Good day, ladies and gentlemen, and welcome to the Q4 2018 Syros Pharmaceuticals Incorporated Earnings Conference Call. [Operator Instructions] I would now like to introduce your host for today’s conference, Naomi Aoki, Vice President of Corporate Communications and Investor Relations at Syros. Please go ahead..

Thank you. This morning we issued a press release with our fourth quarter and full-year 2018 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 will begin the call with prepared remarks by Dr.

Nancy Simonian, our Chief Executive Officer; Dr. David Roth, our Chief Medical Officer; and Joe Ferra, our Chief Financial Officer. Then, we will 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'd 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 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 was filed with the SEC this morning and on the other filings that we 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 our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements. I would now like to turn the call over to Nancy..

Thanks, Naomi. Good morning, everyone, and thank you for joining us today. At Syros our vision is to build a great and enduring company with medicines that provide a profound benefit for patients. In 2018, we made significant progress towards achieving this vision.

Most importantly, we announced pharmacy and clinical data for both of our first-in-class programs, SY-1425 and SY-1365.

These data give us added confidence in our programs and we announced this morning that we plan to expand the ongoing Phase 2 trial of the 1425 azacitidine combination into relapsed or refractory AML patients who are RARA or IRF8 biomarker-positive.

And that we’ve added an expansion cohort in recurrent ovarian clear cell cancer to the ongoing trial of 1365, replacing the primary platinum refractory cohorts. The unmet need in both these patient populations is significant. And we believe these cohorts provide the potential for rapid proof-of-concept.

Together with the cohort evaluating 1365 as a single agent in relapsed high-grade serous ovarian cancer, these new cohorts give us three potential fast-to-market opportunities for our clinical programs. Our top priority is to execute on our clinical trials with the aim of delivering much needed therapies to patients as quickly as possible.

Let me start by talking about our 1425 clinical development strategy. Once a great yard for drug development, the AML landscape is now rapidly evolving with multiple approvals and many agents in the clinical pipeline. Despite these events, significant unmet need remains across the AML and MDS landscape.

Based on the data we reported in December at ASH, we believe we’ve a highly active combination with a favorable tolerability profile that has the potential to be a foundation of care for a biomarker positive ANL and higher risk MDS patients.

Having evaluated the current and evolving treatment landscape, we believe the highest unmet need exists in the relapsed or refractory AML setting, and this population provides the most efficient path to bring 1425 to market locations.

We plan to open a new cohort for involvement in the third quarter of this year, positioning us for potential proof-of-concept data in 2020 that could enable a decision to move towards registration.

Consistent with the guidance we provided earlier this year, we expect to complete enrollment in the ongoing 1425-aza combination cohort in biomarker-positive newly diagnosed unfit AML patients midyear [ph] and report updated data from the biomarker-positive and biomarker-negative cohorts in the second half of 2019.

These cohorts are an important part of our overall development strategy and our vision for 1425 potential broadly in biomarker-positive patients. In addition, the clinical data from these cohorts could be valuable in the development of a commercial companion diagnostic in time for a potential launch.

Turning to 1365, let me take a moment to discuss our rationale for pursuing recurrent ovarian clear cell cancer clinical. Clear cell cancer represents approximately 10% of ovarian cancer and the prognosis for patients with clear cell is dismal. Few respond to existing therapies and there is very little in the clinical pipeline for these patients.

In the dose escalation portion of our trial, we had a patient with ovarian clear cell cancer whose tumor never shrank in response to three prior lines of therapy, but who had a durable partial remission with 1365. When her doctor told her that her tumor was shrinking, she cried.

As at the time of the data presentation in November her tumor had shrunk by 49% and her response has been sustained through six months. Stories like hers underscore the urgency and importance of what we do and inspire us all At Syros to do our best work every day.

Given the tremendous unmet need, our existing focus on ovarian cancer and the data from the dose escalation, we believe 1365 warrants further investigation in these very difficult to treat patients and expect the new cohort in clear cell cancer patients to be open for enrollment in the second quarter.

We believe this timing puts us on track for potential proof-of-concept data in 2020. While the data will ultimately determine our next steps, if positive given the high unmet need in clear cell, we believe this cohort could form the foundation for an accelerated filing opportunity.

In addition, the ongoing cohort in relapsed high-grade serous ovarian cancer patients who have had three or more prior lines of therapy also provides an opportunity for rapid proof-of-concept and a patient population in dire need of new therapies and gives us a third opportunity for an accelerated development path.

Consistent with our earlier guidance, we expect to report initial data from the expansion portion of the Phase 1 trial in the fourth quarter.

Specifically, we expect to report data from three of the ongoing cohorts, including initial efficacy and safety assessment from the cohort I just mentioned in ovarian cancer patients with three prior lines of therapy, safety and PK data from the cohort evaluating 1365 in combination with carboplatinum in ovarian cancer patients who have had one or more lines of prior therapy, and initial efficacy, safety and mechanistic data from the biopsy cohort in patients with advanced solid tumors.

We expect to report additional data from these cohorts as well as the proof-of-concept data for clear cell and the initial data from the cohort in HR positive CDK4/6 inhibitor resistant breast cancer patients in 2020. Moving to SY-5609, as many of you know last year we selected 5609 as our next development candidate.

It is a highly selective and potent oral CDK7 inhibitor and a key part of our strategy to maintain and build on our leadership in CDK7 inhibition.

We believe that 1365 and 5609 together could make for a powerful CDK7 franchise and we see 5609 is having distinct and complementary opportunities to 1365, particularly where oral administration fits more seamlessly into the treatment paradigm such as when combining with other oral therapies or in a maintenance study.

We will be presenting new preclinical data on the selectivity, potency and antitumor activity of 5609 at the upcoming AACR meeting. We continue to advance 5609 towards clinical development and remain on track to complete IND enabling studies this year to support the initiation of a Phase 1 oncology trial in early 2020.

I want to get Eric Olson and his team a lot of credit for discovering this molecule, which is exquisitely selective and really speaks to our expertise in developing small molecule to drugs historically inaccessible targets that control the expression of genes. I am thrilled with our progress and excited about what's to come.

By this time next year, we expect to have three programs in clinical development. This year and next promise to be data rich years for 1425 and 1365. We expect to be executing on eight cohorts in three diseases across two ongoing trials with data readouts from all eight cohorts this year or next.

The cohorts in relapsed or refractory AML, recurrent ovarian clear cell cancer and relapsed ovarian cancer in 3 plus prior line provides potential path to market strategies for both programs, while the cohort in ovarian cancer in combination with carboplatinum and in CDK4/6 inhibitor resistant HR positive breast cancer patients gives us opportunities to move into earlier lines of treatment and growing patient population.

With that, let me turn the call over to David for a more detailed review of our clinical programs..

Thanks, Nancy, and good morning to everyone on the call. I would like to start today by describing our clinical development philosophy more broadly. First and foremost, we take a data-driven approach and pursue indications were we believe there's the greatest likelihood of providing a profound benefit for patients.

We aim to honing on patients most likely to respond to our therapies using our platform to identify biomarkers and other patient selection strategies that enrich for responders. We look for opportunities to simultaneously explore our drug candidates early on in development as single agents and in combination in multiple patient populations.

And we design our trials to be flexible, so that we can rapidly respond when we see a positive signal or just our strategy based on data and in some cases shifting market dynamics. The clinical development plans relating out today for both 1425 and 1365 exemplify how we're putting that philosophy into action. Turning to 1425.

Based on the clinical data to date, its unique tolerability profile and preclinical synergy with a number of AML and MDS therapies, we believe that 1425 has broad combination potential in biomarker-positive AML and higher risk MDS patients.

Realizing that potential starts with the ongoing Phase 2 trial and key to our development strategy is the newly announced cohort in relapsed or refractory AML patients. At ASH, in December, we presented initial clinical data on the 1425-aza combination in newly diagnosed unfit AML patients.

These data demonstrated high response rate and rapid onset of clinical activity in biomarker-positive patients. Across eight response evaluable patients, we observed an overall response rate of 63% with 50% of patients achieving either a CR or a CRI. Additionally, most responses were seen at the end of the first month of treatment.

These data compare favorably to single agent azacitidine as well as to our early data from the biomarker negative cohorts. Importantly for the treatment of AML patients, who tend to the elderly and frail, the combination was generally well tolerated with no evidence of increased toxicities beyond that which would be expected with each agent alone.

Of note, there was no increased myelosuppression, which is often seen when combining drugs to treat leukemia and which tends to result in treatment related morbidity and dose reductions and delays. We believe there may ultimately be a place for 1425 as a combination agent in the treatment of biomarker-positive newly diagnosed unfit AML patients.

And we remain committed to completing enrollment in the ongoing cohorts to gather more mature data to clarify our next steps in this population. That said, the rapidly evolving landscape has made the development path in these patients potentially longer and more challenging than it was when we embarked upon this trial.

Our preliminary data combined with the emerging landscape at AML and MDS form the basis of our decision to expand the ongoing Phase 2 trial into relapsed or refractory AML patients, where we have the opportunity for rapid proof-of-concept and a potential accelerated filing path.

We plan to enroll 25 biomarker-positive patients in the new cohort and expect to have potential proof-of-concept data in 2020. Now let me turn to 1365. We believe 1365, and more broadly, CDK7 inhibition represents a potentially transformative targeted approach for the treatment of cancer.

We completed the dose escalation portion of the Phase 1 trial in patients with advanced solid tumors in September and moved into the expansion portion of the trial. We decided to focus the initial expansion on relapsed ovarian cancer and HR positive CDK4/6 inhibitor resistant breast cancer for several reasons.

The preclinical data in those tumor types was strong and the unmet need high.

We also had a mechanistic rationale for why these patients might be more likely to respond based on data showing an association between 1365 responses and alterations in the RB pathway, which are known to be prevalent in ovarian cancer and in CDK4/6 inhibitor resistant breast cancer.

We will be presenting new preclinical data on the association between RB alterations in response to 1365 in ovarian cancer models at the upcoming AACR meeting. At the EORTC-NCI-AACR meeting this past November, we reported the data from the dose escalation. Notably, these data were the first clinical data reported on a selective CDK7 inhibitor.

The data demonstrated proof of mechanism for SY-1365 at tolerable doses. Adverse events were predominantly low grade, reversible and generally manageable. And importantly, there were no signs of neutropenia, which has been associated with CDK4/6 and pan-CDK inhibitors. We also saw early signs of clinical activity.

This was particularly exciting to us given that the dose escalation was in advanced solid tumor patients of any histology and as is typical in a dose escalation oncology study, the patients were very sick and heavily pretreated and were highly refractory. Many of whom were treated at doses anticipated to be sub-therapeutic.

We saw clinical activity in 7 of the 19 response to valuable patients as of the data cutoff in October, including one who had a confirm partial response and 6 who had stable disease. As Nancy mentioned earlier, the confirmed partial response within a patient with recurrent ovarian clear cell cancer.

Based on this early signal of clinical activity and the unmet need in clear cell, we believe 1365 warrants further investigation in this population. Fewer than 10% of recurrent ovarian clear cell patients respond to existing therapies and progression free survival is only 2 to 4 months.

With only a handful of trials focused on clear cell, there is little on the horizon for these patients. The cohort in recurrent ovarian clear cell cancer will assess 1365 as a single agent.

We expect it to be open for enrollment in the second quarter and plan to enroll approximately 12 patients with data expected in 2020, there's potential for rapid proof-of-concept.

And based on input from our leading ovarian cancer experts, we believe we will have strong support from the investigators, and if the data are positive, we also believe there could be an accelerated development path.

Our other potential best to market opportunity for 1365 is the ongoing cohort assessing 1365 as a single agent in relapsed high-grade serous ovarian cancer patients who have had 3 plus lines of prior treatment. Many of these patients are platinum resistant and have exhausted existing treatment options.

So we expect to have initial data from this cohort in the fourth quarter and potential proof-of-concept data in 2020. As with the clear cell cohort, if the data are positive, we believe there could be an accelerated development path. The clear cell cohort will replace the primary platinum refractory cohort.

When we designed the expansion portion of the trial, we included this cohort based on the significant unmet need and its potential to be a fast-to-market strategy. Given the recent approval of bevacizumab in combination with carboplatin, however, fewer patients are meeting the strict clinical definition for being primary platinum refractory.

And as such, we’ve decided to focus our efforts and resources on recurrent ovarian clear cell cancer, which we believe provides a superior potential fast-to-market opportunity for patients and for Syros.

As we’ve outlined here, the next few years will be busy ones for us with potential proof-of-concept data readouts for our programs in several patient populations that desperately need better therapies. And I look forward to keeping you updated on our progress.

With that, I would like to turn the call over to Joe to review our financial results for the fourth quarter and full-year 2018.

Joe?.

Thank you, David. Syros continues to operate from a strong financial position.

We believe that our existing cash, cash equivalents and marketable securities will support our planned operations and CapEx into the second quarter of 2020, allowing us to advance our clinical programs to key milestones, while also investing in our earlier stage pipeline and in leading gene control platform to fuel our long-term growth.

Now for our fourth quarter and full-year 2018 financial results. We ended 2018 with $99.7 million in cash, cash equivalents and marketable securities compared with $72 million on December 31, 2017. We recognized $0.9 million of revenue in the fourth quarter of 2018. We do not record any revenue for the fourth quarter of 2017.

Revenues were $2.1 million for the full-year 2018 compared to $1.1 million for the full-year 2017. Revenues in 2018 were earned entirely from our collaboration with Incyte, while our revenues in 2017 were earned under our research agreement with a multinational pharmaceutical company.

R&D expenses were $15.1 million for the fourth quarter of 2018 as compared to $11.8 million for the same period in 2017. R&D expenses for the full-year 2018 were $50.2 million as compared to $41.9 million for the full-year 2017.

This increase was primarily due to an increase in contract manufacturing costs and professional fees in support for our clinical trials as well as an increase in employee related expenses. G&A expenses were $4.4 million for the fourth quarter of 2018 as compared to $3.7 million for the same period in 2017.

G&A expenses were $16.2 million for the full-year 2018 as compared to $13.9 million for the full-year 2017. This increase was primarily due to an increase in employee related expenses.

Finally, we reported a net loss for the fourth quarter of $18 million or $0.54 per share compared to a net loss of $15.3 million or $0.58 per share for the same period in 2017. For the full-year 2018, our net loss was $62.3 million or $1.91 per share compared to a net loss of $54 million or $2.13 per share for the full-year 2017.

With that, I would now like to turn the call over to the operator for questions. Thank you..

Thank you. [Operator Instructions] And our first question comes from Phil Nadeau with Cowen and Company. Your line is now open..

Good morning. Thanks for taking my questions. First a question on the 1425 plus azacitidine arm and relapsed refractory AML.

Can you talk about the -- little bit more about the enrollment criteria for that arm? In particular, where patients have to be azacitidine naive to get into the arm or could they have seen prior azacitidine before enrollment?.

Yes, the patient -- thanks for the question. The patients would have to meet the criteria for being relapsed and or refractory AML patients and there will be no specific exclusion for prior HMA exposed patients..

Got it. Okay. And then, second, can you talk a little bit more about the rationale for adding that arm. It sounds like from your prepared remarks, it's partially maybe data that we’ve seen, but then also partially the evolving landscape.

And I’m kind of curious how those elements -- which of those elements predominates? Which was more important, is the data you’ve seen or is it just the competition coming in naive AML?.

I think we're really excited about the level of activity that we've seen in the ongoing azacitidine 1425 combination in newly diagnosed unfit as well as the really favorable safety profile. I think that’s predominant.

And we’re always thinking about what is the most efficient path initially to get the drug to market, and we think with the evolving landscape and the new recent approvals in that setting that a more efficient path to get to market will be in the relapsed refractory.

But we are really excited about the data that we have in the newly diagnosed unfit and I think the key thing will be how -- what’s the best way to develop it in that population..

Phil Nadeau:.

said about the proportion of ovarian that’s clear cell?:.

Yes. So, again, thanks, Phil. So the proportion is estimated at about 10% of patients with ovarian cancer have clear cell. And with respect to the reason for the pivot to clear cell, with the -- as I mentioned earlier, the approval of bevacizumab has been increasingly utilized in early setting in combination with carboplatin.

And so the definition of primary platinum refractory requires progression during or within a month after completing that initial line of therapy. And we’re seeing fewer and fewer of patients in those criteria.

So I think that there is an opportunity to refocus our efforts in another significant unmet need patient population where we have mechanistic rationale and early signal of clinical activity that gives us a belief that we can make a difference for those patients..

I got it. That is very clear. Thanks for taking my questions and congrats on the progress..

Thanks, Phil..

Thank you. And our next question comes from the line of Ted Tenthoff with Piper Jaffray. Your line is now open..

Great. Thanks very much and congrats on really a solid progress across the two programs. My question is picking up on sales. What is the biological rationale in clear cell ovarian.

Is there much of a difference between the two were 1365 might actually be better applied there or just maybe tell us a little bit more about some of the mechanistic differences?.

Okay. So, again, we’ve previously demonstrated data that show that RB pathway alterations in high-grade serous are important and may predict for sensitivity to SY-1365. When you look at ovarian clear cell patients there are different molecular features that distinguish them.

However, they also -- genetic alterations that lead to altered RB function as well as cell cycle [technical difficulty]. Some of those mutations include PIK3CA mutations as well as ARID1A mutations and interestingly the patients who have the confirm partial response during our dose escalation with clear cell had both of those mutations.

So we think there's not only a mechanistic rationale, but we now have an early clinical signal that we feel compelled to follow-up on because we think that the mechanism and the clinical activity really support further evaluation. And the last point is just -- there's such a significant unmet need.

These patients are typically chemo-resistant [indiscernible] very little works. The responses are short-lived. So, again, it gives us another opportunity for rapid proof-of-concept -- clinical proof-of-concept and an accelerated registration opportunity. So we think that’s really all very compelling rationale to pursue it..

Makes a lot of sense. Thanks for that additional detail..

Thank you. And our next question comes from the line of Mark Breidenbach with Oppenheimer. Your line is now open..

Good morning and thanks for taking the question, and congrats on the recent progress. So going back to the new cohort in relapsed refractory AML. Maybe question for David, just trying to get a sense for what you’re viewing as the efficacy bar that you want to clear to support registration in the setting.

And also I’m wondering if there are any lessons learned in the 1425 combination with daratumumab that could be used to guide or streamline patient enrollment into the relapsed refractory cohort that you just announced today? Thank you..

Okay. So I will start with the background. So in terms of the proof-of-concept that we're anticipating -- seeing in 2020, we look at various parameters for response and tolerability. We believe we have a very, very well-tolerated combination that has activity in the newly diagnosed cohort.

And we're going to be looking at things relative to the unmet need and the landscape as well as how that -- how that’s comparing to our target product profiles that we’ve developed. We look at response rates, response durations and safety and tolerability. If you look at the relapsed population, responses are rather low.

So for instance, relapsed patients who get Aza as a single agent typically have responses in the 15% response rate range with response durations in approximately the 6-month timeframe.

Some of the targeted agents that have recently been approved have similar CR rates, maybe about 20% for the IDH or the FLT3 inhibitors response durations maybe bordering 6 to 8 months. So those are the general framework of backdrop that we will be calibrating our results against. And then the second question was related to the daratumumab.

Could you just repeat the specific question about that?.

Yes, just wondering if there's anything that we can extract from that cohort since that’s where we’ve seen 1425 already tested in the relapsed refractory setting, if there's anything that we can learn from that study to help streamline patient enrollment into the new cohort?.

Yes. So I think that our experience with daratumumab combination with 1425 as well as our prior single agent experience really track with the significant unmet need. We expect and we’ve actually already received feedback from the majority of our investigators, the unmet need is so high and the confidence on our approach is also equally high.

And therefore we don't expect there to be challenges finding relapsed patients to support this investigation..

Okay.

But in terms of which types of biomarker patients might be best candidates for response that sort of thing, no directly transferable information from that cohort?.

Right. We are looking at RARA and or IRF8 biomarker-positive patients..

All right. Thank you..

Thank you. [Operator Instructions] And our next question comes from the line of Jotin Marango with ROTH Capital. Your line is now open..

Good morning. Thank you for taking my questions. I have two on each of the program. When thinking about 1425 in myeloid disease, my question is around the population itself.

Over the last year have you gained any insight on the type of disease that these biomarker-positive patients have clinically or is it morphological level? So do the biomarker-positive patients have a different course of disease or respond differently to other treatments?.

Okay. That’s a good question. So we look very carefully. We see at cytogenetic and at the molecular level all of the typical types of abnormalities and mutations that one might expect in a unselected population with AML.

And I pointed out that in our presentation at ASH, the majority of our enrolled biomarker-positive patients had complex or poor risk cytogenetic features and a fair number, more than half had very high blast count AML, all of those are clinical predictors of poor response to treatment.

So the fact that we saw the 63% overall response rate in that very challenging patient population increases our confidence and conviction in this program..

Got it. And a follow-up on that, David, when thinking about the relapsed population, you are headed with the next HMA combo cohort later this year.

Is it clear at this point if the biomarker-positive blast or patients are enriched as the disease moves around to therapy?.

So we’ve found a consistent -- approximately 35% biomarker positivity rate across the populations that we’ve screened over time for the study. And so, we think that we will find a similar percent of patients for this in the relapsed population..

Okay. Switching to 1365, in the last couple of AACR release there was data on CDK7 from you. In fact, even interesting target in myeloid disease as well and I think there was some implication of MCL1 is downstream target.

Any plans at this point to going that direction either with this molecule or at the next gen one?.

Hi, Jotin. This is Nancy. Yes, there are some very strong data in heme malignancies with CDK7 inhibitors. And obviously it's worth thinking about both future development of 1365 as well as our oral compound 5609 coming forward, we certainly are thinking about the potential -- the broader potential across both solid tumors and heme malignancies..

Okay.

On the ovarian cohort, which we will hear about later this year then, as we move towards that data what is your internal bar? So what have you set as the clinically meaningful indicators of efficacy as the data trickles in? Is it just tumor reductions or you have a response bar, so what will represent positive data?.

So, Jotin, as we said we -- for each of the patient cohorts in the trial, we kind of look at those populations, we benchmark it against historical data with other agents in that population and we develop some targets profiles and we set our criteria that we’ve internally about what we'd want to see in order to be -- feel like this is compelling enough to move forward.

So we haven't talked about specifically those numbers for each, so -- but that’s the approach.

I don't know David, you want to talk about what the precedence in that population will be?.

Well, yes, I mean, in the -- there's basically low -- very low response rates and short durations of response.

We think that -- and the three plus line single agent evaluation in high-grade serous, as well as the clear cell, because of their low response rates and short progression-free survival, that should translate into an easily identified clinical signal and that’s why we are comfortable looking at those as fast clinical PoC opportunities for 2020, which we can then translate into an accelerated rapid registration fast-to-market approach..

Thanks very much. See you all at AACR..

Thanks, Jotin..

Thank you. And that does conclude today’s question-and-answer session. I'd now like to turn the call back to Nancy Simonian for any further remarks..

Thank you, operator. And thank you all for your continued interest and support in Syros. I am proud of everything we’ve accomplished in 2018.

Importantly, these accomplishments laid the groundwork for multiple clinical milestones in 2019, 2020 and beyond, that promise to bring us closer to our vision of becoming a fully integrated company with medicines that provide a profound benefit for patients. We look forward to keeping you updated on our progress and thank you..

Ladies and gentlemen, thank you for participating in today’s conference. This does conclude today’s program. You may all disconnect. Everyone have a great day..