Prelude Therapeutics Incorporated (PRLD) Earnings Call Transcript & Summary

Good morning, everybody. Welcome to Barclays Global Healthcare Conference Day 2. My name is Peter Lawson. I'm one of the biotech analysts at Barclays. And I just wanted to thank everyone for joining us this morning, taking time out of their day. And if you have questions, institutional investors can e-mail me at [email protected] or ping me on Bloomberg. But it gives me great pleasure to introduce the management team from Prelude. And this morning, I've got with me Kris Vaddi, CEO; Brian Piper, CFO; and also have Chris Pierce, Chief Business Operations as well.

And just as a starting question I've been asking all our companies this kind of -- there's a lot of oncology companies, what's Prelude's point of differentiation and core competency within the space?

Sure. Thanks, Peter, and thanks for the invitation to join the conference. So Prelude is a small molecule oncology-focused company. And the vision at Prelude that somewhat potentially differentiates us from some of the others in the space is that we take precision oncology in a little bit broader sense beyond simply actionable mutations or specific biomarkers. So we're really a sort of target class agnostic or technology-agnostic company. And the reason for that is we really believe that the personalization of medicine for oncology patients has to have the flexibility to go across target classes to address the key issues for these patients, particularly those with high unmet needs. So the main differentiation, I would say, or the core competency is that we have an exceptional team of cancer biologists and medicinal chemists and drug developers that we've been able to put together in the management team and in the overall company to execute on this vision of creating small molecule medicines for patients. And in a very short period in about a little over 4 years, we've been able to make a lot of progress in building a substantial pipeline, both clinical as well as preclinical.

And then maybe just has another kind of arginine question just the PMRT5 inhibitors. Kind of how do they work? And what's been the, I guess, the competitor data? Or data you're sharing yourself that have kind of helped derisk that program?

Yes. So PRMT5, which is a protein arginine methyltransferase is a key driver of an important cellular event, which includes mainly primarily transcriptional and splicing-driven events. So a number of companies, including 3 large companies, GSK, J&J and Pfizer as well as others have developed highly selective PRMT5 inhibitors that are now advancing in the clinical trials. So the one thing I want to make it clear is that there is no specific mutation in PRMT5 that allows you to select that population. It's rather mechanisms that are known to be controlled with PRMT5, which includes, as I said, transcription. It turns out kind of DNA damage response genes are regulated by this pathway. There are a number of splicing-mutated cancers or splices of function is regulated by this pathway. So different companies have -- actually, all of us have taken an approach of doing in the Phase I study on selected patients. Because it's not -- like I said, it's not an actionable mutation. So a number of cancers have been tested, as you know, [Audio Gap] Phase I clinical trials in solid tumors and even liquid tumors in unselected populations tend to get participation from a broad range of cancers. So the only real clinical data that's out there, although there's tremendous amount of preclinical data from a number of institutions as well as companies, is the clinical data is in a rare salivary gland tumor cell adenoid cystic carcinoma. It turns out, these patients have MYB fusions, almost about 80%, 90% of these patients. Some of them also have marginal mutations. So the biology of PRMT5 that we know of, which controls some of the downstream transcriptional events following MYC and MYB connect PRMT5 to this particular tumor type. So there is a single agent of monotherapy data in these patients that was presented by GSK. But beyond that, there haven't been any reported -- particularly conference reported clinical data. But in terms of preclinical, glioblastoma is one that there is a lot of data there and that continues to evolve homologous combination deficient cancers where DNA damage response can be controlled by PRMT5 as well as myeloid malignancies with splicing mutations. So it's fairly broad across liquid tumors as well as solid tumors.

Then this year is going to be -- looks like an interesting year, I guess, ACC data, HRD positive, GBM and others. Just for ACC, kind of -- if you kind of talk through your strategy, do you have to match GSK's kind of response or do you think it'll do better? Or how should we think about that potential bar?

Yes. No, thank you. So ACC, it turns out is our adenoid cystic cancer, just as a background, has traditionally been very, very unresponsive. A number of agents have been taken in this patient population, including checkpoint inhibitors and other targeted agents that really didn't provide for objective responses or high number of objective responses along progression-free survival. But -- and so there is -- as a tumor guide, there are really no proven therapies here, which is what makes it interesting, particularly for a novel mechanism of action that could address the underlying biology. So the initial data from GSK is intriguing, but more work, obviously, needs to be done in terms of understanding the patient -- given the heterogeneous patient population, we need to have better understanding of the types of patients that can respond to this therapy is broad, is it certain subsets. So that's the part that I think we're all studying at the moment. So I think we're very gratified to be able to work with some of the really world experts in ACC in the United States. We have a number of institutions that really focus on this particular tumor type are part of our thought leaders, [Audio Gap] that we're working with. So it's really additional data from our own trial as well as the competitor trial is really what help us understand what's that best path because the data that was out there is based on very limited patients. But in general, unmet cancers where you can get greater than 20% response rates that have certain degree of durability. In the past, have really we met with -- from the FDA with a fair amount of enthusiasm to support.

You talked about the heterogeneity in the patients. Is that -- are there known diagnostic tests? Or is it done by the presentation of the tumor?

Yes. So it turns out the heterogeneity really comes from -- certain patients will have really long-standing local -- locoregional disease, whereas others, it becomes metastatic. Once it becomes metastatic, then the disease progresses rapidly. So it's just the drivers of -- genomic drivers of what contributes to those aspects is not that well known. Especially when you don't have approved therapies, there's really not much done like every disease, every rare cancer type, until you have the approved therapies, you really don't have much data to rely on. So it's just a paucity of that data that makes it specifically pinpoint. But given interest in PRMT5 and multiple companies studying this, I'm sure we'll learn a lot more about it in the very near future.

And then just on HRD tumors. I mean you've had some intriguing initial result there. What -- I mean, when we think about HRD tumors and testing, could that potentially hold you back? Is it prevalent in ovarian, breast cancer? How should we think about that kind of initial traction that is required from initially testing and then delivering the drug?

Yes. So I think the advances with PARP inhibitors really changed the landscape, as we all know, in ovarian cancer, a dramatic improvement. So as a result -- and most of them require HRD testing. So it's become really standard of care, particularly platinum-sensitive ovarian cancers, which is a fair number. So we don't think it's going to be a rate-limiting factor. We've really engaged with a number of key opinion leaders who care for these patients. So we have Myriad Genetics and Foundation tests that are widely used in these patients. Initially, it was just BRCA mutations, but now it's gotten broader in terms of defining HRD positivity. But yes, from a testing standpoint, again, based on all the interactions we've had so far, we don't think that's going to be rate limiting. And particularly, patients who fail PARP or who progress on PARP currently have no standard of care. And as these drugs -- multiple drugs, very effective drugs are moving into earlier lines of therapy and maintenance setting, you have a large number of patients that would be looking for options. And we think that PRMT5, given its ability to regulate multiple DNA damage response genes, could be a very interesting opportunity to be able to address that need.

Good. And so we get data in the second half. How much data, how many patients, how many different tumor types do you think we can get by then this year or so?

Yes. So let me just step back a little bit and just tell you about where exactly 543 is, and then we can talk about 811. So we are -- as we said it publicly that we've pretty much wrapping up the escalation and already initiated ACC expansion forward. So we're at a point of expanding on the key tumor type. We think there is the strongest rationale for PRMT5 biology. In solid tumors that include ACC, HRD-positive ovarian cancer as well as splicing-mutated cancers and uveal melanoma and others where there is specific splicing mutation. And this really is focused on the idea that splicing as a function is potentially the predominant intervention point for PRMT5. So HRD positive we've had -- as we said again publicly, we had the patient who showed the complete response and which was durable for over 9 months. In addition to that, we had 1 additional patient that came on a little bit later, who demonstrated stable disease, but we only had 2 patients from -- in that cohort as of December 16. So once it opens up, we plan to rapidly enroll the HRD-positive cohort. And again, in talking to the centers where they see a lot of these patients, we think that these cohorts will be enrolled fairly quickly. But exact timing of those things is hard to predict. But our intent is really in the second half of this year, not only present data from the escalation, give you a lot more sense on the safety, which we really think is a key differentiating factor for 543 versus what's out there from GSK, for instance, and target engagement PK as well as data from the expansion cohorts to the extent that whatever we can collect at the time of presentation. So that's really where we are. And as these are opening, it's -- again, the intent is to present as much information as we have, but I can't predict exactly the number of patients we will have by then.

Right. But it would be as full as possible, so escalation, safety, et cetera. We could -- and that would be at a scientific conference or more so kind of a press release?

Yes. No, we really -- the approach for us to release any data that beyond what's out there in the public domain is really to present at scientific conferences in the second half of the year.

Okay. For ovarian cancer, what -- as one of those HRD-positive tumors, what would you kind of think as the bar -- what's the bar to be just kind Of TESARO'S data? Or are there other things if you could point to that kind of help understand what physicians will kind of want to see from that data set?

Yes. Good question. So the landscape of ovarian cancer is dramatically changing, right, even from the time that the TESARO data was published, which where, even though it was at a current setting in the front line or the maintenance setting, those patients have not seen PARPs. So there is limited information out there in terms of how these patients do once they progress on PARPs or had experienced PARPs. But we believe that's a reasonable guide. I think anything beyond -- the response rate is one thing, but the durability of response is also important. PFS is important in that. So we think we have to look at the data as a whole. And if we can achieve 20-plus percent response rate with a reasonable degree of durability, we think, given lack of standard of care in that setting could be very compelling. For -- particularly, the safety is equally important. We have to take that into consideration because right now, maybe they'll -- so the way these patients are treated is if they responded to platinum doublets, maybe they will -- they fail, then maybe they offer that to them. But a good agent with reasonable safety profile and response rate and durability, in our opinion and in the opinion of thought leadership we've spoken with, would be a very welcome addition beyond PARPs.

Do you think we could get, I guess, some form of durability in the update, I guess, narratives around -- individual vignettes around individual patients?

Again, it's hard to predict now. But as we -- we're encouraged by the fact that the ovarian patient that showed the response had a reasonable degree of durability, 9 months plus. But more importantly, even the CA-125 levels in these patients, which is an additional marker of the drug effect have dropped [Audio Gap] really low over all that period. So it depends on how long it takes to achieve. That patient responded fairly quickly. So if we see quick responses, then we potentially have longer durability in data. But if it takes multiple cycles to get to the response, it will be less durability. It's hard to predict based on one patient. But we're intrigued and encouraged by data we have so far and look forward to really enrolling patients into an expansion cohort and collecting additional data.

Got you. And then we also get GBM, I guess. For year-end, we could potentially see some GBM data. So I wonder if you could help kind of frame that data around current therapies or emerging therapies. Again, another landscape that's been difficult to treat, but changing it seems to be.

Yes, definitely. So GBM has always been of great interest for us for this mechanism, and which is why we actually specifically developed 811. We know that there is a fair amount of science that already was there in the past and is even continuing to emerge and get published. But that suggests that the splicing this regulation is a key driver in GBM pathogenesis, but you need a molecule that has high brain penetration. None of the other compounds, at least to the extent that we know of have that. So we'll add that feature. So we built that into 811. And at 200 -- at the doses that we started at a lower dose of 15 or so and we continued to escalate. So we saw the response. As we publicly disclosed, at a 200-milligram 2 weeks on 1 week of dosing, where pharmacologically we had the exposures -- approachable exposures, we predicted based on preclinical studies that could be effective, which is what makes it very encouraging. And so this GBM patient actually had MGMT unmethylation status, which is actually almost nearly half of the patients who don't do well in temozolomide and in already chemotherapy, the only chemotherapy. So we don't have too many reference points in GBM with regard to effective therapies, right? I mean half of the patients who have MGMT unmethylation have very low response rate to temozolomide. Avastin is the only other drug that's approved here broadly in GBM. And again, there, there is a response rate of about 20% or so, but the durability is not long. So you're looking at it in a GBM population where if you can have responses by RANO criteria and GBM responses are harder to quantify unlike other solid tumors. So here, we're looking at potentially the clinical benefit for patients' response rate and durability and clinical symptoms. So there's a whole constellation of aspects of GBM that we need to be looking at. So there's -- what I can say is that, as we said again publicly that even though 811 study is all-comers, including GBM, we were able to actually enroll a number of GBM patients, which actually demonstrates really the huge unmet need here that the patients are coming into sort of a Phase I escalation setting. So we expect to wrap up the escalation -- this -- in the first half. And if we can enroll patients at the same rate as we've been able to do, we should have a reasonable number of GBM patients that we can report the data later in the year, hopefully, at the second neuro-oncology conference in the later part of this year. So in terms of -- again, I can't -- just like I can't exactly predict the numbers. But our goal really is to -- for 811, also provide a comprehensive picture of safety profile, target engagement and any radiographic data, any other data we collect from these patients. Again, the other point I'd like to emphasize here is that safety is always important in these agents because if they're dropping out for other reasons, lack of tolerability or other reasons, they can't really benefit from the treatment. So having a pretty reasonable safety profile like 811, which is very well tolerated, we really don't have discontinuations both 543 and 811s, many discontinuations because of tolerability issues, is what's really encouraging about our molecules that we can truly ask the key scientific questions in these patient populations. Peter, you are on mute.

There we go. The -- you have had, what, I guess, one discontinuation. Was that just kind of early on? How should we be thinking about kind of where you think that discontinuation rate could potentially be? It looks like Avastin has a relatively low discontinuation rate as well. So just kind of your thoughts around where that should really be that kind of discontinuation rate.

Yes. So it's hard to compare our data with Avastin because at the time when we put the data, we had a very few patients. So you will always have an odd patient here and there have tolerability issues because of multiple pills, different reasons. We don't really believe that there is any drug-related AE. So the reasons for discontinuation. That's the key. If you -- if patients are discontinuing because they are not tolerated because of drug-related AEs is what could be a reason for concern or something that could limit the ability to use these drugs effectively. We don't believe that, that would be the case for these agents, at least based on the data that we have.

Okay. And what is now a good kind of ideal conference to present that data? I guess it's the most obvious at year-end.

Yes. Clearly, that is the conference that, where I believe, most of the neuro-oncologists of the community, because the purpose of really to selecting the conferences is beyond -- obviously, data disclosure is a key driver there. Beyond that, we want the broader community that are caring for these patients to be aware of the data be able to engage and participate in the trials, et cetera. So we think that, that's probably where we have the widest audience for this type of cancer. So we would like to be able to -- again, we are still in the escalation. So assuming everything goes according to the plan, and that's what we're ensuring for.

Great. Okay. Thank you. We're at the top of the hour. So I just want to be respectful of the time. Pleasure speaking to you again today, and thanks for joining us for Barclays Healthcare Conference, and I'll hand the line back over to the operator. But thank you, Kris, Brian and Chris.

Thank you, Peter.

Thank you.

Thank you for the opportunity to participate in the conference.