Prelude Therapeutics Incorporated (PRLD) Earnings Call Transcript & Summary

Okay, everybody, good afternoon. Thanks for sticking around to see our afternoon sessions of the BofA Healthcare Conference. It's my pleasure to have my next presenting company, Prelude. Presenting for Prelude today are several members of the management team, including Kris Vaddi, Christopher Pierce, as well as Brian Piper. Gentlemen, good afternoon. Thank you so much for joining us.

Good afternoon, Tazeen. Thanks for having us.

Thanks very much, Tazeen.

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

Of course, so Kris, maybe we could start off the conversation with an overview, if you could, of Prelude. I know it's hard to do, but I've been asking all my companies to talk about their platform in 2 minutes or less, and then we can go into more detailed questions.

Sure. Sure. So Prelude is a precision oncology company. We're very focused on small molecule drug discovery. We have a very talented team and a discovery engine that can really develop, invent and discover and develop very selective and very important small molecule oncology drugs in a truly platform-agnostic or target class-agnostic way, which we believe makes us very unique in the sense that we can really go across different type of classes to really focus on mechanisms that have the highest probability of success, have strong mechanistic links to oncogenic mechanisms and build molecules with optimal pharmacological properties and high probability of success. And in 4 years, a little over 4 years, we've demonstrated that we not only can discover those molecules but rapidly advance them through various stages of discovery and preclinical development and bring them into clinic. And our pipeline of 5, 6 molecules overall, 3 in the clinic and 3 in the preclinical and discovery stages, speaks to the efficiency of the team, the creativity of the team and the passion. So we're very excited to be where we are.

Yes. And you've had a lot of good progress in a short amount of time. Now we didn't do this in the intros. But Kris, you certainly know the space that you're focusing in on now. You started your career off, obviously, at Incyte and know the Jakafi program very, very well. So when people talk to you about Prelude, is it under the context of a company that's developing a drug for patients that simply don't respond to Jakafi? Or do they appreciate the full platform of the company?

Yes. So obviously, for a number of years I was at Incyte, and that's always part of -- going to be part of my own background and was intimately involved in the discovery and development and not only just there that -- throughout the progression of that particular medicine, but I've also been involved with filing 15-plus INDs there. So I had a pretty broad responsibility. And so while initially, maybe that may have been the initial focus. But I think when people see the progress we've been able to make at Prelude and the breadth of our programs, not just hematology but in solid tumors and HIV positive cancers and brain GBM, I think there's better appreciation for what our mission at Prelude is.

Okay. Great. So maybe can you talk about one of your molecules, maybe let's start with 543? Just talk to us about its mechanism of action, how you think it might be differentiated even from those that might be pursuing similar mechanisms. And then we can go into the indications that you want to look at.

Yes. Sure. So 543 is a very selective potent PRMT5 inhibitor. And this is an enzyme that has gained a fair amount of prominence since when I -- we started Prelude about 4.5 years ago or so and we were just beginning, there were -- there was 1 company and other biology was beginning to emerge. But it's kind of gratifying to see that, overall, there is a fair amount of interest in this pathway. And PRMT5 was -- is rationally designed, and we started out really with the [ cluster ] structure. The specific idea of building this molecule and not only focusing on the biochemical potency or enzyme activity and of matters, but it's more having the optimal properties of a -- for a successful drug, right? So when we now look at fast forward a few years, and now we look at the data, it's very gratifying to see not only this molecule is doing what it is designed to do, which is inhibit PRMT5 effectively, as we measure the PD biomarkers, like PD marker, like asymmetric dimethylarginine mark, et cetera. But behaving as we hoped it would, like nice PK and very tight exposures among patients, nice half-life and more importantly, most importantly, the tolerability profile. So we think that it has a real opportunity to ask this important clinical question, which is in what cancer types the PRMT5 halfway has the highest probability of success. And again, there is a -- unlike some of the maybe TKIs that are going after a specific mutation, we always do PRMT5 as a broad mechanism. It's kind of the opportunity and the challenge where the ability to use across multiple indications, but we have to do the hard work ahead of time, right? So -- but I think it's -- we're well positioned. We've completed our escalation phase. We've selected doses we believe have a very high level -- it can achieve very high levels of target engagement. If patients have been on for a long -- a number of patients have been on for a long period, that gives us a confidence that there are -- that the tolerability profile is very good. It's very predictable. And so from all of those standpoints, I think 543 stands to be a well-differentiated and a very good, very high-quality PRMT5 that we have.

Okay. So I believe the first clinical data we are expecting should be in the second half of this year. Is that right?

Right. So we've -- in terms of where we are with the program, we've said that we've completed the dose escalation in the first quarter. And so we've collected a fair amount of data in not only solid tumors where we talked about the HIV positive cancers and ACC and other solid splicing mutated. But we've in parallel also evaluated myeloid malignancies where there's strong rationale for PRMT5 pathway, both myelodysplastic syndrome as well as myelofibrosis. So we think that the way PRMT5 data, PRT543 data is likely to roll out is that we can give a comprehensive summary of all the clinical data accumulated to date that from the escalation. Or first, and the expansion cohorts, and we have, in 3 classes, but we have about 9 different cohorts that are currently enrolling. And these are a range of cancers where, in some cases, they're very aggressive; in other cases, it's more heterogeneous. So we think that the data is going to be collected over time in the each of these cohorts and is likely to roll out over the course of -- in the next couple of quarters once that initial data comes out with 543.

Okay. So for the first grouping, how did you choose the indications that you are studying?

Yes. So there is -- if you look at -- when we look at PRMT5, all the data that's out there, and try to kind of group them into mechanisms that it is this most data that it impacts, and that kind of allowed us to look at the cancer types where those mechanisms have the highest probability of playing a role. For example, DNA damage repair is an area that's been well studied. A number of companies that are approaching is HRD, or homologous recombination deficient, cancers, where it's a fertile ground for DNA damage [ parity ], right? So we know that we can regulate many DNA damage in response to genes through PRMT5. So we're looking at the HRD positive cancers. So there, you have ovarian as a plus, and then there's a number of others [ happening ]. I don't know if cystic carcinoma is one where there is a fair amount of MYB fusions, and we presented the data and the Notch mutations. And PRMT5 inhibitors, because of their ability to regulate transcription, can really down-modulate a lot of the genes downstream of this MYC, MYB, et cetera. So that's -- and there's some clinical data already from competitors. So that's an area that we think we should study. And the third, which is actually really exciting area that kind of evolved over the past couple of years, which we didn't know when we actually started the program, is in the role of splicing in cancer. So there's a fair amount of data now in terms of how important the fidelity of splicing is in cancers. So there's mutations and splicing machinery that allow this to -- basically, what we're talking about is, in order for these cancer cells to grow and proliferate, et cetera, they need these proteins that support that growth, right? And so it -- throughout the process of transcription, translation, you have in [ translate ] need to be spliced out, and mature RNA has to be made. So that process appears to be very dependent on PRMT5. So we are able to select patients based on mutations and splicing machinery. So there are -- those mutations well-known in hematological cancers, but we also are seeing more and more of those in solid tumors, like you have UV and melanoma, a very challenging tumor with no effective therapies has good problem of splicing mutations. There's non-small cell lung cancer has mutations around the [indiscernible], where PRMT5 inhibitors appear to be more active. Myeloid malignancies, both myelodysplastic syndromes as well as myelofibrosis has a range of splicing mutations that make them one of the poor-outcome subgroups. So that's where we're very -- we've designed our expansion program in a very sort of rationale -- scientific rationale-driven way. And so essentially approaching it from that stand.

Okay. So there's a lot that you described actually in there. So let's maybe go into a little bit more detail on some of those aspects. You talked about having data for ACC, and that was obviously the basis of what some investors looked at when you first became a public company. Can you talk to us about how that program has evolved your level of conviction? You aren't doing an expansion cohort, I believe. How is enrollment going in that? And I guess, when should we expect to see the next round of data for that?

Yes. So ACC is one that when GSK originally talked about their PRMT5 program, they pointed out ACC data where they're subject to responses. And we've done -- ever since that we came out and we've done a lot of preclinical work in PDX models of ACC. We presented some of the data at [ ACR ]. and we also engaged with some of the top KOLs in the country who really are very well familiar with the ACC and took their advice. And so this is a cohort that we've -- it's very interesting. So this is a cohort that fully enrolled first. That kind of points to the fact that there is a huge unmet need because there's really no approved therapies in ACC. No effective therapies. A lot of drugs have been taken into the trials in the past with not much of success. So that's kind of the background on ACC and the connection of choosing. What's challenging about ACCs, these patients have sort of a very heterogeneous course. It's unlike some of these -- other cancers where they may progress very rapidly. Some of these patients stay in sort of indolent stage for some period and then [ progress ]. So we've selected metastatic patients who have shown progression to make sure that at least we minimize the number of patients that are -- tend to be more indolent. But it is a new cancer. It is a cancer that we have to study carefully. So it's not that well-known as to the genomic markers that make certain -- there's only like 3 patients that responded, right? So our question is that, are there genomic markers within the ACC subtype that make certain patients more responsive so then we can enrich them? And we're collecting that data throughout our expansion phase. So again, I can't exactly put. And then the other point I want to make, though, here is that we saw the Janssen's data where they had an ACC responder, but it took a long time to reach this point. So it's nothing you can readily predict. We saw in our indicator for HIV, we saw a very rapid response. But with ACC, we may need longer follow-up. So I can't exactly predict when the data will roll out. But at least, we have -- we've been able to recruit that expansion cohort very rapidly, so that we will be well positioned to see the data.

Okay. And is seeing the mature data for ACC rate-limiting and determining what other indications you might want to pursue?

No, not at all. Because there are independent rationale, right, for each of them. So these are enrolling in [ parallel ]. So we expect -- again, the rates of enrollment may differ between the cohorts, but it's not necessarily a stage-gate for other indications. And the rationale is very different. Like DNA damage repair or other myeloid malignancy splicing, they're very different mechanistic rationale compared to ACC. So I would keep that as a separate, unique sort of path.

Okay. And have any of those other indications started to enroll?

Yes. All of the indications started to enroll. So they're unrolling. We haven't guided as to what the time line for the enrollment is. It's just -- as it just started. But I can say that we've done everything we can to make sure that we have the right sites and more because in any one the right patients to come into the trial rather than -- just because they've met the inclusion criteria. So I think we're very engaged with the key opinion leaders in these different areas. Clearly, I've worked in myeloid space for a long time. So we have the opportunity of working closely with the people that we're very, very familiar with. But we're rapidly building a very strong network of KOLs, advisers to help us to ask the right clinical questions in each of these cancer types.

Okay. Great. So let's go back for a minute and talk about the indication that you're pursuing for Jakafi failures. So is it your goal to be used in a highly refractory Jakafi failure patients, and then, over time, move up the line of treatment options? Or in order to move up the line of treatment options, is it best for you to demonstrate some sort of activity in combination with Jakafi?

Yes. Good question. So as we started to think about myeloid malignancies in general, so we have MDS and myelofibrosis. So first thing we did was, as the data on the splicing emerged more and as we got to -- got a better understanding of the role at how the patients with splicing do in my -- MF, myelofibrosis and MDS, we've chosen our myeloid cohort to be selected splicing mutations, right? So we're not looking at patients. And they're fairly prevalent in MDS, like half the patients have it. It's not like a very small subset. Even MF has a significant number. I think 30% of the patients also have these mutations. So we narrowed down to the types of patients who are likely to benefit from that. The second thing we did was knowing that these malignancies are treated in a risk-stratified way, meaning they have low intermediate-risk patients and a high-risk patient, and they have different desired outcomes that people are looking for. So as you know, Jakafi's or other JAK inhibitors, in general, are the main benefit is premium symptoms in low intermediate-risk patients. There is really no impact on disease modification or progression to AML and things like that [ have been ]. So when I look at -- and the cytopenias that are still an issue for low-risk and intermediate myelofibrosis patients. Currently, there are really no approved therapies or effective agents in that space. So that's kind of the -- so the way we're doing this is that in low -- in myeloid malignancies, both myelofibrosis and MDS, a low risk, looking to see if we can comfort clinical benefits, including cytopenia benefits, symptom benefits, et cetera. So myelofibrosis patients tend to come in post the contract setting because they have that option, right? Unless they're not candidates. And some people come in with no RUX products -- RUX because they don't have serious symptoms they have cytopenias, right? But there's still [indiscernible]. So we -- they come into our trial. The high risk, these are patients with [ blasts ]. We have a lot of data, PDX data and other data, where we know that these patients, you want to drive the [ blasts ] down and delay their progression to AML. Because once you have a JAK 2 positive AML, the outcomes are very, very bad. So the longer you can -- the prolonged conversion to that stage, the longer the survival of those patients would be. So I want to point -- I want to answer your question about the RUX combo. Because we have a cohort where we are going into the frontline, where these patients are -- have been on drugs but they're not benefiting as much. So they have the option to go on top of [indiscernible]. So that's kind of what we're looking at there. Basically, there is inadequate response to that. And so we can see if we can improve on that.

I see. Now in that particular indication that you just mentioned for MF, for RUX failures or potentially in combo, there are other companies that are using different mechanisms, of course, that are also trying to tap that market. How big of an opportunity do you think that refractory RUX patient population is in a real-world setting? And do you think it is large enough to support multiple players?

Yes. So if you look at JAK inhibitors, so there's multiple JAK inhibitors, right? Post RUX, there is a fedratinib. And others are looking at -- momelotinib is being looked at just as a symptom benefit sort of space. So there are JAK inhibitor class. But all of those are mainly going for the symptom benefiters that improves state, and the constellation is looking in the combination setting front line to improve on RUX, the BET inhibitor, right? And maybe there's more BET inhibitors. But we still believe that there is opportunity to improve cytopenias in these patients, which none of them can get. That is a clearly unmet need that we can go. So patients are essentially ineligible because they don't have these needs. And in the context of post-RUX, if I have to guess, you really want to see activity in terms of the -- there's the blast phase disease happens. None of these mechanisms are active in that. And these patients, remember, median duration of therapy, ruxolitinib is about 3 years. So as MF patients progress towards more AML-like disease, none of these mechanisms that are currently being studied have been shown to be effective. So we are looking for a true disease -- potentially true disease modification in that setting and delay the progression to AML.

Okay. I just realized I didn't even ask you to complete your thought on a couple of questions earlier when we said that we were going to see some clinical data for 543 later this year. So what exactly should we be looking for as markers of safety, PK/PD and even any kind of early markers of efficacy?

Yes. So I mean, I think when I see -- when I think about the early data, overall, the objective of dose escalation is to demonstrate -- look at the PK, targeting is making sure that we're hitting the target and how [ many are doses ]? How many -- how much dose interruptions or dose reductions patients would have to undergo at the levels that you're getting high levels of target engagement. And then clinical activity side, where you have clinical benefits, how long is the benefit lasting, all of those are typically what are collect data collected. But I want to remind you that these are unselected patients, right? From a biology standpoint, we've always set our goals to get to the escalation, right? Plan select otherwise it would take too long and especially when we have various different types of cancers. So unselected patients who you're really looking for ensuring that you have a dose that you can take to ask these questions in more defined population, which is what we're doing. And in heme, we have -- we do have MF-MDS patients, but these are patients who don't have other options because they've already exhausted all of the options. So they tend to be much later-stage patients. So the benefits could be if they've been able to tolerate and stay on the drug and derive benefit for a long time, that's a very good indication that we're looking for. We haven't talked about 811, but that's another one that also -- yes. It's a very penetrated molecule, but we are also ramping up -- we believe that we've reached fairly -- doses that are very fairly close to the doses where we want to be. And we think that probably a couple more cohorts with that will be done with the escalation. So midyear, we're expecting -- this is '21 cycle, right? So we hope to complete the escalation, transition over to expansions in the second half of the year. Initial focus is going to be GBM. We're engaged with our key opinion leaders. There's a lot of interest. There aren't that many mechanisms that you can go after in GBM that is very specific, right? So this is one of the highest-potential mechanisms in GBM, and we've said that we had a PR by RANO criteria. And the patient, I think, was on treatment as of December 16 for 5 months and maintained PR. So we're working with KOLs to make sure that we have the right design for our expansion cohorts, so that we can then grow. Because half the patients with GBM have no therapeutic options beyond radiation and chemotherapy because they have this -- their dispute called MGMT unmethylated status. So we're looking to see -- now the drugs are being taken as -- into that -- new drug investigation agents are being taken there in that setting because they don't have other options. So you can look at more earlier-stage disease versus in the Phase I setting, you come in with a [ blast-refractor ] GBM who would have failed whatever options that they could get, approved for investigational. So we are hoping to, again, like 543, be in a position to summarize our early data from 811 first, followed by the expansion data in the next several years.

Okay. So there is a lot going on at the company. And the next 6 to 12 months will certainly have a lot more card split to show activity and potential viability in these programs. So we're going to be looking forward to seeing those. For now, we are out of our time slot for 30 minutes, and I don't think we can do justice in 30 minutes, but we tried. We should definitely have a longer conversation to talk in a little bit more detail about the multiple programs that the company is looking at. But for now, thank you so much for participating, and hope you guys have a great rest of the day.

Thank you, Tazeen. Appreciate it.

Absolutely. Thank you, Tazeen. Appreciate the opportunity.

Always good to see you.