All right. Good morning, everyone. Thanks for joining us here in, I think, what is our final session of 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 for business development over the years?
Thank you, Colleen. Thanks for the opportunity to participate in Goldman Conference. The straightforward answer to your question is really to start with why. We didn't build the competencies first. The mission came first. We really exist to bring better treatment options for patients with cancer, right? When you hold that standard seriously, it forces us to build a set of capabilities, right? It told us that you could not be modality-constrained because different cancers, different pathways, different vulnerabilities. The problems call for different solutions. We had to build the capabilities to be able to really design new molecular entities across multiple target classes. Not because we really wanted to be a broad technology or target platform, but the patient problem demanded it, right? It also told us to be really focused, because capabilities without focus becomes a very expensive research experiment.
We had to be the same why that 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. It's basically the why builds the how in this situation. The same logic flows into our 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? Obviously, the more clinical data, the more validation that we have on a particular target, and most importantly, the target candidate profile, and really what's out there.
What we can do really well is to design and build those molecules that are truly differentiated that can address something that couldn't be addressed by what's out there. Finally, your question regarding the business development. I just want to be clear that we're building a fully integrated biopharmaceutical company, right? 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 can we bring this to patients faster and with a broader reach and a strategic collaboration than we can do it on our own.
The capital reality is, as you very well know, sometimes depending on the point in time where we are sometimes dictate what we do. Truly, 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.
All right, great. Maybe we could talk about some of the specific programs with that in mind then. We'll start with the KAT6 program. I guess first, just why did you find KAT6 a relevant target in oncology and specifically in breast cancer against the paradigm you just described?
Yeah. Maybe Peggy can take the scientific question, I'll come back.
Sure. It is emerging as a really important target in a number of malignancies, especially ER-positive breast cancer. If you ask why KAT6, it's known that it's on the 8p11 amplicon and is amplified in a number of malignancies, 12%-15% of breast cancer, 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 KAT6 specifically. I think that led to the development of small molecule inhibitors first that showed a similar biology to the knockdown experiments, that led Pfizer first to move into the clinic, really had some early compelling clinical data that supported the preclinical work.
There were limitations in terms of toxicities, that's what led us to really go after a KAT6A selective degrader. Yeah.
With the data that you just shared or the inhibitors that are more advanced, I guess how meaningfully do you think this target has been validated at this point?
Yeah. Again, I think the early clinical data suggests that there is activity across a broad range of ER-positive breast cancers independent of PIK3CA mutation or ESR1 status, especially in combination with fulvestrant.
I think Pfizer is showing really compelling data that led them to initiate a Phase III study. As I mentioned, there are some toxicities associated with the approach. Pfizer has taken an approach to inhibit both KAT6A and KAT6B. That leads to dose-limiting toxicities like neutropenia.
Yeah
As dysgeusia in a high percentage of patients. 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. We've taken an approach where we want to target KAT6A selectively. As I mentioned, KAT6A is amplified in tumors. KAT6B is not. 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. With our approach, by selectively degrading KAT6A, we think we can more completely impact the KAT6A biology, the tumor biology, and spare some of the bone marrow toxicity associated, especially the neutropenia. Our approach has really been to go after a KAT6A selective degrader to inhibit the pathway more deeply and have some better tolerability. 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.
Alleviating some of the neutropenia with a KAT6A selective approach would really allow us to combine effective KAT6 inhibitors as well as SERDs, PI3 kinase inhibitors.
Yeah. Can you talk a little bit more about the evidence that backs up the hypothesis you just laid out in terms of not touching KAT6B and then being able to show these kinds of differential benefit on safety?
Yeah, sure. There's preclinical data, again, that supports if you knock out both KAT6A and KAT6B, 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 toxicity is mitigated. There's almost no impact. It's really our thinking because you need to knock down KAT6A for the tumor biology, sparing KAT6B should then allow you to have less effect on the bone marrow. 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 the-
Like mitigating the side effect profile. Yeah.
Yeah. I think 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 100 x where we think we need.
You'll start to have an effect. The preclinical data suggests there's a window.
Speaking of preclinical data, you had a poster at AACR recently. Maybe you 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, PRT00,3722. We showed deep regressions, complete regressions in multiple models in all of the animals. If you compare that to the dual inhibitors, really only tumor growth inhibition. As I said, complete regressions across models where the inhibitors really didn't show strong activity. 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 SERDs 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. That was the second point I think that was really important in our poster.
Lastly, goes back to your question of the safety. At those doses where we saw the marked efficacy in the models, we really saw very minimal effects on neutrophils. 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 KAT6A/B dual inhibitor, prifetrastat, which they have in the clinic. The structure of that molecule is known, we were able to do head-to-head studies. In terms of efficacy, whereas they achieve as monotherapy tumor growth inhibition, we have regressions. In combination with something like fulvestrant that they're taking forward in the clinic, in our models, we could show some better efficacy in that combination. Again, with our molecule, our KAT6A selective degrader, we had complete regressions in all of the animals. 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 efficacy at doses that don't have the neutrophil effect.
Looking towards the clinic, I guess, how would you expect these data to translate to clinical results? 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-limiting or other effect that the Pfizer compound shows is dysgeusia, which is the 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 first cycle, the first four weeks. The safety readout should come quickly, and then efficacy may take longer, but as a monotherapy, Pfizer showed around 11% overall response rate. Again, if the preclinical data translates, we should see effects there as well.
Great. 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 PRT13722?
I can take that. Just to take a step back, right? The ER-positive breast cancer treatment landscape is dramatically changing, right? If you look at the backbone therapies like CDK4/6 and estrogen targeted therapies, clearly evolving. And now we have PI3K inhibitors where initial compounds like Piqray had a lot of toxicities and now there's much more mutant-selective inhibitors, right? One of the interesting things, as I was saying earlier with the KAT6, 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 axis that we've uncovered, right, as a community. Consistent with our portfolio strategy, we wanted to build something differentiated that can be readily combined with others.
We've learned that this neutropenia is creating a problem to a point where, you know, palbociclib and the CDK4 selective one, which is moving forward in that class, couldn't be combined, right? We don't know exact reason why that couldn't be, but you could suspect it's related to the overlapping toxicity. The way we're thinking about this really is taking into account of 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. That should read out in the clinic, and it informs a certain path if that is true, and you really didn't need estrogen in combination with palbociclib.
Our base case is that we want to demonstrate safety differentiation as a monotherapy, right, and see what the efficacy looks like. The next step really is making sure that this particular KAT6A selective degrader not only is safer but is as effective as Pfizer, right? The palbociclib combination is the next step that we will do.
The third, potentially parallel, question that we want to address is can we combine safely with the currently marketed CDK4/6? 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 setting. 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 palbociclib combination is what we are most focused on.
Okay. Could 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?
Again, having a molecule ahead of us with a lot of preclinical data and also the clinical PK/PD profile, activity profiles really is very, very helpful as we think through. We use, we benchmark, as Peggy indicated, against palbociclib. We believe based on all the data that we have to date, we would be starting at a pharmacologically active dose. We're not looking at somehow it's requiring multiple doses to get to pharmacological.
We start right off the bat in the range of target inhibition that should be active, right?
Okay.
The question really is that we still have to dose escalate, we still have to pick doses, right, for expansion and et cetera. The way we're thinking about it is that it's sort of parallel execution.
Start at a dose that has pharmacological activity, potential pharmacological activity, or gives you the coverage that is associated with preclinical efficacy. We have a number of questions we can ask. There's the biomarkers that we can look at KAT6 levels in these patients.
Yeah.
If the patients already had either ESR1 or PI3K mutation, we can look at their ctDNA changes, and then potentially backfill those cohorts or add palbociclib at that point.
With that in mind, I guess how long do you anticipate it could take before you start generating clinical proof of concept here?
It's hard to tell before we start, but we've generally guided that by second half of 2027, 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? You could always argue that, have you dosed high enough, right?
If it's safer, you also need to be able to show that you're effective. If it truly requires fulvestrant combo on enough patients to see it, I think probably 18 months or so is a reasonable target.
Yeah. You've talked a bit about this already, some of this might be a little bit repetitive, how are you thinking about the potential combination regimens in breast cancer? What data specifically are you looking to generate before investing more kind of fulsomely into some of those combination approaches?
Yeah. I think, if the safety differentiation emerges early in the development, going to fulvestrant combo is the number 1 thing, we want to be able to show that selectively hitting KAT6A, sparing KAT6B not only gives you safety improvements, 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, that is something that I don't think this current generation of either Pfizer or some of the others that are hitting both KAT6A and KAT6B will be able to do. We've seen some more data from Alema, generally speaking, the profiles may be minor differences, they look like KAT6A/B inhibitors, right?
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 overlapping safety issue. I think we should be able to combine that, it's just really sequential. I think ensuring that we have a dose that we can take forward, in combination, starting with fulvestrant, followed by CDK4/6. That data package is going to be very, very helpful in really constructing the next-
Set of combination and opportunity.
Would you anticipate the same dose going forward into the monotherapy versus combinations or across different combinations? How much dose-finding work will you have to do as you think about pushing forward on the combination strategy?
It's really hard to anticipate exactly, except that CDK4/6 is the number one. If we can combine full dose with CDK4/6, I think that becomes fairly predictable. If you needed dose. If you just look at Pfizer data, right? With the fulvestrant combination at the five-milligram dose, they had to dose modify most patients.
The starting dose was not the dose that patient's on. Being able to maintain the dose density itself is a major differentiation we're looking for.
Yeah.
I think 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. I think we just have to see the data.
Maybe another stay tuned question. I wanted to ask briefly on market opportunities 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?
It's been said by many companies in ER-positive breast cancer, metastatic setting is a significant commercial opportunity, right? $5 billion+ opportunity potentially. If you could actually move into settings where it can be used in newly diagnosed or adjuvant settings is where the biggest opportunity is, right? If you look at ribociclib.
Yeah
It's still growing because they have that activity. 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 driving into the right setting. We just also have to see how oral SERDs are going to be playing out.
Yeah
Ultimately in the ESR1 wild type versus the ESR mutants.
Yeah.
I mean, Athenex is fully enrolled their phase III versus all other CDK4/6s, right?
I think the landscape is going to evolve, actually, it's a great time to be in this space right now.
Yeah.
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, you have any thoughts on that?
I think we're still, as Kris mentioned, focused on CDK4 selective versus 4/6. I think the other point, and we look at it a lot, is we've taken the selective KAT6A approach. Others are moving into even less selective compounds, bringing in KAT7.
Yeah
To try to expand that space. Those are areas we certainly keep an eye on.
Great. All right. I want to shift gears a little bit to the pipeline. One of the things you're working on is a degrader antibody conjugate targeting mCALR, first, can we just take a step back and explain that technology? I think you're calling it a DAC.
Yeah, maybe I can start, and Peggy can add. In the ADC space broadly speaking, because it is a drug, and it is conjugated to an antibody. We know we've seen tremendous advances and really transformational outcomes for patients with cancer with their first ADCs. There's a lot of antibody diversity with really discovery using AI-enabled technologies to identify novel antigens. If you look at the payloads themselves, there's very little diversity.
Yeah.
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.
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.
Because you can design them specific to the tumor cells, you almost get that precision squared, we call it.
Yeah.
Right? I think that is a very unique opportunity to be able to do that, but a number of companies have been talking about it. We've actually formed a collaboration with AbCellera 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 a degrader and slap it on an antibody, and now you have a DAC or degrader antibody conjugate. There's a tremendous amount of chemistry, linkers, and stability, all of that need to be solved, which the team has done.
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 the chemotherapy drugs are.
Yeah.
It expands the reach of the ADC technology beyond life-threatening cancers to indications where you need to be able to deliver a particular inhibitor or a degrader to a particular tumor cell.
Yeah
More effectively, where these are more benign indications. Right. I think that's generally a really promising way of taking ADCs to the next level.
Could you talk a little bit about selecting mCALR as a target for your first DAC program, why does that target in particular make sense for this modality?
I'll start, then maybe Peggy can add. It was very interesting, right? That mutation in CALR, which is CALR is normally sitting inside the cell, right? It's not presented on the cell surface. When you have a mutation, this mutation is only present in a fraction of myeloproliferative neoplasms. In essential thrombocythemia, about I guess 40%-50% of the patients.
Yeah.
30%-40% of patients have it, myelofibrosis, similar numbers. When this mutation happens, you lose the C-terminal tail, now it's all of a sudden on the surface of MPN disease-initiating cells. There you have an antigen that is targetable with an antibody that is only That's been the holy grail, to find the antigens on the tumor cells.
Right? In addition to just being there, it actually signals. Right? It engages that.
Yeah
Signals. It allowed us to go after an antigen with this approach to truly maximize the benefits of just inhibiting the pathway.
Okay, great. 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 take that. Yeah.
With the naked antibodies, the whole mechanism there is to block signaling. It really requires almost complete coverage of the receptors, saturation of the receptors to have that impact. With the DAC approach, we are delivering a payload, you don't need that coverage of the receptors. The receptors are just being used to deliver the payload to those mutant cells, as Kris outlined. What we see preclinically then is a really significant, greater than a 100-fold shift in potency-
using the DAC versus the naked antibody. That we also see a rapid killing of the mutant progenitor cells that we think is more effective than just blocking the signaling. It's important if you follow the antibody, the Incyte antibody that's out there, they're really high doses and really frequent delivery of the antibodies. We think with this DAC approach, we'll have a more potent effect and maybe a more rapid effect-
Okay
In the patient.
In terms of next steps for development, what are kind of the next steps we should be monitoring for this program?
Yeah. 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. Here we see opportunities to really improve, as Peggy indicated. We want something that actually can be broadly used for all mutations, and across both MPN, ET, and MF. From an antibody side, we've already sort of narrowing down onto the antibody that can hit both type 1 and type 2 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. Those are the main drivers, and we're going through the final selection of these. As soon as we have those, then we can talk more about the exact timelines of when we.
Maybe briefly, you have a next-generation JAK inhibitor. There's a partnership with Incyte on that program. Can you just remind us the terms of the Incyte potential opt-in, and what data will be visible to you and your partner there before that option has to be determined?
Yeah, sure. What Incyte has is a option to purchase the asset, right? We entered into that agreement last year, in November timeframe, so we have until February of next year. The decision is not necessary. It's a time-based option. It's particularly somewhat complex because Incyte has their own program, and they are advancing that program. They'll be generating their own data.
Our lead program is in the clinic, and that's.
Obviously moving, generating clinical data. We have a very active backup program, which is actually generating more preclinical data. I think they would have to look at a totality of all of the data and decide, right, whether to exercise the option or not. Again, they could exercise at any time. It's not like there's a specific trigger that we have to have-
X number of patients and X number of duration of therapy, They really have the flexibility to make the decision at any time between-
Between now and February.
Between now and February. Yeah.
Okay. What are the financial terms of that if they do opt-in?
It's $100 million at the time of option exercise, and that's a one-time payment. They take the entirety of the program. There's up to $775 million in milestone payments that are regulatory and clinical.
Not sales-based milestones. There are low single-digit royalties that follow.
Okay
For the life of the program.
Okay. 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?
Yeah. Our current cash is in 2028, having completed the most recent financing. There are the three programs we discussed, right? KAT6A fully funded, mCALR fully funded as well, together with the JAK2 V617F program through the option period. One of the nice things about doing the financing is that we now have that runway to see us into second quarter of 2028.
Great. How, if at all, would the Incyte opt-in kind of inform that runway? Is there a world in which you do the JAK2 program on your own, like if Incyte doesn't kind of opt in?
Yeah. Kris can answer the 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 Incyte would hopefully exercise.
Okay
Of the option agreement. Kris?
Yeah. We're pretty excited about the program and whether Incyte, depending on whatever their business needs are, whatever decisions they need to make-
Yeah
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 Incyte does not opt-in 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 everyone who joined us online and in here in the room. Thanks.
Thanks.
Thanks.
Thank you.