Redefining Therapeutics Through Control of Gene Expression, a Conversation with Nancy Simonian, M.D., President and CEO, Syros Pharmaceuticals

Innovation That Matters

By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and the WuXi AppTec Content Team

Drug development is a very risky business. For more than 20 years, Nancy Simonian, an accomplished veteran drug developer (having served as Chief Medical Officer at Millennium Pharmaceuticals and as Vice President of Clinical Development at Biogen) with a passion for patients, struggled with the realization that most of what we do in drug development does not work and that as an industry, there is a tendency to pursue the same types of targets leading towards a redundancy of programs and drugs.

Simonian was very interested in finding new ways to understand disease and to pursue new avenues of drug discovery, which brought her to the labs of Rick Young, Member at the Whitehead Institute and co-founder of Syros. His research on the control of gene expression was leading to new insights in the biology of cancer and other serious diseases.

Syros was launched in 2013 with Simonian as President and CEO to pursue a new wave of first-in-class medicines based on this theme, with $30M in Series A financing from ARCH Venture Partners and Flagship Ventures and participation by WuXi PharmaTech Healthcare Fund I and other undisclosed private investors.

In 2014, the company closed $53M in Series B financing led by a large, Boston-based public investment firm, which included new investors Polaris Partners, Aisling Capital and Redmile Group. Previous investors Flagship Ventures, ARCH Venture Partners, WuXi PharmaTech Healthcare Fund I and Alexandria Venture Investments also participated in this round. A $40M Series C round added Deerfield Management and Casdin Capital as well as others. The company raised $50M in its IPO in 2016.

Rich Soll and the WuXi AppTec Content Team recently spoke with Simonian about Syros.

“A major impediment to delivering better medicines faster and cheaper to our patients has been our lack of understanding the fundamentals of human disease biology,” Simonian noted. “Once we understand those things, we do a pretty good job of making drugs.”

“Only 2 percent of the genome encodes for proteins, and most genomic work has been focused on this 2 percent. The 98 percent of the genome that does not encode proteins has been a black box,” asserted Simonian.

“In fact, one of the most critical components of the non-coding region of the genome is the regulatory region, which coordinates the expression of genes. If you can understand the coordinated expression of genes and how they are regulated, you can get at the core of the function of the cell.”

Syros has been a leader in understanding the regulatory genome, specifically the enhancers and the super enhancers that control the expression of critical genes for cell state and fate. They hope to get insight into the function of the cell where other technologies have failed. The super enhancers are like a dimmer switch, on, off, up or down, and control the most critical genes in cells. Syros believes that it is through these genes that we can get good insight into human disease.

Syros has developed genomic biology technologies, both wet and computational, that give them a competitive edge.

The company has the ability to rigorously generate, analyze and interpret genomic data and apply those capabilities to all phases of drug discovery and development from target discovery to driving the chemistry to selecting patients for clinical trials.

“By understanding transcription, we get insights into disease, which is really critical,” Simonian stated. “And we’ve developed a variety of assays and technologies that really allow us to do that in an optimal way. We use our regulatory genomics approach to understand the best targets in a given disease.”

Syros has been examining transcription factors and transcriptional kinases; Syros has insight regarding their control of oncogenes in cancer.  

“We can ask the question: are genes changing the way we want,” declared Simonian. “What’s occurring in the normal cell vs. disease cell? We can then profile those genes. Using the Syros platform has already yielded 2 compounds in the clinic, SY-1425 (an RAR-α agonist) and SY-1365 (a selective CDK7 inhibitor). For us, it is an exciting time.”

The SY-1425 program came from an analysis of the regulatory regions of primary tumor cells.

Syros identified a novel biomarker by looking at super enhancers that, when present in the cancers, showed high sensitivity to the drug. Syros is in a Phase II biomarker-driven clinical trial with SY-1425, studying the drug in combination with the hypomethylating agent azacitidine, in AML patients.

“Initial data were presented in December 2018 showing high overall response and complete remission rates in biomarker-positive patients and these rates were higher in biomarker-positive than biomarker-negative patients,” Simonian said.

“Importantly, the drug was well tolerated without any increased signs of neutropenia, an effect which is seen often during combination therapy in AML.”

For Simonian, the results support the importance of selecting patients in this trial based on this regulatory biomarker discovered by Syros’ platform. The company plans to present further data from a cohort of newly diagnosed, unfit AML patients in 4Q 2019 and hopes to have proof-of-concept (POC) data in 2020 in relapsed or refractory (R/R) AML with the same combination with azacitidine. Patients with R/R AML have a very high unmet need as overall survival is less than 6 months.

SY-1365 is a highly selective CDK7 inhibitor.

“We have been working on selective inhibition of CDK7 since the inception of the company because we knew CDK7 was an important component of enhancers and controlled the expression of many oncogenic transcription factors,” stated Simonian.

In November 2018, the first clinical data with a selective CDK7 inhibitor was reported from the dose escalation portion of an ongoing Phase I study in advanced solid tumor patients.  

“The company demonstrated proof of mechanism by showing target occupancy that correlated with efficacy in preclinical models, dose dependent and gene expression changes at doses that were generally well tolerated,” Simonian added.

“We had a patient with a durable partial response and several other patients had stable disease, which is encouraging in this advanced patient population.”

The company is in the expansion phase of that trial in ovarian and breast cancers. The company expects to report initial data in 4Q 2019 with potential POC data in 2020.

Simonian noted that Syros also has an oral CDK7 inhibitor, SY-5609, which should be in clinical development by early 2020. Finally, Syros has a program in sickle cell disease, tackling monogenic diseases by altering the expression of disease causing or modifying genes.

Last year, the company formed a partnership with Incyte in the area of myeloproliferative neoplasms to uncover disease biology and validate new targets.

Simonian also acknowledged the value of WuXi’s enabling platforms.

“Syros is reliant on others’ capabilities, including WuXi. Our general approach allows internal scientists to focus on activities needing our people’s expertise, particularly in the area of genomic-based computational and wet lab work,” Simonian stated.

“With WuXi, we rely on your medicinal chemistry capabilities for all of our programs, process chemistry and scale up of intermediates and starting materials for API as well as for in vivo studies.”

Over the next 3-5 years, Simonian hopes to have a fully integrated company with an eye towards building an enduring company that brings its products to the market. To realize its full potential, Simonian feels that new, different technologies and tools will be needed that focus on human disease to provide target validation. She hopes that by 2030 the industry sees beyond a one-size-fits-all approach and that we will likely see empowerment of patients.

“Syros has built a platform that enables a better understanding of human disease and human biology, and what’s the right population and the right drug. Ultimately, in the future we’re going to be much better at understanding disease in the individual patient and being able to tailor our therapies for those patients,” Simonian said.

“I would love to have therapies that cure cancer, yet at the same time there are really important medicines out there that have turned some cancers into a chronic disease, allowing patients to live a relatively normal life.”

Simonian summed it up in a very optimistic manner: “I’m bullish about the future and I do think the present is the golden era of biology that will bear fruit for patients in need.”

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