From Free Time to First in Class
Enter a new company. Genentech was founded in 1976, five years after Folkman published his paper, with a commitment to commercializing
the then-emerging field of biotechnology, whose novelty demanded a tolerance for diversity against the conventional wisdom
of academic medicine. Genentech built a corporate culture around that necessity, and Avastin was among the first to deliver
A key element of that culture was the freedom given to Genentech scientists to pursue their own research interests, often
on company time. Napoleone Ferrara, an Italian-born physician hired by Genentech in 1988 to help develop a new pregnancy drug,
took advantage of that policy to build on previous work he had conducted on cancer formation at the University of California
San Francisco. Specifically, he began tests on how developing an antibody to VEGF could shut down blood vessel formation and
starve cancerous tumors of the nutrients they needed to grow. His off-hours work led to a successful cloning of the VEGF gene;
in 1993, in a peer-review paper published in Nature, he mapped the contours of a monoclonal antibody for VEGF and presented a preclinical model that demonstrated the antibody
could suppress angiogenesis and tumor growth.
Angiogenesis: The Aspirin Cure?
Four more years of study and testing followed, and in 1997 Genentech filed an IND for the antibody it called Avastin. Another
seven years of human tests went by before the drug secured its first FDA approval in February 2004. In authorizing Avastin,
then-FDA Commissioner Mark McLellan praised it as evidence of "the progress of biopharmaceutical innovation. "
Genentech points to the years of study as the embodiment of its distinct mission to focus on new science, with a high tolerance
for taking big bets around new pathways for attacking the biological roots of disease. Philippe Bishop, Roche/Genentech's
vice president of clinical development for Avastin, told Pharm Exec: "This work shows how individual drive and focused community support can transform a pioneering vision into a useful, life-saving
drug. Folkman and Ferrara's insights into the biology of cancer growth would have lain dormant had Genentech not had the organizational
courage to take this project on and persevere over the eight years it took to prepare the initial IND and create the molecular
basis for an approvable drug."
Managing Risk: Data is Destiny
Genentech took considerable risk early on in amassing the data required to pass FDA muster. The company invested heavily in
Phase II trials for Avastin, using randomized protocols to build more knowledge about the drug that could then be applied
to help structure the Phase III investigations. At the time, scientists at other companies avoided this approach because poor
or inconclusive results in Phase II might serve as a disincentive for management to allow promising projects to go forward.
Genentech, a company run by scientists, took the opposite view—whatever the results, big investments in Phase II could help
overcome the more significant hurdles likely to be encountered during Phase III, which is the essential test ground for commercialization.
This learn-as-you-go stance also helped Genentech manage the big safety risks in conducting the trials that led to FDA authorization
of Avastin against glioblastoma last year. "We knew that Avastin in combination with chemotherapy can cause hemorrhaging in
a few patients, and that one intracranial bleed in our human tests for glioblastoma could shut the whole program down," Bishop
says. Nevertheless, the company took the risk and leveraged hundreds of studies commissioned for other Avastin tumor types
to design appropriate controls for a Phase II study (AVF3708g), the results of which found no new safety signals to limit
the drug's use for this virulent form of brain cancer. The company is now conducting a larger Phase III trial to confirm and
extend the findings.
Maintaining Market Leadership
Genentech's decades-long commitment to cancer as a therapeutic target ensures that financial and human resources, other knowledge
assets and internal organizational structures are all aligned to mitigate the risk in translating innovative science into
commercial success. "It's vital in this increasingly crowded cancer field to have both focus and critical mass, and we have
it," contends John Orwin, svp in charge of sales and marketing for the company's BioOncology group. Orwin told Pharm Exec that the company has always invested in Avastin for the long term, with a particular emphasis on funding postmarketing approval
studies that carry end points meaningful to the patients who use the drug. "Good clinical data based on needs-relevant end
points is our best forum for promotion," he says.
Genentech's marketing for Avastin is geared to distinguishing the drug from "the clutter." The company runs a dedicated, technically
advanced sales force for Avastin that emphasizes specialized medical education and active interpretation of study results.
Commercial teams work closely with the trial investigator community, who serve as thought leaders on cancer and, as prescribers,
comprise a key part of the Avastin customer base.