Merck's Testing Of New Antidepressant Sets Off Scramble With Others
August 13, 1998 12:06 AM
By Robert Langreth, Staff Reporter of The Wall Street
Journal
For much of this century, scientists trying to unlock the
mysteries of the human mind have struggled to
understand the function of a brain chemical known as
Substance P.
It has been suspected of playing a critical role in
conditions ranging from pain to psychosis. Those
hypotheses have remained unproved, but researchers at
Merck & Co. believe they have one confirmed:
Substance P regulates depression.
Substance P first surfaced in 1931, when Swedish
researchers stumbled upon an unfamiliar chemical in the
brains and gastrointestinal tracts of horses. They purified
the substance into a powder (one possible source of the
"P" in its name) and found one of its properties was to
cause muscles to contract. In later decades, scientists
found Substance P concentrated in many areas of the
brains and spines of laboratory animals.
More recent research has hinted that a drug capable of
blocking Substance P might treat a range of conditions
-- chronic pain, migraine headaches, anxiety, asthma --
and perhaps even help poor sleep cycles. But one by
one, almost all the resulting experimental drugs have
failed to work, leaving Substance P's real function more
mysterious than ever.
Following a quiet breakthrough last year, Merck
researchers are moving into late-stage human testing of
antidepressant drugs that work by blocking Substance
P. Early word from scientific meetings about Merck's
progress has set off a race among other big
pharmaceuticals makers engaged in Substance-P drug
research. Companies including Pfizer Inc., Novartis AG,
and Eli Lilly & Co. are retooling research to begin
clinical trials in depression.
An estimated 20% of the nation's 17 million people
suffering from depression aren't helped by such mainstay
treatments as Prozac and Zoloft. The race to test
substance-P drugs could lead to an entirely new
category of antidepressants that could bring relief to
these patients. Substance P research is also important to
the millions more patients who suffer side effects such as
reduced sexual desire, heightened anxiety and insomnia
from existing depression drugs and eventually quit taking
them.
Scientists caution that large-scale tests to confirm the
promise of Substance-P drugs could take at least two
years. But if Merck's new drug works as hoped, it could
shake-up the more than $7 billion market for
antidepressants by introducing a whole new type of
drug.
Merck won't comment on the research findings until they
are published. A major scientific journal is expected to
publish them in the next few weeks.
Substance P is one of several dozen brain chemicals, or
neurotransmitters, that relay signals between brain cells.
Today's top-selling antidepressants work largely by
targeting the neurotransmitter serotonin, which is at
lower-than-normal levels in the brains of many
depressed people. These popular drugs, "serotonin
reuptake inhibitors," boost serotonin levels in key parts
of the brain.
Merck's new drug works by a completely new
mechanism -- inactivating receptors for Substance P.
"It's potentially an extremely important advance," says
Solomon Snyder, a prominent neuroscientist at Johns
Hopkins University, in Baltimore. "To have something
totally new . . . might allow us to attack depression in
two different ways. People who don't respond to Prozac
might respond to this."
Merck is so high on the experimental medication --
code-named MK-869 -- that it is planning further tests
of it for anxiety disorders, manic depression and
schizophrenia. At investor meetings, Merck research
chief Edward Scolnick publicly has proclaimed the
Substance P drug "a breakthrough discovery" in mental
health.
As early as the 1950s, scientists theorized that
Substance P was a neurotransmitter and might therefore
make a good target for drugs influencing pain. In 1970,
an American biologist, Susan Leeman, unraveled the
mystery material's chemical structure almost by accident.
While searching for other brain chemicals, she had
noticed one substance made laboratory rats salivate
excessively. It turned out to be Substance P.
After years of study, she revealed its chemical structure,
making it possible to produce quantities of Substance P
and conduct detailed studies of it for the first time. Next
came an explosion of research to find a chemical to
block Substance P's receptors in the brain.
Substance P was soon a suspect in ailments from
arthritis to schizophrenia. Because so much research
seemed to indicate Substance P played a critical role in
carrying pain signals, myriad teams hoped it was the key
to creating powerful new painkillers. But those hopes
fizzled as numerous efforts utterly failed to demonstrate
any painkilling effects from blocking Substance P.
"Substance P was considered a neurotransmitter in
search of a disease. People have been searching for a
way to make it relevant," says Alan Metz, Glaxo
Wellcome PLC's director of medical affairs for the
central nervous system. Glaxo has developed
experimental drugs for treating nausea and other
conditions by blocking Substance P and now also is
looking at depression.
"Our hope is these drugs will have a faster onset of
action than existing drugs," which often take several
weeks to kick in, says Joerg Reinhardt, head of
preclinical development for Novartis. Researchers there
had been studying a Substance-P blocker to treat
patients with social phobia, and have broadened their
work to include depression, too.
All along there were hints Substance P might be involved
in regulating mood. But the evidence was sketchy
compared with the vast body of literature on pain, so the
mood angle was mostly ignored.
By the mid-1990s, though, Merck had conducted
human trials of Substance-P blockers to treat pain and
migraine headaches -- and come up with no sign that
they were effective. As officials at Merck's neuroscience
research center in England were puzzling over what
direction to take next, a pharmacologist there, Nadia
Rupniak, pursued the mood effects of Substance P.
Her laboratory's findings surprised everyone. In one
experiment, when Substance P was delivered to the
brains of guinea pigs, it made them cry out, a sign of
stress or alarm. When the animals got one of Merck's
Substance-P blockers, the stress response was
reversed. Because stressful events are closely linked to
the onset of depression, the results suggested to Dr.
Rupniak that drugs aimed at Substance P might have
powerful mood-altering effects.
Although some officials were skeptical, Merck decided
to proceed with a trial comparing MK-869 with Paxil, a
Prozac-style antidepressant, and with a placebo. The
test, involving three groups of patients totaling 210
people, yielded more significant results than anyone had
anticipated. Depressed patients who received MK-869
for six weeks experienced at least as much relief as
those who received the standard drug -- but with
significantly fewer side-effects.
"These results are an extraordinary surprise," says
Steven Hyman, director of the National Institute for
Mental Health in Bethesda, Md. "I'm usually a skeptic
about new treatments, but this data looks very
promising. If it holds up, it gives researchers a whole
new target for developing depression treatments."
Because it is concentrated in areas of the brain that help
regulate emotion, some researchers believe Substance P
might be transmitting signals for mental anguish rather
than for physical pain.
"The Merck finding will stimulate a whole new avenue of
research into understanding the biology of depression,"
says James Krause, a Substance-P expert at the
Branford, Conn., biotech company Neurogen Corp. "It
shows how years of basic research can pay off."
Copyright (c) 1998 Dow Jones & Company, Inc.
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