Prelude Therapeutics Incorporated (PRLD) Earnings Call Transcript & Summary

Great. Thank you so much. My name is Peter Lawson. I'm one of the biotech analyst at Barclays, and welcome to Barclays Global Healthcare Conference in Miami. And up on stage with me, we have management from Prelude. So we've got the CEO, Kris Vaddi; and the Chief Medical Officer, Jane Huang. And Kris is going to give a brief introduction to the company.

Great. Thank you. Thank you, Peter, for the invitation to participate in your conference. And for those of you who are new to -- in your audience that are new to Prelude, we're a precision oncology company developing highly impactful medicines for patients with first-in-class or potential best-in-class, really focusing on the patients with high-unmet needs. What really distinguishes Prelude is that the highly productive R&D team led by proven leaders who really discovered, developed and delivered very impactful medicines. And we're very proud of the team that we put together at Prelude. Our 2 lead clinical programs, which we talk a lot about today, is our first-in-class SMARCA2 degrader. That is currently in dose escalation as well as our highly selective and potential best-in-class CDK9 inhibitor both of which are at a very important phase of their development. We're excited about how they're doing in the clinic and really driving to deliver potential POCs on both programs this year and robust data sets. Behind that, we have a highly selective oral SMARCA2 degrader that we're bringing to the clinic in the second half of this year. And the discovery engines, discovery teams are very active and continue to build attractive pipeline. We've recently announced a collaboration with an antibody discovery company, AbCellera. And together, we are building a portfolio of traditional ADC, we call them, which is -- initially will be used in degrader as payloads, which we're excited about that provide us the long-term opportunities to continue to discover and develop important medicines for patients who are not well served.

Perfect. Thank you so much. Lots of -- lot questions around the SMARCA, CDK9 of course and pADC platform. I guess, initial questions on the SMARCA protein degrader. We've got initial clinical data in the second half kind of how's enrollment going there? And where are you in that dose escalation?

Yes. I'll let Jane...

Yes. Just to remind everybody that it's -- our Phase I is a typical Phase I with a dose escalation and [indiscernible] escalation scheme, and we are enrolling patients who have SMARCA4 mutations. And we are enriching with backfill patients who have known loss of function for SMARCA4. So where we will be is we're progressing really nicely through the different cohorts, really quite rapidly they investigate, their enthusiasm is very high. And we are currently in the sixth dose cohort. And we are planning to present our data from some of the backfill as well as the dose escalation in mid-2024.

Perfect. And kind of the -- when do you expect to see activity? Is there a particular dose cohort where you feel you're at that kind of inflection point?

Yes. Extrapolating a little bit from the preclinical work, it's expected that we should see a good level of protein degradation by the dose level 6. So we are looking forward to seeing that data as we enroll these patients into the 6 and beyond and in the backfill cohorts as well.

And then how many cohorts do you think you'll eventually need? Is it kind of predetermined or you can keep on escalating?

Yes. Well, we have a -- the good problem, I guess, of that we are so safe and tolerable. And so we are able to continue to dose escalate. Our goal is to dose escalate until we see that maximal protein degradation in any plateau. And of course, we would stop if there were -- earlier if there were any safety signals.

Got you. How many patients should we see in the second half?

We're planning to present more than 30 patients towards the end of this year.

Okay. Is there a kind of a benchmark for overall response rate? Or like what should we be honed in on and what's good, what's bad?

In terms of all the different tumor types, the most available information with patients that harbor a SMARCA4 mutation is in non-small cell lung cancer. There are several papers out there that really describe the epidemiology quite well. And in that frontline population, we are seeing that patients that harbor SMARCA4 loss of function, have a response rate of about 20%. We -- and that's in the frontline population, patients who have been treated with chemo immunotherapy. Our patients, of course, are a smattering of different disease types, but -- and are in second line and beyond. In second line and beyond an average docetaxel response rate is around 15% in lung cancer. And so we are trying to see response rates in that ballpark north of 15%.

Okay. Is there any bias towards PD-L1 load population?

Yes. We're the first in class for this SMARCA4 mutation. And so we are certainly learning a lot as we go along. The current databases that we're looking at show that patients that harbor a SMARCA4 mutation are predominantly PD-L1 low, although there can be the range. So that's data that we're continuing to collect and explore.

Have you set any exclusion criteria around PD-L1 low, high to get the...

We have belief that we will work regardless of your PD-L1 status in terms of -- what we're focused on is selecting patients for that loss of function, SMARCA4 mutation and missense mutations.

Is there expected similar clinical activity between Class I mutations and Class II?

Yes. So just for the audience that might not be as familiar with Class I and Class II mutations. Class Is are those that have been described as being purely loss of function, either truncating or missing the SMARCA4 mutation or I mean, SMARCA4 protein. The Class II can be missense. So the protein might be existing. There's probably a mix of whether these are just point mutations and whether or not they result in actual loss of function of the protein itself. There is preclinically, the responses were seen and tumor growth regressions were seen in patients that are -- tumor samples that had Class I mutations.

Got you. Okay.

Yes. I mean just to add to that, the science around this SMARCA2 and 4 had been around for a long time. And many companies have been trying to target these because of that, what Jane discussed in terms of these mutations that can render a complete loss of protein, right? And then if you take the other one out, you can potentially be synthetical lethal. So that's where we have most confidence and preclinical data in animal models, et cetera, further validates that concept. But there is a range of other mutations who have not been as well studied, and the teams are trying to understand those that they fall under Class 2 category. And so there's a lot of science that still needs to be done here, it's still early days. And oftentimes, until you have a drug that you can really give to these patients, there's less incentive to study what it is because there's really nothing you can do other than its understanding. So I think we have this real opportunity to first kind of reproduce broader by published data in our own patients, in our own data sets and ask the most important questions, which of these mutations that make them sensitive to this particular modality. And again, your earlier question about the preclinical and predicting the clinical we want to advance these dose escalations and this phase of the development to take out this mechanism -- this protein as much as possible and as long as possible. And if the safety allows it, I think we would have that opportunity to do that.

Got you. And you started with the IV formulation, you've got an oral formulation. Remind us on that strategy and then how do you make that transition? Is it kind of -- can you crosswalk between doses?

Yes, I can start and maybe Jane can add. So when we launched this program, right, we recognized that this is something that has been of great interest of a lot of drug developers, but also very challenging because they're very, very simple proteins. So we set out sort of a strategy where we would use different types of ligases to degrade because we thought that degrading is the best way to go about it. And we had both VHL and Cereblon-based degraders we built. And we started to drive the potency and selectivity, right? So 3789, our first compound, which is VHL based, really met a very stringent criteria of selectivity, preclinical safety and ability to degrade the target really well in animals and cells, et cetera. And we think that, that's a great molecule can go the distance all the way. But we didn't stop there. We continued our work on developing oral molecules because this is an area of importance for patients and we had the lead. We wanted to make sure that we had the best molecules in our portfolio. We're very pleased with the progress team had made on the orals, which we, as I said, will be bringing into the clinic later this year. And these cancers will require different types, different levels of innovation, we can't predict right now because this is first-in-class. But we see the IV program going all the way, and our program actually further adding to potentially in settings where IV is less frequently used like neoadjuvant or adjuvant settings. So we see an opportunity for both molecules.

Got you. Combination studies, when do those start? What dose is the obvious candidate?

Yes. So we recently, and it's available on ClinicalTrials.gov right now that added a docetaxel combination to our Phase I, and that's looking at the combination of docetaxel in the standard doses with -- in a typical kind of Phase Ib setting. And the rationale behind that is that we believe that there is synergy between having 2 different mechanisms towards cell death. And we've shown that in our preclinical models that combining the 2 improves -- is synergistic. So we are exploring that in addition to other combinations will be planned as well. There's another interesting combination potential with checkpoint inhibitors, where it's been seen preclinically to turn cold tumors hot. So we're exploring a variety of things. Right now, the docetaxel is in the protocol and hopefully, we'll have maybe a little bit of preliminary information in the presentation mid-'24.

Interesting. Okay. So -- and that would be kind of a handful of patients or...

So we just added it to the protocol. So we'll have to see how it goes. But at the same time, I do know that the enthusiasm is high. So -- and we're enrolling quite well. So we hope to see a reasonable number of patients.

At the beginning of the year, we said that we plan to start that combination in the first half. And we're very pleased to see the level of interest and Jane's team already got that going. So we're on schedule. We're on track to be able to generate that data that's -- I think it's very informative for this particular lung cancer patients, where ultimately these patients -- these drugs are used in combination. So it's an important part of our Phase I program.

And then on the CDK9, this -- again clinical data in the second half. And how is enrollment going there? And where are you in the dose escalation?

Yes. Enrollment is going quite well. Just to remind people, we had a full solid tumor Phase I that read out last year that was highly tolerable, had very few adverse events, no liver dysfunction and low rates of neutropenia. And that -- we took our learnings from the solid tumor and extrapolated over in terms of dosing toward the heme side. So we knew better where to start. It's enrolling quite well. In addition, in this protocol, we also have a combination with zanubrutinib. So we have guided that we will be approaching our dose selection midyear as well as presenting toward the latter half of the year with some information, both on monotherapy as well as with the combination.

Got you. How much data should we expect in the second half? And then I guess what is it predominantly AML patients you expect?

Yes. So the protocol comprises of predominantly B-cell malignancies. But you have alluded to, we also just added an AML cohort because there's some really interesting data externally with other CDK9 around AML as well as preclinically for us in combination with our own SMARCA2 degrader. So there's multiple different things we're looking at there, but we'll start with the typical dose escalation for AML as well. And we'll have our data through to dose selection and some number of combination patients as well to present in the latter half of the year.

In the B-cell malignancies, would that be most DLBCL or...

We're enriched for DLBCL in the combination and aggressive lymphomas. But we are also looking at CLL and mantle cell lymphoma.

What's the bar? I know it's kind of a mixed population. So what's the best way to think about the appropriate overall response rate?

Really, it's thinking about in -- as monotherapy, whether there's either evidence of tumor lysis, which has been shown with, again, other molecules that have been in development in the past, although we have learned from that and tried to have a more tolerable regimen, but seeing some degree of lymph node shrinkage or regression of this decrease in your lymphocyte counts in the case of CLL, all would be interesting for monotherapy, of course, there's post CAR-T, the response rates are really quite low. So seeing something externally that we've seen, which is from other data is a good benchmark is around 20% to 30% for these different disease types.

Got you. And then would we get any sense of like durability, I guess, is it too early or...

It's probably a little bit early, but also, I would say that again, in these multiply relapsed heme malignancies, patients often, unfortunately, sort of overall survivals can be as short as 3 months, for instance, in some of these diseases. And so we will be looking for a variety of the different end points to surpass that.

Okay. And now there's other CDK9 programs, would that be another way of kind of cross triangulating what a good response looks like or...

Yes. So there's other molecules that are not currently being developed by other companies, probably limited somewhat by some toxicity, but I can't speak to why the company decided to go one way or another. And they did see response rates in that 30% range in the multiply relapsed DLBCL patients when they were given in combination.

Then that was Astra or...

AstraZeneca.

Okay. Perfect. And the combinations that is kind of you're going to combine with the BTK inhibitor, what's the best BTK inhibitor to combine with? Or do you think about combining a degrader or just your approach there?

Yes. So the BTK inhibitor, I'm partial to the one I developed, which is zanubrutinib, which has actually also has 5 different indications at this time across, so it has a very broad label. And it's shown to be very safe and tolerable and with high specificity. So that is a good combination partner for us. In terms of the SMARCA2 degrader, our own, of course, 789 is to date, very tolerable. And so having that optionality with different combinations is very important and we think can really make the difference to improving outcomes.

Perfect. We've got 20 seconds on the clock. With the pADC approach with AbCellera, is there a timing around the IND?

No. We've announced the -- not yet. We've announced that partnership in November of last year. And we're excited about the progress we made because it is a completely novel chemistry and being able to conjugate these on antibodies that have a high level of internalization rates and delivers these degraders to the tumor cells. So at the moment, we are doing a lot of platform development and have -- we've said publicly that SMARCA2, 4 degrader that is not selective for 2 would be a great payload for cancers that are beyond those that have SMARCA4 mutations. And so we're hard at work in building those molecules and evaluating them in various preclinical settings. And our focus there would be the cancers that have pathway this regulation, but don't necessarily have the SMARCA4 deletion. So that, I think, gives us an optionality to further extend the biology beyond what our [indiscernible] programs can do. And the whole partnership is envisioned to have a portfolio of molecules. So there's more to come. We'll put the data out as soon as we think that that's meaningful set of data.

Perfect. Thank you so much. It's was a pleasure, Jane. Thank you, Kris. Thank you, Jane.