Prelude Therapeutics Incorporated (PRLD) Earnings Call Transcript & Summary

First and foremost, glad to see everyone in person. This is Barclays Healthcare Global Conference in Miami, so thanks everyone for coming down to Miami in person, first event for 2 years for Wall Street. So we're really excited to get to see everyone again. And my name is Peter Lawson. I'm one of the biotech analysts at Barclays. Just wanted to thank. We have here with us from Prelude Therapeutics. We have Kris Vaddi, CEO; and Laurent Chardonnet, CFO. And thanks so much for the time. Thanks so much for your support in kind of getting this event back to in person and get us back to seeing each other again. So I guess first point, we've got -- you've got some slides just to kind of set the scene for us, and then we'll dive into Q&A. Thank you so much.

Thank you, Peter. Thanks for the opportunity to participate in your meeting and we're really excited to be part of -- to be here in Miami. And just for those of the audience who are not familiar with Prelude, we're a clinical-stage precision oncology company with multiple molecules in the clinic and a continued sort of investment into building our discovery pipeline and discovery engine to bring new molecules into clinic each year. So I'll make forward-looking statements. Okay, it is -- just as a part of this discussion and for additional factors, you can refer to our 10-Q or 10-K. So just in the way of the vision of the company. So we've launched the company Series A in 2017 and it is with the vision of building a fully integrated oncology company on the foundation of drug discovery excellence to deliver precision medicines to patients with underserved cancers. And in 4 short years, we've already -- 4 to 5 short years, we've already advanced multiple internally discovered compounds into the clinic and advancing them rapidly into the clinical development while continuing our discovery effort to bring new molecules into development and into the clinic. So here are the reasons -- key reasons to invest. And I'm confident, given our business model that we can create sustainable shareholder value because of some core competencies. As I said earlier, it really started the company with I think the building an internal discovery engine that seamlessly integrates our medicinal chemistry, cancer biology and translational medical expertise to rapidly discover -- design, discover and then advance small molecule precision oncology medicines into our pipeline and build that pipeline, take them into the clinic. And in well executed, well designed clinical trials, we want to get to go, no-go decision rapidly, and we have enough capital to be able to advance missions. And we all know it's the teams that make the difference, right? So we're very excited to be able to assemble a very powerful team of scientists and biotech executives that have really delivered several precision oncology drugs that have become standard of care in many cancers today, and we're supported by our Board who also had a rich history of founding and building precision oncology companies. And I'm excited to announce that we've just announced last week our new [ CM ], President and Chief Medical Officer, newly created role, Jane Huang, Dr. Jane Huang, who will join the company on April 4, but she is tremendous global development expertise, bringing molecules all the way from Phase I into global registration and has a really wide range of expertise from hema malignancies to solid tumors. So we're very excited to be able to have Jane on board to be able to move the molecules we discovered internally into clinic and beyond to the patients. Okay. In terms of pipeline, as I said, we have multiple molecules in the clinic. And the way we go about designing and building these molecules is really patient-focused, it's target agnostic, platform agnostic. And as you can see here, we have a PRMT5 target 2 molecules, and I will go into some more detail as we talk through; MCL1 inhibitor, CDK9, which is the kinase inhibitor. These are all highly selective, well-optimized molecules that are designed to specifically address important clinical needs in underserved cancers. And then the 2 new molecules that we are about to bring to the clinic this year are one that is targeting SMARCA2. It's SMARCA4 degraded cancers also known as BRM as well as a highly differentiated, a highly brain penetrant CDK4/6 inhibitor that we're excited to bring to the clinic. I think we can actually move into at this point question-and-answer session. I'll leave this slide off.

That's a great touch point from that. So AACR is -- just if there's any pointers you should give us about what we should focus on particular data sets and then what kind of deep dive into the pipeline after that?

Yes, absolutely. So perhaps -- let's talk about the recent clinical update we've given in the last week, which also kind of addresses this question. So our most advanced program is targeting PRMT5. And we brought 2 distinct molecules to the clinic to address distinct types of cancers because PRMT5 is also well sort of studied in CNS cancers, glioma glioblastoma. And we felt that you need a highly brain penetrant compound, and we designed 811 to be able to do that and 543, which is our first compound, which is a very potent thoroughly bioavailable selective PRMT5 inhibitor. And through the course of development of these molecules, we've taken them through dose escalation, identified the recommended Phase II doses. And we presented dose escalations there at last year -- towards the last at ENA for the solid tumors and ASH for the hematologic malignancies and 543. So what we are really trying to do is, again, a very data-driven strategic decisions that would allow us to make sure that we're allocating capital on the highest provability project. So we are in the expansion phase with both of those compounds, which we plan to report the data later part of this year. We've actually went fairly broad initially given the broad applicability of PRMT5. And based on the data, we're focusing on a limited set of indications. We also decided, given 811s profile, again, we're really being as data-driven and as strategic as we should be and as disciplined as we should be. And 811 is overall a potential best-in-class molecule, not just versus 543, but versus other PRMT5 inhibitors that are in the clinic. So we focus on 811 and we know that based on the clinical data, scientific rationale, the splicing mutated cancers and high-grade gliomas are really areas where there is a potential for demonstrating PoC. So that's what we're driving at for those programs. And we're actively enrolling patients. We've completed the enrollment of -- with 543. So we hope to present the data later this year. And any data we collect from 543, we can use because these molecules are really similarly potent. In fact, 811 has, as I said, is a better safety profile because of its PK properties. No dose-limiting toxicities at the recommended Phase II dose, very high levels of target engagement. So we believe that we can leverage any data we collect from 543 to really take 811 -- use 811 for further development.

And 811 is going to be predominantly focused around cancers that have brain mets, presumably brain penetrant side of things or...?

Not necessarily. We can certainly use 811 for that like glioma and others. But more importantly, because of its safety profile, and its lack of any CNS side effects, it's a very, very good PRMT5 inhibitor all around, not just in the brain because when you measure the plasma markers of PRMT5 inhibition, in this case is sDMA, you can actually see really high levels of inhibition with 811 showing that it is systemically inhibiting the pathway. So we expect to -- it to do similarly in any cancer type. So it just gives us with 1 molecule, we can essentially address both CNS and non-CNS cancers.

Have you synthesized other people lowering PRMT5 is -- how does it stack up [indiscernible] the sensitivity?

Yes. No, they're all, I would say, fairly selective compounds right now that are in the clinic. From a clinical safety profile standpoint, it's clearly differentiated from one of the first ones that came to the clinic. It has really no GI toxicities. From a dose-limiting toxicity standpoint, at the recommended Phase II dose, where we see very high target engagement, we don't see the thrombocytopenia or hematological toxicities, which makes it readily combinable with other agents as well.

Got you. Yes. How does it compare with the kind of the MTA [indiscernible] inhibitors? And kind of your thoughts there about kind of going for all-comers versus select group?

Yes. So the next-generation compounds that are currently coming into the clinic, really, we don't have any clinical data. But what we can say based on our data, that 811, the concern initially was that will they be tolerated enough? Will there be enough therapeutic window where you can really achieve high levels of target inhibition and still be safe? And 811 has proven that you can do that based on the clinical data. So we'll have to see where -- so in MTAP-deleted cancers if it turns out PRMT5 is a good way to go about, we would just have as much activity or as much target inhibition as the next-generation compound. So again, I can't predict with time will tell, but there are very interesting opportunities that we can pursue with this plan.

Would you be tempted to kind of enrich the patients with brain mets just because that does seem to be very novel approach that you have visible?

Right. I think we have the glioma study ongoing. And if we can demonstrate that we can actually see clear clinical benefits there, I think there's a lot of opportunities that we can go after. But we want to be disciplined about and then really focus on -- as a limited set of indications to Demonstrate PoC and then and see where we can take the program.

You have data in the second half in GBM and both solid tumors, what should we be looking for April and [indiscernible]?

So it's really the high-grade gliomas, including GBM is where we're studying them, and they have the IDH positive mutation because that's the way we've seen the activity. So we're looking for essentially demonstrating a clear responses because gliomas are harder to measure in terms of the responses themselves. So we will be looking for PFS benefit, 6-month PFS rates. Any objective responses and all of that would be is what we would be looking at.

Okay. Is there kind of an internal or external goal that you're looking at for GBM of a particular response rate?

As you know that there's really no drugs approved there since the time of temozolomide. So there is -- that we really have to assess once we see the data and engage with the regulatory authorities if that's the -- if we see encouraging data. But there is willingness from regulatory authorities to -- if the drug really has clinical benefit, we can work with them to go forward.

Is there any readthrough from the MTA corporative inhibitors as well as they start generating data that will help inform your decision as well?

Not necessarily. Like I was saying earlier, we have a very diverse pipeline, and we have a number of molecules that we're advancing. So I think we're going to be very disciplined about how much resources we allocate on 1 program. We don't need to be -- we're not a PRMT5 company alone, right? So we -- as I just showed you in our pipeline, we have a number of very exciting programs. So we set a very high bar and we would like to really allocate our resources and move the programs that have the highest probability and success. And if the PRMT5 data supports advancing, we'll obviously do that.

Perfect. Before I move on to MCL, just the best opportunity you think 811 has. Is it GBM or [indiscernible] solid tumors?

I think it will really be data driven at this point. I wouldn't, at the moment, presuppose. By midyear, we should be in a position to have strong data sets from 543 and 811 to be able to make the decision.

Perfect. And then as we think about the MCL1 inhibitor, IV formulation combo with venetoclax in the second half. What's the differentiation for your molecule versus others out there if you kind of lay that out?

Yes, absolutely. Thanks. That's a good question. So when you look at what's happening with MCL1 field, A number of companies went in with IV molecules, Amgen, AstraZeneca, Novartis. And they've all kind of -- we've looked at some of the data that was presented. We engineered our molecules to be differentiated in 2 ways, right? We knew that prolonged inhibition of this pathway is likely to have toxicity issues. So that's one. Number two, there's all IV compounds and we wanted to be differentiated and brought whole. So we've made 1419 to be able to be given either orally or IV. We've generated the data in the dose escalation phase. And we saw the evolution of the competitive molecules. They -- because of their properties, we believe, although none of that data is really presented publicly, but just connecting the dots and based on what's out there, we profile those molecules. We think that they are still hitting the target, particularly when you combine with venetoclax and azacitidine hitting the target for too long. And as a result, have a potential for the cardiotoxicity and other liabilities. We design, like I said, our molecule to have short half-life -- reach high [indiscernible] 1419 levels to be able to induce apoptotic signals and levels drop off within a day, which is what the profile we're shooting for. And we think that we have that profile in the clinic based on the data we're seeing. So we believe that gives us the most rapid path to be able to combined with venetoclax and azacitidine. And the 1 nuance here is that if you can't combine, it's really hard to go frontline, right? If you can combine, you can really go to new diagnosed patients who are not eligible for intensive chemotherapy. So there is a real opportunity for an MCL1 inhibitor that is combinable for venetoclax and azacitidine. It's a really well-known target companies have been going after this for a long time, but it took a while because it's -- you needed to design the right compound. We really believe 1419 has that ability. So we're driving towards by midyear, combining with venetoclax azacitidine demonstrate safety, demonstrate clinical activity and move forward.

Should we view the IV formulation is almost like a tool compound for you?

Not necessarily. IV compound once we get to the PoC, it is very attractive to be able to just once a week. It's very attractive to be developed as a compound. And we will come back to oral and well oral could be a life cycle opportunity for us.

Perfect. Okay. What should we be looking for in that second half data?

So again, we'll be looking for looking to present the PK/PD clinical activity, combination safety. And those are the parameters that I think will demonstrate its differentiation as well as its attractiveness in this class.

Okay.

So I'm having trouble with this clicker. So I want to try to...

I think we have to work away from this.

Yes. Okay. In the last 5 minutes, I'd love to also talk a little bit about some of the new programs.

Absolutely. I've got one final question on just MCL1. Just at what point do you think we start generating data where we can start comparing it to other MC1 inhibitors? Do you think second half?

Yes, absolutely. That's our goal. In fact, the reason why we selected IV is just to be able to do that, that we would have the opportunity to rapidly establish that PoC looking to make sure that we can actually combine because at this point, it's a hypothesis. Until we have the clinical data and that supports the hypothesis that we can actually combine our MCL1 inhibitor 1419 with venetoclax and azacitidine, we won't know whether what the next steps might be. But if we can do that in the second half, I think that the rest of the path is pretty straightforward. There's a lot of excitement from the KOLs for an MCL1 inhibitor to be that can be combined with the venetoclax and azacitidine.

I'd love to talk about the SMARCA2 protein you got, really exciting kind of if you could walk through the mechanism of action and kind of the opportunity in those SMARCA4 mutant indications?

Yes, absolutely. So SWI/SNF complex chromatin remodeling complex is a well-known mechanism to regulate genes. And there is lots of mutations in that complex is including SMARCA2, SMARCA4 [indiscernible], et cetera. So when there is a number of cancers, including non-small cell lung cancer, endometrial and many others that have deletion in SMARCA4. There's mutations, but there is also actually certain mutations that result in absence of protein. When you have that, and this is the enzymatic components of the SWI/SNF complex. And there are these 2 parallel market towards SMARCA4. So if you inhibit both, obviously, there will be toxicity. But this genetic lesions, I was talking about, where you have the lesions of the SMARCA4 allow us to selectively target the tumors like leveraging synthetic lethality. And if you go after SMARCA2 and either degrade it or inhibit it, you can kill the cancer cells. So there is selectable cancers biomarker selectable. You can go into the clinic right from the get-go and leverage the synthetic lethality. But what's been challenging is that they're very, very similar proteins. So targeted protein degradation is one of the ways we actually -- I think the field in general that are targeting this particular mechanism in fact is the right way to do it. And we've started down this path a couple of years ago and built very, very selective compound, is sub-nanomolar compounds that can selectively degrade SMARCA2 and space SMARCA4. So we think that we have the opportunity to be first-in-class, while a number of companies have worked on it, we've been able to make a lot of progress. We have multiple scaffolds and really interesting molecules that are very, very selective. We're presenting some of the data in vivo data as well at AACR, but we plan to bring that into the clinic in the second half of this year.

Got you. What should we be looking for in that data at AACR?

At AACR, you'll see that the for the first time, I think we're showing in vivo efficacy data in SMARCA4 for deleted cancers. You just see the bringing up on science and we'll continue to present the data over the course of next few years as we identify the specific development candidates and actual clinical candidates.

Okay. Maybe a final question just on your CDK4/6. What's the differentiation there?

Absolutely. So while we have -- it's a precedented target, we know CDK4/6 inhibitors work. But we also know that they don't have very hybrid penetration or any for that matter for most of them. And breast cancer with brain mets and gliomas, where there is very, very strong rationale for 4/6. We're not able to take advantage of with a given current molecule. So what we set out to create is a highly brain-penetrated compound that can really engage the target as highly as you need to be and be able to address these patients with brain mets. Hormone receptor positive cancers are 75% of all breast cancers and 5% to 10% of them develop brain mets and right now, other than radiotherapy, there is really nothing that we can do for these patients. So we're very excited to be able to bring a new option for these patients, and we were planning to file the IND midyear and advance it into the clinic -- into the clinical program this year to rapidly move through the early development to really take it to the right patients and be able to test the hypotheses.

Perfect. Thank you so much. Thanks for your time.

Thank you.

It was pleasure chatting with you.