Prelude Therapeutics Inc (PRLD) September 2026 Conference Transcript

Good morning, everyone, and thank you for joining the 2026 H.C. Wainwright 28th Annual Global Investment Conference. My name is Ahmed Mahmood, an Associate Research Analyst here at H.C. Wainwright, and I'm happy to welcome our guests for this fireside chat from Prelude Therapeutics, a biotech company developing precision medicines for cancer.

Joining us today are Dr. Chris Badi, Bryant Lim, who's the Chief Financial Officer, and the CMO, Dr. Peggy Shirley, the Scientific robson so thank you for joining us today and uh chris to get us started and for those who may be unfamiliar with the prelude story could you please provide us a high level overview yeah absolutely first of all thank you for the opportunity to to participate um in in the conference um prelude is a as you said is a precision oncology company uh we're clinical stage and we're advancing multiple differentiated programs uh against clinically validated targets now why is you know our patients with cancer need better therapies and we have the we have the team that we've built uh over the years uh that have tremendous amount of experience in discovering and developing novel uh molecules and we are uh really target uh centric and and modality flexible So given our technical capabilities and expertise, we don't need to be, you know, sort of a kinase or a degrader or any of the specific target types. We are able to go across multiple target types. And we really focus on mechanisms that are clinically validated, meaning that the biology is de-risked. And there is still a significant opportunity to improve upon what's out there. So our current pipeline is very much reflective of that. And I'll spend a couple of minutes going over that. But over the course of next 12 to 15 months, we have a number of very, very important data catalysts and potential value inflection opportunities. opportunities and we are laser focused on executing on uh on what's ahead of us um our lead program or the one that's farthest along is our uh v6 jack 2 v6 17f uh selective inhibitor uh it's a kinase inhibitor um and uh and you know the the space is mpns or myeloproliferative neoplasms where you know there is uh three of them and there's 200 000 patients in the u.s alone that have these disorders and the first generation molecules you know one of which we our team helped develop jackify uh they're good they are very effective from the symptom and other standpoints but they really are not very disease modifying right because they don't target the very mutation that is involved in driving a disease in majority of these patients. So, you know, that our team, based on our not only discovery experience, but understanding of the clinical problems that these patients face, developed a very interesting molecule that is currently in the clinic and we're enrolling patients. And we are going after both PD, a polycythemia vera, which is one of the, you know, the largest number of patients within MPNs, and as well as, you know, more serious disease called myelofibrosis. We can talk a little bit more about that. And our second program, a CAT 6A selective degrader, we just recently announced, we cleared IND, and we are about to start enrollment in the fourth quarter. And this is something that is very, very exciting in breast cancer, HR-positive breast cancer more specifically where you know we're seeing more and more oral surge that are actually coming in but really not meeting the goal of earlier stage therapies where uh earlier lines of therapy where you know you need to be active in all patients and not just only esr1 mutant or the specific population so cat6 emerged as a really exciting novel mechanism And the clinical data with Pfizer, Profetistrat, demonstrated very good response rate and PFS, but it comes with a significant hematological toxicity. And that's a problem because if you want to be able to, you know, deliver a drug with full dose intensity and combined with early lines of therapy, such as CDK4-6s, you need to be able to have cleaner hematological safety profile. And we believe our CAT6A, based on the, you know, biology, genetics, has the ability to really do that and significantly expand the opportunity to create value for patients across all lines of therapy. And so that's about to start clinical trials. And then the third one, which we are really excited about is, but still in the discovery phase, is our mutants, sorry, it's a mutant Cal-R degraded antibody conjugate. Again, it's a clinically validated target. The antibodies that inhibit the signaling of Cal-R receptor in ET or essential thrombocytemia, as well as MF, can have significant, you know, clinical benefit for these patients. but they appear to be primarily the benefits coming from type 1 mutations. So there are almost half of ET patients have non-type 1 mutations who don't seem to be benefiting just by signaling inhibition alone. So we developed a degraded antibody conjugate where we can deliver a very, very important payload that we designed to be safe and can really kill the disease initiating cells so uh we'll be you know giving a little bit more detail on that program relatively soon so you know basically we have these three assets that are uh that you know are going to be generating uh very meaningful data and have the opportunity to leapfrog the ones that are ahead of us and we have the capital to to advance these two key inflection points and so uh you know 2026 rest of 26 and 27 will be pretty exciting years for prelude

thank you so i think to start we want to focus on the uh 396 asset that you have so in the second half or of 2025 or in back half 2025 you enter into an exclusive option agreement with insight uh for your jack to uh v617 inhibitor asset uh 396. so can you explain the precise governance the trigger governance triggers and timelines dictating what insight must opt in and what capital inflections those triggers represent for your balance sheet yeah i'll start and i'll let bryant as cfo go through the mechanics of that uh the idea behind that option agreement is that

you know insight was uh was in the clinic with their lead jack to v617f inhibitor program but this this area is central to their strategy and uh and so we believe that uh you know they have the ability to develop this these assets you know well and so uh we entered into this option agreement where they can it's a time-based agreement where uh they can make a decision in terms of uh you know acquiring our entire program uh and so currently we are responsible for running the phase one trial of our lead program, 396, but if they opted it, they could take it over. Brian, do you want to talk a little bit about that?

Yeah, and just in terms of the mechanics, it was a $60 million upfront broken into two parts, $25 million in cash, $35 million in equity. As Chris just mentioned, there is a time-based option of about 15 months, of 15 months, not about 15 months, uh that expires in february of 2027 with a potential for a three-month extension so that would take you to may call it and that would trigger a hundred million dollar milestone payment then we move into the the milestones section of the agreement which is up to 775 million in milestones together with low single digit royalties on the back end yeah and just to add to that these milestones are primarily uh clinical and regular and regulatory they're not something sales based or a later stage got it thank you and uh speaking of insight so we we did this continued development

of their l5a program following comprehensive review of their data and prioritize next generation uh targeted pipeline and so given that disclosure is there any read through to the option agreement you have in place uh in your view uh no so there's two aspects to it right so one is uh one question that we often get asked is that is there any read through to you know because of the technical challenges issues that they had to our molecules uh an answer to that is no because we're fundamentally completely different scaffold completely different molecules it was not our program is not built on inside's you know chemical scaffold so there is no read through at all uh related to that in terms of um you know what insight might or might not do in terms of option exercise is um is really dependent on um you know their own progress with their programs and their need to have an and you know to have actually a viable molecule to go forward so um i don't think that in specifically that particular decision to discontinue has anything to do with you know what we're doing or what they might do with our program got it and so your phase one trial for 396 which started enrollment mid-2026 uh encompass high-risk polythemia vera and intermediate high risk mf so given the uh biological differences between the those mpn phenotypes how are you allocating your initial dose escalation cohorts and can you help set investor in our expectations around the early data release in first quarter of 27 yeah so we are in terms of the trial design uh these are enrolling patients in parallel so uh basically it allowed for the design itself have allowed for enrolling patients independent of you know each other right so if the pv patients so the trial is open anybody with who meets our inclusion criteria can be will be screened and if they meet our eligibility criteria they get enrolled if they're pv patients they go into the pv arm and if they're mf patients they're going to the mf arm and then once we establish that you know the safety of that you know that particular dose that we've moved to the next dose independently so there is really no you know like a company allocation of patients to one or the other it's just basically a role in parallel in terms of what we're looking for is is really you know our ultimate goal for this program the reason why we chose pv and myelofibrosis is that in PV, greater than 95% of patients have the V617F mutation, right? So that's an important, so you don't really even have to look for, you know, mutant positivity ahead of time. The second aspect of it is there's no approved TEL-JAC inhibitors in PV in frontline settings. So that represents a significant opportunity, right, for us. And so we look for complete hematological response rates, any symptom improvements, and change in the mutant allele burden are the ones that we are looking for, right, as key indicators of clinical activity. For myelofibrosis, these patients would have failed other JAK inhibitors because there's four of them approved. So you're basically looking for, you know, really see if we could actually demonstrate clinical benefits like spleen symptoms as well without the hematological toxicities that the first generation compounds have right that would be a win there got it and speaking of those readouts you already kind of touched on this but could you give us a little bit more color on what benchmark for each indication are and when you when it comes to decide whether or not to advance the program I mean the benchmarks are you know like not having hematological toxicity like the current the first generation compounds have and demonstrating uh demonstrating clinical activity uh like the ones that I described you know achieving complete hematological response rates and uh and spleen symptom benefits and movement of alien burden those are the ones that we're looking for um so um i think uh you know there is uh uh it's hard to come up with a benchmark when there is none that right now that that really can do that thank you so speaking of benchmark so it's a bit of a competitive state uh landscape right now so we have uh alien therapeutics on a radar

cogent as well as a statistic who has a platform for similar allosteric targets so could you explain the specific structural or PK properties that differentiate 396 from these other rivals sure so when we designed our compounds we really designed them to reach into that pocket where the V617F mutation actually resides.

And so we call it the deep pocket, and our chemistry effort was really to bind in there and basically touch that mutation. We don't think the other companies have that same binding feature as ours, so we think that's really unique and really important for getting that mutant selectivity.

And we've also worked really hard to build in the PK and other physical chemical properties of the molecule so that we can achieve target coverage of the mutant but spare the wild type so we think those are really differentiating features that we're taking into the clinic now to um to look for that translation got it thank you so late last week we uh the FDA cleared your IND application for 722 so your first in class oral cat 6a selective degrader for hr positive and a and her2 negative breast cancer currently there are around 13 cat 6a and b inhibitors in clinical development so could you explain to investors and to us why

selective cat 6a inhibition would be preferential to non-selective ab inhibition yeah let me start and then i'll let peggy explain the the biology of it so the fact that there's 13 companies wanting to do this tells you how exciting this target is right so but i think the key is that uh to our knowledge uh because i don't think there's a full understanding of how each of these molecules actually do but based on what we know they all are cat 6ab inhibitors dual inhibitors and that's because you know structurally and we are very very similar right so so we are the first one uh to actually and we've started down this path before Pfizer data even came out that there is a sound rationale for targeting a and sparing b uh to maximally engage this target and and avoid or improve the therapeutic window so so from that standpoint we think uh we think we have a really good opportunity here to uh to you know drive deeper biology and and target inhibition without being that dose-limiting toxicity and where patients have to dose-reduce to be able to stay on therapy. Sure.

So, as Chris mentioned, we really think there are two important ways we differentiate. We're CAT6A selective, and we're also a degrader. And in terms of the selectivity, there's strong preclinical rationale that CAT6A is amplified in a number of tumors and really drives that tumor biology, whereas CAT6B does not. However, they both contribute to bone marrow development and metopoietic stem cell development. And we think, and again, there's preclinical data that supports it, that by sparing CAT6B, you can have much less effect in terms of bone marrow toxicity as read out in the clinic as neutropenia predominantly and anemia. So we think selectivity buys you a much better therapeutic window when we have selectivity for CAT6A. We chose a degrader approach really for two reasons also. One is that the homology between CAT6A and B is very high. So with the degrader, you can have even greater selectivity because you're not only binding in the catalytic pocket, but you have the ternary complex to build that selectivity. It also buys you a tremendous amount of potency because of the catalytic nature of degraders. So, and thirdly, we know that when you degrade CAT6A, which is part of a complex, the whole complex can fall apart, which can give you the deeper biology, which is what we see preclinically. When we compare head to head in the preclinical models, we achieve regressions with our CAT6A selective degrader, whereas inhibitors tend to give more tumor stasis. So we think that's really important. And in terms of the safety, we see less effects on neutrophils in our preclinical models relative to inhibitors. So from both those standpoints, we think we're very differentiated.

Got it. That's a very thorough answer. So you touched on this a little bit about the safety. So the patient enrollment is slated to begin next quarter in Q4, 2026. So how should us and our other analysts benchmark initial safety and PK metrics against the non-selective inhibitors? And is there any particular go-no-go signal that you're looking for in order to advance into later trials?

Yeah, so I think the trial is set up to really ask three fundamental questions, right, that based on what Peggy just described. Can we really see as a monotherapy, you know, significantly differentiated, meaningfully different hematological toxicity profile? Because if we do, that kind of reads through to many of these other things not only combinability which is important right that and to be able to move to earlier lines of therapy so that's fundamental but also even at the at that line of therapy to be able to not have the dose reduced which happens in greater than half of the patients with Pfizer trial and that happens early so if we can actually see differentiator safety thereby being able to see differentiated efficacy in terms of timeline you know what we're just opening the trial uh you know in fourth quarter and uh our goal is to drive hard in we're being really specific to only hr-positive breast cancer and we're not waiting for or reaching the high you know recommended phase to do us to do combinations so a lot of these things will happen in parallel into 27. so we just have to see you know we've guided to uh initial uh early data release in second half of 2027 so so that's really what we're laser focused on and trying to drive to get there thank you we're running very low on time but i do want to ask about your dc uh construct just because they're so novel and exciting so could you tell us about the mechanistic rationale and what targets would be most suited uh for this type of approach thank you yeah so the one that we you know i i alluded to early on uh we're we're testing this in uh as a of the calar uh mutant calar positive uh mpns and you know those of you who are following calar uh field it's just also super exciting it's also going to be very very crowded just like any any interesting target class um so but a lot of those are naked antibodies right and what they do is they inhibit signaling of mutant calar selectively they don't inhibit wild type calar So, as a result, there's multiple mutations, so broadly classified as type 1 and then non-type 1. And it appears that these naked antibodies are very effective in type 1, not so effective in non-type 1. And it's shown in the clinical trials where you look at the mutant allele burden changes, they fairly stay flat with non-type 1, whereas they drop, right? So that is important for disease modification. So, what we've developed, because we've been working on this for a number of years now, where we can selectively deliver a payload that is safe, generally, right? So that only cells that actually see this payload through this delivery mechanism, which is the antibody, galore antibody, you know, would be susceptible. So here, we're trying to not just inhibit the signaling, but really eliminate the disease-initiated cells and and by doing so it should be equally active on all all cells all mutations we're also selected the antibody that actually has equipotent activity on all mutations other than type one so it is again like i said earlier stage but but it is an area where we think has the potential to be like really meaningfully better activity for patients with mpn over what what's currently out there or being in the development got it thank you it's an exciting uh year ahead of us

so i want to thank you chris brian and peggy for joining us today and i want to thank our audience for their attention and for being here today as well thank you thank you thank you