With Fat-Loss Drug, Amgen Takes On a Weighty Challenge : Pharmaceuticals: Biotech firm faces much risk and expense in getting the medication from the laboratory to the marketplace.

A 400-pound woman called to plead her case--that she had tried every weight-loss plan known, none had worked, and could she please have the new fat-reduction drug. Then there was the obese man who didn’t care about how dangerous the new drug might be, he didn’t care how much it would cost, he just wanted it.

So did 1,000 other desperate obese people who contacted Amgen, the Thousand Oaks biotechnology company and its outside research team, all looking for the “fat gene” drug that in dazzling tests cut body weight by as much as 40% in only one month.

Wall Street wants the fat drug too. In two days after the latest lab results, the value of Amgen’s stock climbed by $900 million.

But the only living things that can get this biotech wonder drug right now are laboratory mice. Amgen won’t start testing the new fat drug on people until next year, and it will be five years at best before the Food and Drug Administration approves it for sale.

Between now and then Amgen faces the same expensive, risky, Byzantine road that any experimental drug must travel in getting from the lab to the marketplace. In biotechnology, the odds are 1 in 10 that a drug tested on people will ever win FDA approval, and the cost to create a new drug can top $200 million.

Underscoring that point is the fact that only a week before Amgen released its fat drug results in July, the company quietly announced some disappointing test results on a hepatitis drug it has struggled with for a decade.

Amgen’s hepatitis drug might be a dud, but “the price of innovation is failure,” said Cynthia Robbins-Roth, editor of Bioventure View, an industry newsletter. “In science there is no way to know where success will come from. You have to allow enough room for serendipity.”

Granted, Amgen is the world’s most successful biotech company and is expected to turn a $525-million profit this year on $2 billion in sales thanks to only two wonder drugs. But for years Amgen has struggled to come up with a third.

“Breakthrough drugs for diseases for which there are no cures today” is our goal, said George Morstyn, Amgen vice president for clinical development. Because molecular cell biology is on the scientific frontier, much remains unknown. “So there will be inevitable failures,” he said, but if a drug does work, “the successes are going to be incredible.”

Amgen got a fast start in the obesity drug derby last winter when it outbid several drug companies with a $20-million down payment to Rockefeller University in New York for rights to the school research team’s discovery, the OB gene--as in obese. This gene, cloned from chronically obese mice, may be one of the chief regulators of body fat. It is thought the OB gene causes fat cells to produce a protein called leptin--a name derived from a Greek word meaning thin.

A biotech drug copy of leptin was produced, mice were given daily shots and whammo, the fat mice got thinner fast.

For a month, chronically overweight mice, up to three times normal size, got daily leptin injections, and those mice lost 22% to 40% of their weight. Leptin was also injected twice daily in normal-sized mice, which also lost most of their body fat.

Jeffrey Halaas, a Rockefeller University researcher, knew something was taking place in those mice cages. Each day he would lift the mice out, weigh them and track how much they ate, but he could soon tell the leptin drug was working because the mice were getting harder to catch. The fatties used to just sit in the corner of a cage all day. “In two weeks they were running around in cages. And they just looked much better and thinner. It was clear what was going on,” he said.

So how might leptin work? Amgen’s Morstyn draws a circle on a blackboard. On top are the brain’s sensors that are set to maintain a certain amount of body fat. Below he draws the blood stream. As you eat, fat tissues keep sending out more leptin signals into the blood until eventually, like a gas gauge needle hitting F, the brain interprets that your stomach is full and you stop eating.

But what if, Morstyn says, drawing an arrow like a TV weather forecaster depicting a cold front coming in, leptin is added to the body by injecting a drug copy. “We’re going to tell the [brain’s] sensor mechanism that the amount of fat is already there by tricking it,” he says.

With one of every three Americans overweight and $30 billion spent annually on weight-loss schemes, a genuine fat-reduction drug would obviously be a colossal hit.

Amgen has the early lead because it already has an experimental drug and “so far the animals [tested] haven’t died, turned blue or grown a second head,” Roth said. “Amgen clearly has one component that plays a critical role in obesity. But there are other components.”

One fat-drug rival is Hoffmann-La Roche, the Swiss drug giant, which recently struck a research deal with Millennium Pharmaceuticals near Boston. In July, Millennium said it had cloned a mouse obesity gene called TUB, as in tubby. The firm does not have a drug version of TUB yet, but is pushing ahead so testing on animals can be done.

“The idea that you might be able to take the equivalent of Vitamin C in the morning and maintain or lose weight means there is a tremendous market,” said Geoffrey Duyk, director of genomics at Millennium.

To solve the riddle of whether Amgen’s OB gene and its leptin drug is the answer, Amgen must do more animal samples before launching any tests next year on its first human volunteers.

When leptin is tested on people there are various things to watch for, such as jitteriness--Halaas noted that the mice were very active after getting the drug. Obese people are likely to take the drug for a long time, possibly leading to side effects, he added.

“You can imagine a whole spectrum of responses,” Halaas said. Some people might not lose any weight. “We think that will be a rare occurrence, but there is no way to know for sure,” he said.

Morstyn, however, talked about leptin as a fast-track drug, possibly one that could get to market in five years. Amgen must pick doctors to run its tests and decide how overweight the first batch of patients will be.

There is no shortage of volunteers. The Rockefeller research team is so overloaded with requests from would-be human guinea pigs that a special phone line tells callers where to send letters listing their key medical information, including their weight.

A love of science may inspire all this, but what pays for it is good old-fashioned capital. Any evidence of the enormous creation of wealth possible from two blockbuster drugs can be seen at Amgen’s headquarters. Less than a decade ago Amgen was a sleepy company with a few small offices in a virgin office park, and most everybody there knew everybody else.

Then, in 1989, Amgen’s first drug, Epogen, went on sale. Of 60,000 genes in the human body, an Amgen scientist had found one gene that could produce red blood cells--the scientific equivalent of finding a marble at the bottom of a lake. Kidney disease patients now talk of Epogen as a magic potion, how they no longer need blood transfusions or are bedridden and have resumed their lives with vigor.

In 1991, Amgen’s second drug, called Neupogen, came out. It spurs production of white blood cells, one of the body’s key infection fighters, and is now widely used, including in cancer chemotherapy and AIDS treatment.

Both drugs cost thousands of dollars a year per patient, but since there had been nothing else, they changed medicine and the company.

The result: Amgen’s headquarters today is a massive complex with 2,400 employees. A day care center is on site, the main lobby is choked with visitors, and a receptionist hands out maps to help them sort their way among the maze of buildings, many with elaborate security systems requiring special ID cards to get in.

Getting a new drug out of those buildings is another matter. Amgen’s latest dead-end project is likely to be Infergen, a biotech copy of several human proteins. Amgen started working on the project in the mid-1980s. The drug has been tested on people to see if it can combat the hepatitis-C virus, which can lead to liver cancer.

News tidbits from the company’s latest 700-patient trial left analysts to conclude that Amgen’s test drug does not work any better than a similar drug already sold by giant Schering-Plough Corp.

Amgen’s lab chief, Morstyn, was testy about Infergen. The drug works, he said, and patients “clearly have a benefit” from it. But Amgen probably will drop the drug, said Jim McCamant, editor of the Medical Technology Stock Letter, sparing cash for more promising drugs in the company’s portfolio.

One promising avenue involves MGDF, which stands for megakaryocyte growth and development factor, a gene-spliced copy of a protein that may trigger production of platelets. Platelets are the oval-shaped disks that make blood clot, and hematologists consider this the final blood-cell drug mystery because Amgen has already solved how to force the body to make more red and white blood cells.

A platelet drug could help bone marrow transplant, breast cancer and ovarian cancer patients facing intense chemotherapy. Chemotherapy kills both good and bad cells, often leaving patients with such a low platelet count that their blood will not clot, which can lead to intestinal bleeding, brain hemorrhages and sometimes death. All that doctors can do now is halt the chemotherapy and give patients transfusions of platelets--which cost hundreds of dollars per transfusion. Meanwhile, the cancer cells are free to grow.

If Amgen’s new drug works, financially MGDF “would be a big home run,” Roth said.

Another person excited about MGDF is Dr. John Glaspy, assistant professor at the UCLA School of Medicine, who heads a pilot test of Amgen’s new platelet drug on 12 patients. Glaspy once led a test of Amgen’s white blood cell drug on his patients, saw the drug blossom, and he feels that rush of promise again.

“It’s always nice to have a hand in something that has an excellent chance to change forever the way medicine is practiced. If that happens once in your career you are lucky,” Glaspy said. Amgen’s Neupogen drug did that, and “maybe [MGDF] will too,” he said.

Glaspy listed several worries about MGDF. Many cancer patients already get a white blood cell drug, so will a platelet drug cancel the other? Will MGDF raise platelet counts fast enough? And “is this drug totally safe on humans? It is possible, though unlikely, it could increase the risk of blood clotting,” he said.

Amgen is not just racing to answer scientific questions, it’s also racing with Genentech, its big biotech rival in South San Francisco. Genentech has its own similar platelet blood-clotting drug, called TPO, and expects to start testing it on people this year. “This is a two-team race,” McCamant said.

One of the human pincushions on the receiving end of Glaspy’s needle is Leonard Wilhelm, 73, of Bakersfield. “They don’t like to feel you’re a guinea pig,” Wilhelm said. “I volunteered.”

In June, a cancerous tumor the size of a golf ball was removed from his lung, but he still needed chemotherapy. His doctor offered him a chance to go to UCLA for the chemotherapy and to be tested on MGDF, with the school picking up his extra expenses.

“I was given a shot every day for 16 days. I don’t know if I got the new drug or a placebo,” he said. “But they gave me a lot of attention, and then I had to stay for three hours” as nurses took his vital signs, blood pressure, checked his heart and made sure he was all right.

If it was Amgen’s new drug coursing in his veins, Wilhelm said, he felt no different. What did make him sick was chemotherapy. He turned weak, nauseated, got shortness of breath, the shakes and spent four days in hospital because his white blood cell count was so low. He was given a blood transfusion and a drug to help jump start his white blood cell count. Soon he felt better.