Q4 2019 Earnings Call

Ladies and gentlemen, thank you for standing by and welcome to the fourth quarter 2019, cereals Pharmaceuticals Inc. earnings Conference call.

Operator: Ladies and gentlemen, thank you for standing by, and welcome to the fourth quarter 2019 earnings conference of Syros Pharmaceuticals Inc. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone. If you require any further assistance, please press star zero. It is now my pleasure to introduce the Vice President of Corporate Communications and Investor Relations, Naomi Aoki.

At this time all participants are in listen only mode. After the speaker presentation, there will be a question and answer session.

Ask a question during the session you will need to press star one on your telephone.

If you're worried you further assistance please press star zero.

It's now my pleasure to introduce Vice President corporate Communications and Investor Relations Naomi Aoki.

Naomi Aoki: Thank you. This morning, we issued a press release with our fourth quarter and full year 2019 financial results, along with anticipated future milestones and recent accomplishments. This release is available on the investors and media section of Syros' website at www.syros.com. We will begin the call with prepared remarks by Dr. Nancy Simonian, our Chief Executive Officer, and Joe Farah, our Chief Financial Officer. We will then open the call to questions.

Thank you. This morning, we issued a press release with our fourth quarter and full year 29 team financial results along with anticipated future milestones in recent accomplishments. This release is available on the investor.

There's a media section of Zerust as website at Www Dot zeros dotcom.

We will begin the call with whom we heard remarks by Dr., Nancy Simonian, Our Chief Executive Officer, and Joe Farrell, Our Chief Financial Officer, well, then open the call for questions Dr., David Roberts, our Chief Medical Officer, Dr., Erik Olsson, our Chief Scientific Officer, Dr., Jeremy Spring Horn, our Chief business Officer.

Naomi Aoki: Dr. David Roth, our Chief Medical Officer, 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 statement 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 this morning and any other filings that we may make with the SEC in the future. In addition, any forward-looking statements made on this call represent our views only as of today and should not be relied upon as representing We specifically disclaim any obligation to update or revise any forward-looking statements.

Our also on the call and will be available for human <unk>.

Before we begin I would like to remind everyone that 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.

The result of various risks uncertainties and other factors, including those set forth in the risk factor section of our annual report on form 10-K, how we filed this morning and any other filings that we may make with the FCC and the future. In addition, any forward looking statements made on this call represent our views.

Many of them 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 I.

Nancy A. Simonian: I would now like to turn the call over to Nancy. Thank you, Naomi, good morning, everyone, and thank you for joining us today. At Syros, we are redefining the power of small molecules to control the expression of genes, with the aim of delivering medicines that provide a profound benefit to currently underserved patients with cancer and monogenic diseases. In 2019, we made important progress toward this goal. We continue to advance our lead program, SY1425, a first-in-class selective RAR-alpha agonist currently in a phase two trial, presenting promising clinical data in newly diagnosed unfit RARA-positive AML patients and initiating a trial cohort in relapsed or refractory RARA-positive AML patients. We continue to build on our leadership in selective CDK7 inhibition, prioritizing the development of SY And we entered into a collaboration with Global Blood Therapeutics to expand our efforts in sickle cell disease and beta thalassemia with the aim of accelerating the development of novel oral medicines that could provide a functional cures for patients with these diseases. Together, these accomplishments provide a tremendous foundation as we enter 2020.

I'd now like to turn the call over to Nancy.

Thank you Diame good morning, everyone and thank you for joining us today.

That's true we are redefining the power of small molecule to control the expression of genes.

With the aim of delivery medicines that provide a profound benefit to currently underserved patient with cancer and monogenic diseases.

In 2018, we made important progress toward this goal.

We continue to advance our lead program S. Fyfourteen 25, a first in class selected our <unk> agonists currently a phase two trial presenting promising clinical data in newly diagnosed unfit lora positive email patients.

And initiating a trial cohorts in relapsed or refractory, rather a positive and all patients.

We continue to build on our leadership in selective CDK seven inhibition prioritizing the development of X Y 56, or nine are highly selective in potent orally CDK seven inhibitor, which is now in a phase one trial in patients with select solid tumors.

And we entered into a collaboration with global blood therapeutics to expand our effort in sickle cell disease and beta thalassemia with the aim of accelerating the development of novel oral medicine, the could provide a functional cure for patients with these diseases.

Together. These accomplishments provides a tremendous foundation as we enter 2020.

Nancy A. Simonian: We expect this year to be important for Syros, marked by continued clinical execution and culminating in meaningful data readouts in both 1425 and 5609 in the fourth quarter. In parallel, we continue to enhance our gene control platform, which has proven a productive discovery engine, shedding light on regulatory mechanisms that play a key role in disease, revealing new targets for therapeutic intervention, and generating selective small molecules against transcriptional targets. Let me begin today with an update on 5609.

We expect this year to be important for Cirrus marked by continued clinical execution and culminating in meaningful data read out in both 14, 25, and 56 of nine in the fourth quarter.

In parallel we continue to enhance our gene control platform, which has proven a productive discovery engine shedding light our regulatory mechanisms. The play a key role in disease, revealing new targets for therapeutic intervention and generating selected small molecules against transcriptional targets.

Let me begin today with an update on 56 or nine.

We believe that 56 or nine represents a potentially transformative targeted approach for difficult to treat cancer.

Nancy A. Simonian: We believe that 5609 represents a potentially transformative, targeted approach for difficult-to-treat cancer. It is a highly selective and potent oral CDK7 inhibitor that has demonstrated robust antitumor activity, including complete regressions as a single agent in a range of preclinical cancer models. In January, we dosed the first patient in our Phase I trial of 5609. This multi-center, open-label, dose-escalation trial is expected to enroll approximately 60 patients with advanced breast, colorectal, lung, or ovarian cancer or with solid tumors of any histology that harbor RB pathway alteration. We have designed the trial to move through dose escalation as rapidly as possible while giving us opportunities to expand cohorts at certain doses to gather more data along the way. Importantly, we have focused the trial on patient populations that we believe are most likely to respond to treatment with 5609. 5609 has shown substantial antitumor activity in the tumor types we are studying at doses below the maximum tolerated dose. And in preclinical models of breast, lung, and ovarian cancers, deeper and more sustained responses were associated with RB pathway alteration.

It is a highly selective in potent orally CDK seven inhibitor that has demonstrated robust antitumor activity, including complete regressions as a single agent in a range of preclinical catch your models.

In January we dose the first patient in our phase one trial of 56, so no I.

Just multicenter open label dose escalation trial is expected to enroll approximately 60 patients with advanced breast colorectal lung ovarian cancer or with solid tumors up any histology that harbor RB pathway alterations.

We have designed the trial to move through dose escalation as rapidly as possible, while giving us opportunities to expand cohorts at certain doses to gather more data along the way.

Importantly, we have focused the trial on patient populations that we believe our most likely to respond to treatment with 56 overnight.

56, or nine has shown substantial anti tumor activity in the tumor types, we're studying at doses below the maximum tolerated dose.

And in preclinical models, a breast lung and ovarian cancers.

Deeper and more sustained responses were associated with RB pathway alteration.

Well I enriching for these patient populations in our phase one trial, we believe we will increase our chances obscene early signals a political activity.

Nancy A. Simonian: By enriching for these patient populations in our phase one trial, we believe we will increase our chances of seeing early signals of clinical activity. We expect to report initial safety, tolerability, PK, and PD data in the fourth quarter of this year, and additional dose escalation data, including clinical activity data, in mid-2021. Following dose escalation, we plan to initiate multiple expansion cohorts to further evaluate the safety and antitumor activity of 5609 as both a single agent and in combination with other therapies. Moving to 1425, we believe 1425 has broad combination potential in RARA-positive patients with AML and high-risk MDS. We remain on track to report potential proof-of-concept data in the fourth quarter of this year on 1425 in combination with azacitidine and RARA-positive patients with relapsed or refractory AML. If positive, we believe these data could support an accelerated development path to market.

We expect report initial safety Tolerability, PK and PD data in the fourth quarter up this year and additional dose escalation data, including clinical activity data in mid 2021.

Following dose escalation, we plan to initiate multiple expansion cohorts to further evaluate the safety and anti tumor activity a 56, so nine as both a single agent and in combination with other therapies.

Moving to 14 25, we believe 14 25 had broad combination potential in <unk> positive patients with email and high risk Mds.

We remain on track to report potential proof of concept data in the fourth quarter up this year on 14 25 in combination with eight decitabine and RARA positive patients with relapsed or refractory AML.

It positive we believe these data could support and accelerated development path to market.

Nancy A. Simonian: We also expect to report mature data on 1425 in combination with azacitidine in the fourth quarter in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy, which we think is important in determining the optimal path forward for newly diagnosed patients. Together, we hope these data will bring us closer to addressing the significant need for well-tolerated oral therapies for people with AML. While the AML landscape is rapidly evolving with new medicines coming to market, the disease is not being cured. Patients with relapsed or refractory disease still face a grim prognosis. Recently approved therapies target only limited patient subsets with composite complete response rates in the 20 to 35 percent range and limited duration of response. Survival remains low at less than six months.

We also expect to report mature data on Fortune 25 in combination with eight decitabine in the fourth quarter in newly diagnosed aim all patients who are not suitable candidates for standard chemotherapy, which we think it's important determining the optimal path forward in newly diagnosed patients.

Together, we hope these data will bring us closer to addressing the significant need for well tolerated oral therapies for people with A.M.L.

While the A.M.L. landscape is rapidly evolving with new medicines coming to market the disease is not being sure.

Patients with relapsed or refractory disease still face a grand prognosis.

Recently approved therapies target Oh, only limited patient subset with composite complete response rates in the 20% to 35% range and limited duration of response.

Survival remains low at less than six month.

Nancy A. Simonian: For newly diagnosed unfit AML patients, tolerability of therapy and the ability to combine with other agents are particularly important. More than half of the newly diagnosed patients are elderly or otherwise unfit for intensive chemotherapy, and combination approaches are emerging as the standard of care. The goal in this patient population is to develop combination regimens that improve outcomes while also providing quality of life. Based on the data we presented at Esch in October in newly diagnosed unfit AML patients, we believe that 1425 in combination with azacitidine may offer an important new treatment option for a readily identifiable subset of these very sick patients. Our data showed a high aggregate CR and CRI rate, many of which were deep molecular and cytogenetic CRs in RARA-positive patients.

For newly diagnosed on 50 ml patients tolerability of therapy, and the ability to combined with other agents are particularly important more than half of the newly diagnosed patients are elderly or otherwise and fit for intensive chemotherapy and combination approaches are emerging as the standard of care.

The goal in this patient population is to develop combination regimens that improve outcomes, while also providing quality of life.

Based on the data we presented at Ash in October in a newly diagnosed unfit AML patients. We believe that 14 25 in combination with eight decided they may offer an important new treatment option for a readily identifiable subset of these very sick patients.

Our data showed a high aggregate CRC, our irate many of <unk>, which were deep molecular insight to genetics yard in bar a positive patients.

Nancy A. Simonian: We saw rapid onset of action and early evidence of durability, as well as high rates of transfusion independence, all of this with a favorable tolerability profile. Importantly, these data also give us confidence as we look toward our data readout for RARA-positive relapsed or refractory AML. While our key strategic priority is to advance our clinical stage program, we firmly believe that ongoing investment in our gene control platform is critical to building a robust and sustainable pipeline to support our vision of becoming a fully integrated biopharmaceutical company. In the fourth quarter and in recent months, our leadership in gene control was highlighted in several presentations. In December, we presented new data in an oral presentation at the ASH annual meeting on our identification and validation of NFIX as a fetal hemoglobin repressor.

We saw rapid onset of action and early evidence of durability as well as high rates of transfusion independence.

All of this with a favorable tolerability profile.

Importantly, these data also give us confidence as we look toward our data readout for Rob positive relapsed or refractory AML patients.

Well, our key strategic priorities to advance our clinical stage programs, we firmly believe that ongoing investment in our gene control platform is critical to build the a robust and sustainable pipeline to support our vision of becoming a fully integrated biopharmaceutical company.

In the fourth quarter and in recent months our leadership in gene control was highlighted in several presentation.

In December we presented new data in an oral presentation at the Ash annual meeting on our identification and validation and fix a de Vito hemoglobin reprocessor.

This finding stem from our broader effort in sickle cell disease, and beta thalassemia to develop an oral medicine trip to turn fetal globin gene, which is typically turned off at birth to make healthy red blood cells.

Nancy A. Simonian: This finding stemmed from our broader effort in sickle cell disease and beta thalassemia to develop an oral medicine to turn on the fetaloglobin gene, which is typically turned off at birth, to make healthy red lips. Based on the promise of this approach and our progress in the two years since starting this program, we entered into a collaboration with GBT in December to discover, develop, and commercialize new medicines for sickle cell disease in beta thalassemia patients. Importantly, this collaboration allows us to explore multiple targets and approaches in parallel for inducing fetal hemoglobin, accelerating our efforts and increasing our chances of success. In January, we announced our second monogenic disease program, which is focused on myotonic dystrophy type 1. DM1 is an autosomal-dominant monogenic disease caused by nucleotide repeats in the DNPK gene. It affects organs as well as the central nervous system and can shorten lifespan, with the most common causes of death being respiratory and cardiac symptoms.

Based on the promise of this approach and our progress in the two years since starting this program we entered into a collaboration with GBT in December to discover develop and commercialize new medicines for sickle cell disease in beta thalassemia patient.

Importantly, this collaboration allows us to explore multiple targets and approaches in parallel producing fetal hemoglobin accelerating their efforts and increasing our chances of success.

In January we announced our second monogenic disease program, which is focused on Myotonic dystrophy type one.

Do you want isn't autosomal dominant monogenic disease caused by nucleotide repeat in the D. N P kg.

It affects Oregon as well as the central nervous system and can shorten Weiss fan, but the most common causes of death being respiratory and cardiac symptom.

As with their approach in sickle cell disease. Our goal is to use our platform to elucidate the regulatory mechanisms controlling a single gene with the aim of developing a small molecule medicine to altered the expression of that GE in this case turning off the expression of the faulty copy of the DFT kg.

Nancy A. Simonian: As with our approach in sickle cell disease, our goal is to use our platform to elucidate the regulatory mechanisms controlling a single gene with the aim of developing a small molecule medicine to alter the expression of that gene, in this case, turning off the expression of the faulty copy of the DMPK gene. We were also pleased to present new preclinical data at the 2020 Keystone Symposia Cancer Epigenetics Meeting in January, demonstrating that CDK12 inhibition has different transcriptional effects from CDK7 inhibition. The results suggest that a selective CDK12 inhibitor presents distinct therapeutic opportunities from a selective CDK7 inhibitor, such as increasing the susceptibility of cancer to targeted therapies involved in DNA damage repair, such as PARP.

We were also pleased to present, new preclinical data at the 2020 Keystone symposia cancer Epigenetics meeting in January demonstrating the T.K. 12 inhibition has different transcriptional effect from CDK seven inhibition.

The results suggest they selected CDK 12 inhibitor present distinct therapeutic opportunities from a selective CDK seven inhibitor, such as increasing susceptibility of cancer didn't targeted therapies involved in DNA damage repair such as PARP inhibitors.

Nancy A. Simonian: Also at Keystone, our team presented new data highlighting our platform's ability to identify essential genes and transcriptional dependencies that could serve as potential drug targets for cancer. These presentations underscore our leadership in the field of gene control and the potentially vast reach of our platform to address diseases that have eluded effective treatment. They also reinforce our confidence that this is just the beginning for Syros. The progress we have made with 1425, 5609, and across our pipeline provides a tremendous foundation for growth, and it is a testament to our people, our program, and our platform. We look forward to continuing to execute with excellence as we build Syros into an enduring company with a deep portfolio of transformative medicines for currently underserved patients. With that, I will turn the call over to Joe to review our financial results for the fourth quarter and full year 2019.

Also at Keystone, our team presented new data <unk>, highlighting our platform's ability to identify essential gene and transcriptional dependencies that could serve as a potential drug targets for cancer.

These presentation underscore our leadership in the field, the gene control and the potentially bass from each of our platform to address diseases that have alluded effective treatment.

They also reinforce our confidence that this is just beginning for zero.

The progress we have made with 14, 25, 56 or nine and across our pipeline provides a tremendous foundation for growth and it is a testament to our people our program at our platform.

We look forward to continuing to execute with excellent as we build zeros into an enduring company with a deep portfolio I'm transformative medicines for currently underserved patient.

With that I will turn the call over to Joe to review, our financial results in the fourth quarter and full year 20 Nike.

Thank you Nancy.

Joe Farah: Thank you, Nancy. We are entering 2020 in a position of financial strength. Last month, we announced the closing of a $60 million loan facility with Oxford Finance, including the funding of an initial tranche of $20 million. Proceeds from this tranche extend our anticipated cash runway into 2022, allowing us to advance both 1425 and 5609 through key clinical readouts this year and next, while continuing to invest in our preclinical portfolio in leading gene control platforms. Turning now to our fourth quarter and full year 2019 financial results. We ended 2019 with $91.4 million in cash, cash equivalents, and marketable securities, compared with $99.7 million at the end of 2018. This amount does not take into account the $20 million upfront we received from GBT in January and the $20 million from the initial tranche of the Oxford Loan facility in February.

We are entering 2020 in a position of financial strength.

Last month, we announced the closing of $60 million loan facility with Oxford finance, including the funding of initial tranche of 20 million.

Proceeds from this traunch extend our anticipated cash runway into 2022, allowing us to advance both 14, 25 56 or nine through key clinical Readouts. This year indexed while continuing to invest in our preclinical portfolio in leading gene control platform.

Turning now to our fourth quarter and full year 2019 financial results.

We ended 2019 with $91.4 million in cash cash equivalents in marketable securities compared with 99.7 million at the end of 2018.

This amount does not take into account 20 million upfront we received from GE between January and the 20 million from the initial tranche of the Oxford loan facility in February.

We recognized point 5 million in revenue in the fourth quarter of 2019 compared to 2.9 million in the fourth quarter of 2018.

Joe Farah: We recognized 0.5 million in revenue in the fourth quarter of 2019 compared to 0.9 million in the fourth quarter of 2018. For the full year 2019, we recognized $2 million in revenue compared to $2.1 million in 2018. Revenues in both periods were earned entirely through our collaboration with Insight.

For the full year 2019, we recognize 2 million in revenue compared to 2.1 million in 28.

Revenues in both periods written burned entirely under our collaboration with insight.

R&D expenses were $14.3 million in the fourth quarter of 2019 compared to 15.1 million for the same period in 2018.

Joe Farah: R&D expenses were $14.3 million in the fourth quarter of 2019, compared to $15.1 million for the same period in 2018. R&D expenses for the full year 2019 were $58.2 million, compared to $50.2 million for the full year 2018. This increase in full-year R&D expenses was primarily due to the continued advancement of our clinical trials, as well as the completion of 5609 IND-enabling G&A expenses were $6.4 million in the fourth quarter of 2019 compared to $4.4 million for the same period in 2018. G&A expenses for the full year 2019 were $21.5 million, compared to $16.2 million for the full year 2018. This increase was primarily due to an increase in employee-related expenses. Finally, we reported a net loss for the fourth quarter of $19.7 million, or $0.46 per share, compared to a net loss of $18 million, or $0.54 per share, for the same period in 2018. Our net loss for the full year 2019 was $75.4 million, or $1.88 per share, compared to a net loss of $62.3 million, or $1.91 per share, for the full year 2018. With that, I will turn the call over to the operator for questions. Thank you.

R&D expenses for the full year 29, Gee were 58.2 million compared to 50.2 million for the full year 28.

This increase in full year R&D expense was primarily due to the continued advancement of our clinical trials as well as the completion of 56 or nine I Indeed, enabling studies.

Gina expenses were $6.4 million in the fourth quarter of 2019 compared to 4.4 million for the same period in 28.

Gee expenses for the full year 2019 were 21.5 million compared to 16.2 million for the full year 28.

This increase was primarily due to an increase in employee related expenses.

Finally, we reported a net loss for the fourth quarter of 19.7 million or 46 cents per share compared to a net loss of 18 million or 54 cents per share for the same period in 2018.

Our net loss for the full year, 2019 was 75.4 million or $1.88 cents per share compared to a net loss of 62.3 million or $1.91 cents per share for the full year 2018.

With that I will turn the call over to the operator for questions. Thank you.

Thank you.

Operator: As a reminder, ladies and gentlemen, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, please press the pound key. Please stand by while we compile the Q&A roster. And our first question comes from the line of Kenneth Adkins with Cowan & Company. Hi guys, thanks for taking my question. What profile do you think the 1425 plus AZA combination needs to show in the relapser FRAC BAML setting to be successful in terms of response rate and durability of response?

As a reminder, ladies and gentlemen to ask a question you will lead to press star one on your telephone.

To withdraw your question please press the pound.

Standby, while we've compiled the culinary roster.

First question comes from the lineup Kenneth Atkins with Cowen and company.

Hi, guys. Thanks for taking my question.

I'll do you think the Fortune 25, plus is a combination needs to show in the relapse refractory email setting to be successful in in terms of response rate and durability of response.

Hey, Ken I'm going to ask David Roberts, our Chief Medical officer to ask that question.

Nancy A. Simonian: Hey Ken, I'm going to ask David Roth, our Chief Medical Officer, to answer that question.

David A. Roth: Okay, thanks for that question. Yeah, as you know, we are focused right now on a cohort of patients with relapsed refractory AML, and we're testing the combination in those patients. There is a significant unmet need in those patients, and in total, we'll be obviously looking at the clinical activity and the overall tolerability and safety in order to understand how it works in those patients. Specifically, there is data in the relapsed population with hypomethylating agents that shows response rates of the order of about 16 percent with duration of responses and median overall survival of about half a year. And as you also know, there have been some recent approvals in the relapsed AML setting with some of the targeted agents that have come to market of late, and they've shown response rates in the 20 to 30 percent range with response durations in the four to eight month range. So those types of outcomes are going to provide us with the context to interpret our data, and we're looking forward to reporting on potential proof of concept in the fourth quarter.

Thanks for that question Yeah. As you know we are focused right now on a cohort of patients with relapsed refractory AML and we're testing the combination in those patients there is a significant unmet need in those patients and in total booby obviously looking at the clinical actually.

City, and and the overall Tolerability and safety Oh in order to understand how it's working in those patients specifically there is data in the relapse population Weve Hypomethylating agents that shows response rates on the order of about 16% with some duration of response is a median overall survival of about a half a year.

And as you also know a there had been some recent approvals from the relapse ammo setting a with some of the targeted agents that have come to market of late and they've shown response rates in the 20% to 30% range with response durations and 48 month range. So those types of outcomes are going to provide us with the the context.

To interpret our data and we're looking forward to reporting on potential proof of concept in the fourth quarter.

Got it okay that makes sense and then in the data you showed at ash it seemed as though unlike the raw biomarker. The Iris eight biomarker was not as good of a predictor of response, what do you, but do you think accounts for that difference and have you plenty those learnings to your platform.

David A. Roth: Got it. Okay, that makes sense. And then, in the data you shared at Esch, it seemed as though, unlike the RawRaw biomarker, the IRF-8 biomarker was not as good of a predictor of response. What do you think accounts for that difference, and have you applied any of those learnings to your platform?

Yes. Another good question you know went in the at the beginning of this program we applied.

David A. Roth: Yeah, another good question. At the beginning of this program, we applied our discovery platform approach, looking at the presence of a super enhancer driving high levels of RAR-alpha gene expression. It was an unanticipated observation, a novel discovery that we made, and we translated that into our clinical trial with a specific focus on RAR-alpha. In the course of our preclinical development leading into the trial, we did make the observation that, on occasion, there were certain model systems which had IRF8 positivity which also responded to the drug. And in an effort to make this drug as broadly available to as many patients as possible, we chose to evaluate that prospectively in our trial. You know, the best time to check this out is early on, so you don't leave patients who could benefit behind.

Our discovery platform approach looking at the presence of a super and answer driving high levels of Oreo Alpha gene expression. It was an unanticipated observation on novel discoveries that we made and weve translated that into our clinical trial, well with a specific focus on on already our alpha in.

Of course of our preclinical development leading into the trial, we did make the observation that on occasion, there were certain model systems, which have higher or eight positivity, which also responded to the drug and in an effort to make this drug is broadly available to as many patients as possible we chose to evaluate that prospectively.

Our twilio the best time to check this out as early on so.

So as you don't leave patients who could benefit behind us, but our analysis didn't support that exploration and so we have just basically refocus where we started which was back on.

David A. Roth: But our analysis didn't support that exploration, and so we have just basically refocused where we started, which was back on RAR-alpha. And I think the lesson is that it's always good to work with your data and take the opportunity to, you know, do the best you can to make potentially promising drugs available for patients. And I think we're going to continue to apply those types of approaches moving forward.

And I think the the learning is that it's always good to.

Work with your data and take the opportunity to.

To the best you can see make up potentially promising drugs available for patients and I think we're going to continue to apply those types of approaches moving forward.

Okay. Thanks.

Operator: Okay, thanks. Thank you. And our next question comes from the line of Jason Butler with JMP Securities.

Thank you.

Your next question comes from the line of Jason Butler JMP Securities.

Hi, Thanks for taking my question just one on 56 or nine I'm just as he is he starts to move for enrollment here any updates you can provide on the presence of RV pathway alterations in the the target tumor types. Thanks.

Operator: Hi, thanks for taking the question. There is just one on 5609.

David A. Roth: Just as you start to move through enrollment here, any updates you can provide on the presence of RB pathway alterations in the target tumor types? Thanks.

I, just said Oh, my hats or David to answer that question.

David A. Roth: Hi Jason, I'm going to ask David to answer that question.

David A. Roth: Yeah, so as you presumably are aware, we're very excited about the fact that we initiated dosing in our clinical trial this past January, and we're still anticipating the reporting of our data in the fourth quarter, which will focus on safety and tolerability but also will have some information related to pharmacokinetics and pharmacodynamics on that. And we are focused on patients who have, you know, various tumor types that we think are enriched to see an early signal of activity. I know Nancy mentioned that in her opening comments.

Yeah, So as you.

Zummo, where they were very excited about the fact that we initiated dosing in our clinical trial. This past January and a you know we're still anticipating be the reporting of or our data in the fourth quarter, which will focus on safety and Tolerability, but also will.

I have some information related to the pharmacokinetics and pharmacodynamics on that and we are focused on patients who have.

You know various tumor types that we think are in which to see an early signals of activity I know Nancy mentioned that.

And our opening comments, where including patients with breast cancer ovarian cancer lung cancer as well as colorectal cancer.

David A. Roth: We're including patients with breast cancer, ovarian cancer, lung cancer, as well as colorectal cancer. And importantly, we're focused on patients who have a tumor that may have any other histology provided it has an alteration in the RB pathway. There are common mutations that are routinely identified in screening of patients when they present for treatment and care, and they should have these available to us when they show up to be considered for enrollment in the trial. With respect to the outcomes, just to, you know, preview or review for you, about a third of patients with basal breast cancer are known to have these types of abnormalities, and that is a largely overlapping population with triple negative breast cancer. We know that patients who have hormone receptor positive breast cancer who have been previously treated with CDK4-6 inhibitor and hormonal therapy and then progressed, about a third of them will have abnormalities in the RB pathway.

Importantly, we're focused on patients who have a tumor that may have any other histology provided it has an alteration and be RP pathway theater or common mutations that are mutually identified in in screening of patients when they present for treatment and care and they should havertys I'm available to us when they.

Show up to be considered for enrollment in the trial.

With respect to all the outcomes to preview will review for you know about a third of patients with diesel breast cancer are known to have these types of abnormalities and that is largely overlapping population with a triple negative breast or we know that patients who have hormone receptor positive breast cancer.

Who have been previously treated with CDK for six inhibitor in hormonal therapy, and then progress about a third of them, we'll have abnormalities in RB pathway and that's been now in emerging and well characterized a mechanism for developing resistance to the CDK for six ever. So we think that's a really important in emerging population with significant.

David A. Roth: And that's now an emerging and well-characterized mechanism for developing resistance to the CDK4-6 inhibitors. So we think that's a really important and emerging population with significant unmet needs that we potentially can address with a CDK7 inhibitor. Lung cancer includes a population of small cell lung cancer. It's, in some respects, it's been considered somewhat ubiquitous for having RB pathway abnormalities, RB null, or mutations in about 75 to 90 percent of small cell lung cancer, so there the majority should have this. And, you know, from our prior discussions around our focus on ovarian cancer, we know through analyses of the TCGA database that's been published, about 67 percent of high-grade serious ovarian cancer also has these types of abnormalities. So all told, we think they're fairly prevalent, and, you know, of course, we'll continue to focus on these populations as we move through dose escalation and frame our plans going forward for the expansions.

Unmet need that we potentially can address with a CDK seven inhibitor.

Lung cancer includes a population of small cell lung cancer. Its oh in some respects gets been considered somewhat ubiquitous for having RV pathway after maladies, RB NOL or mutations and about 75% to 90% of small cell lung cancer. So there are a majority should have this ER and from our prior discussions around our focus on ovarian cancer, we know.

No.

Through analyses of the T.C.J. database, it's been published about 67% of high grade Serous ovarian cancer also has these talks about reality. So all told we think there there are fairly prevalent and no of course will yeah. We'll continue to focus on these populations as we move to dose escalation and frame our plans.

Going forward for the expansions.

Okay, Great and then just the platform question can you maybe just speak to how the experience would sickle cell informs how you approach new diseases like a MDT MDT, one obviously different diseases, but are there efficiencies that you game as you move through each program that that's the maybe reads.

David A. Roth: Okay, great. And then just a platform question. Can you maybe just speak to how the experience with sickle cell informs how you approach new diseases like MDT1? Obviously, different diseases, but are there efficiencies that you gain as you move through each program that maybe lead to timelines or helps you think about probability of success?

On on timeline or or helps you think krapfel ability of success.

Eric Olson: Please send our CES team to answer that question.

And our CFO answer that question.

Eric Olson: Thanks, Judy. The efficiencies and the synergies we get from all of our platforms come from our ability to understand the mechanisms and the regulatory networks that are driving sets of genes or specific So that's really the focus of our platform. And when we started the company, it was clear that that platform could be applied to lots and lots of different diseases and settings. In the case of the monogenic diseases, sickle cell, for example, is a disease where we are using our platform to understand the mechanisms of fetoglobin repression and then come up with small molecules that will induce the expression of fetoglobin in DM1 and other diseases where we know turning down the expression of And in this case, we're using exactly our same methodologies and approach, and way of thinking, and sets of technologies to identify the targets to downregulate the expression of DMPK in DM1.

Yes, Thanks Jay.

The efficiencies in the synergies we get from our all of our plan.

It's from our ability to understand mechanisms in the regulatory networks that are driving sets of genes or specific genes. That's really the focus of our platform and when we started the company. It was clear that platform could be applied to lots and lots of different diseases.

And settings.

In the case or the monogenic diseases sickle cell for example is a disease, where we are using our platform to understand.

The mechanisms of fetal globin repression, and then come up with small molecule that will induce expression that Peter will.

Indeed, one and other diseases, where we know trade down the expression of the gene could be really beneficial based on human genetic data and what we understand about the pathophysiology of the disease.

And in this case, where using exactly ours are our same methodology is an approach a way of thinking and set the technologies and identify that targets to down regulate get suppression of the PK in deal.

Okay, great. Thanks for taking the question.

Operator: Okay, great. Thanks for taking the question. Thank you. And our next question comes from the line of Mark Breidenbach with Avan: Hey, good morning, guys, and thanks for taking the questions. Probably both of these are kind of directed at David.

Thank you.

Question for the line of Mark Breidenbach with Oppenheimer.

Hey, good morning, guys and thanks for taking the questions.

Oh, probably both of these are kinda directed at David.

Operator: Maybe first, if you could start by giving us a little more color on dose escalation in the Phase 1 trial of 5609. Can you maybe tell us how many single patient cohorts you have to fill before you move to a 3 plus 3 design? And maybe just give us a sense of how many cohorts you expect to have to move through before you advance into a therapeutically relevant range.

Maybe first if you could serve I give me a little more color on dose escalation in the phase one trial, a 56 or nine can you maybe tell us how many single patient cohorts you have to fill before you move to three plus three.

Design, and and maybe just give us a sense for how many cohorts.

I'd like to have to move through before you would advance into a therapeutically relevant range.

Sure I'm happy to answer that question. So we designed a protocol to be as efficient as possible with them.

David A. Roth: Sure, happy to answer that question. We designed the protocol to be as efficient as possible with an objective to move this program forward and get the drug to patients as rapidly as we can. And again, I think it goes without saying that patients are always driving our approaches and everything we do here at Syros. We started out with single patient accelerated titration cohorts. And so that's how we're going to initiate the trial, and then we plan to transition to the more standard 3 plus 3 design. You know, we haven't specified the point at which that transition might occur.

An objective to move this program forward and get the drug to patients as rapidly as we can.

You know again I think it goes without saying that patients are always driving our approaches and everything we do here a serious.

We started out with single patient accelerated titration cohorts and so that's how we're going to initiate.

The trial and then we plan to transition to the more standards, we plus the redesign.

We haven't specified the point at which that transition might occur, but you know you can anticipate that for instance, if we were to observe.

David A. Roth: But, you know, you can anticipate that, for instance, if we were to observe, you know, changes in these PD markers that we're incorporating to efficiently drive toward the appropriate dose to move forward, we might choose to expand to 3 plus 3 just to better characterize those types of effects and use that knowledge to, you know, influence our decision making. And, you know, just because I'm mentioning that, I do want to remind you all that, you know, we as leaders in the research field of CDK7 and their development of the inhibitors to that drug, that compound have uncovered some novel biomarkers that, you know, biologically help us understand how the drug may be working. And we have worked to incorporate them into our clinical trial design.

Changes in these P.G. markers that we're incorporating to efficiently or drive toward the appropriate dose to move forward, we might choose to expand to three plus three just to better characterize those types of effects and use that knowledge to influence our decision, making and you know just because I'm mentioning that I do want to remind you all.

That.

You know we as leaders in the research field CDK seven in their development of the inhibitors to that drug that come down.

Uncovered some novel.

Biomarkers that biologically help us understand how the drug may be working and we have a works to incorporate them into our clinical trial design, a we've had lots of learnings from our prior experience with our 13 65 program and have really looked very deeply at the pace.

David A. Roth: We've learned lots of lessons from our prior experience with our 1365 program and have really looked very deeply at the patient materials that we've collected from that trial and have done a lot of work to establish PK PD efficacy models with both drugs. And we've been able to sort of, you know, triangulate across both programs to really inform our thinking about how to move 5609 forward efficiently. And, you know, hopefully, we'll be able to report some very interesting information in the fourth quarter of this year as that progresses.

Recent materials that we've collected on that trial and have done a lot of work to establish PK PD efficacy models with both drugs that we've been able to sort of.

You know triangulate across both programs to really inform our thinking about how to move 56 or nine forward efficiently and hopefully we'll be able to report out some very interesting information in the fourth quarter this year as that progresses.

David A. Roth: I just want to say we haven't specifically said the numbers of cohorts.

We haven't spent.

I just wanted to we haven't spent at least at the numbers of cohorts that would be required before we can reaching expansions but in general.

David A. Roth: That would be required before we can reach expansions, but in general, when we have sufficient information to inform our selection of the dose that we want to take into the expansions, you know, that would be the trigger. It wouldn't necessarily be at a particular point in time or after a pre-specified number of cohort levels.

When we have sufficient information to.

Inform our selection of the jokes that we want to take into the expansions.

Yeah that would be the trigger wouldn't necessarily be out in particular point in time or after a pre specified number of cohort levels.

David A. Roth: Okay, got it. And in those expansion cohorts, I see you're already thinking about both single and combination therapy. What are you kind of seeing as the ideal combination agent? Would it be chemotherapy, with a CDK-4-6, with a CDK-12, or something else?

Okay got it and in those expansion cohorts I see you're already thinking about both single and combination agent or a combination therapy.

What are you kind of seeing as an ideal combination agent would be with chemotherapy or what the CDK for six with CDK 12 or is that something something else.

[noise]. Another good question. So you know the nice thing about this particular target is the breadth of activity. It has across so many different tumor types.

David A. Roth: Another good question. So, you know, the nice thing about this particular target is the breadth of activity it has across so many different tumor types. And so, as someone who's helping the organization think through strategically how to approach clinical development, you know, we have many options. We have worked very hard. We have a wonderful translational medicine team here and discovery organization that are working to help define our future paths forward. And we are looking at various combinations that make sense, both from a mechanistic point of view and from an efficiency and clinical development point of view. So we have options to use various targeted agents; there may be hormonal therapies that nicely combine with our drug, and as well, there may be chemotherapeutics which make sense mechanistically. We haven't specified the details of which particular combination partners we want to proceed with, but much of that is in the process, and we're hoping to get there as soon as possible.

And so as someone who's helping the organization think through strategically how to approach clinical development. You know we have many options Oh, we have worked very hard we have a wonderful translational medicine team here in discovery organization are working so helped define our future paths forward and we are looking at various company.

Patients that makes sense, both from a mechanistic point of view and from an efficiency in clinical development point of view. So we have options to use various targeted agents are there may be.

Hormonal therapies that nicely combined with our drug and as well are there may be chemotherapeutics, which mechanistically makes sense.

We haven't specified the details of which particular combination partners. We want to proceed with but much of that is in process and.

You know, we're hoping to get there as soon as possible.

David A. Roth: Okay. One more quick one from me with regard to the Phase 2 study in relapsed refractory AML. I just wanted to make sure that this trial is open to patients who have had prior azacitidine exposure. And I'm also curious if the trial would potentially enroll a few patients with MDS as well, or if the focus is exclusively on AML.

One more quick one for me I'm with regard to the that these two in relapsed refractory or no.

I I'm just wanted to make sure that that this trial is open to patients that had prior is decidedly aegis IDN exposure.

And I'm also curious if the trial would potentially enroll a few patients within the essence law or focuses exclusively on a though.

Okay. So the relapse refractory AML trial. The key inclusion criteria requires you have relapsed refractory AML and you would be Robert causative. So you must be a biomarker positive.

David A. Roth: Okay, so the relapsed refractory AML trial, the key inclusion criteria require you to have relapsed refractory AML, and you would be RARA positive. So you must be biomarker positive. So you need to have either had a prior treatment response, which then you lost, or you actually never were able to attain a prior treatment response.

So you need to either how to prior treatment response, which then you lost so you're right you're relapse or you actually never been able to obtain a prior treatment response. This can include fit patients who are progressing off of intensive chemotherapy without hypomethylating agent exposure or it can include.

David A. Roth: This can include fit patients who are progressing off of intensive chemotherapy without hypomethylating agent exposure, or it can include unfit patients who may have had a hypomethylating agent in their prior treatment history. So we're agnostic to that.

Unfit patients who may have had a hypomethylating agent in their prior treatment history. So we don't we're agnostic to chew that I think we're going to learn important information about that.

David A. Roth: I think we're going to learn important information about. We believe that, you know, it's important to make this as widely available in the early stages so we can understand the best way to move this forward after evaluating the totality of our data. And there was a second question, oh yeah, about whether or not MDS patients, so this is really specifically focused on relapsed refractory AML. You know, there is obviously great excitement about MDS. I think that we have previously explored our drugs as a single agent, including patients with relapsed high-risk MDS, and I'll remind you, we did see evidence of single-agent activity there with hematologic improvement, and we even had a patient with a complete response that lasted for quite a while associated with heme improvement in at least two of their cell lineages.

You know, we believe that it's important to make this is widely available in the early stages. So we can understand the best way to move this forward after evaluating the totality of our data.

There was a second question earlier about whether or not.

Yes. So this is really specifically focused on relapse refractory AML I'm you know there obviously is great excitement about Mds I think that.

We have previously explored our drug that's a single agent, including patients with relapsed high risk Mds and I'll remind you. We did see evidence of single agent activity, there with hematologic improvement and we even had a patient with a complete response that lasted for quite a while associated with human improvement and at least two there's so many users so our our drug has.

David A. Roth: So our drug has the potential for utility in that population as well, and that's further underscored by the presence of the RARA biomarker in patients with MDS. So we're looking at that very carefully, but at the moment, our focus is like a laser beam right on the AML population, and that's where we're looking to make our immediate impact. Okay. Very helpful.

Potential for utility in that population as well and that's further underscored by the presence of there are a biomarker in patients with MTS. So.

We're looking at that very carefully but at the moment, where our focus is like a laser beam right on the middle populations and that's where.

We're looking to make our immediate impacts.

Okay. Okay. Thanks for taking the questions and congrats on progress.

Operator: Okay, very helpful, thanks for taking the questions and congratulations on the progress. Thank you. And our next question comes from the line of Ted Tenthoff with Piper Sandler. Great, thank you very much, and good morning, everyone. Kind of a similar question, but with respect to 1425. And obviously, a society is the ideal agent. But I'm wondering, as you see...

Yes.

Thank you.

Next question comes from a lot of Ted Ted Tenthoff with Piper Sandler.

Great. Thanks, very much and good morning, everyone have a similar question, but with respect to Fortune 20 clients and obviously is society and is ideal agent, but I'm wondering as he is he mechanism and thankfully some.

Operator: Advancements with respect to our agent's novel mechanism in AML. Are you seeing anything that makes sense to evaluate? You know, certainly we're waiting for the relapsed refractory data, but have you done any preclinical work to look at other mechanisms that might be synergistic? Thanks.

Advancement with respect to agents novel mechanisms.

And Bill are you seeing anything that makes sense to evaluate you know certainly we're waiting for the relapse refractory period up but have you done any preclinical Workover Cup other mechanisms that murky synergistic thing.

He Ted.

Operator: Hey, again. Thank you. Thank you, everybody. Thank you. Thank you.

We we have shown in preclinical in vitro.

Nancy A. Simonian: Hey Ted! We have shown in preclinical and sort of in vitro analyses that 1425 is quite synergistic or at least additive with multiple agents that are used in the AML setting, both experimental as well as sort of standard of care. And I think that's always what's been really exciting for us. It looks like 1425 could be a great combination partner broadly, not only because it's a novel mechanism of action, but it appears to be synergistic and or additive with many agents. And also, the tolerability profile doesn't typically overlap with these other agents, and so I think that makes it, in some ways, an optimal combination partner. And so as we think about our ultimate vision for the program, it is to explore it in other combinations and also in other patient settings where ARARA is elevated. So we think there's a lot of opportunity more broadly beyond AZA, but we think right now, kind of, you know, focusing on the AZA combination and getting to proof of concept and an approach forward is the current focus. But it's just the beginning for, I think, a much broader potential for the drug.

Analyses that 14, 25 is quite synergistic or at least additive with multiple agents that are used in the HML setting both.

Experimental as well as I'm sort of standard of care I think that's always what's been really exciting for us. It looks like 14 25 could be a great combination partner broadly not only because it's a novel mechanism of action it appears to be synergistic and or additive, but many agents and.

Also the Tolerability profile doesn't typically overlap with these other agents. So I think that makes it in some ways out an optimal a combination partner.

And so as we think about our ultimate vision for the program it is to explore and other combinations.

And also what other patient settings, where our virus elevated so we think it theres a lot of opportunity I'm more broadly beyond Asia, but we think right now kind of focusing on the ease a combination and getting to proof of concept and an approach Ford is is the current focus but it's just the beginning or.

I think a much broader potential for the drug.

Nancy A. Simonian: Yeah, it makes sense, especially with the safety profile. So, great. Thank you very much, and I'm looking forward to more data this year. Okay. Thank you. And as a reminder, ladies and gentlemen, if you have a question, please press star 1 on your telephone. Our next question comes from the line of Zegba Jala with Roth Capital Partners.

Yeah, It makes sense, especially with the safety profile. So great. Thank you very much and I'm looking forward for a more data this year. Thank you [noise].

Okay.

Thank you and as a reminder, ladies and gentlemen, if you have a question. Please press star one on your telephone.

Our next question comes from the line of jobs with Roth Capital Partners.

Operator: Good morning. I just had a couple of questions here. For 1425, just wanted to know what you are hoping to see in the newly diagnosed patient population, and are you looking for a partner to further develop 1425 in this population?

Good morning, Kinda a couple of questions here.

<unk> 14, 25, just wanting to know what are you hoping to seen in newly diagnosed patient population and are you looking for partners to for that give off fortune 25 and in this patient population.

Oh I'll have David answer the first question about what we're looking forward the newly diagnosed data and then I can address the upgrade question sure. So in the newly diagnosed.

Operator: I'll have David answer the first question about what we're looking for in the newly diagnosed data, and then I can address the partnership question. Sure.

David A. Roth: So, you know, in the newly diagnosed, we're very excited about the data. You know, as you know, we shared that information back at a presentation in October where we showed a very high complete response rate, and these responses were deep responses, the majority being molecular or cytogenetic, which is encouraging because those are the ones typically associated with, you know, a long-lasting effect. And we have early evidence of durability, and we see a high degree of transfusion independence. So, you know, that all coupled with what is really a generally well-tolerated combination safety profile is very encouraging to us. So, the things that we're looking forward to in the more mature dataset are just to see these data in a larger number of patients, and then to get a more robust sense of the We have more time to observe the responses. And so that's the type of information we're looking for.

You know at them at the moment, we're very excited about the data you guys. You know we shared that information back at a presentation in October where we showed a very high complete response rate and these responses were deep responses majority being molecular or cytogenetic.

Which is encouraging because those are the ones typically associated with.

Long lasting effect and we have early evidence of durability and.

We see a high degree of transfusion independence. So you know that all coupled with what is really a generally well tolerated combination safety profile is very encouraging to us.

So the things that we're looking forward to in the more mature dataset or just to see these data in a larger number of patients and then to get to a more robust a sense of the duration of the responses. When we got more time to absorb the responses and so so that's the type of information.

We're looking for.

Nancy A. Simonian: In fact, on the question around, you know, partnership with 1425, I would just sort of step back and say, you know, our vision and goal is to build a fully integrated biopharmaceutical company; we have a discovery engine, a very rich clinical and preclinical and discovery pipeline. And of course, we're always thinking strategically as there is something that we think that we can create more value by doing in partnership versus alone, and the timing of which we might think that there could be more value for patients or for investors. And so I'd say broadly, you know, we think corporate development is going to be important, and we've already done two collaborations on our discovery engine. So it's important, and we continue to evaluate it across our portfolio and pipeline.

In fact on the question around.

You know partnership with 40, 25, I would just step back and say you know our vision and goal is to build a fully integrated biopharmaceutical company.

We have a discovery engine, a very rich clinical and preclinical and discovery pipeline and of course will always thinking about strategically as there is something that we think that we can create more value by doing well in partnership versus alone you know the timing about which we might think that there could be more value.

You for patients are for investors and so I think say broadly we think corporate development is gonna be an important that we've done now chew collaborations on our discovery engine. So it's important.

We continue to evaluate it really cross our our portfolio and pipeline.

Operator: Thank you. I was just asking, since, you know, the initial focus will be the relapsed refractory patient population, and then I was just kind of wondering the strategy for moving forward if the data in the larger cohort does look better. But moving on to 56 and 90, I just kind of want to get a general sense of how you are reaching for the patient population of breast, lung, and ovarian cancer. And then also, I know you mentioned that you couldn't specify what combinations you're looking to explore, but I just kind of want to get a sense of how you may be thinking about, you know, your CDK-12, 13 inhibitor differently from a CDK-7 inhibitor. And then, with respect to how you're going to think about combination approaches for those two different inhibitors.

Thank you just asking since you know they initial focus will first be though relapse refractory patient population and then was kind of wondering skydiving about you know moving forward and if that data in the at the larger core it does look better but moving on to 56 or nine gets kind of want to get a general sense, if I knew reaching for the patient.

Operation of breast lung and ovarian cancer and then also I know you you mentioned that you couldn't specify what combinations you're looking to explore both just kinda Wanna get offensive. How you maybe thinking about you know your T.K. 12, 13 inhibitor differently from I see Keith seven inhibitor and then.

With respect to also how you're going to think about combination approach it for the two different on inhibitory.

Operator: So let me, I think there's a couple questions in there. First, there was a question around how might CDK-7 or 5609's CDK-7 program differ from 12? I'll have Eric answer that question. Then you had a question around the patient population for 5609. I'm not sure, you might need to repeat.

Okay. So let me I think there's a couple of questions and their first there was a question around how might CDK seven are 56 or nine CDK seven program different from 12 I'll hop Eric answer that question. Then you had a question around a patient population for 56, <unk> I'm not sure you might need to repeat that question.

Operator: Yeah, I was just wondering how you're enriching. Do you just assume that with your screen you will just get more of those patients, or do you have particular thresholds that you're hoping to achieve for each of those indications, breast, lung, or ovarian?

Yeah, just wondering how you're reaching out do you just assumed that with your screen you will just get more this patient or do you have like particular threshold that youre, hoping to achieve what you should those indications bass longer varying.

Operator: Okay, all right, so then I'll have David answer that question, but Eric, do you want to first touch on the 7-12?

Okay. All right. So they don't have David answer that question, but aired when it first touch on the seven trial sure.

Eric Olson: Sure. As you know, we've been working on transcriptional CDK inhibitors for many years now, and we actually have a good understanding of how to make selective molecules for both 7 and 12. And in the course of that work, the preclinical work, looking at the mechanism and the tumor types and the types of contexts where inhibition plays a role in cancer, we have a pretty good understanding of how to differentiate between 7 and 12 inhibitors from our preclinical work. As Nancy said at the beginning, clearly, and work that we presented at the Keystone Conference, 12 inhibition really affects the expression of very long genes, many of which are involved in DNA So that's kind of our initial hypotheses about where we might enrich patients in a clinical program with a 12 inhibitor.

We've been working on CDK transcriptions CDK inhibitors.

For many years now and we actually have Oh a.

Good understanding of how to make selective molecule for both seven well.

And in of course of that work the preclinical work looking at the mechanism and the tumor types and the types of a context, where inhibition plays a role in cancer, we have a pretty good understanding of how to differentiate between seven and 12 inhibitors from our preclinical work as Nancy said at the beginning.

Clearly and work that we presented at the Keystone Conference.

12 inhibition really affects the expression of very long gene on many of which are involved in DNA repair and DNA damage. So that's kind of our initial hypotheses about hypotheses about where we might enrich.

For patients in a clinical program with a 12.

And then I think I'm have David answer the question on 56 or nine or so we are we're open to patients who have.

David A. Roth: Okay, and then I'm going to have David answer the question on 5609.

David A. Roth: We're open to patients who have breast cancer, lung cancer, ovarian cancer, colorectal cancer, and patients with RB mutations, regardless of the tumor histology, and there are no pre-specified targets for the numbers of patients of each of those tumor types. However, during the dose escalation phase, we do anticipate significant proportions of the patients that are enrolled to have, for instance, RB pathway abnormalities because intrinsically And also because our investigators are fully aware of our preclinical data that show very compelling preclinical activity in that context. And I'll remind you, we presented data at the ENA meeting this past fall that showed that, you know, 100% of the models we surveyed over a range of different tumor types had significant tumor growth inhibition, but those with RB pathway abnormalities had complete regressions that lasted for quite some time after stopping the drug.

Breast cancer lung cancer ovarian cancer colorectal cancer in patients with RB mutations or just regardless of the tumor histology and the you know there there are no pre specified targets for the numbers of patients.

Okay each of those tumor types.

During the dose escalation.

We do anticipate.

Significant portions of the patients that are enrolled to have a for instance, RB pathway urban properties because intrinsically there just in rich and also because our investigators are fully aware of our preclinical data that show very compelling.

Preclinical or activity in that context, I'll remind you we we presented data at BDNA meeting.

This past fall, which showed that 100% of the models, we surveyed over a range of different tumor types have significant tumor growth inhibition, but those with RB past wherever maladies complete regressions.

Lastly.

For quite some time after stopping the drug so so that tends to influence.

David A. Roth: So that tends to, you know, influence selection of patients into the early phase of the trial. And the last comment I would have is just that we have the opportunity to incorporate additional groups of patients along the dose escalation. You know, we're calling these cohort extensions. There are sort of many expansions during dose escalation, and we can target the populations into those extensions as we see fit based on emerging preclinical or even clinical outcomes from the trial itself to further enrich and build a sufficiently robust data set to appropriately inform our formal expansion strategy. So, I think that's the approach to how we're going to move this ahead.

Selection of patients into the early phase of the trial and the last comment I would have it's just that we have the opportunity to.

To incorporate additional groups of patients along with dose escalation. We're calling these cohort extensions are there sort of many expansions during dose escalation or we can targeted.

The populations into those extensions as we see fit based on emerging preclinical or even clinical outcomes from the trial itself to further enrich and to build a sufficiently robust dataset to appropriately inform our formal expansion strategy later so so.

I think there's.

My approach to how we're going to move to said.

David A. Roth: Perfect. Thanks for taking my questions. Congratulations on a productive 2019 and looking forward to the readouts the rest of the year. Thanks so much.

Perfect. Thanks for taking my questions. Congrats on a productive Twain 18, you're looking for to the lead outside there wasn't there.

Thanks Bye-bye.

Nancy A. Simonian: Thank you, and I'm showing no further questions at this time. I will now turn the call back over to CEO Nancy Simonian for closing remarks.

Thank you know I'm showing no further questions at this time I will now turn the call back over to CEO, Nancy Simonian for closing remarks.

Nancy A. Simonian: Thank you, Operator. In closing, 2020 will be an important year for Syros, with meaningful clinical data expected for both 1425 and 5609. We are focused on executing with excellence to advance those programs as well as our preclinical and discovery pipeline, and we look forward to keeping you updated as we work toward our ultimate goal of bringing small molecule medicines to market that provide a profound benefit for people with cancers and monogenic diseases that have eluded effective treatment with other genomics-based approaches. Thank you all for joining us today and for your continued support of Syros. Have a good day!

Thank you operator in closing 2020 will be an important year for Sarah with meaningful clinical data expected for both 14, 25, and 56 or nine.

We are focused on executing with excellence to advance those programs as well as our preclinical discovery pipeline and we look forward to keeping you updated as we work toward our ultimate goal of bringing small molecule medicine to market that provide a profound benefit for people with cancers and monogenic diseases that have alluded.

Effective treatment with other genomics based approaches.

Thank you all for joining us today and for your continued support of Sarah have a good day.

Ladies and gentlemen, this concludes todays conference call. Thank you for participating and you may now disconnect.

Operator: Ladies and gentlemen, this concludes today's conference call. Thank you for participating, and you may now disconnect. The Bulletproof Executive 2013, BF-WATCH TV 2021

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