Thanks so much. My name is Peter Wilson. I'm one of the biotech analysts at Barclays, and welcome to Barclays Global Healthcare Conference in Miami. Up on stage with me, we have management from Prelude. We've got the CEO, Kris Vaddi, and the Chief Medical Officer, Jane Huang. Kris, you're going to give a brief introduction to the company.
Thank you. Thank you, Peter, for the invitation to participate in your conference. For those of you who are new to, in the audience, that are new to Prelude, we're a precision oncology company developing highly impactful medicines for patients with first-in-class or 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've previously discovered, developed, and delivered very impactful medicines. We're very proud of the team that we put together at Prelude. Our two lead clinical programs, which we talk a lot about today, is our first-in-class SMARCA2 degrader that is currently, you know, in dose escalation as well as our highly selective and potentially 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 a 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. The discovery engine, 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 precision ADCs, we call them, which initially will be used in degrader antibody conjugates, which we're excited about, to provide us, you know, the long-term opportunities to continue to discover and develop important medicines for patients who, you know, got hard cancers.
Perfect. Thank you so much. Lots of questions around the SMARCA2, CDK9, of course, and the DAC platform. I guess initial questions on the SMARCA2 degrader. We've got initial proof in the second half, kind of how's the moment they're in there and, where are you in that dose escalation?
Yeah, I'll let Jane,
Yeah, just to remind everybody that it's our phase 1 is a typical phase 1 with a dose escalation and a patient 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. The investigator 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. Thank you. And kind of, when do you expect to see activity as a particular dose cohort, where you feel you're at a kind of inflection point?
Yeah. You know, 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, and beyond, and in the backfill cohorts as well.
Then how many cohorts do you think you would eventually need? Is it kind of predetermined, or you can keep on escalating?
Yeah. Well, we have the good problem, I guess, of that we are 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 and any plateau. And of course, we would stop if there were any safety signals.
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 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 first-line population, we are seeing that patients that harbor a SMARCA4 loss of function have a response rate of about 20%. And that's in the front-line 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're trying to see response rates in that ballpark, north of 15%.
Is there any bias towards the PD-L1 low population?
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, that's data that we're continuing to keep, correct and explore.
Have you, set any exclusion criteria around PD-L1 low, high to get the best?
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 one mutations and class two?
Yeah. So just for the audience that might not be as familiar with class one and class two mutations, class ones 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 two can be missense, so the protein might be interesting. 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 we're seeing and tumor regressions we're seeing in patients or tumor samples that had class one mutations.
Yeah, and just to add to that, you know, the science around this SMARCA2 and SMARCA4 had been, you know, around for a long time, okay? And many companies have been trying to target this because of that, you know, what Jane discussed in terms of these mutations can render complete loss of protein. And then if you take the other one out, you can potentially be synthetic 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 which have not been as well studied, and the teams are trying to understand those, and they fall in the class two category. And so there's a lot of science that still needs to be done here.
It's still early days and, you know, oftentimes until you have a drug that you can really give to these patients, there's less incentive to study, you know, what it is, because there's really nothing you can do other than just understanding. So I think, you know, we have this real opportunity to first, you know, kind of reproduce the broader five published data in our own patients, in our own cohort, and ask the most important questions, which of these mutations that make them sensitive to this, you know, particular modality.
And again, your earlier question about the preclinical and predicting the clinical. I mean, we wanna advance these associations and this phase of the development to take out this mechanism, this protein, as much as possible and as long as possible. And you know, if the safety allows it, I think we would have that opportunity to do that.
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 a deep crosswalk between doses?
Yeah, I subscribe, and maybe Jane can add. So when we launched this program, right, we recognized that this is something that, you know, has been of great interest of a lot of drug developers, but also very challenging because they're very, very similar proteins. So we set out a sort of a strategy where we would use different types of ligases to degrade, because we, 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 the 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, you know, if this is an area of importance to patients, and we had the lead, we wanted to make sure that we had the best molecules in our, you know, in our portfolio. We're very pleased with the progress team had made on the orals, which we, as I said, we'll be bringing to the clinic later this year. And, you know, these cancers will require different types, different levels of inhibition.
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 neo-adjuvant, adjuvant settings. So we see an opportunity for both molecules.
Thank you. Combination studies, when do those start, and those use the, the obvious candidates?
Yeah, so we recently, and it's available on ClinicalTrials.gov right now, that added a docetaxel combination to our phase 1. And that's looking at the combination of docetaxel in the standard doses with the, in a typical kind of phase 1b study. And the rationale behind that is that we believe that there is synergy between having two different mechanisms towards cell death. And we've shown that in our preclinical models, that combining the two 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 off. 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-2024.
Interesting. Okay. So, and that would be kind of a handful of patients, or?
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.
Beginning of the year, we said that, you know, we plan to start that combination as half, and but at least to see the level of interest and team already got that going. So, so we are on schedule. We're on track to be able to, you know, to, to generate that data that's, I think, is very informative, for, you know, for this particular lung cancer patients where, you know, ultimately, you know, these patients and, you know, these drugs are used in combination. So, so it's an important part of our phase 1 program.
Thank you. And then on the CDK9, with clinical data in the second half, and how's the enrollments going there, and where are you in the dose escalation?
Enrollment is going quite well. Just to remind people, we had a full solid tumor phase 1 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 towards 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 mid-year, as well as presenting towards the latter half of the year with some information both on monotherapy as well as in combination.
How much data should we expect in the second half? And then I guess, what is it, predominantly AML that you'd expect?
Yeah. 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 CDK9s 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 you know, 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.
The B-cell malignancies, would that be specifically follicular or?
We're enriched for DLBCL in the combination and aggressive lymphomas, but we are also looking at CLL mantle cell lymphoma.
Thank you. What's the, I know it's a different population, so what's the best way to think about the appropriate total 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 count 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%-30%, for these different disease types.
Thank you. Thank 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 leukemia malignancies, patients often, unfortunately... So overall survival is, can be as short as three months, for instance, in some of these diseases. And so we will be looking for a variety of the different endpoints to surpass that.
Okay. And there's other CDK9 programs. Would that be another way of kind of constraining what a good response looks like or?
Yeah. 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 the, that 30% range, in the multiply relapsed DLBCL patients when they were given in combination.
That was Astra or?
AstraZeneca.
Okay. The combinations that is kind of what you're gonna combine with a BTK inhibitor, you know, just BTK inhibitor to combine with, combining with zanubrutinib.
Yeah. So the BTK inhibitor, I'm partial to the one I developed, which is zanubrutinib, which actually also has five different indications at this time across. So 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 two degrader, our own, of course, thirty-seven eighty-nine, is to date, very tolerable. And so having that optionality with different combinations is very important, and it can really make the difference to improving outcomes.
I've got 20 seconds on the clock. So, this is the DAC approach with AbCellera. Is there a timing around the IND?
No, you know, we've announced the... Not yet. We've announced that partnership in November of last year. And, you know, 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, you know, high level of internalization rates and deliver, so deliver these to the tumor cells. So, at the moment, we are doing a lot of platform development and have, you know, we've said publicly that SMARCA4 degrader that is not selective for 2 would be a great payload for cancers that are beyond, you know, those that have SMARCA4 mutations. And so we're hard at work in building those molecules and evaluating them in various preclinical settings.
Of course, there would be cancers that, you know, that have halfway dysregulation, but don't necessarily have the SMARCA4 deletion. So that, I think, gives us an optionality to further extend the biology beyond what our IDMO programs can do. And the whole partnership is envisioned to have a portfolio of molecules. So, there's more to come. You know, we'll put the data out as soon as, you know, we think that that's a meaningful set of data.
Thank you so much. It was a pleasure, Jane. Thank you, Kris. Thank you.