Kura Oncology, Inc. (KURA) Earnings Call Transcript & Summary

Good morning, ladies and gentlemen. Thank you for standing by, and welcome to Kura Oncology Clinical Update Conference call and Webcast. [Operator Instructions] I would now like to hand the conference over to your speaker host today, Pete De Spain, Vice President of Investor Relations.

Thank you, Olivia. Good morning, and welcome to Kura Oncology's KO-539 Clinical Update Conference Call. I'm joined on the call by Dr. Troy Wilson, our President and CEO; Dr. Marc Grasso, our CFO and CBO, is also with us and available to answer questions. Before I turn the call over to Dr. Wilson, I would like to remind you that today's call will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to Kura's filings with the SEC, which are available from the SEC or on the Kura Oncology website for information concerning risk factors that could affect the company. With that, I'll now turn the call over to Troy.

Thank you, Pete. Thank you all for joining us this morning. Earlier today, we announced FDA has placed our KOMET-001 Phase Ib study of KO-539 in patients with relapsed or refractory acute myeloid leukemia on a partial clinical hold. This partial clinical hold was initiated following our recent report to FDA of a Grade 5 serious adverse event or patient death in the lower 200-milligram dose cohort, a dose that was determined to be safe and efficacious in the Phase Ia dose-escalation portion of the study. The event has been potentially associated with differentiation syndrome, a known adverse event related to differentiating agents in the treatment of AML. We share the FDA's commitment to patient safety, and we're working closely with them with the agency and our site investigators on our mitigation strategy for differentiation syndrome and to resolve the partial clinical hold as quickly as possible. Differentiation syndrome is known to be an on-target effect associated with therapeutic agents that induce differentiation, and we want to ensure that physicians are fully informed and prepared to address these events if they occur. Importantly, patients currently enrolled in the Phase Ib study may continue to receive KO-539, although no additional patients may be enrolled until the partial clinical hold is resolved. Until we have more clarity regarding the impact on timing, we are suspending guidance on the completion of enrollment in the KOMET-001 Phase Ib study and determination of the recommended Phase II dose of KO-539. We appreciate our ongoing dialogue with FDA, and we're working diligently to address their request for information. We look forward to providing an update as soon as we have additional information to share. Based on the totality of data, including the overall safety and evidence of clinical activity, we continue to believe that KO-539 has the potential to address the significant unmet medical need of AML patients, including those with NPM1 mutations and KMT2 rearrangements. With that, operator, we're now ready for questions.

[Operator Instructions] And our first question coming from the line of Jonathan Chang with SVB Leerink.

First question, I guess, beyond this 1 Grade 5 event, can you speak to the experience of differentiation syndrome broadly in the study?

Yes. Sure, Jonathan. So we have seen fewer than a handful of cases of differentiation syndrome across all the patients that have been treated with 539. The other cases were manageable and resolved with treatment of steroids. This case, in particular, was more complicated and was confounded. And unfortunately resulted, of course, in the Grade 5 SAE. But we've seen relatively few examples of differentiation syndrome. And in our experience, in general, it's been manageable with steroids, provided that the physicians get on top of it quickly. And if necessary, escalate the mitigation strategies, which are well-known and well sort of have been well-developed through APL, through the IDH inhibitors. What -- really, the point of this hold, I think, is to ensure that all of the physicians on the study are doing proper surveillance and have a very well-developed and well-understood strategy if needed to address differentiation syndrome. So it's been a relatively rare event in our experience.

Understood. And second question, I guess this is just a broader catch-all question. Is there additional color here you can provide in terms of patient background, pharmacology and exposure level, time to onset, et cetera?

Yes. So -- all good questions. So as I mentioned in the prepared remarks, this patient was on study at the 200-milligram starting dose. And what we have observed with KO-539 in certain patients, not in all patients, but in certain patients, is that you see, initially, a rise in accounts in the periphery. And that seems to be related to trafficking out of the viscera and the bone marrow as the blasts are maturing. That was what we've seen in this case. That was -- and that typically happens in around the end of the first week. This patient actually had ongoing -- this patient was pretty heavily confounded. This patient had failed 4 prior lines of therapy, had really not responded to anything, was a KMT2A patient. A patient, actually, initially, we saw this elevation in counts. There was a concern that perhaps the patient was progressing. But the -- and there was a request to potentially to escalate the dose. The dose was not escalated, and they -- actually, the counts began to come back down, again, which is consistent with our observation of this mechanism of action. But some of the symptoms of differentiation syndrome continued, shortness of breath and so forth. And ultimately, several weeks into therapy, the patient had a cardiac tamponade, which is fluid surrounding heart. It's not typically associated with differentiation syndrome, but it's -- the patient clearly had differentiation syndrome and the patient passed away. So that's what we know. The other cases, as I've mentioned, have been relatively readily managed with count elevation, which you could manage by treatment with steroids.

Got it. And maybe just one last one, if I may. And that is, how should we be thinking about next steps and time lines for enrollment and data from here?

Yes. Yes. So let's start with next steps and then talk about time lines for data. So the FDA has asked us for -- really, for 3 pieces of information. The first is to review the safety database and, in particular, to look at the changes in the counts as a function of time and of dose. Just to be clear to everybody on the call, in our trial, if there's ever even a hint of anything that looks like differentiation syndrome, our clinical team raises it with the investigator and escalates it to the safety review committee. So we're not expecting to find any other instances of this. But just for the sake of completeness, we'll provide that safety database to the FDA with particular attention to what the various counts are doing as a function of time, that's number one.. Number two is a very clear articulated mitigation strategy. I want to emphasize, we have and have had a mitigation strategy for differentiation syndrome in our investigators' brochure. This is something that is fully expected with this mechanism of action. But as I've said, one needs to be vigilant. And there is a series of steps of increasing intervention. You start with steroids, if necessary, withdraw the drug. If needed, if that doesn't work, you can induce either urea or leucopheresis to reduce the counts and again, potentially withdraw the drug, if that doesn't work, then you can work on cytoreductive therapies. And that's -- again, that's well known. That's well established. In fact, Dr. Montesinos, who developed the Montesinos criteria for differentiation syndrome is one of the investigators on our study. So we have some of the leading experts in differentiation syndrome. What I think we really have to make sure we do is that everyone is being very vigilant. And if you see any hint of it, jump on it and make sure that it's well managed. So that's the second piece. And then the third piece is in that context to reaffirm the rationale for dose selection of the 200 and 600 milligram dose. And I can tell you, from our experience, both in the safety and tolerability and the evidence of clinical efficacy, we feel those are the right doses. But the FDA, I think, is doing the right things and looking at the data, looking at the mitigation strategy and then saying, okay, are we using the right dose going forward? We expect -- this is an information request. We expect to have this back to them in a very, very short order. We began working on this as soon as we learned of the Grade 5 event. We had actually put ourselves -- we paused enrollment, which is effectively what the FDA has done. So we'll be well prepared to respond to the FDA quickly. What we, of course, can't control is the timing of the FDA responding to us once they have that information in hand. As for the second part of your question around the timing to full enrollment and data, unfortunately, we had a number of patients in screening sort of ready to go on study this week and next week. We've now had to pause that. At this point, Jonathan, we can't really give guidance on that until we know how long it's going to take the agency to respond to us. We're clearly in control of our timing, and that's going to be very quick. But I can't speak for the FDA. We do -- we are optimistic that this will be a relatively short partial clinical hold. The FDA's request is not complicated. And everyone, the investigators are all working with us and very supportive of moving forward. But we just need to get through these steps. Once we're through it and the hold's lifted, I think we'll be able to then provide more clarity on the timing for full enrollment of the Phase Ibs and ultimately, for data on the other side of that.

And our next question coming from the line of Peter Lawson with Barclays.

Troy, thanks for the call today. Just -- on your thoughts just around the effect. Do you think it's a class effect? Or is there anything particular to your molecule versus others? And are there any parallels here with other drugs in AML team that we should be thinking about, such as the IDH1, 2s that have a differentiation syndrome?

Yes. Yes. So there are 3 parts to that question, Peter. It's absolutely a class effect. There's no question. If you have a potent menin inhibitor, you will see differentiation syndrome, and you will need to manage it. And in fact, one of our competitors, who everyone on this call knows well, has reported differentiation syndrome. I don't think that should surprise anyone. That is part and parcel of this mechanism of action. That is, in fact, what this drug is designed to do is to differentiate leukemic blasts. The issue is, if patients have such tumor burden, the -- if patients have such high tumor burden, that can induce a more rapid differentiation syndrome or a more severe one, and I think you have to watch out for it. But in our opinion, it's absolutely a class effect. There are parallels to the IDH inhibitors as well as to arsenic in the treatment of APL, which is also -- or I should say, retinoic acid, which is known -- agents that are known to induce or be associated with differentiation. There does seem to be -- I don't want to speak for the FDA, but there does seem to be sort of a heightened awareness of differentiation syndrome out there. And I think the FDA is being careful in putting patient safety first as are we. And again, this is manageable. It's now well-managed with the IDH inhibitors. It's -- this is an unfortunate reality of drug development. You learn as you go. You asked, is there a difference. What I can tell you, in our experience is 539 is a very potent menin inhibitor. It's very, very active. And as a consequence of that, I think this -- there's sort of 2 sides to this coin, right? I think we have to be vigilant and watch for differentiation syndrome. That's going to -- that will, at some level, be something that you have to watch for as a potential adverse event when you have an agent that's designed -- or yes, that's designed to induce the differentiation of leukemic blast. So I think I've answered all your questions, but let me know.

Our next question coming from the line of Ren Benjamin, JPM Securities.

Troy, you mentioned that you already had a mitigation strategy in place. And so I'm kind of curious how different can a new mitigation strategy be? How are you thinking about that? And you also mentioned that this did occur before, did that -- did this occur across kind of all doses? Or was it kind of grouped a little bit more? And did it occur in responders? Or was it just kind of more broad?

Yes. So let's -- so Ren, they're all good questions. So let's take them actually in reverse order. As someone said -- someone -- a knowledgeable MD said to me yesterday, a drug that isn't working doesn't do this. This is part and parcel, again of the mechanism of action. So you see this in situations where you're getting -- you're inducing differentiation. Now are those responders? That depends, right? Are you clearing blast counts? And are you seeing a recovery of normal accounts? That's a technical definition. But this is what you see in a leukemia patient when the drug is doing what it's designed to do. But interestingly, it doesn't happen in all patients. It doesn't actually happen that often. It can happen. I think, as to your other questions, we've seen it again in fewer than a handful. I mean it's several isolated cases. The others were relatively benign. So it's hard to say. It doesn't appear at this point to be dependent on dose. But to be frank and to be fair, I don't think we have enough data to say that for certain. I think it's more a reflection of the underlying disease and potentially, patients with higher blast counts might be more susceptible to it. You do see, as I mentioned in the response to Jonathan's question earlier on, it's not uncommon for us to see an elevation in the counts in the periphery in the first week. That's actually, in our experience, been a biomarker that things are going in the right direction. So that's -- paradoxically, that's actually a good thing, right? Where you have to be careful is that, that doesn't then tip over into the complications of differentiation syndrome, which are the edema, the shortness of breath that can very -- can get out of control. So you're walking a fine line. In most cases, steroids are sufficient. If necessary, you can go to more -- to measures, as I mentioned, treatment with urea, leucopheresis, potentially cytoreductive agents. Those are available if needed. When I talk about -- and to your first question, I'm taking them in reverse order. Yes, our mitigation strategy now doesn't look a lot different than it did before. It's just reinforced that we -- the physicians and we as a sponsor, need to be monitoring for this closely. Where you get into trouble is if your -- you don't get on top of this and treat quickly. And the most immediate and obvious thing to do is to put the patient on steroids and if necessary, withdraw 539. So it's more, Ren, I would say, an education and an awareness that this -- this, I've said consistently in response to questions. 539 is -- has a very attractive safety and tolerability profile. The one potential adverse event that I've commented on in the past is the potential for differentiation syndrome, because it's part of the mechanism of action. And that is something I think that we're going to need to continue to be vigilant about. But our investigators have all signed off on the guidance, again, a number of the leading investigators in differentiation syndrome. From their perspective, I think as soon as the FDA gives us the green light, we're good to go. Our investigators are good to go, and they're actually quite enthusiastic about putting additional patients on study. So we'll work through this, not unlike the IDH inhibitors, not unlike venetoclax. This is the reality of drug development, but it's something we were expecting. We feel terrible for the patient and the patient's family, but this is -- we'll learn from this and continue to put patient safety first.

Got it. And just you mentioned cardiac tamponade and it's not necessarily something that you would see with differentiation syndrome. And you talked about kind of the next 3 pieces of information or the next steps that are required, I would have thought kind of really pinpointing exactly what's happened to this patient would also be a key gating item. And I guess, I'm kind of curious, how do you kind of solidify whether this -- this was due to the drug, this was differentiation syndrome or something else?

Yes. So this is where theory meets reality. In theory, all patients are available at all points in time for blood draws, for sampling for autopsies. In reality, that's not the case. This patient's family, unfortunately, didn't consent to an autopsy. So we may never know for certain what was involved. This -- as with many AML patients, this patient had extensive disease. I mentioned, had failed 4 prior lines of therapy, had a number of confounding factors. What I think we can say for sure is there was evidence of differentiation syndrome. And that's why the investigator and we are characterizing it as potentially related to differentiation syndrome. And I don't want to minimize that in any way, right? We do need to be vigilant for that. Was that ultimately the cause of death? Not sure that we'll ever know. It likely contributed. It's certainly something that we want to make sure that we mitigate. But the reality, Ren, is when reality butts up against theory, if you can't get an autopsy, it's hard -- and even with the autopsy, I'm not sure we'd know, but it'll be hard to know. It's sufficient, though, to say that we need to make sure that we're being vigilant about differentiation syndrome. And I think it was the combination of the Grade 5 event and the differentiation syndrome that ultimately was what sparked the FDA to put -- to place us on a partial clinical hold. But that's why I think we're -- we see a path forward. We know what we need to do. I think we're -- we're hopeful that this partial clinical hold will be resolved relatively quickly, because it's -- this the reality of treating patients with AML.

Our next question coming from the line of Joe Pantginis with H.C. Wainwright.

Thanks for all the added details today. Hopefully, I'm not going to sound like I'm parroting back, but I just want to just -- what appears to me is that you've taken the responsible steps for something that's very well-known and mitigation strategies are all in place. So it really almost just sounds like -- even though it's unfortunate, a housekeeping issue at this point because you have to report these. You're taking the responsible moves. The FDA is taking the responsible move and you appear to have the right strategy in place. So I guess what I want to ask then is even though it appears that this should be resolved pretty quickly. I guess, I want to see if there's any difference from a comment you made on your recent third quarter call and not to take away from the menin pathway. But I guess, when you look at the overall corporate strategy of the company, you obviously have an oral presentation upcoming for tipifarnib in PTCL, especially the AITL patients. So I was just curious, do news events like this -- have you reevaluated any of your strategy to say maybe we'll also look to bring forward the PTCL study into more advanced studies?

Yes. It's a good question, Joe, and I understand why you're asking it. And the short answer is no. I think as a strategy, we -- yes, we have to look at the integrated whole, but we also have to compartmentalize. So with regard to menin, this doesn't really put us off in any way from the promise of this drug. I know it's distressing to us. It's distressing to investors. No one likes to have setbacks. But drug development is a business of working through setbacks. We continue to believe we have the potential for a best-in-class menin inhibitor. As I've mentioned, we've seen encouraging signs of activity. This is a very potent compound. We're learning how to use it. And that is what you do with a new mechanism of action in a disease that has been as challenging as AML. We have investigators that want to put patients on the KOMET study. We have investigators that want to do a whole litany of other studies, including combinations. We're all working together, our team, the investigators, to work through this partial clinical hold as quickly as we can. I don't think this puts us off of menin at all. We will work through this relatively quickly and be back on track. With regard to a potential opportunity for tipifarnib and AITL, that is potentially interesting. I think as we indicated on the Q3 call, we need to understand potential next steps and possibly get some regulatory input before we can say what the next steps there would be. But no one on this call should take from this, a shift away from menin at all. I would say, quite the opposite. This is a -- as far as toxicities go, this is toxicity or an adverse event that's spot on the mechanism. We just have to make sure that our physicians are extremely well prepared to manage it if it occurs. And we'll do that, and we'll work through this just as quickly as we can.

[Operator Instructions] Our next question coming from the line of Phil Nadeau with Cowen.

Troy, 1 question on the drug levels. You mentioned that this doesn't seem to be dose-related. Do you have a sense for what the drug levels were in this patient? Is there any evidence of accumulation?

So there is accumulation, Phil, there's accumulation -- so there's accumulation in every patient. The half-life of KO-539 is beyond 24 hours. So the drug accumulates over the first couple of weeks and then reaches a steady state. And as far as we can tell, there's nothing unusual about the exposure in this patient versus any other patient. The -- at this point, what it appears to us, and we may learn more, we're obviously going to be interrogating this as we go. As I mentioned, it seems to be more in the nature of the biology than it is anything relating to the dose level. If you're inducing differentiation, you're inducing it. And we have evidence that both the 200 6 hundred milligram doses are sufficient to drive biological activity. This patient was actually responding to therapy, which was great. The differentiation syndrome is unfortunate. But I don't think there's anything -- I don't think the -- at least on the basis of the information we have now, it doesn't appear that there's some sort of super exposure or anything like that. It's more this is -- as with the IDH inhibitors and other things, this is just something you have to watch out for. Maybe more relevant in patients that have really a lot of extensive diseases. One thing just -- that you might appreciate, Phil, is one way to treat this, of course, would be to give 539 in combination with a cytoreductive agent, right, so that you're keeping the counts down with a cytoreductive agent while you're differentiating the leukemia. That's, of course, one of the next things that we'll do once we move through this and move to the recommended Phase II dose and then on into the combinations. The -- actually, menin inhibitors, they'll ultimately be registered likely as a monotherapy, but they'll probably, in the real world, won't be used as a monotherapy. And that will help to further mitigate across the class, any risk of differentiation syndrome.

Perfect. And then I guess, second question, also on dose. In light of this adverse event, is there any contemplation of looking at lower doses or eliminating the 600 milligram dose from the trial? Or is this -- as you said, something that would be generally anticipated from an AML drug, so no reason to change the protocol in any way affecting the doses being investigated.

At this point, I mean, I don't want to speak -- I can't speak for the FDA. What I can tell you is that we will be addressing the FDA's questions, and we will be recommending that we restart enrollment at the 200 and 600 hundred milligram doses. And our investigators are on board with that and actually have patients waiting for a green light from FDA. I don't see us changing. Now could FDA have a different view? They could. I think that would surprise us. But again, I don't -- unless and until the partial clinical hold has been lifted, we're not adding any additional patients, but it'll be our recommendation just to restart and to make sure that the physicians and we, the sponsor, are being vigilant to watch out for differentiation syndrome. We think we have the right doses. This is just -- this is an unfortunate case and something that I think we need to really make sure that we're watching for. But as far as we can tell, it's really -- the only toxicity that we've seen thus far with the drug or the only, really, drug-related adverse events that I think we have to keep an eye on is this potential for differentiation syndrome, which is, again, as I mentioned, likely a class effect.

Great. And then last question from us. In terms of that vigilance. I guess we're a bit unclear if there are any changes to the brochure or on internal requirements? Are there...

There will be some minor tweaks. We're going to beef up the section on differentiation syndrome just a bit more to make sure that it is overkilled, if you will, to bring it in line with IDH and everything else. Substantively, it really won't change anything, but it's laid out very specifically to say, if you get this, then this. If you get that, then that. So we've already -- we're already in the process of working through that, and we'll revise the investigator brochure and ultimately kind of work this into a future amendment to the protocol.

And we have a follow-up question from Peter Lawson with Barclays.

Great. Just as you think about restarting, will there be any requirement to go back to preclinical data or do further preclinical work to start the trial?

Sorry, Peter, say that again, preclinical data?

Yes. Is there any requirement from the FDA that you would have to go back to any preclinical data to...

Oh, I see what you're asking. No. Yes, in the written notification that we received from FDA relating to the partial clinical hold, they didn't indicate any preclinical data. Really, what they're looking for, Peter, is for us to analyze the safety database from the ongoing study to fully articulate the mitigation strategy, which is straightforward. And then to make a recommendation on benefit-risk around the 2 doses. This isn't -- I can't even think of preclinical data that would help to inform this. This is really, at this point, firmly within clinical development. And I think in fairly short order, we'll have all of that information back to the FDA. I don't expect any additional preclinical studies and they haven't asked for any.

Okay. And then does the differentiation syndrome limit any potential combination therapies?

No. In fact, as I was saying to -- I believe it was Phil, there's been a lot of questions. As I was saying earlier. No, in fact, it actually argues in favor of combination. Because by combining with, for example, FLAG, FLAG-IDA, that is a way of mitigating differentiation syndrome is giving a menin inhibitor in combination with a potent cytoreductive agent. So -- there's nothing that we've seen that would limit our ability to combine with anything else out there that would be a potential combination partner for menin. And in fact, there's a good rationale for moving to combinations even -- with all due urgency. And we indicated on our last quarterly call that, that's our intent. We're -- once we have the recommended Phase II dose, we're looking to get into combinations in the frontline and the first relapse as quickly as we can or I should say, early relapse.

Got you. And then would margin differentiation mean you would potentially start at a lower dose with patients with high disease burden?

No, not initially. More -- and that -- the risk there, Peter, is this is often rapidly proliferating leukemia, right? So you're -- you have to be careful. I know where you're going. You have to be careful with dose-escalating because the leukemia can get away from you. More likely is monitor the patients a bit more intensively in that first couple of weeks to make sure that they're not showing symptoms of differentiation syndrome. And you can do that both quantitatively by looking at counts and you can do it qualitatively by looking at things like do they have shortness of breath? Do they have unexplained weight gain or fever? A number of the symptoms that are associated with different syndrome. The physicians will do both. So I think better to give them a dose, a dose that we believe is going to drive maximal efficacy, monitor them for the first couple of weeks, few weeks. And then if you're seeing elevated counts, then consider -- or even consider steroids prophylactically, if a physician wanted to do that. In our view, that makes more sense than doing a dose-escalation or titrating the dose up, I guess, is a better way of saying it. That's probably not going to be as effective with a rapidly proliferating disease such as AML.

I'm showing no further questions at this time. I would now like to turn the call back over to Dr. Wilson for any closing remarks.

Thank you, operator. I -- we appreciate everyone's participation on the call today. We'll be participating in the Evercore ISI conference and the JMP Securities' Hematology and Oncology Summit over the next couple of weeks, and we look forward to seeing many of you there. In the meantime, if you have any questions, please reach out to Pete, Marc or myself. Thank you all for participating, and have a good rest of the day, and Happy Thanksgiving. Thank you.

Ladies and gentlemen, that does conclude our conference for today. Thank you for your participation. You may now disconnect.