Hey, welcome everyone. My name is Roger Song, one of senior analysts covers mid-cap biotech at Jefferies in the U.S. Our next company is Kura Oncology. Welcome, Troy.
Thank you, Roger. Nice to be here.
Excellent to have you. All right, so before we dive into your program, the competitive landscape, for your lead program, you know, what is your updated elevator pitch in a short manner? So what's the high-level overview of the company with the recent, kind of progress?
Sure. So we have two parts to the business. The first part is our menin inhibitor program, ziftomenib. There, we think we have a transformational treatment for acute leukemia. The opportunity to really drive a multi-billion dollar, sort of multiplayer market, looking to both drive deeper and more durable responses in acute leukemia. We'd like to do what has been successfully done in non-Hodgkin's, Hodgkin's, myeloma, should be possible with AML and ALL as well. Menin inhibitors are unique in that they have the potential to combine with everything, that's used as standard of care, and so we have a rapidly evolving, and rapidly expanding development program for ziftomenib. We do have additional opportunities for menin inhibition beyond that, in other disease indications.
On the other side of the business, our farnesyltransferase inhibitors, we're referring to our new compound, KO-2806, as really a companion therapeutic. And there again, you know, the theme in precision oncology, I think should be: how do you combine agents to be able to drive deeper responses, to go to larger patient populations, and to be able to keep patients, you know, to keep their disease under control for longer periods of time? The FTIs, we just announced a clinical collaboration with Mirati, combining with the first KRAS G12C inhibitor. We'll be moving forward with cabozantinib in renal cell carcinoma. And there again, what we're trying to do with that compound is to address the innate and adaptive resistance that arises when you treat a tumor with a potent signal transduction inhibitor.
So both liquid tumor, solid tumor sides of the business, we have $450 million in cash. We have a, as we'll talk about, I'm sure, a pretty exciting rest of this year in 2024. We're well-capitalized, looking for the markets to continue to improve, and, you know, hopefully next year will be a good year.
It will be. It will be. Okay, so, I believe that most of the conversation today will be focused on menin inhibitor, but I do want to just put this up front, you know, FTI could potentially become a bigger story, in the coming months and years.
Yeah, I think that's right. I think, you know, we've been impressed by... I was involved in the invention and the development of the KRAS inhibitors, and that's wonderful for patients, but at the end of the day, you're looking at response rates that are 40%-50%, you know, 6 months, duration of response. The question is: how can we do better? And, you know, let's see. I think we'll be dosing in combination middle of the year. One of the advantages that we have with FTIs is we know so much about them. We, Kura, you know, we've spent a number of years working on them, that the FDA allowed us, I think, a pretty clever approach. We can do-- really do 2 dose escalations as a monotherapy, and then we're right into combination.
So, we have the potential, I think, to go much faster and to be, to be more readily combined than things like MEK or TOR or potentially SHP2, SOS1. Should be an exciting time.
Yeah, absolutely. I know you're excited about this.
I'm excited about everything.
Okay, so and then shift back to menin inhibitor because I believe that's most of the-
Sure
... near-term value driver and the interest or the focus from the investors.
Yep.
We start from the monotherapy-
Yep
in the NPM1 mutated, which is 30-ish % plus % of the AML in total. So broad question is, what give you the confidence your monotherapy will generate very competitive and approvable profile based on the current data and the mechanism, the design of the molecule?
Yeah. So, what I find is that people often wanna jump to clinical activity. They want to jump to efficacy. And the reality from drug development, what holds you back, now, particularly in a realm of combinations, is safety and tolerability. Efficacy is usually not your problem. If you look at ziftomenib, we have no QT prolongation, we have no myelosuppression, we have no predicted or observed drug-drug interactions, we're not a sensitive CYP3A4 substrate. These are characteristics of other compounds that are competitors to ziftomenib. What does that mean? If you look at chemotherapy or things like venetoclax, they're highly myelosuppressive. Chemotherapy and FLT3 inhibitors have cardiac toxicity in the form of, particularly for the FLT3s, QT prolongation.
So it's not efficacy that's going to hold you back, it's do you have overlapping toxicities that are going to be exacerbated in combination? We don't have anything, any of that. And you've seen 20 patients at our recommended phase 2 dose. You've seen a full sort of phase 1, you know, phase 1 experience. And the fact that we've now committed to showing the first 20 patients' worth of data from our combination study 007, we started enrolling that study, like, four months ago. And so the fact that we've enrolled 20 patients and we'll have sufficient durability to show you data, tells you enrollment must be going pretty well. Enrollment goes well when you don't have safety and tolerability issues. That, Roger, is what's going to drive, you know,
Again, this is, you know, a lot of, a lot of drug development, a lot of biotech investing is pattern recognition. Look at the KRAS space. The challenge was not that the KRAS inhibitors were active, the challenge was who could combine with checkpoint inhibitors? Who can combine, you know, who has the best tox profile? That's the question. Same question for menin. I think we look like we're probably best in class, and that will allow us to then have best-in-class activity. You mentioned it: we already have a 35% full CR rate with full count recovery. That means no myelosuppression in our phase 1b monotherapy study. That sets us up nicely for the combination data that you're going to see in early Q1, January 1 to February 15.
Okay. All right, good. So, I understand eventually you're going to move into the combo, and then before that, you even better, you already have the single-agent activity, very, you know, clinically meaningful activity, potentially can file for approval for that trial. So you mentioned the enrollment pace, that's very critical for the combo and also even the, the pivotal monotherapy enrollment also pretty quick. And maybe tell us-
Yeah
... what's that enrollment look like and, when you expect to announce the data? Maybe not the formal guidance, but-
Yeah
depend on the enrollment pace.
Yeah. So our first trial for approval is what we call KOMET-001. That's an 85-patient, single-arm trial for full approval by the FDA. The FDA allows for full approval in the palliative setting for AML. It's one of the only places where you can actually run a single-arm trial for full approval. So there's none of these questions around accelerated versus full approval.
Yeah.
We started that trial enrolling this year in February.
Mm-hmm.
It's 85 patients. We've consistently guided that it will be no later than the middle of next year. Our nearest competitor has now, you know, changed guidance three times. And they're guiding to full enrollment between Q1 and Q2, so I think in the worst case-
Very close.
Yeah, we're in the worst case, we're three months behind.
Yeah.
What we've said now consistently is we're not going to change guidance, we're just going to enroll the trial.
Mm-hmm.
If we come in early, that's great, we're going to surprise people, we're not going to. You know, don't expect us to update our guidance. Enrollment is going well. To your question about timing, you need to enroll, you need to have sufficient durability, you need to clean your data, and then ideally, you line it up with a major scientific or clinical meeting, an EHA or an ASH or an ASCO. We'll be looking to do that, but the trial will be fully enrolled next year. That puts us on a, you know, on a very good path, I think, to next year and then on into 2025. And it also, as you said, it sets the stage for then the next wave of development, which is the combinations.
Yeah. No, yeah, let's talk about the combination. I think you already mentioned the safety portion of the combination. So you also say, you know, by the end of this year, probably as early next year, for the combination the initial 20 patients from the combination therapy in 7+3 and the venetoclax, which is two major standard of care-
Yes
... combination. So what should we focus on for this? Safety, for sure, and any other, you know, specific kind of data points you wanna point us to, to pay attention, say, "Okay, if we achieve that, you will be happy and, you know, kind of very confident can move forward?
Yeah. So, good question. So, the things that you're looking at, this is a phase 1 dose escalation. Maybe let's just talk about the design of the trial-
Yeah
... and what we're trying to accomplish. So overall, assuming it fully enrolls, you have 72 patients. The way we're doing it is we are treating NPM1-mutant and KMT2A-rearranged patients separately under two different regimens, doing dose escalations by each genetic cohort. So think of it as 7+3 , KMT2A and NPM1 in the front line, six patients each per dose, three different doses. That's 36 patients. Then you have NPM1 and KMT2A, ziftomenib plus venetoclax and azacitidine in KMT2A and NPM1, six patients each, three doses, another 36 patients. Importantly, we're starting in the front line with 7+3 . We're starting in the relapse setting with venetoclax. That's really from a safety perspective.
You wanna get experience in the relapse population, then we can make the determination to move forward into the front-line population with venetoclax. We're not there yet. What are you looking for? You're looking for safety, tolerability, the ability to combine. Are there any dose interruptions? Are there any dose reductions? Are there any DLTs, right? There's been a big question for us in particular of why do the ORRs or the CR/CRh rates look so different between NPM1 and KMT2A? And as we've said, you see different and more severe differentiation syndrome in the KMT2A. Our hypothesis has been that by combining with a cytoreductive regimen, that should address that. It should allow you to manage the differentiation syndrome and pull the efficacy through. You'll be looking for that.
Of course, there will be clinical activity. The backbones alone are clinically active. The CR/CRi rate in 7+3 is 60%-80%. In venetoclax azacitidine, it's 30%-40%. So you're looking for a meaningful amount of activity. I would be careful not to draw too many conclusions from a phase I dose escalation, comparing it to literature values or, you know, phase III trials, but of course, there will be efficacy. What I suspect Roger will show you is something like a swim lane plot, and you'll be able to see, when did patients go on? When did they respond? When did the counts recover? Like, how long are they on therapy? That'll give you a lot of information.
If you're moving through, you know, there's minimal toxicity, no DLTs, you're on a path to dose escalating, you've addressed DS, you know, it's Grade 1, Grade 2, I think you're feeling pretty good about the combinations. That's what I would be looking for. We will also this update is not meant to be comprehensive, it's meant to address the question that we frequently get from investors of, and I'm going to just paraphrase, "What's going on with KMT2A?" We think it will address that. We'll give another update later in the year, with more phase I experience from that trial, and also our FLT3 trial, we expect to start dosing in Q1. So you'll start to see a lot of combination data coming next year.
That should help to fill out the picture and answer some of these questions around clinical activity, how do we think about it? What is the effect size, et cetera. That's, you know, that's—those are subsequent questions. We're looking forward to sharing the data. The fact that we've guided so precisely to early Q1 tells you we already have the patients, right? Now, it's just a matter of getting sufficient durability. You want to get them through a couple of cycles to really be convinced, have you mitigated differentiation syndrome? What does the safety and tolerability look like? And something I should have added, our clinical team did something clever. They actually dosed the patients for the first seven days on the backbone.
So what that does is, it debulks the patients, so they're less at risk of DS. It allows you to genotype them, so you're confident, particularly in the case of NPM1, that they have the right genetics, and importantly, it provides a safety baseline so that each patient is his or her own control. You do see these patients have adverse events, but oftentimes it's due to the backbone. So you'll be able to see, "Oh, okay, they had that on 7+3. That isn't a ziftomenib-related effect," right? I think that'll be very helpful in terms of understanding the overall safety and tolerability profile. So it'll be a good update. We're going to do it as a corporate update. We'll put it out, as I said, in early Q1.
We would've liked to have done it, you know, late this year, but again, we only started dosing patients in July. It, you know, you can only go so fast.
Yeah. It's already pretty impressive. Maybe just homing on one point in terms of the follow-up. I think the early 1Q with the fast enrollment, you still need to wait until the kind of a meaningful follow-up for the safety and the efficacy. Maybe you tell us what is the optimal kind of initial, kind of a follow-up for the patient, 20 patients, to be able to, to detect the safety difference. As you said, you have a seven days debulk-
Mm-hmm
... but you also need to be on the combo for-
Yeah
a while to see, okay, the difference for differentiation syndrome and the CR/CRh.
Yeah. So DS, differentiation syndrome is usually—it usually resolves within the first two cycles, maybe three cycles. In that, if it doesn't, either the patient has... You know, the leukemia is gone, in which case, there's no differentiation syndrome, or the patient isn't responding, and they go on to something else. They don't stay in a state of differentiation syndrome. So you can address that question. That's, call it Cycle 1 to Cycle 3. The other thing, Roger, is these patients, you're trying to get them—you're trying to clear their leukemia, and then either they're going to remain in response or they're going to go on to transplant. So there again, you know, that's—we'll share as much data as we have.
The patients who came on the study earlier will obviously have a bit more data. In our estimation, you know, early Q1 will give you a good understanding of the emerging safety and tolerability, combinability for ziftomenib and these two, as you said, critical standards of care. It won't be complete, but I think it'll be meaningful. It'll. I think it'll address a lot of investor questions, and it'll also. The other thing we're trying to encourage people to do and help them do is, there's just been, for the last couple of years, so much discussion on the relapsed refractory setting, right? And that's important, but at the end of the day, that's a, you know, perhaps a third or a quarter of the total market.
We need to start. If you wanna get to a multi-billion-dollar product, you need to get to the earlier lines, you need to get into combination. This makes us all do the work. We have to start to think about, okay, what does a development plan look like for venetoclax and azacitidine? How do we think about FLT3? It's also useful to just now move the discussion on. Menin inhibitors, I think we've addressed, they're clinically validated. They work, right? Now the question is: Can we combine? And if so, who has the best combination potential? That's what's going to vault you into the multi-billion-dollar market. Frankly, that's what I think pharma is looking for. J&J is one of our competitors. J&J wouldn't be working in this space, you know, if they thought this was a couple hundred million-dollar market.
Mm-hmm.
So, we wanna be also able to move the discussion along, and the best way to do that is to give the investor community data.
Yeah. No, that's critical. We will see kind of meaningful data from the combination therapy early next year, and I think you mentioned last time, you know, this probably will be the most robust combination data out there as the first one-
Yeah
... even a little bit later into the clinical.
Yeah. Two of our competitors. Let me just underscore that. Two of our competitors have been dosing combinations for two years, and they're going to how you 10-15 patients. We've been dosing for four months, and we're going to show you 20 patients. So again, enrollment is a biomarker for how drugs do, and generally, enrollment speaks to both operational execution, our team is just crushing it, but also how easy is the compound to work with?
Yeah. Yeah, makes sense. Okay, so, at upcoming ASH in December, I will be there, you will be there. And then, if I remember correctly, Kura does not have real kind of a clinical update there. But quite a few competitor will have some data-
Yeah.
- including J&J, Sumitomo, and the Syndax, a few other smaller players. So what investors should be focused on there, and what at the, you know, competitor, also the field kind of player there, what will you be pay attention to-
Yeah.
- update, updates?
So I'm at the risk of sounding, the risk of repeating myself: safety-
Yeah
. safety, safety, tolerability. It's, it's the same thing over and over again. For— let's just take them in turn.
Yeah.
I don't think Daiichi's moving forward. Sumitomo's early. They have an active compound. We'll see. J&J's abstract is very complicated. I think we'll look forward to an update. That's as of an April data cut. It didn't look like they had a recommended phase 2 dose yet. I couldn't tell, we couldn't tell, as a company, where did they start dosing? Where were they? They had multiple DLTs. You know, everybody's seeing DS. They were seeing some evidence of myelosuppression. I think you want to look at safety. For the Syndax, there'll be the Augment 101 update and the SAVE trial. I think Augment 101 should be consistent, more durability. You know, hats off to that compound in the KMT2A space.
Yeah.
The SAVE data, you know, there's a lot of Grade 3, 4 heme tox in that combination. Now, there's a lot of Grade 3, 4 heme tox with decitabine alone, but I think that'll be important as you then look forward a few weeks later, and you look at the Kura data in combination with venetoclax and azacitidine. Right, that's. There again, it-- are you going to want to put patients-- Grade 4 myelosuppression is life-threatening, right? Let's just be clear. That requires hospitalization. It's life-threatening. Ideally, you want to minimize the amount of Grade 3, 4 toxicity for any combination. That's what we're going to be looking at. We know these drugs are active, and at the stage they're at, you're not really comparing. I know everybody wants to, you're not comparing CR rates, you're comparing safety.
Safety will tell you everything about ultimately who's going to win this race. I would, I would look at all of those, and we'll be looking at them, and then we'll put our data in early Q1 in context of the competitive landscape.
Awesome. Okay, so look forward to it.
Yeah.
Uh.
Should be fun.
Hopefully, we can have another conversation there. Okay, I think we talk a lot about the menin inhibitor as expected, but FTI, as I mentioned earlier, can be a big story moving on. Recently, you reported some HRAS head and neck data.
Yep.
It's at the potential pivot, but, you know, you're not moving forward, but as a monotherapy.
Yep.
And then you also have a couple ongoing combination therapy. How should we maybe start from the head, neck?
Yeah.
What is the alpelisib combination therapy kind of status?
Yep
... and the when, and how you're going to move forward? And of course, the KRAS and other combination therapy.
Yeah. I appreciate the question. So, you know, I'm a drug developer. I've been a drug developer now for +20 years. There's a checklist that you step through with any target, and people want to rush. You have to resist that rush. What do you need to know? You need to know you can hit the target, you need to know you have selectivity, you need to know you can modulate pharmacodynamics, you need to know you have safety as a monotherapy, you need to know you have, ideally, clinical activity in a given population, that you can drive clinical benefit. You now know all of that for farnesyltransferase. That data at ESMO, that was the, I would argue, the most impressive monotherapy data in recurrent metastatic head and neck, full stop, right? With a small molecule therapy.
We are pausing development as a monotherapy, pausing before we go to approval or commercialization, because we also try to be good fiduciaries, and we have so many things we can invest in on the menin side, on the KO-2806 side, we have to pick our spots. But it should give you great confidence that we understand how to use an FTI. And that—and I have to say, you know, those who remember, 25 years ago, every pharma company had an FTI program. None of them could figure it out. We've now figured out how to use them. Now, roll forward. The combinations with alpelisib, with adagrasib, with cabozantinib, those are not HRAS. Those are targeting farnesylated proteins. In the case of both cabo and adagrasib, you're targeting Rheb. Rheb is a uniquely farnesylated protein.
It controls the PI3 kinase, AKT, mTOR side of the pathway. People have been trying to arrest the MAP kinase and the PI3 kinase pathway for 25 years, and, you know, we keep hitting the same wall of toxicity. The interesting thing is, you can now. We've shown with alpelisib, you can combine alpelisib and tipi. They're actually very combinable. K- does it have enough efficacy to justify later development? Let's see. We've said we'll give an update later in the year, but it. But again, I sound like a broken record. You got to start with safety. You got to prove that you can actually combine things... what everybody's trying to do in the KRAS space is figure out, do I use SHP2, SOS1, CDK4/6, MEK, right? What do I use as a companion therapy to drive deeper and more durable responses?
I will put FTI up at the top of that list because it we know the safety. With Tipifarnib, we've treated 5,000 patients, some of them for five years, 10 years, right? We know what the the near-term and long-term safety looks like. We know we can block Rheb. Now, the question is, can we drive better activity in combination with that aggressive? I like that study. Chuck and Jamie at Mirati were, you know, hugely helpful in getting that, getting that up and running. You know, we're looking forward to, to collaborating with them, and, and hopefully that's the first of multiple collaborations. Cabozantinib is another opportunity there. Second-line renal is a huge opportunity. Can we do better? Can we, can we provide these patients with longer responses? That'll be the story in, in 2024, 2025.
I like it because, you know, we're not afraid to take on novel targets. We were the first on menin, we're the first on FTIs. You know, it's lonely being first, but it pays off.
No, sometimes, so when you have some success there, you will have fast follower, and you were people kind of fitting in.
Yeah.
But not easy to do that. As you said, everyone has that but not figure out yet.
Yeah.
So, but you do have a second generation, KO-2806?
We do.
Yeah. So what, what's the status of there? What's the strategy for that to fit into the FTI franchise?
Yeah, good, good question. So Tipi, to the extent it goes forward, will stay in head and neck. 2806, because of the Inflation Reduction Act in the United States, you now have to both be a drug developer and kind of an expert in regulatory strategy. We have 2806. This is a next-gen FTI. It's a Ferrari as far as... I guess we're in England, it's a McLaren. You know, as far as FTIs are concerned, there's another FTI behind it, that's that you know, we haven't nominated yet. Ideally, you'd have an FTI for each, each kind of big application, and think about it that way. We will take 2806 forward, Roger, into lung, into renal cell carcinoma. That's where we're going to go first. I would love to see us go into pancreatic. I think there's a great opportunity.
We've seen some exciting data from Revolution Medicines in pancreatic. That would be a logical combination. We're not there yet. We're going to focus in lung, we're going to focus in renal cell, and let's get some proof of concept of the combo. And then, as you say, I think, there will be probably more than one fast follower.
Awesome. Okay, I think you mentioned the cash and the runway early on in the beginning. Anything else you want to impress on us we haven't discussed?
I think just maybe I'll pick up on that. We do have $450 million in cash. We're well capitalized. We have a lot to do. I think, you know, this has been a tough year for biotech. Hopefully, 2024 is better. I think we're really well positioned with the data flow and the resources, both operationally and financially, to create a lot of value. So it's exciting.
Excellent. Thank you, Troy, for the time.
Our pleasure. Thank you, Roger.
Thank you, everyone.