Like several of its established oncology drugs, Pfizer acquired Sutent in the 2003 merger with Pharmacia. The company submitted
an NDA to FDA in August for GIST (gastrointestinal stromal tumors) but the range of off-label uses may be quite broad early
in the drug's lifecycle. Judah Folkman, MD, of Harvard's Children's Hospital, believes sunitinib will be used as a combination
agent with Genentech's Avastin. He also notes that adding it to Gleevec has reduced resistance to that drug.
"Sutent...certainly could be a billion-dollar drug," says Ryan. "I think Pfizer specifically is building a portfolio of oncology
drugs to complement that. We think over the next five years, that will be an important source of growth for Pfizer—that will
be one of the focal areas the company has."
Fresh Mechanisms to Fight Resistant Viruses
NEW HIV TARGETS
L 870810 integrase inhibitor by Merck
JTK 303 integrase inhibitor by Japan Tobacco
Maraviroc entry inhibitor by Pfizer
GW 873140 entry inhibitor by GlaxoSmithKline
Vicriviroc entry inhibitor by Schering-Plough
PA 457 maturation inhibitor by Panacos
The first quarter-century of AIDS therapy produced two main classes of drugs: reverse transcriptase inhibitors and protease
inhibitors. When the virus becomes resistant to these drugs, there are few options—one of which is a fusion inhibitor called
Fuzeon (enfuvirtide), discovered at Duke University, and launched by Roche and Trimeris two years ago.
But now three new types of AIDS drug are in clinical trials: integrase inhibitors, which interfere with an enzyme that allows
the virus to replicate and incorporate into the host DNA; CCR5 entry inhibitors, which keep the virus out of the host cell;
and a maturation inhibitor that prevents the precursor viral cells from becoming fully infectious viruses.
"The interesting thing about these drugs is that they act on entirely different targets than we have studied before," says
Martin S. Hirsch, MD, professor of medicine at Harvard, who saw his first AIDS patient in 1981. "What we basically have now
is a number of protease inhibitors and reverse transcriptase inhibitors, so everybody is interested when a new agent comes
along that gives us alternatives for resistant viruses."
Merck's L 870810 was the first integrase inhibitor, but since Merck established proof of concept last year, another half-dozen
companies have begun work on similar compounds. Japan Tobacco licensed JTK 303 (beginning Phase II trials) to Gilead Sciences
for milestone payments of up to $90 million plus royalties.
"Merck may be the first one out there with an integrase inhibitor, just like they were the first one out there with a protease
inhibitor," says Hirsch, who worked on the original AZT clinical trials. "But the others may turn out to be better."
Even more crowded is the field of entry inhibitors—so-called CCR5 antagonists that block the virus's access to the cell by
deforming a G-coupled protein receptor called CCR5 in the cell wall. Pfizer (maraviroc /UK 427857), GlaxoSmithKline (GW 873140),
and Schering-Plough (vicriviroc) are all running late-stage clinical trials. Meanwhile, companies have 18 other compounds
in preclinical development or early clinical trials. Clinicians are hopeful, but not all analysts believe the hype.
"These drugs are probably more important medical advances for patients than huge commercial opportunities," says Deutsche
Bank's Ryan. "The HIV market is one where discounting gets fairly aggressive."
Maturation inhibitor PA 457 inhibits HIV infection by targeting the process that produces mature, infectious virus particles
from infected cells. PA 457 has a distinct mechanism of action that targets a precursor protein in the virus's protective
coating and disrupts its conversion to the mature protein.