Regeneron brings its antibody chops to gene editing’s biggest problem

TARRYTOWN, NY — For over three decades, Regeneron has been synonymous with one thing in the drug industry: antibodies. Blockbusters like Dupixent, Eylea, and Covid-19 antibodies have transformed what started as a scrappy startup into one of biotech’s biggest names.

But the billionaire co-founders who still run the $91 billion giant, CEO Leonard Schleifer and CSO George Yancopoulos, have spent nearly the last decade working on the company’s next act. They have partnered, built, and bought their way into genetic medicine, going beyond antibodies into CRISPR, RNA interference, and other technologies that manipulate the genetic code of life.

It’s an audacious bet on the future of the drug industry. And even though Regeneron’s success has come from antibodies, its leaders believe new therapies may dominate its next age.

Not only is the biotech co-developing the most clinically advanced in vivo CRISPR therapy with Intellia Therapeutics and an Alzheimer’s RNA interference drug candidate with Alnylam Pharmaceuticals, it’s also quietly working on — and increasingly excited about — some earlier, less heralded research that could change the field. Its leaders believe it can crack the delivery problem that holds back the entire space. Doing so would bring genetic medicines beyond the liver to reach more parts of the body, in the process greatly expanding the medical — and commercial — possibilities of the technology.

“While everybody else was so hyped and giving Nobel Prizes for CRISPR and all that, we realized those weren’t really the limitations,” Yancopoulos, Regeneron’s chief scientific officer, told Endpoints News during an interview at the company’s Tarrytown headquarters. “The limitations were really delivery.”

Regeneron is tapping its decades-long expertise in antibodies, attaching these proteins to standard viral vectors so they hunt for specific types of cells in the body. Research is early, with no timetable on reaching the clinic, but results in mice and non-human primates have emboldened the company’s scientific leaders on the promise of the idea. If it works, Regeneron could crack the delivery challenge that has held the entire field back for years, ultimately bringing technological breakthroughs like CRISPR and RNAi to far more diseases.

“We believe we’ve become leaders in that space,” Yancopoulos said of the delivery idea. “We will hopefully be announcing programs where we’re using biologicals to deliver genetic payloads, which we think has the chance to really continue to change the field.”

There’s still a long journey ahead into making this reality. Academics first tried the idea of attaching antibodies to viral vectors in the 1990s with moderate success, but challenges in making such a complex product have deterred industry interest. Before this idea reaches the clinic, Regeneron will need to convince regulators it has the manufacturing chops to attach these antibodies to viruses in a consistent way so batches look the same. Gene therapy experts said scaling up will be a key challenge.

Still, Regeneron carries unique credibility with its deep pockets and decades of antibody experience.

“Regeneron has certainly been the leader in designing and producing specific antibodies that could be used for this purpose,” said Barry Byrne, director of the University of Florida’s gene therapy center. “They’re the ones who will probably make this work.”

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Whether using a hollowed-out virus or a lipid nanoparticle, delivering genetic cargo in the body is frustratingly hard. These carriers predominantly wind up in the liver, the body’s clearinghouse organ.

While that can address diseases caused by genes expressed in liver cells, that’s not most illnesses. The brute force approach, upping doses to try to reach other organs, comes at the expense of the liver, leading to patient deaths in some gene therapy clinical studies.

Christos Kyratsous

“You have to give so much vector that you’re overwhelming your liver, and your liver enzymes go crazy,” said Christos Kyratsous, co-head of Regeneron’s genetic medicines team. “That becomes the major limitation for delivering the interesting payloads.”

The delivery problem has caused the field to crowd into the same liver-based targets, such as PCSK9, to slash cholesterol. Other efforts, like the sickle cell CRISPR gene-editing program now being reviewed by the FDA, avoid delivery altogether by using an ex vivo process closer to arduous transplant surgery than a typical drug.

The delivery work is one part of a sprawling genetics strategy at Regeneron, which started in 2014 with the launch of its Regeneron Genetics Center. That has become one of the world’s largest DNA-reading efforts, having sequenced 2 million genomes and counting, leading to over 10 new genetic targets tied to diseases like obesity or liver disease.

Walking around the RGC, sequencing machines tower over and outnumber white-coated scientists toiling at lab benches. It’s far more common for its 170 employees to log on remotely to check experiments or let robotic systems whiz around to handle routine tasks like pipetting.

Regeneron has inked collaborations with Decibel Therapeutics and Alnylam over the past few years, respectively working on CRISPR gene editing, gene therapy, and RNA interference to advance that RGC research. In August, Regeneron made an extraordinarily rare M&A move, agreeing to buy Decibel and its gene therapy work.

Regeneron now has six genetic medicines in its pipeline and more than 30 preclinical programs. But even as the field has generated excitement with the first US approvals for gene therapies, RNAi drugs, and mRNA vaccines all since 2017, its potential still dwarfs its current impact. The pesky delivery problem looms over the entire field.

Regeneron hopes its antibody idea can reach more organs, starting with the muscle and the brain. Preclinical data are encouraging, independent experts told Endpoints.

Regeneron’s most advanced program attaches an antibody targeting a protein found in muscle cells called CACNG1 to a viral vector. Mice and non-human primate studies showed massive boosts in reaching muscle cells, alongside big drops in entering the liver and heart compared to an unmodified version of the virus, according to data presented at this year’s American Society of Gene & Cell Therapy meeting.

“This is unlocking an entirely new space in terms of delivery and what you can actually do with all these genetic medicines,” Kyratsous said.

Christina Pacak, a University of Minnesota gene therapy researcher, called the data exciting, adding she’s hopeful for the approach.

“If we can increase safety, reduce costs, and just lower what patients are exposed to, that’s an enormous advantage,” said Pacak, who’s not involved with Regeneron’s research.

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For Regeneron’s early results, other experts said they are encouraging but not industry-shaking.

“Super-beautiful data. It’s impressive,” said Nicole Paulk, CEO of the gene therapy startup Siren Biotechnology. “But it doesn’t look different magnitude-wise on either purposeful targeting or detargeting to any of the novel capsids. Competitive, but not different.”

Startups like Dyno Therapeutics, Solid Biosciences, Capsida Biotherapeutics, and Apertura Gene Therapy are all tinkering with AAVs, or adeno-associated viruses, to get beyond the liver. (Paulk sits on Dyno’s scientific advisory board.) Outside of AAVs, other startups focused on delivery include Aera Therapeutics, Ensoma, and ReCode Therapeutics.

Even as more startups take on delivery, Regeneron stands alone with its antibody idea. In a sign of its progress, its AAV-focused team has grown from the single digits about seven years ago to now several hundred people.

Outside experts repeatedly mentioned scaling up production as the key challenge to watch. Siren’s Paulk said manufacturing challenges have limited the idea’s potential for decades, as attaching antibodies can be inconsistent and finicky. Paulk said Regeneron would need to have a production trick up its sleeve to address those challenges.

“Every lot becomes a snowflake, and that becomes a challenge for the FDA,” Paulk said. “I don’t see a way this moves forward. I hope I’m dead wrong.”

David Schaffer, a bioengineering researcher at UC Berkeley, called Regeneron’s results “interesting” but noted in an email it may be “technically challenging to scale reproducibly and robustly.”

Regeneron’s leaders said they are confident in meeting that challenge. Kyratsous said they are advancing two methods of attaching antibodies to viruses, adding they’ve seen consistent results in scaling both ideas so far.

“We don’t want to over-engineer something and make something that is very cool on paper or works very well in small animal models, and you cannot scale it up for human use,” he added.

Regeneron’s leaders pointed to their experience in mass-producing antibodies and the expanding AAV team.

“We’re moving toward clinical-scale virus production,” said Leah Sabin, executive director of Regeneron’s genetic medicines unit.

Sabin said they are debating what muscle diseases to prioritize for the clinic, while a brain-targeting program is now being tested in non-human primates. The team is already mulling what tissues to target next.

“The current capsids are not good enough,” Sabin said. “They’re fine, but what would be industry-altering is having this completely new, way more efficient way to get them there.”

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