Good afternoon, and welcome once again to TD Cowen's fifth annual Oncology Innovation Summit. I'm Phil Nadeau, one of Cowen's biotech analysts. It's my pleasure to moderate a fireside chat with Syros Pharmaceuticals. We have with us today, Conley Chee, the CEO; Jason Haas, CFO; and David Roth, the Chief Medical Officer. So first, I thought I'd hand it to Conley to provide a brief state of the company overview, what are Syros's key strengths, notable challenges, and what must the company do over the next 12 to 24 months to create shareholder value?
Sure. Well, thanks, Phil, first of all, for having us. It's a great opportunity for us, and so we really appreciate it. It's a really exciting time for Syros. The team is focused on delivering top-line data sometime this year, later this year, I should say, and so I'm sure we'll be talking a bit more about that. Beyond that, we're preparing for our filing of the NDA upon success of that data, and the team's already thinking about building our commercial organization for launch. So lots of exciting things for the team to work on. Strengths of our company are pretty clear. I mean, we have a fantastic program that we hope will deliver great results again later this year. And the team, we have a world-class team that's really dedicated.
We're really patient-focused, and once we get closer and closer to this pivotal data and the realization that we could potentially be delivering this medicine to patients, I think we're all really excited about that. And as a testament to the dedication of this team, you know, we had a restructuring in December, and we've had no turnover since then. And we're really proud of that, our patient focus and our real commitment here as an organization. So really exciting 12-24 months ahead for Syros.
One of the most common questions we get from investors is about Syros's valuation, actually. It's... The stock's trading at a valuation well below that of other companies with a candidate in pivotal development. Why is that? What do you think is most misunderstood about Syros?
Yeah, it's a great question. I'd say it's a little perplexing. There's probably several reasons for it. One is that I describe our situation as we've had Phase III sort of for a while now in our program, and we haven't had a lot of value inflection points during that time. I sort of call it this valley of quiet for the last couple of years, and we're just coming out of that. And so we're building a lot of momentum based on a lot of the dialogue that we've had now with potential investors and our current investors. The second challenge with our, I would say, our stock is that, and it's a bit of a good problem to have, if you will, our top investors are incredibly dedicated to Syros.
They're long-term holders, and, you know, it's a who's who of investors, well, in our top 10 or 12. But the downside of that a little bit is, we have a very small float, like very small volumes. No one's really selling, and so it's really hard to sort of generate a lot of momentum in the open market. And so we're really working on broadening our investor base, as we sort of move into these pivotal value inflection points. And the last thing I'll say is that there may be a bit of hesitation or misunderstanding about the MDS market, particularly the higher-risk MDS market, which is, I think, from our perspective, an incredible opportunity, right? So massive unmet need, which I think David will talk about in a few minutes.
A bit of the challenge with the indication has been that there's been a lot of failures, very prominent failures, if you will, in this indication. If you really look at that, the folks that invest in us believe is that many of those failures were really driven by the intolerability of the drug and side effect, and so forth. That's one of the real advantages of our program in tamibarotene, is that it's highly tolerable. I think it definitely lends to optimism that it will be successful in this indication. The other is just really about the opportunity itself. This is in MDS, about 10,000 patients in the US, of which there hasn't been a new treatment for really decades, right? It's a large opportunity with tremendous unmet need.
Great. That is a good, good foundation. David, we'll turn to you. As Conley suggested, there's Phase III pivotal data in MDS coming during Q4. Can you remind us of the design of the trial? In particular, what's the primary endpoint that will be analyzed during Q4, and what's the powering of the trial around that primary endpoint?
Sure. Thanks, Phil. So the trial, it's a global randomized Phase III registration-enabling trial. It's a placebo-controlled, double-blinded, 2-to-1 randomization. The treatment arms are tamibarotene plus azacitidine, and the control arm is placebo plus azacitidine. The trial is set up to assess the difference in the complete response rates across the two arms, but that's the primary endpoint. It's powered at over 90% to demonstrate a difference between the CR rates across those two arms, and that's gonna be based on the enrollment of 190 patients, so the analysis is gonna be based on the initial 190 patients.
The study also is continuing to enroll to achieve the key secondary endpoint of overall survival, and that's 80% powered to determine a difference in survival across the two arms of the trial. As you can see, the image behind me speaks to the 190 patients. We're very excited that we enrolled the 190 patients in the first quarter of this year. We had previously announced that, and that gives us clarity on the timing for the delivery of the primary analysis data. So we would expect that to be by the middle of the fourth quarter of this year. And yeah, I think that pretty much answers your questions. I mean, we're very excited about the use of the CR rate.
Obviously, that analysis will come forward by the, you know, middle of the fourth quarter of this year. It will be followed at a point in the future with the key secondary of overall survival. And just one extra comment, which is the reason why that's very important, is because it gives us an early opportunity to make this drug available to patients. You know, survival endpoints take quite some time to deliver, and, you know, we've had feedback from the Food and Drug Administration on more than one occasion, at various points when we've been discussing our program with them, about the suitability of the complete response rate with supportive durability data in, in supporting either a full approval or an accelerated approval.
If we were fortunate enough to even get an accelerated approval based on the data that we would submit, we're well on our way to delivering the confirmatory endpoint because we have the same trial is moving forward to deliver that. So we've, you know, we've got a very efficiently designed study that we are confident about the technical parameters of.
With the CR data in hand before the overall survival data is available, what other measures will be important? For example, things like duration response or adverse events, kind of what will be key in determining the benefit risk of tamibarotene in high-risk MDS?
So benefit-risk is always assessed based on the totality of the data, both the efficacy data as well as the safety. You know, if there's a balance of efficacy and, you know, trade-offs with safety, then, you know, that gives you the benefit-risk assessment, and that's what enables a regulatory OK, you know, endpoints, that other, like, secondary endpoints. Not only would it be the CR rate, which are the primary endpoint, but how quickly does that occur, the speed to CR? How long does it last, the duration of CR? We also look at other parameters that are associated with the CR. So keep in mind, the complete response requires the improvement of peripheral blood counts, the red blood count, the white count, and the platelet count. So we also look at, like, transfusion independence.
These patients have cytopenias, low blood counts, and they often need to get platelet transfusions or red blood cell transfusions. So you would think that if you normalize those in order to attain a CR, you should reduce your blood transfusion requirements, which is an important clinical benefit. And then there's also the overall response. So there's other parameters that are important but less important than the CR, like the overall response rate, which includes partial responses, marrow complete responses, and the heme improvements without the responses. So those all get added up into an aggregate response called the OR. So we will look at that, the time to the initial response, and how long the ORR would last as well. So those are the types of other endpoints that we will be analyzing, along with all of the safety data.
So clearly, the safety is gonna be paramount, and we'll look at toxicities that are potentially generic, you know, non-specifics, non-blood , and then we'll look at the hematologic toxicities, which to date, we've had a very favorable profile. We don't exaggerate toxicities that are known to be associated with azacitidine, and so we're hopeful that we have a very favorable safety profile.
Syros recently announced that the trial passed a pre-specified interim futility analysis. Can you comment on the nature of the analysis and the specific areas that the independent committee evaluated?
Absolutely. So the futility was based on the CR rate, so it was an early look at the CR rate across the two arms. It was based on at least 50% of the enrolled patients having been observed over a pre-specified period of time, and so it's a very significant proportion of the final analysis. And just to remind you, the study is a randomized, placebo-controlled, blinded study, and we, Syros, has no insight into the data that they saw. But what we do know is that they looked at the CR rates across the arms, and they told us that, you know, the study should continue without any modifications.
They also look at safety as a matter of course, and they specifically stated that they saw no safety signals of concern that would be of, you know, of importance. And so, you know, we were really excited. It's a really important threshold. In order to be successful, we got to pass the futility, so we passed that important milestone, and we're looking forward to delivering the final data of the primary endpoint in the, by the middle of the fourth quarter.
What, more generally, what gives you confidence that the trial is likely to succeed? In particular, how do the data in newly diagnosed AML provide information about the efficacy and safety in MDS in the absence of earlier base data in MDS itself?
Sure. Well, so to start with, we have a wealth of preclinical information in systems that have given us confidence about how tamibarotene can modulate the biology of the RAR alpha pathway. And so that was really what set the stage for getting into this whole program to begin with. We have single-agent data in both AML and MDS, in particular for the high-risk MDS patients, relapsed patients, that is. We saw bone marrow blast reductions, we saw evidence of myeloid differentiation objectively with cell surface phenotypic markers, and then we also even saw a marrow complete response in an MDS patient that was durable to at least six months. So that's very important.
And then in combination with azacitidine, which is the exact regimen we're using in the trial, not only did we demonstrate the safety of that combination, but we looked at newly diagnosed unfit AML, where we saw high response rates. They occurred quickly, they had durability. The responders had a meaningful prolongation of survival out to, like, 18 months. And when we looked at the subset of patients who had lower blast count AML in the 20-30% range, which is very much like higher risk MDS, we saw an even higher CR rate, about 67% CR rate. You know, a small number of patients, but still a directionally higher rate.
So those types of data, the relationship of MDS and AML, the overlap, the common mutations associated with these diseases, and the fact that RARA elevations are present in both diseases, gives us confidence that the biology matters, and that the trial is designed in such a way that it should see a difference in the CR rates if the drug works. So that's why we have confidence.
In your previous remarks, you discussed the approval based on the CR primary endpoint. There has been some debate, I think, in the MDS field generally, about the data necessary for approval. How confident are you that the CR primary endpoint will support approval? Can you give us some flavor for your discussions with the regulatory agencies?
Sure. So we've actually vetted our trial design with the FDA at the initial moment, and we were informed that CR can serve as the basis for full or accelerated approval. At the time of the trial amendment to include the key secondary endpoint of overall survival, that was reaffirmed, so it's been a very consistent message from them. And, you know, there's ample data that has analyzed studies that have been successful in MDS, namely other studies with hypomethylating agents, that have shown a strong correlation between the complete response rate and the overall survival. Overall survival, obviously, in oncology, is the gold standard of proving your point. But when you have a good surrogate marker that correlates to overall survival, you know, we think we're in good shape.
So we have confidence. There's ample publications. There's even a publication by the FDA itself, who looked internally at 20 years' worth of data in almost 800 patients with high-risk MDS in trials that have been successful that they have reviewed, and they've reported the correlation of CR to overall survival. So it's really not surprising that they themselves have a conviction in making an approval decision based on the CR rate, with the expectation that the overall survival will deliver, you know, the expected outcome.
Yeah, maybe last clinical question on MDS. The overall survival data, what's the best estimate when that could be available?
We haven't forecasted the specific availability of that. So we'll need to obviously enroll additional patients and look at our data, and, you know, when we have better clarity on that, we'll be happy to provide an update on that. But it... We just haven't guided to that just yet.
Conley, there's a partnership with QIAGEN for a companion diagnostic necessary for the RARA positivity. Can you discuss what needs to happen to validate that diagnostic, and will the diagnostic be included in the initial FDA filing?
Yeah, so the plan is that we're working with QIAGEN to commercialize a kit which would be readily available for distribution across the US. It's a blood-based test, as I think David mentioned. And so QIAGEN is responsible for driving the development and the eventual approval for that. But as part of the companion diagnostic, that would be accompanying tamibarotene.
And does that need to be approved at the same time as tamibarotene in order for tamibarotene to be-
It can be, yeah, it can be. There's certainly variations to it, but it's something that we would need to discuss with the FDA and so forth.
Okay. In your initial remarks, you mentioned that 10,000 patients in the US with MDS. Can you maybe dive in a little bit more deeply into the HR-MDS market opportunity? What's the prognosis for those patients, and what is the unmet need?
Yeah, again, tremendous unmet need there. It's roughly 10,000 patients, of which 50% we project are RARA overexpressers, right? So a significant portion that our drug would target. Within this class, these patients are typically in their mid-70s, but they would be treated in the community, right? So tolerability is really quite, quite necessary, if you will, for, for treatment of these patients so that they don't need to come into institutions and, and so forth for their treatment. The overall, survival is still only about 18-18.5 months for these patients, and so it's still quite dire. And these patients are pretty sick, right? So they have low blood counts, they have tremendous fatigue, bleeding, and so forth.
And so the current treatment, which is azacitidine, has been around for, you know, 15 years, and it has a CR rate of 17%, roughly. So again, tremendous unmet need, a significant portion of the patients and a significant percentage of which are RARA overexpressers.
Conley, we'll stay with you. How would the treatment landscape change, should the Phase III VERONA trial of azacitidine plus venetoclax in newly diagnosed HR-MDS succeed? Do you have a different strategy for marketing Tami should VERONA succeed versus fail?
Yeah, it's a great question. I, I think VERONA offers certainly another option for these patients, but, as I said, I think our value proposition is very different than VERONA. Both in terms of the tolerability and safety. As you know, venetoclax is a challenging drug to give, pretty toxic, and, requires some real oversight, if you will. For us, it looks like we have a very manageable adverse events profile. We're a targeted drug, and so there is certainly, a strong number that really prefer targeted therapy, so that it's really the right drug, for these patients. And so I, I think our value proposition doesn't change, and our strategy most likely, won't differ dramatically, whether it's a venetoclax or a non-venetoclax market.
What are Syros's commercialization plans? Do you plan to commercialize Tami yourself?
Yeah. It's a fairly targeted group of physicians in the U.S. And so in the U.S., our plan absolutely is to commercialize ourselves, build a very efficient infrastructure, and target these physicians within the U.S. I think we can do that quite effectively. In Europe, it's much more fragmented, as you know, multiple countries requiring separate organizations and approvals, and particularly around pricing and so forth. So our plan would be to partner that out in Europe.
Got it. Turning to AML here in the last several minutes. David, initial data from SELECT-AML-1 were released in December 2023. Can you provide highlights of that, those results?
Sure. Thanks again. That's a very important data set for a number of reasons. It was an evaluation, a randomized evaluation of tamibarotene plus Aza and venetoclax versus Aza and venetoclax, randomized one-to-one. The study's objectives are to enroll a total of 80 patients. We did a pre-specified analysis of about 23, the first quarter of the enrollment, and that was reported in December. We showed that we had a 100% CR/CRi rate, compared to a 70% CR/CRi rate in the control arm. We showed that 78% of the responses were CRs, the higher quality response, compared to 30% in the control arm. All of the responses, you know, the CR/CRis all occurred during cycle one, and so it was a high response rate with rapid onset.
We also showed the safety was very encouraging. We had no evidence of added toxicities in either the non-heme or heme safety profile. And we thought that was very important because oftentimes, when making an effort to, you know, improve upon the efficacy of a drug, you lose a little bit with the safety, and in this case, we didn't. And in fact, some of the trends in the safety for heme tox looked favorable toward the triplet compared to the doublet, which meant that we saw less neutropenia, less febrile neutropenia, and less leukopenia, 9 versus 47%, approximately, across those various parameters. And that may very well be related to the mechanism where our drug is known to promote differentiation of the myeloid compartment, helps those cells get out of the marrow and mature normally in the peripheral blood.
So it may have provided an opportunity to offset some of the myelosuppression that one may see with the venetoclax regimen. Of course, that remains to be seen, as we have additional data that we're looking forward to sharing, you know, in the third quarter of this year. And you know, we'll have data on at least half of the enrolled patients, so that'll be a minimum of 40 patients randomized. And so that should be a nice update to help continue understanding the performance of that.
The last point I wanna make about why that's an important data set is that it helps us really have some insight into the fact that, you know, we believe the opportunity to achieve a CR in the MDS program is further enhanced by the fact that we can normalize the blood counts in the context of Ven and Aza. In our MDS trial, we're just combining our drug with Aza. So the absence of added toxicity on the heme end really supports the ability to deliver CRs in the MDS setting. And so, you know, for us, it's just a very exciting data outcome that, you know, we were happy to share, and we look forward to the next one.
What are the likely next steps in AML? Will you be ready to disclose what those are after the Q3 data, then? When could we know what the path forward is?
So, we haven't disclosed when we're gonna disclose the information. But, what I will say is, obviously, what we do is gonna be very determined by the data we see. An obvious next step would be a Phase III registrational trial. And then the ability to do that trial will be determined by what that looks like. So how big the trial needs to be, what the exact powering assumptions would need to be, what kind of difference we could expect to achieve. It's all gonna be determined by the data. So we need to have enough data with enough confidence to help set the stage for that discussion, and we're not there yet. We haven't shared that data in the third quarter, so I'm gonna have to leave your question with the answer of, like, stay tuned.
Okay. Conley, can you discuss the market opportunity in first line unfit AML?
Yeah, tremendous-
What?
... Yeah, tremendous opportunity. About 30% of the AML patients are RARA overexpressers. So again, very high percentage. We're not looking for sort of this needle in the haystack as some targeted therapies. There's roughly 10,000 patients as well in the US, slightly north of that. And as David said, you know, the key here is that we're adding to the backbone of venetoclax and azacitidine, so we're not competing against the standard of care. We're actually adding on top of that. And so that really broadens our market reach, if you will, in the space. And if we can really achieve that without added toxicity and, you know, knock on wood, if it even reduces some of the toxicity, I think it'd be a tremendous opportunity for us in the AML space.
Great. We are just about out of time. Jason, we'll direct the last question to you. Can you discuss Syros's balance sheet? What's the current cash balance, and how long is that expected to fund operations?
Sure. We announced our first quarter a couple weeks ago, and we have $108 million of cash. You know, based on our forecast, that will take us into the third quarter of 2025, which is well past the pivotal data readout that David described earlier, and the additional AML data that we'll have in the third quarter of this year.
Great. With that, I think we are out of time. I'd like to thank the Syros team for a very interesting discussion, and we wish you the best of luck with all your second-half events.
Thanks. Really appreciate the opportunity.
Thanks very much.