As president and CEO of upstart Repare Therapeutics, Lloyd Segal was instrumental is arranging the initial funding to create Repare while he served as an entrepreneur-in-residence at Versant Ventures, a leading healthcare investment firm with a hands-on approach to company building. Repare is developing precision oncology drugs that target specific vulnerabilities of tumor cells. Mr. Segal previously was a managing partner at Persistence Capital Partners, a leading healthcare private equity investor. He has held CEO roles at Caprion Pharmaceuticals, which he co-founded, Advanced Bioconcept and Thallion Pharmaceuticals, and has served as a director of several public and private companies in the U.S. and Canada. In 2013, the Financial Times selected him as Outstanding Corporate Director of the Year. In this interview with BioTuesdays, Mr. Segal discusses Repare’s unique technology and how it is being adapted for the treatment of cancer.
Let’s begin with a brief history of Repare.
The company was originated in late 2015 by Versant Ventures around a technology platform and a first drug target that didn’t come from that platform but has since helped to validate the platform. The platform is a CRISPR-enabled system for novel “synthetic lethal” target identification, first developed in Toronto at the Lunenfeld-Tanenbaum Research Institute labs of Dr. Daniel Durocher, a scientific pioneer and one of the leading voices in DNA damage repair biology – and also a co-founder of the company. The drug target came from Dr. Agnel Sfeir’s lab at the Skirball Institute of Biomolecular Medicine at NYU Langone Medical Center. Dr. Sfeir is also a Repare co-founder, and her research focuses on how mammalian cells maintain the stability of their genomes – a critical component in cancer. When I got involved in the spring of 2016, we had an opportunity to build a company around the CRISPR platform for discovering new synthetic lethal targets against cancer, with a focus on DNA damage repair, and a lead program, targeting DNA-directed DNA polymerase theta (PolQ), a central component of a genetic pathway that repairs doublestrand breaks in cancer cells and mediates genome stability.
Can you elaborate on CRISPR?
In its simplest form, our CRISPR screens engineer into highly controlled cellular environments a set of genome-wide, targeted site-specific mutations, using a proprietary library of guide mRNA for precise genomic editing. This model system allows us to search for synthetic lethal interactions important in cancer, representing a platform for the development of new, precision oncology drugs. Thanks to Dr. Durocher’s pioneering work in this area, Repare has now established a world-class CRISPR screening platform that is already generating many new and very interesting targets that are specifically lethal to common genetic alterations essential to the viability and proliferation of cancer cells.
According to Segal, In its simplest form, our CRISPR screens engineer into highly controlled cellular environments a set of genome-wide, targeted site-specific mutations, using a proprietary library of guide mRNA for precise genomic editing.
What is the core concept of synthetic lethality?
Synthetic lethality represents a promising avenue to identify molecular pathways uniquely essential to cancer cells. Basically, it describes a genetic phenomenon where one of two gene products is essential for cancers to survive and proliferate. If either one of the genes is missing or mutated, the cancer can thrive, but if both are disabled through mutation or drug targeting, the cancer cannot survive and will actually self-destruct. When we can identify these synthetic pairs, we explore whether we can target the function of one of these genes in the context of a natural mutation, or lesion, such as BRAC1, commonly found in many cancers. If a patient has a particular lesion, they will then be most likely to respond to the drug for that lesion’s synthetic lethal partner. We are thus now able to develop highly specific precision oncology drugs, where we can identify and treat only the patients who are most likely to respond to our drug. As importantly, the drug targets cancer cells with the lesion, while sparing normal cells that lack the cancer-associated lesion, with the goal of reducing off-target toxicity. This kind of genetically guided therapy ultimately yields safer, more effective drugs for patients. Not a silver bullet, but certainly headed in that direction.
Can you describe an example of synthetic lethality?
In oncology, PARP (poly ADP ribose polymerase) inhibitors were developed for the treatment of cancers with mutations in BRCA1 or BRCA2, and they are revolutionizing cancer treatment. However, they often only work in a subset of patients and also fall prey to evolving resistance, reflecting the need for new, improved, and complementary approaches to treat many cancers.
Is it safe to say that you’re exploiting a genetic weakness in cancer cells?
Yes. For example, several forms of cancer are more dependent on PARP than regular cells, making PARP an attractive target for cancer therapy. PARP inhibitors improve progression-free survival in certain women’s cancers. For example, PolQ, which is also a BRCA1 synthetic lethal partner, is over-expressed in many tumor types and associated with poor clinical outcomes in ovarian cancer and breast cancers. However, we are working with many other lesions beyond BRCA1. This is really just the beginning.
What are the advantages of synthetic lethality?
We think this is among the emerging class of agents that can deliver on the promise of precision – if not personalized – medicine, allowing us to develop drugs that only focus on very specific patients, so, for example, the one woman in ten who is BRCA1 mutated will very likely respond to treatment. Because these drugs are designed to target only the cancer cells with lesions that confer synthetic lethality, they provide an enhanced therapeutic window and understanding of when and how drugs are going to work in solid tumors with a high-unmet medical need, while ideally sparing normal tissues. An additional advantage of synthetic lethality is its potential to work synergistically with chemo and immune checkpoint inhibitors.
How many programs to you have underway?
Our first lesion to be publicly disclosed is BRCA1, which is most often associated with women’s cancer but is also evident in cancers of the prostate, lung and colon. We have three active drug development programs underway, but the only one we’ve disclosed is PolQ, an exciting new target which our founder, Dr. Agnel Sfeir, helped pioneer. We have not disclosed details of our other programs.
How close are you to the clinic?
Our goal is to be in the clinic in 2019 with our first small molecule inhibitor of a synthetic lethal target for cancer.
And a final word about your financing in June.
Founding investor, Versant Ventures, coled a $68-million Series A round with MPM Capital. It is the largest global Series A biotech investment so far this year. They were joined by other syndicate investors, including Fonds de solidarité FTQ, Celgene Switzerland, and BDC Capital’s Healthcare Venture Fund. We are funded to achieve our goal of testing multiple precision oncology therapeutics in a clinical setting.
