Curis, Inc. (CRIS) Earnings Call Transcript & Summary

Good morning, and welcome to Curis' Call for the 2022 ASH Conference Call. [Operator Instructions] Please note this event is being recorded. I would now like to turn the conference over to James Dentzer, President and CEO of Curis. Please go ahead.

Thank you, and good morning, everyone. Thank you for joining us. On the call today, we have Bob Martell, our Head of R&D, who will be sharing the latest clinical data from our TakeAim Leukemia study. We're also pleased to have Eric Winer, our Clinical Director of Adult Leukemia at Dana-Farber joining us to add his perspective. With that, let's get started. Bob?

Great. Thank you, Jim. So I am very excited to share the updated clinical data for emavusertib in AML and high-risk MDS, which further reinforce monotherapy activity of emavusertib. From preclinical work and past clinical studies, we've identified targeted populations that are most likely to respond to emavusertib monotherapy. These include patients with disease harboring FLT3 mutations or 1 of 2 splicing factor mutations, U2AF1 or SF3B1. And on this waterfall diagram, they are represented by the green bars on the left. With the ASH data, we have nearly doubled the size of this targeted population database and we continue to see consistent deep monotherapy anticancer activity, including additional objective responses. Given this level of anticancer activity, we believe there is opportunity for monotherapy as an initial registration strategy for emavusertib. Now for patients without targeted mutation, and these are on this graph represented in the middle, in the blue bars. Here, we know that the majority of these patients also harbor excess IRAK4-L compared to nonmalignant labs. This likely explains why we are seeing such cancer burden reduction with emavusertib monotherapy here as well, including objective responses. Our updated data continue to demonstrate this. For these unselected patients, based on our preclinical data, we believe that the optimal treatment will involve a combination. This slide highlights specific monotherapy disease groups. In the FLT3 mutated AML population in the upper left of this chart, we know from prior work that IRAK4 specifically is a key driver of resistance to FLT3 inhibition. And our data bear this out with 3 of these patients achieving deep objective responses as well as the fourth patient who previously was completely refractory to gilteritinib and then with emavusertib monotherapy achieved in near normalization of their blast counts as well as ablation of the FLT3 and [indiscernible]. In the bottom graph, we show the subset of patients with high-risk MDS where the primary driver of disease is a splicing factor mutation, which results in excessive uncontrolled Oncogenic IRAK4-L production. In these cases, FLT3 mutations do not play a role. This is an extremely difficult population to treat. All of these patients had disease with a splicing factor mutation and in the absence of FLT3 mutation and all had previously been treated with a hypomethylating agents. Yes, we continue to see strong anticancer activity with monotherapy. We also saw strong activity in patients with splicing factor mutated AML shown in the upper right. While some of these patients also had FLT3 mutation, which is represented by the light green hash bars, others did not, including 1 patient with a durable CRh. We have initiated combination therapy in both AML as well as in non-Hodgkin lymphoma and CLL. Just briefly in the non-Hodgkin lymphoma and CLL population in the upper box, we see -- we know, for example, that NF-kappaB is a key driver and the NF-kappaB activation is stimulated by 2 parallel pathways, which include the BCR pathway which is actually well covered therapeutically by BTK inhibitors and the parallel pathway, including TLR, myddosome and IRAK4, where there are no drugs currently approved and where emavusertib is the lead candidate in the clinic. Targeting both of these pathways yield superior efficacy and is synergistic when evaluated in preclinical models. Our study found that emavusertib can be nicely paired with the BTK inhibitor ibrutinib and induced strong anticancer activity, including from patients previously treated with the BTK inhibitor. I'd like to actually highlight one patient with primary CNS lymphoma. This patient is the light blue bar on the far right of the upper graph. This patient's disease was progressing on ibrutinib. And then when the emavusertib added, their disease went into complete response. The bottom graph represents patients with AML and high-risk MDS treated with emavusertib plus venetoclax. In this population, treatment resistance is often dependent on expression of anti-apoptotic factors such as MCL1 and BCL2. While venetoclax is limited to BCL2, targeting IRAK4 has been shown to reduce MCL1 and blocks oncogenic IRAK4-L. Our early results found at combining emavusertib with venetoclax induced strong anticancer effects in patients. On the final slide, I'd like to just highlight this elegant work presented today by Professor Metzler using next-generation sequencing and PCR of patient samples that were taken before treatment and during treatment. These data show deep molecular responses induced by emavusertib monotherapy. The top graph shows an example where a slicing factor mutation is the primary driver and where there is no FLT3 mutation, emavusertib induced loss of not only the mutated splicing factor U2AF1, but also of STAG2, DNMT3A and BCOR. Let me actually jump now to the other end of the emavusertib spectrum where a disease that has FLT3 mutations as the primary driver without a splicing factor mutation. That's shown in the bottom graph by case 3. This shows rapid loss of FLT3 mutation in this situation. Finally, we have treated several patients with both FLT3 and splicing factor mutation as exemplified in the middle graph. This particular patient achieved a complete response with complete hematologic recovery as well as loss of BCOR, U2AF1, WT1 and NRAS. FLT3 mutation for this patient is tracked on the bottom graph in case 1 showing rapid loss of the FLT3 mutated clone by PCR. So these examples in summary demonstrate the disease modifying effects of emavusertib in 3 important disease scenarios: one with splicing factor mutation without FLT3 mutation, another with FLT3 mutation without splicing factor mutation and thirdly, disease with dual mutations. With that, I appreciate the opportunity to present these exciting updates and would actually like to invite Dr. Eric Winer, Professor at Dana-Farber Cancer Institute to talk about these data and his views on the perspective of emavusertib in this disease? Eric?

Hi. My name is Eric Winer. I'm at Dana-Farber. And as you mentioned, I'm one of the Clinical Director of Leukemia and take care of a number of these patients. I think just in general, to start off, I always think that it's important to know where we are in the AML landscape to sort of determine where we have roles for these drugs. And with the advent of some of the numerous therapies, it really changes how we look at efficacy and how we look at where these drugs are going to have a role. As many of you know, venetoclax has completely changed the landscape of AML. And now at this point, we're actually looking to say, can we even remove 7 plus 3 from a lot of the AML induction patients and think about using HMA and venetoclax instead. And this is going to be coming up in a number of different trials, including it has already had some arms in the BAML trial. And when you look at the MyeloMATCH trial, which will be a long overarching trial coming forward, we're going to be seeing more HMA and venetoclax going forward. That poses obviously some tremendous benefits, but it also poses some concerns. As many of you know, when we think about HMA and venetoclax, the issue that we have is, yes, it is excellent at inducing remissions, but one of the problems that we have is when patients fail HMA and venetoclax and they lose this efficacy, we have a tremendous difficulty getting any other type of remission. And I think this has to be taken into effect and taken into account when we're looking at novel drugs moving forward. So for example, in looking at the data that Bob presented, it's very difficult not to look at data and compare that to something like gilteritinib. But I think we have to recognize that we're looking at 2 extremely different populations. In the admiral study from New England Journal that Sasha Perl published, it's very notable and it was a very important study comparing gilteritinib chemotherapy alone. But it's also noteworthy that 2/3 of those patients have never received a FLT3 inhibitor and also that based on the timing of that publication, very few of those patients had received venetoclax. Furthermore, when looking at sequencing of how we think about this treatment, we're finding that people that relapse after venetoclax, if you look at the data that was presented and published by MD Anderson, the median overall survival time is about 2.1 months. And so that really is a different indicator than what we've seen in a lot of the other studies. And so I think it's important to note that looking moving forward in terms of drug approval that there is a different level and a different bar that needs to be crossed over that really isn't the same for gilteritinib as we've seen in the past. There's a nice soon-to-be published article by one of my colleagues, Max -- that looks at the CR rate of treatment after venetoclax. And after venetoclax, while the CR rates and the CRi rate was about 20% and 34% for gilteritinib. After venetoclax, it goes down to about 10%. So that's a very different model, especially when you're looking at where the -- the emavusertib falls in sort of a historical comparison. In our study that we've been doing in coordination with Curis, the emavusertib has actually been extraordinarily well tolerated, and it's something that we've been using in all populations, but definitely in an elderly population that's extraordinarily well tolerated. We've had patients that are in their 80s and the patient that he had mentioned was -- that had the treatment refractory to gilteritinib and then basically clears his marrow was actually my patient, and he was an elderly gentleman that had no side effects from the chemotherapy itself or from the emavusertib itself and tolerate it very well, and it definitely extended his life with quality, which I think is the most important aspect. When looking at the data with FLT3, it's important that we're seeing CR rates somewhere around 21%, which looks similar, as I said, to the gilteritinib, but it's actually markedly improved. It's built or it in 2 ways. The first is, as I said, all of these patients or virtually all of these patients have received venetoclax. But also in the FLT3 trial, those patients most of them, 2/3 of them haven't received a FLT3 inhibitor. So I think when you add that in and when you look at sort of what the adjustment is for those patients, it really looks to be somewhat of a superior drug to gilteritinib and quite possibly due to this breakthrough mechanism that the FLT3 inhibitors don't attack, which is the IRAK4-L inhibition. And so by combining those 2 aspects, I think we're getting a lot -- we have the potential to have a lot more improved responses. Furthermore, we're also just in terms of the landscape of lysosome inhibitors are also an area that we really are at a standstill as they tend to be somewhat a little bit more refractory. They tend to have a worse prognosis and having a target, which, as you said, Dr. Meztler has presented some data and Amit Verma has done a lot of work in this. But looking at these -- that as a target and seeing these success rates definitely create an area of potential opportunity in terms of drug development, but also in terms of remissions for the patients, which all of us realize is the endpoint here and then the most important aspect of this research. And I'll be happy to take any questions if there's any or any other thoughts or concerns.

Thank you, Dr. Winer. Yes. Are there any questions. And Jim, Jim Dentzer if you'd like to speak as well?

No, I'm fine. I think we do have some questions, Bob. So operator, why don't you walk us through the first ones?

[Operator Instructions] And our first question will come from Li Watsek of Cantor Fitzgerald.

I guess for Dr. Winer. First question for you is perhaps maybe put today's data in the context of other approved targeted agents? And how do you think it can potentially fit in, in spliceosome versus FLT3 mutated patients? And also, can you comment on what the duration of responses?

So the duration of responses, I'm going to leave to Bob because he has that primary data in front of him for the whole cohort. Where I think it falls in the landscape, I think there's a couple of different opportunities. I think that looking at the FLT3 data, as I said, I think the FLT3 landscape basically is gilteritinib and midostaurin upfront -- maybe gilteritinib upfront -- gilteritinib definitely -- we're just not seeing the same effects that we're seeing in the ADMIRAL study. And so I think there's definitely going to be opportunity in that arena and looking at it in terms of combination therapy in frontline, I think that's going to be the next step. And what's interesting around this compound is it has some dual effect with IRAK4-L. Furthermore, I think with this compound, there's a nice opportunity to move forward in a combination standpoint because they've already have the safety data with venetoclax from the lymphoma study. So I think that's something that is actively being pursued and there's a trial that's opening right now with the doublets and triplets. In terms of where it falls in sort of the global aspect of all of this. I think there's a couple of different opportunities for it to fall. Everybody is talking about the magrolimab data and that triplet study, which is going on in the randomized study, that's going to be more for, I think, a FLT3 -- I'm sorry, for p53 population, although there may be some benefit in upfront. I think there are some other drugs that are interesting like sabatolimab. But I think the way I look at this drug is it not only has a strong potential for some targeted aspects like FLT3 and also for the spliceosome but given this novel IRAK4 inhibition will that end up being a breakthrough mechanism or resistance mechanism, I think that it has opportunity on a more global path, particularly when it's combined with a different agent.

Yes. Thank you, Eric. And you're right. So TLR signaling in general, which requires IRAK4 is a very common mechanism for resistance to other therapies. In fact, with HMA therapy in general, TLR signaling goes up and activation of NF-kappaB has increased. And that's exactly why targeting this pathway and the subsequent anti-apoptotic factors are extremely helpful in overcoming resistance. In terms of the duration of responses, it's been quite good. So in our AML patients with CR, CRh, these responses have been over 6 months. In fact, 1 patient was in response and ended up coming off of therapy for another comorbidity and couldn't participate in the trial anymore, but remained in response for out to a year. So these are quite durable and patients do not develop cumulative toxicities or side effects over time. As Eric said, the drug is fairly well tolerated. Next question?

The next question comes from Soumit Roy of Jones Research.

Apologies in advance for any ambient noise. One question trying to understand the -- there was a little muted response in terms of -- in the new slices of mutant population versus ASH '21 data. Could you give us any color, like last time, we saw like 2 out of 5 responded this time 2 out of 11ish. So if the new patients had a higher baseline blast percent or kind of would be helpful.

So maybe I'll start and then, Eric, you could comment as well. So overall, in the targeted population, which includes the FLT3 and the spliceosome or splicing factor mutations with the new data, these are consistent. Overall, as an example, with the additional population, the patients with FLT3 clearly expanded their numbers of objective responses. And as I mentioned, the 3 patients in the FLT3 population were having objective responses as well as the fourth patient who had, as Dr. Winer mentioned, a pretty dramatic effect on their disease. What we're finding is that patients who have extremely high prior treatment, by numbers of prior treatments tend to be the ones less likely to respond. And so one of the things that we're trying to do is move this drug into a little bit earlier settings, not necessarily first line, but second or third line with 2 or fewer prior therapies, these are the ones who are responders. So patients who had received higher numbers of treatments than that tended not to respond well. So this is one of the selection factors that we're using going forward. Did you want to comment Dr. Winer?

No, I would agree with that. I think that this is one of the issues that we see as we move forward with efficacy in AML is we get these large number of accumulations of mutations. We get increases of p53 mutations. And so when you're looking at people that have 4 or 5 lines of chemotherapy, you just generally are seeing shorter objective responses. This is an issue across all the initial studies on Phase I of the field. I don't think that it's really difficult for any drug to have a response when you're on your sixth or seventh line of AML therapy. And I think moving forward to a more reasonable Phase II concept that uses shorter lines of chemotherapy are going to give you a better expense of efficacy, especially when with these upfront triplets, people will have seen a lot of these drugs earlier in their care such as a previous FLT3 inhibitor.

One quick question follow-up. Just one quick question. Could you tell us like from the previous ASH '21 data, we had 7 responders from spliceosome mutant AML, 4 in spliceosome mutant MDS and 1 in FLT3, how many of those were proceeded towards getting a stem cell transplant, if any of them became eligible?

I believe -- so certainly, one of the MDS patients -- and we had mentioned this that the ASH on date as well had gone on to stem cell transplant. At the top of my head, I don't have that information, but we can provide those details at a future time.

Yes. Just to add on to that. I think when you look at who became transplant eligible, I think it's important to note who has the ability to become transplant eligible. So for example, if -- of those initial patients, 78% of them were over the age of 80, they were never going to be transplant eligible. So I think you have to look at what your age is under 70 to see if somebody would be transplant eligible in the first place as opposed to looking at it from a generally older population.

Is there another question?

The next question comes from I-Eh Jen of Laidlaw & Co.

In terms of venetoclax and the failure of patients just for Dr. Winer, what percentage of patients could fail after that treatment as well as the duration of response for how long that will disease progress in your projects or in your real-world situations?

I'm sorry, can you just repeat the question, you're saying what percentage of patients of the venetoclax failures in that practice?

Yes. In AML and what percentage of patients sort of failed the treatment as well as typically how long the disease progress in other words, the duration of responses in the real-world practice?

In the world we practice with venetoclax you're saying?

Yes.

So in the real world, I mean, I think our experience somewhat echoes what we're seeing in the [indiscernible] data that Courtney presented and Keith presented sort of an update too. We're seeing still about for people that respond, we're seeing response rates of about 18 months. There are some long responders, but there are also some people that don't respond at all. So I think the average of 18 months is reasonable to look at. But the reality is, even looking at the long-term data, there isn't anyone who secured with hypomethylating agents and venetoclax alone. Some of those patients can go to transplant for a potential cure. But again, that's no different than induction chemotherapy in terms of the goal of treatment and the cure rate of that treatment. And I would think that, again, with an older population and the population continually getting older, where venetoclax doesn't unfortunately sure everyone as an initial outset treatment.

Eric, could you put this into context of patients who have previously received venetoclax in an HMA? So how well can you get responses in those patients?

As I mentioned…

Yes, that's the population we're looking here as most of these patients have had prior HMA and venetoclax.

And as I mentioned before, MD Anderson and my colleague had published something both recently. My colleague, Dr. [indiscernible], what he published was, can you look at targeted agents after venetoclax? And what he saw was overall survival rates were extraordinarily low in that population, median survival was about anywhere between 3 and 6 months, depending on the targeted agent. It was much lower in the patients with IDH -- previous IDH in the past, about 6 months for patients who have received previous FLT3 inhibitors. And then the MD Anderson data when they published their data, they were saying that there's a median overall response or your overall survival rate for all patients of about 2.5 months. So you're looking at extraordinarily low response rates and yet you seem to be having -- if you were comparing head-to-head of these patients who are receiving emavusertib are definitely having longer survival than 2 months because they're basically continuing on trial for a number of months, and then that doesn't count the people that are having responders. So I do think that this plays a tremendous role in the change of landscape because the previous survival, if you were to look at it, was probably triple that before HMA then. And so I think it does make a big difference.

The next question comes from Ed White of H.C. Wainwright.

So maybe if you can give us an update, you said you continue to enroll patients at the 200-milligram dose. Can you allow us to know where you are with that? And will you have that data in hand and release it to us before you talk to the FDA in the middle of next year? And then considering the data posted today, how should we be thinking about the pathway to approval?

So I'd say that, first, as you know, the FDA wanted us to put a couple more patients on at 200 milligrams. We expect to have those data available and meet with the FDA sometime midyear. I would assume we're not going to make the data public before we talk to the FDA, but coincident with talking to the FDA, I think we would -- I think everybody, of course, wants to know what the FDA knows at that point. Is that is a sufficient data set to agree on the recommended Phase II dose going into next -- in the next phase of the study. In terms of the path forward, I think the path forward for us is clear. These data are now doubly in the data set, and they're confirming what we've seen so far, which is the underlying scientific thesis held out in the lab and how it's holding up in the clinic that across the spectrum of AML and MDS there's a core population genetically defined patients, who will be amenable to monotherapy, and that's going to be the FLT3 population and the spliceosome population. And we're going to proceed with those in monotherapy path that will be AML FLT3, AML spliceosome and MDS spliceosome. And then for everybody else, they still express IRAK4 and we're seeing that in the data more data today, as you've seen in the data center. Those patients are going to be amenable to combination therapy. I think those studies will naturally take a little bit longer. But as long as the data continue to come back consistent with deep responses, I think we've got a very compelling therapy moving forward, and I look forward to the discussions with the FDA about next steps.

Operator, are there any more questions?

This concludes our question-and-answer session, and I would like to turn the conference back over to James Dentzer for any closing remarks.

Thank you, everyone, for joining us today. Again, it's very exciting to be talking about the data set that continually gets larger and yet shows consistent results as we move through. We appreciate the opportunity to share that with you today, and thank you for your support. Take care.

The conference has now concluded. Thank you for attending today's presentation, and you may now disconnect.