All right. Good morning, everyone. Thanks for joining us here, and I think what is our final session at the Goldman Sachs Global Healthcare Conference? I'm thrilled to be joined on stage today with the team from Prelude Therapeutics, and maybe I'll let you introduce yourselves, and then I'd love if you could just start with a conversation on what you view as the core competencies for Prelude, and how has that informed the portfolio construction and your process kind of for business development over the years?

Thank you. Thank you, Corinne. Thanks for the opportunity to participate in Goldman Conference. The straightforward answer to your question is really to start with why. Because we didn't build the competencies first. The mission came first. So we really exist to bring better treatment options for patients with cancer. And when you hold that standard seriously, it forces us to build a set of capabilities. So he told us that you could not be modality constrained because different cancers, different pathways, different vulnerabilities. So the problems call for different solutions. And so we had to build the capabilities to be able to really design new molecular entities across multiple target classes. You know, not because we really wanted to be a broad technology platform or, you know, target platform, but the patient problem demanded it, right? And it also told us to be really focused because capabilities without focus becomes a very expensive research experiment. And so we had to be the same why that kind of told us to be broad but also forces us to concentrate on the rigor of the science that really tells us which patients to go after, the strength of evidence supporting a particular mechanism. And so it's basically the why builds the how. in this situation. The same logic flows into a portfolio construction. We really look at each of these potential opportunities on three axes, the first one being how strong is the evidence that this particular patient population need a better therapy, and what are the molecular interventions in these patients, number one. Number two, what is the strength of data that validates, And obviously, the more clinical data, the more validation that we have on a particular target. And most importantly, the target candidate profile and, you know, really what's out there. Because what we can do really well is to, you know, design and build those molecules that are truly differentiated that can address something that could be addressed by what's out there. And finally, your question regarding the business development, I just want to be clear that we're building a fully integrated biopharmaceutical company. So the question that we actually don't have on each of the programs is, can we do a deal on this? It's more about if we actually, can we bring this to patients faster and with a broader reach in a strategic collaboration than we can do it on our own. You know, the capital reality is, as you very well know, sometimes depending on the point in time where we are, sometimes dictate what we do, But it truly, you know, we think about Prelude as a fully integrated biopharmaceutical company, which means that we bring to the market some of the discoveries that we make.

Okay, great. Maybe we could talk about some of the specific programs with that in mind then. And we'll start with the CAT6 program. I guess first just why did you find CAT6 a relevant target in oncology and specifically in breast cancer against the paradigm you just described?

Yeah, maybe Peggy can take the scientific question, and then I'll come back.

You know, it is emerging as a really important target in a number of malignancies, especially ER-positive breast cancer. If you ask why CAT6, it's known that it's on the 8P11 amplicon and is amplified in a number of malignancies, 12% to 15% of breast cancer, and it's overexpressed in an even greater percentage. It was also shown in the early preclinical studies that if you knock it down, that you can impact tumor cell growth, colony formation, even cancer stem cells, and that normal cells were not impacted if you knock down CAT6 specifically. And I think that led to the development of small molecule inhibitors first that showed a similar biology to the knockdown experiments, And that led Pfizer first to move into the clinic and really had some early compelling clinical data that supported the preclinical work. There were limitations in terms of toxicities, and that's what led us to really go after a CAT6A selective degrader.

Yeah. With the data that you just shared, or like the inhibitors that are more advanced, how meaningfully do you think this target has been validated at this point?

Yeah, again, I think on the early clinical data suggests that there is activity across a broad range of ER-positive breast cancers, independent of, you know, PIK3CA mutation or ESR1 status, and especially in combination with fulvestrant. I think Pfizer is showing really compelling data that led them to initiate a phase three study. As I mentioned, there are some toxicities associated with the approach. Pfizer has taken an approach to inhibit both CAT6A and CAT6B and that leads to dose-limiting toxicities like neutropenia as well as discusia in a high percentage of patients. And so we do believe it's a validated target, but there's room for improvement.

Yeah, you're starting to speak to my next question, which is, with that in mind, where do you see the residual unmet need that you could address with your own approach?

Yeah, so we've taken an approach where we want to target CAT6A selectively. As I mentioned, CAT6A is amplified in tumors. CAT6B is not. But both of them seem to play a role in bone marrow development. and that's where the toxicity comes in with the dual inhibitors that Pfizer and others are taking forward. So with our approach by selectively degrading CAT6A, we think we can more completely impact the CAT6A biology, the tumor biology, and spare some of the bone marrow toxicity associated, especially the neutropenia. So our approach has really been to go after a CAT6A selective degrader to inhibit the pathway more deeply and have some better tolerability. So I think that's the area for improvement. It's important, I think, when you think about combinations, especially CDK4-6 inhibitors, which are a backbone therapy in ER-positive breast cancer, also have neutropenia. So alleviating some of the neutropenia with a CAT6A selective approach would really allow us to combine effectively A4-6 inhibitors as well as, you know, SIRDs, PI3 kinase inhibitors.

Can you talk a little bit more about the evidence that backs up the hypothesis you just laid out in terms of not touching CAT6B and then being able to show these kind of differential benefit on safety? Yeah, sure.

There's preclinical data, again, that supports if you knock out both CAT6A and CAT6B, that the bone marrow toxicity is much more severe. It has an impact on the hematopoietic stem cells. Whereas if you knock out either one as a single knockout, that that toxicity is mitigated. There's almost no impact. So it's really our thinking, because you need to knock down CAT6A for the tumor biology. Sparing CAT6B should then allow you to have less effect on the bone marrow. So that's been our hypothesis, and I think some of our preclinical data, supports that.

What degree of mitigation do you think you can achieve with a selective approach? Like, what's realistic here? In terms of mitigating the side effect profile, yeah.

Yeah, I think, you know, in the preclinical models, it suggests that there's certainly a wide window. We can be at concentrations or doses that have really strong efficacy in the models and not have an impact on neutrophils. I'm sure if you get to really high doses, maybe a hundred of times where we think we need, you'll start to have an effect, but the preclinical data suggests there's a window.

Speaking of preclinical data, you had a poster at AACR recently. Maybe you could just walk through the key highlights from those results and speak to both the efficacy and the safety you were able to achieve.

Sure. I think we showed three pretty compelling points in that preclinical poster at AACR. One was the monotherapy activity of our lead molecule, PRT-13722, we showed deep regressions, complete regressions in multiple models in all of the animals. And if you compare that to the dual inhibitors, only tumor growth inhibition, as I said, complete regressions across models where the inhibitors really didn't show strong activity. So that was one. I think the combined activity that we also showed with a number of standard of care agents in ER-positive breast cancer like SIRDS and PI3 kinase inhibitors as well as CDK4-6 inhibitors, it was really remarkable the efficacy that we were able to see in the models with all of those agents at really well-tolerated doses. So that was the second point I think that was really important in our poster. And lastly, it goes back to your question of the safety. And at those doses where we saw the marked efficacy in the models, we really saw very minimal effects on neutrophils. So again, better efficacy and better safety.

Can you talk about any benchmarking you're able to do in the preclinical setting to show how this could stack up versus the other agents that are more advanced in the setting?

Yeah, we did a lot of benchmarking to the Pfizer CAT6-AB dual inhibitor, Profetrostat, which they have in the clinic. The structure of that molecule is known, so we were able to do head-to-head studies. And in terms of efficacy, whereas they achieve as monotherapy tumor growth inhibition, we have regressions in combination with something like fulvestrin that they're taking forward in the clinic. they showed in our models we could show some better efficacy in that combination but again with our molecule our cat 6a selective degrader we had complete regressions in all of the animals and then in terms of safety when we benchmark at doses where they achieve that efficacy in the models there's a clear effect on neutrophils whereas we can show you know efficacy at doses that don't have the neutrophil effects.

So looking towards the clinic, I guess, how would you expect these data to translate to clinical results, and in particular, how will it show up if this differentiation is real?

Yeah, I think we're hoping to see that pretty quickly in terms of the safety effects. We can see the effects on the neutrophils, and the other dose-limbing or other effect that the Pfizer compound shows versus dysgusia, which is the, you know, negative taste effects. We think both those things will read out really quickly in the clinic. I think at the recent ASCO, Pfizer had data that the neutropenia shows up within the, you know, first cycle, the first four weeks. So the safety readout should come quickly. And then efficacy may take longer, but as a monotherapy, Pfizer showed around 11% overall response rate. So, again, if the preclinical data translates, we should see effects there as well.

So on that point, you're now moving towards IND and clinical development. I guess what do you envision in terms of initial study design for 13722?

I can take that. So just to take a step back, right, the ER-positive breast cancer treatment landscape is dramatically changed. So if you look at the backbone therapies like CDK4-6s and estrogen-targeted therapies, clearly evolving. And now we have PI3K inhibitors where initial compounds like PCRAE had a lot of toxicities and now has much more mutant selective inhibitors. So one of the interesting things, as I was saying earlier with the Cat6, is that it has the potential to offer something truly unique that could be combined with each of these agents because it's a completely independent access that we've uncovered as a community. So consistent with our portfolio strategy, we wanted to build something differentiated that can be readily combined with others. And we've learned that this neutrophenia is creating a problem to a point where, you know, perpetrostat and the CDK4 selective one, which is moving forward in that class, couldn't be combined, right? although we don't know the exact reason why that couldn't be, but you could suspect it's related to the overlapping toxicity. So the way we're thinking about this really is taking into account the changes of the evolving landscape. The first order of business is, as Peggy pointed out, our preclinical results indicated that we have the potential to have higher monotherapy activity. Just simply we're taking down the whole oncogenic complex for whatever mechanism, maybe deeper hit of the target, all of those reasons. So that should read out in the clinic, and it informs a certain path if that is true, and you really didn't need a combination. But our base case is that we want to demonstrate safety differentiation as a monotherapy and see what the efficacy looks like. and the next step really is making sure that this particular CAT6A selective degrader not only is safer but is as effective as Pfizer, right? So the Falveston combination is the next step that we will do. So and then the third potentially parallel question that we want to address is can we combine safely with the currently marketed CDK4-6? Because if the answer is yes to that, We have opportunities not only in second-line settings, but you can actually move to the front-line settings. So I think ultimately it's going to be a lot of different combinations will be tested, but the sequence is that a monotherapy first, safety, and potential efficacy differentiation followed by further strength combinations is what we're most focused on.

Can you speak a little bit about which doses you'll be taking forward into the clinic, and could you map from the preclinical data to where you would expect to start seeing clinical activity?

Yeah, so, you know, again, having a molecule ahead of us with a lot of preclinical data and also the clinical PK, PD profiles, activity profiles, really is very, very helpful as we think through. So we use, we benchmark, as Peggy indicated, against preventive stat. So we believe based on all the data that we have to date, we would be starting at a pharmacologically active dose. So we're not looking at somehow requiring multiple doses to get to pharmacological. So we start right off the bat in the range of target inhibitions that should be active. And then the question really is that we still have the dose of sclered. We still have to pick doses, right, for expansion and et cetera. So the way we're thinking about it is that it's sort of parallel execution. So start at a dose that has pharmacological activity, you know, potential pharmacological activity, or gives you the coverage that's associated with preclinical efficacy. And then ask, you know, we have a number of questions we can ask. You know, there's a biomarker side. We can look at CAT6 levels in these patients. If the patient's already had either ESR1 or, you know, PHDK mutation, we can look at their ctDNA changes and then potentially backfill those cohorts or add, you know, focus strength at that point.

Okay. So with that in mind, I guess how long do you anticipate it could take before you start generating clinical proof of concept here?

You know, it's just before we, it's hard to tell before we start, But, you know, we've generally guided that we, you know, by the second half of 2027, you know, we should be in a position to have enough patients to be able to start understanding the profile of the molecule. Like I said, the safety data will come first because we saw from Pfizer's recent ASCO presentation that the neutropenia shows up within one cycle, right? So, but then you could always argue that it's, have your dose die enough, right? If it's safer, you also need to be able to show that you're effective. And if it truly requires pulverstone combo and enough patients to see it, you know, I think probably 18 months or so is a reasonable target.

You've talked a bit about this already, so some of this might be a little bit repetitive, but how are you thinking about the potential combination regimens in breast cancer, and what data specifically are you looking to generate before investing more kind of ultimately into some of those combination approaches?

Yeah, I think, you know, if the safety differentiation emerges early in the development, going to follow stent combo is the number one thing because we want to be able to show that selectively hitting cat six hairs sparing CAT6B not only gives you safety, you know, improvements, but also can match the efficacy. That's a must, right, that we should be able to show. If we can see the safety differentiation, we will rapidly move to CDK4-6 combo, because that is something that I don't think this current generation of, you know, either Pfizer or some of the others that are hitting both CAT6A and B will be able to do. because there's, I mean, we've seen some more data from OLEMA, but generally speaking, the profiles may be minor differences, but they look like cat-6, A, B inhibitors, right? So our operating assumption at the moment is that if we can actually show combination data with CDK4-6, it opens up a whole host of opportunities. We're not concerned that much on the PI3K, inhibitor, you know, overlapping safety issue, I think we should be able to combine that. And, you know, so it's just really sequential. I think ensuring that we have a dose that we can take forward in combination with either starting with Fulveston followed by CDK4-6. And that data package is going to be very, very helpful in really constructing the next set of combination.

Would you anticipate the same dose going forward into the monotherapy-verse combinations or across different combinations, and how much dose-finding work will you have to do as you think about kind of pushing forward on the combination strategy?

I mean, it's really hard to anticipate exactly, except that, you know, CDK4-6 is the number one. If we can combine full dose with CDK4-6, I think it has become fairly predictable. But if you needed dose, because if you just look at Pfizer data, right, even at the, you know, with the follow-strand combination of the five milligram dose, they had to dose modify most patients. So the starting dose was not the dose that patients are on. So being able to maintain the dose density itself is a major differentiation we're looking for. And so I think, you know, we just want to be guided by the clinical data once it emerges, but we'll be the first ones to really ask this question in the clinic. So I think we just have to see the data.

It should be another stay-tuned question, but I wanted to ask briefly on market opportunity at this stage of your development, is just what different opportunity sets do you unlock if you can move into the different combinations versus monotherapy regimens?

I mean, you know, it's been said by many companies in ER positive, you know, breast cancer, metastatic setting is a significant commercial opportunity, $5 billion plus opportunity potentially. But if you could actually move into settings where it can be used in newly diagnosed or adjuvant settings is where the, you know, biggest opportunity is. If you look at ribocyclic, it's been growing because they have that activity. So, I mean, regardless of where exactly it's going to be used, which is going to be dictated by the data, I think we're going to be really, you know, driving into the right settings. And we just also have to see how four of thirds are going to be playing out, ultimately the ESR wild type versus the ESR mutants, and where CDK, what CDK, I mean, Etermo is fully enrolled, they're phase three versus all other CDK4-6s, right? So I think the landscape is going to evolve, and actually it's a great time to be in this space right now because I think the future of breast cancer treatment or ER-positive breast cancer treatment is about to be completely transformed.

On that point, are there any other mechanisms or strategies that you think are interesting in the breast cancer space that you're monitoring with respect to either learnings you can take away or how it will shape the competitive landscape?

Yeah, I don't know, Peggy. Do you have any thoughts on that?

I think we're still, as Chris mentioned, focused on, you know, CDK4 selective versus 4.6. I think the other point, and we look at it a lot, is, you know, we've taken the selective CAT6A approach. Others are moving into even less selective compounds, bringing in CAT7 to try to expand that space. So those are areas we certainly keep in mind.

All right, I want to shift gears a little bit to the pipeline. One of the things you're working on as a degrader antibody conjugate targeting MCAL-R. But first, can we just take a step back and explain that technology? I think you're calling it a DIC.

Yeah, maybe I can start and Peggy can add. So, you know, in the ADC space, broadly speaking, right, because it is a drug and it is conjugated to an antibody. So we know we've seen tremendous advances and really transformational, you know, outcomes for patients with cancer with their ADCs. There's a lot of antibody diversity with really discovery using AI-enabled technologies to identify novel antigens. But if you look at the payloads themselves, there's very, very little diversity. And so you really need, I think it's widely recognized, you need better payloads that are more sort of targeted to the cancers rather than broad-spectrum cytotoxics. I think the degraders are uniquely capable of actually doing that because you couldn't deliver enough of an inhibitor, regardless of how potent it is, in enough quantities as a payload to an antibody. So because degraders are catalytic, that if you can give the concentrations you need to really get to the tumor are substantially lower. So they lend themselves to be good payloads. And because you can design them specific to the tumor cells, you almost get that precision squared. So I think that is a very unique opportunity to be able to do that. But a number of companies have been talking about it. But we've actually formed a collaboration with Abcelora almost three years ago. And the team worked very hard to try to solve the chemistries because it's just not like you take an antibody and slap it on or degrade it and slap it on an antibody, and now you have a DAC or degraded antibody conjugate. There's a tremendous amount of chemistry, linkers, stability, all of that need to be solved, which the team has done. And so I think time has come to now really deploy this. The second interesting aspect of it is that these are not genotoxic and cytotoxic the way that chemotherapy drugs are. So it expands the reach of the ADC technology beyond, you know, life-threatening cancers to indications where, you know, you need to be able to deliver a particular inhibitor or a degrader to a particular, you know, tumor cell, you know, more effectively, where these are more benign indications. So I think that's generally a really promising way of taking ADCs to the next level.

Can you talk a little bit about selecting MCAL-R as a target for your first DAC program, and why does that target in particular make sense for this modality?

I'll start, and then maybe Peggy can add. So it was very interesting, right? So, you know, that mutation in CAL-R, which is CAL-R is normally sitting inside the cell, right? So it's not presented on the cell surface. So when you have a mutation, and this mutation is only present in a fraction of myeloproliferative neoplasms, right? So in essential thrombocytemia, about, I guess, 40-50% of the patients, 30-40% of the patients have it, and myelofibrosis, similar numbers. So when this mutation happens, you lose the C-terminal tail, and now it's all of a sudden on the surface of MPN, disease-initiating cells. And so there you have an antigen that is targetable with an antibody that is only for, but that's been the holy grail, to find antigens on the tumor cell, right? But in addition to just being there, it actually signals, right? It engages that pathway and it signals. So it allowed us to go after an antigen with this approach to truly maximize the benefits of just inhibiting the pathway.

Okay, great. And maybe you could just refresh us on what you've seen in the preclinical setting to validate the hypothesis you just laid out. And then what are you solving for as you push towards getting a development candidate here?

Yeah, maybe you can think of that, yeah.

So, you know, with the naked antibodies, the whole mechanism there is to block signaling. And so it really requires almost complete coverage of the receptors, saturation of the receptors to have that impact. so with the DAC approach we are delivering a payload and you don't need that coverage of the receptors the receptors are just you know being used to deliver the payload to those mutant cells as Chris outlined and so what we see pre-clinically then is a really significant greater than a hundred fold shift in potency using the DAC versus the the naked antibody and that we also You'll see a rapid killing of the mutant progenitor cells that we think is more effective than just blocking the signaling. And it's important if you follow the antibody, the insight antibody that's out there. They're really high doses and really frequent delivery of the antibodies. So we think with the STAC approach, we will have a more potent effect and maybe a more rapid effect on the patient.

And then in terms of next steps for development, what are kind of the next steps we should be monitoring for for this program?

Yeah, so again, it's the same as I described our portfolio strategy. We have to be convinced that what we bring to the table truly moves the needle for patients. So here we see opportunities to really improve, as Peggy indicated. We want something that actually can be broadly used for all mutations, you know, and across both MPM, CT, and MF. And so from an antibody side, we've already, you know, sort of narrowing down onto the antibody that can hit both type I and type II mutations. we want to make sure that the payload is the overall safety profile of our DAC has to be as good as the naked antibody so those are the main drivers and we're going through the cellophinal selection of these and as soon as we have those then we can talk more about the exact timelines of when maybe briefly you have a next generation JAK inhibitor there's a partnership with Insight on that program.

Could you just remind us the terms of the Insight potential opt-in and what data will be visible to you and your partner there before that opt-in has to be determined?

Yeah, sure. So what Insight has is the option to purchase the asset. So we entered into that agreement last year in November timeframe, so we have until February of next year. So the decision is not necessary. It's a time-based option. So it's particularly somewhat complex because Insight has their own program, and they are advancing that program. And so they'll be generating their own data. And then our lead program is in the clinic, and that's obviously moving, generating clinical data. And we have a very active backup program, which is actually generating more preclinical data. So I think they would have to look at a totality of all of the data and decide whether to exercise the option or not. And so, again, they could exercise at any time. It's not like there's a specific trigger, but we have to have X number of patients and X number of duration of therapy for them to... They really can have the flexibility to make the decision at any time.

Between now and February?

Between now and February, yeah.

And what are the financial terms of that if they do opt-in?

So it's $100 million at the time of option exercise, and that's a one-time payment. Then they take the entirety of the program. Then there's up to $775 million in milestone payments that are regulatory and clinical, not sales-based milestones. And then there are low single-digit royalties that follow for the life of the program.

Maybe that's a good segue to my last question, which is, what is your kind of current cash balance and runway, and what activities, as we just described, are embedded in that?

So our current cash is ABA, having completed the most recent financing. There are the three programs we discussed, right? CAP6 fully funded, MCALR fully funded as well, together with the JAK v617F program through the option period. And one of the nice things about doing the financing is that we now have that runway to see us into second quarter of 2028.

How, if at all, would the Insight opt-in kind of inform that runway? And is there a world in which you do the JAK 2 program on your own, like if Insight doesn't?

Yeah, so Chris can answer sort of the second part of that question for sure, But as it relates to that second quarter of 2028, it's a great clarifying point that that does not cover the potential $100 million option payment that Insight would hopefully exercise or be a part of the option agreement.

Yeah, and we're pretty excited about the program, and whether inside this, depending on whatever their business needs are and whatever decisions they need to make, we believe that this is a really exciting area and in need of very targeted agents, and we certainly can take it forward if there's a situation. If the data merits taking it forward and inside, that's not often for business reasons. We're certainly prepared to take it forward.

Great. That brings us to time. Thank you so much to all of you for joining us here, and thanks to everyone who joined us online and here in the room.

Thanks, Kerry.