Note: This story has been updated to reflect that Regeneron has not sequenced samples for All of Us.
CHICAGO – Regeneron Pharmaceuticals has about 110 different research partnerships involving genetic sequencing, but none is larger than the recently announced Mount Sinai Million Health Discoveries Program.
The New York-based biopharmaceutical company aims to enroll and sequence at least the exomes of 1 million Mount Sinai Health System patients over a five-year period, offering researchers the dataset to assess the potential of genetics-based precision medicine as well as to generate new insights for potential new therapy discoveries and development.
The new program will be administered by the Charles Bronfman Institute for Personalized Medicine, serving both Mount Sinai Health System and the Icahn School of Medicine at Mount Sinai, and will work in concert with other initiatives within the Bronfman Institute, including multimodal data science, deep phenotyping of patients, and testing of new treatments.
This dwarfs other Regeneron sequencing collaborations, including those at Geisinger Health System, the Colorado Center for Personalized Medicine, and the University of California, Los Angeles. "To really help us understand what we know about why people get sick, about biology, we need not just tens of thousands. We will need millions of individuals," said Gonçalo Abecasis, VP and head of analytical genomics and data sciences at Regeneron Genetics Center in Tarrytown, New York.
It is among the largest sequencing programs to originate in the private sector, perhaps surpassed only by a still-nascent one led by South Africa's Aurum Institute, Global Health Innovations, and startup IndyGeneUS. Others of this size such as All of Us and the Million Veteran Program in the US and the UK Biobank in Britain, are government-sponsored.
The Regeneron Genetics Center performs sequencing for UK Biobank.
For the Mount Sinai program, Regeneron will profile 1 million people mostly through whole-exome sequencing, though the company will perform whole-genome sequencing on a subset of patients of non-European ancestry because people of color have historically been underrepresented in genetic research. Regeneron will also be conducting microarray-like genotyping to profile "common variants in a subset of regions in the genome" on all 1 million patients, according to project leader Alexander Charney, associate professor of psychiatry and genetics and genomic sciences at Icahn Mount Sinai.
Charney said that the ultimate goal is to sequence whole genomes of every Mount Sinai patient, but not necessarily within the context of the Regeneron partnership.
"I don't think we have a specific commitment to do a precise number of genomes there, but I would be surprised if a few years down the road we have actually done zero genomes," Abecasis said. He noted that Regeneron's standard approach is to start with sequencing exomes because the company believes that protein coding variation is "the most informative about what are the benefits [and risks] of targeting a particular gene."
Abecasis said that Regeneron is probably in the minority among pharma and biotech companies in doing its own sequencing for target identification and drug development rather than primarily relying on public databases. "We think there's an advantage to being able to guide what's generated and not wait for public projects," he said.
The company has been able to advance several research projects from other genomics-focused collaborations.
Notably, Regeneron has developed the IL-4 blocker Dupixent (dupilumab) to treat severe asthma. In researching the genetic roots of that compound, Regeneron also found that the same variants are associated with other conditions, including eczema, according to Abecasis. The company is also working on an IL-33 inhibitor for asthma and chronic obstructive pulmonary disease based on insights gained from its genomic database.
More recent research, published in the New England Journal of Medicine last month, discusses the identification of rare coding variants in CIDEB that could protect against liver cirrhosis, based on the analysis of more than 500,000 exomes. "That would not have been possible without our large-scale sequencing partnerships," Abecasis said.
"We're going to move from this idea that you design drugs by trial and error like you did 50 years ago to something that's much more driven by biology," Abecasis said. "We really need data at scale to learn these relationships in people."
The new program, which leaders are referring to as Mount Sinai Million or Million Health Discoveries, is an outgrowth of sorts of a collaboration between Mount Sinai and Regeneron that started in 2016 to sequence and profile whole exomes from DNA and plasma samples from the health system's BioMe biobank. Charney said that the earlier program eventually enrolled about 70,000 patients.
All 1 million patients in the new program will come from within the Mount Sinai Health System, which has about 133,000 inpatient admissions and 3.7 million ambulatory visits a year.
Charney said that keeping a program of this size within a single healthcare system has the advantage of tying the genomic data to intake surveys as well as de-identified patient records. "If your goal is to understand how genetics can be used in the real world of clinical practice, a design like All of Us is not really the way to do that," he said.
The Million Veteran Program, run by the US Department of Veterans Affairs "is more in line with that goal" since all participants receive care in the VA health system, which has had electronic health records for decades, Charney added. However, he noted that the VA is heavily skewed toward men just because of the nature of the veteran population.
The general aim of Mount Sinai Million, according to Charney, is to enroll a diverse pool of patients to understand the effects of genetics on health. Individual researchers will have their own goals, of course.
"This program will allow me to understand the mechanisms by which specific genetic variants are causing severe illnesses like schizophrenia [and] bipolar disorder in individual patients and their families," said Charney.
"The true value of a resource like this is that it's not going to achieve just one end," he added. "It will achieve many ends for different research groups."
Software firm Vibrent Health, which also supplies the technology platform for All of Us, is providing Mount Sinai Million with the central informatics platform and digital tools to support recruitment, patient consent, data collection, engagement, and retention of participants. Patients will not be forced to download an app and create a profile on the Vibrent platform to participate in the study, though Charney said that a patient portal for enrollees is "on the table" in the future.
"The real challenge of our study is how do you perform informed consent on a million people in a rapid time frame at a single center?" Charney said.
Abecasis explained that the traditional method of having humans approach patients about clinical studies is not scalable to a program that seeks to enroll 1 million people.
"Because it's online and because it's samples that already have been collected, it's a little more efficient than saying, 'I'm going to ask you in person, and I'm going to schedule a follow-up visit for you to provide the blood sample,'" Abecasis said.
This online approach toward obtaining consent grew out of the early days of the COVID-19 pandemic, when New York was an early hot spot in the US and Mount Sinai was setting up a field hospital in Central Park to handle an expected patient surge.
Charney noted that physician researchers at the health system knew they needed to study COVID-19 patients while also treating them, but they quickly learned that sick people in isolation wards did not want hospital personnel approaching them about studies when their families could not even come to visit. Instead, Mount Sinai came up with an alternative plan to set aside blood samples until patients were more comfortable being asked to consent for research.
"When we did this, we found that 90 percent of the people wanted to participate when we approached them about it," Charney recalled. "It was an eye-opening experience."
To promote Mount Sinai Million, the health system is assembling a team of about 20 staff, from clinicians to researchers to marketing personnel, to educate care providers and patients alike about this research opportunity.
Charney pushed back at concerns over privacy raised by a Yale University biomedical informatician in a New York Times article about the program.
"I lose sleep over this question of making sure that all the data that we collect from our patients is going to be protected, that only a very small number of people who report directly to me will even know the name of people who participate," Charney said. "As the principal investigator of the study, the buck stops with me."
Charney did acknowledge that there is a "larger question for society at large to discuss" about the safety of participating in genetics research in general. "It's a big question that the field needs to think about deeply at all times, not just now, but always."