There was a time not long ago when biomedical research and industry were almost exclusively focused on proteins and the genes that encode them. Once termed “junk”, the non-coding regions of the genome were relegated to the sidelines. These non-coding regions comprise a regulatory network that can reconfigure the 3D structure of DNA into a menagerie of molds, exposing certain combinations of protein-coding regions to be read, often in a cell-specific manner, to generate different cell types and regulate their responses. Today, this knowledge is a rule enshrined into our biological understanding.
At the helm of the concept for a regulatory non-coding DNA network that controls gene expression and, thus, cell fate and function, was the pioneering collaborative work of Whitehead Institute professor Richard A. Young, PhD; President of the Novartis Institutes for BioMedical Research (NIBR) Jay E. Bradner, MD; and Dana-Farber Cancer Institute professor Nathanael S. Gray, PhD. In 2012, this trio of leaders within the field of gene regulation and translational medicine launched Syros Pharmaceuticals. By elucidating regulatory regions of the genome, Syros aims to develop medicines that can treat patients with diseases that have eluded other genomics-based approaches.
Syros is advancing a robust clinical-stage pipeline, including: tamibarotene, a first-in-class oral selective RARα agonist in RARA-positive patients with higher-risk myelodysplastic syndrome and acute myeloid leukemia (AML); SY-2101, a novel oral form of arsenic trioxide in patients with acute promyelocytic leukemia; and SY-5609, a highly selective and potent oral CDK7 inhibitor in patients with select solid tumors and blood cancers. Syros also has multiple preclinical and discovery programs in oncology and monogenic diseases.
GEN Edge spoke with Nancy Simonian, MD, Syros President and CEO, about the initial scraps of paper that were used to light the fire fueling the foundation of Syros and their transformative journey into an integrated biopharmaceutical company.
GEN Edge: How was Syros founded?
Nancy Simonian: Nine years ago, ARCH Venture Partners and Flagship Ventures were talking to leaders in the field of gene regulation. These venture capitalists saw this whole different way of treating human disease by understanding what genes go awry in disease and then using approaches to modulate gene expression for therapeutic benefit. At the time, a lot of drug discovery and development was focused on protein-coding regions of the genome. The non-coding regulatory regions had been a black box. The founding scientists—Rick Young, James Bradner, and Nathanael Gray—had developed tools to understand that regulatory region of the genome. The vision was using this whole new approach and understanding of cells and disease to intervene differently than had been done before.
I joined in 2012, and the company had its first Series A financing in 2013. We started the company with a blank sheet of paper! We thought we could use small molecules to regulate gene expression for therapeutic benefit. The excitement for me today, eight or so years later, is that we have one program in Phase III development, a second one we expect to go into Phase III next year, and another program behind that moving into the subsequent phases of a Phase IB study. So, the vision of the original idea is being realized, which is pretty exciting.
GEN Edge: How did Syros become such a fully integrated biopharmaceutical company?
Simonian: I’m a physician by training. I was at Biogen when they launched their first drug and transformed the landscape for patients with multiple sclerosis. I was at Millennium as their chief medical officer working on VELCADE (bortezomib)—the first drug that had been approved in myeloma in decades transformed the lives of those patients. I came from a view that if you do great science, work on challenging disease areas, and are successful, then you can transform and build a fully integrated company that can continue to invest in discovery and development of more therapies coming forward.
When I came to the company and spoke to the original scientific founders and venture capitalists, I said I wanted to build a fully integrated biopharmaceutical company. I wanted to be part of a company that discovers, develops, and commercializes transformative therapies for patients with severe diseases.
Our drug discovery efforts will be used to fuel our pipeline across many diseases. One critical thing when you think about a company early on, when you have an approach that can be used broadly, is how do you think about realizing the full value while making sure that you’re investing enough capital in a more focused way. To build the company, we decided that we were going to focus on software discovery efforts for our own internal pipeline. Some of the discovery efforts were going to be focused on partnerships to broaden the reach of our science and technology.
GEN Edge: How did Syros choose to target specific medical conditions?
Simonian: When we started the company, we knew we could apply the platform in multiple disease areas. We initially decided to focus on oncology and started looking at what was happening in enhancer regions of the genome in primary human tumor cells. We made this discovery about a novel subset of patients that had overexpression of the RARα [retinoic acid receptor-alpha] gene. That led to our most advanced program in the clinic, which is now in Phase III clinical trials.
We made that discovery early on by analyzing the enhancer regions of AML tumor cells. We were also very interested in thinking about particular regulatory proteins involved in the expression of genes, one of those being CDK7, and we developed the first selective CDK7 inhibitor. We just presented some data showing that we have proof of activity of that molecule in patients and moving forward into expansion cohorts and pancreatic cancer and mantle cell lymphoma. That came from using our transcriptional chemistry discovery efforts to target these regulatory proteins selectively.
The basis for our two programs in the clinic came directly from the early work we did at the company’s initial stages. A couple of years ago, we also started to explore the potential for our drug discovery engine into modern genetic diseases. We began to work in the sickle-cell disease space with the idea of using a small molecule to up-regulate the expression of fetal globin, almost using a gene therapy approach but in a pill. We were very excited a year and a half ago or so to do a partnership with Global Blood Therapeutics [see Close to the Edge Ep.4 with Global Blood CEO Ted Love] to work on that approach for a functional cure for patients with sickle-cell disease. We are focused on both the oncology and the modern genetic disease space. We’re moving forward both our clinical programs and continuing to have a robust discovery engine.
We started as a discovery-stage company with a technology, but we never thought about ourselves as a platform technology company. We always thought about ourselves as a company that develops medicines to help patients. We’re not here to do science just because it’s interesting; we’re here to work on things we think are going to make a big impact on patients. That orientation early on—we’re about making medicines to help patients—has continued to be what we’re all focused on. It has been very helpful in that transition from being a pure discovery company to a discovery and development company because, ultimately, we’re going to be successful by translating our work to help patients.
GEN Edge: What does the trajectory look like for Syros?
Simonian: We have three clinical-stage programs with two potential NDAs (new drug applications) in 2024. We are moving aggressively towards becoming a commercial-stage company. That’s what makes it so exciting to think that not too long ago, it was a blank sheet of paper and an idea, and here we are on our path to becoming a fully integrated commercial-stage company. That’s very exciting. We just hired our Chief Commercial Officer. That’s a testament to moving in that direction. We’re on our path to building and becoming that fully integrated biopharmaceutical company.
GEN Edge: What’s standing in the way of Syros achieving its goals?
Simonian: As you start to move from discovery into development, the natural thing one has to do is think about some areas that we want to focus on. One challenge is you need to have enough expertise in a particular disease area or the right capital to invest in the right amount to start focusing on specific areas. For us, that was in the oncology area.
The people aspect is vitally important, probably the most important thing. As I think about people, I also think about culture. How do you build a culture where there’s excellent collaboration because discovering and developing drugs is challenging. It’s probably one of the most complex team sports there is. You want to have an environment and a culture that celebrates the collaborative nature of our work. You want people to innovate, take risks, and recognize those successes but be okay when everything doesn’t work. To do innovative things, you’ve got to take some risks, which means that not everything’s going to work. That’s a crucial mindset to have at the company as well. We’ve put a lot of effort into building a culture and hiring people that fit in with those company values. We think that’s important to hiring and retaining an outstanding workforce, which is so important.
GEN Edge: What influence has going public had on Syros since it was first listed in the NASDAQ about five years ago?
Simonian: We just had our five-year anniversary. We did a virtual bell ringing at NASDAQ, which was fun. Back in 2016, when we went public, we were a preclinical company. There were not a lot of preclinical companies that were publicly traded companies. That’s changed over the last five years, where there’s a lot of companies that are not in the clinic that are public, but it was less common back then. I realized that this whole approach to treating disease was a new way to think about doing this and a new approach was going to require a significant amount of capital. The greatest source of capital was going to be as a public company as compared to a private company.
Going public made larger pools of capital accessible. In addition to the scientific ideas and the great people, it’s having capital. Becoming a publicly traded company means that you live in a glass house. When you’re a private company, you can do things that may not work, but nobody knows except the people investing in you. When you’re a public company, many of the things you do need to be in the public domain. You have to be okay with that. For me, the benefits of working with and having a wonderful group of investors that bring in the capital that we need is far more beneficial than any of the downside for being in a glass house. That’s helped us build the company that we’re trying to build and to bring our assets forward and we’ll get them into later stage development.
GEN Edge: How has Syros grown from the initial meetings scribbling on a pieces of paper to where you are now?
Simonian: I still have those pieces of paper someplace! I remember the conference room we sat in because it was very memorable. The combination of the scientific founders and the two venture capitalists were trying to think about that intersection between the biologic insights that we had and how to apply them to human disease. Initially, it was a lot of talk about which areas we want to be in and why, where do we think the greatest potential for that overlap between the technology and the types of drugs that we would be developing for the unmet need.
From all of that, we initially said, we’re going to focus on a couple of different areas in the cancer space. We did have some technology coming out of academic institutions around chemistry approaches to target some of these regulatory proteins selectively. So, that was a part of that mix too. Then we set out and did some of the things from the original plan. Some things worked, and others didn’t. But we kept moving forward. It was never a straight line. One thing that we worked on early on at the company was the profiling of enhancer regions in primary AML cells and making this discovery that is now literally in Phase III. I’m very excited that some of those things that were on that early sheet of paper have actually made it all the way through.
In some ways, eight years is a long time, but it goes by so quickly. We’ve made this much progress in such a little time. We’re benefiting patients, and that is why we come to work every day.