Curis, Inc.

Welcome to QRIS's third quarter 2021 earnings call. Before we begin, I would encourage everyone to go to the investor section of our website at www.qris.com to find our third quarter 2021 earnings release and related financial tables. I would also like to remind everyone that during the call, management will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. For additional details, please see our SEC filings. Joining me on today's call are Jim Dentzer, President and Chief Executive Officer, Bill Steinkraus, Chief Financial Officer, and Bob Martel, Head of Research and Development. We will also be available for a question and answer period at the end of the call. I'd now like to turn the call over to Jim. Jim?

Thank you, Relief. Good afternoon, everyone. It's my pleasure to welcome you to QRIS's third quarter earnings call. As we look back on the year, we have come so far as a company, making important progress with both of our lead clinical programs, CA4948 and CI8993. Every day at QRIS, we strive to develop the next generation of transformative cancer therapies that meaningfully improve and extend patients' lives. In the third quarter, we made significant progress towards that goal. To start, let me review our lead asset, our novel small molecule IRAC4 inhibitor, CA4948. CA4948 is the most advanced IRAC4 inhibitor in clinical development for cancer and is currently being evaluated in nine distinct patient populations across AML, MDS, and B-cell cancers. There is a critical unmet need for safe, fast-acting treatments for patients with AML, the leading cause of leukemia deaths in the United States. In MDS, the need may be even more critical. as so many patients are left with only supportive care as their best option for treatment. We are excited that the original scientific rationale for CA4948 and IRAC4 inhibition has been followed by consistent and encouraging results in the lab, and so far, consistent and encouraging results in the clinic. In both our B-cell cancer and AML and MDS studies, CA-4948 has continually demonstrated a well-tolerated safety profile and the ability to demonstrate improved efficacy over multiple cycles of treatment. These findings were most recently presented at the EHA meeting in June, where we shared data from the monotherapy arm of our Phase I-II AML-MDS study, demonstrating clear efficacy with no dose-limiting myelosuppression a potentially key differentiating factor that may allow even extremely sick patients with low thresholds for drug tolerability to be treated with CA-4948. Our second lead program is for our first-in-class monoclonal anti-VISTA antibody, CI-8993, a novel immune checkpoint inhibitor that we are developing in collaboration with Immunext. CI8993 is a clinical stage human IgG1 kappa monoclonal antibody designed to antagonize the VISTA signaling pathway by increasing T cell mediated immunity and reducing myeloid derived suppressor cell or MDSC activity. VISTA is a key checkpoint for holding T cells in a quiescent state, preventing their transition into effector cells facilitated by CTLA-4 and PD-1 therapies. In addition, VISTA is a key driver of MDSCs. These are two fundamental and unique roles of VISTA that are not captured by existing immune-mediating therapies. VISTA expression is also believed to be a key resistance mechanism to PD-1 and CTLA-4 therapies, as VISTA expression is dramatically elevated as patients become resistant to those treatments. Finally, VISTA is highly expressed directly on certain tumor cells themselves in addition to the surrounding immune cells, including mesothelioma and subsets of breast, lung, and gynecologic malignancies. Treatment with anti-VISTA antibodies has been shown to suppress the growth of both transplantable and inducible melanoma in preclinical models. CI8993 is currently being evaluated in a phase one dose escalation study for the treatment of relapsed or refractory solid tumors. With that, let's dig into some detail on our ongoing programs, starting with the IRAC4 study in leukemia. As I mentioned, We were pleased to present at EHA earlier this summer our positive updated data from the monotherapy arm of our AML MDS study, which expanded upon previously observed findings of single agent efficacy across the spectrum of late line AML and MDS patients. Despite these patients having already experienced several unsuccessful prior lines of therapy, We also demonstrated that near total IRAC4 inhibition was achievable at every therapeutic study dose. With these data, we saw that 300 milligrams BID struck the optimal balance of durable anti-cancer activity and extended tolerability. And accordingly, we selected it as the recommended phase two dose going forward. This was in line with the findings from our earlier monotherapy study of CA4948 in NHL, where we also selected 300 milligrams BID as the primary study dose for further evaluation. We continue to be pleased with the pace of enrollment in our monotherapy study of CA4948 in patients with a U2AF1 or SF3V1 spliceosome mutation. As we have noted previously, Our goal is to have 10 to 20 patients with a spliceosome mutation on study by the end of this year. We believe data from these patients may provide for an opportunity to explore discussions with the FDA on the registrational path forward in the first half of 2022. We expect to hit that 10 to 20 patient goal and plan to provide a high level update of safety and efficacy data from a subset of these patients in January. While we obviously don't have data for all 10 to 20 patients just yet, we do expect in January to have initial efficacy data for eight to 10 spliceosome patients and three FLT3 patients, or nearly three times the data we presented at EHA just five months ago. This update will include all patients enrolled by mid-September, which allows the opportunity for at least two disease assessments. to determine marrow response. Not all patients achieve responses this quickly, but we believe this two-assessment view will provide a nice interim snapshot of the clear progress we are achieving in this study. For these patients, we hope to see consistency with the data we shared at EHA. That is, we hope to see clear anti-cancer activity and reduction of tumor burden across the population, that a majority of patients can see their blast counts drop all the way down into the normal range, achieving an objective response, and highlighting CA4948's compelling ability to fight cancer as a monotherapy. Further, we would hope to see additional evidence of hematologic improvement. perhaps even a second patient with complete response, to determine whether some patients may be capable of achieving a CR despite the effects of damaged marrow from both their disease burden and from their prior treatments. Additionally, we would like to see that the finding of rhabdomyolysis previously seen at higher doses does not limit treatment at the recommended phase two dose of 300 milligrams BID. So this will be an early look at the data. We expect to have a more comprehensive data update with the full 10 to 20 patients at a medical conference next year. On the heels of our promising monotherapy data, we were very excited to be able to announce the recent initiation of our Phase 1-2 combination therapy trial of CA4948 in AML and MDS. With the positive preclinical data in combination therapy that we presented at EHA featuring CA4948's synergistic antitumor activity when used in combination with azazitidine and venetoclax, we are optimistic that this combination study will allow us to advance CA4948 as a new treatment for patients with AML and MDS across the broader AML and MDS patient population. where there remains a great unmet need with many patients ineligible for intensive chemotherapy. The combination portion of this study includes two arms, CA4948 plus azacitidine for patients naive to HMA and CA4948 plus venetoclax for patients naive to venetoclax. The primary goal of this combination study is to determine the recommended phase two dose for CA4948 in combination with azazitidine and in combination with venetoclax based on safety, tolerability, and biologic activity, including pharmacokinetic and pharmacodynamic findings from the study population. We expect to have initial data from this combination study in 2022. I would like to briefly touch on the ongoing Phase II Lucas IST for patients with lower risk MDS being led by the co-chairman of EHA's scientific working group on MDS, Dr. Uwe Platzbecker. We realize there's a lot of interest in this study because success in this study could lead to a potential breakthrough in the MDS field. So even though we have a longer time horizon for this study, and it is not a company-controlled study, we hope to be able to provide an update on the progress of the Lucas IST in 2022. The current standard of care in low-risk MDS is supportive care, such as EPO-stimulating agents, which can be effective for patients with low serum EPO, or loose patercepts, which enhances production of red blood cells. Unfortunately, these interventions do not alter the underlying disease. Their effect is often transient and they do not prevent progression to AML or further disease complication. In contrast, CA4948 is disease modifying, targeting a key driver of the underlying disease. Given the direct non-myelosuppressive targeting of IRAC4, and its demonstrated safety profile, we believe CA-4948 could potentially offer a safe and transformative disease-modifying alternative for patients in this earlier stage of disease. In conclusion for AML and MDS, our success earlier this year led us to expand our clinical investment to include both monotherapy and combination therapy and to include patients across the spectrum of disease from low-risk MDS to high-risk MDS to AML. We look forward to providing data updates on all of these studies in 2022. Moving to our B-cell cancer program. We have made steady progress with our CA4948 clinical development in B-cell cancers. Data from our monotherapy phase 1-2 study highlighted clear reduction in tumor burden and a strong durability profile, which is particularly notable with a novel monotherapy agent in such extremely sick patients. Based on these findings, as well as our preclinical work, we believe CA4948 is the ideal candidate to combine with BTK inhibitors to maximize the downregulation of NF-kappa-B. Earlier this year, we initiated the combination study evaluating CA4948 with ibrutinib, which is expected to enroll approximately 18 patients in a 3 plus 3 design with CA4948 starting at 200 and escalating to 300 milligrams BID. Ibrutinib dosing will be determined based on the appropriate dose for the patient's type of cancer. We are pleased to share today that CA4948 administered at the 200 milligram twice daily dose has been well tolerated in combination with ibrutinib with no DLTs observed. We are currently evaluating the 300 milligram twice daily dose of CA4948 in combination with ibrutinib. The trial is progressing well, and we expect to report initial data from this study at a medical meeting in 2022. While we are obviously excited about our ongoing studies in AML, MDS, and B-cell cancers, we are equally excited by the breadth of its potential application in other cancers and are working with our collaborators at NCI and in the broader KOL community to evaluate additional opportunities for CA4948. In October, we announced at the triple meeting conference on molecular targets in cancer therapeutics new preclinical data highlighting the potential benefit of CA4948 in multiple new applications. These data demonstrated that CA4948 can cross the blood-brain barrier and enhance survival in patients with primary central nervous system lymphoma, an incredibly aggressive and rare form of lymphoma in which malignant cells form in the lymph tissue of the brain and spinal cord. Additional data at the meeting highlighted CA4948 as synergistic with small molecules targeting BCR signaling, including both idelalicid and ibrutinib. These data suggest it may help overcome secondary resistance to these therapies in marginal zone lymphoma. Last but not least, turning to CI8993, our first-in-class monoclonal antibody targeting VISTA for patients with relapsed or refractory solid tumors. Enrollment remains on track in this Phase I study, and we expect to report initial safety data in our January 2022 update. VISTA is highly differentiated from other existing checkpoint inhibitors because of its primary role in enforcing T-cell quiescence. When unblocked, VISTA is capable of sequestering a large proportion of T cells in a quiescent state, preventing them from being acted upon by anti-CTLA-4 or anti-PD-1 antibodies. VISTA is also a primary driver of MDSCs, which independently promote T cell exhaustion and suppress pro-inflammatory tumor-associated macrophages. This year, our primary objective is to evaluate safety and tolerability and confirm that using our revised protocol, the on-target side effects of CI8993 can be safely managed, enabling dose escalation up to and beyond all doses studied with this anti-VISTA therapy in prior clinical studies. Achieving of this critical milestone which we hope to report on in January, will enable us to begin the exploration for efficacy at higher dose levels in 2022. I would also note that earlier today, we announced that a preclinical data submission for CI8993 was accepted for a poster presentation at the annual meeting of the Society for Immunotherapy of Cancer, or CITSE, being held from November 12th to the 14th. We look forward to sharing additional data from this program at that time. In summary, this has been an incredibly exciting year for QRIS, and we have even more to look forward to. Specifically, we expect to report in January both initial safety data from our anti-VISTA program, the phase one monotherapy study of CI8993, and an update of safety and efficacy data from our Phase I-II monotherapy study of CA4948 in AML MDS patients with certain spliceosome or FLT3 mutations. This update will be followed by a more comprehensive update later in 2022. Also in 2022, we plan to report initial data at a medical meeting from the ongoing Phase 1-2 combination study of CA4948 plus ibrutinib in patients with B-cell cancers. Before turning the call over to Bill to discuss our financials, I always like to extend my gratitude and appreciation to the entire CURIS team for their dedication and hard work. We are eager to build upon our efforts and advance our next generation targeted cancer programs to help patients in need. With that, I'll turn the call over to Bill to review our financial results for the quarter.

Bill? Thank you, Jim. For the third quarter of 2021, we reported a net loss of $11.1 million, or 12 cents per share, on both a basic and diluted basis, as compared to a net loss of $6 million or 11 cents per share on both a basic and diluted basis for the same period of 2020. For the nine months ended September 30th, 2021, we reported a net loss of $31.8 million or 35 cents per share as compared to a net loss $22.4 million or 52 cents per share for the same period 2020. Revenues for the third quarter of 2021 and 2020 were $3 million and $2.7 million, respectively. Revenues for the nine months ended September 30, 2021 were $7.5 million, as compared to $7.8 million for the same period in 2020. Revenues for both periods comprised primarily of royalty revenues recorded on Genentech and Roche's net sales of AeroVeg. Operating expenses for the third quarter of 2021 were $13.1 million as compared to $7.5 million for the same period, 2020. Operating expenses for the nine months ended September 30, 2021 were $37 million as compared to $26.4 million for the same period in 2020, and were comprised of the following. Cost of royalty revenues, primarily amounts due to third-party university patent licensors in connection with Genentech and Roche's AeroVegNet sales, were $0.2 million for the third quarter of 2021, as compared to $0.1 million for the same period in 2020. Cost of royalty revenues were $0.4 million for both the nine months ended September 30, 2021 and 2020. Research and development expenses were $8.6 million for the third quarter of 2021 as compared to $4.7 million for the same period in 2020. The increase in direct research and development expenses for the quarter is primarily attributable increased clinical and manufacturing costs for our clinical programs. Additionally, employee-related R&D costs increased by $2.3 million, primarily attributable to increased stock-based compensation and personnel costs as a result of additional headcount. Research and development expenses were $24.1 million for the nine-month-ended September 30 2021 as compared to $17.5 million for the same period in 2020. General and administrative expenses were $4.3 million for the third quarter of 2021 as compared to $2.6 million for the same period 2020. The increase in general administrative expense was driven primarily by higher costs for stock-based compensation, personnel, professional, and consulting services. General and administrative expenses were $12.5 million for the nine months ended September 30, 2021, as compared to $8.6 million for the same period in 2020. For the third quarter of 2021 and 2020, Net other expense was $1 million and $1.3 million, respectively. Net other expense primarily consisted of imputed interest expense related to future royalty payments. Net other expense was $2.3 million for the nine months ended September 30, 2021, as compared to $3.8 million for the same period in 2020. As of September 30, 2021, QRIS's cash, cash equivalents, and investments totaled $149.8 million, and there were approximately 91.6 million shares of common stock outstanding. We expect that our existing cash, cash equivalents, and investments should enable us to maintain our planned operations into 2024. With that, I'd like to open the call for questions. Operator?

We will now begin the question and answer session. To ask a question, you may press star then 1 on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then 2. At this time, we will pause momentarily to assemble our roster. Our first question is from Althea Young with Cantor. Please go ahead.

Hey, guys. Thanks for taking my questions. Just a couple. One, I wanted to start with, you know, maybe to kind of, I don't know if you're ready to kind of give this granularity, but should we be thinking that kind of the FDA conversation probably would happen, you know, after kind of the second more robust update? So maybe perhaps like a little bit later in the first half of 2021. I guess my, and this kind of leads to my second question, which is, you know, I guess with 10 to 20 people, do you think that's going to be sufficient? I know you have safety and other stuff from other studies, but just do you think that's, what's your confidence interval in that being kind of enough to trigger a conversation that can inform potential pivotal strategy, even though I know it's a much smaller population? And then my third question was, you mentioned, I guess you mentioned the complete response, which exists, but then you mentioned potential for another complete response. So I just wanted to confirm that that's not been seen yet. It's just what you hope to see. Thanks.

Yeah, thanks, Alethea. This is Jim. So let me start with that last one because I know that's of high interest. It's what we're hoping to see. This obviously is not a call where we're discussing the data that we have seen. We've got a couple months for the data to mature. But when we think about what we're hoping to see with this drug, this drug has shown a really unique ability as a monotherapy to reduce cancer burden across the spectrum with a majority of these patients are getting their blast counts all the way back down in the normal range. That's what we want to see. We've already seen one CR. We'd love to see another one. We want to give that update in January. We don't have all those data yet. But, of course, if you ask for what we were hoping for, that was sort of our guidance. In terms of the FDA meeting, we have always planned, and we've been very clear about this all year, we have always been planning to get the concentration focused on spliceosome patients and FLT3 patients. When we saw that the data we had at EHA were so compelling, we really ramped up our efforts to get patients on drug. Our regulatory consultants have given us guidance that in order to meet with the FDA, we probably need 10 to 20 patients, and that's our goal, to get 10 to 20 patients on drug by December 31st. Whether or not the FDA agrees with those consultants and takes our meeting and has this discussion we hope for, of course, we don't have any control over. But the general consensus seems to be that if we can get 10 to 20 patients and the data look consistent, then we should have a good shot at having a successful discussion with the FDA. The reason for the new update that we're offering in January is, of course, we're very pleased with where we sit. We don't have all the data yet, but the data that we have, we think, do look compelling and consistent with what we've been And we think that if we can make that cutoff to have eight to 10 patients at your end with spliceosome mutations and another three with FLT3, that does go a long way to giving everybody, you know, our investigators, the KOL community and investors a very good sense of where are the data trending. We've only seen three patients so far. Where are the data trending? so that we have a good sense of how that discussion with the FDA might go. That's the point of that update. So we're very happy with where we sit, but, of course, we've got more data internally, and we'd like to make it public. So that January plan is to make all of that public.

And then maybe just to follow on on the safety, with the combination that you mentioned, you haven't seen anything related to rhabdo or anything. I think you said there was no DLT, so I just wanted to confirm that.

Yeah, actually, Bob, would you mind talking about that?

Yeah, so we've obviously continued to dose patients with our 300-dose level in the monotherapy study. That's going along well, and as Jim said, we'll update the safety on that. We probably won't be giving an update on the combination study at that point, but yes, there were no dose-limiting issues at that initial dose level, so it was quite well tolerated, which is really exciting because, you know, as you know, now we're able to dose escalate up to the full dose of both drugs.

Great. Thank you.

The next question is from Dane Leone with Raymond James. Please go ahead.

Thank you for taking the questions and congratulations on the progress. I guess in light of the announcement that you're going to host an update call in January now, you know, maybe given this isn't going to be the full data set of what you hope to have in splice and zone and FLT3, could you maybe just clarify how to set expectations You know, I guess the worry is if you're giving this update in January, you know, everyone tries to interpret it in terms of a data set that you'd actually walk into the FDA with, maybe something akin to the meta-inhibitor class. But it seems like from your commentary, you're trying to give more of an anecdotal update. So maybe you could just provide some caveats to what this data analysis is actually gonna look like and the context that you're trying to hope to pull out of updating people publicly without maybe the full data sets here for the splice zone group.

Sure, why don't I make an initial comment on that and I'll ask Bob to expand as well. So I think the thought process is of course we gave a terrific update of three patients, but it was only three patients at EHA with the spliceosome mutation. And in fact, one FLT3 patient. FLT3 patients did exactly what we hoped, exactly what the literature would suggest. You know, a patient that did not respond to other FLT3 inhibitors coming onto our study and within two cycles not only getting a response, but seeing complete eradication of the mutation. I mean, both data sets, the first three and the one, look terrific. And we've then moved fast and furious to have the discussion with the FDA. And I think what we're just trying to respond to is it's a long time between EHA and that discussion with the FDA. We have a lot of confidence and we are seeing terrific progress in that study. And we wanted to give everybody else a chance to see what we're seeing. So it's not the full update that we'll have in six months from now. But we think the data that we have now and the data we're going to have by year end is a nice update, and it gives a significant upgrade. Just five months after EHA, we're going to triple the data set. We think that's going to be, I think, a very robust discussion. It's not anecdotal, and it's not the complete total of all patients that will ever be on the drug, but it's a significant increase of the data size and really should give everyone a chance to share our enthusiasm for the progress of the study. Bob, would you like to add to that?

I think you described it well, Jim. So basically, as we said, we've been so excited about the disease-modifying aspect of this drug, especially in this population, seems to have a really potent effect on limiting blast growth and reducing blast. And, you know, we think that this is a therapy that the FDA will be very interested in, in a population where, you know, no other drugs are approved. And so based on our EHA data, You know, we sought to really build our case around that and really focus on the FDA with our goal being, you know, we would like to update the community publicly along the way with data when we have, you know, relevant updates. And so that's the goal here. in January. This isn't going to be the exact data set that we take to the FDA, but it'll be, as Jim said, a tripling of the number of patients that we've presented publicly so far. So we think it should give the community a lot more confidence about the drug and the anti-cancer activity of the drug going into that, you know, potential discussion with the FDA.

Great. Sorry, just to clarify one thing. point of follow-up for the cohort of spliceosome mutations, are you going to go to the FDA? Are you looking to have that fully enrolled with clinical follow-up for all those patients to properly evaluate efficacy before having that discussion with FDA, or are you doing that before you have a more mature data set in that cohort?

Well, obviously, when we do go, there will be... you know, a range of patients in terms of duration on study. We'd obviously like to have, you know, a minimum duration for all the patients that we present to them. It's an ongoing process. And, you know, even the data that we present to them will be interim data to some extent. But we think, you know, by the first half, and so we've committed to, you know, considering that as a possibility in the first half of 2022. And we believe that we'll have enough data that's mature enough at that point to speak with them, at least we'll request to speak with them.

Okay, so to be clear, you won't actually have feedback from the FDA when you give the update in January, correct?

That's right. Okay.

Yeah, no, no, no, no. Yeah, we should be really clear, Dane. We haven't already spoken to the FDA. The plan has not changed. We are planning on meeting with the FDA in the first half of 2022. This is just a chance to give everybody a snapshot to see all of the data that we are now seeing, triple the size of the data they've seen so far, to give them a greater confidence that we really do have something. The skepticism that you get in developing a new drug in this space should be high. In monotherapy, there is nothing approved for these patients because nothing works. The data that we've seen so far are remarkable, but it's small, N of three and N of one. So I think you know, being able to provide people a greater sense of confidence that this really is something that nobody has seen before, that we really do have a drug in monotherapy that can address cancer in these patients, I think is tremendously exciting. And so we're very interested in providing that update. Okay, thank you.

The next question is from Justin Walsh with B. Reilly Securities. Please go ahead.

Hi. Thanks for taking the question. Maybe can you give us some color on what we should be looking for in the B-cell cancer combo data? I believe that you have a Simon two-stage design to help explore signals in the expansion portion, but maybe you can remind us what response rates do you think would be meaningful in the various lymphoma indications you're looking at?

Yeah, that's probably a better question for Bob. Bob?

Yeah, so obviously we started that. That's a combination with ibrutinib, and just to recount, you know, ibrutinib hits the other primary pathway that activates NF-kappa-B, and other BTK inhibitors inhibit that pathway. 4948 is really the only drug that's targeting the other primary pathway activating NF-kappa B in these malignancies, and that's, you know, TLR signaling through the mitosome, and that drives the, you know, the combination that we're putting in here. You know, right now, clinically, we've seen activity with our drug as a monotherapy targeting this pathway. Obviously, Brutinib and other BTKs have monotherapy activity there. What we would like to do is enhance that activity is part of this combination. And the study that you mentioned really has four different cohorts each of which is a, you know, what we consider a low-hanging fruit for, you know, targeting IRAC4. These are indications where, you know, there is a high incidence of mid-88 mutation, which is a key part of the midosome, and strong signaling through NF-kappa B via that pathway. And it's also indications where we think there is a straightforward registrational path as well. And so we'll be expanding in each of these. You know, we'll be looking to gain estimates of the efficacy of these combinations. As one example, the fourth cohort is a cohort where we're looking at adaptive resistance. That's where a patient has experienced progression on ibrutinib. In this case, we add, you know, 4948. And so to address your question, Any efficacy that we see there suggests sort of proof of concept of adding 4948 to ibrutinib as part of that combination. Ultimately, once we get those estimates of efficacy, we'll discuss with the FDA what we think is a relevant target for a pivotal study going forward from that. but we haven't put a stake in the ground specifically for a target response rate. We would obviously hope to get a reasonable percentage of patients having durable responses and hopefully deep responses, and in many cases, deeper than what we would expect with a BTK inhibitor by itself.

Got it. Do we have a sense of roughly how many patients we can expect at that readout, and if those include patients from those four specific cohorts of interest?

Yeah, so just to reiterate the four cohorts, I already mentioned one, which is the adaptive resistance, and that can be any patient across any indication who's had a root nib. The other three include primary CNS lymphoma. This is a very deadly and difficult to treat disease that actually has a very high incidence of mid-88 mutation. You know, marginal zone lymphoma is another one that has a high activation of NF-KpB, you know, through this pathway. And so, you know, with those, we, you know, we hope that we'll see, you know, strong efficacy there.

Got it. All right. Thanks for taking the question.

Again, if you have a question, please press star then one. The next question is from Salman Roy with Jones Trading. Please go ahead.

Hello, everyone. Thank you for taking the question. If you could remind us a little bit on the natural history progression of the MDS from low risk to high risk. Do we see an increased accumulation of these spliceosome mutation? And what would a standard of care response rate look like, some kind of benchmark to look at?

Yeah. Hi, Sumit. Thanks for your call. Bob, would you mind commenting on that? I know this is more your area of expertise. Okay.

Yeah, so the natural history, you know, it's interesting. These spliceosome mutations occur extremely early in the natural history of the disease. You know, as you may know, they've been known for quite a while and correlating oftentimes with one of the first mutations found in the disease. And it wasn't until about a year and a half or two years ago that it was even known what the spliceosome mutations were. did in terms of their oncogenic role. And it was some work by Amit Verma and Dan Sarskinowski who determined that it's actually this alternate splicing of IRAC4L. And so, you know, as I mentioned, it's what some people call a founder mutation, these spliceosome mutations. And they tend to persist throughout the disease. So, Normally, you know, a patient may start out with low-risk MDF with one of these spliceosome mutations. And over time, their disease starts to accumulate other changes and ultimately becomes more aggressive. Unfortunately, some patients die along the way because of the complications of the disease, such as neutropenia and low platelet counts, thrombocytopenia. But in general, these spliceosome mutations persist if the patient does evolve their disease and ultimately can transform into leukemia, AML. And again, during that transformation, you know, most of the patients still retain that IRAC or the spliceosome mutation, suggesting that this is a really critical component that's important for the survival of the disease itself. And that's why we think that this drug has a very important role for all stages and exactly why we're going after the low-risk disease as part of the Uwe Platzbecker collaboration, as well as these later lines with the high-risk MDS and ultimately the AML. The response rate and information that you look for in terms of endpoints across the spectrum ranging from low risk to high risk MDS all the way to AML differs depending on the specific disease setting that you're looking at. So, for example, in low risk MDS, you know, an appropriate endpoint there might be, you know, transfusions, the number of transfusions required or frequency or maybe even achieving transfusion independence. As you get to higher risk disease, you're, you know, you're looking for, you know, disease control, you know, reduction in blast counts, as well as, you know, reduction in transfusions and hematologic improvement. And same with AML. Again, you're looking for a variety of different endpoints. When we think about you know, this population that we're looking at with the spliceosomes, it's important to remember the very potent inflammatory microenvironment that develops because of these spliceosome mutations and because of IREK4L. And that creates a damaging effect to the marrow, including the healthy marrow. You know, I often liken it to hepatitis where in hepatitis C causes liver cirrhosis. You can even get rid of the hepatitis C, but the cirrhosis of the liver remains. This can be the case as well in the bone marrow. So healthy marrow may be damaged. It makes it difficult in these spliceosome mutations to recover. And so that's important to think about when we're thinking about potential efficacy hurdles. There was a nice publication a few years ago that looked at intensive induction chemotherapy in AML, actually. In the broader population, 80% of patients achieve a full hematologic recovery. But when you break out those patients with spliceosome mutations, only about 22%, almost three or four-fold less of the patients were able to achieve a full CR if they had an SF3B1 mutation. That's a spliceosome mutation. So dramatically reduced ability to achieve, you know, hematologic recovery in this population. So that's what we want to think about. And when we're thinking about precedence for response rates, it's important to take that into consideration. but that'll be a really big goal of ours when we actually speak to the FDA. We've seen really striking, um, anti-cancer efficacy with this drug so far. And we've also seen, you know, good, strong evidence of other potential endpoints. And, you know, we'll put all those data together and the additional patients that we will now be able to take to the FDA I think will help us, you know, in that discussion with them and ultimately coming to an agreement in a population, for example, with spliceosome mutations where, you know, the endpoints that we need to shoot for are likely to be different than what you might see in a typical de novo AML, for example. Does that answer your question? It's kind of a long way to go.

Thank you, Bob, for the really detailed call. Really a lot to look forward to in January and beyond. Last question is, can you remind us if you're... FLT3 mutant patient, can they be FLT3 inhibitor experienced or do they have to be naive?

They can be FLT3 inhibitor experienced. In fact, you know, the patient we actually presented at EHA was FLT3 inhibitor experienced. So that patient had been treated with giltaritinib and had absolutely no response to giltaritinib, which is, you know, one of the primary FLT3 inhibitors that are approved by the FDA. Okay. And then they came on to this study and had a dramatic reduction in the bone marrow blast, achieved a PR, and, you know, done quite well. So, you know, I think the important point to note here is that for patients who are on FLT3 inhibitors, it's been demonstrated that, you know, one of the primary mechanisms of resistance to those inhibitors is, in fact, signaling through TLR pathways and specifically through IREC4. So, you know, the suggestion in the literature is combine an IREC4 inhibitor with a FLT3 inhibitor. Well, fortunately, 4948 is the perfect drug in this case because we hit both IREC4 and FLT3. So, yes, we'll definitely be open to both of those possibilities.

Got it. So you'll continue to enroll FLT3 experienced. Okay. Thank you so much for taking the questions and congrats on the progress.

Thank you very much. This concludes our question and answer session. I would like to turn the conference back over to the company's president and chief executive officer, James Denser, for any closing remarks.

Thank you, Gary. And thank you everyone for participating in today's call. As always, thank you to the patients and families participating in our clinical trials. to our team at QRIS for their hard work and commitment, and to our partners at Origen, Aminext, and the NCI for their ongoing help and support. We look forward to updating you again soon. Operator?

The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.