Okay, my name is Peter Lawson. I cover Prelude Therapeutics and a number of companies in the mid-cap oncology space and I&I space. I am really pleased to have on stage with us Prelude Therapeutics CEO and founder, Kris Vaddi, and also Jane Huang, Chief Medical Officer. I guess first questions are really around kind of the macro and kind of the impact of the current administration, kind of your views on anything that could be disrupted in the supply chain as we kind of think about tariffs, etc.
Yeah, so I think, you know, I mean, at the moment we are kind of deer caught in the headlights situation. We just, you know, we're just dealing with all the things that are happening on a regular basis. As far as, you know, I'm aware, at the stage of the company we are, I'm not sure the tariffs themselves will be that impactful for us at the moment. Clearly, you know, being able to source the materials for our research and development, those are, we just have to see how any of these new policies are likely to impact. I think it's really early days to really know. From the regulatory standpoint, obviously there's going to be a lot of changes, but again, we just have to see what the, you know, what the policies are going to be as we, you know, as we get further into.
I just add, like, you know, as Prelude, we have anticipated some of this and tried to protect against it so that we have some manufacturing and the API all ready to go. We have thought about these implications and wargame those so that we are prepared. We do not think in the short term that it will have any impact on us as a company.
Did COVID kind of give a prelude to this essentially because of the supply chain?
Supply chain, FDA inspections, etc.
Yeah. Have you heard any worries about the FDA? Have you had a slowdown in any kind of communication with the FDA or any changes in those meetings?
We haven't had any recent interactions. Anecdotally, I haven't heard of anything. I know that they're retaining all the people that they need to make sure that drug development moves forward.
I know recently, just as recently as a couple of weeks ago, you know, there was a good representation from, you know, pharma CEOs to FDA making sure that they hear, you know, our points of view in terms of potential impacts if there were to be, you know, too many cuts or other things that are made because we really depend on FDA being able to give us the feedback on the things that we ask them for on a timely basis. We plan everything accordingly. We are very hopeful that the new administration, you know, is aware of our needs and hopefully any changes that might happen will take them into account.
Gotcha. Thank you. I guess a final macro question before we kind of bring it back to you and kind of maybe a few points that kind of frame the discussion. On NIH budgetary cuts, are there any kind of trickle-down effects that we should be worried about? You know, is that going to impact any of the projects you're running or even in clinical trial sites?
Yeah, I mean, from the clinical trial side, we're certainly watching what the universities are doing because we know that there's been some caution. At the same time, we are often independently funding most of the research. That has really had no impact in terms of that I can see directly from patient enrollment, etc., in the recent months. We've been trucking along as planned.
I would, yeah, I mean, for the short term, yeah, we have good plans. We are probably not going to be impacted. The one thing that is going to happen though, if the NIH, you know, experiences a lot of cuts, is there is a lot of fundamental research that actually supports our ecosystem, right? The reason why the biotech industry is as strong as it is in the United States is because, you know, of the groundbreaking research that they do and the symbiotic relationship that we have. I know from firsthand experience a number of friends who have been in academia who are funded by NIH are actively looking for jobs, you know, outside, are very concerned about, you know, the future. I mean, it is going to impact it, but it is probably going to be longer term than immediate term.
Okay. Thank you. Maybe before I dive into my questions, were there any kind of opening remarks you wanted to make or we can?
Yeah, no, absolutely. I just like to take the opportunity to thank you for this, you know, opportunity to participate. Just as an intro, Prelude Therapeutics is a clinical stage targeted oncology company developing novel first-in-class medicines for patients who really don't have effective options today. We built this team from scratch to be able to really discover and develop these agents, these medicines. The team is really pretty broad. Like we have exceptional medicinal chemistry, cancer biology, and clinical development capabilities. We're really developing various classes of therapeutics, degraders, allosteric inhibitors, and even precision antibodies because not every mechanism that is driving these cancers is amenable to a single line of therapy. We're not a kinase company or a technology company. We're going to spend, you know, obviously a lot of time in our lead program, which we're very, very excited about.
These are degraders that go after the SMARCA pathway that is really present in a very wide range of cancers, up to 5-10% of cancers. It's been well known that there are two members in this pathway, two and four, SMARCA2 and SMARCA4. It's been well known that this is important for cell survival. You know, cancers have somewhat co-opted this pathway. Many of them developed these SMARCA4 mutations. In fact, that allows us an opportunity to go after two because you need one or the other to selectively hit the cancer, right? That's really the idea here. While the science had been there and ideas have been there, it's really to have those molecules, small molecules that we can give to patients that actually can go after the cancers has been elusive.
We are really excited to be the first ones to advance not one, but two agents into the clinic, which we are going to talk about, 3789, which is an IV administered once weekly medicine that we advanced into clinical development in 2023. We have generated some really compelling and validating information in the clinic, including first clinical POC for this mechanism and really focusing on the tumor types where we have the best opportunity. We did not stop there. We recognize that there potentially is an opportunity for an oral therapy as well based on the patient needs, pathway, etc. We advanced the second molecule, 7732, into the clinic late last year. There has been great enthusiasm from investigators. It is a very high unmet need. These patients do not have other actionable mutations or other approaches.
We feel fortunate to be in a position to, you know, to advance these. In 2025, we're really focused on advancing these programs to key inflection points. The research is still going very strong. I'm excited and looking forward to potentially talking more about some of the things that we're doing in the research as well.
Gotcha. Thank you. As we think about your lead molecule, so 3789, the degrader, the IV version of it, kind of how much time does it take for these responses to deepen? As time goes on, do we see deeper responses? Just kind of your take on durability and the depth of those responses over time.
Yeah, so a little bit depends on the disease type. The esophageal patients that responded very early on to our IV, they had very brisk responses and they were PRs at the first scan. The lung cancer patients took a little bit longer. Over time we have one patient who has maintained their PR and slightly deepened their response for over eight months at this point. This is far and beyond what they had gotten from their prior therapy. We are seeing in those patients that have susceptibility to this pathway that those loss of function patients that we are targeting, that the responses are good and are exceeding what I might expect for this patient population, not just by responses, but by also durability and stable disease continuing on for quite some time.
Maybe you can have level status just on the patients where you've seen data so far, kind of what kind of response rates would you expect and where your response rates and likewise for the durability?
Yeah, so if you think about lung cancer in particular, in second line and beyond, docetaxel in all comers would be 10-15% response rate. If we extrapolate from what we know from the frontline experience with SMARCA4 mutations, those patients respond about half if you have a SMARCA4 mutation. In frontline, your overall response rate to chemoimmunotherapy is 40% if you're wild type, and it's 20% if you have a SMARCA4 mutation. If I were to extrapolate that to the docetaxel experience, 15% with docetaxel, half of that would be seven and a half. I would be expecting single digits in a phase one patient population in patients who have these SMARCA4 mutations.
Do you expect a typical dose response curve from the data as you dose escalate or?
I think the data that we've shown that is showing that we are having more responders at the higher doses. It is a complex interplay probably with between how much SMARCA2 you have in the tumor tissue, how much you're degrading, and at what speed you're degrading. The duration and depth of degradation are also important. We are seeing a dose response curve as we keep going, not only in exposure, but also having the extra responders show up. The gastric patient that we've added since the Triple Meeting as a responder, really they've deepened their response over time and they were at the 500 mg dose.
Gotcha. Thank you. As we think about these Class 1, Class 2 mutations, kind of what's driving the difference in those response rates?
Yeah, going in, we already knew that there were patients that did not have loss of function of the SMARCA4 protein. They were going to be less likely to respond. We wanted to understand the biology carefully and be able to dose escalate quickly. We have learned quite a bit. We know that, similar to the preclinical hypothesis, clinically you do need that loss of function in order to see activity.
Okay. The dose limiting toxicities, have you seen any so far? Kind of when do you think you'll get the recommended phase two dose?
Yeah, I'm really excited by the most recent data because we've basically shown that as we've dose escalated, we haven't seen any further toxicity. We had no DLTs so far. We only had one infusion-related SAE. This is very tolerable. That recapitulates our preclinical hypothesis that having that exquisite selectivity, that very good selectivity for SMARCA2 degradation will translate into a very good therapeutic index. You know, we are imminent, I would say, in deciding the dose. We are going to be meeting with our investigators to think about next steps and how we move the program forward for the IV.
Gotcha. Will you have to do Project Optimus two doses or do you think you kind of handle that with the dose escalation?
We would have to add some patients before registration, most likely. Sometimes people do it during your registration type trial. Those are the things we'll be considering as we move the program forward with the monotherapy.
Gotcha. Do you think you do get to the like a maximum tolerated dose or is there something very clear about the program?
We have not to this point. That is why I say we will be looking at the complex interplay between all the different factors to decide on our dose. Because at the end of the day, you do need to pick a dose. Seeing that we had responders and extra responder at 500 may not need to continue to push the dose higher and higher.
Because we may not, I mean, for certain pathways that you're really hitting, you know, a mutation or a genomic lesion, you may not ever get there, right? I think we're triangulating. We have all the information we need and we should be pretty comfortable with the doses we want to take forward.
How would you move it forward as regards to patients, indications, the class of mutation?
Yeah, so while I do believe that there's probably more tumor types that would be susceptible to this pathway and are dependent on this pathway, we know from our clinical data the lowest hanging fruit right now is the upper GI and the lung cancer patients. What we need to do is also because we have the additional oral that's in the clinic, think about which is the most expeditious way to move forward. There's probably multiple different considerations, whether or not we wanted to do IV for things like esophageal cancer where patients might have more trouble swallowing pills. That might be one pathway. You save the oral for lung cancer. There are many different permutations we are iterating and then we'll see where the data drives us.
When is the next data update we should expect?
We've disclosed that it'll be the second half of 2025.
that a medical conference or?
Medical conference.
Okay. Perfect. What's the kind of internal benchmark you need to move forwards?
Yeah, so as I mentioned, like the docetaxel, if standard of care would be single digits, I think in the 20-30% range would be extremely interesting.
Perfect. Thank you. Just on the IV combination, kind of where are you in that process?
We're very close because we were, again, we try to keep learning as we conduct our trials. As the it's at 500 mg in combination, the monotherapy was 665. It is very close behind. We will give an update on the activity at also second half. We just presented at GSMO that again, the safety profile is very clean. The only things we've seen are mainly docetaxel related adverse events, which is like the neutropenia, some fatigue.
Okay. And you know, just broadly speaking, the combinability is really a very, very important aspect in cancer drug development. So many drugs, you know, you couldn't dose them high enough in combinations because of overlapping toxicity. And having an agent that actually can be readily combinable gives us additional options in the way we think about developing this agent.
Gotcha. Have you seen a dose response there or do you expect to see a traditional dose response? Do you get increasing number of dose interruptions as you go up in dose?
If you look at our data, we haven't really seen any related dose interruptions other than it's almost the same as what I described at ENA. It is the same. There was one fatigue, one AST, one ALT in the patient that had liver met. The profile that we just presented is very similar. We haven't seen with increasing doses, more dose interruptions per se.
Do you think activity is additive, synergistic, or somewhere in between?
Preclinically, the chemotherapy with docetaxel has synergy. That is why we're very pushing forward the docetaxel combination because our preclinical model thinks we can even derive more benefit.
Yeah. Okay. Maybe if we can move on to the oral degrader, does that ultimately just replace the IV or how do you think about moving forwards with these two?
No, I think we're just going to at this point in time, you know, again referred to this earlier, there may be an opportunity for both. You know, we are learning about how oral could be better, right? If by giving it daily, if you're able to drive the target down to much, much more deeply than IV, you may see better responses, in which case in certain cases we may just go with oral. Whereas in other cases where if you just simply cannot give oral, esophageal or others, you may need IV therapy. I think we'll let the data help us defining which direction we go.
There's a difference in the degrader that's used between the two, is that right?
They're different molecules. One's a cereblon based, which is the oral, which is typical, and one is VHL based. That also is a different variable. We don't think that's going to affect the activity per se. It's just it's a different molecule.
That allows it to be either oral or IV or there are other kind of additional components that you get from switching the degrader.
Go ahead.
No, it's just that that's VHL ones are harder to give orally. Sorry, go ahead. My throat is not.
Yeah, so you can't get the oral bioavailability that you needed with the VHL. It was really we needed to switch to the cereblon, which is typical for degraders. Most of the oral degraders are cereblon based.
Gotcha. Okay. Kind of how's enrollment proceeding and kind of where are you for like backfilling various different cohorts?
We are not, we have not yet disclosed where we are with oral. What I've said is I'm very happy with how it's going. I have a good team that executes well. Really, the investigators remain highly enthusiastic about this pathway given what we have shown with the IV. The oral is going well and we will share a little preliminary data toward the end of this year.
Do you think from your experiences have the same therapeutic window or different as you look at those IV versus oral?
I think it is recapitulating what we had said from the preclinical work. We are really happy with how that's playing out in the clinic.
Gotcha. With like a few minutes left on the clock, I just wanted to touch upon the antibody degrader platform and kind of where you are and kind of when we start to see Phase I trials, what they look like and what you want to achieve with those.
I mean, first this is really first we all have to acknowledge this is entirely new modality, right? It's required. We formed the collaboration with Absci in 2023 to go after initially, you know, to extend the reach of SMARCA2/4s beyond just these cancers with these mutations. It required engineering super important two folds and attaching them to the antibodies. The team has done a phenomenal job. We presented some preclinical POC last year. Both Absci team on the antibody side and our team on the degrader side are working very well together. We hope to make some announcements in terms of where we are towards the clinical programs sometime this year. We're working very closely with Absci. In terms of timelines, as you know, these ADCs have longer lead times because we just have to make the cell lines and the antibodies, etc.
As we get closer, once we declare the development candidate, we'll be able to give some more clarity around the timelines for that. SMARCA2 is only one of several degraders that we're currently planning to arm the antibodies with. The team has some really exciting ideas that we are advancing. It is clearly an area for ADCs for the next generation, you know, to sort of circumvent some of the payload-related resistance pathways, you know, payload-related toxicities that we currently have with the chemotherapy payloads. There is actually, as a field, a great deal of interest in that. We have the opportunity to have two, you know, highly technical teams working together to do this to really create a leadership position. We are very excited about that.
Now, is that something you go your partner to take forwards or?
The Absci relationship is that we are 50/50 partners in this. The economics are shared. We are responsible for the payload side of things as well as the clinical development and regulatory aspects. Absci is responsible for the antibody side of things. Teams work very, very closely all the way from the sort of ideation, you know, through development.
Okay. Gotcha. Just in the sense that it's a very broad platform, so I'm just curious if there must be plenty of ideas coming out. Would that potentially drive in a partnership between your partners?
Yeah. You know, there is, you know, in this capital environment, you know, obviously we are going to be looking at every possible way to continue to resource these programs, right? Because at this cost of capital to be able to do what we need to do is challenging, as you can imagine. There is a lot of interest in the research we're doing. We are evaluating opportunities to potentially, you know, create partnerships around the platform as well.
Great. Thank you so much. It was a pleasure chatting. Thanks for your time.