Well, good afternoon, everyone, and welcome to the second day of the Citizens JMP Life Science Conference. It's my pleasure to introduce Prelude Therapeutics. Here for the company is Kris Vaddi, CEO, and Jane Huang, CMO. Thank you guys both for coming and joining us. I never know, you know, with these Q&A sessions, I never know exactly who's in the audience, who might know Prelude, or who's listening in on the webcast, who might know Prelude. So I like to start off these sessions with maybe a two-five-minute overview of what the company is about before we dig into some of the specifics. If you can tell us, that'd be great.
Right. Yeah, and thanks, Ryan. Thanks for the opportunity to participate in the conference. Prelude is a clinical stage biopharmaceutical company with a mission to deliver precision oncology medicines, starting with patients who have highest unmet needs, but ultimately extending to as many patients as possible. And there are three things I'd like your investors to know about Prelude. It's our strategy, it's our team, and it's obviously everybody's interested in our pipeline. So those are the three things I want to focus on today. In terms of our R&D strategy, the central focus, right, we're really focused on the patient and patient needs with cancer. We're not really driven by the technology platform or a therapeutic class, but rather build the right solutions for the right patients, right?
We're really focused on finding solutions to problems rather than building solutions and look for problems. We're not afraid to go after very challenging, very difficult to drug or undruggable targets. So that takes us into the area of really first-in-class molecules. But that we only do that because, you know, those are the—we believe that those potential medicines can really be, you know, provide new options for patients. And I can be confident we can do this because I have the team. You know, we've built an exceptional team of both discovery and development at Prelude. And it's because from the beginning, our focus is on the patient rather than big. You know, build large teams of technologists.
We've really focused on teams that have actually the expertise in discovering and developing these novel medicines. In research, we have Peggy Scherle, who is our CSO, who leads our biology, and Andrew Combs, who's our Chief Chemistry Officer. Both bring you know, decades of experience and track record of really going from an idea to a molecule and apply really rigorous science to advance these molecules to the clinic. You know, our President and Chief Medical Officer, Jane Huang, and the team that she brought not only have a lot of experience bringing compounds to the clinic, but really seeing them through phase III trials and registering these medicines in you know, globally in multiple countries.
That's really what gives me a lot of confidence that we can execute, you know, our strategy and deliver on our mission. In terms of the pipeline, you know, we'll talk a lot more about it today, but clinically, our focus is really on two molecules that we are really excited about. Our first-in-class SMARCA2 degrader, called PRT3789, which is an IV molecule, that's currently in phase I development in dose escalation. It's really, this is an area of significant interest, but it's been very, very challenging to develop a highly selective molecule, and our team has succeeded in advancing that to the clinic in the first half of last year. It's about a year since, you know, we started the trial.
2527 CDK9 is another area where there's always, belief in the biology, but it's not been, it's been a very challenging target, so, you know, we think that we have a really good molecule. And beyond that, you know, we are extending the scope of SMARCA, you know, SMARCA class of drugs by, you know, potentially developing precision antibody therapeutics, where we can use them as payloads to deliver to specific tumor types. We have an oral SMARCA2, degrader that we're gonna, bring to the clinic this year. So there's a lot happening. So, Prelude is, really well-positioned in 2024 to, you know, to, advance these, programs into, you know, in the clinic and beyond.
So let's jump right into it. Everyone is focused on, on, 3789, the SMARCA asset. You know, we're gonna see data in the second half of this year. Maybe you can just talk to... You know, this is a selective targeted, protein degrader, and, I guess I'd, I'd love to know, it's a, it's a first in class, so, you know, what exactly would you like to demonstrate in terms of safety and efficacy, right? When this, when this data comes out.
Yeah. So thanks. Just to remind you, we are in the synthetic lethality pathway, so we look at patients who have SMARCA4 mutations. And because those cancer cells are dependent on SMARCA4, we have SMARCA2 degrader that comes in, degrades the SMARCA2, and initiates synthetic lethality. And so our phase I dose-escalation study is in patients selected for SMARCA4 mutations, and it is your typical phase I dose escalation, where you have a Bayesian escalation. And we announced this last February that we are already in the sixth dose cohort. So we are planning to show more than 30 patients' worth of data toward the end of this year. And just as a reminder, those patients are not selected necessarily for loss of function. Those loss of function patients are in the backfill cohorts.
But about half of them have that loss of function, and about half of those patients are also non-small cell lung cancer. We've already enriched for that. We would really like to demonstrate the safety. We've been happy with our progress to date. We're seeing dose-dependent degradation, as well as increasing duration of degradation, as we dose escalate. So the PK and PD properties are behaving like we would expect with the from the preclinical data. The preclinical data also noted that we would start to be seeing the maximal degradation or clinically active degradation by dose level six. So we're right in that sweet spot as we continue to dose escalate, because we have a very safe drug and tolerable drug to date.
We hope to show the safety, the preliminary activity, in the latter half of this year.
So that's great. You know, and I'm glad you kind of made us take a step back to remind us that, okay, you need this SMARCA4, you know, mutation that's in there. Can you talk a little bit about maybe the patients, right? That, you know, within non-small cell lung cancer, who, you know, might have the SMARCA4 mutation, and, you know, what's the ideal kind of comps, right? 'Cause once you start taking sort of, slices of any pie, right, people wonder right away, like, how small are we getting? I don't think that's the case here, but maybe you can remind us of the opportunity.
Yeah, so just for, you know, the world and the universe, this could be beyond non-small cell lung cancer because SMARCA4 mutations occur in GI cancers, in ovarian cancers. So there is a potential for a tumor-agnostic type population that we would target. We do initially plan to go into non-small cell lung cancer, and the epidemiology around that is that around 10% of all non-small cell lung cancer have that SMARCA4 mutation. And about 6%-8% of all non-small cell lung cancer might have that loss of function, where we expect, by our preclinical data, to have maximal activity. That population is about double what, say, ALK inhibitors would be. But Kris might have something more to add there.
Yeah, no, I think, from a overall opportunity standpoint, you know, the comps are... Obviously, there's approved agents in ALK, right, like the, Xalkori and, and others, Alecensa. And so you can think of, you know, a significantly double or more higher, you know, level of commercial opportunity in lung alone, and obviously, as Jane mentioned, there's a number of other cancers who also have the same mutation. So, you know, being first, obviously we're learning a lot in specific mutation types and, you know, what we could address with this mechanism. Another thing that, Jane, maybe you wanna talk about is how these patients do, right, when they have these mutations.
Yeah, so we know the most about patient outcomes in non-small cell lung cancer in the front-line setting. In that setting, the median progression-free survival, if you harbor a SMARCA4 mutation, is under three months. So, in terms of the overall response rate, it's about 20%, when in front line, again, if you have chemo immunotherapy. In contrast, if you don't have that mutation, your overall response rate is about 40%, which is almost double what you would see. So there is a significant unmet medical need. We're still diving into what is the prognosis of those patients in second line and beyond, but conventional wisdom is that you do poorly after your, if you've failed your first treatment. So, we are expecting that the unmet need is really quite high in these patients.
you know, for the investors in the room, the team's being, you know, humble in that, you know, the ALK market, right, is a billion-dollar-plus market, right, to kind of begin with. So you can easily do the math to kind of figure out where the SMARCA2, SMARCA4, you know, market could be as well. You mentioned, you know, the several. You know, what the front line is. I think a path forward will involve combination therapy. You've talked about that. I believe you're choosing docetaxel and gemcitabine as the combination agents. Kind of wanted to get your thoughts, the rationale for that, versus, you know, in this day and age, where everyone is just focused on, you know, immuno-oncology, why not, you know, checkpoints in this setting?
Yeah, there are multiple areas that the preclinical data direct us toward. We saw that, preclinically, if cells were treated with 3789, our SMARCA2 degrader, that it would induce cells that were susceptible to DNA-damaging agents. So, a place for 3789 would be to combine with these DNA-damaging agents, of which chemotherapy is of a primary backbone, right, cell kill. And then in terms of immuno-oncology, we also are very interested in that. So in again, preclinically in SMARCA4 mutated patients that are not patients, the cells that are treated with 3789, we do see that perhaps we can turn the cold tumor hot, meaning that the PD-L1 expression goes up, T-cell engagement goes up. So that is another possibility that we are considering in the future.
But the easiest path right now was to look at chemo combos because we know that that's what's used traditionally in front line.
So investors, you know, they, of course, wanna see monotherapy activity, right? Like, that's a, that's a box that every investor wants to check, and we'll be seeing that, you know, in the second half. You have a combination, the combination study underway as well, correct me if I'm, I'm wrong. But as you think about kind of the, the therapeutically effective dose, you know, what's that kind of starting dose, if you will, for that combination study that, that you're going to? Did you have to kind of go back to the drawing board, or were you able to, you know, to escalate a little bit more quickly?
Kind of related to that, similar to the monotherapy question, what's the ideal kind of safety and efficacy hurdles that you'd like to, you'd like to hit, you know, so that you get that kind of go decision, you know?
Yeah
... from the data?
Yeah, so in terms of your latter question first, in terms of efficacy, right? So docetaxel in second line, non-small cell lung cancer, all comers, has an overall response rate of about 15%. We know from front line that the overall response rate to chemo immunotherapy is about half. So we might anticipate, and we're doing a little more epidemiology work into this, that an overall response rate, if you harbor a SMARCA4 mutation to docetaxel, would be about half of that 15%. So in terms of efficacy and activity bars, I think that anything north of that would be interesting, and that it's able to be combined. There's no reason to believe that we'll have any overlapping toxicities, so we do believe that that's very feasible and doable.
In terms of where we are with the dose, you're absolutely correct. We did not have to start at the bottom and dose escalate, but we were able to take advantage of the dose that we were at in order to combine. We didn't start our combinations until we felt like there was a reasonable chance we might see activity because you want that level of degradation to be persistent. And as I had mentioned earlier, we are approaching that dose levels where we feel that that will have durable degradation of SMARCA2.
And I, and I probably just missed this, but the monotherapy activity, or data, is what we're expecting in the second half. Any combination or too early?
It's probably too early, but we'll see where we are when the presentation time comes around.
Sure, fair enough. You're also developing, I think, Kris, you mentioned in your prepared remarks, kind of an oral SMARCA2 degrader. You have the AbCellera, you know, collaboration, again, targeting, you know, SMARCA2, so kinda like a lot of bets on SMARCA. And so I guess I'm kind of curious, like, one, why, right, so many assets? And then, two, how do you, kind of as an organization and as a clinical trial, you know, developer, kind of manage enrollment between trials so that, you know, one isn't necessarily cannibalizing another?
Yeah, I'll start, and then Jane, I'm sure, can comment on this, some of the key parts of your question. Just as an overall strategy, right, like from the when we started this program, I mean, this is an area of interest for many companies for many years. This is not a new target, and but it's just was not tractable. So we took a pretty comprehensive approach initially to go after the two well-known de- so the first decision we made that we wanted to go after it as a with a degrader approach because we felt that that gives us the best chance to really selectively degrade to, and not, you know, not hit the floor. So that was the first decision to go after the degrader.
The second decision was, you know, the VHLs and cereblons are the two most well-characterized degrader, sort of ligases, right? So we took a pretty comprehensive approach, recognizing that we need the optionality, you know, for this mechanism, because we don't know it's first in class. We don't know whether, you know, one is better tolerated than the other, one gives a different pharmacology than the other. But as we developed the program, we actually saw the opportunity for both. We think that, you know, the biology is complex, and that the cancers are different, the they have other different genomic backgrounds. So we feel that there is a need, potential need for both. And then, if they're identical, at some point, you may consider figuring out what the strategy might be.
But at the moment, we feel that they should be developed in parallel. With regard to your antibody question, that's going after, actually, additional cancers that are not targetable by the oral or IV. Because, you know, we can only, at the most, target 10% of patients who have these mutations, but there's many other cancers that actually have dysregulated pathway in this SWI/SNF complex that could potentially be addressed by a dual inhibitor, but that's not safe enough to give it systemically. So we're actually getting tumor selectivity in a different way, by using it as a payload, and we're very excited about that. And AbCellera, you know, has really a very powerful antibody engine, and you know, our team, as we demonstrated, we have a very strong medicinal chemistry, degrader capabilities.
It's just joining hands with, you know, between the two companies to actually, you know, to deliver again on the promise of the, you know, SMARCA biology.
I mean, ultimately, when might we see the oral, you know, SMARCA2 degrader, right, in the clinic? Same as, you know, the partner program.
Yeah, we've announced that we will put the oral into the clinic in the second half of the year. And just to add on to what Kris was saying, you know, you never know the... It's the age-old question: Is it your peak? Is it your trough? Is it your AUC that contributes to clinical activity? And so having that optionality and multiple shots on goal, I think is very important for the company. In terms of your question about cannibalization in trials, I have an exceptional team that has run global trials, and we're very confident that we can execute on what we need. And because this is a high unmet need, novel mechanism, also, the investigators and even patients are very interested in our trials.
The other piece, as I also mentioned, it's already on the foundation panels, et cetera, and so we do have some populations that we can access for these clinical trials quite quickly.
Got it. And so just to clarify, though, the mutations you will routinely pick up on a foundation panel, which is, you know, typically seen in, I mean, not just a lot of the clinical trials, but a standard of practice, you know, now.
That's correct.
Okay. So, you know, we've talked about, you know, obviously SMARCA, it's the star of the show. I know a lot of investors are focused on it, but it's not the only pipeline drug that you guys have. Would love to, in the last kind of four minutes we have, talk about 2527, your CDK9, you know, inhibitor. I'll cut right to the chase, right? Like, what is the efficacy and kind of safety hurdles that you want to overcome with this asset? And how do you... You know, there are other CDK9 inhibitors that are out there. I'm kind of curious, you know, how do you differentiate yourself from those?
Yeah, there's actually been a very long history with CDK9s showing activity, but unable to hit that safety benchmark that people are looking for. And just to remind folks, we actually did do a very small phase I trial in solid tumors that did demonstrate that safety profile that we are seeking, meaning, no Grade 3, 4 nausea, vomiting, GI symptoms, and that it was very tolerable for patients to continue on. And so we've pivoted to go toward the tumor types in heme, where we do believe is the highest chance of showing activity, because there's already precedence for showing activity in heme. We are looking at multiple different tumor types.
When we are at dose for monotherapy, for instance, in AML, you might want to see some bone marrow clearance of blasts, as preliminary activity, in combination with zanubrutinib, which we've already started. There's a parallel study showing a combination of a CDK9 plus BTK inhibitor can induce response rates of approximately 30%-40% in multiple relapse diffuse large B-cell lymphoma. So those are the areas that we are quite focused on, and we'll be presenting toward the end of this year as well.
Excellent. So maybe in the last kind of remaining, you know, three minutes, would love to get an update on the cash position that you have that's gonna drive this entire pipeline, right, to value inflection points. You know, and, and kind of how you're, how you're thinking about it, how long does it last?
Yeah, so, you know, we just had our quarterly update. At the end of first quarter, we have, we had, $201 million, $201+ million, you know, in cash and, and, you know, equivalents. So, you know, we are very efficient in the way we deploy our capital across the programs, and we're very focused on driving these two programs to the key data inflection. So this current cash runway guidance is into 2026. And, you know, beginning second half of 2024, we expect to, you know, to, have additional clinical data over the course of, you know, this year and then, and next year. So, so we're well-capitalized to, to drive the programs through all these important data catalysts.
Yeah. So, you know, maybe just to sum it up, kind of the key drivers, you know, when they're expected for, you know, let's call it the next six-12 months, that, you know, investors should be paying attention to. I know we kind of sprinkled it in throughout our discussion, but a good way to end it is like, hey, you know, exactly what's coming up over the next six-12 months?
Yeah, absolutely. So, you know, the three key drivers that we're all, as an organization, we're laser-focused on driving to is, as we talked throughout, that 3789, our IV degrader, to, to potential POC, and later this year, and we described what that- what we're looking for in that data set, the initial POC. It's, it's really the industry's first SMARCA2 degrader, right? So, so there's a lot of excitement about that, and, and we, we, you know, hope to continue that throughout, the course of, you know, next 12-18 months. And bring the oral SMARCA2... Just, just keeping the, on that SMARCA2 theme, bring the oral compound into the clinic, you know, the second half of this year.
And you know, and again, dose escalating in selected patients there in launching that clinical trial is a key driver for the company in the second half. And 2527, you know, Jane's team is doing a great job, and actually, you know, it's a difficult, you know, AML trial or you know these B-cell malignancy trials are hard to execute, but you know we have a global plan to get through those, so that. Those are the, those are the major clinical, you know, drivers for us. But you know the discovery teams are really... I'm excited about some things that they're doing now, that I hope we can, we can talk about.
And the precision ADC with the SMARCA2/4 payload is something that, hopefully, and again, we're talking about a six-12 months timeframe, that we can talk a little bit more about as well. So there's a lot going on, where I think the company's really well-positioned to, you know, to start to show some of the key, you know, key deliverables that we've worked hard, you know, for a number of years on.
Yeah, so I don't wanna try to peg the exact timing, but, you know, Jane, whenever we talk, I always do.
Mm.
Could it potentially be at a conference that rhymes with Gajesmo- ... and a place called Bash?
That is entirely good instincts.
Gotcha. Excellent. Well, with that, I want to thank the team for being here. Thank you guys very much.