Entact Bio: Victoria Richon, CEO
“The reason I went into science was to challenge myself.”
The language of drug development is often militaristic. Medicinal chemists build arsenals of small molecules—looking for inhibitors or “warheads” that can hit “targets” and “combat” disease. Block, eliminate, disrupt, halt.
For decades, drug makers have sought “magic bullets” that can precisely destroy pathogenic proteins. Small molecules, biologics, siRNA and CRISPR offer different modalities to reduce or impede the activity of therapeutic targets: “I have spent my entire career inhibiting protein targets,” explains Victoria Richon, CEO of Entact Bio and a veteran drug maker. An en vogue approach in drug discovery over the past decade has been to employ proteolysis targeting chimeras (PROTACs) to degrade proteins. PROTACs consist of two chemically-linked components: i) a molecule that can bind a given disease-causing target and ii) a distinct chemical moiety that can recruit an enzyme called E3 ubiquitin ligase. Ubiquitin ligases attach small tags to proteins, condemning them to proteasomal degradation. Though there are no FDA approved PROTACs, there are dozens in clinical development.
Sometimes, complex disease calls for a different type of weapon. Rather than inhibiting proteins by reducing their abundance or blocking their activity, a drug may need to increase the levels or improve the function of endogenous molecules: “the exciting challenge is to create a new class of medicines that enhance these beneficial proteins,” says Richon. Entact was founded to take on that challenge.
Entact seeks to build molecules capable of recruiting de-ubiquitinating enzymes (DUBs)—these enzymes remove ubiquitin (opposite to E3 ubiquitin ligases). Ubiquitin tags can both interfere with a target’s normal function and promote its degradation. By engineering “ENTAC” molecules to bring target proteins together with DUBs, Entact seeks to bolster the function of beneficial cellular pathways and restore homeostasis. Though no specific indications or targets have been disclosed, this approach can be leveraged across many distinct disease types.
On December 6, the company announced it had raised $81 million in series A financing to develop its proprietary Encompass™ platform, which seeks to identify promising ENTAC candidates that can act as molecular matchmakers: bringing together the right protein targets with the appropriate DUB. This is no small feat: “There are over 100 DUBs…we are using our platform technology to understand the activity of these different proteins with respect to a given target,” explains Richon. The series A was co-led by Qiming Venture Partners USA and venBio Partners, with participation by new investors Abingworth, Brandon Capital, Janus Henderson Investors, Logos Capital, Surveyor Capital, Walter and Eliza Hall Institute of Medical Research, and founding investors 4BIO Capital and Arkin Bio Ventures. The company’s founders are Sara Buhrlage, Michael Clague, David Komander, Jarrod Marto, Ueli Nachbur, David Sheppard and Sylvie Urbé.
Victoria Richon is CEO of Entact Bio. After studying mechanisms of chemotherapy resistance as a graduate student in the ‘80s, the newly minted Dr. Richon sought to leverage her work to help patients: “I went to Sloan Kettering because I wanted to continue doing cancer research, but with a translational focus.” At MSKCC, she became an expert in cancer biology and post-translational modifications. Her work uncovered a compound that inhibited histone deacetylases (HDACs), which can be dysregulated in certain cancers. She co-founded Aton Pharma (acquired by Merck) and left academia to continue developing this molecule, which became the FDA-approved therapy Zolinza. Post-acquisition, Richon continued at Merck in a leadership role: “With my experiences at Aton and Merck, I learned how to do team-based drug discovery, which can be very powerful.” She left Merck to help run Epizyme (maker of EZH2 inhibitor Tazverik), before returning to Big Pharma as the Global Head of Oncology Drug Discovery and Translational Medicine at Sanofi. In 2015, she got the opportunity to lead Ribon Therapeutics (first as CSO and then CEO), which has developed novel PARP-family inhibitors targeting mono ADP-ribosylation in cancer and inflammatory diseases. After over 6 years at the helm of Ribon she assumed the CEO role at Entact Bio in 2022. She was attracted by the opportunity to lead the charge into a “tantalizing” new area of biology: “It is very exciting to go into unexplored territory because of the opportunity to develop important new medicines for patients.”
Below is an interview with Dr. Victoria Richon, CEO of Entact Bio from December 2022:
What first made you interested in science? Was there an early mentor that set you on this path?
I wasn't the kid that got a microscope and said: “Oh, this is what I know I want to do.” But my father was a chemist, and my mom was a nurse. I had really great science teachers in my high school. I also grew up in New Jersey, and lived close to Princeton—so I was exposed to great teachers and academia [early on].
Personally, I think the reason I went into science was to challenge myself. I was a chemistry undergrad…that felt very challenging and I also liked its quantitative nature. It felt a bit natural, since my father was a chemist.
[What led you to pursue a PhD?]
I think that labs in college do not give the true sense of research, and I didn't find them to be particularly fun or interesting. But I had an opportunity when I was a junior in college to join a lab and do a summer research project in the biochemistry department. I was the “chemist in the lab,” and my project was to synthesize steroid analogs and test them for activity in cell-based assays. I just loved it. At that point I basically said: “I want to do research.” I realized if I was going to do research, I needed to learn more. I was in John Cidlowski’s lab—he was really a terrific mentor and supporter. He was one of the early mentors that set me going on this path.
[What was your experience as a grad student like?]
I went to the University of Vermont. I was an undergraduate there, and I stayed for graduate school. I worked on mechanisms of cellular resistance to cisplatin in the Eastman laboratory—scientists at UVM had discovered some of the cisplatin analogues, so there was a focus on platinum drugs, and I felt that it was an interesting and important project. It was an exciting time as one of the mechanisms of methotrexate resistance was found to be due to DHFR gene amplification. Then Bresnick and Eastman lab’s moved to Nebraska, and I had to decide what to do. So, I went to Nebraska for three years. Ultimately, it was interesting to move to a different area of the country that I had never lived in before. Also, the Eppley Institute for Research in Cancer was interesting in that the center had a focus on lymphoma and carcinogenicity and was started due to the high rates of lymphoma in farming states like Nebraska, likely due to the use of pesticides. To this day, the University of Nebraska cancer center has an important lymphoma clinical practice.
[What was your postdoctoral work at MSKCC like?]
After grad school, I went to Sloan Kettering for my postdoctoral studies because I really wanted to continue doing cancer research, but with a more translational focus. I went to Sloan Kettering and worked on a project to identify small molecules that induce differentiation of cancer cells. This was a time when oncogenes and tumor suppressor genes were just being discovered and before targeted cancer therapies. The mainstay of treatment was still mainly chemotherapy. So the idea was, could you induce differentiation rather than kill the cancer cells outright? I worked with Paul Marks and Richard Rifkind at Sloan Kettering and Ron Breslow, a chemist at Columbia. During that time, we identified vorinostat as an inducer of differentiation and then discovered that the cellular target was histone deacetylase, at that time a newly discovered chromatin-modifying enzyme. We completed all of the necessary studies and then wrote an IND to start clinical trials working closely with Kevin Kelly who wrote the clinical trial to support the IND. This was a very exciting time as we received clearance from the FDA and initiated the clinical development of vorinostat.
What was your first transition to industry like coming from MSKCC? Was there a steep learning curve coming from academia, and what were the adjustments you made?
When we treated the first patient, I just felt that drug discovery is where I need to be. I wanted to take all the great science that I learned and apply it to drug discovery. I had the opportunity to co-found a company based on our discovery and development of vorinostat and the emerging area of chromatin-modifying enzymes.
At this time, I had a big decision to make: do I want to go the company route or stay at Sloan? I really wanted to see the project we started at Sloan through. It was a great opportunity for me to continue the development of vorinostat. We founded Aton and hired a terrific team that was highly experienced in drug discovery from both pharma and biotech. At Aton, I really had my first exposure to drug discovery from a hardcore perspective—I realized that how you look at it in academia is different from the biotech setting. It was a great experience. But within two years, we were acquired by Merck.
So, I then had an opportunity to go to a large pharma company, Merck, which was just opening its research facility in Longwood in Boston. There were about 40 of us that started in Longwood when the building opened—I had a wonderful opportunity to head a department and to continue the development of vorinostat, which became Zolinza once it was approved by the FDA. It was just a great experience to go to Merck: it is such a strong science driven company. I also really learned how to do project team-based drug discovery. One of the main differences between Big Pharma versus a small biotech is that you get to see many programs at different stages of drug development. For example, every week we had program reviews that the whole site attended, so you saw every program being worked on at the site.
What were the biggest lessons learned from working at Merck? For a trainee looking to enter into biotech, would you recommend spending time in big pharma?
Everyone thinks in academia that you're working as a team, but you are really working as an individual contributor: it’s about your experiments and your science. But when we work on a project in pharma, we really work on a project collaboratively. There is often one person who's the “biology lead,” one person who is the chemistry lead, or someone who is really experienced in assay development or DMPK [drug metabolism studies] as the lead depending on the stage of the project. So, you form interdisciplinary teams that drive the project forward. The success of the project is dependent on every team member contributing to the project.
Another point is that in pharma you have to make very hard decisions regarding the project. In academic research you set up an experiment to test a hypothesis, and you can follow that experiment and data—to wherever it's going. In pharma, we know what we want and that is to make an important new therapeutic for patients. If it looks like the work is not going down the right path, or the target is not associated with disease, we will stop the project. And that can be very challenging for the team. You [in industry] have to turn a corner from how you were trained academically—to pursue a hypothesis and follow it—and instead make sure that your experiments are decision-making and focused on development of that new therapeutic agent.
I encourage students who are interested in working in pharma and biotech to think about doing an industrial postdoc: Many pharma companies have good postdoc programs. You work on a program that you can publish, but you can also see if a career in Big Pharma is for you.
How did you make the jump to Ribon as its founding president? What do you look for when identifying a promising biotech or Newco?
After working at Merck and then Epizyme, I went to Sanofi because it was a great opportunity for leadership. I was Head of Global Oncology Drug Discovery and Translational Medicine. It was a group of about 300 people when I joined and it was a terrific leadership opportunity. After a few years I received a call from Larry Lasky, who is a partner at a venture firm called the Column Group. He's a really great scientist, and I had met him a few months earlier. He said: “I have this company that I'm starting, would you be interested?” We started a longer discussion, and I thought the idea [for Ribon] was very exciting.
When I evaluate an opportunity with a new company, I really think about three things. Number one is that you have to deeply believe in the science. I thought Ribon was really interesting because it was taking a very novel approach that I thought could make a difference for patients, because we were targeting a novel class of stress-induced proteins. I believed we had an opportunity to discover important new, first-in-class therapeutics.
A second consideration is the team. At Ribon, I was able to bring together a terrific team of drug creators, including Kevin Kuntz and Heike Keilhack - great people I had worked with in the past. And then the third part is to have the company vision aligned with the investors. What we were trying to build was closely aligned with the investment thesis for the company [from Column and other investors].
[On her first time leading a company]
When you lead a company you have a much greater sense of responsibility. Additionally, I learned many things, including a lot about myself and my capabilities. The other thing I learned was that it is very important to have a very strong mentorship network. I reached out to many of my past colleagues; for instance, Kazumi Shiosaki, who was the CEO when I joined Epizyme. She was a terrific mentor to me. In addition to Kazumi, Bill McCulloch, Marian Nakada, Mike Bonney and many others have been important mentors for me… It is so important to have a strong mentorship group at all stages of your career and to not hesitate to seek advice.
What do you look for when making key hires who can contribute to a positive company culture?
I look for people who are passionate and committed—they have the “fire in the belly.” Another key element is finding people who work as a team and are transparent—transparent about their values and culture. Lastly, I also want to build a culture of diversity. We worked to bring people in from diverse companies, with different experiences and people from different backgrounds. When prospective hires would come in, we would have them interview with team members from all levels of the organization. Then we would have a debrief, and sometimes the most junior person would say something like: “I went to lunch with this person, they would only talk to the director, they wouldn't even look me in the eye.” Well, then, I’m not going to hire that person. We really listened to feedback and had feedback sessions for every single person that we hired. We also had everyone give a talk when they interviewed. This would help us determine where they fit in the organization.
How did you first get involved with Entact Bio and meet the founding team? What about the vision of the company grabbed you?
One of the things I really love is the new. To me it's not as exciting to make the “fifth inhibitor” for a given target, though it could be very important [for patient care]. It is very exciting to go into unexplored territory that has the potential to create new medicines for patients.
So Entact stood out to me, in part, because of the scientific challenge and opportunity to develop a new therapeutic approach. I have spent my entire career inhibiting target proteins [e.g. HDACs at Aton, ADP-ribosylation/PARPs at Ribon, histone methyltransferases at Epizyme]. It’s a chance for me to leverage everything that I've learned so far, and bring really great science to a new goal, which is enhancing the function of beneficial targets. We know that there are proteins in our bodies that are not working properly—because their levels are too low or their activity is modulated by ubiquitin tags. To me, the challenge is to now work on a new class of medicines that enhance the function of these beneficial proteins. This has the potential to greatly expand our drug target space and treat diseases that do not have therapies today.
Initially, how did I hear about it? I’ll say first that I love to build companies. I love the early stage of a company: putting teams together and forging new areas and strategies. After it was announced that I was stepping down [at Ribon], I got a call a couple days later from someone involved in Entact; and so that phone call started my discussions with them. Entact fit all three of my criteria for a new opportunity.
What made me really excited was working on an emerging area of biology. We have assembled at Entact an incredibly strong group of academic scientists focused on deubiquitylases (DUBs) and ubiquitin signaling research. DUBs are enzymes that remove the ubiquitin tags, which can alter a protein’s function or mark it for proteasomal degradation. We are also assembling a terrific internal team of highly skilled drug discovery and development experts.
We are combining our deep drug discovery expertise with an understanding of ubiquitin biology and chemistry from our academic founders to work in a new area that hasn't been done before, to open up our minds to the types of therapies that we can develop, is really exciting and holds the promise to develop important new medicines for patients that do not have therapies.
Coming out of stealth with a nice series A, what are you working hardest on in the near term at Entact? As CEO what are your priorities?
This year is about integrating the DUB and ubiquitin signaling expertise of our academic founders with our drug discovery expertise to build out our pipeline and moving our ENTAC programs forward, as well as building out the [Encompass] platform. Encompass will identify which DUB and target pairs are going to be the best fit for this technology and aid us in discovering the best ENTAC structure to bring the DUB and the target protein together and enhance the target protein’s function. We are focusing on enhancing protein function in three distinct ways, including increasing protein levels, correcting protein location and optimizing protein activity.
This year we are also focusing on building a diverse team of highly talented drug discovery experts.
In today’s climate what is one short piece of advice you would give to prospective biotech entrepreneurs interested in starting companies.
I encourage prospective biotech entrepreneurs to pursue their ideas. One terrific place to learn about company creation is a venture firm. This is because today, many new companies are started by venture firms. If trainees are really interested in building companies you can learn a lot about starting companies in venture. Additionally, getting strong drug discovery experience in pharma and biotech prior to starting a company is a big asset in understanding how to build a company and conduct drug discovery.