Prelude Therapeutics Incorporated (PRLD) Earnings Call Transcript & Summary

Welcome, everyone, to the Prelude Therapeutics presentation at the Goldman Sachs Conference. It is my honor to introduce Kris Vaddi, Founder and CEO of Prelude.

Thank you, Rob. Thanks for the opportunity to present at the Goldman Sachs Healthcare Conference. I'm Kris Vaddi, CEO of Prelude Therapeutics. During this presentation, I'll be making forward-looking statements, and please refer to our 10-K for more detail. The Prelude Therapeutics is a clinical-stage biopharmaceutical company. The focus on oncology and a mission to deliver or extend the promise of precision medicine, patient need. And we strive to develop first-in-class and potential best in class molecules targeting really challenging pathways oncogenic mechanism. We've made a lot of progress in developing new medicines for cancer, yet far too many patients still have no good options and the treatment with chemotherapy that are often not safe or effective. And we set out to change that. We believe we can do that because we have a team of experts that we've assembled that have a passion to turn groundbreaking science into medicine and we are excited to advance this mission, developing the whole medicine. Prelude started in 2016, as really a discovery stage start-up company and there we evolved into a mature R&D organization with a suite of very exciting first-in-class SMARCA [indiscernible] therapy is a very compelling pipeline, highly selective CDK9 inhibitor as clinical stage molecules that are moving through Phase I clinical trials and a discovery pipeline of first-in-class molecules that we hope to speak in the near future. And the team has actually discovered internally a number of molecules and brought them to the clinic. And we made important strategic decisions with regard to prioritizing certain programs for our internal development while taking some programs outside the partnerships. We even made no go decisions on some programs because there isn't enough data to support further investment into those programs. We've selected SMARCA2 and CDK9 as our prioritized programs because we believe these programs have tremendous potential to address a broad range of hematological cancers as well as solid tumors. And with [indiscernible] focused SMARCA, where we're actually leading the science, we see a tremendous potential to turn this program into a pipeline. It's actually a pipeline and the program is what we believe it has the potential to. And looking ahead, we intend to take these molecules through registrational trials as we evolve into a fully integrated precision oncology company. The reason why I believe we can do that is we have the management team. We've assembled carefully a management team with proven track records and exceptional capabilities across all facets of what we do, starting with medicinal chemistry, cancer biology, translational medicine, clinical development portfolio strategy and execution. You can see on this slide that this team not only brought molecules into the clinic, but actually brought them into the market where they become standards of care in many cases. So this is the team that worked across all different modalities first-in-class or best-in-class TKIs to ADCs. And then you can see all of them on this -- on the slide that we have the ability to really not be tied to a single technology platform or a target class to be able to tailor the best medicine for the right patient. We're rapidly advancing our pipeline. Our lead SMARCA2 degrader, which is an IV, PRT3789 is in dose escalation. We're driving towards the initial proof of concept later this year. Behind it, we have the oral SMARCA2 degrader PRT7732. That's -- we've initiated the ppreclinical development last year and is on track to enter clinic in the second half of the year. And the -- we didn't stop with this SMARCA2 selective molecules. Both of these are highly selective SMARCA2 degraders. But we see opportunities to leverage what we've built internally beyond just those patients that have a specific type of mutations. So to do that, we've actually taken a very novel approach of bringing the SMARCA2 for dual degraders as tailors to ADCs and that is in discovery stage. And the reason why we believe that we need multiple assets because patients -- this -- our approach is to really address the patient needs in the best possible way and not all patients have the same need. Beyond our SMARCA program, our next-generation CDK9 is a highly selective and potent CDK9 PRT2527 is moving through Phase I dose escalation. And we're also driving this program to initial POC later this year. And our discovery engine continues to be very productive with a number of potential first-in-class opportunities that we're working on and we'll be able to talk more about them as we get into -- closer to our IND. So let me spend a few minutes talking about SMARCA2. Why is it so interesting? And we have 2 molecules, as I said, 3789 on [ IB ] and 7732 on oral program. And while I will spend the next few minutes talking about the science of it, it is there's a lot more information on this particular mechanism that's on our website. You can access those video series where we have KOLs and our leaders walking through the science and medicine of SMARCA2. So SMARCA4 mutations are quite prevalent in various cancers, including up to 10% of all of non-small cell lung cancer. While the -- you can see on this list, they're present in a number of cancers, they're most well characterized in non-small cell lung cancer. And in lung cancer, about half of the mutations are worth known as type 1 are loss of function mutations, meaning when these mutations occur, the protein is completely lost. The remaining half of them, we don't know as much about. Some of them may have loss of function, but the protein still may be there and others may have no real impact on the function of this particular protein. The other really important aspect of these mutations is that they very minimally overlap with other targetable mutation that are listed here. We have very active agents who do those mutations. So as a result, because there is not much of an overlap between SMARCA4 and other mutations, patients who carry these mutations really are not candidates or other targeted therapies, and they often are treated with chemotherapy or chemo immunotherapy. So what? There's lots of mutations, and they don't overlap. The real reason why we and others have been very, very interested in this is because the patients who have this mutation outpour outcome. As you can see, these patients SMARCA4 mutations have a PFS of under 3 months in the frontline setting when they're treated with chemo immunotherapy. And their response rates are about half of what you see in the patients who do not have these mutations and this is all in frontline. And in the second-line setting, the outcomes are even worse, pretty dismal. So that highlights a very, very high unmet need in these cancers that have the SMARCA4 mutation. So how does SMARCA4 work and why targets market to? Unlike some of the gain of function mutations that you might be familiar with like the driver mutations in EGFR and others. SMARCA4 mutations are not gain of function mutation. They in fact would result in a loss of protein. So when one thinks about developing medicines for the patients with these mutations, you can't go after the standard approaches. So researchers have been really long interested in this -- in trying to come up with ways of treating these patients or developing new therapies for these patients. And I really relied on what's known as synthetic lethality as a way to go after that. And what does that mean? So synthetic lethality is when you have 2 very similar proteins, that can share the function. And if one is absent, by taking the other one out, you can kill the tumor cells, and it's been proven to be effective in other cancers. So in this case, SMARCA2 and SMARCA4 are 2 ATPase that are part of a large protein complex. And this protein complex drives [ permit ] in remodeling meaning that it winds and unwind DNA so that the relevant genes to support the cellular functions can be turned on or turned off. And there are mutations that are known beyond even the SMARCA4 mutations that are known to be associated with various cancers. And so because SMARCA4 and 2 are very homologous and compensate for one another, when you have loss of function mutations or mutations that impair SMARCA4 function by taking out SMARCA2 or by inhibiting SMARCA2, you can essentially induce synthetic fatality. So all of this is really cool and a lot of genetic work that showed that this all works. But what's been the most challenging aspect of all of this is that really come up with a small molecule or other approaches to really accomplish that because you don't have the selectivity of SMARCA2, you would impact healthy cells as well because you need one or the other. So this is exactly the kind of problem that Prelude was created and set up to address. Leveraging our strong medicinal chemistry experience, expertise and cancer biology capabilities, we set out to leverage an emerging pathway or targeted protein degradation as a way to go after selective SMARCA2. Because as I said, the ATPs binding pocket is quite similar between 2 and 4. And what our scientists have achieved is really an unprecedented level of selectivity for 2 over 4, and that's over 1,000 [indiscernible] a lead molecule that's now in the clinical trial, 3789 has been shown to be highly, highly selective for SMARCA2 over 4. And there's a lot more data that's in the presentations that you can look at. But at a very high level, blocking selective this SMARCA2 is well tolerated in animals. It doesn't impact the tumors that don't have the mutations and show strong antitumor activity in tumors that have SMARCA4 mutation. And based on a lot of this work, I mean we've selected a 3789 clinical candidate and started our Phase I dose escalation in the second quarter of last year, it's about a year ago, and that dose escalation is underway. And we've said a couple of months ago that were fixed dose cohort, dose escalation cohort highlighting the enthusiasm of the investigators and the safety of the molecules to be able to rapidly advance through early dose escalation. And we're looking forward to industry's first initial proof-of-concept data later this year for this compound. So let me just describe to you what the study design of our Phase 1 is and what takes the second half. The study population in communications because we wanted to understand while lots of function makes more sense, given the biology and the science, we still need to understand what the other half of the patients who don't have that -- those loss of function mutations do when they're on these therapies. And any tumor type, even though I spoke about non-small cell lung, there are a number of cancers that have these mutations and those are all eligible for this. And the monotherapy phase of it is pretty standard the dose escalation, which, as I said, we initiated about a year ago. And the study design also allows including backfill cohorts along the way when we reach a certain pharmacological doses. And the backfill cohorts allow us to enrich for the loss of function patients and also non-small cell lung cancer patients. And based on the synergy, a very highly synergistic activity of this mechanism, SMARCA2 our aggregation and docetaxel chemotherapy in the preclinical models and also given that docetaxel standard of care in the second-line non-small cell lung, we've also initiated the combination of this, this year. And the goal of this program really is to establish the initial POC and identify mono and combination recommended doses for expansion. And so this year, we plan to present the initial safety and our ability data from the monotherapy dose escalation cohorts and early look at the PK/PD because here, again, selectively hitting SMARCA2 is key. And so that, obviously, we're going to be able to talk about as well as initial review of the monotherapy clinical activity across different doses and different [indiscernible]. Beyond that, next year, we will have -- we hope to have a full safety and tolerability data of the monotherapy dose escalation and the backfill cohorts as well. We have further data and the docetaxel combination that I mentioned. And we plan to assess the PK/PD profiles to be able to support a recommended dose for expansion and assess the clinical activity and objective response rates, et cetera. And should the data support it, start engagement with the regulators to understand and plan for potential registration studies. And further development in earlier lines of therapy and other combinations are planned beyond 2020. So let me move on to the second pillar of our SMARCA2 strategy. This is a SMARCA2 selected strategy. So as I said at the very beginning, we think that there's a very broad potential for SMARCA program and different patients will have different needs. And so we've -- from the very beginning -- and are developing an oral compound. And is that oral degrader. And those of you who are familiar with this space, understand how challenging it is to really achieve high oral bioavailability this molecule. So we continued the work with our oral program to be able to have an additional option. And that effort resulted in the discovery of 7732, the first-in-class, highly selective oral SMARCA2 degrader. And you can see from the graph there, it has a level of selectivity that is very, very hard or nearly impossible to beat because it really doesn't touch SMARCA4. And it is in terms of potency, it is as good as highly potent as 3789. And in addition, it has really good order by availability that our scientists -- molecule, and we're on track to advance into the clinic in the second half of this year. And similar to 3789, 7732 when administered orally at fairly low doses, is able to show strong antitumor activity as well as you can see in the western blot and the graph that it can significantly reduce the levels of SMARCA2 and not impact SMARCA4. So all of this preclinical data that was generated supported advancing 7732 into the clinical trial, and we expect this will be a once-daily dosing in the clinic. And moving on to the third pillar of our SMARCA strategy. Again, there are patients about 10% of the patients may benefit in various tumor types. But we know based on a lot of science, promoting modeling disregulation can be an important mechanism in additional cancer types where there are no SMARCA4 mutations. And so to be able -- and we know that if you inhibited both 2 and 4 that you would impact the healthy cells and unlikely to have the therapeutic index you need. So we've started to think about a novel way to really take out SMARCA2 and 4 selectively in the tumors. And antibody ADCs offer really interesting approach to do that. And so we've created a precision ADC approach for that. And again, while -- we're thinking about and talking about precision ADCs as part of our SMARCA strategy, we think that precision ADCs have a much, much broader potential. So we formed a partnership with our leaders in antibody technology, AbCellera late last year. And we bring the chemistry, the greater capabilities and clinical development expertise that we have in our organization to the table and to an AbCellera brings the antibody technology together we intend to discover and develop up to 5 novel precision ADCs forward. So coming back to this SMARCA2, 4 dual degrader it is our initial program and the collaboration is going really well. And we were prioritizing -- the program is based on high unmet need and opportunity to really have a very tumor-targeted payload that is optimized and as well as novel antibodies that are potentially differentiated from those that are out there. And the SMARCA2 first program where we're actually linking a [ picomolar ] potent market for dual degrader on an antibody. And we believe that docel approach has the potential to go beyond where our SMARCA2 selective degraders are able to grow. So I talked about 3 different approaches that we're taking, IV, oral and precision payload. But -- and that's because we think that we can address an expansive pool of patients with our SMARCA strategy. If you just look at non-small cell lung, which the data supported is our -- is an area of initial focus for us. Across different lines of therapy, second line -- starting the second line into frontline as well as earlier stage of disease. There are over 50,000 patients that actually have these mutations and that can be potentially candidates for our -- that's just non-small cell lung alone. And as we further understand the role of this pathway in other cancers be able to select and with the increasing use of next-gen sequencing, more and more patients are identified each there and they become eligible for these therapies. We expect this approach to have broader potential than non-small cell lung alone. And now you can see why we are very focused and prioritize this program. Let me turn to our other clinical program, CDK9, a highly selective CDK9 molecule 2527. We have, again, in hematological malignancies, a number of new treatments that have come into the field and have really been addressing both myeloid and lymphoid malignancies. But patients who are refractory to these or actually become a relapse on these have very poor outcome. Take AML for example, once patients fail and many of them do, the standard of care, which is venetoclax and hypomethylating agents, which are really used for patients who are ineligible for intensive chemotherapies, the outcomes are very poor. The overall survival is about 5 months or less. Similarly, in CLL, where we have very effective medicine with BTK inhibitors and BCL2 venetoclax and when they become refractory to the -- when there is relapse on these 2 drugs, they have similarly poor outcomes, highlighting the need for novel therapies beyond what we have currently. CDK9, we believe, has that potential as a scientific rationale and the potential to be able to address hematological malignancies broadly. And the reason for that is it's a transcriptional regulator. It's a transcriptional CDK that controls no oncogenic drivers like [ mech ] and anti-apoptotic mechanism known as MCL1. Many companies, including us, trying to develop direct inhibitors of MCL1, but that approach had insurmountable toxicities. CDK offers an alternative and a very compelling way to down modulate these known drivers of oncogenesis in all cancers, but more so in hematological cancers than solid tumors. And many companies have tried to develop molecules targeting CDK9 but either because of lack of selectivity or other pharmaceutical property issues that these -- many of these molecules have significant GI toxicity and that really did not allow them to be effectively developed or effectively blocking CDK9. So we focused on this as a challenge and developed 2527 is a highly potent and selective CDK9 inhibitor. And you can see here on the left, across other family members, CDK family members. It's highly selective, but even across the entire kinome, it really does not touch most of the other kinases, which is really what's needed. Some of the other CDKs have been associated with toxicities like neutropenia or GI talk, et cetera. So by avoiding those, we think that we can hit CDK9 more strongly than the previous generation CDK9 inhibitors. And you can also see that the panel on the right that it depletes both MCL1 and make a fairly low nanomolar concentrations. In vivo shows strong antitumor activity, both as a monotherapy in lymphoid malignancies as well as myeloid malignancies. And interestingly, I mentioned about the poor outcomes in patients who fail venetoclax. These regimens in models that are vendor resistant to venetoclax, the bottom right panel. You can see by combining CDK9 or CDK9 inhibitor with venetoclax we can restore sensitivity to venetoclax. So we've taken 2527 to solid tumors first and that allowed us to -- because there is some rationale that allowed us to gain some important insights into how this molecule behaves. And we were pleased to see its favorable tolerability and manageable neutropenia properties. And in absence of most importantly, significant GI tox or hepatotoxicity that was seen with other CDK9 inhibitors and a dose-dependent down-regulation of CDK9-dependent genes, the ones that we're interested in and MCL1. And for solid tumors, we've selected 12 milligrams per meter square once weekly as the regimen. And this study allowed us to actually advance at a higher dose than you would normally start with in hem malignancies, which we started last year. So this is the overall design of 2527 malignancies. Again, patient population is pretty diverse. B and T cell malignancies we recently added AML cohort as well based on some emerging data with CDK9 in AML. And we are in monotherapy dose escalation in B and T cells. As I said, we recently started AML trial, but we're also evaluating it in combination with zanubrutinib, and that study is enrolling patients as well. And the goal, again, of this particular program is to establish an issue POC, either as a monotherapy or as a combination and see which tumor types are most sensitive to this mechanism. And later this year, we expect to present that as initial safety and tolerability in heme malignancies, both as monotherapy. I think most data has monotherapy this year and maybe initial data with zanubrutinib combination. As you look at trailer as a potential investment opportunity and ask why invest in Prelude and why invest now? I'll give you 3 reasons. One, our mission of really developing compelling for potentially transformative precision oncology medicines. And with a pipeline of first-in-class and potentially best-in-class molecule positions us very well in this space. Number two, we have the leadership team with a proven track record and success in not only discovering novel molecules, bringing them through global Phase III registrational studies and really delivered to the patients. And third, we have a cadence of multiple data catalysts starting second half of this year and into the next several years as we evolve to build a fully integrated precision oncology company. Thank you.