Good afternoon. Welcome once again to TD Cowen's Oncology Innovation Summit. I'm Phil Nadeau, one of the biotech analysts here at Cowen, and it's my pleasure to do a fireside chat with Kura Oncology. We have with us today Troy Wilson, President and CEO, and Mollie Leoni, the CMO. Now, Troy, maybe I'll kick it to you to begin. Can you give us a brief state of the company overview, biggest strengths, biggest challenges, and what do you think Kura needs to do to create shareholder value over the next year or two?
Sure. Yeah. Thanks, Phil Nadeau, and thanks for the opportunity to participate. In terms of the state of the company, we have KOMZIFTI approved for adult patients with relapsed/refractory NPM1-mutant AML. As we reported, we've had robust new patient starts, early launch momentum. We're advancing the program, ultimately to address, we believe, up to 50% of all AML patients. We have multiple data readouts this year that we think will support ziftomenib as a broadly combinable backbone in AML. More recently, in fact, this morning, we shared proof of concept data, which we believe positions darlifarnib as a new mechanism of action and a foundational backbone therapy in kidney cancer and KRAS-driven solid tumors. We're well-financed to be able to achieve our goals. Our biggest strengths, great team, momentum, two potential blockbusters with a steady cadence of commercial and clinical updates throughout the next 12-24 months.
Biggest challenge, probably to maintain focus and momentum. We're at a point now where everything is working, and we need to stay laser-focused on execution. Finally, to drive out performance, we need to continue to generate quarter-over-quarter growth, establish market leadership in NPM1-mutant AML, execute on our phase III trials, continue to put out data updates that reinforce ziftomenib and its ability to be the market leader in AML, and increasingly to advance tipifarnib as a foundational backbone therapy in those large solid tumor types.
That's really helpful. Maybe turning to adagrasib where, as you noted, there were some initial data disclosed in an ASCO abstract and updated data press release this morning. Can you review the highlights of the data with particular focus on response rates across the various tumor types?
Absolutely. We're very excited about these data. Obviously, we had almost all of our patients experience some form of tumor regression. This patient population is both in the previously treated and in the KRAS inhibitor-naive. To put things into perspective, the data that we've seen generated with monotherapy adagrasib was in these indications but in earlier lines in adagrasib-naive patients. Our data are in the third-line plus, with a large proportion having already seen a RAS inhibitor of some sort. Our data is also from the dose escalation, and thus the data are best looked at in aggregate, even though we do believe that there is a dose response that we're seeing as well.
Just to boil it down, for non-small cell lung, with adagrasib monotherapy, you'd expect somewhere between 30%-40% ORR with an earlier line of adagrasib, whereas we saw 50% response rate in later line patients. PDAC, you'd expect maybe 30% in a second-line patient, whereas we saw 67%. In colorectal, 19% would be expected with ada alone. We saw 14% cumulatively, but 29% in the KRAS inhibitor-naive, which is probably the appropriate patient population to be comparing to, and that would be most likely to obtain benefit.
Can you talk a bit about the adverse event profile and how the combo compares to monotherapy?
Really, we're just seeing the two individual drugs' contributions alone. We're seeing the cytopenias that are known to happen with farnesyltransferase inhibitors like tipifarnib. As a reminder, this was a dose escalation, so we were not permitted to use mitigating tactics. However, in the future, we will be using things to mitigate, so you won't see things as much of the cytopenias, the anemias, et cetera. You could actually prophylax for those. Then, of course, adagrasib's well known to be associated with GI toxicity. Again, we saw really what we'd expect with adagrasib alone with Avrgard, so no cumulative tox, and again, we'd be able to really pre-treat these patients and make them more comfortable as we move on.
Was there any difference in the rate or severity versus what you'd expect for monotherapy? Was the duration the same, severity the same, coverage?
We didn't see any evidence of overlapping tox, really. It was all just the individual alone and what we'd expect to see in the background. Even down to dose adjustments or dose interruptions, it was very similar to what we'd expect to see with adagrasib alone, for instance.
Great. Can you help frame the expectations heading into the ASCO presentation? In particular, will there be any additional data that's going to be presented at the meeting that weren't in the press release from this morning?
You'll be seeing a slightly updated data cut. There's about 30 patients across two doses that we would bring forward for further development, and those are the 3 mg and 5 mg of darlifarnib , plus the 400 mg of adagrasib. We're not taking 8 mg forward just because it didn't really have the right benefit-risk profile and didn't justify further development. You'll be able to see some durability data, of course, because we'll show you some swim lanes to really help you visualize the stability of these responses. Of course, my favorite, the waterfall plots that show you the depths of the responses.
I can hear you, Troy.
Phil Nadeau appears to be frozen. Here we go. Now he's back.
We're back.
It's okay. No worries.
You mentioned that you're going to bring the 3 mg and 5 mg doses forward. Can you talk a little bit more about why the 8 mg dose is not being advanced?
It just had more risk than benefit. These lower doses, because we're so lucky to have a broad therapeutic window with darlifarnib, they produced sufficient efficacy with sufficient safety.
Great. In terms of tumor types, I'm sorry if you mentioned this, but are there some that you're particularly focused on, and how will you decide which ones to promote versus which to deprioritize?
This was a phase I-A, so we would take anyone really that was coming on, just so we could establish the safety of the combination. It wasn't an attempt to really enrich with any particular patient population in general. We got a rather good spread of colorectal, pancreatic, and lung cancer. All the cohorts enrolled really quickly. Moving forward, we'll be updating you more at our investor event as to what we're going to be looking at to carry on with this development program.
Got it. Then, I think what was particularly impressive from the data, at least in our opinion, was the non-small cell lung cancer patient who had been previously treated with a KRAS inhibitor but had a confirmed partial response. What do you think adagrasib is doing in that patient? Do you think it's potentially an anti-tumor response, mitigating a resistance pathway, or maybe some combination of both?
Yes, I think it's absolutely doing both. I think that many of the tumor cells are probably able to escape some of the targeted therapies via the RAS mTORC1 signaling that goes on. We know specifically that darlifarnib targets that RAS mTORC1 signaling. By taking that off the shelf right from the start, you're going to be able to get deeper responses. You're also going to be able to prevent escape, overall escape, and resistance by inhibiting that same pathway. This is the third time we've shown that this particular way of inhibiting mTORC1 is significant. We've shown it to you now with PIK3CA combinations, we've shown it to you in RCC with TKI combinations, and now we're showing it to you with KRAS inhibitors.
All very significant targeted therapies that have this one problem in common, hyperactivity of mTORC1 once you start putting pressure on the system. darlifarnib really helps to mitigate that activity.
How will you prioritize development across all those indications going forward? Which ones are of particular interest, and what's Kura's capacity for broad development versus focusing on one or two tumor types or one or two combination agents?
As Mollie mentioned, Phil, darlifarnib, we think represents a mechanism-driven sort of targeted therapy, agnostic combination platform. We will articulate a couple of go-it-alone areas where we think we can move forward and create value for patients. We also have optionality to be able to pursue combinations with others. As she said, look for us to provide more detail on our strategy and the next steps at our analyst investor event on June 3rd.
Great. Maybe turning to EHA, where Kura's going to present updated data from KOMET-007. Can you maybe review the highlights of those data that were in the January abstract or the abstract as of the January cutoff?
Again, really impressive data that we're very excited to be able to share. This is from our phase I dose escalation and expansion portion of our trial for the combinations in the frontline, particularly the 7+3 combination in both NPM1 and KMT2A patients. What we saw out of about 100 patients, 99 to be exact, treated at the dose level that we're proposing to take forward or have taken forward into the pivotal trial. At the earlier cutoff that you saw in the abstract, you saw complete response rates that were hitting 82% for KMT2A and 94% for NPM1. If you go up to CRc, which is kind of more reflective of benefit in this patient population, you were hitting 90%-96% complete response rates that had maybe incomplete count recovery at that time. These patients are also extraordinarily high levels of MRD negativity.
We'll look to show you those data. We'll show you a slightly updated data cut. We'll show you some more sensitive MRD data. I think that these data will not only reassure everyone that we've appropriately designed our frontline KOMET-017 trial, but also really start to continue to encourage robust enrollment into that KOMET-017 trial.
Can you remind us what 12 month overall survival rates would be expected for 7+3 only in these patient populations?
It's a great combination, but it certainly has room for improvement. If you look at AML 17 or 19 or RATIFY for maybe a control arm, you'd expect to see a one-year overall survival for NPM1 to be in the high 80s. We're already exceeding that right now with our 94%. For KMT2A, unfortunately, you'd only expect to see it at around 50%. Again, seeing it at 70% here is extraordinarily encouraging.
What about in terms of CRc MRD negativity rates? You're in the 82%-83% range. What type of MRD negativity does 7+3 generate?
There's various ways of looking at this. What you've seen in that abstract is the local assessments, and local assessment is generally on blood, and they are typically about 60%-70% in an NPM1 mutant patient population. We'll be showing you more sensitive central analyses that's actually more focused on the bone marrow, as we think it's more predictive. KMT2A looks good. It's very difficult to comment specifically on the MRD negativity rate with KMT2A because there's no real method developed. What we're saying right now is we can't visualize it with FISH when we say 82% of these patients are MRD negative. That's why we chose to design our frontline trial around NPM1 MRD negativity, because it's a much more accepted, much more clean way of looking at the MRD negativity.
How does central MRD negativity compare to the plasma? What would an 82%-83% in the plasma be expected to equate to in bone marrow?
That's a tough question for me to answer. I can tell you that bone marrow is the more sensitive assay, and I can tell you that in these patients where you would see a 70% peripheral MRD negativity, you'd be looking to see, with 7+3 alone, about a 45% MRD negativity in the bone marrow. Obviously, it does decrease rather severely when you go to the bone marrow, since it is more sensitive and predictive.
Got it. In terms of transplant, do patients go to transplant in the study? If so, how many did, and did any patients go on cyto maintenance therapy after transplant?
Yep. They have the option to go to transplant, but I would remind that an NPM1 patient in the frontline, transplant's almost a treatment failure unless they have other adverse risks. As long as they are not heavily co-mutated and they get to an MRD negative status, you wouldn't want to take them to transplant because the risk outweighs the benefit. KMT2As, you of course, want to get there as soon and as often as you possibly can. We will be sharing with you at EHA. It is an evolving number. What's interesting is that for patients returning, yes, we absolutely have patients returning to this post-transplant maintenance. I find it funny that some of the patients we "lost" have been lost to our other studies ongoing in post-transplant maintenance, our colleagues at MGH.
Not all patients that appear to not pursue maintenance actually don't pursue maintenance. It's simply just using another method.
These data are really impressive. They seem to de-risk the pivotal development in the frontline. What are the risks of replicating the results in a larger randomized control trial? Anything that we should be aware of?
That's why we continue to evaluate these data and continue to present you updated data sets with more durability to them. It's also why we did such a large study. We enrolled more than 200 patients into this trial, so it gives us a real confidence in the ability to reproduce it. We think that we made very sensible assumptions as well within the randomized control trial, and we actually used a lot of statistical modeling from the data we had on these over 200 patients in order to make the assumptions that went into that frontline trial. Overall, there's always risks. I don't think about them at all for this particular trial. I feel very confident.
One last question on upcoming data before moving to some commercial questions. You are presenting positive data on the use of zifto post veneto with a published manuscript expected sometime here in the second quarter. One, what will be in the manuscript that we haven't seen before? Two, could that publication support updates to the NCCN guidelines?
Obviously this will be the full data set. You'll see every piece of data that we were able to collect in this relapsed/refractory veneto setting, which is very supportive of practice and practice informing. We will submit it to NCCN. Obviously, it will be for their consideration. No matter what, having robust data published will absolutely help physicians make a choice as to how to use menin inhibitor therapy.
Great. With that, we'll move to KOMZIFTI's commercialization. Earlier this month, Kura reported $5.8 million in Q1 revenue with 85 new patient starts and 157 TRX during Q1. Troy, can you discuss how KOMZIFTI's early launch is tracking compared to your internal expectations?
Yeah, Phil, we're really pleased with the launch. I think it's ahead of our expectations in terms of the early launch dynamics, market access, new patient starts, TRX. Momentum continues. We feel like we're in a good place.
Great. Maybe on the subject of combo therapy, you disclosed 40% of patients are receiving combo therapy today. How do you expect that proportion of patients to change over time, and could that impact duration of therapy and therefore reported revenue?
I think it's important to note we're only promoting KOMZIFTI for the monotherapy relapsed/refractory NPM1 mutant population. We're aware of physician-initiated use of KOMZIFTI in combination with both venetoclax and azacitidine, as well as gilteritinib in the FLT3 mutant population. That physician-initiated use, I think, reinforces our view and Mollie Leoni's development plan that we think ziftomenib has potential to be a highly combinable backbone. To your point about duration of therapy, it's early. We're a full quarter in at this point. I think if you see the data that is due to come out in the publication that Mollie Leoni referenced, you will see a longer duration of therapy, as you would expect. The earlier that one goes and the more that one goes in combination, generally the better outcomes for the patients, hence why the physicians are taking it on themselves to initiate these combinations.
Can you discuss the key areas of focus of your commercial team as the launch gets underway? Is it taking share in the NPM1 market? Is it expanding the use of menin inhibitors within NPM1? What is the team working hard to do?
Yeah. Our goals are twofold with respect to our commercial effort. One is strong quarter-over-quarter growth. The other is market leadership in the relapsed/refractory NPM1 mutant setting. We had, we believe, approximately 40% share of new patient starts in that first full quarter relative to the other competitor. I think that caught a lot of people by surprise. Generally, the narrative that we heard was sort of first to market wins. It's all about efficacy. That's obviously not what we're seeing. We're going to continue to try to drive to market leadership. We're also going to work with our development and medical affairs colleagues to continue to put out data, whether it be in conferences or publications, to help educate and inform physicians on how best to use ziftomenib in those combinations and in those other settings.
What is Kura's current estimation of the addressable market in relapsed/refractory NPM1, and how quickly could it be penetrated? Can you discuss the pushes and pulls of getting a new therapy adopted in that patient population?
We continue to maintain that the total addressable market for relapsed/refractory NPM1 mutant AML is $350 million-$400 million. That could go larger if, as you say, you see longer duration of therapy in combination. At this point, we're not changing any of our internal numbers. If you're looking at a duration of therapy of six to nine months, you need at least six to nine months, probably longer, to really understand if you're having that impact in the market. Our goal, Phil, is to take, as I said, majority share of that $350 million-$400 million and really provide benefit for patients while those frontline trials are enrolling quite rapidly. As we've said many times, that's really where the large commercial opportunity is. The frontline setting is 20 times larger than the relapsed/refractory.
Can you remind us how big a role EU plays in the commercial strategy and where you are in getting KOMZIFTI in the EU market?
Yeah. We wouldn't expect at this point to file for approval and reimbursement in the EU. The regulators there typically want to see, well, even if they do accept it, the payers, the countries, typically want to see randomized data with the survival endpoint. That's what the frontline trials are intended to do, and that's in contrast to some of our competitors. As Mollie indicated, we have two parallel phase IIIs running, one in fit, one in unfit, which should provide the data to be able to register globally. They'll have the accelerated endpoints for the US, survival-based endpoints for both the U.S. and rest of world.
On those frontline trials, can you give us an update on the enrollment? Is everything going according to plan?
My team is exhausted. Yes, it's going to plan. It's going very well. I think the sites being so enthusiastic that sites are getting up and running, both the U.S., EU, and Asia countries so quickly, and enrollment keeps pace with that. I'd say that we were really robust in our phase I, our KOMET-007, getting hundreds of patients enrolled in a fraction of the sites. Imagine how much more explosive it is when you're looking at over 200 sites to be enrolling your trial. It's going very well.
Can you review why you decided to do two parallel studies? Why is that a strategic advantage?
Yeah. Essentially it's a two for one. These patients, when they walk into their physician's office, one of the first things the physician's going to decide is, are you able to tolerate intensive chemotherapy or are you not? That is how they're going to decide upon the next treatment courses. Rather than making them have to choose between trials, once they make that determination, we put both those options within a single trial. Now when our trial gets up and running, the patient walks into the office, they say, "You would be appropriate for a clinical trial with menin inhibitors.
I deem you fit, therefore you'll go to this arm," or, "I deem you unfit, therefore you'll go to that arm." Thus they get two trials up and running with two different backbones for just one round of the bureaucratic red tape of getting through all of the contracting and getting the trial up and running.
In terms of competition, are there any abstracts from competing menin inhibitors that you're going to pay particular attention to at either ASCO or EHA? Anything notable?
Not really.
No. Okay.
No.
How would you quantify the market opportunity in the first line in particular for the menin inhibitors?
First line is, as I said, quite a bit larger. You have 11, we think approximately 11,000 incident patients per year. Our estimates, Phil Nadeau, based on the data that you're going to see here shortly at EHA, is in the intensive setting, you're keeping patients on therapy 18+ months. In the non-intensive, maybe 12+ months. Could go longer, where that's the value of running these phase I-b trials, as Mollie Leoni articulated. If you run the numbers out with the pricing that we see currently, you're looking at $7 billion-$10 billion for that incident patient population. We're being very conservative, as we always are, assuming we take approximately a third. That's how we get to a peak sales number of about $3 billion per year in the U.S. Then you've got the ex-U.S. component as well, Phil Nadeau.
That's how we get to our numbers.
Great. With that, I think we are actually just about out of time. I'd like to thank Mollie and Troy for a very interesting discussion. We look forward to the further updates at ASCO and EHA.
Thank you, Phil.
Thank you.
Yeah.
Thanks guys.