Prelude Therapeutics Incorporated (PRLD) Earnings Call Transcript & Summary

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 from Prelude Therapeutics, CEO, Kris Vaddi; CFO, Brian Piper; and CBO, Chris Pierce. Welcome. So for those who may not be familiar with Prelude, can you provide a brief introduction?

Absolutely. Thank you very much for the opportunity to participate at Morgan Stanley Healthcare Conference. We're very excited to be talking about Prelude and all the progress we've made so far. We're a precision oncology company, really small molecule based. We were about 5 years old now. We're a clinical stage company with not just one but multiple compounds progressing through various phases of clinical development as well as a very rich pipeline of molecules that are going to enter clinic soon and then -- in the next several years. So like I said, we were about 5 years old. And we're very -- we began the journey of building the company with a strong discovery engine, with a very strong medicinal chemistry capabilities and cancer biology translational expertise. And I would say, one of the differentiating aspects of our companies were not tethered to a technology platform or a target class. We really want to go after mechanisms that drive various cancers where there's a high unmet need and that are underserved. So as a result, we've been able to build a very strong pipeline very rapidly. It really speaks to our ability to focus and execute and the expertise that we've been able to bring together into the company. So, again, happy to talk about specific programs and molecules in the pipeline in the next 30 minutes.

You have multiple PRMT5 programs. Can you talk about your co-factor approach? And how is that different from other approaches? And what advantages does that provide?

Yeah, absolutely. So, let me [begin] the company. PRMT5 was the first target we've chosen. And again, we are a very rational drug design company. We don't screen or do library screening, et cetera. So, PRMT5 appealed to us because of its links to various cancers, various mechanisms and pathways that drive oncogenesis and resistance. And we built our molecules as SAM competitive or co-factor competitive because there's very good access structures of this PRMT5 proteins. And we were able to design rationally molecules that can very -- selectivity is key, not broad methyltransferase, but very specific to the arginine methyltransferase. So, we believe -- and we have 2 molecules that are in the clinic. And the reason why we brought 2 molecules, first one being PRD543 that recently completed the Phase 1 dose escalation and currently being explored in expansion -- in multiple expansion cohorts in select tumor types. And 811, which is slightly behind it, the reason for 2 compounds is that the 811 is a highly brain-penetrant compound. And a number of cancers have been shown to be dependent on PRMT5 or a critical role for PRMT5 that are in CMS. And so you really need a brain penetrant and we think that 811 really fit the bill very nicely in terms of differentiating it from others in the clinic, which are currently multiple -- in large pharma compounds. So we believe that our molecules, the profiles we've seen to-date overall PK, safety, target engagement, initial signs of clinical activity, all of them speak to the quality of compounds that we've been able to discover and develop and their ability to have a true differentiation.

And as you mentioned, your lead PRMT5 inhibitor is PRT543. Can you talk about the profile of this candidate and why you believe that it can be best-in-class?

Yeah. So let me speak about both of the molecules. 543 is ahead of 811, but they are -- both offer really interesting opportunity for the company. So we went in with 543 where we built in -- selectivity is very important, optimized profile, physicochemical properties, PK, et cetera. And we went for a low clearance and long half-life compound that it clearly showed in the clinic it's got 12 to 15 half-life. It can nicely provide target engagement. And more importantly, it's safety profile. We think that it has very limited off-target effects. And we have one dose-limiting toxicity, which when you have very high levels of PRMT5-inhibition that you have this reversible thrombocytopenia, which we can manage. With 811, which has a shorter half-life, even though we went for a brain penetration, it actually has a 5 long half-life. And so, interestingly we get very high levels of target engagement and that has high [track levels] as 543. So we believe that between the 2 molecules, we have the opportunity to truly have a molecule or both molecules to have a potential best-in-class opportunity. And then the last point I want to make around this is that with PRMT5 different companies, there's a number of companies that are interested in this. Companies are pursuing SAM competitive, substrate competitive, MTA cooperative, so there's different approaches. And they lend themselves to target different cancer types. That's one important feature. And the second aspect of it is that some of the concerns around dose-limiting toxicity or inability to generate high levels of target engagement and target occupancy, I think that the clinical data that came out from our compound, Pfizer compound, to a large extent put to rest that you can get very high levels of inhibition of target without major dose-limiting toxicities. So, I think, we really -- obviously you need clinical data -- more clinical data from all these molecules, but I think we're very well positioned to ask the fundamental questions in which tumor type, which selected populations are really driven by PRMT5. And thereby we can rapidly advance a dose that really [chucks] the target down in a significant way.

And 543 is now in Phase 1. Can you talk about what you've seen so far on safety and efficacy in the interim results?

Yeah. So what we've kind of talked about publicly and we have some more detailed presentation coming up shortly is that in the escalation phase, we were very -- again, we're at the very, very early PRMT5 inhibitors to enter clinic. So we've kind of escalated from less frequent dosing first to a more frequent dosing and with the goal -- in unselected patients with the goal of identifying the dose-limiting toxicities and safety and PK profile. So, we've learned quite a bit in how to dose these molecules, what should we be watching for, et cetera. In terms of clinical signals, there is -- there are 2 or 3 key hypotheses that we're currently testing in the expansion cohorts. But we were fortunate enough to have an HRD+ patient in the escalation phase where DNA damage repair pathways are one of the key mechanisms that PRMT5 can modulate and HRD+ cancers are cancer tied where we can leverage that biology. So, seeing a response in a patient with HRD phenotype in escalation was encouraging for us to be able to expand in expansion cohorts, both ovarian and non-ovarian. The other asset of PRMT5 biology in splicing mutated cancers. And a number of companies have studied and academic institutions studied and demonstrated a critical role for PRMT5 in splicing. So there are splicing mutated cancers such as uveal melanoma, non-small cell lung cancer in solid tumors as well as in heme, a significant number of [ splicing cell ] mutations. So we are encouraged with what we're seeing so far. And in terms of specifically addressing those populations, we are -- we need expansions. And we're very encouraged with the interest from investigators in enrolling patients into our expansion cohorts. And to really ask the critical questions within those populations, HRD+, ACC and splicing mutated cancers, how best to develop these agents.

And you'll be presenting the Phase 1 data for 543 next month, as you mentioned. What should we expect to see from that data?

Yeah. So it's really -- like so we've completed 543. In fact, the data will be presented on both 543 as well as 811 at the Triple Meeting. And for 543, we've completed the dose escalation, identified the expansion dose at the end of first quarter. So, the data that's going to be presented is from the escalation cohorts because expansion cohorts are enrolling now, and we expect to present data from those next year. So, in terms of what you can learn from both compounds, I'll just speak for both molecules, is that you can see the overall safety profile, the PK profiles. The target engagement both from the standpoint of sDMA or symmetric dimethylarginine inhibition at different doses, schedules, et cetera. And also a little bit more biology on modulating the specific mechanisms of PRMT5. And you'll be in a position, it's kind of similar to what Pfizer presented recently and others. So you learn about the overall profile and be able to compare it with other compounds, et cetera, and gain further conviction that we can truly take these molecules into select patients and ask the fundamental questions. And that's the data set we will hope to present.

And so you mentioned that the expansion cohorts is enrolling, how is that going? And can you remind us which tumor types you're focusing on?

Yeah. So, happy to. So, I don't know if cystic carcinoma is one that other companies have demonstrated early signals. And this is a tumor type with no approved therapies right now, right? So, there is a lot of interest from investigators on -- for our molecule, given its profile. And so that is a cohort that opened first time and very rapidly enrolled because there's a very, very high demand for new agents for these patients because there's really nothing out there. And for this particular cancer type, safety profile is very important because the patients need this therapy for a long time. And so that's enrolled. I think we said that we have enrolled and we're following up on those patients. And we're very focused on the HRD and splicing mutated and they're enrolling well as well. And we're pleased with overall the progress we've made in all of those. And the heme cohorts also -- we're also enrolling our heme cohorts, MDS and myelofibrosis and they're a little bit the solid tumors. But overall, we have to get that we're going through this pandemic and everything. So there's so many things have to come together to make sure that we're all executing at pace. So we're very pleased overall with what we've been able to accomplish this year.

And maybe if you can talk kind of along the same lines of the last couple of questions, but for 811 in terms of what should we expect from the upcoming data and then what types of cancer you're focusing on, on the expansion?

Yeah. So, good question. 811, we've announced recently that we've completed the escalation. We started at a fairly low dose, 15-milligram dose and we've escalated. I think, as of -- I forget, early this year, we were up to 400 milligrams. So we've also started -- because it's a brain penetrant compound, we wanted to make sure that there's no CNS liabilities associated with that. So we've escalated so we did it 2 weeks on, one week up initially, but the drug is so well tolerated. We went to a daily regimen, right? So we're very pleased to see that there are no CNS liabilities. And also, its profile is actually lending itself to be really very well tolerated, very good therapeutic window, high levels of target engagement and inhibition of the PD markers with no dose-limiting toxicities to a point where we disclose. So overall, I think 811 is proving to be not only brain-penetrant molecule. This particular escalation allowed glioma patients -- glioblastoma patients. So we have more representation of that in this trial compared to others. But again, it's a very relapsed-refractory late-stage outcome of GBM. So we're learning more about how to develop these drugs in these particular cancer types. So, an expansion port, we just finished our escalation. So we're in the midst of finalizing the designs for the expansions. There's lots of opportunities overall. Glioma -- glioblastoma is one. There is HRD+ cancers with brain mets, certainly like triple-negative breast and others and splicing mutated cancers like non-small cell lung with brain mets. So those are all interesting cancer types for us to look at. There's primary CNS lymphoma where there's a big need. So, we can -- and as we think about 811, we need to think about the fact that in addition to CNS cancers, it really may have a very good profile. So we just need to be thinking about it as a good differentiated PRMT5 inhibitor beyond just CNS. So those considerations are going into...

Right. And you're expecting data from the expansion cohorts for 543 and 811 in '22, right? It might be a little bit early to ask, but I'll just go ahead anyways is what should we expect to see from those data readouts? Like what kind of things are you going to be focusing on for those readouts?

It's really each of these cancer types have a very different sort of unmet need, right? For instance, for ACC, no approved therapy. So it's an opportunity for us to demonstrate clinical benefit and we look at all different ways of doing that. In HRD+ space, there's PARPs obviously have been very, very entrenched and there is opportunity to go after PARP to address PARP resistance. And based on the DNA damage repair pathways, that's opportunity as well as in combination with PARPs. A lot of the company is looking at that space with specific agents like either ATR inhibitors, RAD51 or others. Here, PRMT5 is a broad modulator of DNA damage repair pathways. So, we'll learn as to -- as we enroll these patients, are there other features of these cancer types beyond just HRD itself that make it more sensitive to PRMT5 inhibition. Similarly, when looking at RBM10 mutated, U2AF1 mutated non-small cell lung, SRS -- SF3B1 mutated uveal, all of those kinds of patients will come into their splicing mutated cohort that we want to study and see if we can demonstrate clinical benefits. So there's a lot of different opportunities for us. We may choose strategically the ones that have the highest need and that we can move rapidly and continue to explore other ways [ for continuing of the patients ].

Okay. Your third candidate is PRT1419. Can you talk about this program, the opportunity that 1419 compared to competing candidates? And what gives you confidence that could be a leading MCL1 inhibitor?

Yeah, absolutely. So, thank you for that question on MCL1. Because we're a young company, we have a number of compounds. Often we don't have a chance to talk much about that. But MCL1 is a well-known target and a number of companies have been targeting it for a long time. So there's 3 companies that we are aware of right now that are develop -- are advancing their IV that MCL1 inhibitor, all are IV, Amgen, AstraZeneca and Novartis. And we've launched the program with the idea that if you have an oral MCL-1 inhibitor, initially in venetoclax failures where MCL1 is believed to be a major resistance mechanism in AML and perhaps MDS would be a more immediate opportunity to explore. So there, we would be looking at venetoclax is used in combination with azacitidine, which is a backbone therapy. We would be looking at that. So we're having an oral compound would differentiate us. That was an idea. And we thought that we've developed -- we could do it and we've got 1419, which demonstrates really attractive properties to do that. But it also has a really good properties to be given as ID. So we're developing both because it's the same compound, different formulations, we can learn a lot. And the other aspect of MCL1 that's more recently is emerging is opportunity in solid tumors as MCL1 being potential resistance mechanism TKIs. So we thought we would develop -- we would take IV into solid tumors and oral in the heme and just learn about how best to use these and hopefully converge into an oral if that fits the profile for everything because that's the easiest way to develop in differentiated way. So that's kind of where we are. And we have 4019 is very, very potent and very attractive molecule. So we're currently in dose escalation with both oral and IV, IV started recently, oral started some time ago. So we hope to generate data from both of these molecules and hopefully talk about it in 2022 as well.

Can you talk about the monotherapy and combination activity that you've seen with 1419?

So we really were in the monotherapy dose escalation. The design is such that we want to combine with azacitidine and venetoclax. Ideally to get to front line, you want to be a triple combination, I mean that's [indiscernible]. So, first, we would be looking at combinations with both agents and to demonstrate that we have clinical activity, mainly in the AML space, that's where venetoclax is now approved as a clear signal. That's what we would be looking at initially. So monotherapy, we don't know. I mean, venetoclax didn't have a lot of monotherapy activity, whereas azacitidine combination is very impressive, has become the backbone now, right? So I think that is the key for us to be able to get to those combinations and look at that data.

Great. You also have multiple preclinical programs. Can you talk about PRT2527? And what remains outstanding ahead of the IND submission?

Yeah, sure. So, the PRD2527 is a very, very selective CDK9 inhibitor. And again, this is a program that we've initiated after MCL1, knowing CDK9 is an important transcriptional CDK that regulate the expression of MCL1 as well as MIC and other immediate early genes. So, our goal was to really develop with selectivity as the key. A number of compounds that went in that wanted to inhibit CDK9, but they have other CDK activities that created dose-limiting toxicities and low ceiling. So, hypothesis here is by having a very selective compound, you can avoid that. So, 2527 is really a great compound. And we were planning to file the IND this year and get that clinical program ongoing. We've completed a lot of the work and just in one of the final phases of some of the CMC work and others to finish and get the IND filed.

Okay. And then, another preclinical program you have is PRT-SCA2. What excites you about this program?

Yeah. So, very good question. So, it is a targeted protein degrader. So it's a completely new approach. Obviously there's many companies now that focus on targeted protein degradation as their main platform. So we felt that it targets SWI/SNF chromatin remodeling complex member called SMARCA2. And there is SMARCA2 and SMARCA4 are 2 parallels that you require for the [ combitant ] function. And so, there are a number of cancers that have SMARCA for deletion and that becomes synthetically -- there's a synthetically [indiscernible] opportunity if you can selectively target SMARCA2 without touching SMARCA4. We've looked at different ways of going after it, but we felt that the degradation is the right way to go after it because there isn't really ATPAs binding is the other approach and there is not much difference between ATPAs binding pocket for 2 and 4. So, our program really focuses on building very selective SMARCA2 degraders and which we have accomplished early in the year. We've demonstrated we presented a poster at AACR. We have sub-nanomolar degraders of SMARCA2 that start to show that selectivity both in vitro cellular assays and colony-forming assays and the degrow models. So we are very excited about that. And several companies are -- it's a target of interest for the community because there are a number of non-small cell lung cancer patients and others who have these this particular deletion. So it's a very highly selectable patient population. You've been going very quickly and find out whether this approach makes sense. And so that's the drive. We have the opportunity. We're not aware of anyone who is in preclinical development, have actually publicly stated that they have a molecule that they're developing. So here, we have an opportunity to be potentially first-in-class as well in addition to just have a very unique molecule that we could take forward.

Great. Well, maybe one last question. I guess, are there any aspects of the Prelude story that you think investors either misunderstand or underappreciate any parts of the story that you think people haven't maybe spent enough time on?

Yes. I think we are really -- we've launched the company with the mission of rapidly discovering internally and advancing our molecules through various stages of discovery development and into the clinic. And so, we remain fully committed to that vision and that business model. And so, our commitment to bring one new IND every 12 to 18 months. It's something that's a part of our longer-term vision. So, because PRMT5 is most advanced, we often get a lot of questions on that. So, we appreciate the opportunity to talk about CDK9, which now has really generated a lot of interest. Many companies are now actually -- this a lead program for several companies, which is we're excited that a target we've chosen a few years ago has generated that degree of interest. So, I think I just want to reaffirm that we are excited about what we started out with as a broad vision of discovering small differentiated small molecules, targeting multiple pathways in a target class and technology platform-agnostic way. And we're -- while discovery engine is continuing to produce very high-quality molecules. We're excited about the clinical progress we've made and we're really building Prelude as a long-term company. And so, the growth so far even beyond the pipeline, the talent we've been able to recruit and build the company is what we believe in the long run will differentiate Prelude in this space.

Great. It looks like we'll have to leave it there. Thank you so much for your time. I appreciate it.

Thank you very much for the opportunity. Thank you. Bye.