Hey, everyone. Welcome to our next session with Curis. My name is Lee Walthek, a Biotech Analyst here at Kenter. I'm very pleased to have Jim Dentzer, CEO of Curis, with us today. Maybe start. I'll just hand it over to Jim to give us some quick overview. Thank you. I appreciate it. Thank you for having me. The overview of Curis is we're really at an exciting crossroads. We've got one drug that we're finding. We've got a pretty good pipeline, but one drug is all of our resources, all of our time, and all of our money. It's an IRAK4 and FLT3 inhibitor. Its utility is in NHL and in AML, maybe in solid tumors as well. We have a bunch of studies funded by the NIH in solid tumors. What most investors are focused on right now is NHL. We've got a proof of concept data set in PCNSL of 34 patients that look quite compelling. It's an add-on therapy to BTK inhibitors. You may remember that in NHL, disease is driven by NF-kappa B. NF-kappa B is in turn driven by two pathways, BCR and TLR. BTK inhibitors block one of the pathways, we block the other. We are approaching all of the NHL subtypes just as we approach PCNSL, which is the smallest subtype. Use a BTK inhibitor to block the BCR pathway, use our drug to block the TLR pathway, and it should lead to higher response rates and potentially complete remission. Right now, as I say, the proof of concept data is in PCNSL with 34 patients, but we've recently announced that we're moving into CLL as well. That's where most people's attention is because it's the largest indication within NHL. Yeah, we're certainly going to talk about CLL just in a little bit. Going back to PCNSL, that's the CNS lymphoma. It's a small subset of the lymphoma population. I'm not sure many investors are super familiar with the treatment regimen here at the end. On that need, maybe, Jim, you can talk a little bit about that. Where do you think you can fit in in this landscape? Sure. You're exactly right. Most people don't pay attention to PCNSL. It is the smallest of the six NHL subtypes. Standard of care in frontline is chemo and radiation. Once you progress, standard of care is ibrutinib. It's the only BTK inhibitor currently in the NCCN guidelines as standard of care in relapsed refractory PCNSL. That's because it has the best BBB penetration, blood-brain barrier penetration data. Our view is that while BTK inhibitors work, the largest study ever conducted, a study in France, showed an ORR of 39% in those patients. We believe we can improve that by adding immunosuppressants. So far, in a small population, we've got an ORR of 63%, so quite a bit better. In a secondary data set of patients who are on a BTK inhibitor and failed, so now their brain tumors are growing, we find that in the majority of patients, we can reverse the disease, shrink the tumors, and get responses in 27% of them so far. That's in a patient population who doesn't have an alternative. There is no standard of care once you've failed BTK. They would likely be going to hospice. Yet, we're getting patients into complete remission. It's very exciting. It's just a very small market. Okay. It sounds like you guys believe that you might be able to get accelerated approval based on single-arm study. Obviously, you've shown some nice data early, and you're going to have an update for us later this year. Maybe set the expectations for us what the bar for success might be? Sure. Yes, you're exactly right. It's a phase I II study, but we now know, as of a couple of months ago, that both agencies have accepted it as pivotal. All we need to do is add more patients. How many patients do we need? That's a statistics question, but the answer is somewhere between 45 and 60. What we reviewed with the FDA and EMA was that if we have a lower bound of 10%, then we need to have an ORR of 22 in 45 patients or 20 in 60 patients. As long as we're in that 20% - 22% ORR range, 45 t- 60 patients is the right end to get a 95% confidence interval. Right now, we're at 27, so we're in good shape moving forward. The hardest part moving forward is not data related about whether the molecule is working. It's finding the patients because it's an ultra-rare disease. Both agencies have agreed now that the current study is pivotal. In terms of enrollment, Jim, what can you do in terms of maybe try to accelerate the enrollment a little bit, just given there are some challenges here? It's all about the number of sites. We've got 30 sites now globally in Europe, the U.S., and three sites in Israel. With 30 sites, our expectation to hit our goal is we need one patient per site per calendar year. We'll talk to the investigator at MSK, for example, and they'll say, how many patients do you need? The answer is, we need one in 2025 from you. Some sites will have two or three patients. Some sites might not have any. But as long as we get one patient per site per calendar year, we'll hit our goal, which is full enrollment in 12- 18 months. Follow them for another six months, get their data, and file an NDA. You're exactly right. It's an accelerated approval single-arm study. And then we will follow it with a confirmatory study that's randomized. It'll be randomized against ibrutinib. That study, of course, can take much longer and likely will. Okay. Just given recently, the FDA put out the new guidance for oncology drugs and seems to have a very strong focus on OS. Just you think about a single-arm trial for accelerated approval, do you see any risks there in terms of what the agency wants to see? Do they want to see OS benefit? Obviously, in single-arm, it's not reliable. Just based off your interactions with the agency, do you see any sort of shifting the bar at all? Yeah. The short answer is there is always uncertainty whenever you're dealing with a regulatory agency, especially in the current environment. There's not a whole lot of constancy, and that is a concern. I'd say in our case, in PCNSL, we are less concerned for a couple of reasons. First, it's an ultra-rare indication where there are currently no drugs approved. Patients do receive ibrutinib because there are NCCN guidelines, but there are actually no drugs approved. We would be the first one, and that's encouraging. Both agencies are eager to have a drug that has gone through all of the regulatory testing needed. I think they're willing to be more flexible rather than if we were going after a disease where we're the fourth or fifth drug to market. The second thing is, in PCNSL, we're talking about tumors in the brain. Unfortunately, survival statistics are fairly grim. These patients don't live for very long. They'll respond fairly well to chemo and radiation in frontline, but by the time they get to second line on a BTK inhibitor, their survival is typically measured in months. If we needed to pivot in our discussions with a regulatory authority, we're already going to include survival statistics. If they wanted to put more weight on survival, in our case, it wouldn't take very long to generate those data because the patients don't live very long. Okay. Jim, you talked about a confirmatory trial. I know the agency also has some requirements for recruitment of a confirmatory trial to support AA. I think you mentioned before the part C of the study where you have BTK naive patients could potentially serve as a confirmatory study. Yeah. Have you had that discussion with the FDA and how feasible that would be? We've had the high-level discussions with the FDA and EMA, and they're both supportive. We need to have more discussions about confirmatory trial design. That said, you're exactly right. We designed part B and part C to support accelerated approval and confirmatory approval or full approval intentionally. Part B is in the experienced patients. These are the patients who failed ibrutinib and don't have an option. That'll be a single-arm study. We leave them on ibrutinib, add emavusertib to it, and see if we can reverse their disease. For the confirmatory study, that needs to be randomized. Because it's randomized, it'll have to go one line earlier. You can't have one arm of your study being ibrutinib if they just failed ibrutinib. Both agencies agreed with that approach. They like the idea of randomizing against ibrutinib. We have a very small patient population that's been treated so far. As I say, versus an expectation of 39%, we're at 63%. I think that's very encouraging. Certainly, we would expect that over time, we'd see a consistent result in survival as well. We need to have a more detailed discussion with the FDA to follow up on the high-level discussion about exactly what that clinical design looks like. If they are consistent, what they did in accelerated was they said our existing data count, the part B data can roll in and be included in the NDA. I expect that they'll do the same thing with part C. In an indication where there are no drugs approved, if we already have a population that's being treated and being treated successfully, as long as the criteria are the same, it is reasonable for them to allow us to expand part C, and that becomes the confirmatory study. When are you going to maybe approach the FDA to sort of have more follow-up discussions around the confirmatory study? Yeah, that's over the coming year. We've already started that study. We're enrolling it now. There's no big rush to have that discussion with the FDA since we already know directionally that we had the high-level discussion, and they were fine. Our view is let's go to them when we have some data. We have a small, but we would like to go back to them over the coming year. We'll give them an update of here's where we are on the single-arm study, and here's where we are on the randomized study. Now that you see these data, and they're hopefully going to be consistent with what they've seen in the past, they would be amenable to coming to the same conclusion, which is the current population, as long as you haven't changed enrollment criteria, should be amenable to inclusion in the confirmatory design, which means part B was converted into the pivotal. Presumably, part C will be converted into the confirmatory. Worst-case scenario, if they say no, it just means the confirmatory study takes longer, which isn't the end of the world because you'll already be approved. For patients' sake, it'd be nice if we could include them. Have you had any high-level discussion in terms of size of the confirmatory study and what the primary endpoints might be? Size, no. The primary endpoint is almost certainly a survival endpoint, whether it's PFS or OFS. In either one, because in PCNSL, the survival stats are fairly grim, prognosis is difficult for these patients, we don't have a strong feeling between PFS and OS. We had a discussion with the FDA and EMA already, as I said. As long as it's one of those two, I think both agencies will be fine. We'll look to lock that down, as I say, when we have the follow-up discussion. Okay. Just in terms of the timeline for the part B, and Jim, you mentioned, you know, ideally, you're going to have one patient per site per year. You have 30 sites, and perhaps you're going to enroll other patients in 12- 18 months. As we think about when to expect the top line, number one, any interim analysis, and two is help us understand after you finish enrollment, what the final top line could come in. Yeah. It's an open-label study, so we are able to provide updates every six months at ASH and at ASCO if that's what investors would like to see. We've just given an update in mid-year. While we're planning on having a presentation at ASH, just to put expectations into perspective, when you're talking about adding a patient a month, it's not a dramatic update. The conclusion before was the drug's effective. The conclusion at ASH is going to be the drug's effective. It's not a big movement of the needle. That said, as we get closer to the 45 patients, it will be very encouraging for us and for investors to know that things are on track and that we continue to be above that 20%- 22% hurdle. Right now, I think we are. Even if every patient that we enroll over the next three months does not do well, we would still be above that. I'm actually not seeing that that's going to be a big needle mover for investors. Certainly, over the 12 - 18 months time frame, it will be. Okay. I think one interesting update from your Q2 is you're going to initiate a new trial in CLL. I think that's a really interesting opportunity. Maybe talk to us about the thought process behind that and where do you see the opportunity is? Sure. There's been a lot of excitement about that, which is interesting. We're in a pivotal study in PCNSL. Every question we've gotten over the last two months from investors has been about CLL. Not shocking. CLL is much larger. PCNSL is maybe a $500 million, $600 million market. CLL, of the $11 billion in BTK, 7.7% of it is CLL. That's where all the interest is. We're going at it with two primary thoughts. The first is the biology for NHL holds through all six subtypes, and that is the disease is fundamentally driven by NF-kappa B overactivity. Two pathways drive it. One is addressed by BTK inhibitors. The other is addressed by us. We would go with a combo therapy in CLL the same as we did in PCNSL, and we would look to have the same outcome, meaning when you add immunosuppressant to BTK, it makes BTK better, get higher response rates, deeper responses, and presumably that will lead to better long-term clinical benefit as well. Specifically, the unmet need in CLL, while there are exciting developments scientifically, things like venetoclax and obinutuzumab or CAR-T, this one-and-done idea is really compelling. They don't have a whole lot of traction among patients for various reasons. They're difficult. The side effect profile is tough. CAR-T, in particular, you need to have a site that's capable of doing it. The market is still a BTKi market, and that's despite the safety effect profile. The safety effects are very concerning for an elderly population. The lead side effects for BTK are bleeding, bruising, fatigue, cardiac events. It's exactly what you don't want as an elderly patient. What we look to do by adding EMA to a BTK inhibitor is to provide that same kind of outcome that you get with CAR-T or VO, but with an oral-oral regimen. That's really compelling for patients. They want to be able to move to either a CR or MRD negative so that they can take a time-limited approach to BTK treatment. You can stay on EMA as a maintenance therapy, get them into CR with the doublet, and then drop the BTK. If the disease comes back, add the BTK back in, knock it back down, and then go on that sign curve. The value for that is two reasons. It is twofold. Time-limited treatment is important because the side effects of BTK are so difficult to tolerate, but also, BTKs as monotherapy don't get you to complete remission. They get you to partial response. As long as disease is active and you're in chronic therapy, you have the opportunity for the disease to mutate. Mutations in CARD11, CD79B, these BTK-resistant mutations mean that you run the risk that your BTK will stop working. For those reasons, we want to be able to offer the one-and-done kind of outcome that you can get with a CAR-T, but do it with an oral-oral therapy. That's our goal. Okay. The population you're going to look at is the patients who have been exposed to BTK inhibitors, but they don't get good response to BTK. Is that the population you're going to? Yeah. We look for patients that are already on a BTK, which is effectively all of them, who are in partial response but have not been able to get to CR and are still MRD positive. That's virtually all of them. Patients don't get CRs or MRD negativity on BTK inhibitor monotherapy. We'll take those patients in. Once they're stable in PR, we'll leave them on whatever BTK they're on, any one of the four. We'll add immunosuppressant to it and see if we get the same outcome that we do in PCNSL. Are we deepening the response? Can we get them from PR to CR? Can we convert them from MRD positive to MRD negative? If so, that has the potential to fundamentally change the treatment paradigm in CLL. We need the data to show that we can do it. Given our experience in PCNSL and given the limited data we have in Waldenstrom, CLL, and mantle cell in our earlier part A study, we feel pretty good about it. I think the study or the patient population you're looking at is sort of like in between the first line and second line. It's not patients that progress or become refractory to BTK. It's just inadequate response to BTK. You talk about CR rate, MRD negativity rate. Can you use these endpoints to support approval, or do you have to get the PFS and OS benefit as well? Obviously, we need to have this discussion with the FDA. I think certainly over the last 12- 18 months, there's been a big move towards MRD as an endpoint. We know of at least six different studies in CLL that have used MRD as an endpoint. Publications as recent as two months ago, one of the lead publications talking about using MRD as a novel endpoint in clinical trials was co-authored by Prasad. I think there will be, since he's running the FDA, I think we're expecting to get a favorable view. As I would say, MRD negativity is a recent goal and a recent clinical endpoint for clinical studies. We need to have that discussion with the FDA to be sure that they're okay with that. My anticipation would be that's where the market is going. Okay. Now, just looking at the landscape of CLL right now, obviously, BTK has been the standard of care for the longest time. We're seeing, for instance, the doublet is moving into the front line in combination with BCL2. We also have BTK degrader coming shortly after that that has shown really, really strong data that probably can even max out the front line treatment. There are several BTK inhibitors out there. This landscape is definitely evolving. As you think about designing a trial, which BTK to choose from, how are you thinking about that? What is the impact on the trial design from your standpoint? Yeah. There are a couple of different interesting nuggets to your question. I'll address the first one first. There are some really interesting scientific approaches. BCL2 is one. As I said, venetoclax, the leading BCL2, gets combined recently with anti-CD20 with ibrutinib. I would say that and CAR-T are both really interesting scientifically. They haven't had much traction in NHL to date. The lion's share of the revenue is the lion's share of patients still go on BTK inhibitors. I think the reason for that is the side effect profile is considerable, both for venetoclax and ibrutinib and also for CAR-T. That's been the primary reason why we hear from investigators that they're resistant. Within BTK, I think you're right. There are some really interesting degraders that are coming along. Our view would be whether you block the BCR pathway with a BTK inhibitor or a BTK degrader has no impact on us. It's just how well do you block that BCR pathway. We block an entirely different pathway. It's complementary, but it's the toll-like receptor path. Whether you use a degrader or an inhibitor to block the BCR pathway, you're not blocking the toll-like receptor path. We do. Our view would be today, there are four approved BTK inhibitors. There will likely be another two over the coming years. There may well be a degrader or two that get approved. Our view would be pick your favorite way to block the BCR path, write a script for that, then write a script for immunosuppressant to block the TLR path. It will provide a better outcome. So far, that's what the data we have support. I would presume that moving forward, it should be a very compelling approach for physicians and patients. Okay. Do you have MRD negativity data from your existing? We don't. It's a little premature. It's one of the things, of course, that we want to have in hand before we go have the discussion with the FDA about that. Presumably, what we would be able to do is every instance that we've gone after the combination within non-Hodgkins of immunosuppressant and a BTK inhibitor has led to higher efficacy, has led to being able to convert to CR s, and has led to long-term survival, whether it was preclinical, clinical data in PCNSL, or admittedly small N, but in other indications in NHL, Waldenstrom, CLL, and mantle cell. My presumption would be that it would be consistent for us to see patients go to MRD negativity as well. We need a higher level of N to get there. Specifically in CLL, if that's the indication that we want to have MRD, we need to have some patient data first. Right now, our goal is to get our first patient dosed by year-end. We'll have an interim readout by mid-year. Presuming that we see a consistent result in those data, we would, of course, go take those data and talk to the FDA and try to lock down what the endpoint would be in a registrational study. How many patients will we get to the middle of next year? I would guess it's a question of how many do we have on drug and have on drug long enough that we'll start to see patient results. I'd say somewhere in the mid-teens is likely by mid-year. Somewhere closer to 25 or so would be a good number for year-end by next year. You may remember in PCNSL, we saw clear signs of activity in just the first 10- 15 patients. My hope would be in CLL, we'll see the same thing. In the first 10- 15 patients, we should see that we can add to the efficacy of a BTK inhibitor. I assume you're going to report the CR rate and MRD negativity. Yeah, we would report whatever we have. What should be the bar here? I'm sorry? What's the bar here in terms of CR rate and MRD negativity? It's premature. I think our goal long term, and let's kind of step back from there. Yeah. Our goal long term is to get patients to have time-limited treatment as an option, that we can get them to the point where their disease is controlled, whether it's complete remission or MRD negative, that they can safely stop taking their BTK inhibitor for a period of time, 6, 12, 18 months. Can they go off the BTK inhibitor for a period of time safely? If their disease comes back, go back to the doublet, add the BTK back in, and then follow that curve as they go. That's the end goal. I would suggest that CR and MRD negative are indicators of whether or not we're on track. They certainly would be endpoints from a clinical perspective. But more importantly, they're biomarkers of have we had sufficient success with the patient that we can get to that end goal, which is time-limited treatment. We'll be collecting all the data that we can on these patients. Certainly, in the early days, it'll not just be a smaller N, but smaller opportunity for complete remission and MRD negative. We'll be looking for everything that we can point to to suggest that we've got something that's additive. As the data set builds over time, of course, we'll find the data very interesting. We would take those data right to the regulatory authorities, as I mentioned. It sounds like ASH this year, you guys are also going to share some combo data in AML. That's AML plus azacitidine. What the expectation should be for that data readout, and as you balance different indications, obviously, CLL is a great opportunity. How are you thinking about prioritization? Yeah. Which indication to go into? First, within AML, our goal is to give a status update of patients. What we're looking to do is something similar to what we're doing in NHL. In NHL, we're combining with BTK and looking to add to its efficacy. In AML, we're looking to add to azacitidine and add to that efficacy, whether we can get a higher response rate, deeper response rate, MRD negativity. All of these things are what we're going to be looking for. MRD negative would be the ideal. In a small data set, are we showing indications that we can do that? That's first and foremost. The second thing is, of course, we know that BCL2 inhibitors, venetoclax in particular, are really difficult to dose. They lead to a lot of side effects. It's hard just to get azacitidine to work well together. With a triplet, there's a lot of work that needs to be done to adjust the regimen to make sure that you've got a triplet profile that patients can tolerate for an extended period of treatment time. That will be something that's an ongoing portion of the trial, of course. In this interim readout, can we see, even though we've only got a couple of patients in and a couple of the regimens tried out, are we already seeing signals that we've got something that can provide a benefit for patients by adding emavusertib to azacitidine? That's what we're hoping to present. Okay, great. Thank you so much. Oh, thank you.