Manifest Boston Change Maker: Paul Wotton, Ph.D.

CEO, Obsidian Therapeutics

Manifest Boston Change Maker Paul Wotton —Manifest Boston

Dr. Paul K. Wotton is Obsidian’s Chief Executive Officer, bringing significant experience spanning scientific research, product development and corporate growth gained over a thirty-year career. Dr. Wotton most recently served as the Founding President and CEO of Sigilon Therapeutics, Inc. Prior to Sigilon, Dr. Wotton served as President and Chief Executive Officer of Ocata Therapeutics until its acquisition by Astellas Pharma where he was also Co-Chairman of the Office of Integration. In previous roles, he served as President and Chief Executive Officer of Antares Pharma (NASDAQ:ATRS) as well as Chief Executive Officer of Topigen Pharmaceuticals. Dr. Wotton is a named inventor on numerous patents and was the Ernst & Young Entrepreneur of the Year Regional (NJ) Winner Life Sciences in 2014. He serves on the Boards of Directors of Vericel Corporation (NASDAQ: VCEL), Veloxis Pharmaceuticals A/S (Copenhagen: VELO) and Cynata Therapeutics (ASX: CYP) as its Chairman.

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Lindsay Gearheart: Tell me about your background and how you got started with Obsidian.

Paul Wotton: I’m a scientist and spent most of my career in business development and strategy. I first moved to Boston around six to seven years ago to manage a company called Advanced Cell Technology, which was a stem cell therapy company. We sold to Astellas Pharma in 2016. That was my first venture into cell and gene therapy.

I then went on to start up a company with Bob Langer and the guys from Flagship called Sigilon in 2016, and I managed that for a couple of years through the big transaction with Lilly to fund a project to develop an artificial pancreas using pancreatic cells that have been derived from stem cells and be able to use an implant technology to hide cell transplants from the body’s immune system, which is a really important advancement. I stepped back from that a couple of years ago because at the time my wife was going through chemotherapy, so I took a year off to look after her. 

One way or another, I ended up talking to Peter Barret at Atlas and he told me about the Obsidian story. It seemed like a pretty cool technology and a really good idea. So what our technology at Obsidian is designed to do is to answer a lot of the questions that are sometimes raised about both cell and gene therapies regarding how you actually control the therapy once it has been given to a patient and how you are able to regulate the dose of a protein, for example, that either a cell or gene therapy is making. Obsidian has the technology that for the first time enables us to give that control to the physician and to be able to regulate protein manufacture. A protein would be something like a blood factor or, in our case, cytokines, which are used a lot in cancer chemotherapy these days, particularly with cell therapies. To be able to control them is really important because these are quite potent molecules. 

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What we are able to do is take a technology that came out of Stanford University and control a couple of things. One is turning the protein manufacture on and off. The second thing is being able to move the level of manufacture up and down. So now you can control that protein activity very precisely, and you’re allowing a physician to be able to dose patients with both cell and gene therapy producing proteins the same way that they would typically dose any of us if we were getting an oral drug molecule. It’s pretty powerful stuff. The drug we are using, our lead drug, is like 70 years old. It’s got a great safety record. It’s known as acetazolamide, but it’s mainly used these days to treat altitude sickness. It’s a very old diuretic drug which used to be used to treat high blood pressure and things like that. 

LG: That’s impressive! So that control is what sets Obsidian apart from other cell and gene therapy ventures. Were you the first to do that, or are you currently the only one doing that?

PW: We’re the only ones that are able to regulate cytokines or protein expression and activity using a small molecule approach. There are other companies that are able to turn things on and off, but they can’t change the levels up and down like we can. 

LG: What advancements in tech are making it easier to develop new gene therapies? 

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PW: The way we do this is we actually genetically engineer cells to produce a cytokine that is able to respond to the presence of that small molecule. Our technology is probably best described as a synthetic biology platform. We also use typical technology used in manufacturing of cell and gene therapies like viral vectors and all of the genetic engineering techniques that are commonly used. It’s really important to be able to access technology that others have already worked on, particularly when you’re trying to develop a product that needs to go into patients, which is what our goal is. Our little piece of our technology, which is what we call drug responsive domains, we spent four years developing that in the labs, and now we’ve got one that responds to this drug acetazolamide. That’s the key thing for us, being able to engineer cells to respond to the small molecule drugs.

LG: Are there particular diseases that you’re working on fighting with this technology?

PW: We actually have a really good partnership with Bristol Myers Squibb, who go after some forms of cancer. We have two programs with them both based around CAR T therapies and the two processes we’re controlling are known as IL12 and CD40L. The IL12, for example, helps T cells to proliferate and be stronger acting within a tumor environment. What you want to be able to do is to control the amount of IL12 you are producing in the human body, because it’s a very potent drug. You want to make sure that you maintain the potency, but that it doesn’t lead to all the side effects, and that’s what we can do with our technology. So we’re looking at those with cancer. 

We’ve also started developing our own programs based around a similar cytokine to IL12 called IL15. We’re looking at three different cell types at the moment, which are: NK cells, natural killer cells, a CAR T program of our own, and we’re also looking at engineering tumor-infiltrating lymphocytes or TILs, which are very amenable to the approach we’re taking here. A simple way of thinking about this is: All these cytokines we’re talking about help cells to proliferate in the body or they last longer and are more robust. So basically we’re arming them with a little battery pack that we can turn off and on and off and up and down to help them grow and last longer.

LG: So shifting a bit to speak about COVID-19, what are some of the challenges you’ve been facing as a company with the pandemic, and how have you shifted your strategic approach?

PW: One of the people I work with is an epidemiologist by training, and even in February, she was pointing out that the pandemic was coming. We shifted into gear pretty quickly to identify the key programs we wanted to keep on moving forward rapidly. We were in the middle of a complex set of experiments and we couldn’t afford to stop them, so we kept them going, and in that February time frame, we triaged all of our programs to work out which were the most important. 

We then sent everyone home the week of March 9, except for a small skeleton crew that we kept in the lab. That was about three to four people to start with. Now we have almost everyone that works in the lab in there today, but during that period we had to create a system for people to be able to socially distance properly. It required things like mapping out the labs, changing the workflow in some cases, moving through a shift system — not for the people per se, but also for the equipment, because the ones in high demand we obviously had to do proper planning around being able to use those. We allowed all of our employees to use their own transportation, and we’re renting cars for people. We aren’t asking them to use public transportation, and are just making it easier for them to get to work. 

One of the things that came out of that was a really interesting piece of innovation our IT guy developed with the guys in the lab in the early days. It’s allowed the people in the lab to go into a software program, work out the piece of equipment they needed to book, book them, and then anyone else coming in could see that someone else was using that equipment on a certain time and date and could work around it. We know where people are and who has been in the lab, so we can do contact tracing if we have to. We can also make sure that we keep the right amount of distance between workers. 

It’s simple things, like where you place the lab supplies. Typically they are at a central station, which is what you don’t want, so dividing those up into smaller stations on each bench was helpful. We had to put all the procedures in place like temperature checks, and we’ve got Purell everywhere in the facility. Everyone’s really embraced it, and that software program now is being trialed at over 30 companies. We basically donated it to the industry working through a software provider here in Cambridge. We have some large companies using it too. What we were able to do was use our own experience as a beta test for everyone else, and we adapted our practices throughout the last three months. Quite frankly, we remained productive throughout the whole time, which I’m really proud of. 

LG: I love hearing about that kind of collaboration within the industry. Has there been any other kind of collaboration that Obsidian has done with others in Greater Boston? 

PW: One of the companies that’s based in Cambridge is Magenta Therapeutics, and they’re using our software as their basis. That’s run by Jason Gardner, who also happens to be on our board. His company is a similar size to us, and they adopted our IT system to use for their own purposes.

The other thing that happens here, which I find pretty interesting, is that I came to the company just over a year ago and recruited a whole new team. We have 30 new people since I started, and doubled the size of the company in a year. Then in the fall, we all recognized that we needed to have a proper information technology system in the company. We brought in this guy, Nic Betts, who is an IT guy who worked in R&D for 25 years or so, including a big spell at Pfizer. 

Nic was able to come in, put in what I call a strategic IT system — he’s more than just a guy who fixes your computer — but it really is an information system and a communication system. He put in an intranet for us, and we put it live at the end of December along with Microsoft Teams. That was really important because we had no idea that COVID was coming, but when it did arrive suddenly, we were in a position where we were all able to communicate properly.


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