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Okay, awesome. Let's do our next session. We have Prelude Therapeutics. My name is Gautam Chukar. I'm a biotech analyst here at Shorin Capital. And on stage with me, we have Brian Lim, CFO of Prelude Therapeutic and Peggy Shroll, CSO, Prelude Therapeutix. Thank you guys for joining. Thanks, Brad. Okay. So we have about 15 minutes or so, actually, maybe less. So let me just jump into it, right? So you had a very interesting last year or so, right, with the SMARCA program, you know, shelving and then moving into the CAT6A and then the 617F pocket that you found. Also the NCALR story, which is evolving and very interesting. Just frame us through what happened and what is the next 12 to 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 CAT6 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 Chris our founder and CEO we have been just focused on execution making sure that we're able to advance Jack into the clinic which we did in the second quarter of 2026 advancing cat6 as fast as we can for breast cancer and having that program in the clinic of which we just had the IND clear for and we anticipate enrolling fairly soon, and then advancing the MCALR program, which is an important target for the MPN community. In terms of the next 12 to 18 months, it's really going to be marked in two halves. The first half is we're going to have clarity, if you will, on whether or not Insight will exercise the option, and that should give us, if the option were to be exercised, is $100 million in non-dilutive financing. Number two, by the second half, or in the second of half of 2027, we anticipate revealing initial proof of concept data for our Cat6 deGrader program, which as I suggested a minute ago, is just entering into the clinic shortly. So I hope that gives you a little bit of a sense of where we are in 2027 as well. Yeah, I'm really excited, you know, 2027 ahead. So maybe let's just start with the biology of it, Cat6. So tell us, like, you know, CAT6 is amplified in subset of breast cancer, right? How does it drive HR-positive breast cancer? And what has Pfizer shown? And how are you guys, what is your approach that's different? Yeah, I can start with that. So with the CAT6 biology, it's pretty clear that CAT6A is amplified in ER-posative breast cancer and being amplified and overexpressed. It really drives the whole estrogen signaling biology as well as MEK 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-positive breast cancer monotherapy responses of about 10 percent, and especially in combination with fulvestrant, they have responses in the mid-30s, and then progression pre-survival of, you know, 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 CAT6 targeted therapies target both CAT6A and CAT6B, and they're inhibitors. Our's is very different. OUR's is a CAT6a selective molecule, and we're a degrader. And we think that's important for a couple of reasons. One is, We think by targeting Cat6A selectively, because it drives the tumor biology, and sparing Cat6B, which has a role in bone marrow development, that we could have a greater therapeutic index. The main dose-limiting toxicity observed with the Pfizer compound is utropenia, and 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 Cat6a and Cat6b 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 thousand-fold selectivity and we think that's really important Yeah, I was gonna ask about the you know degraded degradation versus inhibition strategy, right? You know, you probably got this a lot too for the SPARCA program back when you're developing that 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. CAT6 is part of a complex. And so 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. So we think both of those really are benefits from a degrader approach. So how confident are you that sparing CAT6B will actually solve the neutropenia issue? Because I think CAT6A is also involved in the bone marrow and cell making process right now. Yeah, there were preclinical data from a few years ago that if you knock out both CAT6a and CAT6b, the bone marotoxicity is much more severe. Whereas if you spare one or the other, you can really mitigate that. And we've seen that in our preclINICAL models with the CAT6 a selective degrader that we have less effects on neutrophils. So we hope that 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 neutropinia as a dose of toxicity, and really move into the front line, which none of the inhibitors, which we think are likely very similar to the Pfizer drug that inhibit both family members, we that will be limiting for them. Perfect. So maybe put the preclinical data and your clinical strategy into perspective, right? So clearly, my study shows that you shrank the tumor and Pfizer just stopped the growth, right. So put that into context. And why would that translate, in your opinion, into humans? Yeah, I mean, you know, as we all know, you have to do the clinical study to know that the pre-clinicle biology and the models translates. But I think our data in PDX and CDX models that we get those complete regressions at doses that, you know, just cover the CAT6A 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-positive breast cancer, like CDK4-6 inhibitors, SIRVs, VI3 kinase inhibitors. We combine really well with that across all those different mutations. So, you know, we're really encouraged by the preclinical data. But, you now, 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 fulvestrin. So, you know, we're really looking forward to starting that study very soon. Okay, perfect. If you look at, like, Pfizer and OMS drugs, right, they both hit cat sticks almost fully, inhibited them, right? But you only get, like 10% monotherapy efficacy. So 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 CAT6-targeted agents hit both A and B, and at least OLEAMA and Pfizer seem to have similar data in terms of that response. You know, I think a degrader approach can, in theory, buy you better activity. Again, we see that preclinically where we have regressions, very deep regressations in multiple models where the inhibitor just doesn't show that. So we think there's absolutely the potential. The other thing I think, you know, with the Pfizer drug being limited by neutropenia, they have to reduce the dose and give holidays in over 50% of the patients. So if we can mitigate some of that toxicity and have patients stay on longer at an active dose, I think that could, of itself, give you better efficacy. Yeah, I thing your answer basically probably covers my next question, but I'll ask it, right? So Pfizer and all these other guys, they're probably ahead of you. Pfizer probably is going to reach the market before you, and every other cat sex is going into combo therapy. So what is your strategy to differentiate? Is it basically what you said, like 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 CDK-4 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. So 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. And that's really where the opportunity is in the combinability. And just remind me, where is the program right now? Is it in clinical stage and moving forward? Yeah. IND just cleared, and we hope to be in the clinic very soon. Okay, awesome. All right, so let's move to the 617F program. It's really cool. What is your secret sauce? Inside just couldn't crack it. They canceled it. They shut the program down, right? So what have you done? What is the GH2 binding pocket? How is that unique? Yeah, so we used structure-based design and a lot of MedChem effort to really reach into that, what we call the deep pocket, where the B617F mutation resides. And that phenylalanine, the F, along with two others, really hold JAK2 in an active confirmation. And by reaching into that pocket, we can reverse that and lead to an inactive confirmation. So that was really our approach. And 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 Insight, 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. So based on our preclinical data, we think that we've been, you know, able to achieve the potency and selectivity to effectively hit the mutant target. And then in terms of the selectivity, right, so I think Insight said about 5x selective for their inhibitor, and then you're about 10x or so. And there are a bunch of other, you Know, companies, Cogent and Eliant, 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 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, and 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. So 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 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. So thank you so much for joining. Thanks for having us. Yeah, cheers. Thank you. Thanks. Yeah, I'll be back.