Q3 2020 Syros Pharmaceuticals Inc Earnings Call

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Good afternoon, and welcome to this year's Pharmaceuticals third quarter 2020 financial results Conference call.

Operator: Good afternoon, and welcome to Syros Pharmaceuticals' third quarter 2020 financial results conference call. At this time, all participants are in a listen-only mode.

This time, all participants I know listen only mode.

Operator: This call is being webcast live on the Investors and Media section of Syros's website at www.syros.com. Please be advised that today's call is being recorded. Following the formal remarks, we will open the call up for your questions. At this time, I would like to turn the call over to Naomi Aoki, Vice President of Corporate Communications and Investor Relations at CIRA.

Call is being webcast live on the investors and media section of <unk>.

Lets site at Www, that's U.S. dot com. Please be advised that todays call is being recorded following the formal remarks, we will open the call up for your questions. At this time I would like to turn the call over to nail me Aoki, Vice President of corporate Communications and Investor Relations at Stephens.

Thank you. This afternoon, we issued a press release with our third quarter 2020 financial results, along with anticipated future milestones and recent accomplishments.

Naomi Aoki: This afternoon, we issued a press release with our third quarter 2020 financial results, along with anticipated future milestones and recent accomplishments. This release is available on the Investors & Media section of Syros' website at www.syros.com. We'll begin the call with prepared remarks by Dr. Nancy Simonian, our Chief Executive Officer, Dr. David Roth, our Chief Medical Officer, and Joe Farah, our Chief Financial Officer. We will then open the call for questions. Dr. Eric Olson, our Chief Scientific Officer, and Dr. Jeremy Springhorn, our Chief Business Officer, are also on the call and will be available for Q&A. Before we begin, 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, our quarterly report on Form 10-Q that we filed this afternoon, and any other filings that we may make with the SEC in the future.

This release is available on the investors and media section Osiris is website at www Dot Sierra Dot com.

We will begin the call with prepared remarks by Dr., Nancy Simonian, Our Chief Executive Officer, Dr., David Roberts, Our Chief Medical Officer, and Joe Farah, Our Chief Financial Officer.

We will then open the call for questions.

Dr., Eric Olson, our Chief Scientific Officer, and Dr., Jeremy Spring Horne, our Chief business Officer are also on the call and will be available for Q anyway.

Before we begin I would like to remind everyone that statements. We make on this conference call will include forward looking statements.

Naomi Aoki: In particular, the extent to which the COVID-19 outbreak continues to impact our operations, and those of the third parties on which we rely, will depend on future developments, which are highly uncertain and cannot be predicted with confidence. Any forward-looking statements made on this call 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.

Nancy A. Simonian: We would now like to turn the call over to Nancy. Thanks, Naomi. Good afternoon, everyone, and thank you for joining us today as we review our recent progress. At Syros, we aim to redefine the power of small molecule medicine and control the expression of genes to provide profound benefits for patients with cancer and monogenic diseases. To do that, we invest in three core pillars of our business.

Nancy A. Simonian: Advancing SY1425 is a foundational therapy for RARA-positive patients. Delivering on the Promise of CDK7 Inhibition and building a robust pipeline in oncology and monogenic diseases using our gene control platform. As we advance through the second half of 2020, our efforts are bearing fruit. As David will review, we recently presented initial data from our ongoing Phase 1 trial of SY5609 at the EORTC, NCI, AACR, or ENA meetings. These early data reinforce our conviction in CDK7 inhibition as a potentially transformative, targeted approach for difficult-to-treat cancer. The data demonstrated biological activity at tolerable doses, and importantly, the level of biological activity observed was associated with tumor regressions in preclinical models of 5609 and with clinical activity with our first-generation IV CDK7 inhibitor. As we move forward in this trial, we are robustly evaluating 5609 with the goal of identifying optimal next steps toward delivering the greatest potential benefit for patients. Meanwhile, we are advancing toward key readouts from the Phase 2 trial of 1425, which, as we announced this morning, will be highlighted in oral presentations at the upcoming ASH annual meeting in December. This is a very important milestone for Syros.

50, 609 at the E O R. T C N C. I a C. R. R E in a meeting.

These early data reinforce our conviction and C. D K seven inhibition as a potentially transformative targeted approach for difficult to treat cancers.

The data demonstrated biologic activity at tolerable doses and importantly, the level of biologic activity observed was associated with tumor regressions and preclinical models of 56 O nine and with clinical activity with our first generation I V. C D K seven inhibitor.

As we move forward in this trial, we are robustly evaluating 50 609 with the goal of identifying optimal next steps toward delivery the greatest potential benefit for patients.

Meanwhile, we are advancing toward key readouts from the phase two trial, a 14th 25, which is we announced this morning will be highlighted an oral presentation at the upcoming ash and you'll be eating in December.

This is a very important milestone for ciros.

14 twenty-five has shown promising clinical activity in combination with a society and.

Nancy A. Simonian: 1425 has shown promising clinical activity in combination with azacitidine in newly diagnosed AML and has broad potential for a range of rara-positive patients. However, despite recent advances, about a third of newly diagnosed unfit AML patients still don't respond to upfront treatment, virtually all eventually progress, and upon relapse, there are limited options for patients. As David will share in a few moments, we are very encouraged by the data that continue to emerge from our Phase 2 trial. We are also excited to share new data at ASH suggesting that 1425 may be a promising option for patients who may be refractory to upfront treatment with Venetica. We look forward to discussing all these data and providing next steps for development at AAS. Turning to our third pillar, our leading gene control platform is critical for fueling a robust and sustainable pipeline. While both of us have been working from home,

Newly diagnosed AML and has broad potential for a range of rubber positive patient.

Despite recent advances about a third of newly diagnosed unfit AML patient still don't respond to upfront treatment.

Ritually, all eventually progress and upon relapse their unlimited options for patients.

Nancy A. Simonian: Our lab-based employees will continue to go into our labs to advance our preclinical and discovery programs. We are making excellent progress on our early stage pipeline, and we remain on track to nominate our next development candidate by the end of 2021. Our progress across our three strategic pillars lays the foundation for significant growth for Syros as we strive to build an enduring company with a portfolio of medicines that make a profound difference for patients. With that, I'd like to turn the call over to David to review our recent Phase I data for 5609 and our upcoming ASH presentation. David?

With a portfolio of medicines that make a profound difference for patients.

With that I'd like to turn the call over to David to review, our recent phase one data for 56, so nine and our upcoming Ash presentation Dave.

David.

Thank you Nancy and good afternoon to everyone joining us.

David A. Roth: Thank you, Nancy, and good afternoon to everyone joining us. Let me begin by reviewing the initial Phase 1 data for 5609 that we announced last month at the virtual ENA meeting. As a reminder, the Phase I Dose Escalation Study is enrolling patients with advanced breast, colorectal, lung, ovarian, or pancreatic cancer or with solid tumors of any histology that harbor RB pathway alterations. The study is also evaluating 5609 in combination with fulvestrin in patients with CDK4-6 inhibitor-resistant HR-positive breast cancer. The data at ENA focused on safety, tolerability, PK, and PD. As Nancy mentioned earlier, we are encouraged by the data we are seeing at this stage of the trial. As of the August 21st data cut-off, 17 patients had been enrolled in the ongoing dose escalation trial, including 13 patients treated in single-agent cohorts and 4 patients treated in the fulvestrant combination cohort. Across all the enrolled patients, the majority of adverse events were low-grade, and the most commonly reported AEs were nausea, diarrhea, fatigue, low platelets, and vomiting. Importantly, we demonstrated proof of mechanism for 5609.

Let me begin by reviewing is the initial phase one data for 56 or nine that we announced last month at the virtual DNA meeting.

As a reminder, the phase one dose escalation study is enrolling patients with advanced breast colorectal lung ovarian or pancreatic cancer or with solid tumors of any histology that harbor RB pathway alterations.

The study is also evaluating 56, so nine in combination with Fulvestrant in patients with CDK four six inhibitor resistant HR positive breast cancer.

The data at DNA focused on safety, Tolerability PK and PD.

As Nancy mentioned earlier, we are encouraged by the data we are seeing at this stage of the trial.

As of the August 20, Onest data cut off 17 patients had been enrolled in the ongoing dose escalation trial, including 13 patients treated in the single agent cohorts and for patients treated in the fold restaurant combination cohort.

Across all the enrolled patients the majority of adverse events were low grade and the most commonly reported eightys were nausea, and diarrhea, fatigue, low platelets and vomiting.

Importantly, we demonstrated proof of mechanism for 56 or nine through.

David A. Roth: Through our work on CDK7 inhibition, we discovered that inhibiting CDK7 leads to increases in Pol R2A messenger RNA, and we're measuring Pol R2A as a PD marker in the trial. The data at ENA showed dose-dependent increases in PolR2A in patients treated with 5609. At the three milligram daily dose, PolR2A reached levels at steady state associated with tumor regressions in preclinical studies of 5609 and with CDK7 target engagement at which an adorable clinical response and apoptosis were observed in a trial of patients with our first generation IV CDK7 inhibitor.

Through our work on CDK seven in addition, we discovered that inhibiting CDK seven leads to increases in Paul or to a messenger Arnie and we're measuring Paul our two way as a PD marker in the trial.

The data at DNA showed dose dependent increases in Paul our two way in patients treated with 56 or nine.

At the three milligram daily dose Paul our two eight reached levels at steady state associated with tumor regressions in preclinical studies of 56 million.

And with CDK seven target engagement at which a durable clinical response and ebook ptosis were observed in a trial of patients with our first generation Ivy CDK seven inhibitor.

As we move forward and dose escalation, where further focusing on patient populations. We believe are more likely to respond to 56 or nine exploring combinations and evaluating ultimate dosing regimens all with the goal of identifying optimal next steps for both single agent and combination development.

David A. Roth: As we move forward in dose escalation, we're further focusing on patient populations we believe are more likely to respond to 5609, exploring combinations, and evaluating alternate dosing regimens, all with the goal of identifying optimal next steps for both single agent and combination development opportunities. We opened an extension cohort in lung cancer to further evaluate the 3 mg daily dose in a select patient population. We believe there's a strong rationale for CDK7 inhibition in both small cell and non-small cell lung cancer based on our preclinical data and the genetics of these tumor types. Small cell lung cancer has a high prevalence of RB alterations, which we've shown preclinically to be associated with deep and durable responses to 5609. And non-small cell lung cancer is often driven by oncogenic activation of MAP kinase signaling, which we identified preclinically as another dependency susceptible to CDK7 inhibition.

Entities.

We opened an extension cohort in lung cancer to further evaluate the three milligram daily dose in a selected patient population.

We believe there is a strong rationale for CDK seven inhibition in both small cell and non small cell lung cancer based on our preclinical data and the genetics of these tumor types.

Small cell lung cancer has a high prevalence of RMB alterations, which we've shown pre clinically to be associated with deep and durable responses to 56 or nine.

And non small cell lung cancer is often driven by oncogenic activation of map kinase signalling, which we identified preclinically as another dependency susceptible to CDK seven inhibition.

David A. Roth: We also opened the trial to patients with advanced pancreatic cancer, a tumor type in which oncogenic activation of MAP kinase signaling and RB alterations also play key roles. And we expanded the combination cohort in CDK4-6 inhibitor-resistant HR-positive breast cancer patients to further characterize safety, tolerability, PK, PD, and anti-tumor activity of 5609 in combination with fulvester. Finally, we're exploring alternate schedules and doses to position ourselves for various single agent and combination opportunities. The exploration of alternative regimens is also supported by preclinical data showing that we can achieve similar robust responses in preclinical models with daily and intermittent dosing schedules. Together, we believe these approaches will enable us to identify optimum next steps and ultimately best deliver on the promise of CDK7 inhibition. We'll look forward to reporting additional data from the ongoing dose escalation, including clinical activity data, in mid-2021. Let me now turn to SY 1425.

We also opened a trial to patients with advanced pancreatic cancer, a tumor type in which oncogenic activation of map kinase signalling and RV alterations also play key roles.

And we expanded the combination cohort in CDK four six inhibitor resistant HR positive breast cancer patients to further characterize safety Tolerability PK PD and anti tumor activity of 56 to nine in combination with Fulvestrant.

Finally, we are exploring ultimate schedules and doses to position ourselves for various single agent and combination opportunities.

The exploration of Ultimate regimens is also supported by preclinical data showing that we can achieve similar robust responses in preclinical models with daily and intermittent dosing schedules.

Together, we believe these approaches will enable us to identify optimal next steps and ultimately best deliver on the promise of CDK seven inhibition.

Well look forward to reporting additional data from the ongoing dose escalation, including clinical activity data in mid 2021.

Let me now turn to S.Y. 14 25.

As Nancy mentioned in two oral presentations at Ash we.

David A. Roth: As Nancy mentioned, in two oral presentations at ASH, we will be detailing clinical data from our fully enrolled ongoing phase 2 trial in newly diagnosed unfit AML patients and relapsed or refractory AML patients. While we'll save the detailed discussion of the data for ASH, we're very encouraged by the results that continue to emerge from this study, beginning with the newly diagnosed unfit patient population. As noted in our abstract, the combination of 1425 and azacitidine continues to show high response rates in RARA-positive patients with rapid time to response and high rates of transfusion independence. We also saw evidence of clinical activity in RARA-positive relapsed or refractory AML patients. And importantly, the 14-25 azacitidine combination continues to be safe and well-tolerated across both patient populations.

We will be detailing clinical data from our fully enrolled ongoing phase two trial in newly diagnosed unfit AML patients and relapsed or refractory AML patients.

While we will save the detailed discussion of the data for Ash, we're very encouraged by the results that continue to emerge from this study.

Beginning with the newly diagnosed unfit patient population.

As noted in our abstract the combination of 14 25 and Asia cited team continued to show high response rates in RARA positive patients with rapid time to response at high rates of transfusion independence.

We also saw evidence of clinical activity and we are a positive relapsed or refractory AML patients.

And importantly, the 14 25 basis hydrogen combination continued to be safe and well tolerated across both patient populations.

Also at Ash, we will present, new data showing that the majority of Rama positive patients have a disease phenotype thats associated with resistance to upfront treatment with venetoclax highlighting the opportunity for 14 25 to also address this emerging high unmet need in the newly diagnosed.

David A. Roth: Also at ASH, we will present new data showing that the majority of RARA-positive patients have a disease phenotype that's associated with resistance to upfront treatment with venetoclax, highlighting the opportunity for 1425 to also address this emerging high unmet need in the newly diagnosed unfit AML patient setting. Taken together, we believe the data we will be presenting at ASH describe compelling evidence for the potential of 1425 and support multiple opportunities to advance 1425 in combination in the RARA-positive patient population. We look forward to providing additional detail on our phase two clinical results and our future plans at ASH next month. With that, I'll pass the call over to Joe to review our financial results for the third quarter. Thank you, David. We ended the third quarter in a strong financial position, with $93.1 million in cash, cash equivalents, and marketable security, compared to $91.4 million on December 31st, 2019.

Most unfit AML patient setting.

Taken together, we believe the data we will be presenting at ash described compelling evidence for the potential of 14 25 and support multiple opportunities to advance 14 25 in combination in RARA positive patient populations.

We look forward to providing additional detail on our phase two clinical results and our future plans at Ash next month.

With that I'll pass the call over to Joe to review, our financial results for the third quarter.

Thank you David.

We ended the third quarter in a strong financial position.

With $93.1 million in cash cash equivalents and marketable securities compared to 91.4 million on December 30, Onest 2019.

Based on our current plans, we believe we have sufficient cash to fund our operating expenses and capital requirements into 2022.

Joe Farah: Based on our current plans, we believe we have sufficient cash to fund our operating expenses and capital requirements into 2022, beyond the next wave of expected data readouts for 1425 and 5609, while also continuing to invest in our preclinical programs and in discovery. We recognized $3.8 million of revenue in the third quarter of 2020 compared to $0.6 million in the third quarter of 2019. This consisted of $3.5 million under our collaboration with GBT and $0.3 million under our collaboration with Insight. All revenues recognized in the third quarter of 2019 were under our collaboration with. R&D expenses were $17.7 million in the third quarter of 2020 compared to $15.9 million for the same period in 2019. This increase was primarily due to continued progress in our ongoing clinical trials, our preclinical programs, and employee-related activities. G&A expenses were $5.2 million in the third quarter of 2020, compared to $5 million for the same period in 2019.

Beyond the next wave of expected data Readouts for 14, 25, and 56 online while also continuing to invest in our preclinical programs and then discovery.

We recognized $3.8 million of revenue in the third quarter of 2020 compared to $2.6 million in the third quarter of 2019.

This consisted of 3.5 million under our collaboration with GBT and point 3 million under our collaboration with Incyte.

All revenues recognized in the third quarter of 2019 or under our collaboration with Incyte.

R&D expenses were $17.7 million in the third quarter of 2020 compared to $15.9 million for the same period in 2019.

This increase was primarily due to continued advancement of our ongoing clinical trials, our preclinical programs and employee related expenses.

Operator: Finally, we reported a net loss for the third quarter of $19.5 million, or $0.43 per share, compared to a net loss of $19.8 million, or $0.47 per share, for the same period in 2018. With that, I will turn the call over to the operator for questions. Thank you. As a reminder, to ask a question, please press star then 1 on your telephone. If you would like to remove yourself from the queue, you may press the pound.

Operator: Again, that's star number one to ask the question. Our first question comes from Kenneth Atkins of Cohen. Your line is open. Hi guys, thanks for taking my questions. For the frontline unfit setting in AML, what kind of durability in that setting do you think you would need to demonstrate to have a competitive profile versus the current standard of care, which I guess in most cases is gonna be a NETCLAQ flood estimate.

David A. Roth: David's going to answer that. Yeah, thanks for the question. So when we look at the frontline setting, we really have to look at the totality of the data, not only the duration of the response but, you know, the response rates, the depth of the response, and as well, the tolerability profile. We continue to see a great opportunity for SY1425 in the frontline setting. And when we, you know, present the data at ASH, we'll be able to provide, you know, more context. But I think the most clinically relevant benchmark for durability is, you know, against the backdrop of what we're using as an add-on. So, in the context of azacitidine, we see duration of responses in the frontline setting on the order of 10 months. And so that would probably be the most clinically relevant benchmark for the study. Okay, thanks.

<unk>, a great opportunity for S Y fortune twenty-five in in the frontline setting and when we you know present the data ash will be able to provide you know more context, but I think the most clinically relevant benchmark for durability is you know in the backdrop.

Of what we're using it as an add on so in the context of <unk>, we see duration of responses in the front my setting on the order of 10 months, so that would probably be the most clinically relevant benchmark for this study.

Okay. Thanks that makes sense.

And then for the the C. D case of an inhibitor study recently open some cohorts kicks blur intermittent dosing at four milligrams uhm.

David A. Roth: And then for the CDK7 inhibitor study, you recently opened some cohorts to explore intermittent dosing at 4 milligrams. Just based on the preclinical work that you've done, could you characterize how you expect the intermittent schedules at 4 mg to compare to the continuous at 3 mg in terms of exposure and target engagement and what you hope to achieve? Sure. But I think it's really important to appreciate, you know, these are early data. Actually, we find them very, very exciting at this early stage.

Just based on the preclinical work that you've done could you characterize how you expect the instrument scheduled at four milligrams to compared to the continuous at three milligrams in terms of <unk>.

Exposure and target engagement and and what you hope to achieve there.

Sure. So I think it's really important to appreciate you know. These are these are early data actually we find them very very exciting at this early stage, we've been able to show that at a continuous daily dosing regimen three milligrams.

David A. Roth: We've been able to show that at a continuous daily dosing regimen, three milligrams is the maximum tolerated dose. So, that's with continuous daily dosing. And we've also achieved proof of mechanism already at this early time in this study, where we see increased levels of PolR2A, which is a biomarker for CDK7 biological activity. And the importance of that is related to the fact that we get PolR2A up to sustained levels at the three milligram dose, which correlates with regressions in preclinical models, and as well as with CDK7 target occupancy, as well as So, we're very excited about the position we're in.

Is the maximum tolerated dose so that's what the continuous daily dosing and we've also achieve proof of mechanism already at this early time in the study where we see increased levels of Paul or to a which is a biomarker for C. D K seven biological activity and the importance.

Of that is related to the fact that we're getting paul or to a up to sustained levels at the three milligram dose, which correlate with regressions in preclinical models and as well with CDK seven target occupancy as well as clinical responses any pop ptosis that were demonstrated with our first.

C D. Two $7. So we're very excited about about the position where in.

David A. Roth: You know, we also have data that shows intermittent dosing can deliver the types of preclinical activity we've seen with continuous daily dosing, and we're in the midst of evaluating doses and dosing regimens to best optimize our position moving forward into the future. We were aiming to, you know, develop single agent and combination opportunities. It's a little difficult to specify exactly what we're going to see at the four in an alternate regimen versus the three in continuous daily dosing, but we want to push the dose limits to define our MTDs and the range of doses and dosing schedules so we're best positioned to move forward. I got it.

We also have data that shows intermittent dosing can deliver.

Deliver the types of preclinical activity that has as we've seen with continuous daily dosing and we're in the midst of evaluating various doses and dosing regimens to best optimize our position moving forward into the future we were aiming to develop a simulation a combination opportunities.

It's a little difficult to specify exactly what we're gonna see at four and also your bedroom versus the three and she was gonna go see but we want to push the dosing limits to define our emptied to use in the range of doses and dosing schedules. So we're best position to move forward.

David A. Roth: Thank you for taking the time to answer the question. Yeah, maybe I'll just add that we know that hitting the target or covering it for some period of time is important, and we can measure that with the POL-R2A. I think the question and what's emerging from some of our data is we may not need to have it completely covered for the full, you know, continuously, and still get the same efficacy. And so that's exciting; that allows us flexibility and also helps us with thinking about, you know, combination regimens and things that we might wanna use. So,

Got it maybe get ahead of us.

Yeah, maybe I'll just add that I think we we know that hitting.

Hitting the target are covering it for some period of time, it's important.

So they can measure that by the <unk>.

Think that question and what's emerging from some of my data is we may not need to have it completely covered for the fall you know continuously.

Continuously I'll send that to say that that gets me. So that's exciting that allows us flexibility and also helps us I'm thinking about combination regimens and things that you might want to use uhm. So I'm just.

Operator: I'm just trying to add that. Okay, thank you. Our next question comes from Ted Tenthoff of Piper Sandler. Your line is open.

At that point.

Okay. Thank you.

Huh.

[noise]. Our next question comes from Ted sent off of Piper Stanleigh. Your line is open.

Great. Thank you very much.

David A. Roth: Great. Thank you very much. I just wanted to follow up on the poster that you presented with respect to Venetoclax and really kind of get into a little bit more detail. What kind of market is emerging for Venetoclax refractory patients? Ted, thank you.

I just wanted to curl up on the poster that you're presented with respect to vanilla correct.

I'm I'm really kind of get into a little bit more detail what kind of market is emerging in terms of the debit card perfect because.

I cut out at thank you that that's nice to hear your voice.

You know what we know right now is that you have been the nine o'clock a decided being has become.

Nancy A. Simonian: It's nice to hear your voice. What we know right now is that venetoclax azacitidine has become a standard of care in the unfit AML setting. What we also know is that about a third of patients never respond to Venezo, and they are refractory, they progress quickly, and, in fact, some recent data have shown that they have an overall survival of less than three months. So I think what's very exciting to us is, obviously, one of the things we all want to understand when we have new drugs is, you know, why do some people respond and why do some not. And with some data that came out from some AML doctors earlier this year, they started to characterize sort of the phenotype of those resistant tumors.

A standard of care and the unfit M. L study.

What we also know is that about a third of patients never respond to that email.

And a a refractory they progress quickly in fact, some recent data.

His shell that they have overall survival of left set up <unk> three months. So I think what's very exciting to US is obviously one of the things we all want to understand but we have new drugs is you know why do some people responded <unk> some not N with some data that came out some some AML doctor.

Earlier this year they started to characterize the phenotype at those resistant tumors.

And as David said, the based on our work we've been able to show that.

Nancy A. Simonian: And as David said, based on our work, we've been able to show that patients that have the RARA biomarker are enriched for that disease phenotype that's resistant to Veneza. And I think that is a really exciting finding because we want to be able to treat patients up front with a therapy that's going to put them into complete remission. And so I think this offers a really exciting opportunity to think about making a difference for those patients that aren't responding to the standard of care. Excellent Great

Patience I've had the Robert biomarker are enriched.

<unk> for that disease phenotype, that's resistant to vent Acer.

And I think that is a really exciting finding because we want to be able to treat patients upfront with a therapy, that's gonna put them into complete remission and so I think this offers are really exciting opportunity to think about making a difference for those patients that aren't responding to standard of care.

Great. Thank you very much really need to update.

David A. Roth: Thank you very much. A really neat update. Thanks, Ted. Our next question comes from Jason Butler of J&P Securities. Your line is open. Hey, it's Royan for Jason.

Okay.

Our next question comes with Jason Butler of JMP Security, you're one is open.

Hey, it's Roy in for Jason. Thanks for taking a question that had a coupla to start on 50 609. So uhm following up on the E. R. T. C results are you presenting how does that help us help inform what we should look for mid next year in terms of results and then I Wonder if you go into a bit more detail about how important this new poll.

Operator: Thanks for taking our questions. I had a couple to start on 5609. So, following up on the EORTC results that you presented, how does that help us help inform what we should look for mid next year in terms of results? And then I wonder if you could go into a bit more detail about how important this new Polar 2A biomarker is to the program. And then I had a few on 1425.

Or to a uhm biomarker as to the program and then I had a few on the 14th 25 six.

Yeah, So where encouraged by the early data with 56 O nine and <unk> and have been guiding too mid next year, having more mature dose escalation data, including clinical activity data.

David A. Roth: Yeah, so we're encouraged by the early data with 5609 and have been guiding to mid next year having more mature dose escalation data, including clinical activity data. And so we're, we're still on track for that for the readout mid next year. David, do you want to take the next question? Sure. So we think the Polar2A biomarker is actually important. Polar2A is a gene that codes for RNA polymerase II. The activity of RNA polymerase II is regulated by CDK7.

And so we're we're still on track with that for the readout mid next year.

David do you Wanna take the next question.

Sure. So we think the power to a biomarker is actually important Palmer to a <unk> is a gene that codes for or any preliminaries to the activity of already preliminaries too is regulated by Cdk's seven and we've shown with our research on C. D K seven.

David A. Roth: And we've shown with our research on CDK7 that when you inhibit CDK7, you increase the levels of Polar2A messenger RNA. So the transcripts go up in response to inhibiting the activity. And we were able to develop assays to look at this in preclinical models, and then we translated that to an assay we can use in patients, which is really sort of a special opportunity to probe the biology in our treated patients. The reason why it's particularly exciting is because we have learned so much from our initial work with our first generation CDK7 inhibitor. There, it was covalent, you may recall, and we understood the target coverage we wanted over the dosing interval. We were able to actually look at the patients from that trial. We're always trying to learn from our patients, and we could see how the target engagement correlated with the Polar-2A, and we were able to show that if you could bring the Polar-2A and the target engagement up to certain levels, you could see responses, which is what we did see in that trial, as well as apoptosis.

That when you inhibit Cdk's Avenue increase the levels of par to a messenger RNA. So the transcripts co op in response to inhibit the activity and we were able to develop assays to look at that in preclinical models and then we translated at two and ask you we could use can patients which is really.

Sort of a special opportunity to probe the biology and are treated patients. The reason why it's particularly exciting is because.

David A. Roth: And now we're getting those levels in our 5609 patients, correlating with our preclinical models in 5609. So it's a very informative biomarker for helping us hone in on the dose and the dosing schedule and the way to optimize how to use this drug. And so I think we're in a good place in terms of honing in on exactly how we wanna use 5609, both as a single agent and in combinations, and we're setting the stage for a really robust forward-moving plan as we move forward. Okay, great.

David A. Roth: And then for 1425 at Ashe, you know, abstracts have results through May 27th. How much more treatment time do you think we might see in the presentations themselves? And then for the relapsed refractory population, how do you think about the 20% response rate in terms of, you know, respect to the stage of the disease and the other patient characteristics? Sure.

David A. Roth: So I believe the data cuts for the abstract were in the mid-May timeframe. And for the presentations that will be coming up, you know, we'll probably get another five months or so of information coming out of the trial. You know, we're going to be reporting on the completely enrolled study in 1425 plus AZA in the newly diagnosed unfit and as well in the RARA positive relapsed refractory AML patients. And so, you know, those updates will all be present next month. Okay, great. Then I had one last thing to sneak in.

In the mid May timeframe.

And for the presentations.

That will be coming up we probably get another five months or so of information coming out of the trial, we are going to be reporting.

On the.

The completely enrolled study in fortune 25, plus age in the newly diagnosed unfit.

And as well in the RARA positive relapsed refractory AML patients.

And so those updates will it will all be present next month.

Okay, Great I had one last point sneak it in so the monocyte coaster.

David A. Roth: So the monocyte poster, also Ash, kind of made me wonder about combinations with venetoclax. Can you remind us if you've looked pre-clinically at that combination? Is it something that might be interesting? And then, if so, how soon do you think you can explore that?

Also at Ash kind of many wonder about combinations of that Venetoclax can you might have said it looked pretty good pre clinically at that combination something that might be interesting.

And then if so how often do you need to explore that thanks.

Yes so.

David A. Roth: Yeah, so at the ASH meeting, we can provide a bit more context and detail about things like that, but I can say we really view 1425 as something with the potential to serve as a foundation of care for all types of RARA positive tumors, not just in the hemolygens but potentially in solid tumors as well, where some of our preclinical data would support that. And in that context, yeah, we've done a fair amount of work looking at various combinations with targeted agents, as well as with various cytotoxic chemotherapies. And we do think, given the tolerability profile, which is generally well tolerated, there's great combination potential for this drug, and it can be used in many creative ways. We're particularly excited about that poster, and we're really looking forward to going through the details of that data with you next month. Thank you. Our next question comes from Zeg Bajala of Roth Capital Partners. Your line is open.

So at the Ash meeting, we can provide a bit more context in detail about about things like that but I can say, we really view 14 25.

As such.

Something with the potential to serve as a foundation of care for all types of RARA positive tumors, not only just on the heme malignancies, but potentially in solid tumors as well.

Where some of our preclinical data would support that.

And in that context, yes, we've done a fair amount of work looking at various combinations with targeted agents as well as with various cytotoxic chemotherapy and we do think given the tolerability profile, which is.

Finally, well tolerated, we think there's great combination potential for this drug and it can be used in many creative ways.

We're particularly excited about that poster and we're really looking forward to going through the details of that data with you next month.

Thank you.

Our next question comes from that but dollar of Roth Capital Partners. Your line is open.

Hi, Thanks for taking my question really excited to see the data at Ash.

David A. Roth: Thanks for taking my question. I'm really excited to see the data it asks. As it relates to the data set, I was just wondering, can you talk a little bit about transfusion dependence and how important of an endpoint you think that is for patients as well as clinicians? Um, sure. If you think about what the problems are that patients have when they have leukemia, in addition to having this uncontrolled tumor circulating through their bloodstream, it fills up the bone marrow and prevents blood from being generated.

As it relates to the guidance that we just wondering can you talk a little bit about our chances.

Then how to pull and at the end point, you think battle for patients as well as acquisition.

Sure so.

If you think about what the problems are that patients have when they have leukemia.

In addition to having this uncontrolled tumor circulated to their bloodstream it fills up the bone marrow and prevents the blood from being generated so you have low light counts low platelets low red cells, you have anemia, and those low blood counts.

David A. Roth: So you have low white counts, low platelets, low red cells, you have anemia, and those low blood counts lead you to the blood bank where you have to get transfused. And it's sort of, you know, it's a burdensome side effect of the leukemia that, you know, impacts quality of life. So when you have a complete response, your blood counts normalize because the bone marrow is no longer diseased. And you should be, if there's, you know, if it's not just a lab improvement but a clinical benefit improvement, you should see liberation from needing to go to the blood bank for blood products. So we look at that as an important objective, a parameter of clinical benefit. And that's why we report on the transfusion of dependency. And we think it's a really good surrogate for clinical benefit and meaningful drug effects. Thanks, David.

Lead you to the blood Bank, where you have to get transfused, and it's sort of it's a burdensome side effect of the leukemia that impact quality of life. So when you have a complete response your blood counts normalized because the bone marrow is no longer diseased and you should be if there if it's just it's not.

Just the lab improvement, but a clinical benefit improvement you should see liberation from needing to go to the blood bank for blood products. So we look at that as an important objective.

Parameter of clinical benefit and Thats why we report out on the transfusion independence, and we think it's a really good surrogate for clinical benefit and meaningful drug effect.

Well, David I, just thought that was interesting and point out there's a little bit too and then other classes is ever looking forward to seeing that more mature data and then classic capex on the line.

David A. Roth: I just thought that was an interesting endpoint as it related to venetoclast, but I'm looking forward to seeing the more mature data. And then for 5609, you mentioned using ProR2A even in patients. So can you elaborate a little bit on that? Because that is a little bit different from your strategy with DHRS3, which was used for 1425. Oh yeah, so that's interesting.

David A. Roth: So what we like to do is look at the various molecular pathways. We have a really strong discovery group who helps us with our science and understanding how to use our drugs effectively. And the DHRS3, you're pointing out for others, that was something that we evaluated as well in the 1425 program way back at the beginning where we showed how its levels changed upon drug exposure. These are things that are important to help monitor that not only is the drug being measured in the blood, but it's having effects in the tissues, and you can often correlate those types of effects with tumor shrinkage or disease, you know, favorable disease responses.

David A. Roth: And so that's why they're so helpful when we use PD-guided dosing in our clinical trials. You know, not only do we look at the drug exposures, but we look at the PD effects to help refine how to use the drug in terms of the dose and the dosing schedule. So, I hope that answers your question. Yeah, yeah, that was really helpful. And it's nice to see that you guys are also using it to kind of figure out, you know, whether or not the intermittent dosing will also be really effective. And then I think the last one here for me is for Joe.

Joe Farah: With regard to the cash runway, I don't know if this is a tricky question or not, but can you talk about what's in there? You know, is it 56 or nine plus, perhaps going far with both, you know, strategies for AML as well? You know, what's in there that kind of gets you to 25?

Joe Farah: Yeah, sure. Thanks for the questions, Edwin. So, as I said, $92.1 million at the end of the quarter, cash into 2022, and that runway does incorporate part of our preclinical research funding in conjunction with the collaboration with GBT. As far as the go-forward plans, of course, as Nancy and David said, we'll be talking more about that at ASH, and you can expect that at that time we'll also be talking more about the effects that may have on our go-forward runway Thanks, guys. Congratulations again on the DAS. Thanks, Sykha. Our next question comes from Mark Breidenbach of Oppenheimer. Your line is open. Hey guys. It's Matt.

The millionaires at the end of the quarter cash.

Cash into 2022 and that runway does incorporate part of our preclinical research funding in conjunction with a collaboration with G. B.

E.

As far as they go forward plans of courses Nancy and David said, we'll be talking more about that at Ash and you can expect that at that time will also be talking more about the effects that may have on I'll go for a run away.

As we always do.

Operator: I'm from Mark. Thanks for squeezing in. Really nice looking 1425 data in the newly diagnosed setting. Obviously, I don't want to get ahead of ourselves here, but what are your maybe preliminary thoughts on a regulatory path forward in that particular setting, and do you think it would likely require a randomized trial maybe compared to Venclexa plus HMA? Hey Matt, we're very encouraged by the data with 1425 in combination with azacitidine. And, you know, as you know, there continues to be a very large unmet medical need, both in the AML setting and also in some related disorders to AML.

Nancy A. Simonian: And, you know, we think there's a lot of opportunities for the 14-25 combination, giving such a high CR rate, deep CRs, transfusion independence, and well tolerated, especially in this elderly population. So I'd say look forward to Ash, where we can update you a little bit more on what our next steps are for the program. And then, you know, maybe investors are trying to benchmark, you know, what would be a good estimate for how Benklexa plus HMA would do, you know, in the newly diagnosed Rauhara positive setting. As you mentioned, Rauhara positivity seems to be correlated with Benklexa resistance.

Program.

Got it and then maybe as investigate as investors are trying to benchmark.

It would be a good estimate.

Four how then click the plus HMA would do you know in the newly diagnosed router a positive setting as you mentioned router of positivity seems to be correlated with and collects the resistance. So you know they got about 66% C. R. C. R. I right in the V. L trial do you think it would be appreciably lower in this patient pop.

Nancy A. Simonian: So, you know, they got about. [inaudible] I think, I mean, the data... based on the fact that we're seeing this disease phenotype in the RARA-positive patients that sort of correlate with Venn resistance would suggest that to be the case. And I would just say stay tuned for sort of the overall ASH presentation. We can provide much more detail on that. But I think it's, you know, what's exciting is that we've identified that this resistance phenotype is enriched in the population that we have in the RARA-positive patients. Cool, thanks for taking our questions. As a reminder, to ask a question, please press star then 1. Our next question comes from Matthew Cross of AllianceGlobal. Your line is open. Hi all, congrats on the recent CDK7 data and looking forward to Ash coming soon. I had a couple of questions around 1425.

Operator: Again, won't try to get too ahead of your ASH presentation here and stay high level, but in the same vein as what it sounds like, Ash regarding Rara Positivity conveying... On the flip side, have you seen anything preclinically or clinically that would suggest physiologic, brought upon by prior, may convey any differential sensitivity to 1425 as we get a better sense of the activity, and Relapse Refractory Population? So that, you know, that's a good question.

That's a good question I think.

David A. Roth: I think I could refer back to our most recent presentation at the ESH meeting at the end of last year. You know, we see activity across a range of cytogenetic risks and various mutations, both poor risk, intermediate, and good risk type mutations. So at the outset, I would say that we had not anticipated that there would be those types of influences on the response.

I could refer back to our most recent presentation at the S.H. meeting at the end of last year, we've we see.

Activity across our.

David A. Roth: We do see a high complete response rate, and early time to response, and that's all been put into our abstract. So I think we could get into a bit more detail at the upcoming ASH meeting to provide more context. Yeah, absolutely, fair enough, and looking forward to discussing that. Transcripts provided by Transcription Outsourcing, LLC, over to the newly diagnosed cohort, at what point is it pertinent to stop testing or enrolling in these RARA negative... What is the kind of confirmation? you can say this is the right biomarker, and ethically, maybe patients who are positive. Is there a realistic use case, in your view, for 1425?

Nancy A. Simonian: that you're seeing so far to be used in RAR negative cases as well. Hey, Matt, it's a good question. You know, we have strong preclinical data to suggest that 1425 is going to work and the RARA positive versus the negative. But it's always important to test that in the clinic. And so we tested, you know, the RARA-negative patient population, which we presented some initial data last year and now updated data at ASH, which really goes to show that the RARA biomarker is enriching for patients most likely to respond, where we saw a much higher CR rate than the RARA-negative population. And so I think that gives us a lot of confidence that we are, that the RARA-positive patients are the ones that are So, while we haven't talked specifically about sort of plans going forward, you know, when we started the relapsed refractory cohort, that's only in the RARA-positive patient population.

At this suggests that 14 25 was going to work and there are a positive versus a negative but it's always important.

To test that in the clinic and so we tested you know rather negative patient population, which we presented some initial data last year and no updated data at ash.

Nancy A. Simonian: So. Hopefully, that helps you. Answer that.

Nancy A. Simonian: Yeah. Absolutely the direction of the Relapse Refractory, and glad to see this all fully tested out. Both rates don't look, you know, terrible.

Nancy A. Simonian: But thank you for the clarification. I appreciate it, and I'm looking forward to the presentations next month. Great, thank you.

Nancy A. Simonian: There are no further questions. I'd like to turn the call back over to Nancy Simonian for any closing remarks. Thank you, operator. In closing, I want to thank you all for joining us today, especially with everything going on in our country the last few days and for your continued interest in Syros. We look forward to updating you as we continue to advance toward our vision of building a fully integrated biopharmaceutical company with a portfolio of medicines that provide profound benefits for patients.

<unk> pharmaceutical company with a portfolio of medicines that provide a profound benefit.

Patients.

Operator: Thank you. Ladies and gentlemen, this does conclude the conference. You may now disconnect. Everyone, have a great day.

Thank you.

Ladies and gentlemen, this does conclude the conference.

You may now disconnect everyone have a great day.

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