Outfoxing pathways of pain 'COX-2' drugs are easier on stomach
US News - Science & Ideas 12/14/98
MEDICINE
BY SUSAN BRINK
It was a vote with resonance from Wall Street to the
homes of America's 23 million arthritis sufferers.
Last week, in a stuffy hotel ballroom in Silver
Spring, Md., the Food and Drug Administration's
arthritis advisory committee's nine members
unanimously recommended approval of Celebrex,
G. D. Searle & Co.'s new arthritis drug. Those in
the standing-room-only crowd of more than 300
industry scientists and market analysts stood up to
watch the show of hands, and many reached for
their cell phones the minute the vote was tallied to
capitalize on the news. This is a nearly $2
billion-a-year market they're talking about.
But one arthritis-care expert remains skeptical. As
a rheumatologist and spokesman for the Arthritis
Foundation, Doyt Conn is as eager as anyone to
see arthritis sufferers spring from their rocking
chairs. But he says "time will tell" whether
celecoxib, a new class of drug, to which Celebrex
belongs, that targets arthritis inflammation and pain
with fewer side effects, is worth the hoopla.
Conn's concern is that the drug, while it has been
tested in more than 14,000 people (about 10 times
more than typically submitted to the Food and Drug
Administration, though no single patient has taken
it for longer than about a year), may present
unexpected side effects when used by millions for
many years. "There's no reason to expect them to
be any better than what we've already got. But
there's good reason to hope they're safer," Conn
said.
Bad enzyme. Doctors have long known that
nonsteroidal anti-inflammatory drugs, or NSAIDs,
can relieve arthritis pain by blocking production of
cycloöxygenase, or COX for short, an enzyme that
helps make prostaglandins, the substance largely
responsible for the pain and inflammation of
arthritis. Philip Needleman, then chair of the
pharmacology department at Washington University
in St. Louis, was instrumental in figuring out in the
1980s that two enzymes help make prostaglandins,
dubbed COX-1 and COX-2, and that COX-2 was the
driver of the disease's symptoms. Needleman
moved to Monsanto Corp., parent company of
Searle, and, with an army of chemists, began
working on a theory of "good enzyme, bad
enzyme," to develop a drug that targets only
COX-2. It doesn't affect COX-1, which protects the
digestive system from its own erosive acids.
Therein lies the benefit of COX-2 inhibitors: They
ease pain just like common NSAIDs, including
aspirin and ibuprofen, but without interfering with
COX-1, thus reducing the risks of serious side
effects like bleeding ulcers. About 107,000 people
are hospitalized each year for upper gastrointestinal
complications resulting from NSAID use; 16,500 of
them die.
The theory that COX-2 inhibitors don't interfere with
COX-1's stomach-protecting ability has proved
largely true. But competitors of Searle, including
Robert Palmer, group director of rheumatology
clinical research and development for SmithKline
Beecham, are eager to articulate the complications.
Palmer points to a growing body of research that
suggests that COX-1 and COX-2 may have
overlapping functions and that neither is purely
"good" or "bad." The FDA advisory committee urged
that the drug's label warn of potential harm to the
stomach and intestines, even though the risk is
likely to be smaller than that of available arthritis
drugs.
Celebrex awaits final FDA approval, likely by
year-end. (Merck & Co. is close behind with Vioxx,
a similar drug.) Celebrex will treat both
osteoarthritis, which affects some 21 million people
and results from wear and tear on the joints, and
rheumatoid arthritis, an autoimmune disorder that
affects about 2 million people.
Needleman, now co-president of Searle and chief
scientist at Monsanto, is a rare scientist who has
seen an idea through, from tissue in a petri dish to
the imminent prospect of a new drug on the
pharmacy shelf. "In science, a hypothesis is
something you usually throw away," he said. "This
one didn't melt."
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