Great. Okay, awesome. Let's do our next session. We have Prelude Therapeutics. My name is Gautam Chukka. I'm a biotech analyst here at Chardan Capital, and on stage with me, we have Bryant Lim, CFO of Prelude Therapeutics, and Peggy Scherle, CSO, Prelude Therapeutics. Thank you guys for joining.
Thanks for having us.
Okay, so we have about 15 minutes or so, actually, maybe less. Let me just jump into it. You had a very interesting last year or so with the SMARCA2 program shelving and then moving into the KAT6A and then the V617F pocket that you found. Also, the mCALR story, which is evolving and very interesting. Just frame us through what happened and what is the next 12- 18 months going to look like?
Sure. Great. Gautam, thanks for having us. It's great to be here. It was almost a year ago to the day that we announced a pivot of the company in which we were going to focus on three programs. The first being our JAK2, JH2 program. The second is our KAT6 degrader, and then third is the mCALR program. Each of these have one sort of thing in common, if you will, and each of them are clinically validated targets, and that really formed the basis of our pivot.
Since then, and as led by Kris, our Founder and CEO, we have been just focused on execution, making sure that we are able to advance JAK into the clinic, which we did in the second quarter of 2026, advancing KAT6 as fast as we can for breast cancer, and having that program in the clinic, which we just had the IND clear for, and we anticipate enrolling fairly soon. Then advancing the mCALR program, which is an important target for the MPN community. In terms of the next 12- 18 months, it is really going to be marked in two halves. The first half is we are going to have clarity, if you will, on whether or not Incyte will exercise the option.
Right.
That should give us, if the option were to be exercised, $100 million in non-dilutive financing. Number two, by the second half or in the second half of 2027, we anticipate revealing initial proof of concept data for our KAT6 degrader program, which, as I suggested a minute ago, is just entering into the clinic shortly. So hope that gives you a little bit of a sense of where we are in 2027 as well.
Yeah. No, really excited, 2027 ahead.
Thanks.
Maybe let us just start with the biology of it, KAT6. So tell us, KAT6 is amplified in subset of breast cancer, right? How does it drive HR+/HER2- breast cancer, and what has Pfizer shown, and how are you guys, what is your approach that is different?
Yeah, I can start with that. With the KAT6 biology, it's pretty clear that KAT6A is amplified in ER+ breast cancer. Being amplified and overexpressed, it really drives the whole estrogen signaling biology as well as MYC regulation and cell cycle genes. So it really has a strong role in driving breast cancer growth and survival. I think the Pfizer data has really validated that. They see in ER+ breast cancer monotherapy responses of about 10%, and especially in combination with fulvestrant, they have responses in the mid-30s.
Yeah.
Then progression-free survival of 10, 11 months. So it's pretty striking data. Ours is a differentiated approach to build on that. Pfizer as well as Olema and maybe 10 more KAT6-targeted therapies target both KAT6A and KAT6B, and they're inhibitors. Ours is very different. Ours is a KAT6A selective molecule, and we're a degrader. We think that's important for a couple of reasons. One is, we think by targeting KAT6A selectively because it drives the tumor biology, and sparing KAT6B, which has a role in bone marrow development-
that we can have a greater therapeutic index. The main dose-limiting toxicity observed with the Pfizer compound is neutropenia.
Yeah.
So by sparing KAT6B, we hope to improve on that. The other point with the degrader, it really allowed us to have selectivity. All of the inhibitors target both KAT6A and KAT6B because that binding pocket is so similar. With the degrader, we can use the whole ternary complex to build what we show is greater than a thousandfold selectivity, and we think that's really important.
Yeah, I was going to ask about the degradation versus inhibition strategy. You probably got this a lot, too, for the SMARCA2 program back when you were developing that.
Yeah.
Is that just mainly for the selectivity part of it, or could it also drive steeper efficacy?
Yeah, it's twofold. One was selectivity, but you're absolutely right. KAT6 is part of a complex, and when you degrade it, that whole complex falls apart, and we think that does give us deeper biology. We've seen that in all the preclinical models where we can achieve regressions, whereas inhibitors are more tumor stasis. We think both of those really are benefits from a degrader approach.
So, how confident are you that sparing KAT6B will actually solve the neutropenia issue? Because I think KAT6A is also involved in the bone marrow and cell-making process, right?
Yeah. There were preclinical data from a few years ago that if you knock out both KAT6A and KAT6B, the bone marrow toxicity is much more severe, whereas if you spare one or the other, you can really mitigate that. We've seen that in our preclinical models with the KAT6A selective degrader, that we have less effects on neutrophils. We hope that allows us to reduce the neutropenia in the clinic. Again, we think that's important. It allows us to combine with CDK4/6 inhibitors that also have neutropenia as a dose-limiting-
Right.
toxicity and really move into the frontline, which none of the inhibitors, which we think are likely very similar to the Pfizer drug that inhibit both family members, we think that will be limiting for them.
Perfect. So maybe put the preclinical data and your clinical strategy into perspective. Clearly, the mice study shows that you shrank the tumor, and Pfizer just stopped the growth. So put that into context, and why would that translate, in your opinion, into humans?
Yeah. As we all know, you have to do the clinical study to know that the preclinical biology and the models translate. But I think our data in PDX and CDX models that we get those complete regressions at doses that just cover the KAT6A target and lead to its degradation, are really compelling. And I think our data, in combination with all of the standard of care agents used in ER+ breast cancer, like CDK4/6 inhibitors, SERDs, via PI3Kα inhibitors, we combine really well with that across all those different mutations. So, we're really encouraged by the preclinical data. But we'll test it in the clinic. The protocol is set to look at three things: monotherapy activity, the safety, and then early combination with fulvestrant. So, we're really looking forward to starting that study very soon.
Okay, perfect. If you look at Pfizer and Olema's drugs, they both hit KAT6 almost fully, inhibited them. You only get 10% monotherapy efficacy. Is that a biology problem, or is this the efficacy where you can degrade it and therefore drive it further?
Yeah. I think, again, it's probably twofold. Olema, Pfizer, and all of the other KAT6-targeted agents hit both A and B. At least Olema and Pfizer seem to have similar data in terms of that response. I think a degrader approach can, in theory, buy you better activity. Again, we see that preclinically, where we have regressions, very deep regressions, in multiple models where the inhibitor just doesn't show that. We think there's absolutely the potential. The other thing, I think, with the Pfizer drug being limited by neutropenia, they have to reduce the dose-
Right.
and give holidays in over 50% of the patients. If we can mitigate some of that toxicity and have patients stay on longer at an active dose, I think that could, of and in itself, give you better efficacy.
Yeah. I think your answer basically probably covers my next question, but I'll ask it. Pfizer and all these other guys are probably ahead of you. Pfizer probably is going to reach the market before you, and every other KAT6 is going into combo therapy. What is your strategy to differentiate? Is it basically what you said, no dose holidays and that sort of tolerability angle, or how are you positioning your differentiation in the market?
Yeah, I think what we're trying to show is that we do have better tolerability and that we can combine, as I mentioned, with CDK4/6 inhibitors or CDK4 selective inhibitors that also have neutropenia as a dose-limiting toxicity. We don't think that Pfizer can go there. I think they've tried and haven't been able to, and all of the other ones that are dual inhibitors like that will likely have that same issue. Our goal is really to be able to combine with CDK4/6 and move into frontline, whereas the others may be limited more to second and third line.
That's really where the opportunity is-
Right.
in the combinability, yeah.
Just remind me, where is the program right now? Is it in clinical stage? Is it moving forward? What-- Yeah.
Yeah. So we
I-
Go ahead.
IND just cleared, and we hope to be in the clinic very soon.
Okay, awesome. All right, let's move to the V617F program. It's really cool. What is your secret sauce? Incyte just couldn't crack it. They canceled it. They shut the program down. So what have you done? What is the JH2 binding pocket? How is that unique?
Yeah. We used structure-based design and a lot of med chem effort to really reach into that, what we call the deep pocket, where the V617F mutation resides. That phenylalanine, the F, along with two others, really hold JAK2 in an active conformation, and by reaching into that pocket, we can reverse that and lead to an inactive conformation. That was really our approach. We've been able to show potent and selective compounds that have the appropriate pharmacokinetic properties to hit the mutant, but spare the wild type and have that therapeutic window, which was really the premise of the whole program. I think Incyte, as they reported, really struggled with being able to achieve the PK profile to do that. They tried different formulations and really struggled, I think, to do that.
Based on our preclinical data, we think that we've been able to achieve the potency and selectivity to effectively hit the mutant target.
Then in terms of the selectivity. I think Incyte said about 5x selective for their inhibitor, and then you are about 10x or so. There are a bunch of other companies, Cogent and Eli Lilly. I don't even know if I'm pronouncing it correctly. They have 170x and 500x. These are different assays, et cetera. But on a cross-comparison basis, what is the right way to look at it, and what is the minimum required for you to show efficacy?
Yeah, I think it's really hard to judge, and they haven't released the structure, so we can't cross-compare. You're absolutely right. Many people use one mutant cell line and one wild-type cell line to derive those selectivities. We really tried to do it across a panel of wild-type cells and mutant cells to get that 10x. If we chose the most potent mutant cell line and the weakest wild type, we would also have 100-fold selectivity. So I think it's fairer because you'll have variability across patients to use a range of cell lines in both. That's really how we view the selectivity. I also think the selectivity, it's two ways. It's your PK, how flat your profile is.
Yeah.
with your selectivity. If you have a flat profile, which is what we think we'll have, then that tenfold is more than enough, rather than having a high peak where you need more selectivity.
Perfect. I have a bunch of other questions, but I think we're at time, so we'll probably connect again. Thank you so much for joining.
That's great. Thanks for having us.
Yeah. Cheers.
Thanks.