Innovation in Retina

George D. Yancopoulos, MD, PhD, And the Regeneron Story

JERRY HELZNER, SENIOR EDITOR

EDITED BY EMMETT T. CUNNINGHAM, JR, MD, PHD, MPH, AND PRAVIN U. DUGEL, MD

The retina community is now familiar with the success of Eylea (aflibercept), the anti-VEGF therapy for wet AMD, macular edema associated with CRVO, and potentially other retinal diseases that Regeneron Pharmaceuticals (Tarrytown, NY) launched less than two years ago. Sales have skyrocketed, and today Regeneron estimates that Eylea will record more than $1.3 billion in sales in the United States alone this year.

Less well known is the long struggle by the Regeneron management triumvirate of Chief Scientific Officer George D. Yancopoulos, MD, PhD, company co-founder and CEO Leonard Schliefer, MD, PhD, and board chairman Roy Vagelos, MD, to develop and commercialize Eylea. The drug was originally called VEGF-Trap because of its elegant mechanism of action that employs a decoy receptor that attracts and “traps” VEGF before harmlessly flushing it out of the eye.

In this rare thoughtful and some-what personal interview with Retinal Physician, Dr Yancopoulos details his own career as an innovator, describes the proprietary mouse model that now powers Regeneron’s multi-faceted drug pipeline, and recounts the long and difficult road that led to Eylea’s success in the marketplace.

George D. Yancopoulos, MD, PhD.

Q. You were an academic prodigy at a young age. Were you always interested in developing new scientific ideas and concepts or did that come later?

A. I was always fascinated by science. As a young child I wanted to understand how the body worked - and I was always fascinated by the concept of regeneration. I went to the Bronx High School of Science, mainly because it has science in the name.

Q. Can you remember the first idea you came up with that represented a real innovation, and how the scientific community received that concept?

A. The first time I ever got any outside recognition was when I did a Westinghouse Science Talent project, and I came in fourth nationally. The project was about studying regeneration in a small organism. The recognition made me think that I might have the ability to do something important in science.

Q. Did you have any mentors who inspired you and encouraged you to move forward with your ideas?

A. I was blessed to have many people who encouraged and inspired me. It started with my father, who was a Greek immigrant who never finished his education because of World War II. He gave me the example of my grandfather, who had lived a remarkable life starting as a freedom fighter when Greece was still under Turkish rule, and managed to go on to become an electrical engineer, building many of Greece’s first power plants. My dad always talked of my grandfather as an example.

Then, when I told my dad that I wanted to be a medical scientist, he was reading the Greek newspapers and came upon the story of Roy Vagelos, another first-generation Greek immigrant who had left academia to become head of research at Merck, and was emerging as a driving force for the entire pharmaceutical industry.

Roy went on to discover the statins, and lead Merck to become the most admired company in the world. My dad followed Roy’s career, cut out every article about Roy, and always held him up as a great example for me, as someone who could not only do groundbreaking research, but directly apply it to treat human disease. It is a remarkable honor for me that Len [Schliefer] and I managed to have connected with Roy, and that Roy is now our chairman at Regeneron.

When I was doing my PhD, I was lucky enough to be one of the first graduate students of Dr Fred Alt, (PhD) who went on to become a leading figure in molecular immunology. Fred was like the older brother I never had, he really took me under his wing, and he taught me everything I know.

Q. When and how did you come up with the idea of the mouse that mimicked the human immune system? What was the magnitude of the effort that made this innovation a reality?

A. As a PhD candidate working with Fred Alt, we studied the basic genetics about how immune genes rearranged during lymphocyte development. We published several seminal papers in the field, and we were the first to put human immune genes into mouse cells — in vitro — and show they could be successfully rearranged by the mouse cells.

This led us to propose — back in 1985 — that one could use that same approach to make a mouse with a human immune system. A couple of companies followed up on this work, and indeed made mice that had human immune systems. But these immune systems did not work optimally; they were immune-compromised, to a degree.

When we started Regeneron, I went away from my immunological roots for a while, but then became interested in these first-generation humanized immune mice and why they didn’t work optimally.

I had a few ideas about how to make the mice better and we had developed a very powerful technology — VelociGene — that would allow making the mice in a very different way which I thought would work better.

One of the first things I then did was talk to Fred Alt about this and in fact he collaborated with us on making these mice, which we now call VelocImmune mice.

Indeed, the genetically humanized immune system of VelocImmune mice seems to work optimally, and VelocImmune mice are emerging as the new standard for making fully human monoclonal antibodies. We have used them to already put more than a dozen fully human antibodies into the clinic — several in record time — including our leading programs for cholesterol-lowering, allergic asthma and atopic dermatitis, arthritis, and cancer.

Q. What led you to make the switch from the academic community to the corporate world?

A. My dad had always held up Roy Vagelos and Merck as an example for me. So when I got a call from Dr. Len Schliefer, who was trying to start up a biotech company and was looking for somebody like me to help him out, I heard my father’s voice in the back of my head and I couldn’t resist thinking about the opportunity seriously.

Regeneron’s management team has been together for many years. They are (from left) Drs Roy Vagelos, Leonard Schliefer and George D. Yancopoulos.

At that time — the late 1980s — there was a lot of bias against going into industry. But I really hit it off immediately with Len. I could tell he was not only very smart, but very ethical and, in many ways, shared many of my views. He was very different than anyone else I had ever met, in a good and exciting way. Just to be sure, though — believe it or not — I had my dad interview Len to confirm my perspectives. My dad ended up loving Len, and recommending I join up with him, and Len and I have been partners and best of friends since then, and we have had great adventures over the last 25 years.

Q. I believe Regeneron began as a company seeking treatments for nerve disorders. What caused the company to switch focus to the ophthalmic arena?

A. Yes, Regeneron started with a focus on nerve disorders. In the early days, we used our technological approaches to discover several new nerve growth factors, and advanced them into human trials for a variety of neurological diseases, including ALS. Unfortunately, these trials did not work. However, we had already realized that we could apply several of our new technologies to areas outside of the nervous system.

One example, spearheaded by Neil Stahl, Aris Economides, Sam Davis, and Nick Papadopoulos was the development of our Trap technology, which could be used to come up with potent blockers to a variety of cytokines and growth factors. The first Trap we developed was to interleukin-1, now known by the brand name Arcalyst (rilonacept), and it was approved for a rare, cold-induced auto-inflammatory syndrome, where it provides substantial symptomatic control for patients.

Our Traps to VEGF led to the approval of Zaltrap (ziv-aflibercept) injection for previously treated meta-static colorectal cancer, and Eylea (aflibercept) injection for wet AMD and other eye conditions.

At Regeneron we don’t limit ourselves to one disease area. We always had a belief and focus on genetics and on developing empowering technologies. Traps were an important early technological advance for us and led to our first three drug approvals. But our early belief and commitment to genetics led us — most notably David Valenzuela, Drew Murphy, Aris Economides, Tom DeChiara, Wojtek Auerbach, Nick Gale, Bill Poueymirou, and David Frendewey — to develop the world’s leading mouse genetic technology, known as VelociGene, that allows us to manipulate the mouse genome with unprecedented speed and scale, as well as precision, to make almost any humanized mouse model we can dream of. And as I mentioned, we exploited VelociGene to make the VelocImmune mouse — primarily developed by Drew Murphy and Lynn MacDonald — and turned into a machine by Nick Papadopoulos.

Dr. Yancopoulos in his element, his lab.

It is VelocImmune that now powers our pipeline, by producing fully human antibodies very effectively and efficiently, and it has allowed us to have one of the most robust, exciting and diverse pipelines in the industry — addressing targets as diverse as those for cholesterol-lowering to allergy and asthma.

Q. Regeneron had a bumpy ride in its early years. What were the factors that kept the management team together?

A. As you say, we had a bumpy ride, and a lot of people thought we were failing. But I really think that many of us felt we were really just learning to succeed, and always on our way to making really big advances.

From the scientific and technological side, we were always succeeding; we just hadn’t translated the advances into the clinic. We always felt we were building the most exciting company in the world and even in the bleakest of times it was always fun coming to work. We all felt like we were in it together, that we were a real team. I think the outside world is now seeing that all that experience and learning has begun to pay off and that we have built a great foundation based on the science and technologies we developed. We hope to provide many more important therapeutic advances for patients in the coming years.

Q. How important to success was the stability of the management team?

A. I think it was extremely important. But it is not only the management team — many of our key employees have been here for over 10 years. In most companies, there is a lack of continuity, as well as a lack of institutional knowledge. I think we are pretty unique in having a team that has grown up together, worked together, and learned how to succeed together.

We use the lessons we have learned, every single day. And people stay here because it is one of the most exciting places to work in the world. Even when the outside world thought we were failing, on the inside we knew we were making progress toward great success and we all wanted to keep this going together. We just do not have the turnover that you see at many other companies. We do think of Regeneron as our second family, and it is at the core of our company values to treat the employees well. As a matter of fact, Regeneron was voted the number one biopharmaceutical company to work for by Science magazine in 2012.

Q. Scientists have called the trap mechanism you developed as elegant. How did you arrive at the conclusion that it would work?

A. A number of our leading scientists were involved in understanding how receptors worked — people like Sam Davis and Neil Stahl — and published some of the most highly cited papers in the world on this subject.

Then Neil and Aris Economides developed a way to turn this knowledge into a new kind of blocker, which we now call Traps. Traps worked great as blockers to certain cytokines and growth factors.

Around the same time, two scientists, Dan Kastner at the NIH and Harold Hoffman at UCSD (University of California, San Diego), had been studying patients with a rare hereditary condition in which cold-exposure induced severe flu-like symptoms — a hereditary condition known as CAPS. Scott Mellis — whom I had first met at Fred Alt’s lab and then recruited here to Regeneron — spearheaded the efforts with these outside folks to test our interleukin-1 trap for this disease, and showed it worked. That resulted in Arcalyst, the first FDA-approved drug for Regeneron, which helps a few hundred patients in the United States who have this rare condition, and then influenced the development of our VEGF-Trap for both ophthalmic use and oncological use.

Regeneron’s corporate headquarters in Tarrytown, NY. The company’s recent success with Eylea and a strong pipeline has led to the addition of more facilities.

Q. Were you ever discouraged that VEGF-Trap would be discarded or unfunded as a therapeutic concept?

A. We believed in the science behind VEGF-Trap, so it was disappointing when our collaborators didn’t see the potential.

We first started working on the VEGF Trap with Procter & Gamble in the 1990s. They declined to move it into clinical development for either the eye or cancer. They didn’t believe in the clinical or commercial opportunity. Then, they returned it to us and, for quite a while we could not convince any other company to partner with us. It was hard to get funding for the development program until other companies started publishing information from their trials with VEGF inhibitors in cancer.

Our first partner, Sanofi, decided they did not believe in the eye opportunity and only wanted to pursue it in cancer and returned the VEGF Trap-Eye to us. All these setbacks did push us back, but again, we believed in the science that said that VEGF Trap-Eye had the potential to be best-in-class even if it had missed its opportunity to be first-in-class, so we kept the program alive and now we have Eylea as a marketed product, one of the top five launches in biotech history.

Retinal specialists have already given about 1 million Eylea injections, which means that Eylea has helped a lot of people and given back a great deal of vision. It may have been a bit of an uphill climb, but we couldn’t be more pleased with the result.

Q. In your career of innovation, what would you do differently if you had the chance to go back?

A. If we knew then what we know now, we could have short-circuited the process and only focused on the efforts that ultimately proved successful. But in retrospect, it seems as if you need to go through the trials and tribulations so as to really learn from these experiences, and often you learn more from the difficult situations, as compared to the successful ones.

I think all this experience, and the fact that we went through it as a team and most of us are still here, leaves us in an extraordinarily strong position as company, with regard to our institutional knowledge and our ability to now make better decisions.

Q. Do you have any advice for ophthalmologists who have an idea or concept they believe has the potential to help people?

A. Certainly pursue it, as it can be wonderful to try to develop something that can help patients. But in their efforts, I would recommend getting together with someone who has had a lot of experience in such efforts, to try to shorten the necessary learning curve.

Q. With the delivery of wet AMD drugs by intravitreal injection creating a burden on patients and retinal specialists, what might be the next advance in delivering these anti-VEGF therapies to the back of the eye.

A. We have received great feedback from practitioners about their use of Eylea. Intravitreal injections may sound a little scary to patients when they first hear about them, but we have heard from patients who say they do get used to it.

As the population ages, the number of people at risk for developing wet AMD increases, and it is certainly a challenge for some retina specialty offices to accommodate the number of patients requiring treatment.

Currently, we see numerous efforts under way involving longer-acting agents, sustained-release formats, gene therapy and more. Some are more promising than others and we are pursuing several ourselves. Unfortunately, none of these approaches have really shown the convincing data to show that they are on the right path. But because of the time it takes to develop such agents, it will be quite a while before these are broadly available to patients.

The good news for patients is that intravitreal injections of anti-VEGF agents is really making a difference, and is well-tolerated by most patients. They now have a couple of good choices, including Eylea. RP