in the frontline setting. Quizartinib has a black box for QT. Why is it used in the frontline? There is no alternative, right? There's midostaurin. But I would say among midostaurin, quiz, and gil, probably quiz and gilt are preferred. Gilt is very much preferred in the relapsed/refractory setting, exactly as you say. When physicians and patients have choices, they look at the overall benefit-risk. And that benefit-risk, it's one thing in the relapsed/refractory setting because I don't mean to sound cruel, but this is a palliative setting, right? We're not going to cure very many of these patients. We're trying to improve their quality of life, extend their quality of life. In the frontline setting, you can cure them.
You can either get them to transplant or take them into continuation therapy. There, the benefit-risk shifts even more in favor of don't put them at unnecessary risk. So I think this difference between the two agents will become even more significant as we move into combinations and into earlier lines of therapy.
Yeah, absolutely. Another thing, investors may be a little bit confused by the DDI in terms of the CYP3A4. So you do have that language say increase or decrease the exposure level, but you also don't have the dose adjustment. That's very clear. So how did you reconcile this? You're changing the PK, but not require you to do the dose.
Yeah. So again, yeah, the FDA's guidance is very clear, right? You have to alter the exposure by an amount that is clinically meaningful. Pretty much newsflash. Everything you put in your body interacts with everything else you put in your body. It's not that complicated, right? Everything goes through your liver. 50% of it goes through CYP3A4. So you are going to see variations. And you're talking about a 112-patient study. So this is a pretty small data set. But what the FDA is saying is we acknowledge it's there. It's not clinically meaningful. To your point, no need for dose adjustments. That is not the case with the competing compound. Their compound is a sensitive CYP3A4. There's an entire dosing algorithm based on which of the ASOLs are you taking. Here's the problem. Patients don't always tell you the truth. They don't always tell you what they're on.
Grapefruit juice, St. John's wort, like dramatically affects CYP3A4. Again, it metabolizes half of what you put in your body. If you have a sensitive CYP3A4 liability and a drug-drug interaction, you're going to pay attention, particularly if the consequence is sudden cardiac death. The FDA is a little bit like the SEC. They always err on the side of more disclosure, right? So that's why it's in the label, but it's not clinically meaningful.
Got it. Yeah, makes sense. Okay, great. So I think you are conservative in terms of the relapsed/refractory AML, the opportunity, which is the prudent thing to do because we will see. But I think on the other side is how ready Kura is to launch the drug because you have a partner with KK, and then you already have a very successful launch meeting with the whole team. And then how should we think about the REMP? And then also in terms of the NCCN guideline and all the prep related to the commercial, just tell us a little bit.
Yeah. So let me take two or three questions in there. In terms of NCCN, we're on track. We've done everything needed. Now we are at the mercy of the NCCN committee, and they decide when they meet. So stay tuned. We'll see where we end up. I'm optimistic. We have the publication and, of course, the drug's approved. In terms of the launch, we've been ready for two months. We've been fully ready for two months. You might have seen if you actually go and click on the approval letter, zifto was actually, the file was complete two weeks before the approval. So we've been ready to go for quite a while. Everything is on track. We guided the drug would be in channel a few days after approval. Everything's on track.
I will tell you, in the very near term, we don't think sales between now and the end of the year are going to be material. You have two major holidays and ASH that takes many of the practitioners sort of out of commission in terms of getting access to them. Doesn't mean patients don't get AML, but there's just the holidays. In terms of we haven't really guided to the REMP. What we've guided to is a TAM of $350 miilion-$ 400 million. Let's assume a 50/50 split. I think that's reasonable. We'd like to take greater than 50% share, but let's be conservative. You're not going to get to peak in the first year. I think we'll do everything we can to have sustained quarter-over-quarter growth. This is the fun part, right? That nobody really knows. Let's see what the market looks like.
I think what we've heard is physicians are very excited to have menin inhibitors both to use in trials and to have in the commercial marketplace. So I think there'll be good uptake. I think our competitor has done a great job of raising awareness of menin inhibitors. I think the two of us, within a couple of years, we'll get to that TAM, would be my guess.
Awesome. All right. And then leading to the first line, which is you said multibillion, 10x, 20 x in the relapsed/refractory population. So just before we wrap up the RNR, so how likely you will get the NCCN listing for the first line? Or that's something it's not necessarily you were guiding to or the strategy for Kura?
I would be surprised if the NCCN committee agreed to put frontline data in absent a randomization. And the reason I say that is their job is first do no harm. Let's see. It doesn't mean you don't try, but I think that's a long putt. I think putting ven/aza combo relapsed/refractory, gilt combo relapsed/refractory, we're doing low-dose Ara-C. I'm optimistic about all of those. Frontline may just be that may be a bridge too far. We'll see. We've got to publish the data first, right, to have it available to them. If they're open to it, we'll absolutely do it. I also, Roger, just a question you didn't ask. I don't know to what extent we're going to see spontaneous off-label use in the frontline. You have three sponsors. So our KOMET-017 phase III trials are enrolling 1,200 patients. Our competitors' trials will be similarly sized.
Most physicians we speak to have said, "If I can get a slot on one of those trials, I will put my patient on the trial." Better for the patient. So I don't know how much spontaneous frontline usage we'll see. We've not baked it into any of our thinking or our guidance. That would be pure upside surprise. Our goal is, and we've said this before, the first top-line results in the phase III trial with intensive chemotherapy, we think we'll have top-line results in 2028, sufficient to support a pathway to accelerated approval. If we do that, that means the trial is nearly fully enrolled because the FDA's willingness to consider a pathway to accelerated approval is driven by enrollment. It's not event-driven. They want to ensure that the survival-based part of the trial is fully enrolled at the time you unblind it.
So you can work backwards and say that means enrollment is probably largely complete by 2028. And I think we'll be in a good spot.
Okay, good. And we spent a lot of time on RNR, which is probably surprising to you because it isn't more near-term, right?
It's near-term.
Event. But also you have another near-term event. You just mentioned the ASH data will be one of the key data set, going to be first line, right? So give us some teaser and the preview and then what we expect to see, what kind of data points you really want investors to drive home, and then how meaningful that is.
Yeah. So we're going to show you data from our ongoing phase I-B with venetoclax, azacitidine, and zifto in the NPM1 mutant population in the frontline. The reason this is interesting is, again, the FDA has agreed to a randomized phase III with an accelerated endpoint of CR rate and a dual primary endpoint of overall survival. So what you're looking for, Roger, is what's the CR rate? Here, CR/CRh, which was the endpoint in the relapsed/refractory, is not relevant in the frontline. The only thing the agency cares about is CR rate. They want full count recovery. So look at the CR rate. Look at the rate of MRD negativity. Although MRD negativity is not a dual primary endpoint, it is the best surrogate for survival that we have. And that benchmark is fairly clear.
Ideally, we're at a point where we're not able to tell you we haven't reached the median overall survival, right? That would be a good thing. The median OS for ven/aza is about 14.5 months. So ideally, at this point in time, we can't say anything to you about survival. The final thing I'll say to you is look at, and I keep coming back to this, safety, particularly myelosuppression. And some of our competitors, and there are several, have to interrupt or dose reduce in order to allow the counts to recover. The significance of that is if you hold the menin inhibitor, menin inhibitors take a week or two to work. So if you hold them, now you're really falling back to ven/aza, right? And so I will tell you, and we've said this before, with zifto, there's no clinically meaningful myelosuppression.
We don't have to hold the dose. We don't have to really do any dose reductions. With venetoclax, it all combines very nicely. It should give everybody confidence in that common KOMET-017 non-intensive phase III.
Got it. Okay. And then another thing is we all know you're also guiding first line is a much larger opportunity. And then some of the investors think this can be just a bridging therapy to the transplant, but also you still can use on the other side of the transplant as a maintenance therapy. So do you see the efficacy and the safety profile will be different before and after transplant? I believe you have in your phase, the pivotal first line, you do have the design. So what's the expectation between before and after transplant?
So it's a big question with two minutes left. Let me see if I can.
That's all right.
Yeah, let me see if I can answer it for you. Before any of us started, the expectation in the intensive setting was that most of the patients would go to transplant. That's the reality of what we've seen. And then they would go back on the drug in a post-transplant setting. With KMT2A, that's by and large what you see. KMT2A patients are younger. They're generally more fit. Their goal is to get to transplant. It's their best chance for a cure. As a footnote, nearly all of the KMT2A patients in the frontline go to intensive chemo. Very few go to ven. That's why we're not running KMT2A in the ven study. There's no point. There's no patients. They go to ven in the second line once they've failed intensive chemo. So I said that was what we expected. What did we actually see?
We see far fewer NPM1 patients going to transplant than we expected. And the reason for that is this relates to MRD negativity. So just for everybody's benefit, if you're a CR, it means you have 5% or fewer leukemic blasts. If you have 5% leukemic blasts, you still have leukemia. You're in a complete response. Only 5% of your blood cells are leukemic blasts. That means you still have active leukemia. MRD negativity, there are various measures. It's 10 to - 5 or 10 to - 6. If you are MRD negative, it means you have no detectable leukemia as detected by PCR or NGS. That's why MRD negativity is a surrogate for survival because it's pretty obvious, right? You don't have detectable leukemia. If you are MRD negative CR, transplant's contraindicated. What leukemia are you getting rid of? There's nothing to detect.
So zifto is so good at clearing the leukemia and getting a much higher proportion of patients to MRD negativity in the intensive setting. And I think you'll be pleasantly surprised by the ven/aza setting that at that point, the physician says, "Do you want to go to transplant with a one in five chance of mortality? Or would you like to take this once-a-day pill?" They're choosing to take the once-a-day pill. The phase III is designed, a three-arm study to get a label for that continuation therapy. And this is what I can say nothing but good things about the FDA. They were very cooperative. We redesigned that trial with them in real time to do a three-arm study to allow continuation therapy. That unlocks the commercial potential. The intensive and non-intensive are roughly equal size.
The total addressable opportunity is 10 patients - 12,000 patients a year at 12 months - 24 months. At peak, that's $10 billion a year. Look at our frontline 7+3 data. All the patients are out at a year, and they're all still going. I don't think that's crazy, right? I think that's very doable. We've never seen a class of agents that are this well tolerated and have the ability to manage MRD negativity. So that's the significance of the trial design and the commercial opportunity. And we're going to have the answer. You're going to get updates all throughout the next couple of years across the different trials. And our goal with 017 is to get there first and get there fastest. We're now.
Welcome, everyone, to Jeff. Welcome, Troy.
Thank you, Roger. Thank you to you and Jeffries for the invitation.
Absolutely. I have to say in the very beginning, it's an exciting time for oncology, for oncology, and then for the ML, menin and the AML population, patient population. So maybe we just kick this off right away. You just got an FDA approval, which is a fantastic milestone for oncology. So how do you see the label for this RNR population AML with the NPM1 mutation? And then how do you think about the potential launch with this label?
Yeah. Thank you for the congratulations. I think menin inhibitors are the most important thing to come along in AML, probably in two decades. And they will do tremendous good for patients. In terms of the label in the relapsed/refractory setting, we think about four pillars: efficacy, safety, combinability, convenience. And we've tested this with KOLs. We've tested it with payers. We've tested it with strategics. And so let's take them in turn. There are two approved agents now in NPM1 mutant AML. Both of them have good activity, right? Which is why the agency gave full approval. You're seeing good CRH rates. You're seeing durable responses. You're seeing the cases if the men have good transfusion independence. I would say it's probably a draw between the two compounds there on an efficacy basis. They have slightly better CR/CRh rates. We have slightly better duration of response.
Let's call it a draw. Safety. There, I think there's a pretty stark difference. Both drugs have black box warning for differentiation syndrome. That's part of the mechanism of action. We have QTC prolongation in the warnings and precautions. They have a black box warning for QTC and torsades. That's significant, right? And in case people aren't familiar, you can go and read the FDA's regulations. The FDA doesn't have any discretion. If you have greater than a 10-ms elongation of QT, you can draw a warning and precaution. Just means watch out. If you're greater than 20 seconds, that's life-threatening. Ours is 7.7 ms, a mean of 7.7 ms. The upper bound of the confidence interval is 12 ms. That's why we have a warning and precaution. Our competitor is 23 ms. The upper bound of the confidence interval is 25 ms. That's a significant signal.
They have one nearly fatal event, one fatal event in 100 patients, 100 NPM1. That's one in 100 risk of sudden cardiac death. There's nothing to sneeze at. So I think they are I think zifto stands tall. Combinability. We do not have any clinically meaningful drug-drug interactions. There is people have asked in the label. It does say there's a moderate interaction with CYP3A4, but there's no dose adjustment required. What that tells you is it's not clinically meaningful. The significance of that we'll talk about in a second, but those two relate to one another. The fact that our competitor has a drug-drug interaction and they have a risk of sudden cardiac death, that makes that very challenging. We have neither. Finally, on convenience. Ours is once a day. Theirs is twice a day. You might say, "Why does that matter?
This is oncology." The issue is the average patient in NPM1 is 65 and older. They're often on a lot of other medications. They may have other comorbidities. If you're BID and you have to fast twice a day, that can be rather inconvenient for an elderly patient. So I think as we go down from efficacy, safety, combinability, convenience, zifto looks very good. Now, at Kuro, those who have followed us know we are always conservative, whether it's enrollment, whether it's revenue, whether it's timing. We like to underpromise and overdeliver. The total addressable market, in our view, in NPM1 relapsed/refractory is $350 million-$ 400 million, the TAM. And that is between one and 2,000 patients, an average duration of treatment of six months. I would love that we outperform that number. That's what we're seeing.
And the difference between that and the launch with our competitor that has happened to date is in the KMT2A rearranged setting, there really isn't any other competition. Nothing works well. So kudos to our competitor for getting approval because that gives KMT2A patients hope. In NPM1, there are co-mutations. So not only do you have in-class competition between two SMID-cap biotech companies, but you have venetoclax, IDH inhibitors, and importantly, gilteritinib. Half of your NPM1 mutant patients are FLYT3 mutant. So you got to worry about sequencing. Are patients going to get venetoclax, gilt, and then a menin inhibitor? We're being conservative. And we know that you can overcome that with data. What do I mean by that? So we have two presentations, two orals coming at ASH, one in frontline ven/aza combo with zifto, one in relapsed/refractory. Look forward to that data.
Where you want to go is you want to educate physicians that they should think about giving the triplet right up front. Don't wait. If you wait, the patients are going to do suboptimally. If you can give ven/aza a menin inhibitor right up front, do that. You will see our gilteritinib combo data next year. Same thing. Again, don't wait. Don't put them on gilt. Let them progress and then try to rescue them. Ideally, give those in combo. Let me come all the way back to the end. And we're just talking about relapsed/refractory. Our competitor in their abstract at ASH has data combining gilteritinib and their compound, and you can see they have dose-limiting QT, right? And the end of the abstract says effectively, we need to evaluate this combination in a non-ASOL population. Why is that? Because of the DDI and the risk.
You're not going to see that with zifto. So I think we're assuming 50% share, a TAM of $350 million-$ 400 million. If we're wrong to the upside, that's great. Everybody will be pleased. I think that's a good place to start. You know I've said it before. You will see the numbers go up as we see off-label usage, longer durations. That will come with data. And we're generating that data, and others are as well. The frontline, 10 x larger, at least 10 x larger, possibly 20 x larger.
Excellent. Great. That's a good.
And so we're done.
Yes. We have first line and then also the launch as well. So just to drill down a couple of specifics, you mentioned the QT prolongation, and then obviously it's very clear you don't have the black box warning. That's a stark difference. I totally agree. You do have the monitoring requirement, very similar to [Hughes] Index. So how should we think about that? Because people say this is a common thing. I think you said that well, but what's the difference between with the black box warning, with this monitoring requirement versus not?
So very simply, don't confuse convenience and risk, right? Monitoring is a question of convenience. And ours is in warning and precautions, which we had a KOL on our call last week. In her view, if it's warning and precautions, you need to think about it. If it's black box, you need to do it. The difference, Roger, is the FDA could have put a black box warning on zifto. They put a black box for differentiation syndrome. Zifto did not draw a black box. The data didn't support a black box. You have to ask yourself, why is that? Why did the FDA go to short of a REMS, the most significant kind of risk reduction algorithm with the competitor? And it goes to the magnitude of the QT prolongation. That's the whole ballgame.
We have said, and I think this is right, we have data that says zifto menib doesn't have clinically meaningful QT. We could have tried to share that with the agency. I think that would have extended our PDUFA. I felt like that was an IQ test.