Good morning, and welcome to Syros Pharmaceuticals conference call. At this time, all participants are in a listen-only mode. This call is being webcast live on the Investors and Media section of Syros' website at www.syros.com. Please be advised that today's call is being recorded. At this time, I would like to turn the call over to Karen Hunady, Director of Investor Relations and Corporate Communications at Syros. Please go ahead.
Thank you. This morning, we issued a press release announcing initial data from our SELECT-AML-1 phase II clinical trial. The full release is available on the Investor and Media section of the Syros' website at www.syros.com. We also have slides today that are viewable if you're listening using the webcast, and the slides can also be found on the Events section of the Investor and Media section of our website. We will begin the call with prepared remarks by Conley Chee, our Chief Executive Officer, and Dr. David Roth, our Chief Medical Officer. We will then open the call for questions. Kristin Stevens, our Chief Development Officer, and Jason Haas, our Chief Financial Officer, are also here on the call and will be available for Q&A. Beginning on slide two, I would like to remind everyone that the statements we make on this conference call will include forward-looking statements.
Actual events or results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in the Risk Factors section of our annual report on Form 10-K that we filed earlier in the year, our quarterly reports on Form 10-Q that we have filed subsequently, and any other filings that we may make with the SEC in the future. Any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements. So with that, I'd now like to turn the call over to Conley. Conley?
Thanks, Karen. Good morning, everyone, and thanks for joining us. Today is an exceptionally exciting day for our company as we share the first data from a randomized clinical trial of tamibarotene that we believe support our path forward, both in AML and the closely related disease, higher-risk MDS. But before we get to the data, I'd like to just take a few minutes to provide some background of our company, its focus, and why today's data is so important to our mission. I'll start on slide three. At Syros, we're focused on a singular goal: developing new standards of care for frontline treatment of patients with hematologic malignancies, which have largely eluded current approaches. We're applying this strategy to advance tamibarotene, an oral selective retinoic acid receptor alpha agonist, to genomically define subsets of higher-risk MDS and AML.
To remind everyone, these subsets are significant. Approximately 60% of the higher-risk MDS patients and 30% of the unfit AML patients are positive for RARA gene overexpression. Moving on to slide 4. Higher-risk MDS and AML are both complex diseases in need of better treatment options. Despite the recent treatment advances, roughly one-third of newly diagnosed unfit AML patients did not respond to current standards of care, and virtually all patients eventually relapse, leaving them very few therapeutic alternatives. Higher-risk MDS is closely related to AML, and it can be considered on a disease continuum with shared biology, with more than half of the higher-risk MDS patients eventually progressing to AML. Hypomethylating agents, or HMAs, are the existing standard of care, both providing limited efficacy, with many patients continuing to suffer significant mortality and morbidity.
Aside from HMAs, no new therapies have been approved since 2006. Moving on to slide 5. This is why we're so excited about the potential opportunity for tamibarotene. This is based on tamibarotene having a unique profile. As shown on the table to the right, tamibarotene has biologically targeted, has a high complete response rate, rapid time to response, and its favorable tolerability with no additive myelosuppression, leave it a great, combination partner. Moving on to slide 6. The data we share today provides critical proof of concept for our approach and support our path forward, both in AML and the closely related higher-risk MDS.
As David will detail shortly, the initial data from our randomized portion of our SELECT-AML-1 phase II trial demonstrated a 100% CR/CRi rate in patients treated with a triplet regimen of tamibarotene, venetoclax, and azacitidine, compared to 70% CR/CRi rate in patients treated with ven/aza alone. What's equally impressive is that the triplet arm demonstrated a CR rate of 78% versus 30% in the doublet arm. This initial data suggests that the addition of tamibarotene not only has the potential to deliver high quality and rapid responses, but also the potential to improve upon existing standards of care without added toxicity. We're incredibly encouraged by this data. We plan to continue enrolling SELECT-AML-1 and look forward to reporting additional data next year.
In addition, we remain on track to complete enrollment for the CR endpoint in the SELECT-MDS-1 in the first quarter of 2024, and to report pivotal CR data by mid-Q4 next year. With that, I'll turn it over to David to review the phase two data in greater detail. David?
Thanks, Conley. I wanted to say that I think you really laid that out and the potential opportunity for tamibarotene very nicely and helped to explain why we're all so excited to share these promising initial randomized data from our SELECT-AML-1 trial today. And if I may, I also want to share my personal excitement for you as our new CEO at Syros and I look forward to working with you. Okay, for everyone who's listening in, let's turn to slide 7 so I can begin to walk you through our data. As a reminder, SELECT-AML-1 is a randomized study focused on evaluating the addition of tamibarotene to the standard of care regimen of venetoclax and azacitidine versus ven/aza alone in 80 patients who are going to be randomized one to one across the two arms.
We're only enrolling newly diagnosed unfit AML patients who, by definition, have not been treated for AML previously. All patients must be positive for RARA overexpression based on our blood-based RT-PCR clinical trial assay, which has been in use in our trials since we initiated tamibarotene development. The goal of the study is to evaluate the clinical activity and, of course, safety of the tami/ven/aza triplet versus the ven/aza doublet to set the stage for a future registration-enabling study. This is what we call a phase II randomized proof of concept trial. The primary endpoint is the CR/CRi rate, which was selected based on the primary endpoint data of the ven/aza pivotal trial, to allow for consistency in comparison of the outcomes across the arms of this study, as well as to the historical outcomes of the ven/aza pivotal trial itself.
The drugs were dosed, as noted on the right, with tamibarotene being administered starting on day eight and going through day 28 of each 28-day treatment cycle. Tamibarotene is given orally at 6 milligrams twice a day, and ven and aza are administered according to their approved labels. There are 28 sites open for enrollment across the United States and France, and we believe the wide range of centers and the large numbers of investigators contributing patients to the study increases the robustness of our data outcomes and the reproducibility and consistency of our data as we move this program forward with ongoing enrollment.
Okay, so now if you turn to slide 8, you'll see that there were a total of 23 patients who were enrolled into the study and who initiated treatment in one of the two arms by the data cutoff date for this pre-specified interim analysis on November 13, 2023. Twelve patients were randomly assigned to the tami/ven/aza arm and 11 to the ven/aza arm. You'll notice that nine patients were response evaluable for the tami/ven/aza arm, and 10 were response evaluable for the ven/aza arm. The non-evaluable patients either came off the study before their first assessment without disease progression or hadn't yet reached their first assessment because they had just recently enrolled. The details are noted on the right side of the slide.
Turning to slide 9, we analyzed the baseline characteristics of the enrolled patients and compared them across the two arms to be sure that the clinical features were consistent, so we could compare the outcomes across the two arms in a fairly straightforward manner. As you can see, these patients were typical for elderly, unfit AML patients, and the features are well balanced across the two arms. It's important to see that ELN risks were consistent across the two arms as well. On the next slide, slide 10, you'll see that the tami/ven/aza triplet delivered a 100% CR/CRI rate, with the majority of responses, 78%, being complete responses or CRs, and the rest CRIs. In the ven/aza doublet arm, the CR/CRI rate was 70% and the CR rate was only 30%.
Other responses were noted to support secondary endpoints, and they're shown below in the table. The time to response was rapid across both arms, with similar median times to response and with all patients 100% in the triplet arm responding by the end of cycle one, compared to 60% in the doublet. I want to point out that these are early data, with enrollment just beginning during Q1 of 2023 and our data cut on November 13... So we don't have information yet on response duration, event-free survival, or overall survival. These are longer-term outcomes that will be evaluated as the study continues, and we enroll more patients. We'll also be looking at molecular features that may be associated with response, with failure to respond, or with loss of response after one may occur, and we plan to report more data on, in 2024.
I also wanted to point out that the doublet treatment failure patient literally just entered part 3, which is the salvage arm of the study, with tamibarotene being added to ven/aza as a test for its ability to rescue someone who has primary refractory disease. So as you can see, these are very exciting data, and we really can't wait to see more clinical activity and share it with you next year. Okay, now turning to slide 11, which starts to talk about safety. Here we focus on hematologic safety. It's important that this data slide, you know, represents the outcomes because we know that myelosuppression is a side effect of the ven/aza standard of care regimen, with high rates of grade 3 or grade 4 cytopenias, febrile neutropenia, and sepsis. This data demonstrates that there is no additive myelosuppression associated with adding tami to ven/aza .
The reported rates are either similar or, in some circumstances, higher for the doublet. We were not aiming to demonstrate improvement in the safety profile, and one should not overly interpret this outcome, although tamibarotene is a differentiating agent, and if this holds as the study dataset matures, it would certainly be interesting. We take this as early evidence that continues to support our belief that tamibarotene is generally well-tolerated, is not known to be intrinsically myelosuppressive, and may well combine with other drugs that have distinct mechanisms of actions associated with narrow suppression. I also want to comment that this may be contributing to the high complete response rates noted on the prior slide, where blood count recovery is needed to achieve a complete remission, and which bodes well for the use of tamibarotene in our higher-risk MDS pivotal trial, where the CR rate is our primary endpoint.
As you know, hematologic improvement is required to achieve a CR in MDS as well. On our last data slide, slide 12, we show that the non-hematologic adverse events are represented across the two arms, with the majority being low grade, either grade 1 or grade 2, and generally similar across the two arms, with no new safety signals to note and with similar treatment duration across the two arms. Moving now to slide 13. In conclusion, these represent exciting data. These initial randomized data demonstrate clinical activity as well as safety that supports the potential for tami in combination with standard of care in the frontline treatment of hematologic malignancies, specifically AML, as well as higher-risk MDS with RARA overexpression.
We saw a 100% CR/CRi rate with a very rapid onset of response and no new safety signals associated with the addition of tamibarotene to venetoclax standard of care. Over the years, we've amassed a body of consistent clinical evidence using tamibarotene in both AML and higher-risk MDS, which gives us confidence that a tamibarotene-based combination treatment in patients with RARA overexpression is a novel, targeted approach with potential to improve current frontline treatment in both AML and in closely related higher-risk MDS. With that, I'd now like to turn the call back over to Conley for our last two slides. Conley?
Thank you, David. I want to take a moment to comment on why we believe this data are so transformational. It's because they open the door for us to positively impact the care of many, many people and deliver better outcomes to the thousands of families. During my 20+ years in the industry, I've had the privilege and good fortune to bring several important targeted medicines to the market, including the first combination therapy for BRAF inhibition and a cMET inhibitor, both in lung cancer, as well as a PI3 kinase inhibitor in breast cancer. And through these experiences, I've learned firsthand the tremendous power of a targeted therapy to improve treatment outcomes. I've also experienced physicians' willingness to rapidly adapt new genetic testing into their practice when novel and compelling targeted medicines are available.
As I think about tamibarotene, I see many parallels to these other therapies, which reinforces my confidence in the commercial opportunity for our compound. I believe tamibarotene, with its potential profile, has the ability to capture significant market share, and I look forward to working alongside my colleagues to bring this novel targeted medicine closer to patients. Moving on to slide 14, let me speak specifically about the market. With tamibarotene, I believe we have the potential to deliver meaningful benefit to a large population. You've heard us talk many times before about the prevalence of RARA overexpression, but the data suggests that there are 21,000 newly diagnosed higher-risk MDS patients annually in the U.S. and in the E.U., of which 50% have RARA overexpression. In unfit AML, 25,000 newly diagnosed unfit AML patients are in the U.S. and the E.U. annually.
... with 30% RARA overexpression. In engaging with key opinion leaders and treatment decisions, it's obvious that there's a need for new options for these patients. Medicines that can consistently deliver a high response rate, a rapid time to response, and with a favorable tolerability profile. And now with multiple consistent and compelling data sets in hand, we believe tamibarotene holds the promise to deliver that profile to the higher-risk MDS and MDS, I'm sorry, and AML patient population. And that tamibarotene has the potential to establish a new standard of care. Moving on to slide 15, in conclusion, I'd like to just remind you of the meaningful catalysts that we expect in the near term. As I mentioned at the start of the call, we continue to enroll patients in SELECT-AML-1, and look forward to reporting additional data in 2024.
In addition, we remain on track to complete enrollment for the CR endpoints in SELECT-MDS-1 in the first quarter of next year, and to report top-line pivotal data by mid-Q4 of next year. And with that, I want to thank you all for your attention, and I'll now turn it back to the operator for questions. Operator?
Thank you. Ladies and gentlemen, we will now begin the question-and-answer session. Should you have a question, please press the star followed by the number 1 on your telephone keypad. You will hear a 3-tone prompt acknowledging your request, and your questions will be pulled in the order they are received. Should you wish to decline from the calling process, please press the star followed by the number two. If you're using a speakerphone, please keep the handset before pressing any keys. One moment, please, for your first question. Your first question comes from the line of Ted Tenthoff from Piper Sandler. Your line is open.
Great, thank you.
Hi, Ted.
Good morning. Congratulations on really unprecedented response. I was wondering, Dave, you touched on this a little bit, just the importance of the safety profile. I mean, that beyond the efficacy, that really stands out. I'm wondering if there's anything mechanistically that might speak to why you're seeing such a clean safety profile, again, just through the mechanism of tamibarotene. Thanks.
Yeah, thanks for that question, Ted. So, you know, we have evaluated tamibarotene in various contexts over several years and have consistently demonstrated that the tolerability profile is generally well tolerated, with the majority of adverse events being low grade and reversible. And, you know, the underlying mechanism being one of a differentiating agent, may work or operate to increase the numbers of blood cells and to help promote their normal maturation. So, you know, mechanistically, it's distinct from the other drugs that it's being partnered with, azacitidine and venetoclax don't work in that fashion. So there may be some complementarity there.
You know, and so for those reasons, we've always believed it would be a drug that could be readily combined with other drugs, just because its properties don't overlap, and we wouldn't expect to add to the toxicity. You know, just one comment really is that, you know, obviously we're incredibly pleased with these outcomes and the reports. We do need to see these data evolve over time. You know, obviously we find them very exciting and, you know, promising, but we do wanna continue to observe this and make sure this holds up.
Thanks, Dave. Congrats.
Thank you.
Your next question comes from the line of Eva Privitera from TD Cowen. Your line is open.
Hi. Congratulations on the data, and thank you for taking our questions. Just a couple from us. Did the ven/aza arm perform in line with your expectations? I know that, previously you've mentioned that RARA-positive patients typically have a monocytic phenotype that has a lower response than aza. And what proportion of patients in SELECT -AML had this, had a high monocytic expression score?
Okay, that's a great question. So you're referring to previous data where our translational data have shown enrichment for the monocytic expression score associated with being positive for RARA overexpression. And we had made the correlation that because there have been reports of ven resistance in that situation, the ven/aza arm may perform differently than in all comers. So that, you know, just to put that out there, that's something that we've previously reported on.
We have an effort now ongoing to continue gathering additional molecular data on our patients, which include the MES signature, as well as the molecular characteristics of these patients at baseline, the mutations, all the cytogenetics and those things, so that we can actually do a formal correlation of those outcomes with, you know, with their baseline characteristics, and we can better dig into that. Now, that said, you know, ven/aza delivered a 70% CR/CRi rate. It's reported in its pivotal study to have a 66% CR/CRi rate. So it's performed as it's been reported to perform. You know, we have been saying all along that we believe tamibarotene has a great opportunity to fulfill an unmet need, and that the current standard of care, you know, delivers responses in about two-thirds of patients....
and that the majority of responders ultimately relapse, and it's been our aim to address unmet need. So, you know, this early data set takes us up to address that unmet need from the 70%-100%. And I think that we're really excited to see that it's delivering as expected in that context. And again, you know, we're gonna continue to follow that data, and we'll have more information on the monocytic features in the future, along with other molecular characteristics.
That was really helpful. Thanks. And so a second question: so given the current pace of enrollment, when do you expect to complete enrolling the SELECT-AML trial? And how should we think about future updates? Will they be, you know, more incremental in terms of patient numbers and follow-up, or will it give us a closer picture of what the full data set might look like?
Yeah. So we're very pleased with our enrollment. The tactics for operationalizing the trial have been quite successful. As you know, we have 28 sites actively recruiting into the trial as of the time of our data cutoff, operating both in the United States and France with great enthusiasm. We have not specified the timing of our next data update other than to say it'll be in 2024, and the amount of that data, you know, at the time of its presentation, you know, we haven't really specified. Obviously, as always, we try to provide as much information as we have available at the time. You know, now, given this is a randomized trial, there are you know, some pre-specified analyses that will govern the timings by which we can take looks at our data.
And so, you know, it's all a bit of, you know, a slightly, you know, uncertain moment at the moment in terms of how to exactly forecast when it will be in 2024 that we present the information. But we'll let you know when we know.
That's great. Thanks for taking our questions.
Thank you. I'm showing no further questions at this time. I would like to turn it back to Conley Chee for closing remarks.
Okay, thank you, operator, and thank you all for joining us. We look forward to providing updates again soon. Have a great day.
Thank you, presenters. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.