George Yancopoulos, MD, PhD, Regeneron’s founding scientist, president & chief scientific officer, with Caitlin Forsythe, a research associate at the Regeneron Genetics Center. [Regeneron Pharmaceuticals]
More than two years after reaching the 250,000 mark, the Regeneron Genetics Center (RGC) has surpassed 1 million exomes sequenced since it was established in 2014, with plans this year to exceed the annual sequencing rate of 500,000 exomes it reached last year.

“We are committing to around 600,000 samples sequenced by the end of the year,” said Aris Baras, MD, general manager of RGC, a wholly owned subsidiary of Regeneron Pharmaceuticals, where he is also a senior vice president. “We’ve built the lab for the future and we always want to be prepared for new projects, new opportunities, great things we can’t pass up on.”

RGC’s sequencing rate has multiplied since November 2017, when the Center marked the quarter-million-exome milestone and was sequencing 200,000 exomes per year. Baras said RGC’s faster pace since then reflects increased research activity; improved technology, from sample prep to sequencers; and greater R&D investment by Regeneron. The biotech giant doesn’t disclose RGC’s budget but the company’s overall R&D spending jumped nearly 50% last year to just over $3 billion from about $2.2 billion in 2018.

Baras discussed RGC’s sequencing milestone, its recent operations, and its approach to research and collaborations in an exclusive interview with GEN Edge.

Much of RGC’s sequencing activity comes from two ongoing collaborations. In one of them, Regeneron leads a $70-million consortium of eight biopharmas that have committed to generating sequencing data from the UK Biobank’s 500,000 volunteer participants, with the aim of providing new genetic evidence to researchers in developing new therapeutics across a broad range of diseases. The data is being coupled with the participants’ detailed and de-identified medical and health records, including measures of brain and heart activity and body imaging.

AbbVie, Alnylam Pharmaceuticals, AstraZeneca, Biogen, Bristol-Myers Squibb, Takeda Pharmaceutical subsidiary Millennium Pharmaceuticals, and Pfizer agreed to invest $10 million each to join the Regeneron-led precompetitive sequencing project.

Biobank project nears completion

“We’ll be done by June [2020] with the 500,000,” Baras said. “We’re somewhere around 400,000 or more of the way through that. We still have to wait on some final batches from the UK team, which has been absolutely terrific, shipping extremely high-quality, 500,000 samples in about a year and a half or two years.”

RGC is also partnering with Geisinger to leverage large-scale sequencing and de-identified data from electronic health records, with the aim of guiding genomic medicine and genomics-guided therapeutic discoveries.

RGC carries out testing and generates genetics reports for patients enrolled in Geisinger’s MyCode Community Health Initiative. In December, Geisinger announced that the pioneering precision medicine project reached 250,000 participants in Pennsylvania and New Jersey. As of December 19, the project had both DNA sequence and health data on 145,000 of those participants and had returned medically actionable results to nearly 1,500 participants.

Honey Reddi, PhD, FACMG

“Regeneron’s effort to be able to use the data for drug discovery and development is integral to improved patient care,” said Honey Reddi, PhD, FACMG, chief medical director of Clinical Diagnostics, Genomic Sciences & Precision Medicine Center (GSPMC), Medical College of Wisconsin. “It is however important that similar efforts across the U.S. and globally be consolidated as much as possible to maximize the results of these efforts.”

According to Reddi, the significance of Regeneron’s million-exomes milestone is “truly remarkable,” addressing a key component of the Precision Medicine Initiative launched in 2015; its research cohort, now known as the All of Us Research Program, has brought to fruition the vision articulated in 2011 by Eric Lander, PhD, for a “one million genomes” large-scale sequencing project to fulfill the promise of genomics for medicine.

“It is the diagnostic odyssey of rare and undiagnosed genetic disorders that are best served by such efforts. It is such scenarios that motivates labs to use WES [whole exome sequencing] to identify genetic causation where possible,” Reddi said. “It is getting fast access to the data that is important for a healthcare provider.”

Ongoing challenge

The challenge for providers still remains in obtaining reimbursement, said Reddi, who recalled how in 2010, researchers at the Medical College of Wisconsin and Children’s Hospital of Wisconsin successfully used WES to provide a life-saving genetic diagnosis for Nic Volker, a severely sick four-year-old child. The researchers reported details in “Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease,” published in Genetics in Medicine.

“As sequencing costs fall and genomic data sets with phenotypes expand, we predict an increasing utilization of sequencing data in a clinical environment,” concluded the study’s corresponding author, Elizabeth A. Worthey, PhD, then of the Medical College and now director for the Center for Genomic Data Sciences in the Departments of Pediatrics and Pathology in the School of Medicine at The University of Alabama at Birmingham.

“In the interim, there is a need for development of multidisciplinary teams and large clinically useful data sets to fully use this approach as a clinical tool, as well as a need to build the infrastructure to enable this powerful tool to be practically implemented,” Worthey and colleagues added.

“At the GSPMC, while we have not reached the whole exome sequencing numbers of Regeneron, we continue our efforts to build a support program that will help the underprivileged and underserved get access to WES and WGS (whole genome sequencing) as needed,” Reddi added.

RGC has established more than 80 collaborations with companies, integrated medical systems, academic institutions, and government organizations.

After RGC in 2018 identified a variant in the hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene associated with reduced risk of, or protection from, various chronic liver diseases for which there are currently no approved therapeutics, the company partnered with Alnylam Pharmaceuticals to discover RNA interference (RNAi) therapeutics for nonalcoholic steatohepatitis (NASH) and potentially other related diseases. The partnership blossomed last year into a potentially $1 billion-plus collaboration to discover, develop, and commercialize RNAi treatments for diseases of the eye and CNS—as well as advance preclinical programs for liver disorders.

One of those preclinical programs—NASH candidate ALS-HSD, which targets HSD17B13—is among a handful of programs for which Alnylam plans to submit IND filings this year.

“Tip of the spear”

“With the scale of the data and the amount of really top-notch people we have here, who are dedicated to mining the data, there are hundreds of hits,” Baras explained. “When I say hits, I mean a really interesting, intriguing, exciting thing that a company like Regeneron is going to want to follow up on. These are things that have a very large effect on diseases of interest.”

“The path from hit… to a bona fide drug discovery program, where you’re now inventing the molecule, screening and selecting a lead molecules for whatever the modality is, and moving as quickly and thoughtfully as you can to the clinic, we have a couple of those examples. That’s really exciting and perhaps the tip of the spear,” Baras added.

In June 2019, the Center and Mayo Clinic agreed to generate whole exome sequencing and genotype data from 100,000 DNA samples of consented participants in research studies at Mayo, including the Mayo Clinic Biobank. In recent years, Baras said, the growth of national genetic data projects such as “All of Us” in the U.S. and the 100,000 Genomes Project in the U.K. has sparked increased activity from global governments.

RGC’s growing number of collaborations, Baras said, have focused in part on specific diseases, including inflammatory bowel disease, multiple sclerosis, neurodegenerative diseases, and obesity, as well as metabolic and immune-related disorders.

Diverse data partnerships

Another growing area of focus for RGC is partnerships designed to gather, analyze, and interpret data from more diverse collections of samples beyond those generated by individuals of European ancestry.

An example of the latter is an RGC collaboration with researchers from Penn Medicine and Icahn School of Medicine at Mount Sinai. In December, the researchers published in JAMA the discovery that a genetic variant in the gene transthyretin (TTR)— found in about 3% of people of African ancestry— was a more significant cause of heart failure than previously thought.

The study, “Association of the V122I Hereditary Transthyretin Amyloidosis Genetic Variant With Heart Failure Among Individuals of African or Hispanic/Latino Ancestry,” also showed that a disease caused by that variant, hereditary transthyretin amyloid cardiomyopathy (hATTR-CM), was significantly under-recognized and underdiagnosed.

“We have made a real big push and had a lot of success over the last couple of years, working in disease-focused projects,” Baras said. “We have been trying to get very large collections—10,000 or 50,000 individuals with certain diseases and we’ve made a lot of progress.”

The Penn Medicine-Icahn Mount Sinai collaboration, for example, involved DNA sequencing of 9,694 individuals of African and Latino ancestry enrolled in either the Penn Medicine BioBank or the Icahn School of Medicine at Mount Sinai BioMe biobank.

“Taking it to another level”

“I can’t stress enough that the main goals and approaches of the Center have largely stayed the same. It’s just that there’s been a lot of success in the program, and there has been a lot of availability of resources,” Baras said. “It’s more kind-of taking it to another level, what we’ve been able to do.”

RGC’s work has helped shape development of several Regeneron drug candidates. One is evinacumab (REGN1500), an investigational monoclonal antibody to angiopoietin-like protein 3 (ANGPTL3) being developed to treat hypercholesterolemia in patients with homozygous familial hypercholesterolemia (HoFH).

Following positive topline Phase III results in HoFH, Regeneron plans this year to file for U.S. and European approvals for evinacumab this year. The other is Dupixent® (dupilumab), an approved blockbuster drug co-marketed by Regeneron with Sanofi Genzyme for indications in atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis.

RGC has about 100 staffers, with plans to grow to 140 to 150 eventually: “That’s what we need to accomplish our goals, our vision, the kind of things that are on our plate immediately and in the near term. The only thing that’s hard to project is just how fast you being in those folks.

Looking ahead, Baras said, RGC plans even more partnerships, in areas that go beyond drug development, including smart and mobile technology development—and especially digital health.

“That’s an amazing space to think about,” Baras said. “You can really just simply improve how you can stratify risk, how you can predict risk, and how you can use healthcare resources—not just medicines, but certain interventions or screening approaches. You could just do a much better job if you knew where the risk was coming, and then how to manage it better. That’s a field that I think is ripe for the taking and is developing in front of us.”