Regeneron's current success is due in large part to the persistent development of new tools, which enabled the company to
build on the failure of nerve growth factors as products, without starting over from scratch. The technology narrative also
illustrates the company's approach to drug discovery, which is to begin with an important biological insight, and to develop
technologies that can address those insights with drugs to cure disease.
In the beginning, Yancopoulos and his team developed cloning technologies to study orphan receptors on the surface of cells,
to identify the factors that bind to them. Once those factors are identified, they can be studied to uncover their biologic
function. This process led to Regeneron's first clinical candidates, the nerve growth factors.
While working on the nerve growth factors, Regeneron's scientists discovered a way to engineer a new kind of blocker, which
would "trap" specific signaling proteins in the body, and prevent them from binding to their natural receptors. At the same
time, Dan Kastner at the NIH, and Harold Hoffman, at the University of California, San Diego, were studying patients that
presented flu-like symptoms—and sometimes more severe symptoms like hearing loss or nerve damage—as a result of mild temperature
change. The disorder, called cryopyrin-associated autoinflammatory syndrome (CAPS), is hereditary, and Kastner and Hoffman
were involved in mapping the gene that caused it, according to Yancopoulos.
Kastner and Hoffman's research pointed to a genetic mutation that caused an excess of interleukin-1. Regeneron was in the
early stages of developing its VelociGene platform, which allowed Yancopoulos and his team to put human genetic mutations
into mice, to reproduce the disease. Through a collaboration with Kastner and Hoffman, Regeneron tested the genetic theory
by creating mice with CAPS, and then treating them with an interleukin-1 "trap." The mice were cured, which gave Regeneron
the confidence to do clinical studies in human patients with CAPS. The result was Arcalyst (rilonacept), the first drug on
the market to treat the condition. Patients with CAPS have to keep taking Arcalyst, but it's curative, or nearly so; it decreases
patients' symptoms by 80 to 90 percent, says Yancopoulos.
There aren't many patients with CAPS, only a few hundred in the United States, and the drug isn't considered a huge commercial
success. But for Yancopoulos, it was incredibly satisfying. After meeting with patients who'd been cured by the drug, "that
alone, if we hadn't made a nickel, is more gratifying than anything that most people could ever do in academia," he said.
Yancoupolos credits "a think tank of key people" at the company, including Neil Stahl, Drew Murphy, Aris Economides, Sam Davis,
Nick Papadopoulos and "a slew of others" with bringing the Trap technology forward. One of the Traps became Eylea, a blockbuster
eye treatment indicated for wet age-related macular degeneration. Another became Zaltrap, for metastatic colorectal cancer.
Those two products transformed Regeneron, and provided a first real taste of the commercial side of the drug business, after
20-plus years of waiting for a breakthrough.