This morning at the Citizens JMP Life Science Conference. Excited to be joined next by Syros Pharmaceuticals. With us is the company's CEO, Conley Chee. Conley, welcome, really appreciate you being here. Maybe I'll just turn it over to you, and a really exciting year of data ahead of us. So maybe just give us the quick overview of Syros, and we'll jump into some questions.
Yeah, sure. So Syros was founded about 11 years ago. It was based off of a gene expression. We focused on the non-coding part of the genome that really, what we felt drove sort of this gene expression, rather than looking at specific mutations, and we look for targeted therapies around that. 11 years later, we have some really exciting news ahead of us. We've progressed our lead asset to phase 3 in MDS. We recently announced in March that we've finished recruitment of the 190 patients that we need to look at our primary endpoint of CR, and we're well on track to deliver the top-line data from that in mid-Q4 of this year. As well, we also have a phase 2 in AML, which we shared some pretty exciting data back in December as well.
Yeah. We'll-
So-
- definitely go through that.
Yeah, exciting times.
So, you've been at the company for a little longer than this, but you've been CEO now for several months. Can you maybe just give us your initial perspectives as, you know, coming into the leadership role and how you think about the vision for the company?
Yeah, really, you know, coming in at a really tremendous time of the organization. So as you mentioned, I took on this position in December of this year, or last year, I should say. I think the same week we announced our data, our initial data in AML, and that was well-received. We did a raise, I think a week after that, and then we haven't looked back, so we've continued to move forward. We have a world-class team of clinical leaders and operational leaders, and just a really dedicated organization that's really focused on delivering this MDS data and potentially AML data because it's just a tremendous unmet need, I should say. So but the organization's really focused on that, and again, we'll be delivering in mid-Q4.
The lead candidate for and the drug for both of these indications is tamibarotene. Can you just give us a little background to the drug?
Yeah
... mechanism and, you know, product profile?
Yeah, so it has a really cool mechanism. It's, we call it a RARA overexpression. So, it's retinoic acid receptor alpha. And so it's, again, it's sort of we see the overexpression of this in MDS or higher-risk MDS and also in unfit AML. And so we, we've been building our clinical trials around that. It's a, it's a fairly novel mechanism that's also a targeted mechanism, if you will, for the treatment of MDS and AML.
Got it. Let's start with MDS. You've completed enrollment for the primary endpoint. Maybe we should talk a little bit about trial design in a second, but just, you've said and reiterated this morning that the data's coming by the middle of the fourth quarter. Just give us an update on the progress of the trial now that everybody's enrolled, and operationally, how you're preparing to get data out in a timely manner.
Yeah, so as you know, we're gearing up for that. So maybe take a half step back. The trial is enrolled to 190 patients, which will be enough for the CR, which is our primary endpoint. It continues recruitment to 550 patients, for OS, which is one of our secondary endpoints. And so the team is laser-focused on ensuring that we continue recruitment, it's going very well, as well as making sure that we're going to be able to get that data that we need for the 190 patients, in a timely manner so that we can deliver that top-line data again in mid-Q4.
So then just dialing into that trial design a little bit more, you said that the primary endpoint is CR, but you're also looking at survival. What was the rationale behind that trial design, and how do you think about the regulatory path?
Yeah, so, it's a great question. Primarily, the CR is a good proxy, as you know, or surrogate to OS, and we've had this conversation with the FDA multiple times, and they've confirmed that certainly from a CR as a primary endpoint perspective, it's enough for them, given the totality of the submission, that they will assess it as either an accelerator or a full approval. Originally, I think a couple of years ago, we had designed it in a way that we would reach a CR endpoint with a trial, and then we would start a second trial for OS, just as a confirmatory.
We took sort of the initiative to combine those two trials, if you will, and continue as one because it's much more efficient to do that, rather than starting a second trial, just statistically. The FDA, this is really their guidance, this sort of one trial design, and so we were happy to modify it in that way. I think the FDA really encouraged is that type of design. So again, we'll deliver on the 190, and then we'll continue to 550.
Got it. Just lay out for us the competitive landscape here. How do you think the drug fits into the MDS treatment landscape? Then ultimately, what kind of CR rate do you think you need to show to be competitive?
Yeah, so for those of you that aren't fully familiar with MDS, and particularly higher risk MDS, there hasn't been a good therapy in years, right? And so the standard of care being azacitidine, as a single agent, I think that was discovered and approved, you know, 17, 18 years ago. And the CR rate, at least based on meta-analysis that we've seen, is somewhere in that 17% rate, and so tremendous unmet need in high-risk MDS. And so we feel a new offering in that space is... It'll be an incredible opportunity to meet that unmet need. And as well, on top of that, we're a targeted therapy, which is actually very key in this group of patients... and maybe to talk about the MDS patient for just a minute.
These patients are often very elderly, but they're treated in the community, and so what you really are looking for is not only an efficacious drug, but one that can be really well-tolerated, right? And so this is where, as you mentioned, sort of like, what is our competitive edge here? I think that tolerability is really key in this group of patients, as we go forward.
Got it. And then just to tie back into the CR rate, how should we think about durability of the CR? And obviously we won't have all of that data when we see the primary endpoint readout, but when we think about the read-through to overall survival.
Yeah, we'll certainly want to see some durability, and we track for that, and we've built that accordingly with our development timelines and the way the data's reading out, and so forth. What we're currently seeing with our compound in AML and some of our earlier data is that it's a very fast-acting response, and so typically in the AML, for example, what you see is a response rate of a majority of the patients in that first cycle. So what we'd like to see in MDS, obviously, is a pretty fast response rate, but then some durability as well, and that'll be key for the regulators.
So you mentioned the unmet need is high. What are the other aspects of MDS and the drug's mechanism that, you know, the data that drove you to moving into a phase 3 program in MDS?
Yeah, it's a great question. We get this one a lot. So I think it's a combination of things. So as you know, MDS and AML, it's sort of a continuum of disease, right? And so really, there's this line drawn with the percentage of blast count that decides which disease it's in, and so what we've seen is a couple things. We have a lot of data in AML, particularly with the doublet of tamibarotene and azacitidine. And in the lower blast count of AML between that 20%-30% range, which traditionally used to be MDS and now is classified as AML, we saw a 67% CR rate, and so that's...
If you think about that versus the 17% of azacitidine alone, that's where we felt like, wow, that's, that's really, we felt impressive data that signals a bit of a read-through, if you will, to our MDS. We've also, if you go back in, a little bit in time, we have some single-agent activity as well in, relapse refractory MDS, and we had hematologic improvements across, all bloodlines, and molecular CR as well, even in that challenging space. And so that's what where we've got really excited about, a potential to, to really help this, this higher-risk MDS group of patients that, that again, hasn't had good treatment in years.
Got it. So moving over to AML for a second, you've generated data in frontline AML and in relapse refractory AML. Standard of care over that time was shifting, and now your focus is on the triple combination with standard of care, which is venaza. Can you just walk us through that evolution and the data that you generated along the way to get to the start of the SELECT-AML trial?
Yeah, it's a great question. We had a Phase 2 with tamibarotene and azacitidine, and we had fairly impressive response rates and CR rates, and so forth. I would say similar to venetoclax and azacitidine in this space, and so, with the potential advantage that we have, quite a tolerable safety profile. And so instead of going head-to-head in which, you know, the CR rates were sort of comparable, we thought that we could potentially have a triplet of tamibarotene, venetoclax, and azacitidine.
The key to this triplet is that venetoclax and azacitidine are pretty challenging to give from a toxicity perspective, and so we felt that with our highly manageable toxicity profile, that putting together a triplet may make a lot of sense, and this is how we initiated the idea of doing the current phase 2, which is a triplet versus venetoclax azacitidine being the doublet. And again, in December, we released data, and it was 100% CR/CRI rates in the triplet versus 70% with venetoclax and azacitidine, which is about what you'd expect, that, that they show in the more broad population. So we're very excited about that.
But again, the main purpose was to see whether the triplet could be tolerable because that's a real challenge with venetoclax and azacitidine combinations, and what we saw was, at the very least, that the adverse events rates were not unexpected or higher than venaza alone.
Got it. Okay, so just take us back and give us an overview of the trial design. You mentioned, obviously, you're comparing the two arms you're comparing, but just other aspects of the trial design, and then reminders of the number of patients that we've seen so far.
Yeah, so again, triplet versus a doublet. It's 80 patients is the full recruitment projection. We showed the first 20 or so patients back in December, and what we just announced this morning was that we would show at least another 40 in Q3 of this year, and so that'll sort of substantiate or not the data that we saw at the end of last year. It's one-to-one randomization, and it's unblinded.
Okay. Beyond, obviously, you can't beat 100% CR rate. Tolerability looks great, but what, what other-
We can match it. We can match 100%.
Right.
You never know.
Just what are the other data that you've generated from the trial so far that you would highlight as reinforcing the drug's overall efficacy profile?
Yeah, again, it's a little early for durability, but what we saw with the 20 patients was, again, this incredible CR/CRI rate, and then within that, I think CR is really critical, right? For two reasons. One is that the CR is really highly linked with OS. The other is that people are thinking about a read-through of, well, will this azacitidine and tamibarotene work in MDS? And again, in MDS, CR is really what's critical. And so within that, we saw 78% in the triplet arm versus 30% in the doublet, so an even larger delta, when we looked at CR. So that was really exciting to us. The other thing that was not surprising, but it was good to confirm, was just the speed of the response.
In the triplet, a majority of the patients had their response in the first month of treatment, versus the doublet, it wasn't the case. So that was also great to see and reinforce the real activity that tamibarotene could add to that doublet. And then the last is the AE, which again, we were very keenly interested in, and what we showed again, was that there does not seem to be any added effects, particularly in the hematologic side of things. So what we saw was actually a slight reduction in some of those measurements.
Is there any rationale for there to be a reduction, or do you think it's just the, you know, sample size?
Yeah, it could be. And not to overpromise-
Yeah
... but, but there, there is certainly a mechanism that could explain it, right? And so venetoclax is very myelosuppressive, and so you expect a lot of these blood counts to drop across the board. tamibarotene is actually a differentiator, and so it expands that myeloid compartment and encourages the maturation of these bloodlines, and so it could be counteracting some of the venetoclax myelosuppression, and it's acting so quickly that the patients aren't even having a chance to get there. That's reducing those adverse events, the those grade 3 neutropenic events, and so forth.
Got it. Looking a little bit forward here and just thinking about, you know, the commercial opportunity, it seems pretty straightforward, right? You have the doublet standard of care, and you're not trying to convert away from that, you're trying to add on top of that. So just how do you think about the commercial strategy for AML?
Yeah, super easy from a prescriber perspective, right? You're familiar with the standard of care. You're kind of not happy because it... You can do better, and by adding tamibarotene on top of it, and with a fairly simple test to understand whether your patient is a RARA overexpresser. It's a PCR test, with the results coming back fairly quickly, and so it wouldn't disrupt your regimen of delivering treatment to patients. I think it's a fairly compelling story.
I guess just thinking about the early launch, do you think this is a drug that if a patient's already on the doublet standard of care, you think there's benefit to adding it to that treatment regimen during?
Yeah, absolutely. You want to make sure that you put your best foot forward-
Yeah
... and this is a front-line therapy.
Yeah.
So, that's certainly been the case in other areas as well, you know, use your best regimen upfront, and then we'll kind of figure it out later. Now keep in mind, our expectation is that we'll be commercialized based off of our high-risk MDS indication first.
Right.
Right? And so, again, the readout will be Q4, and then we'll apply for the NDA and launch with high-risk MDS. So physicians will be familiar, not only with the RARA test, using our drug in MDS, as we then hopefully will be approved in AML in a subsequent date, and it sort of flows from there.
And just before we talk about the commercial readiness activities, just last thing on AML, can you talk about the regulatory path here? What should we expect after this first... this next update of 40 patients? How quickly can you be into a registration path?
Yeah, it's probably too early to tell. We'd like to see the data first and really understand the data in terms of the response rate, durability. We'd probably want some conversations with our, the regulatory agencies and so forth before we make a determination. But if all things continue to be positive, there shouldn't be any sort of question mark as to, you know, proceeding into a registrational trial and so forth.
So then, let's talk about the numbers a little bit. So MDS and actually, we can do both, MDS and AML. Can you talk about the percentage of patients that are RARA overexpressers? How... What data you have to support that, and-
Yeah
... what you think physician awareness is of the RARA biomarker?
Yeah, so, really good question. So let's start with MDS. There's about 10,000 high-risk MDS patients. About 50%, we project, are RARA overexpressers, so this is a pretty big market, and this is just in the U.S. If you include Europe, it's about double, right? And so when we talk about targeted therapies, it's not finding that needle in a haystack. You know, half your patients you would expect to have this RARA overexpression, and so that really is incentive to test for it. Now, it's going to be a new test, one that's, that physicians haven't used before, and so there's some education, to your point, that we'll need to do between now and launch. But I think, you know, with the excitement around the first potential therapy in years, I, I think the, the educational path will be fairly easy.
We've just, I would say, just initiated that educational process in the US, as we've sort of focused our MSLs from recruitment and helping us with recruitment for the 190, to now sort of this educational role to a broader audience of physicians and prescribers. And so we'll continue that transition in terms of their efforts to launch. In AML, it's about 11,000 patients or so, slightly more than, and this is unfit AML, slightly more than the MDS volumes, if you will. But it's 30% RARA overexpression, and so slightly less, but still a significant amount of those patients. And the physicians that treat AML are used to doing sort of molecular tests and so forth, and so it'll be part of their regular routine, we hope.
Okay. You mentioned the genetic testing piece. You have a companion diagnostic. Just where are you on that, and will it be available at the time of launch for MDS?
Yeah, so maybe two thoughts around that. The first is that we've been using the same assay continuously through our trials, and ours is the same assay for MDS and AML. We get that question a lot because I think there's been some trip-ups from previous companies that have sort of switched somewhere in the middle, which caused some differences in terms of results. So we've stuck with the same clinical assay. For the commercial assay, we're working with QIAGEN, and they're leading the development and the future commercialization of that, and so they're a great partner, and they're a very sizable one and have done this many, many times, so.
Got it. Putting your commercial hat back on, what's the work that's happening now, that's already happened, and what needs to happen as we head, you know, over the next, you know, several months into data, but then importantly, as we look after Phase 3 data for MDS?
Yeah, there's a... It's exciting, but there's a tremendous amount of work that the team is doing. First, in terms of planning around every step that we would need to build infrastructure and create the best-case scenario, and if you will, for our launch, and so that's across both med affairs, commercial, manufacturing, and IT infrastructures, and those are sort of the buckets of work that the team is engaging in. I would say that's clearly been their focus in getting us ready, and then the other side of the house is continuing to deliver on the development of getting to the 550 of OS, making sure that we have our data generation for the readout, and then obviously our AML trial, and so there's a lot of work there that's ongoing.
How do you think about the commercial organization and how what size it needs to be? You know, is this, are there indications here that you would, or are these two indications for things that you would think about bringing on a partner for?
Yeah, so clearly in Europe, that's not our focus, right? Europe is much more fragmented. It would take quite a bit of infrastructure, and so our intent is to partner that out in Europe at the right time, and there's a little bit of time that we have before we need to make those decisions and start planning out for Europe. In the U.S., it's a very targeted prescribing audience, I would say, and so a focused sales force, with, you know, I would say not minimal infrastructure, but enough infrastructure to deliver would not be a very costly venture, and so certainly we would engage in that, and it probably wouldn't make much sense to have any sort of co-promote and so forth. It's...
The market's focused enough that I think we can deliver that ourselves.
Last couple minutes, let me just check if there's any questions from the audience before I move on. Can we talk about other indications? Where else do you think you can take tamibarotene?
Oh, that's a great question. I think the team's wheels are spinning around other indications. There's certainly many aspects of diseases that we could look into with gene expression and particularly with RARA overexpression. Right now, I think the team is very focused on delivering the higher-risk MDS and AML indications.
Then from just a broader portfolio perspective, you have other assets in the portfolio that... You're focused right now on tamibarotene, but when do you think you could be at a point where it makes sense to start expanding the allocation of those resources?
Yeah, we unfortunately, as you know, we had to sort of put on hold 2 significant programs, just so that we could focus our resources on delivering tamibarotene. The first is an oral arsenic, SY-2101. This is a Phase 3-ready asset that, you know, once we have, I would say, funding availability, we would... Our intent is to turn that back on. Now, we could also partner that out, because it's, as I said, Phase 3-ready in our minds, and so that would be a fairly attractive asset to monetize, if you will. SY-5609 is a CDK7, and so we've, you know, again, this is sort of a Phase 2-ready CDK7 that we're looking to partner. This is a tremendous opportunity.
We feel it's best in class, but it potentially serves in many broad indications that would take significant resources, and so I think probably in the better hands of a more monetized partner.
Great. Well, thank you, Conley, for being here. Obviously, a really exciting year ahead.
Yeah
... with two really key data sets coming, so we look forward to waiting and watching. Thank you.
Thanks for having us. It's great.