The Regeneron Genetics Center (RGC) has surpassed 250,000 exomes sequenced since its creation three years ago—with a vision of sequencing up to double that number.

RGC, a wholly owned subsidiary of Regeneron Pharmaceuticals established in 2014, has increased its sequencing rate since then to 200,000 exomes per year, with plans to ramp up to between 400,000 to 500,000 people a year.

“We were going to do 100,000 in five years, which means that we should have been at 60,000 by now,” recalled George Yancopoulos, M.D., Ph.D., Regeneron co-founder, president, and CSO. “We’re at 250,000, and pretty soon, we’ll be doing 500,000 a year. At our current rate, it would take us 10 years to do 5 million people—at the rate that we’re at pretty much now.”

RGC is on track, he said, to sequence between 5 million and 10 million exomes over 10 years.

“We have line-of-sight on a million in just a few years,” Aris Baras, M.D., VP, co-head, RGC. “We will find a way, we’re going to make it happen. And if it’s on a five or 10-year timeline, or whatever it is, who knows how history will unfold, but we will find a way.”

Drs. Baras and Yancopoulos discussed the RGC’s milestone, its progress in generating genetic data, and what they termed its success in its objective of expanding the use of human genetics for discovering and validating genetic factors that cause or influence a range of diseases where there are major unmet medical needs with reporters at Regeneron’s headquarters in Tarrytown, NY.

“You know how you know that we believe that this is delivering way past all of our expectations? We’re doubling our investment in it,” Dr. Yancopoulos said, without quantifying that investment.

Informing Drug Development

Both said that RGC’s focus on genetics has informed the drug development efforts of parent Regeneron, citing two treatment candidates now in clinical phases.

One is evinacumab (REGN1500), an investigational monoclonal antibody to angiopoietin-like protein 3 (ANGPTL3), an inhibitor of lipoprotein lipase and endothelial lipase that appears to play a central role in lipoprotein metabolism. The other is Dupixent® (dupilumab), an approved blockbuster drug for moderate-to-severe atopic dermatitis for which Regeneron and development partner Sanofi plan to submit a supplemental Biologics License Application (BLA) to the FDA by year’s end seeking approval for the additional indication of asthma in adults and adolescents.

Evinacumab is in Phase II development for hypercholesterolemia in patients with homozygous familial hypercholesterolemia (HoFH)—an inherited disorder that can lead to premature cardiovascular disease due to very high levels of low-density lipoprotein cholesterol (LDL-C; “bad” cholesterol)—as well as severe forms of hyperlipidemia. In April, evinacumab won the FDA’s Breakthrough Therapy designation for hypercholesterolemia in patients with HoFH, with Regeneron saying that a Phase III trial was being planned.

The following month, Regeneron published a study in the New England Journal of Medicine (NEJM) showing that people with inactivating mutations of the ANGPTL3 gene had significantly reduced risk of coronary artery disease and significantly lower levels of key blood lipids, including triglycerides and LDL-C. The study also showed that blocking ANGPTL3 activity with evinacumab exhibited similar lipid-lowering effects in animal models and a first-in-human clinical study.

RGC researchers sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study, a precision medicine collaboration between RGC and Geisinger Health System designed to leverage large-scale sequencing and de-identified data from electronic health records to guide genomic medicine and genomics-guided therapeutic discoveries.

The collaboration with Geisinger is one of RGC’s two largest collaborations; the other is a partnership with GlaxoSmithKline (GSK) and UK Biobank to generate genetic sequence data from the health database'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.

RGC joined an international research team in analyzing genetic data and health records from more than 180,000 participants in DiscovEHR as well as three major studies in Copenhagen, the Penn Medicine Biobank, the Duke CATHGEN cohort, and the TAIwan MetaboCHIp (TAICHI) consortium. The team identified individuals who had loss-of-function mutations for ANGPTL3 and found that those who carried loss of function mutations had lower lipid levels and an approximately 40% reduction in the risk of coronary artery disease.

And in September, Regeneron and Sanofi said Dupixent when added to standard therapies met its two primary endpoints in the pivotal Phase III LIBERTY ASTHMA QUEST trial by showing reduced severe asthma exacerbations and improved lung function.

Dupixent is an antibody to the interleukin-4 receptor (IL-4R) alpha subunit. In addition to asthma in adults and adolescents, Dupixent is also in Phase III development for nasal polyps, as well as Phase II development for atopic dermatitis in children ages 6 to 11 as well as in eosinophilic esophagitis (EoE). Regeneron and Sanofi in September won European Commission approval for Dupixent in adults with moderate-to-severe atopic dermatitis. Phase III studies are in progress in atopic dermatitis in adolescents, and in asthma in children ages 6 to 11.

Last month, Regeneron and Sanofi said that Dupixent met its primary endpoint in a Phase II trial in adults with active moderate-to-severe EoE.

“Our initial perspective was, how many things is this initiative going to produce?” Dr. Baras recalled. “We can talk about things already in the clinic, and that’s fantastic. And we’re looking at new molecules that will hopefully follow them soon into the clinic, and that’s also fantastic.

“There are brand new discoveries uniquely coming from this discovery initiative. But the bigger picture that has happened is, genetics—human genetics, as we RGCers call it—is now one of the key staples of how Regeneron does R&D. and yet again, differentiates itself then from others in the R&D approach.”

Automation and New Sequencers

Drs. Baras and Yancopoulos said several factors helped explain RGC’s ability to ramp up its sequencing capacity, including advanced automation and a recent upgrade in its sequencers.

One factor is advanced automation: RGC uses a custom-built system with liquid handlers to carry out pipetting, a robotic arm to handle samples, and an automated refrigerator. Samples are stored in a biobank with a storage capacity of over 1 million samples

The Center upgraded to a second-generation system earlier this year—becoming first operational in August—after transitioning from Illumina HiSeq 2500 sequencers to four Illumina NovaSeq 6000 sequencers acquired this year.

Genotyping is done via Illumina Infinium® Global Screening Array. Exome capture is carried out using an IDT platform, with precapture reagents, a custom kit combining reagents available from New England BioLabs (NEB) and Roche-owned Kapa Biosystems.

The exome capture process can be done start to finish, from biobanking through sequencing, with five full-time employees, said John Overton, Ph.D., senior director, head of sequencing and lab operations.

He said RGC has 60 to 70 employees, with plans to add another 10 or so short-term over the next year.

“We needed to push the technology even further to accommodate the NovaSeq, so we created a system that can work autonomously for days at a time,” said Dr. Overton, a former associate director of the Yale Center for Genome Analysis. “The real goal here when we set out was, we wanted to load this on Friday afternoon, and we wanted it to run through the weekend, so nobody had to come back.”

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