I've been working on it for a while, but now we have two molecules, one an IV and one an oral agent, both in the clinic that are targeting a very unique pathway called SMARCA pathway, and these are SMARCA2 degraders. There is a high unmet need in patients who have this mutation since SMARCA4, a related family member, that results in, you know, in pretty aggressive cancers across multiple cancer types. We have made a lot of progress. We demonstrated the initial proof of concept with our IV, which we presented last year. Based on all the knowledge we gained and, you know, the better understanding of the patient population, we are expeditiously moving both of our molecules with the idea of being very data-driven and select the best path forward for this program. We continue to advance our discovery efforts.
Recently, we presented first-in-class KAT6A degrader at AACR, and Peggy will get into a little bit more detail on what, you know, what's KAT and why we were interested in it. But we're really excited about the promise of this pathway and our molecule in particular to address some of the major deficiencies of this validated mechanism. Beyond that, you know, we are continuing to actually bring additional molecules. We'll be talking about our degraded antibody conjugate advances that we've made to address, again, not only take the ADC field to the next level, but in fact be able to address otherwise difficult to target or unable to target mechanisms. We are well capitalized at the moment to be able to prosecute our mission. Like every biotech company, you know, we are operating in the same cash constraints.
We're being very efficient, as efficient as we can be, and strategic with the assets we have to be able to really move the company forward.
Excellent. Thanks for that overview. You know, I usually start with the clinical products, right, because that's what a lot of people are interested in. AACR was actually quite unusual in that there were quite a few KAT6 therapeutics that were being developed. It was great to see you guys are entering the field as well. Can you maybe just talk to us a little bit more about this target? What differentiates your KAT6 inhibitor, which I believe is a 6A versus 6B? You know, what differentiates it from what's out there?
Sure, I can start there. There are a number of KAT6A/B dual inhibitors that are either in the clinic or advancing through preclinical studies. The most advanced is a dual inhibitor from Pfizer that's shown really good early clinical data in positive breast cancer. They're advancing that molecule into phase III in combination with fulvestrant. What they are limited by, though, are bone marrow toxicities like neutropenia. What we've been able to show and what's been published in the literature is that dual inhibition of both family members leads to those bone marrow toxicities. Our approach has been to make a KAT6A selective degrader. Similar to what you'll hear about with our SMARCA program, we use that degrader technology to build in the selectivity for KAT6A over KAT6B.
What we've shown preclinically is that we have very strong efficacy regressions in all of the animal models and good tolerability. Our hypothesis that by selectively targeting KAT6A over KAT6B could lead to better efficacy as well as better tolerability appears to hold true in the preclinical models. You know, we're very excited by that program.
What's the difference between, let's say, targeting KAT6A as a degrader versus, you know, estrogen receptor as a degrader?
Sure. CAT6A is a histone acetyltransferase. In addition to regulating expression of the estrogen receptor as well as the progesterone receptor, it also regulates a number of other genes that are important for driving tumor growth, like the MYC pathway and cell cycle regulation. It is broader than just targeting the estrogen receptor pathway. That allows it to have better activity and also broader applicability beyond positive breast cancers. There is CAT6 amplification and overexpression in other tumor types like non-small cell lung, ovarian, in addition to positive breast cancers. We think targeting that pathway gives us broader activity than singling in on the pathway.
Excellent. As we think about next steps, right, because this is early data that you reported at AACR, when do you think we'll have maybe lead candidate selection? When do you think an IND will be filed? You know, how do we think about that?
Yeah, so we've made really good progress on this target. We expect to have a development candidate this quarter and then are moving toward an IND in early 2026.
Excellent. I'm going to take you off the hot seat. Jane on the hot seat for the next discussion. The clinical program, SMARCA2, right? You've shown some data with your IV product 3789. We have some updated data that's coming up, both as a monotherapy and as a combination. I kind of want to say that the monotherapy data is really well known, but maybe I'm wrong. Maybe there's something new that you're looking for from that monotherapy data. I believe you've reached an RP2D. You can correct me if I'm wrong. I guess most importantly for me, can you help set expectations as to the potential for the combination and what you're really looking for for the combination data with those attacks?
Yeah, so you're absolutely right. At the Japanese presentation that we just did back in March, we showed that there was a response rate of 23% in the patients that had been treated at 283 mg or higher for monotherapy. And that's, you know, when I think about recent news about, let's say, Werner's helicase, for instance, that's four out of 35 responders. We've had five out of 32 responders. We're right on par with, for monotherapy, where we want to be. Those were at multiple different doses in loss of function patients. On top of it, we had three out of three responders in upper GI cancer. That's in one tumor type, 100% response rate, which is really a nice proof of concept for the pathway. At the same time, we know that this disease is very aggressive.
You do need potentially combinations to enhance that durability because these patients in the frontline setting, we're expecting if we know that with chemoimmunotherapy, that progression-free survival is under three months. We really want to enhance that durability. The combinations that we have that we've shown are safe. We had some preliminary safety data in combination with docetaxel, which is one of them that we will be presenting toward the end of the year with about 10 patients that have loss of function, specifically in lung or upper GI. On top of that, we also have the pembrolizumab combinations that just got kicked off. We think that will be very interesting. All of this clinical data will help inform us not only for registration paths, but also to move us into earlier lines, which is where ultimately everybody wants to be.
Let me ask you just regarding metrics and kind of go, no go, you know, decision, you know, matrix markers, if you will, right? Like what is it that you want to see in that combination study outside of safety? Because we've already seen a sneak peek that's looking really good.
Yeah, there's no overlapping toxicity between these. If you think about lung cancer, for example, a docetaxel treated patient, my expectation for that response rate is around 5%-10% if you're just treated with chemotherapy alone and you harbor a SMARCA4 mutation. What would be nice to see is something north of 30% to move forward into registration.
Got it. You have both an IV and an oral version. You have competitors at your heel. You know, we have some of those competitors have presented here at the conference as well. I'm kind of curious how you're thinking about, you know, developing both assets. You know, does the oral just kind of take over at one point, or are there specific indications for which the IV would be, you know, ideal and you'll continue, you know, driving that forward as well?
The beauty of being first to the clinic is I now have a year and a half worth of clinical data to be able to really leverage and understand this patient population, where it's more likely to work, where it's less likely to work, which tumor types to go into. We've been able to be even more efficient with the oral compounds so that we can advance that very quickly. As I think we put in our most recent release, we're up to the fifth dose level, which is 60 mg. We just had our IND cleared at the end of last year. It is very, very rapid. From there, I think if we can show equal efficacy and activity between IV and oral, it's a natural progression to go into the oral to bring that forward to the earlier lines, like first-line lung cancer.
I think there still remains potential for some of the IV in certain tumor types or, for instance, upper GI esophageal cancer, where if you have difficulty swallowing pills, if you can't absorb pills well, if you don't have a stomach for gastric cancer, you need maybe a different modality. The IV may have a certain place there. All of the information we'll look in totality. I think all of the information we're getting from the IV has given us the ability to really rapidly progress the oral.
As you think about the development of both, we're going to see, you know, data from both programs in the second half, kind of have, you know, a bogey, if you will, to hit, right, to advance both these therapies going forward. As we think about next steps in advancing, assuming that everything hits, what are the next steps for both these programs? Are they just further expansions? Are they randomized studies? How do you think about it?
Yeah, I'm really happy with our progression in typical phase I fashion for the oral. We want to get to our dose where we see the maximal degradation, the best safety profile across different doses. Then we will think about what type of registration trials. There might be some lower hanging fruit where you go into the relapse setting as a monotherapy if you have the activity you want. The other is to think, start planning for our frontline trials, which we're well poised to do because we've already done the chemoimmunotherapy type experiments and understand what the interaction is between our drug and the combinatorial partners.
As we think about the competitive landscape, can you maybe help kind of, you know, frame that for us? Where are you? Where are the other competitors? How do you differentiate, you know, from them?
Yeah, you know, at the end of the day, you don't know which drug has the better activity until you get to the end of your phase I. At the same time, because we have this amount of knowledge, this is a complex pathway. This is not a straightforward oncogene mutation driver type pathway. It's a complex interplay between in synthetic lethality with also what's downstream and then what's in the tumor itself and what are the drivers within the tumors. From there, you know, I think we have an advantage because we have tumor biopsies, we have our degradation data, and we have a good understanding of how the pathway works. As a competitive landscape, we have been in the clinic a year and a half longer than our competitors. That, I think, will give us an advantage because it is a biomarker-selected population.
You have to understand which biomarkers to go after, as well as it is a limited patient population in terms of number of patients available at any one time. As you have more competitors come in, it gets harder to enroll. We have been doing really well because we have had that lead time advantage.
Maybe just to expand further on the oral degrader, we're going to get data from that. Do you, I mean, I would already kind of anticipate just based on the once daily coverage of the enzyme now, SMARCA2, that the potential for better, you know, objective response rates, longer duration of response is likely what, you know, we would be looking for in that first data update. Do you think we might see that? Because you mentioned you're at dose level five, 60 mg, kind of, you know, are we still in subtherapeutic ranges? Do you think by the time you're reporting, we should be focusing on efficacy, or is it really going to be a safety update?
You know, I want to focus on safety. When we come out with our efficacy, we want that robust data set. As you probably already noted, our competitors that are in the clinic probably have the ability to wait until they have a certain number of patients. In this current environment, we know that people want to see 20, 30, 40 patients treated with a certain response rate. You know, you do not want to have a dribble of, you know, three patients with, you know, one responder or something like that in terms of data. When we come out, we want to come out because we have the ability to do that and wait and show the full data set in the indication that we want to go into for registration.
Just to add to that, right, just to remind, dose escalation includes all patients, right, both types of. I think for us, you know, you have to have enough patients in the, you know, right biomarkers to be able to ask that question, is the response rate better, right? The N becomes very, very, the right N becomes very important. Yeah, we're going to be, you know, very sort of thoughtful about at what point, you know, that we would put that data out. You know, and because as you said, obvious comparisons are, how does this compare to the IV, right? You're absolutely right. I think the reason for bringing this is twofold.
One, oral patient convenience factor, but also at the same time, the opportunity of daily administration, which you could not do with IV, has the potential to drive the target down further, right? I think those two are what we are also squarely focused on. We will be looking for the data. That is, you know, that is a good situation to be, like Jane said, that we had a strong knowledge base that we have internally generated based on IV, which is helping us to rapidly advance our oral program.
Getting back to what could be the ideal dose, I guess there's two ways to look at it. The inaccurate sort of like, hey, this is the dose at which preclinical models were showing good things. And if we convert, you know, this is the dose we should see it in humans. You have an IV drug that you've declared an RP2D for. I believe it's 500 mg.
That's correct.
If you kind of look at that coverage, maybe Peggy will jump in here with PK, is there, you know, a particular dose that you think, 100 mg, 60 mg, where the oral should start to show some sort of efficacy?
I mean, I think we'll have some learnings of, at the end of the day, you want to see it in the tumor tissues. We are getting that tumor tissue to see that degradation throughout. We are very happy with where the program is right now in terms of what we're seeing. I haven't said what we're seeing, but I've already said before, we're at 60 mg. That means our safety profile is very clean to be able to get this fast to 60 mg. That's five dose levels. That tells you that we'll be able to push the dose. Ultimately, you want to push the dose so that you see that degradation in the tumor cells for as long as possible because we think that's what's driving the cancer cells to grow if you don't suppress it continuously.
That's our plan is to push the dose. But there will be a point where you're probably right. We can say, okay, we think that's enough. You don't necessarily need to go, even if we have no toxicity, you may not need to go higher than that.
Got it. As you think about, you know, again, sticking with the oral kind of path forward, right? Once an RP2D is determined, you will have had data from IV with docetaxel. You'll have had potentially some data in combo with Pembro. How do you guys navigate kind of the ideal combination with an oral degrader to move forward? Because I'm imagining that regardless, at the end of the day, no matter how good the monotherapy data might be, that ultimately these drugs are going to find themselves in a combination.
Yeah. In the frontline setting, every single even targeted agent is in combination with chemo IO. At the end of the day, that's where we want to be. We'll test those partners, the chemo, different chemos that are used in those tumor types. Preclinically, we already know, like docetaxel, Gemzar, those others are synergistic. Pembro turns cold tumors hot. We think we can easily move to the frontline.
Got it. You guys reported results yesterday. We have Bryant here. I kind of want to get a sense. What is the cash position right now? You're, you know, in early stages, right, of both the IV drug development as well as oral. How long does this cash last, especially if you take into account Jane's combination studies?
Thanks, Brant. Our cash position, as reported, is $103.1 million of cash and cash equivalents. We anticipate, based on our forecast and our budget, to be into second quarter of next year. That gives us sufficient runway to think through the different scenarios that our clinical program can take us. It's a saying around the company that the data will lead us where we go, but we are taking into consideration all those options.
How important is BD here, right? Is this something that at the end of the day, the data is enough for you to, you know, let's just say, you know, fund it yourself and take it to completion, or are you looking right now, or is there any interest, right, ex U.S. or even potentially sharing rights here in the U.S.?
Yeah, absolutely. The business development efforts have been robust, and they're across all of our programs, right? We're, of course, open to every source of capital funding, as most biotech is right now, especially. Business development can certainly be a nice way for us to be thinking about cash and how we proceed with all of our programs. You know, we have a lot of opportunities to be able to capitalize on those. Kris, I don't know if you have anything you want to add on the business development.
Yeah, I mean, some we talked about publicly, some we have not. But, you know, as I was saying earlier, for a company like Prelude Therapeutics, which has a very robust discovery engine, has the capability to come up with very novel molecules that would be of interest to strategics. In this capital environment, we can't take all of them all the way ourselves, right? To your even other question relating SMARCA to how we would do, yes, if we had the money, we should be doing all combinations and making the decisions, right? That's not a situation we're in. I, you know, we're very, very sensitive to that, obviously, like everybody else.
Figuring out among the assets that we have that are in the public domain, not in the public domain, and some of the platform technology that we developed around the degraded antibody conjugates, we are talking to a number of people and ensuring that we are able to be very strategic and be able to bring the capital into the company to really create that long-term, you know, shareholder value on the assets that have the highest probability of success. That is what we are squarely focused on right now.
I feel like for the next question I have, I need like a round bar table here with some barstools and a couple of pints of beer, but I'll ask it in 20 seconds. Given the kind of, you know, regulatory environment we're finding ourselves in and lots of people saying like, you know, oh my gosh, you know, it's the end of the world, I'd love to kind of hear your takes on how's your interactions been and how do you, you know, how do you feel it'll be going forward?
I'll just start, but since Jane is in the frontline, I want her to talk about it as well. But, you know, you know, this is a very dynamic environment and things are changing on a daily, weekly basis. But overall, you know, I think the direction is that the molecules that are truly making a difference for patients, we will find support. And we can, I think we can find alignment with FDA to be able to move them forward. And so far, you know, we have not been impacted by anything that happened, but we're also an earlier stage company.
I just say you can't keep a good drug down. If you have effective therapies, those will move forward because they're benefiting patients. At the end of the day, that's our goal. My personal goal is to advance cancer therapies for these patients that have unmet needs. We're always flexible. My team is extremely experienced in regulatory interactions. There are always curveballs, no matter what you are doing in every single regulatory environment. We're confident that we can handle whatever comes our way.
On that note, it's a great way to end it. Thank you guys very much.
Thank you, Brant.
Thank you.