Excellent. Good morning, everyone, and welcome to the Citizens JMP Hematology and Oncology Summit. It's my pleasure to welcome Prelude as the next presenting company. Presenting for the companies include Kris, who's the CEO; Jane, the President and CMO; and Peggy, CSO. Bryant is here as well, you know, as CFO. Welcome, guys. Thank you for joining us. You know, Kris, I never know exactly who's in the audience and whether they're familiar with the Prelude story or not. So I was wondering if you could maybe just take two to five minutes on giving us an update and overview of what Prelude is about.
Great, great. Great. Thank you for the opportunity to participate in your conference and to introduce Prelude to your audience who are new to the company. We are a clinical stage biopharma company, you know, with a mission of discovering and developing novel medicines to deliver on the promise of precision medicine for patients with cancer. And I'd like to highlight three reasons why Prelude is a compelling investment opportunity: our team and approach, our pipeline that I believe holds tremendous potential, and the key milestones and data catalysts we're driving to deliver over the course of the next 12 months. And to start with the team, which is the fundamental reason why I believe we'll succeed in our mission. Our leadership team and the scientists and the clinical development experts that support them are creative, motivated, and highly experienced with proven track records.
Just to name a couple, our team played crucial leadership roles in the discovery and development of two very, very important transforming medicines, Jakafi and Brukinsa, in our previous roles. And the success of these medicines really speaks for the impact that they're having on all patients. And our approach is to really discover first-in-class or best-in-class medicines and targeting the mechanisms that are complex, that are highly challenging, but you have a compelling rationale. And so let me turn to the second reason, which is our pipeline, which I'm excited to highlight our success in developing our highly selective first-in-class degraders of a novel mechanism called SMARCA2. And we're leading this class of novel treatments. It's a very attractive target because there are mutations in a related gene called SMARCA4 that are present in a large number of patients, 5%-10% of many cancers.
These patients have very poor outcomes and no effective treatments. That's the reason why many companies, including large pharma, have been very interested in this target. We've been able to really lead this class with a number of highly selective SMARCA2 degraders. We advanced two of these molecules. Our first one, which is an IV molecule, PRT3789, and our second one, an oral molecule, PRT7732, into the clinic. We think that it gives us the optionality to have two molecules with distinct pharmacological properties, chemical features, to really tailor these molecules to the needs of the patients. With our lead program, we're gratified to have obtained the industry's first clinical proof of concept that we recently presented. Jane will spend time going through some of our learnings from this program.
And we also advanced our second molecule, like I said, oral molecule, which is currently enrolling patients in the clinic. And in addition to our SMARCA2 pipeline, we made a great deal of progress with our highly selective and potent CDK9 inhibitor 2527. And we'll be presenting some data from this molecule later this month at ASH in San Diego. Finally, we expect a number of milestones and catalysts in 2025. We're really excited and looking forward to this year from our ongoing studies as well as discovery progress. You know, with regard to our first, the IV program, we're on track to complete the dose escalation shortly with the monotherapy. And the combination with the docetaxel is not that far behind. So we are hoping to present the clinical data from these programs sometime in 2025.
And we've also initiated our pembrolizumab combination study and will be generating data from that as well. And again, as I said, we're enrolling our Phase 1 dose escalation with our oral molecule 7732. And we're targeting to report some initial clinical data towards the later part of 2025. I can't be too specific at this time, given these are ongoing studies and enrollment and emerging data will set the specific timelines. Finally, we will also be disclosing some additional preclinical programs that we're very excited about. And we believe these are a good strategic fit with our current pipeline. So that's in a nutshell, Prelude. And we're happy to turn to your questions.
Excellent. Well, let's jump right into it. This was a banner year for, you know, the SMARCA franchise, the first time we've ever seen, you know, some of the data from these molecules. You had two updates this year, the initial one at ESMO and then a follow-up, you know, translational data at the Triple Meeting. Would love to, you know, kind of talk a little bit about the key efficacy and safety data, you know, that you obtained. And then maybe dig in a little bit more specifically because, you know, it seems to us like you've already reached an RP2D, but it seems like you're exploring even higher doses, which seems to obviously suggest a safe molecule.
I guess I'd love to maybe probe a little bit more in terms of, you know, how do you ultimately wind up, you know, declaring an RP2D, especially if you can't, if you don't see a, you know, deleterious side effect profile?
Yeah, just to recap just a little bit, as you said, that we presented data and this is our preliminary data from the dose escalation cohorts, which included all patients with SMARCA4 mutations. We do believe that the optimal patient profile of patients that are most likely to benefit would be those patients with loss of function mutations. So more specifically, Class 1 and some additional Class 2s that have that loss of function. And so as a first-in-class agent, we are really excited that we had responses because this is proof of concept of the pathway that you can induce responses that in these very difficult patient populations. This tumor type with the SMARCA4 mutation we know is very aggressive. And we know that these patients often have a very low response rate and highly aggressive disease within the front line. Patients progress after under three months.
So in terms of our preliminary data, it was really to demonstrate that we are highly selective because that's critical to the safety profile for this pathway. If you have selectivity of SMARCA2 over SMARCA4, you can have a clean molecule. I think we demonstrated that by, as from the adverse events that you saw. And then secondly is then to hone in on a homogeneous patient population with that loss of function. And we're approaching some of those and starting to enrich for having uniform patient populations, meaning lung, esophageal, plus loss of function. And so in our doses, to address your question about RP2D, in our doses of greater than 283 in the lung patients specifically, we saw an overall response rate of 22%. Two patients responded, as you can see from the waterfall in the higher doses.
We do believe that the responses are a complex interplay between how much degradation you have, your PK profile, and your disease type. And so to address your question about RP2D, as per Project Optimus, we will be thinking about two doses to move forward. And the selection will be a combination of safety, activity, target engagement overall in PK. And so your question about whether or not we've actually already hit it, we do believe that there's more room on the table to achieve higher levels within the tissue as we increase the doses. The degradation that you're referring to is from the peripheral blood. And we want to make sure that we have high degradation in the tissues. So we are continuing to see increasing, let's say, PD as we increase the dose and proportional to the PK.
We'll be on target to select our doses to move forward by the end of the year.
As you guys think about, you know, this monotherapy data, the path forward, you know, what sort of other parameters might be adjusted to kind of enhance the profile outside of dose, right? So we're already increasing the dose for sure. The easiest one for me comes with, you know, combining this agent with something else. And I know you have some combination studies ongoing. Just kind of what are the different things that you're looking at so that, you know, you have the optimal profile kind of moving forward?
Yeah, certainly we'll take the data where it takes us in terms of a registration plan. And as you mentioned, we have the ongoing chemo combinations as well as pembrolizumab immunotherapy combinations to look at, to see what we can do to maximize activity. Just to level set everyone about where we want to be for activity, if you look at some recent Phase III trials that had docetaxel as a comparator, you know, docetaxel in second line and beyond, overall response rate is under 10%. So beating that would be very important in lung cancer, in esophageal, we have to gather some more information. And in terms of combinations, of course, we want to have that durability.
So that may be a possibility where we want to look at the combinations because this is such a highly aggressive disease and people do so poorly that we want to be able to maximize the benefit for patients as much as we can.
Yeah, well, I guess we'll jump into more of the combinations. I know you have those two combinations that are ongoing right now. We'll ask some more questions about that. I guess just sticking right now with these data, the monotherapy data, you know, when might we see, I think Chris mentioned, you know, we'll see data at some point next year, you know, kind of based on current enrollment rates, the doses you're expanding, you know, when might we see that next set of data? And I guess just to set expectations, you know, what would be your kind of internal bogey for a, you know, no go, no go criteria, go or no go criteria as a monotherapy? Or does it really not matter? Because ultimately, this is something that you'll see, you know, in combination.
And so it's really more about getting the RP2D, if you can just help us, you know, level set.
Yeah, so certainly a lot of the investigators have been very excited about the esophageal at the lower doses, seeing responses so quickly. And for monotherapy, that might be interesting enough to take forward. We do have to enroll enough patients to do that. In terms of the non-small cell lung cancer, we should have an enriched population by, if we're on track to do the RP2D by end of the year, you can sort of back calculate that we can get some patients enriched in the beginning of next year. So those would be the time points that we think about how we want to move it forward. And then combinations, of course, will want some enriched patients. And it's a little bit behind in terms of when it was started. And so you'll also see that at hopefully multiple medical conferences throughout the year.
Jane, in terms of like internal or, you know, kind of what's that hurdle that you want to meet, you know, as far as the monotherapy is concerned?
Yeah.
Is there one that you have or, you know, how should?
Yeah, the most data that's out there, right, is, as I mentioned, for KRAS and docetaxel as the comparator arm for KRAS. KRAS is an aggressive disease. But SMARCA4 mutations actually confer even equally aggressive disease and maybe even more so as we gain more information around it. And so I look toward the docetaxel comparator. And as I mentioned, those are in the single digits. So doubling that, tripling that would be pretty interesting.
Got it. Got it. It was interesting before we kind of transitioned to combination. The reason why we like the combination, you know, idea so much is we've seen other protein degraders in the space with, you know, kind of monotherapy data that was lackluster to use better words. But, you know, when we saw the combination, it seemed to be significantly better. Do you think this is maybe a class effect among kind of degraders in general, just given, you know, how much needs to be, you know, degraded in the cell or is it more just target specific?
Yeah, it's hard to extrapolate, I think, to degraders as a class because clearly, like for instance, BTK inhibitor, BTK degraders have high single-agent response rates. And so it's probably a combination of tumor type where your target is, target engagement, and how much you can penetrate the tissue. And each pathway may have slightly different parameters around what's necessary in order to achieve the activity you want to see.
Got it. So I do want to end in the kind of the last kind of five to seven minutes that we have, you know, about the ongoing combination studies. You're at, correct me if I'm wrong, 500 milligrams, you know, dose with docetaxel. You know, how are the two combination studies kind of looking, enrolling? You know, would love to just get some more details as to how that's progressing.
Yeah, we showed some preliminary safety information at the Triple Meeting showing that the combination with docetaxel and 3789 is highly tolerable and that we haven't had any treatment-related SAEs as of that data cut that we presented and that there was only one docetaxel-related adverse event. All the patients are continuing to enroll very briskly. Again, I think highlighting two things. One, that the molecule itself is tolerable and the pathway is interesting as a novel pathway. And two, that there is such a high unmet need. So we are continuing that. And then we are also initiating the pembrolizumab combo with some sites just getting on board. So we're in the initiation process for the immunotherapy combo.
Yeah. And I may have already heard this, but just maybe for my benefit and investors, kind of the internal go/no-go criteria for both combinations, both the docetaxel combination as well as the pembrolizumab combination, ultimately when we see it, you know, and you see the data, you know, what do you feel, you know, what would you like to see, you know, in order to make sure it's a definite go?
Yeah, it's sort of unchanged from the monotherapy because the comparator would be very similar, right? The docetaxel second line and beyond. And so again, you just want to beat docetaxel, even if you're in combination with docetaxel. And that's again, doubling or tripling the docetaxel response rate, which is already quite low. And then for pembrolizumab combo, very similar because what's interesting about pembrolizumab is that most of these patients are actually PD-L1 low when they're tested in the front line. And so many of these patients are actually a little probably less responsive to PD-L1 immunotherapies inhibitors. So again, the second line and beyond benchmarks are unchanged in any of these shots on goal, let's say mono combo with docetaxel or combo with pembrolizumab. If it meets that bar, we will move it forward.
If everything's a go, let's just say by the end of next year, right? How are you thinking about potential registrational studies kind of, you know, moving forward? Because you'll have to, right? I mean, we're in biotech. There's a significant amount of spend. You'd have to prioritize. How would you, you know, how would you do that?
Yeah, the most obviously it would be somewhat dependent on the response rates. But if you met the bar across the board, we would have to take things into consideration, including our oral, right, which is coming online. And we already mentioned that we initiated our oral. And so there may be some patient populations that you would start because we have the leader advantage and get a registration in and then reserve others for the oral. And so we would think about what's the best way to combine this registration path? At the end of the day, of course, we want to benefit the patients as much as possible, as quickly as possible. And we would take that route over with the area with the maximum of benefit as fast as we could.
Got it. Okay. And speaking of the oral, that's, you know, it's, as you mentioned in the clinic, how should we be thinking about it in terms of, you know, call it the advantages, right, of, I mean, outside of, you know, the fact that it's oral and more convenient, what are the other advantages that you see from that molecule that ultimately, I don't want to call it will leapfrog, you know, IV, but could very well, you know, I guess become the lead?
Yeah, I mean, obviously with an oral, like you said, there's advantages from a convenience standpoint. And because it's highly selective and daily dosed, you may be able to, I think of it as like chipping away and peeling the onion on a daily basis rather than waiting once a week for the IV to hit and then degrade. So if there's an additional proliferating tumor with a more SMARCA2 that's being regenerated at different rates because you might be able to get higher levels of degradation across the board with daily dosing. So that's just one potential PK advantage, PK/PD advantage an oral could have over IV. And because we have the selectivity, we can achieve that.
Maybe just in the last couple of minutes, I know Chris already talked about several of these milestones because we had it listed with the pipeline slide. The biggest ones to me, you know, are of course, you know, determining the optimal dose kind of going forward for 3789. You did, Chris, mention 2527, the CDK9 inhibitor, right, with some data that's coming out at ASH. That's also in combination. We didn't really touch upon that. So maybe just in the last minute or so, you know, the key milestones, should investors, you know, be uber-focused on ASH as well, or is it really a 3789 story moving forward?
Yeah, I can take that. So, you know, clearly, you know, we have the two molecules moving forward and both really expanding within the SMARCA2 itself. We just have to look at, you know, the opportunities across the, you know, across the different cancer types and where we can make the most impact. And, you know, these SMARCA2 molecules have the benefit of being first in class, and we want to preserve that and add to that. Obviously, they require a lot of capital allocation. So, you know, that doesn't mean that CDK9 is less important for those patients who benefit from it.
But I think it's going to be, you know, as you said earlier, the biotech in the current environment, we just need to be even more, you know, bar set even higher to ensure that we are optimally resourcing, you know, the programs of highest level of success, so we'll let the data dictate, but we are truly excited about being where we are, you know, with the programs being really poised to be transitioning into the next phase of development, and, you know, having the cash to really bring them through the key milestones is very, very important for us.
Excellent. Chris, Jane, Peggy, Bryant, thank you guys very much for giving us an overview of the company, and look forward to speaking to you again.
Thank you. We really appreciate the opportunity.
Thanks.