Peggy: really important for delivering a drug. So, yeah, so we've, as Chris mentioned, just filed the IND and are moving into the clinic.
Moderator: So I think by our count, we probably saw about six, maybe five to six other inhibitors, all targeting the V617F mutants. And so I'm kind of curious, right? Like one of those developers is actually Insight, and then they did a deal with you for your inhibitor, right? So they have their own inhibitor. They now have an option for your inhibitor. Clearly, there are things that are happening in the space that you're probably aware of. Can you help just maybe differentiate your molecule from the other competitors that are out there? And then maybe even while you're answering that, answer kind of why Insight would partner with you guys when they have their own inhibitor.
Chris: Maybe I'll just start and turn it over to Peggy. So again, one of the major breakthroughs in this field is really the elucidation of the structure of the domain. So naturally, that would lead to different groups trying to make molecules that would attack. So I'm not surprised at all that there are a number of companies making good progress, which ultimately is beneficial for patients. Again, having been involved in the discovery and development of Jackify, there's a lot of learnings in the clinic, in the preclinical stages that we really could use to guide the the discovery of our own molecules, right, doing head-to-head comparisons and et cetera, to really convince ourselves that not only we have the selectivity profile needed, but actually have the overall properties. And so, I don't know, you can comment on other molecules, but we just believe that we have a really good molecule that we think has the potential to really make a difference for patients.
Peggy: Yeah, and we saw the data that was presented at ASH as well, but we don't know a lot beyond that. A lot of the structures haven't been published, and really until you can do that cross-comparison, it's sometimes hard to understand the specifics of the molecule. But as Chris said, we worked really hard. We compared across multiple cell lines to get our selectivity. We looked in primary cells to ensure that that selectivity selectivity translated and also in vivo and built in the properties that we think make it a really good drug.
Moderator: So as we think about, you mentioned that the IND has been filed. You guys had your, you released your K today, and I believe you said that you'll be in the clinic by the second quarter. I think you're going to beat it, but that's just me. Can you talk a little bit about the clinical development plan? Right. What is this? What is this phase one study look like? What are the the efficacy and safety parameters that you will be looking at as you as you kind of, you know, state the.
Chris: Yeah, no, absolutely. So so we've thought long and hard and. We're fortunate enough to have the advice of some of the key opinion leaders in the MPN space that helped shape the development of many drugs that came out. And so the design that we ultimately ended up with is a parallel design. So some of the JAK inhibitors are being developed or were developed in myelofibrosis first, followed by others. Here we've taken a position of advancing the molecule 396 into both myelofibrosis as well as polycythemia vera. And the reason for that choice is PV, or polycythemia vera, is about, like I said, more than 90% of patients have the mutation. And this is a mutant selective inhibitor. So it made sense to do that. Similarly, myelofibrosis offers a rapid development path. So being able to do both of them in parallel and actually convincing FDA to allow us to do it, I think is a significant differentiator for us. And also the scientific reason and disease biological reason is that the doses that you need for a disease like PV where you have too many red blood cells, too many white cells, could be very different from a disease like myelofibrosis, especially if they are later stages, they've already experienced other JAK2 inhibitors. And so I think from a design perspective, that I think is a very important distinction, number one. Number two, we were also able to write the protocol in a way that would allow us to enroll the right types of patients and not have to come always behind a JAK2 inhibitor. So we're hoping that we could actually have some patients who could potentially be eligible for our trial that are not eligible for other JAK2 inhibitors that would allow us to study this drug in an earlier stage of disease. So I think that's important too. So we have the right investigators. You know, we have global travel, U.S., Europe, and Australia, and a lot of enthusiasm from the investigators. So we are very hopeful that we actually not only enroll the trial, but enroll the trial with the right patients that could give us meaningful information and early developments.
Moderator: So there's a potential for JAK-naive patients to... If they are ineligible, yeah.
Chris: If the patient is deemed ineligible for other JAK-2 therapies, then they can be enrolled into our trial.
Moderator: Perfect. Okay. And as we think about clinical data and readouts, is it possible that we'll get kind of early clinical data this year, or is this really like an early 2027 sort of event?
Chris: Yeah, it's hard to predict as we're just about to get started, so we'll just wait until we have some meaningful data. And maybe you also asked about why Insight as part of your question. So, again, you know, as we were thinking about the two programs that we had, both are very, very attractive, the CAT6 and JAK2, and looked at potential partnerships that we could do with either of the programs. Insight was a natural partner as they have a strategic focus on MPNs. They have their own program, but as they said publicly, that they are doing some additional formulations and they also wanted to. So they approached us and we thought that of the different things that we could do, it's a really meaningful collaboration. agreement with them that not only provided us the upfronts to extend our runway, but also has the potential to bring in a meaningful influx of cash should the program advance meaningfully.
Moderator: So before leaving this, I think I'd be remiss to not kind of explore your involvement in Ruck's development. So maybe very quickly, so a lot of people say, like, hey, I was involved in, you know, this development or that development, and it could be tangential. But I think it's very important for people and investors to understand this kind of going back to the roots approach at Prelude. How actually involved were you with Ruck's development? Sort of tangentially or, like, did you discover the molecules?
Chris: It's hard for me to speak about that, but I started the program. I was always very interested in the JAK-STAT pathway, and so I started the program, and Peggy led the pharmacology of the program at Insight. So we were involved all the way through advancing it into the clinic and through registration, made multiple discussions with FDA. So I would say I was pretty central to the discovery and development of JAK-STAT. Terrific.
Moderator: Okay. So with that, let's switch gears to CAT6, the CAT6 degrader. Can you talk to us about that target? Clearly there are other CAT6 inhibitors that are out there, right? Maybe how your molecule is differentiated and kind of what's the opportunity?
Chris: Yeah, I'll just start and then let Peggy. Peggy is a real expert in that space. But again, like I said, as we were looking at different ways of advancing our pipeline prioritization, Cat6 really struck out because we were already working on Cat6 before Pfizer announced their Cat6 AB inhibitor data in Alaska 2024. So we had the thesis that if you really targeted Cat6A, which is actually the amplicon, or the one that's amplified, and avoid B, you could have a potentially better safety profile. And we looked at the inhibitor versus degrader, and a lot of science went into, and thinking and data went into making the decision to go down that degrader path.
Peggy: Yeah, I think we decided on a degrader for really two reasons. One is it really allows us to build in the selectivity for Cat6A over Cat6B. We had seen that with our SMART-A program that, you know, you don't have to just have selectivity based on the binding site, but you can use the whole ternary complex that's part of a degrader to get that selectivity. And secondly, Cat6A is part of a complex, and we thought by degrading the protein, you could perhaps have deeper... responses because you're eliminating the protein. And it's a target where, you know, if you look at the Pfizer data, they really have to cover it around the clock. So I think for both of those reasons, we really thought a degrader approach was attractive for this. And as Chris mentioned, Cat6A is clearly driving the tumor biology. and Cat6B plays a role in bone marrow. So we thought by sparing Cat6B, we could have better tolerability, less bone marrow tox, and greater efficacy.
Moderator: And when I think about your preclinical work, right, and the work that you do prior to getting into the clinic, is there a comparison to, you know, like the Pfizer, right, CAT6 inhibitors and others that might be in development that you have to, you know, replicate in order to move your molecules forward?
Peggy: Yeah, we usually, if the structure of those other molecules are known, we try to do head-to-head comparisons in our own systems. We think that's the best way to really see how comparable we are. And with CAT6A selective degraders, we actually get regressions in all of the tumor models, whereas head-to-head with an inhibitor, it's more tumor stasis. So that is preclinically why we think that we could potentially have better efficacy in And on the same front, if we look at effects on neutrophils, which is what Pfizer is seeing in the clinic, right, the neutropenia, if we compare a dual inhibitor to a selective degrader, we see less neutropenia in the models. So preclinically, our hypotheses seem to be playing out.
Moderator: You'll be filing an IND by the middle of this year. How are you thinking about the clinical development program from a CAT6A degrader perspective? Are you a fast follower for Pfizer and their program? Do you go into different indications? Is there patient selection or biomarker selection in certain tumors? How should we be thinking about it?
Chris: So our hypothesis is based on what Pfizer has seen, right? Differentiating on efficacy and differentiating on safety in ER-positive breast cancer. I mean, there's potentially other opportunities beyond that, but we're currently focused on that, right? So we know what the neutropenia rates are with that dual inhibitors and what limitations that neutropenia rates pose, which is really getting into earlier lines of therapy, being able to combine with CDK4-6s, which also have the same side effect profile, right? So our clinical plan is really, because it's a degrader, We don't have to get to the concentrations, high micromolar concentrations that the inhibitors have to get because these are picomolar degraders. So we could be 104 lower plasma concentrations from them. And all the preclinical packets so far, we still have to wait for the final histopath data from the GLP-TOG studies. But so far, the data is supportive that they should have no worse inhibitors adverse event profile, generally speaking, and better hematological profile, right? Coupled with very low plasma concentrations, which in and of itself is an advantage, right? So we plan to go to the clinic in ER positive breast and rapidly do the dose escalation. We don't expect to need, based on what Pfizer has seen, too many dose cohorts. and go to Fulvestrin Combo, which is where there's a 35-40% response rate in post-CDK4-6 setting. But at the same time, we are actively working with experts to design our expansion cohorts where we could look at 4-6 combinations, which Pfizer has not been able to look at so far. I think that is something a priority for us to be able to run potentially. Fulvestrant for sure, because that's something that we can do at direct head-to-head comparison with the Pfizer compound, but also at minimum do a CDK4-6 combo to see if we can actually demonstrate that better tolerability.
Moderator: So as if you don't have an impressive enough pipeline, you also have a mute Cal-R degrader as well. Can you just maybe in a minute just kind of tell us what's happening there?
Chris: Yeah. So, you know, mutant Cal-R is sort of a hallmark of a certain fraction of ET, essential thrombocytemia, and myelofibrosis patients. It's expressed on the cell surface, where it is not expressed in wild-type Cal-R on the surface. So it gives you an opportunity to target with an antibody. And we've seen very compelling efficacy data from a naked antibody. So our idea, which we were also working on for a while, is to really have a degrader payload on it. And the reason why that makes a lot of sense, at least preclinically for us, is that without having to saturate all the mutant KLR that you need to do with the naked antibody to inhibit signaling, you can actually kill the disease initiating cells with minimal receptor occupancy because you're delivering a payload. And these payloads are extremely important on MPN cells. So it is an earlier stage program. It requires an antibody. There's multiple ways of differentiating from the previous, you know, there's lots of mutant calor antibodies that are going into the clinic. But we think that we are the, you know, this is an area where we focused on really building that know-how and expertise to create these degraded antibody conjugates. You know, we've announced a few years ago this collaboration with Abcelera that allowed us to build that know-how, that expertise internally, which we are able to leverage on this. And there's clear areas of differentiation from the first-generation CalR antibodies that we see in terms of having that up to 100x or more potency that allows potentially down the road subcutaneous patient self-administration that many KOLs actually like to see in a product for ET particularly. and being able to target all mutations and not only one of the two. So there are some real advantages, but we can talk about it more when we actually have a development candidate.
Moderator: Yeah. So I guess one of the questions, I'll just throw it out there, but you don't have to answer, is just how much data do you need before Insight acquires you? I'm just kidding. Leave it like that. Brian, you're here looking handsome as ever. Let me have you answer a question. What's the cash position at the company? You got $60 million from Insight. There's an option for an additional $100 million. Just kind of take me through how long this will last.
Brian: Sure. As you identified, we released our year-end results, and we announced $106 million. In cash, taking us into second quarter of 2027. That taking us into second quarter of 2027 does not account for the $100 million potential option payment. From inside.
Moderator: Excellent. Well, we've run out of time, guys. Thank you very much for coming. Really appreciate it. Thanks, Frank.
