Good afternoon, everyone. Thank you for joining us today here in our Jefferies Healthcare Conference in New York. I have the pleasure today, joined by Kris Vaddi and Peggy Scherle of Prelude Therapeutics. Why don't we go ahead and get started? Kris and Peggy, if you could introduce yourselves and a little bit about your company. Thank you.
Sure. I'm Kris Vaddi, Founder and CEO of Prelude Therapeutics.
I'm Peggy Scherle, CSO at Prelude Therapeutics.
Maybe I'll just take a couple of minutes to introduce the company. First of all, thank you very much for the opportunity to participate in your conference. Just to frame up Prelude, we're a precision oncology company with a very specific mandate. Go after cancers where the patients really do not have good therapeutic options today, they're underserved, and bring something better, genuinely better, to the table for them to move the needle. Why do we think we can do that? It's the team and the pipeline that the team built. Our discovery and development team has done this before. They actually designed and built molecules that matter, and they know how to move these compounds through. Every single asset in our pipeline was internally discovered. They were not in- license, they were not bolt-ons, but they were specifically designed to be better than what's out there.
We're well-capitalized. We have a number of data catalysts in the next 12- 24 months. We're not waiting for any binary data. We have multiple, highly differentiated molecules that we're very excited to talk about today. The first one is PRT12396. I'll call it 2396. It's a selective JAK2 V617F inhibitor. Probably you're familiar with MPNs or myeloproliferative neoplasms. There are more than 200,000 patients, 300,000 patients in the United States alone and many, many more worldwide that have this mutation in JAK2 enzyme. Majority of these patients have this mutation, and they currently live with the first-generation. Some of them are treated with the first-generation JAK2 inhibitors. In fact, several of them don't even have that option. We know about those molecules because our team invented the first one called Jakafi, which is still most widely prescribed JAK2 inhibitor.
While they work great, they treat the symptoms primarily. They really do very little to modify the disease. Why do they do that? It's because they hit the normal JAK2 that your body needs, and the mutated JAK2 that drive the cancer equally. We designed 2396 to fix that. It selectively targets the mutated JAK2 and thereby eliminates some of the toxicities or potentially significantly reduce the toxicities. Better therapeutic window, potentially better responses, and most critically, the opportunity to modify the disease for these patients. We are in phase I, currently in dose escalation, enrolling patients globally for this trial. The second molecule in our pipeline is a KAT6A selective degrader, targeting ER+ breast cancer. It's been shown that this is a pathway that is effective with Pfizer and others showing hitting KAT6A and B could be very effective for these patients.
However, they also uncovered an important liability, which is hematological toxicity. We designed our molecule to selectively degrade KAT6A to not only get that selectivity and reduce the potential hematological liability but essentially dismantle the entire oncogenic complex. We believe that this is a pathway. This allows this type of a molecule to be used much more widely, better combinably, and across all lines of therapy. The third molecule that we're very excited about targets CALR, again, back to the MPN that I mentioned earlier. These mutations in CALR allow this particular protein to be expressed specifically on the disease-causing cells in about 30%-40% of MPNs. The first-generation compounds showed that you actually. These are antibodies. They've demonstrated the proof of concept and showed that you can actually get good responses, but they leave a lot of efficacy on the table.
By delivering a payload, we deliver a degrader as a payload on this antibody to specifically the cells, the disease-causing cells, we can drive deeper responses, be a better patient-friendly formulation, and truly be a best-in-class medicine for these patients. That's a pipeline that we're building. We're very excited about the next 12-24 months. I think we have the science, we have the capital, and we have the focus. Looking forward to the conversation today.
Yeah, thanks for that overview of the pipeline. Focusing on your first asset, as we look at MPN, we know that some of those subsets, like PV versus MF patients, they do have some different baseline physiologies and then dose tolerabilities. How do we think about that phase I profile between those two?
Yeah, sure. The way we designed this program exactly for that reason, to recognizing that myelofibrosis, where patients have a very compromised bone marrow function versus polycythemia vera, where have hyperproliferative bone marrow. We designed our trial to independently dose escalate in each of these populations separately, and be able to find the right dose for these patients. Again, at baseline, the mutant allele burdens are different between these two patient populations. The outcomes we're driving to are quite different. For example, in myelofibrosis, where they have spleen and symptoms have been the traditional endpoints, and ultimately improving the outcomes and improving survival are important. For PV, they undergo phlebotomies as first-line therapy, so reducing phlebotomies is an important objective for the low-risk patients. Patients with high-risk PV, they have high levels of thromboembolic events, cardiovascular events, and most importantly, conversion to myelofibrosis.
We have to really understand what level of target inhibition is needed for each of these patient populations and be able to advance beyond the dose escalation into these populations with the right dose. We're well-positioned to be able to do that with our phase I program.
Thank you. Also, you highlighted the differentiating points of this asset. I guess as this phase I is continuing, what would get you excited? Any early signals that you would expect to see almost?
Yeah. Again, in MPNs, one of the good things is you can track the disease pretty much in real-time basis, unlike solid tumors. What we would be looking early on is normalizing the blood counts in PV, ultimately driving to complete hematological responses. That would be the earliest signal we think we'll see. Beyond that, we would like to see as markers of disease modification, reducing the mutant allele burden, change in what they call variant allele fraction would be another marker we would be tracking. Also, a significant number of PV patients have symptoms, we would be tracking. In terms of MF, I think the spleen and symptoms are pretty well-validated by a number of JAK inhibitors, we would be looking for in the early part of the trial.
For between both of them, we would definitely be tracking the variant allele fractions to look for the early signs of disease modification.
Thank you. Then I know that the early cohorts are focused on that high-risk population. How do you think about expanding this to the ET indications?
Yeah. We've thought quite a bit about that and actually consulted with a number of KOLs in our Advisory Board. What we've ultimately decided is to really focus on PV because about 95% of patients with PV have this particular mutation, so that seemed like the most ideal first-in-human study. MF is, again, still in need of therapies beyond the first-generation JAK inhibitors. We felt that once a dose is identified for PV, that could be the grounds to actually open an ET trial and potentially be able to treat those patients at that dose. That's coming, but that'll be part of our expansion program.
Thank you. As you guys are ongoing, Incyte is advancing its own internal JAK2, along with the option in your program. I guess, any comments on your asset and how differentiated it is from others?
Yeah, I'll start, and I'll ask Peggy to comment on the molecule itself. With regard to Incyte, we only know what they present publicly and based on what they said, and actually based on the way we designed our molecule, we believe that we are in a very different chemical space than everybody else and different sort of mode of action, if you will, on the JAK enzyme. That would be the major differentiation and just in terms of mechanism of action, I don't know if you want to add.
Yeah, I'll just add. As you know, the V617F mutation is not in the ATP binding pocket, but it's actually in a separate JH2 domain. We designed our molecules to bind deep into that pocket where the V617F mutation actually resides. We think, as Kris mentioned, that that's a really unique chemical space that's different from what we know in patents and what's been presented by other companies. We also really worked hard on the PK properties of the molecule, building in excellent solubility and protein binding properties. We really think with the molecule we're taking forward, we can effectively inhibit the mutant and spare the wild type.
Thank you. Taking a step back, we just came back from ASCO and now focusing on the KAT6 area. We saw some long-term data from Pfizer as well as some efficacy data from another company, Olema. How do you see the read-through from these to your asset and anything differentiating with your KAT6 degrader?
Yeah, I'll start with my own learnings from ASCO and then turn it over to Peggy to speak about some other aspects of this particular target. Yeah, the two important pieces of data with regard to KAT6 is, one, we saw more longer-term safety data from Pfizer. I think efficacy data was already presented before, and now they're in phase III. From safety data, it's still very clear that the neutropenia primarily and dysgeusia are the two safety parameters that we would be tracking. With regard to neutropenia, it seems like a significant number of patients had to be dose-reduced. I think they've talked about neutropenia within the first four weeks is something that emerges that leads to reducing the dose from the starting dose of 5 mg .
That's important because if you're not able to maintain the patients at the starting dose, that could be a challenge there. Majority of the dose reductions seem to have come from neutropenia. Olema is another further validation of the pathway. Now a second molecule going into the same patient populations. It, to us, numerically, maybe there are some differences, but this is early data, but again, showing the same two safety aspects. I think they're too early to comment on the efficacy side. Overall, I think it strengthens the case for targeting KAT6, but still points out the need for potentially better therapies.
Yeah. I'll just add, both those molecules that Kris just described are inhibitors of both KAT6A and KAT6B. When we designed our program compounds, we really thought it was important to selectively target KAT6A and spare KAT6B, and the reasons for that were twofold. It's pretty clear from the preclinical biology that KAT6A drives the tumor biology. It's amplified in ER+ breast cancer as well as in a number of other tumor types, and regulates a number of key genes like MYC and cell cycle genes, as well as the estrogen receptor itself. KAT6B, on the other hand, as well as KAT6A, are both important for bone marrow cell development, hematopoietic cells. What was shown preclinically is that if you knock out both KAT6A and KAT6B, the toxicity to those bone marrow cells is much more severe than if you knock out either one alone.
We really started the program with that in mind, to build KAT6A selective degrader compounds to try to improve upon the efficacy and mitigate some of the toxicity. Our preclinical data supports both those aspects, I think. We show very strong anti-tumor effects, regressions, in fact, in a number of ER+ breast cancer models, and we also show less impact on neutrophils in the preclinical models. We think from both those standpoints, our KAT6A selective degraders are differentiated. We look forward to advancing our molecule in the clinic.
Thank you. As we think about sequencing in this indication with other agents like oral SERDs, PI3K inhibitors, how do you see a degrader fitting in, and what are you hearing from feedback from physicians?
Yeah. I think the breast cancer landscape is really evolving in different ways, right? You have in the estrogen-targeted therapy space, the oral SERDs are slowly moving through. So far, the activity seems to be interesting in ESR1-mutated breast cancer, others unclear. Other biomarker-selected tumor types like PI3K mutated, obviously the selective PI3K mutant inhibitors are being advanced. What's really interesting with the KAT6 pathway is that it was really shown by Pfizer that two things. One, this mechanism, which is sort of orthogonal to other mechanisms, seem to be effective, or at least the early responses and PFS endpoints are similar, regardless of whether you have ESR1- mutant, wild-type, small numbers, PI3K mutated or not.
More importantly, if you look at the ctDNA drops of either of these mutations, they're pretty dramatic, and you actually can see a good correlation for the responses and stable diseases in patients who can achieve those kinds of ctDNA drops. The way we see it is, obviously we'll start based on the preclinical data that we presented recently. We think that this degrader approach could actually has the potential to significantly improve on the efficacy and perhaps match the efficacy of what Pfizer and Olema have been attempting to do with the combination, and we'll see what happens in the clinic. Beyond that, we would be looking at fulvestrant combination early. Also try to combine with CDK4/6 early in development, because that is the one thing that, so far we haven't seen a KAT6A inhibitor, a KAT6A/B inhibitors, being able to do.
That's what we're focused on early development, monotherapy, fulvestrant, and CDK4/6, and then go from there.
Thank you. As we're thinking about the clinical development, as we approach the phase I, how do you think about designing the dose escalation cohorts?
I think, again, we have a number of biomarkers we can follow. It'll be, because it is a degrader and because it's a very potent degrader, sub-nanomolar, we think that our initial starting doses would be in a pharmacological range, just based on the preclinical data so far. If that's the case, that we would actually potentially start incorporating backfills and fulvestrant combinations earlier in dose escalation phase, rather than wait all the way to finish the dose escalation and then start the combinations. That's what we're thinking. Again, we will be obviously guided by the data, which we don't have yet. That's our approach, to be able to really start to get the data, the combo data, sooner in the development, rather than wait for the entire phase I to complete.
Thank you. Just the degrader-antibody conjugate class as a whole, how do we think about this as a field moving and how it's differentiated from ADCs? Could you give us your views on it?
Yeah. Peggy, you want to take that?
I can start with that. We really think it's an exciting class and a really novel therapeutic approach. What it does is, we take a degrader molecule that's targeted to a specific protein and couple it to an antibody that's also specific for a surface antigen that's on a subset of tumors. That approach, unlike your standard cytotoxic ADCs, is really what we call our precision times two. You have precision from the payload being targeted as well as the antibody. We really think it's a novel approach. We've been doing this in collaboration with AbCellera for several years now and have really been able to successfully design the payloads and the linkers to optimize that degrader antibody conjugate.
The important point is that, by using a targeted payload rather than a cytotoxic, we think that we can have better tolerability and be able to move into patient populations that may not be able to be served by a standard cytotoxic agent. One of our examples of that now is our mutant CALR degrader antibody conjugate to SMARCA2 degraders, SMARCA2/4 degraders. We're again really excited about that approach to be able to deliver specifically a payload to, in this case, patients with mutant CALR.
Yeah, just to add to that, as this field is evolving, ADCs obviously are here to stay, and they've proven the important point that if you can deliver potentially a toxic agent for a tumor type selectively and specifically, you can really get very good efficacy and minimize the toxicity. Right? There's been a lot of innovation in terms of the antibody side, that are biparatopic, bispecific, different types of antibodies. There's a tremendous amount of innovation there. When it comes to the payloads, it's still really, we still are using the same, broadly speaking, the payloads that the field has used. Here is an opportunity to really bring in the payload diversity. Of all the classes of payloads that you could use, degraders are very well-suited, right? Because they are catalytic.
You don't need to be delivering huge amounts of molecule to the tumor cells. As a class, we see tremendous potential for degrader-antibody conjugates. As Peggy said, beyond just simply being specific to the tumor cells and then actually further reduce the toxicity, systemic toxicities, this approach actually makes it feasible to treat cancers or other diseases, actually, broadly speaking, that you couldn't otherwise target with ADC. We think that this is going to be a really exciting new class that is here to stay and we had the opportunity to be leading and shaping the way this class is going to evolve.
Great point. I think at ASCO, a lot of us saw that, the over 200 TROP1 payloads in development. I think a lot of us saw that slide. Now again, on the degrader-antibody conjugates, and I want to also make time for the mutant CALR.
Anything we should know about the manufacturing, and how you guys think about the manufacturing of them as a drug class, and anything to know about the safety there also? Thank you.
Yeah. Again, in terms of manufacturing, if anything, it should be simpler than your cytotoxic payloads and chemotherapy agents. Yes, there are some new chemistries that you need to bring to bear, particularly from the linker side, and even the payload side. We have the opportunity to now engineer different properties. Like if you want a high clearance or whether cell permeable or non-permeable payloads, thereby you're completely eliminating exposure to any cell, unless it is attached to the antibody. Those are the parameters that we can actually add to the profiles of these degrader-antibody conjugates. In terms of issues or challenges, the chemistries have to be solved, but beyond that, we don't really see anything else that would actually be problematic here. I don't know if you want to add.
No, I think Kris is right. I don't think we see any additional challenges. That does take a little bit more time in terms of the preclinical side and the tox studies for antibodies versus small molecules. Other than that, we don't really see any challenges associated specifically with the degrader-antibody conjugates.
Thank you. On that mutant CALR, could you talk to us about why you're excited about it?
Again, just keeping in the theme of our pipeline where we're really targeting validated pathways and looking for ways to make them better, drive deeper responses, better safety. In this case, in addition to deeper responses and better safety, we have the opportunity to really turn this into a truly patient-friendly population, which is patient-friendly formulation. This ET population is, really, they would be on this drug. They essentially normalize their platelets, right? That's what the idea is, and reduce the mutant allele burden. They have to be on it for potentially decades. The ultimate product need to be amenable to be self-administered by the patient. That's our view, and I think that is the view of other companies that are building these antibodies. The first-generation antibodies as good as they are, they inhibit signaling.
They don't necessarily kill the cells the way a degrader payload delivered to the cell could do. As a result, we think that they are going to end up with challenges of actually truly patient self-administered formulation. Again, this is early days, but we think that given the high potency and very low doses we anticipate needing with this degrader-antibody conjugate, we think this modality has the potential to be better.
Kris and Peggy, thank you.
Thank you.
Thank you very much.
Thank you very much for the.