Prelude Therapeutics Incorporated (PRLD) Earnings Call Transcript & Summary

Good morning, and welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have Prelude Therapeutics with CEO, Kris Vaddi; and CMO, Jane Huang. Welcome, Kris and Jane.

Thank you, Jeff, and thanks for the opportunity to participate in the conference.

For those who may not be familiar with Prelude, can you provide a brief introduction?

Sure, absolutely. So Prelude is a clinical-stage precision oncology company with the mission of developing transformative medicines for patients with genomically-defined cancers. To execute on this mission, we have built a truly exceptional team of drug developers, discovery scientists, clinicians led by Jane to really discover and develop a highly differentiated potential best-in-class or first-in-class molecule. And in a very short period of time, we've built a really exciting portfolio of medicines that are currently in clinical and preclinical development, 4 of them going through clinical already and more to enter. So very excited to talk today more about the company and the portfolio.

Great. Well, your lead program is PRT811, a PRMT5 inhibitor. Can you talk about the profile of this candidate and why you believe it can be both best-in-class?

Yes. So I'll start about the compound, and I want to turn it over to Jane to talk about some of the clinical pieces. So PRMT5 is an interesting target that had a broad applicability both in CNS and non-CNS indications of cancers. So we've taken 2 compounds in and felt that 811, our second compound, which is also brain penetrant, has a significant benefit over the first compound as well as others in the clinic. So we've prioritized that compound to advance. And the reason why we think it has a best-in-class possibility is that it's very, very selective. It's very important, but most importantly, the clinical data to date has really demonstrated how has that once-daily application can really significantly inhibit the pathway and had a very, very favorable safety profile compared to others. And that's one of the reasons why we believe that it has that potential.

Expansion cohorts for the Phase I are ongoing. Can you just talk about the study, the indications you're focusing on, what you're looking for to determine like a go, no-go decision later this year? And then maybe just broadly, like what we should expect from that update?

Yes. Jane will...

Yes. So the ongoing study has dose escalation, which was not selected for specific patient types. And then we have dose confirmation in IDH-positive gliomas, as well as splicing-positive uveal melanoma and splicing-negative uveal melanoma. It's been very tolerable in the clinic. And with very few discontinuations, the adverse event profile with very few grade 3 or above adverse events. And we are planning to look at the data later this year and update on our strategic planning for the study toward the end of the year.

Great. Your second program is PRT1419. Can you just talk about MCL1, and why has it been a challenging target?

MCL1 has traditionally been challenging because of the cardiotox that other molecules that have been out there in the clinic have demonstrated our MCL1 inhibitor has been specifically designed to have high clearance. And so as a result of that high clearance, our hypothesis is that we will initiate the apoptotic pathway, hit the target hard and the tumor cells hard, but then come off the target so that you don't have cardiotoxicity. So we are in the Phase I dose escalation in solid tumors as well as heme malignancies.

And how does 1419 compare to others in the class? And what gives you confidence that it can be a leading MCL1 inhibitor?

Yes. I can start, and maybe Jane can add. So as Jane was saying, when we started developing our MCL1 inhibitor, we had the benefit of seeing some of the challenges others had, right? And so as the intrinsic properties of the molecule is very, very important because once you're in the clinic, you cannot control that. So we've spent a lot of energy and really thought through about the profile, and we would like the profile that of 1419 and the clinical data to date has been confirming our expectations. So we think that there's a lot of opportunity for this mechanism. Jane, I don't know if you want to talk about the indications in a little bit more detail, but...

Yes. In particular, we're going to focus on areas where -- and we've announced this in our last release, areas where we know that there's MCL1 elevation when you have venetoclax resistance. So CLL is one of those indications. We're interested in AML and then the other lymphomas, including mantle cell lymphoma.

So what remains outstanding for the monotherapy dose escalation? And then can you just remind us when you might see the initial data?

Yes. We selected our solid tumor dose, and so we're going into dose escalation and dose confirmation and heme, and to present some early safety data from the solid tumor cohorts at the Congress early next year.

And then how are you thinking about the combination strategy with 1419?

Yes. That's certainly one of the things where we've said that we will be initiating toward the end of this year. It's important to know how we combine with venetoclax and/or azacitidine in a variety of the different indications. And given what we have seen so far with the safety profile, we are very encouraged that we will be able to safely dose escalate and combined with these other molecules.

And that would be a key differentiation, right? So when we speak about the data, I think you and the investors can see the safety profile of the compound, and being able to combine with other agents because that's where our significant opportunity still remains. And if we can differentiate there that we can really think that we can benefit the patients who really very much in need when they fail venetoclax.

Great. Your third program is PRT2527 that's targeting CDK9. Can you just talk about CDK9 as a target and what has been the limitation of other inhibitors in the class?

Yes. So generally speaking, CDK9 is a transcriptional CDK, and it's been long recognized as an interesting mechanism. I think some of the earlier compounds didn't have that kind of selectivity we need. We believe that 2527 is exquisitely selective for CDK9 enzyme versus other, not only CDKs but other kinome in general. And that's what gives us the confidence that we can hit the pathway hard without many off-target effects.

Yes. And the prior molecules out there, the flavopiridols, the dirty kinases, they did show efficacy, but they were limited by toxicity. So with this improved selectivity, PK profile, we do think that we will be able to see activity as well as tolerably dose escalate to areas where there's high target engagement.

And what evidence do you have that supports the potential for a wider therapeutic window than others?

Well, in terms of the safety profile in the solid tumors, we are dose escalating quite nicely with a very nice safety profile. And seeing target engagement that we really wanted to see. So mit depletion, monocyte depletion for the MCL1. So we're seeing the level that we want to see, and we are going to be expanding the study to look at more specific tumor types.

Yes. Just to add to that, it's in Phase I dose escalation data, we don't really have a lot of information from others. So we do know that other CDKs, for example, CDK1 and CDK3 have been traditionally, historically, have been contributors of some of the [indiscernible] effects, right? So until the data matures further, obviously, we cannot say with a high degree of certainty that we can avoid those things. But again, like Jane said, we are encouraged by what we're seeing to date and particularly paying attention to some of the GI tox and things like that, that could interfere with the tolerability, not having those would be a good thing to have.

Yes. And we're on track to select our dose towards the end of this year.

Yes. And so you mentioned about [indiscernible] Phase I dose escalation. And any other updates on the study that you...

Yes. We're about to embark on our heme study as well, looking at, of course, the [indiscernible] tumor types as well as the tumor types that were historically seem to be sensitive to CDK9 pathway.

And then you talked about you have selected a dose soon for the Phase II. Can you just talk about your current thinking on the design of the Phase II? What do you hope to see from that study? And then obviously, maybe it's a little bit too early to even talk about when we might actually see data from that study, but...

Yes. So we're not -- what we'll do is actually dose expand and dose confirm in the Phase I, with the Phase I dejour these days are very large Phase Is. And so those are the plans to really interrogate specific tumor types. And we're considering a variety of tumor types. Those include the [indiscernible], the prostate cancer sets for the solid tumor side and then for the heme side, again, the [indiscernible] as well as the CLLs mantle cell lymphomas.

Okay. So let's move on to PRT3645, that's targeting CDK4/6. Multiple CDK4/6 inhibitors have been approved. So what are the challenges with current inhibitors? And how might 3645 be better?

Yes. Again, I'll start with the compound itself and turn it over to Jane. So when we look at the opportunity to truly expand the use of a validated pathway to address the unmet needs in other cancers, we felt that our next-generation CDK4/6 inhibitor could clearly address that, and brain penetration was one of them, but it's beyond that. There's a number of features of 3645 that would make it very, very attractive to not only go into HR-positive breast cancer, but really take the CDK4 inhibition, 4/6 inhibition into a variety of other cancers, either as a monotherapy or really to address the resistance of some of the emerging drugs, including KRAS inhibitors and tucatinib and others. So that's where we started. And Jane is obviously driving the clinical.

And this is a really nice addition to the portfolio and it's a known target. But we have improved upon the selectivity and potency so that you have high tissue penetration. And as a result of having that high tissue penetration. I think we saw at ASCO that there was evidence from the MAINTAIN trial that there's ability to improve on progression-free survival if you cycle through multiple CDK4/6s. So that's one area that we can explore. We're also exploring the other areas of high unmet need that may have a quicker registration path, so including like gliomas, CDK altered pathways. So we're approaching it from many different targets and thinking ahead as well to combinations because if we are better tolerated, more selective, have brain penetrants, then that also expands patient population to include things like non-small cell lung cancer, combinations with KRAS inhibitors, there's a lot of really nice preclinical data with combinations there, as well as combinations with HER2-positive, HR-positive disease in breast cancer like with tucatinib.

Can you talk about some of the data that you've generated on brain exposure and [indiscernible]?

Yes. So again, as with all of our programs, when there are benchmark compounds that are out there, it is our standard practice to make them, profile them extensively in preclinical models. So one of the things, as we said, we were most focused early on is to really get that high tissue and brain penetration. So we measure them, give abemaciclib, palbociclib, et cetera, from a biodistribution profile standpoint. And we compare them with the CDK4/6 selectivity profile. At a whole panel of things that we do in vivo efficacy models, we look at head-to-head comparisons to see whether we can get the visceral disease and intracranial disease. So we presented some of that data. We'll be presenting more in the near future. So overall, again, we're pretty excited about the opportunities this molecule presents. I think what Jane said very, very important, it's not known until this year ASCO that you can go from one CDK4/6 to a different CDK4/6 and actually see a benefit for these patients. And so then investigators are willing to evaluate our drug in business again in post CDK4/6, which I think is something that many companies couldn't have done it before until this data came out, right? So I think there's a number of things that are going for this program, and we're pretty excited to be in a position to see if this can address some needs of the patients.

Okay. Great. Well, maybe in the last few minutes, let's talk about PRT-SCA2, which targets market. Can you talk about the mechanism and your approach to develop SCA2 as a SMARCA2 degrader?

Yes, absolutely. So SMARCA2, for those of you who are not familiar with the biology because it's not too many agents that have been taken into the clinic yet. But there are 2 enzymes, SMARCA2 and SMARCA4 that have an ATPase domain in them. And they're identical ATPase domain. So you cannot just develop ATPase inhibitor to treat the patients, the patients that have the SMARCA4 deletion, right? So some companies are developing those, but for the different indications. But our therapeutic hypothesis, which has actually been well-published is that patients who has SMARCA4 deletions are dependent on SMARCA2 because you need one or the other. So we felt that the greater is the only way to create that kind of selectivity. And we've been able to achieve 100 to 1,000 fold selectivity for SMARCA2 over SMARCA4, which I think is really a major feed that our chemists and biologists really working hard for a while to get that. So we're very excited about what we've been able to do. And our first compound is progressing rapidly towards IND filing. And Jane, do you want to address the clinical?

Yes. So again, there's high enthusiasm from the investigators about this compound in that not only is it selective, but it's a biomarker driven. So we'll be able to select for SMARCA4 truncated or loss of function mutations in the clinic. It's already on the foundation panel. It's on many homegrown NGS panels. And so in dose escalation, we'll go probably in tumor agnostic, but biomarker-selected populations. We know that in lung cancer, based on our research that it's up to 20% of all non-small cell lung cancer. And so we're -- we'll be looking very carefully, as well as the lung cancer-specific cohort. So this is rapidly progressing. A lot of enthusiasm. And as mentioned, we are on track to file our IND and clear it before the end of the year.

And maybe if you can just talk about like what kind of preclinical data have you generated for this program so far? And what kind of activity have you seen?

Yes. So the premise, as I was saying earlier, was to be able to develop a molecule that selectively inhibit cells that have SMARCA4 deletion. So we've done extensive panels of non-small cell lung and other cancer lines to look at that. And we do not want to see the effect broadly, right? So that's what makes it more interesting than a broad spectrum SMARCA2, SMARCA4 inhibitor. So we've seen that. These compounds are very, very selective, and we've done animal models where we look at who have the deletion and would not have the deletion. We don't want to -- we don't touch the tumor growth in wild type where we make a significant tumor growth inhibition in the patient -- in the xenograft models. And we're expanding that. It's not a lot because it's first in class. There's not a lot of tools available. So we'll continue to further refine preclinical data, and we'll be presenting at the various conferences in the coming months.

Okay. Well, maybe one last question is, maybe can you talk a little bit more about your current thinking for the upcoming Phase I dose escalation study? I know that a bit early, but what kind of indications might you include?

Yes. We will be doing the biomarker-selected indications looking for that SMARCA4 loss of function mutations, truncations and then we will be heavily enriching for the lung cancer patients, non-small cell lung cancer. And we expect this to go quite quickly because this is such an exciting new area with a very novel, not only target, but mechanism of action using our degrader technology.

Yes. So it's a first-in-class agent. And the other piece about it is that as with the degrader class that you can look at the target in circulation, and we have developed -- the team developed very good assets to be able to see the elimination of the target and not really impacting the others. So I think will be guided by the data, obviously, in the clinic, but we have very, very good guides that we can utilize to rapidly get to the dose that we think is -- should be maximally pharmacologically active.

And just to add to that, we are focusing on the solid tumors and not the heme tumors.

Great. Looks like we'll have to leave it there. Thank you so much for your time.

Thank you.

Thank you.

Thanks for the opportunity. And over the course of next 12 months, there should be a lot of data coming out of the company. And so we're very excited about participating in a meeting and we looking forward to the next time.

Great. Look forward to the updates. Thank you.

Thank you.