From traps to antibodies
Despite Regeneron's success with the Traps—Zaltrap pricing snafu notwithstanding—Yancopoulos wasn't satisfied. The VelociGene
technology allows researchers to manipulate the mouse genome at high-throughput speeds, and the VelociMouse technology expedited
the generation of genetically engineered mice, using embryonic stem cells, to research the function of single genes. In 2006,
the NIH selected the VelociGene platform as the anchor of its Knockout Mouse Project, who's mission was to target some 3,500
genes, one at a time, to understand their biological function and relationship to specific disease.
But those technologies, despite improving significantly on the state-of-the-art, and enabling the development of the Trap
products, still had limitations. So Yancopoulos and his team invented the VelocImmune technology to create fully human monoclonal
antibodies. The VelocImmune mouse is an elegant solution to problems with creating antibodies, in that it enlists the mouse's
immune system in selecting the best antibody, in vivo. When the molecules are cloned out of the mouse, they're optimized for
humans because "we replaced six million base pairs inside the mouse DNA, with human DNA, to allow the mouse to make antibodies
that would be fully human...but selected by the mouse to bind to the target," explains Stahl. The difference between "humanized"
and "fully human" antibodies in this context is that with "humanized" antibodies, "they still have in the range of three to
five percent mouse DNA and mouse protein," says Stahl. "Whereas ours are fully human because we took the entire human genomic
region encoding the target binding variable domains of the antibodies and put it into a mouse; there's only human sequence
there, and no mouse sequence."
Regeneron's newest platform technology for creating fully-human monoclonal antibodies led to its biggest deal to date. The
collaboration, again with Sanofi, was first signed in 2007, and essentially pays Regeneron to continue its research on monoclonal
antibodies, and test them in the clinic. In 2009, the collaboration was expanded to provide $160 million a year, for seven
years, including another $30 million for manufacturing expansion costs in Rensselaer. In return, Sanofi has the right to co-develop
and license promising antibodies, on a 50/50, profit-sharing basis, globally.
Several of these antibodies have already reached Phase III trials. Alirocumab, an antibody targeting PCSK9—"the biggest target
in cardiology right now," according to Stahl—is the closest antibody to market, according to Michael Aberman, Regeneron's
VP of strategy and investor relations. Like the orphan drug Arcalyst, the idea for PCSK9 followed a biological insight from
academia; a study published by Helen Hobbs in the New England Journal of Medicine linked a genetic mutation to very low cholesterol levels. Aberman says he expects alirocumab to launch in 2016, and sarilumab,
a Phase III drug for rheumatoid arthritis, around the same time, followed by dupilumab, for asthma, soon after. Regeneron
has entered clinical trials with over a dozen antibodies already. The company's next stage of growth depends on the VelocImmune
platform, the latest iteration of Regeneron's self-made technology.
The object lesson: break the creative paradox
There's a paradox inherent to any creative pursuit that depends on generating a commercial return: if the primary objective
is to make money, then creativity is constrained by narrow, prescriptive pathways proven to meet that objective. On the other
hand, creativity allowed to flourish in a vacuum, unencumbered by a sense of market need, usually leads to failure—it may
be spectacular or brilliant, but it's a failure nonetheless.
No one understands the commercial imperative more than two New Yorkers like Schleifer and Yancopoulos. Even though Schleifer
says "science and innovation is probably more important than the business side of things," he knows the science can't proceed
without the business. Regeneron's science is succeeding over the long term, because Schleifer gave it time to grow; he didn't
fret over short-term failures, because he was confident in Yancopoulos, and in himself, and he wanted to build a business,
not create a flash-in-the-pan payday. "To be successful, continually successful, you have to be investing in the near-, mid-,
and long-term constantly," says Schleifer. "Companies rot when senior management no longer cares about the long term."
Yancopoulos, in choosing a career in industry over academia, brought the best aspects of the latter to bear on the former.
Too much focus and constraint in R&D is "anti-science and anti-biology...it goes against how things work," he says. Scientific
discovery is tangential; it's the side path that brings you, unexpectedly, out into a beautiful vista, says Yancopoulos. "That's
why there's so much failure [in R&D], because the straight path doesn't lead you to success."
In May, Regeneron bought back the rights to two novel ophthalmology antibodies it invented, from Sanofi. They paid a combined
$20 million upfront, and will pay a combined $45 million in milestones, if the PDGF and ANG2 ophthalmology indications succeed
in the clinic. "If we execute on our goals, if we are successful with what we want to achieve with PCSK9, if we're successful
with our IL-4 and our IL-6 receptor antibodies, and if Eylea delivers what we hope it can deliver, then I believe we will
have a good stock performance," says Aberman. "There are all kinds of risks associated with that, but it's a thesis you can
hang your hat on." If those plans don't work out, Schleifer and Yancopoulos are confident that something else will.
Ben Comer is Pharm Exec's Senior Editor. He can be reached at email@example.com