THE JOURNEY OF AN IDEA: REGENERON GENETICS CENTER

TWO SCIENTISTS WALKED ONTO A PLANE...

While it may sound like the opening line of a joke, a chance meeting in 2010 was a key catalyst to the creation of the Regeneron Genetics Center (RGC) — an idea that had already been stirring among Regeneron scientists, given recent technological advances and the company's long history in genetic-guided drug discovery.

Officially launched in 2014, the RGC helps to identify novel targets for Regeneron drug development, verifies and informs ongoing programs, and provides clinically valuable information to physicians and patients. The RGC showcases the open, collaborative culture at Regeneron, a place where big ideas are encouraged and a commitment to "following the science" is paramount.

ARIS MEETS DAVID

In 2010, Aris Economides, Executive Director of Genome Engineering Technologies and Skeletal Diseases Therapeutic Focus Area at Regeneron, was on a plane flying to a medical conference. Flipping through Science, he noticed the man sitting next to him was reading Nature. "We looked at each other, and I said to him, ‘I think you're going where I'm going.' He says, ‘No, I think you're going where I'm going,'" Aris E. recalls.

As it happens, Aris' traveling companion was David Galas, then at the Institute for Systems Biology in Seattle. Aris was reading Galas’ paper on family-based genome analysis supported by whole genome sequencing.

Galas' paper highlighted that the technology and cost revolution in genomics would now make it possible to fully recognize the potential of genomics in drug discovery. The knowledge gleaned from sequencing would then drive the future of precision medicine, focusing research and discovery programs and delivering personalized treatments.

And so Aris and David began a conversation — one that would ultimately add value to Regeneron's ongoing exploration of human genetics led by visionary Chief Scientific Officer George Yancopoulos and one that was an early example of the RGC's close working relationships across the genetics research community.

"WE TRULY BELIEVE THAT IF YOU'RE NOT EXPLORING HUMAN GENETICS,
YOU'RE NOT DOING MODERN-DAY DRUG DISCOVERY."

– ARIS BARAS, MD, HEAD OF THE REGENERON GENETICS CENTER

SOLVING FOR EARLY CHALLENGES

Back at Regeneron, the team recognized the power of human genetics in drug development, as demonstrated by the company's very first approved medicine for a rare autoinflammatory condition. George and his team knew their expertise and best-in-class technology made them uniquely suited to apply large scale human genetics to drug discovery…but robust “real-world” data from a large consented population of patients combined with the ability to inexpensively sequence samples were critical to truly be successful.

Various workstreams were underway to explore possible approaches to unlock human genetics on a broad scale.

"WE WERE ALREADY HAVING SOME SUCCESS, SEEING TARGETS THAT CAME OUT OF HUMAN GENETICS SUCH AS PCSK9, AND THERE WAS A GENERAL FEELING THAT WE NEEDED TO LEARN MORE ABOUT HUMAN GENETICS TO USE IT TO DRIVE DISCOVERY."

– SCOTT MELLIS, VICE PRESIDENT, EARLY CLINICAL DEVELOPMENT, RARE DISEASE

"It really happened organically," reflected Aris E. "People felt there was a need that had to be met, so we set out to try to solve for the problem. It was not prescribed from above."

The vision was to obtain diverse samples to pursue multiple research approaches, including:

  • Large-scale population studies, to explore the varied ways that a single mutation might present in different people
  • Mendelian population studies, to explore how a rare disease like cystic fibrosis manifests within multiple generations of a family
  • Founder population studies, such as the Amish or Mennonite communities, who have lesser genetic variation than the general population due to geographic or self-selected relative isolation, resulting in amplified genetic patterns

And discussions were ongoing with various potential partners, such as Geisinger Health System, the Clinic for Special Children and Columbia University — among others — to provide samples and collaborate on important research. Simultaneously, the team also was engaged in discussions with Iceland's deCODE Genetics about a potential collaboration to sequence and study their Icelandic founder population data.

A DEFINING STRATEGY SHIFT

In December 2012, deCODE was acquired by Amgen, changing the genetics industry landscape at the time and closing the door on the potential partnership that had been under discussion. Rather than be deterred, the team saw this change as an opportunity.

"I really wasn't fazed by deCODE's decision to collaborate with another company," said Aris B. "Our culture accepts twists and turns as normal steps in the process. We want people to be innovative here, and it often takes overcoming roadblocks to beget success. We all really rallied around the fact that there was a new, a better opportunity," Aris B. continued. "As with so many other programs, we just shifted our focus to building this organically at Regeneron. After all, that's the way things have been done here for decades and what our leadership team encourages every day."

And so the team began to plan for how to bring the capabilities in-house to build one of the largest sequencing centers in the world.

A KERNEL OF AN IDEA BECOMES A BEANSTALK

In early 2013, the Regeneron team — known internally as the Human Genetics Initiative (HGI) — began to map out the scientific strategy, collaborations and operational plan. Each member brought a unique perspective and skill set to the internal collaboration. Many other colleagues — from business development to human resources to legal to finance — also contributed time and perspective, highlighting the focus on cross-functional partnership that is a hallmark of Regeneron's culture.

"We had the benefit of a clean slate," said Aris B. "We wanted to build something, and we could use the best design principles, applying cutting-edge technology for sample prep, automation, sequencing and cloud informatics. We were building on the decades of innovation and technology development at Regeneron and bringing in-house the best external technologies and approaches."

In less than six months, senior management provided input and approved the strategy and initial budget for collaborations, hires and operations. The team was off to establish a wholly owned subsidiary of Regeneron, focused on a goal to sequence 100,000 people in five years to enable the company's gene discovery goals.

"To put that number into context, at the time the entire country of the United Kingdom was planning their 100,000-person initiative. And here we were, a relatively small company in New York, and that's the discussion we're having at dinner," explains Aris B.

SEQUENCING MORE THAN 250,000 PEOPLE

CONNECTING PIONEERS

The immediate priorities were hiring an exceptional team and putting leading technology in place to support the sequencing.

Turning to academia to bring the best skills to the nascent organization, John Overton from the Yale Center for Genome Analysis, the first RGC hire, was appointed head of sequencing in August 2013. Jeff Reid from Baylor College of Medicine joined as head of genome informatics in November. Internal colleagues not directly involved with the RGC also contributed — like Russell Chernomorsky, who works in the DNA Core, and helped set up the robotics and the biobank. Many more steller RGC hires from within and beyond the company soon followed.

"JEFF REID WAS VERY PROUD OF A GREAT BIG EMPTY ROOM THAT WAS OUR DATA CENTER, AND HE CALLED IT THE CLOUD LOUNGE. HE EVEN BROUGHT IN A FOG MACHINE TO HELP EMPHASIZE THE CLOUD THEME. BUT THEN, ONE EVENING AFTER TURNING ON THE CLOUD MACHINE, THE SMOKE DETECTORS WENT OFF, WE HAD A VISIT FROM THE FIRE DEPARTMENT AND THAT WAS THE END OF THE CLOUD MACHINE."

– SCOTT MELLIS, VICE PRESIDENT, EARLY CLINICAL DEVELOPMENT, RARE DISEASES

Building the RGC also involved creating an Advisory Board, to help guide the initiative's scientific focus. The Board consists of clinical scientists, geneticists, cancer specialists, metabolic specialists and sequencing experts.

"When they first got together, I think they were a little bit bemused and a little bit skeptical about what we were doing," recalls Scott Mellis, Vice President of Early Clinical Development, Rare Diseases. "By the second meeting, they were absolutely blown away by the productivity, and they've been a great source of ideas and of reality testing."

While the vision was sound and the team was strong, there were numerous challenges that the team had to overcome. "There are hundreds of operational and logistical issues from putting together a big technology center, hiring all the right people, getting deals done," said Aris B. "You can take my word for it, something went wrong in every single one of those places. But in true fashion we pulled together and innovated around every one of those challenges to get where we are today."

A PIVOTAL, LIKE-MINDED PARTNER

When the Regeneron Genetics Center officially launched in January 2014, a collaboration with Geisinger Health System, widely recognized for its innovative use of electronic health records, became a cornerstone of the overall initiative. It was a somewhat unconventional partnership of a healthcare organization and biotech industry partner.

"They had to worry about perception, since their primary mandate is to take care of their patient population. But they saw that we were serious about the science and about having a positive impact on human health," said Scott.

Aris B. continues, "In our early discussions with them, we shared our thoughts and aspirations around this program — to sequence 100,000 people. When you mentioned this to most people at the time, they thought we were crazy. But Geisinger just glanced at us and said, ‘Absolutely.'"

DISCOVERIES AHEAD

In March 2014, the RGC received its first 1,000 samples in the biobank, and by October of the same year, the team had sequenced the first 10,000 exomes. It was remarkable progress in a very short period of time. In fact, the RGC, through collaborations with Geisinger and others, beat its original goal by sequencing 100,000 patients in just two years.

Also in October 2014, Alan Shuldiner joined as Vice President of Founder & Special Populations, underscoring Regeneron's commitment to bring in top talent to drive scientific exploration. Alan — who coincidentally completed his internal medicine residency at Columbia Presbyterian Hospital alongside Scott — left his position at the University of Maryland and a career in academia to bring his human genetics expertise, especially in Mendelian and Amish founder populations, to advancing genetic discoveries and medicines.

10,000 EXOMES

"I wasn't looking for a job," Alan recalls of his visit to Regeneron earlier in 2014 to give a seminar on his work with the Amish community and the Clinic for Special Children. "But once I learned about the RGC progress and plans, I was so excited; my wife can tell you, I didn't sleep for three days!"

Now nearly four years in, the RGC is delivering key insights into the biology of human disease that is driving drug discovery. In 2016 and 2017, The New England Journal of Medicine published RGC papers showing that inactivating mutations of the angiopoeitin-like 3 and 4 (ANGPTL3 and ANGPTL4) genes are associated with a significantly reduced risk of coronary artery disease in humans. The data enable the linking of genetic mutations with real-world health outcomes to make actionable discoveries.

"WITH THE RGC, REGENERON HAS TURNED THE WHOLE PARADIGM OF DRUG DISCOVERY ON ITS HEAD, WITH HUMAN GENETICS INFORMING THE ENTIRE PIPELINE. WHERE ONE USED TO START WITH PRE-CLINICAL MODELS TO IDENTIFY NEW DRUG TARGETS AND THEN ADVANCE PROMISING CANDIDATES TO HUMAN CLINICAL TRIALS, WHICH OFTEN FAIL, WE NOW BEGIN WITH HUMAN GENETICS TO IDENTIFY SUPERIOR TARGETS AND THEN VALIDATE THESE DISCOVERIES IN PRECLINICAL MODELS BEFORE MOVING INTO CLINICAL TRIALS."

– ALAN SHULDINER, VICE PRESIDENT OF FOUNDER & SPECIAL POPULATIONS

FROM SCIENCE
TO MEDICINE

Today, the RGC is building one of the world's most comprehensive genetics databases, comprised of data from large-scale, founder population and disease-specific cohorts that is projected to exceed 500,000 exomes within five years. The team is working closely with Regeneron's Therapeutic Focus Areas and clinical programs to understand how the RGC can help identify new targets and move programs forward, and it continues to bring on new collaborations and partners to augment the diversity of data and catalyze future innovations.

"We're looking for cohorts that are really poised for gene discovery, that have high yield approaches — whether it be family-based approaches or large population studies looking for loss of function mutations or drug targets that we're studying. Our goal is to have enough genetic resources and capabilities so that we can support all of our targets and all of our programs at Regeneron," said Aris B.

The current challenge is deploying resources to mine all of the data. "There are many diamonds in those mines, and it's going to take a lot of diligence to find them," said Scott.

But regardless of the challenges ahead, the RGC team remains focused on unlocking the human body's most complex mysteries. "We're building our fundamental core of new targets to work on," said Aris B. "But most importantly, we're building the resources to really understand the impact of target biology on medicine, and of medicine's ability to help people live better, healthier lives."

"GOALS ARE A FUNNY THING AT REGENERON BECAUSE THEY'RE ALWAYS MOVING TARGETS."

– ARIS BARAS