Drug firms, scientists go back to nature

[Guest guest]

Drug firms, scientists go back to nature

By PETER LANDERS, The Wall Street Journal

Tuesday, January 10, 2006 1:11 AM PST

http://www.napavalleyregister.com/articles/2006/01/10/business/storie

s_from_ap/iq_3247116.txt

TOKYO -- It took two years and thousands of moldy broths for Akira

Endo to find something that reduces cholesterol. His breakthrough,

drawn from a mold like one that grows on oranges, turned out to be

the first in a class of medicines that today bring $25 billion a

year to pharmaceutical companies.

Dr. Endo's 1973 discovery of the first anticholesterol statin has

been relegated to obscurity. Yet the feat spotlights a long-

denigrated craft now experiencing a revival: the discovery of drugs

from nature's treasure chest.

The fungal byproduct that Dr. Endo originally discovered shares the

same basic chemical structure as three of the biggest-selling

anticholesterol drugs: Zocor, Pravachol and Mevacor. Millions of

people have taken these drugs to lower their heart-attack risk.

" Whenever we have started with the natural molecule, we have been

building on three billion years of natural selection, " says Sir

Black, who developed the first beta blocker for heart

conditions and the antiulcer drug Tagamet at British pharmaceutical

companies in the 1960s and 1970s.

For much of the past 15 years, the pharmaceutical industry was " in

no mood to be sympathetic to these views, " says Sir , who is 81

and still active in drug discovery. Companies jumped on trendy areas

such as synthesizing and testing thousands of artificial chemicals

unknown in nature. More recently, they have tried to use the

decoding of the human genome to figure out the root causes of

diseases and discover cures.

For the most part, those efforts have yet to pan out. Just 20 new

drugs were approved by the U.S. Food and Drug Administration in

2005. Several top drug companies are facing flat revenue and

declining profits, including Pfizer Inc. and Merck & Co., the two

companies that have profited most from statins.

Many drug companies scaled down or eliminated divisions focusing on

natural products starting in the 1990s. In 2001, Merck closed its

natural-products drug discovery department, though it still does

some research in the area. In early 2003, Eli Lilly & Co.

transferred its library of natural products to a small company in

Albany, New York.

But now, in some corners, natural products are returning to fashion.

One of the biggest hopes for multiple-sclerosis patients, a Novartis

AG drug now in large clinical trials, is derived from a chemical

found by Japanese scientists in a fungus called the vegetable

cicada. Drugs derived from chemicals in sea squirts, Gila monsters

and vampire bats now are in large-scale testing or recently came on

the market.

" The ball is turning. What was fashionable in the past few years

hasn't delivered, " says Ian Paterson, a University of Cambridge

specialist in natural products who consults for drug companies. The

story of Dr. Endo's discovery shows the power of this approach and

how it led to one of medicine's biggest groups of blockbusters. It

also is a reminder that developing drugs was easier in a day when

there were fewer limits on testing in humans.

Dr. Endo, now 72 years old, was born on a farm in the snowy north of

Japan and recalls being taught by his grandfather about the fungi

that grew there. He was fascinated by one poisonous mushroom that

kills flies but not people, marveling that a natural substance could

have such a subtle effect.

He came of age in an era of excitement about revolutionary drugs

from natural products to treat infections. Penicillin, a chemical

produced by a mold to kill bacteria, was discovered accidentally by

Fleming in 1928. He had let lab plates containing bacteria

sit during a vacation. He returned to discover that mold had grown

in one plate and the mold had a bacteria-free area around it.

Penicillin was first mass-produced during World War II and has saved

millions of lives.

After the war a new miracle cure arrived, this time for

tuberculosis. The drug streptomycin was developed by Rutgers

University scientists who systematically examined microorganisms in

soil.

Dr. Endo joined the Tokyo pharmaceutical company Sankyo Co. after

college, researching food ingredients. He says he searched through

250 kinds of fungus to find one that produced an enzyme to make

fruit juice less pulpy. The product was a hit, and in 1966 the

company let Dr. Endo go to Albert Einstein College of Medicine in

New York to pursue his interest in cholesterol research.

At the time, cholesterol was a hot area for ambitious scientists and

the U.S. media was reporting evidence that it played a role in heart

disease. Dr. Endo says he was surprised to see the attention

Americans paid to diet. " I thought it was really strange that people

would cut off the fat before eating their steak, " he recalls. " This

was a culture shock, something inconceivable in Japan. "

There already were anticholesterol drugs, such as clofibrate, but

they had problematic side effects. Several companies had recognized

that blocking a crucial enzyme in the body's production of

cholesterol, called HMG CoA reductase, could be the key to a better

drug. But they couldn't find a substance with this mechanism that

worked in living animals, says Steinberg, an emeritus

professor at the University of California in San Diego who was

involved in early cholesterol research.

Dr. Endo, with his unusual background, hit upon an idea: Search for

something in fungi that would block the enzyme. He knew the

penicillin and streptomycin stories well, and in college he had

devoured a Japanese translation of a Fleming biography. Dr. Endo

knew that bacteria, like humans, need cholesterol to keep their cell

walls together. He reasoned that some fungus probably had evolved a

substance that would knock out the enzyme as a way of depriving

enemy bacteria of cholesterol and killing them.

Now it was a matter of finding the right fungus. Dr. Endo persuaded

Sankyo to give him help: Masao Kuroda, a chemist who had just joined

the company, and two lab assistants. In April 1971 they set to work,

brewing fungal broths and testing each for its ability to block the

enzyme, a supply of which they got from pulverized rat livers. " It

was a bet, just like the lottery, " Dr. Endo says.

For more than two years, he and his team worked into the night at

their lab next to a train depot in southern Tokyo. " We were doing

grunt work every day until we got sick of it, " he recalls. Some

chemicals blocked the enzyme well but were rejected because they

were toxic.

After testing 6,000 fungal broths, they found the right one in

August 1973. A substance made by a mold called Penicillium citrinum,

similar to the mold that grows on old oranges, produced a potent

inhibitor of the enzyme that helps the body make cholesterol. It was

the first statin.

Dr. Endo almost immediately ran into a problem: The substance, soon

to be dubbed compactin, barely worked in rats. Later research would

reveal that rats differ in how they make cholesterol, but Dr. Endo

was stymied until he happened to meet a colleague at a hangout near

the labs one night. The colleague offered some hens for testing,

saying they were about to be destroyed. The substance worked in hens.

The scientific successes were followed by dissension among Dr. Endo

and his colleagues. As he tells it, Sankyo's brass was

unenthusiastic about his discovery because there was no precedent

for it. They preferred to develop refinements of then-existing

cholesterol drugs, he says. A Sankyo spokesman says it is common for

a company to hedge its bets by pursuing research on multiple tracks.

With the support only of his boss at the research labs, Dr. Endo

embarked on a secret experiment at Osaka University. A doctor at the

university hospital named Akira Yamamoto was treating patients who

had extremely high cholesterol because of a genetic defect. Dr. Endo

recalls phoning Dr. Yamamoto from home at night so colleagues didn't

learn about the experiment. He personally prepared the samples of

the drug and carried them to Osaka. Nowadays such a trial would

require permission from the Japanese equivalent of the FDA, but that

step wasn't necessary at the time.

The first patient in the world to receive a statin, an 18-year-old

woman, also was the first to suffer a side effect that occasionally

occurs with statins: muscle pain. Because Dr. Yamamoto had given her

an extremely high dose, she became so weak she was unable to walk.

Dr. Yamamoto says his boss at the university advised him to halt the

tests.

Dr. Yamamoto insisted on carrying on. He discontinued the drug on

the first patient, and she recovered. He tried compactin on other

patients in lower doses. It succeeded in lowering cholesterol in

nine patients by an average of 27 percent, according to a paper he

later published. Dr. Yamamoto concedes he didn't give the patients

much information about the treatment he was testing on them. " They

trusted me, and I think I responded to that trust, " he says.

The first patient later was treated with other drugs, had a daughter

and still is living today in southern Japan, according to Dr.

Yamamoto, who showed a picture of her but declined to disclose her

name.

When Sankyo saw Dr. Yamamoto's results, it agreed to put Dr. Endo's

drug in formal clinical testing. Dr. Endo figured he had brought it

as far as he could, and decided to quit Sankyo for a professor's

post at Tokyo Noko University. It wasn't a friendly parting: Dr.

Endo still complains that the company ordered the scientists in his

lab not to help him carry his boxes of papers to the moving truck.

Sankyo wasn't the only company working on statins, because it had

inadvertently helped a competitor, Merck. In a one-page 1976

agreement, Sankyo granted Merck access to its data and methods

connected with Dr. Endo's statin. Companies often release such

information to potential business partners, but this agreement left

a gaping hole: Merck didn't owe Sankyo anything if it found the same

anticholesterol properties in another fungal byproduct.

Sure enough, in 1978 Merck discovered in a different fungus a

substance that was nearly identical to Dr. Endo's, this one called

lovastatin. Dr. Endo says he also discovered this substance

independently, during his first months at Tokyo Noko University.

Merck held the rights in the U.S., and in 1987 began marketing it in

the U.S. as Mevacor -- the first FDA-approved statin.

Sankyo eventually gave up on compactin and pursued studies of

another statin with a similar chemical structure, which it licensed

to Bristol-Myers Squibb Co. Bristol-Myers began selling it in the

U.S. in 1991 as Pravachol.

By the mid-1990s, statins were the talk of the medical world, as

studies showed they significantly reduced heart-attack risk.

Mevacor, Pravachol and another chemically related Merck statin sold

as Zocor, which went on sale in 1992, would each bring in billions

of dollars in sales. Today Pfizer's Lipitor, which is a statin but

has a chemical structure unrelated to Dr. Endo's original find, is

the world's best-selling drug, with $12 billion a year in sales.

Even as the drugs became famous, Dr. Endo's anonymity remained. A

lengthy company history on Sankyo's Web site describes the discovery

of compactin but never mentions Dr. Endo by name. A Sankyo spokesman

says Dr. Endo was a " central figure among the discoverers " of the

first statin, but declines to go as far as Western scientists in

describing his contribution. S. Brown and ph Goldstein,

who won the Nobel Prize for their work in cholesterol, wrote in

2004: " The millions of people whose lives will be extended through

statin therapy owe it all to Akira Endo. "

The broader lesson of Dr. Endo's discovery -- that natural products

such as substances in fungi can be an important source of new drugs -

- also tended to get buried. In the 1990s, companies became

frustrated with natural products, which often are hard to make in

quantity, and turned to artificial chemicals. But those chemicals

often turned out to work poorly in humans. Meanwhile, scientists

have gotten better at figuring out the structure of chemicals found

in nature and at reproducing them in the laboratory.

Dr. Endo says he never earned a cent from his statin discovery. When

he left Sankyo in 1978, he was earning less than $2,000 a month at

the exchange rates of the time. Later in his university research he

discovered yet more fungal byproducts, this time for use in chewing

gum, cosmetics and other products. Now retired from the university,

he keeps an office in a neat two-room apartment in western Tokyo,

with closets full of files he has kept meticulously over the years.

A few years ago, Dr. Endo went in for a day-long health examination

and found out he had slightly high cholesterol. He says the doctor

didn't know who he was and informed him, " We have good drugs for

that. " Dr. Endo says he took Mevacor for a while but stopped.

At his checkup in 2004, his LDL, or " bad " cholesterol, was 155, a

level at which many U.S. doctors would prescribe a statin. Dr. Endo

says he didn't take anything and brought the number down to 130 last

year by exercising more.

Why would the inventor of statins bypass his own invention? Dr. Endo

can only cite a Japanese proverb, " The indigo dyer wears white

trousers. "

[Guest guest]

This is pure hype.. First thing, the 'idea' - the fact that 'natural

substances can be made into drugs' is as old as drugs themselves..

Second thing, LIVING THINGS SHOULD NEVER BE PATENTABLE...

Especially, when a NEW patent on a longstanding medicinal use of a

plant is used to MONOPOLIZE and CONTROL medicinal use of that plant..

If a patent should be issued to anybody, it should be issued to the

people who TRADITIONALLY and HISTORICALLY developed the original

medical treatments based on the plant. The healers and

native-ethnobotanists who preserved the knowledge..

Not the foreign corporations who come in to steal and then cynically

exploit that knowledge... claiming that it is 'their' 'invention'.

Right.. NO WAY...

Often, they then try to make that medicine so expensive as to be unaffordable..

That is THEFT and MURDER...

[Guest guest]

The one big problem the THEIVES have is that they isolate the *active*

ingredient in a botanical and ASSUME that the other parts can be

discarded. If it wasn't there to begin with it would not be needed.

I forget which plant they tried to synthesize and claimed it didn't work.

Naturopaths and others in the alt med arena knew that all the parts were

needed if only for a small % of the drug.

I agree that ANY patent needs to go to those who *found* it not tho those

who are bastardizing it for thier own bottom line.

On Tue, 10 Jan 2006, LiveSimply wrote:

> Date: Tue, 10 Jan 2006 15:25:14 -0800

> From: LiveSimply <quackadillian@...>

> Reply-

>

> Subject: Re: [] Drug firms, scientists go back to nature

>

> This is pure hype.. First thing, the 'idea' - the fact that 'natural

> substances can be made into drugs' is as old as drugs themselves..

>

> Second thing, LIVING THINGS SHOULD NEVER BE PATENTABLE...

>

> Especially, when a NEW patent on a longstanding medicinal use of a

> plant is used to MONOPOLIZE and CONTROL medicinal use of that plant..

>

> If a patent should be issued to anybody, it should be issued to the

> people who TRADITIONALLY and HISTORICALLY developed the original

> medical treatments based on the plant. The healers and

> native-ethnobotanists who preserved the knowledge..

>

> Not the foreign corporations who come in to steal and then cynically

> exploit that knowledge... claiming that it is 'their' 'invention'.

> Right.. NO WAY...

>

> Often, they then try to make that medicine so expensive as to be

unaffordable..

>

> That is THEFT and MURDER...

>

>

>

>

> FAIR USE NOTICE:

>

>

>