All right, hello everyone. Thanks for joining us. My name is Jonathan Chang. I'm part of the Leerink Partners Equity Research Team. It's my pleasure to host the management team of Kura Oncology. We have with us today President and CEO Troy Wilson, and if anyone has any questions for us, feel free to raise your hand and we'll certainly try to get to you. So thanks for joining us, Troy. Would you please briefly introduce the company?
Sure. So thank you, Jonathan, to you and everyone at Leerink Partners for the invitation. I think this is the first time you're doing this meeting. We definitely encourage you to do it again. It's a great spot. Kura Oncology is a precision oncology company. What that means is we're trying to develop small molecules that allow patients with cancer to lead better, longer lives. We have two principal pillars in the business. The first is our menin-MLL inhibitors. Initially, our molecule, a compound called ziftomenib, is being developed for certain genetic subtypes of acute leukemia. We have a registration study ongoing that we hope will support registration for full approval. That study is due to finish middle of this year. There's a whole broad development plan that I'm sure we'll talk about in the questions to follow that support that initially in leukemias.
We do, though, Jonathan, believe that there are other opportunities for menin inhibitors both in solid tumors, other heme malignancies, and even outside of oncology. So that occupies much of our focus. The other pillar that's coming up quickly is our farnesyl transferase inhibitor program. This is a program that we've been working on for a number of years. The way I would characterize that program is a farnesyl transferase inhibitor, in this case our molecule KO-2806, which is in a first-in-human study, is the ideal companion therapeutic to a number of other targeted therapies. Targeted therapies in oncology are very good. They're effective at shrinking tumors. They give patients some disease stabilization. But at the end of the day, many patients develop resistance and go on to relapse. And so there's a focus now in the industry on addressing mechanisms of innate and adaptive resistance to targeted therapies.
This is actually one of the very first targets in oncology that was pursued, same time as sort of EGFR and BCR-ABL. But it's taken a number of years to get it to the point where we understand the biology, we understand how to use it, and we understand the patients in which to use it. We just announced last week that we are dosing 2806 now with a tyrosine kinase inhibitor called cabozantinib in patients with clear-cell renal cell carcinoma. The hope, the promise there is that one can do better for patients with RCC than cabozantinib alone. You will see us extend the reach of 2806 to KRAS inhibitors and potentially beyond. This is an opportunity to really be able to drive better outcomes for patients with large solid tumors. I mentioned lung, RCC. There are other places, obviously, where KRAS is relevant.
We're very fortunate to be well capitalized. We have $540 million in cash as of our last update. That takes us into 2027. Very strong team from R&D through development to pre-commercial. It's an exciting time at Kura.
Great. Thanks for the introduction. Let's start with ziftomenib. How do you see menin inhibitors positioned in AML?
Yeah. So I'm going to pick up a theme that I introduced with the farnesyl transferase inhibitor. And that is the goal of a menin inhibitor, the goal of drug development in acute leukemia, is how do you bring combinations of drugs to patients that have excellent safety and tolerability and yet keep the disease at bay. That really is what we should be trying to do. Ultimately, we'd like to cure patients. We'd either like to make their transplants more successful or to postpone or even obviate the need for transplant. But that's a very ambitious goal. In the near term, we want to be able to, again, drive better responses, deeper responses. What does that mean? It means that you want to be able to use these drugs, menin inhibitors, throughout the continuum of care, in the front line with various combinations. There are three.
We're pursuing all of them. They are standard chemotherapy of 7+3, venetoclax and azacitidine in the unfit population, and then targeted therapies like FLT3 inhibitors. You want to be able to combine with each one of those. You want to be able to combine you want to be able to use monotherapy and then combination in the relapse refractory setting. And then ultimately, you want to be able to have patients remain on a menin inhibitor to help keep their disease in remission. AML is a very aggressive, often polyclonal disease that can come roaring back if left untreated. The promise of a menin inhibitor is it has incredible therapeutic potential and a very promising safety and tolerability profile. We have no DLTs. We have no drug-drug interactions. We've had patients who've been on for months or even years.
It's really an ideal therapy to combine with the other drugs in the armamentarium and then as a monotherapy to keep patients in remission when they're in the maintenance setting. So when you sum all that up, Jonathan, what we're trying to do is begin to sort of turn the disease from it's called acute leukemia for a reason to try to turn it to more of a chronic, long-term, manageable condition. And so far, things are very encouraging. Things look good.
How big could the opportunity be for menin inhibitors in AML?
So it definitely looks to be a multi-billion-dollar multiplayer market. I would say at present, there are two companies that are in the lead. And I'm sure everyone in the audience knows who those two are: Kura and another. There are a number of other companies that are working to follow behind. I think, again, you can look by analogy at other diseases such as multiple myeloma. If you go back to the time when we were treating multiple myeloma, before we had IMIDs, before we had proteasome inhibitors, before we had CD38 antibodies, myeloma looked much the way AML does today. Now patients with myeloma have the promise of living 10 years, maybe even more, with these regimens that are combination regimens. That's where you want to take AML. If you can get there, the incidence population is approximately 20,000 in the U.S., 60,000 globally.
But these patients have, relatively speaking, a short lifespan, a short time on therapy. A menin inhibitor, much the way we think about IMIDs, proteasome inhibitors, CD38, in combination with other agents offers the promise to bend that curve. And that's, Jonathan, what ultimately drives you to a multi-billion-dollar market. It's all about time on therapy. So if you can extend the front line treatment, if you can get patients into maintenance, keep them on, just run the numbers of 12-24 months, these become meaningful oncology drugs quite quickly.
Got it. And you've already touched on this, but it's an important point. So I'll give you a chance to elaborate on this. What are the reasons for confidence in the combinability of ziftomenib with other drugs in AML?
Yeah. I have this is I sound like a broken record, but I'll repeat myself again. When you think about drugs in oncology now, this is different than the way we did it 10 or 15 years ago. You have to, in most cases, assume that drugs are going to be used in combination. There are very few instances where drugs are going to be a single drug is all that a patient is ever going to need. And that's true, again, on both sides of our business. You have menin inhibitors with venetoclax and azacitidine, with chemo, with other targeted therapies, farnesyl transferase inhibitors with KRAS inhibitors, with TKIs, EGFR inhibitors, et cetera. So that puts a premium on safety, tolerability, combinability. What do you worry about when you're thinking about combining drugs? Well, the first and foremost is do you have drug-drug interactions?
If you have drug-drug interactions, that's not per se insurmountable. It's just something you then have to adjust. A common one is a drug can either be an inhibitor or a substrate of one of the prevalent CYP enzymes, the cytochrome P450 enzymes. Ziftomenib is not a substrate. It's not a clinically meaningful substrate. It's not a clinically meaningful inhibitor of CYP3A4. But that's something one worries about. Why do you worry about it in this class? Well, if you have a dose-limiting toxicity and your exposure is changing as a function of other medications or even other things that the patient may take, for example, grapefruit juice, St. John's wort, a lot of anti-anxiety drugs, antidepressants, those all interfere, many of those interfere with 3A4. So if you have a toxicity that's exposure-driven, that can put the patient at risk.
What we've seen, and it's now been I think we dosed the first patient in 2019, I want to say. It took us a while. You learn about the drug. The drug kind of reveals itself to you over time in patients. We have no drug-drug interactions. We don't affect in any way, in any clinically meaningful way, CYP3A4. We don't have any requirement of adjusting venetoclax or chemo. We don't have any dose-limiting toxicities. The one blemish, if you will, that's on ziftomenib, or was on ziftomenib, was a phenomenon called differentiation syndrome. That's an on-mechanism toxicity that you see. It's a consequence of the drug being potent. The mechanism of action for menin inhibitors is that they differentiate leukemic blasts. Just like tumor lysis syndrome, if you do that too quickly, you can put the patient at risk.
What we've shown in our initial update from our combination studies is that by dosing in combination, we can actually greatly mitigate the risk of DS. So right now, Jonathan, I would say it looks pretty bright. We don't have any predicted DDIs, DLTs. We don't have any kind of dose adjustment. We haven't seen anything in the clinic. We are currently dosing all 4 cohorts now in our 007 study at 400 milligrams. I think in our last earnings call, we alluded to the fact that we were waiting for the KMT2A-rearranged AML cohort to catch up. It's now also at 400 milligrams. We don't have any wood here on stage. So I'll talk on my head. So far, so good. I think we're encouraged by what we're seeing. And it's testament to the absence of DDIs and DLTs and other things one would worry about.
It actually, I think, puts ziftomenib in a very competitive position relative to the competition. Because if you think about a patient in the maintenance setting, the fewer interventions that you need, the fewer things you need to worry about, patients want to live their lives. If they want to drink grapefruit juice, they want to drink grapefruit juice. These are patients with cancer. The fewer things you have to worry about, the better for the patient, we think, the better the market potential.
Got it. First patient 2019.
I think that's right.
Time flies.
Time flies. I think it was pre-pandemic. Yeah.
All right. How have the stories evolved?
I know.
Can you discuss the reasons for confidence in the ability to move ziftomenib into earlier lines of treatment for AML?
Yeah. So let's separate two things. The confidence of moving it to earlier lines is principally safety and tolerability. That's what almost always limits our ability to use therapeutic agents in combination and in earlier lines of therapy. We did an investor update at the end of January. We showed data from the first 20 patients in the KOMET-007 study, which is a study evaluating ziftomenib in combination with venetoclax and azacitidine on the one side, 7+3 on the other side, dose escalating four cohorts independently, KMT2A-rearranged AML, and NPM1-mutant AML for each of those two regimens. Those four cohorts are all escalating independent of one another. As of that update, as I said, no DLTs, no DDIs, really encouraging activity. We are, by design, in the relapsed/refractory patient population with ven/aza.
We are in the adverse risk population with 7+3 that is at the request of FDA. When we reach a recommended phase II dose, our safety monitoring committee has the ability to relax those restrictions. We can then dose front line patients in the ven/aza cohorts. We can dose patients who are not adverse risk in the 7+3. In general, the safety and tolerability, as you go earlier, gets better. The efficacy gets better. Patients are less heavily treated. They're healthier. They're better able to respond to therapy. So if our audience goes back and you look at the data that we shared from those first 20 patients, you think about, OK, this probably represents a floor for both safety, tolerability, and activity. And I say that because we showed data at the 200 mg dose.
We're now at the 400 milligram dose in all four cohorts. If we can escalate to the 600 milligram dose, go back and look at our monotherapy data, there's a very wide difference between 200 and 600. 600 is where all the clinical activity is. People were pretty excited about the data at 200. I'm not exactly sure what the 600 combination data will look like if we get there. But I think there's reason for optimism.
Got it. How is ziftomenib differentiated from other menin inhibitors in development?
So the menin inhibitors for which we've seen clinical data and there are four or five of them, I think, actively in the clinic, by and large, maybe with one exception, they all do the same thing. They all bind at the interface between these two critical proteins that are critical for the immortality of leukemic blasts. They separate those proteins. And they induce leukemic blasts to differentiate into fully mature cells. It's pretty remarkable, actually. You're not killing these cells. You're actually inducing them to become non-malignant, to become mature cells. They live a few weeks, and they die off. By and large, all the menin inhibitors do that, Jonathan. They do it to differing degrees. There are, in our view, sort of several key points of distinction between ziftomenib and the other agents. On the safety and tolerability side, again, nothing remarkable.
In our phase 1b study, our KOMET-001 now, we showed a 20-patient phase 1b study. We had a 35% CR rate, 40% sort of CRC. What that means is we've reduced the leukemia to less than 5%. The patients have fully recovered their counts. That's important because you're trying to get patients back to full-count recovery. You're trying, in particular, to avoid myelosuppression. Myelosuppression is the real enemy of AML patients. Many of these patients die of infection, opportunistic infections, frequently fungal infections. If they have a full-count recovery, they're better able to fight off infection. That's why it's so important, why you want to get patients back to a full-count recovery. Ziftomenib is unusual in that we are seeing a 35% CR rate. I don't think that's going to be the rate we'll see in the pivotal.
I think it'll probably come in, as we've said, between 20%-30%. But it sets a high bar. The other thing, Jonathan, is the combinability just looks better. No DLTs, no DDIs, no toxicities that we can see. The only AE we had was DS. We know that's mitigated in combination. So that all, I think, sets up very nicely. The better the safety and tolerability, the higher you can push the dose. And I make a joke and say, all the menin inhibitors, there's still dose escalating in combination. Raise your hand. We're still dose escalating. That's a good thing. The more drug you can put on board, up to a point, the better off you are. The other thing is the physicochemical properties of ziftomenib. And I'd like to say this was all by grand design. But in some cases, you work hard, and you get lucky.
ziftomenib is extremely tissue penetrant. It has unusual PK and exposure. It has time-dependent accumulation. So there's never a time if the patient stays on therapy, taking daily dosing, there's never a time when you're not getting whole-body exposure to ziftomenib. And again, this is not rocket science. Where does cancer hide? It hides anywhere it possibly can. It hides in the bones. It hides in the muscle. It hides in the vital organs. If you can keep that drug pressure on because you have high tissue penetrance, good biodistribution, what does it do near term? It drives differentiation syndrome. That's why we saw what we saw. What does it do long term? It's probably able to keep the disease in check longer. And ziftomenib, as far as we know, is the only drug of all of the members of the class that has those unique drug-like properties.
I think that's the ability to combine, the ability to push the dose, the ability to dose systemically, those will all work to our favor, to the drug's favor, to the patient's favor as we go earlier and as we go into the maintenance study.
Got it. So with about 10 minutes left, a couple of other topics I wanted to touch on and also give you an opportunity to flesh out your Oscar views as well, time permitting. I want to check with the audience, see if they have any questions for Troy.
Barbie got short-changed. Spoiler alert. That's one of my views.
I'm seeing a few pink, a bit of pink in the audience. All right. So maybe what do you see as the opportunities for ziftomenib or maybe a different menin inhibitor that you're developing beyond AML?
So let's take solid tumors and then take other indications. We haven't disclosed yet sort of specifically where we're going. This is a competitive field. As I said, there are multiple entrants who are all kind of jockeying for position. An interesting thing about oncology is when you find an important mechanism of action, and you find a drug that is safe, well-tolerated, and able to modulate the target in a clinically meaningful way, people find other things to do with these drugs. This is historically a good example: why is imatinib used in GIST? It's used in GIST because it's a KIT inhibitor. It was developed as a BCR-ABL inhibitor. There was a Japanese report and then, I think, a doctor in Finland who dosed a GIST patient with imatinib. And lo and behold, it hits KIT hard enough to keep GIST in check.
And the rest is history. Now, there are whole companies that focus on GIST. So if you follow the biology, it often takes you to new and exciting places. We'll disclose the first solid tumor application probably later this year. It is in combination. And it is completely unrelated to the mechanism of action that you see with AML. It has to do with other roles of menin. We're keeping the cards close to our chest. It's not anything, as far as we know, that anybody is pursuing clinically. But it's an interesting opportunity. And we think it is one of probably several in the solid tumor context. There are other opportunities as well. These same malignancies that we talk about in AML, you can move them forward to areas like myelodysplastic syndrome. You can go to ALL.
We actually just dosed the first couple of patients in a non-KMT2A, non-NPM1 cohort in our 001 study. We think we can expand the reach of ziftomenib from 35% of AML to perhaps as much as 50% of AML. You'll do it in combination, not as monotherapy. But if you can get traction in that additional 15%, we think that's exciting. On the non-oncology side, I think completely agree with your sort of baited me with your question. You probably want a different menin inhibitor. You want it for drug-like properties. You want it for IP reasons. You likely want it for pricing reasons and other regulatory reasons. We are doing work in multiple non-oncology applications of menin inhibitors. And when the time is right, we'll share that data as well. It's a great target. And incidentally, we started dosing patients in 2019.
I initially in-licensed the program in 2014, 2015. I can't believe almost 10 years ago. At that time, we didn't even know about NPM1. It was a KMT2A rearrangement story with potential application to hepatocellular carcinoma. That didn't pan out. But then Dr. Armstrong, Scott Armstrong, and his team figured out NPM1. And the rest is sort of history. But there's a lot more that this target, I think, can teach us.
Got it. Maybe at this point, we'll switch over to your farnesyl transferase inhibitor efforts. You mentioned some of these in your intro remarks. What are the opportunities here? And what are your latest efforts?
Yeah. So the opportunity is, as I said, this notion of companion therapeutics. How do you take good drugs that are clinically effective and ideally approved and make them better? Again, it's not a complicated concept. People have tried to do this. We draw these pathways in oncology as sort of straight lines with targets hanging off of them like Christmas ornaments. Biology is not quite that simple. There's feed-forward, feedback loops. There's crosstalk. People are exploring different combinations. Just go down the list: MEK, ERK, SHP2, TORC1/2, PDL1, PD1. I mean, you just go on and on and on. Most of those combinations don't make it. Why? Because they're not sufficiently well-tolerated. You can't combine the combination agent with the active agent. You can't get to a dose. Or you get to it, but the patient feels badly and doesn't want to stay on therapy.
FTIs are unusual in that so a number of resistance mechanisms that tumors use to evade targeted therapy and again, take the two examples we're doing TKIs in renal cell carcinoma and KRAS inhibitors, the cell uses different machinery or different pathways to try to escape those drugs. It just so happens that those escape pathways are farnesylation dependent. So whereas the initial disease is not farnesylation dependent, if you use an FTI in a KRAS-driven tumor, it doesn't do anything. That's where the field started 25 years ago. That's a fool's errand. But if you actually wait for the or give it in combination with a KRAS inhibitor, the cell upregulates the PI3 kinase/AKT/mTOR pathway. People are trying to block that, largely unsuccessfully. But it just so happens that FTIs block a critical farnesylated protein called RHEB. RHEB controls mTORC1.
And if you look at the preclinical data that we showed late last year, you get dramatically better activity with the FTI on board with a KRAS inhibitor. Here's the punchline, though. The FTI doesn't care what the mutation is. It doesn't care if it's G12C, G12D, G12S. It, in principle, works with any KRAS-driven therapy in any tumor type. So we have seen this kind of commoditization or specialization of targeted therapies. You get these niches. This actually cuts against that. Because the tumor uses a common resistance mechanism to all of these different mutations, if you attack that, your TAM goes way up. And you have to show activity. So what do you worry about in combination? Well, you worry, can I hit the target? Can I do it safely? Do I know it's clinically meaningful? Can I combine? If I combine, do I get activity?
Go to the work that we've done with our first-generation compound, tipifarnib, both as monotherapy and in combination. You'll see that we've checked all but the last box. Yeah, I think all but the last box. We can give it safely. We know we can block farnesyl transferase, the key target. We know we've had patients on it for years. We know it can be given chronically. We know we can combine it. We've combined it with things like alpelisib. It was previously combined with erlotinib. We know we can drive activity that's additive to the monotherapies alone. Again, we've done that with alpelisib. So now, what's the one question we haven't answered? Can we do it in these KRAS-driven tumor types and in RCC? If we can, that is a targeted therapy that's applicable to large solid tumors.
You haven't really seen anything that's come across like this. But it's a pretty exciting and interesting opportunity. It sets up nicely. We've spent almost a decade laying the foundation for this. Now, we're doing the critical experiment. I'll just note for you, tip my hat to my team. We started dosing patients in this FIT-001 trial in November as a monotherapy. We dosed the first patient in combo last week. That's how fast the team is going. Whether you look at ziftomenib monotherapy, ziftomenib combos, the new indications, the FTI trial, the team's just crushing it in terms of operational execution. So it gives me a lot of exciting things to talk about.
Great. And then maybe just last question from me. How are you guys thinking about potential business development opportunities?
So it's like that Willie Nelson song, right? You were always on my mind. It's always on our mind. We can't speak to specifics. But we are looking kind of both directions. Are there potential things that we could add to the portfolio? And then are there relationships we can develop that would enhance the value for shareholders and the value for patients, ultimately, either for ziftomenib or FTIs? You've seen us do that now with a couple of clinical collaborations. We did the alpelisib clinical collaboration. We did a clinical collaboration with Mirati, now Bristol, to get access to adagrasib for the KO-2806 trial. We're evaluating kind of all of the options right now. We're fortunate, Jonathan, as I said, that we're in a strong cash position. It's really like heads down. Let's create value as fast as we can for shareholders.
Got it. I don't think I'll be able to fit in any Oscar questions in the time we have left. So thank you very much, Troy, for joining us. Thank you for the people in the audience for joining us.
My pleasure. Thank you.