[Paleopsych] Slate: Someday, There Will Be a Fat Pill

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Someday, There Will Be a Fat Pill
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The science of hunger management.

By Amanda Schaffer

Posted Tuesday, April 26, 2005, at 1:32 AM PT

Last week, the USDA cast aside its iconic food pyramid for a new design,
with color-coded wedges and a stair-climbing stick figure, which was
greeted with mostly mediocre reviews. The graphics still don't tell
people to avoid junk food, the most obvious factor contributing to
national chub. As McDonald's celebrated its 50th birthday with 50-cent
cheeseburgers and Domino's promoted a new cheeseburger pizza with the
help of Donald Trump, government regulators looked like small fries, as
usual.

Fortunately, the scientists and drug developers working on appetite and
weight loss are better at what they do. As any dieter knows, it is
amazingly difficult to trick the body into shedding pounds. From an
evolutionary perspective, we have adapted to gorge and store energy in
case of famine, not to negotiate a world filled with deep-fried Snickers
bars. The molecular pathways that mediate eating urges are cunningly
intertwined, with one ready to take over when another is thwarted.
Efforts to suppress hunger or promote weight loss with drugs have ranged
from not particularly effective (Meridia) to downright disastrous
(fen-phen). Still, the list of candidate molecules that may someday
prove useful as hunger-curbing and fat-fighting drugs is growing
rapidly, and researchers these days dare to get their hopes up-a little.
Even if obesity doesn't cause as many deaths as it used to, because of
better treatments for heart disease and other related ailments, there
will be plenty of reason to cheer if a safe fat pill is somewhere on the
horizon.

Much of the science of hunger centers on the hypothalamus. Since it's
the area of the brain that regulates appetite along with other visceral
urges, it's where some researchers are focusing their energies. But
eating is also bound up in brain pathways that mediate pleasure and
emotional reward. We eat in part because food is delicious. We eat more
when with friends and when larger portions are put in front of us, or
sometimes to comfort ourselves when we feel bad. Given all these
signals, some researchers have chosen to steer clear of the brain's
complexities and turn their attention to fighting fat in the digestive
tract or the belly. Here's a roundup of the latest scientific approaches
to suppressing appetite and promoting weight loss, ranked on a scale of
1 to 10 (from lowest to highest) for potential promise and potential
downside.

Strategy No. 1: Stimulate brain pathways that decrease appetite.

Leptin. Potential promise: 1. Potential downside: 2.
High levels of the hormone leptin, which is released by fat cells, tell
the brain that the body's reserves are already ample. In 1994,
researchers at Rockefeller University found that mice lacking normal
supplies of leptin became obese. The biotech company Amgen bet at least
$20 million-unwisely-on the hope that leptin could be given to
overweight people to help them to eat less. As further research showed,
most obese people already have high levels of the hormone; the problem
is that their brains are resistant to its appetite-blunting message. The
main contribution of leptin-inspired research was to kick off a new era
in the basic science of hunger and a surge of interest in other possibly
druggable targets in the hypothalamus.

Melanocortin-4 receptor agonists. Potential promise: 4. Potential
downside: 5.
One of those targets is the melanocortin-4 receptor, which helps to pass
along the eat-less message that leptin sends to the brain.
Unfortunately, drug compounds that bind to and stimulate this receptor
also tend to give men unwanted and sometimes painful erections. And
molecules in the same chemical family, called melanocortins, make skin
darker. So as one researcher joked, drugs aimed at the melanocortin-4
receptor (called agonists) could make men "thin, tan and horny." Which
might be less pleasant than it sounds.

Serotonin receptor agonists. Potential promise: 6. Potential downside:
9.
Drugs that bind to certain serotonin receptors (which transmit their
message through the brain's melanocortin system, much as leptin does)
are known to suppress appetite. But they can also have unwanted side
effects for the heart. Fen-phen, which caused cardiac valve disease in
some patients, is a case in point. Now Arena Pharmaceuticals is wagering
that a more selective molecule, which acts on one subtype of serotonin
receptor, may yield the benefits of weight loss without the heartache.
The company's candidate compound, known as APD356, is in Phase 2
clinical trials. Since cardiac ills sometimes do not appear for years,
it will take a while to know whether Arena has a winner.

PYY. Potential promise: 7. Potential downside: 3.
Another molecule that has lately made the rounds is a modified version
of the gut hormone, PYY, also an appetite suppressor. Since PYY is a
naturally occurring signal from gut to brain, some researchers believe
it is likely to make a safe drug. PYY cannot be taken orally because it
is a peptide and so would be digested by the stomach and in the process
made useless. Nastech Pharmaceutical Co. has formulated it as a nasal
spray, however. The company's product, PYY 3-36, is entering Phase 2
trials.*

Strategy No. 2: Inhibit brain pathways that make people feel hungry.

Ghrelin blockers. Potential promise: 7. Potential downside: too soon to
say.
The discovery that a gut hormone called ghrelin (rhymes with gremlin)
may be the cause of pre-meal hunger pangs has been one of the most
exciting of the past few years. A drug that blocked ghrelin might well
dampen appetite, and since ghrelin levels rise markedly when dieters
begin to shed pounds, might be particularly useful as a means to prevent
rebounding. One reason gastric-bypass surgery seems to be so effective
in keeping people thin is that the procedure cuts down on the amount of
ghrelin released from the stomach.

Cannabinoid receptor antagonists. Potential promise: 8. Potential
downside: 4.
Everyone knows that smoking pot gives people the munchies. Now
Sanofi-Aventis has a product called rimonabant in late-stage clinical
trials that's designed to decrease appetite by blocking the same brain
receptors that marijuana stimulates. In addition to causing weight loss,
rimonabant seems to increase patients' levels of HDLs or "good
cholesterol" and decrease their insulin resistance, bonuses for staving
off heart disease and diabetes. A concern, though, is that by blocking
pathways that also mediate pleasure, the drug might have a negative
effect on mood. So far, at least, the clinical trials haven't borne this
out.

Strategy No. 3: Forget the brain. Prevent the body from digesting fat.

Drugs that block digestion. Potential promise: 8. Potential downside: 4.
Since the fat we eat must be broken down and absorbed in the small
intestine in order to affect weight, Roche's Xenical, which blocks the
digestion of fat, is relatively effective in helping people to shed
pounds. Experimental compounds from Peptimmune and Genzyme as well as
others also aim to block fat digestion. The downside is that undigested
fat causes diarrhea, flatulence, and other unpleasantness.

Strategy No. 4: Target fat cells directly.

Drugs that attack fat. Potential promise: 9. Potential downside: too
soon to say.
To attack fat itself-the number of fat cells and the amount of fat
within them-researchers at AdipoGenix are exploring compounds that could
arrest the development of these cells. They are also investigating ways
to block the formation of triglycerides, to hasten their breakdown, or
to stimulate the burning of blubber in general. AdipoGenix has a
research advantage: a hefty supply of human fat-acquired through special
agreements with surgeons at Boston Medical Center and their patients,
many of whom have undergone gastric bypass surgery-on which to test
potential fat-busting candidates. (In the past, compounds that
stimulated the breakdown of fat in rodents have failed to work in
humans.) The company is currently screening compounds for phase-one
trials; and while it's too early to know for sure, its approach is
highly promising.

The quest for fat-fighting drugs is not a winner-take-all competition.
More than one drug compound will be needed; and many patients will end
up taking a combination of different pills or sprays. The big shift is
toward thinking about obesity in most cases as a problem that must be
managed over time, rather than cured. This raises the bar in terms of
safety, since drugs that are taken for years must be scrutinized more
carefully for long-term effects. It also aligns with pharma's general
preference for endlessly refillable prescriptions. With the possible
exception of rimonabant, as well as Meridia and Xenical, these products
won't be available for years. But when they are, a lot more dieters may
become pill poppers, for better or worse.