Follow the Science
Without a doubt, Gleevec (imitanib) is the Excalibur of the Vasella mythology. Without that "magic cancer bullet," he would
be, at best, CEO of a very successful, highly diversified pharma—not a radical redesigner of R&D or a hero to CML patients.
Gleevec is the ultimate in rational drug design. Once the genetic mutation associated with CML was fingered, Novartis began
screening tyrosine kinase inhibitors until they got a hit in 1999. In early human trials, the drug produced sudden, near-total
remission with minimal toxicity. There remained only one hurdle: The commercial forces inside Novartis "argued against rushing
and taking risks for a drug that would produce such little return on investment," according to Vasella
The good doctor, of course, prescribed taking risks. Recognizing that if word got out, armies of patients and their advocates
would demand the cure, he put the manufacturing of imitanib on fast-forward. After three short-term, early-stage trials FDA
sent it to market. Since then, Gleevec's label has been expanded to include GIST and other cancers. In the first half of 2009,
it garnered nearly $2 billion in global sales. Last month, the scientists who discovered Gleevec were awarded the 2009 Lasker
Award for clinical medical research.
Vasella seems to have embraced the Gleevec moral ("follow the science") like a true believer. In the boldest gamble of his
career, in 2002 he moved Novartis global R&D headquarters from Basel to Cambridge, MA, investing $4 billion in a new Institute
for Biomedical Research and hiring Mark Fishman—the Harvard cardiologist who decoded the zebrafish genome—to lead the company
into the translational-medicine future Gleevec had augured.
Refocusing R&D was not an entirely novel notion—GSK was unveiling its Centers for Excellence—nor were biologics completely
off Big Pharma's radar. Yet the idea of staking the company's future pharma business on an academic outsider, an untested
model of drug discovery, in the Harvard-MIT biocluster made some wonder whether Vasella was crazy like a fox or just plain
crazy. The kicker? "'And we won't even know if it works for another decade,'" Vasella says he told the board.
Russ Somma, who worked 30 years at Ciba and Novartis, helping to develop Gleevec, recalls: "Back in 2001, the Novartis pipeline
definitely needed work, so moving the early-development stuff to Cambridge made sense. But translational medicine, genomics,
biomarkers? There were plenty of people who thought Vasella was just blinded by the 'Gee-whiz!' factor'."
Says Jeff Elton: "It was a time when the industry was pulling in double-digit margins with primary-care blockbusters, so
the argument was against taking risks, let alone embracing a new paradigm. All credit to Vasella, but also to his team and
to the board, too, for trusting in his vision."
Eric Lander, director of the Whitehead Institute-MIT Center for Genome Research, told The New York Times in 2003 that it was a "watershed move that sent tremors through the pharmaceutical industry. This move says that the lifeblood
of the industry is changing from chemistry to molecular biology, from art to engineering."
For Fishman, molecular pathways were the holy grail, the "missing grammar," compared to which the genome's 22,000 genes are
merely words without sense. And his model makes sense: "Take rare diseases and use them as an entrance to more common ones—wherever
science is strong and disease mechanisms are understood, we'll be able to make progress quite quickly," Fishman said in 2004.
In June, after a five-year wait, Fishman's first compound, Ilaris (canakinumab), won FDA approval for cryopyrin-associated
periodic syndrome (CAPS), a rare inflammatory disorder caused by a single gene mutation that causes the overproduction of
IL-1. Like Gleevec, its targeted gene-specific mechanism provides stunning efficacy. "All you have to do is touch a patient
with the medicine, and the symptoms start to disappear," says Hal Hoffman, associate professor of medicine at the University
of California, San Diego.
Still, the drug lay in limbo for 18 months. With the means to chemically control the expression of IL-2, an inflammatory protein
involved in some 30 diseases, there was confusion about where to start. "It got completely bogged down in these debates around
value that have paralyzed drug companies for years," says Trevor Mundel, Novartis' global head of development. Once again,
Vasella rode to the rescue—or so the PR goes.
Whether or not Ilaris will validate the translational-medicine concept remains to be seen. As a treatment for CAPS, it's a
slam dunk. But CAPS is an ultra-rare disorder, and rarely fatal; nor is it an unmet medical need, since Regeneron has a rival
drug carrying an annual price tag of $250,000. To pay its way, canakinumab will have to prove effective against bigger diseases,
and Novartis is rolling out tests in gout, juvenile rheumatoid arthritis, diabetes, and respiratory disease—whose causes are
far more complex than the single-gene target.
Elton points out that Ilaris is only one drug, while the number of compounds that have moved from discovery to the clinic
increased nearly 50 percent from 2004 to 2008. "A Phase II/III bottleneck" is how Mundel described the fruits of Fishman's
R&D. The current Novartis pipeline does reflect a possible bottleneck—17 NMEs to be submitted in 2012 and beyond, but mainly
in common cardiovascular or oncology indications, not rare diseases.
For now, most analysts give Novartis the benefit of the doubt "Every Big Pharma has been looking for the magic bullet for
R&D innovation. Vasella picked this early on, and took a big gamble. In a few years, if we don't see a bunch of compounds,
it may look like the bet didn't pay off," says Miller Tabak's Les Funtleyder.