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http://www.nytimes.com/2002/10/02/business/02DRUG.html

Mystery Effect in Biotech Drug Puts Its Maker on Defensive

By JOHN TAGLIABUE

ARIS, Oct. 1 — As director of hematology at the Hôtel Dieu hospital here, Nicole Casadevall had seen such cases before. A patient in her 60's had developed pure red cell aplasia, in which the body's germ-fighting defenses go haywire and attack its own bone marrow, leaving her severely anemic and facing a lifetime of transfusions to survive.

 

Dr. Casadevall knew of several diseases — lymphoid cancer, rheumatoid arthritis and systemic lupus — that could cause red cell aplasia. But this patient had none of them. Indeed, the woman had regularly been injected with a drug to stimulate the production of red blood cells while she received dialysis twice a week. Why, then, was she now unable to make any red blood cells at all?

Four years after Dr. Casadevall began to investigate this mystery, answers remain elusive. But the pattern that she uncovered — that her patient was just one of scores in the same condition, nearly all of whom had taken a drug made by Johnson & Johnson — has raised doubts about not just the company but about a whole class of drugs that are a cornerstone of biotechnology.

The Johnson & Johnson drug, Eprex, is the market-leading version of a protein known generically as erythropoietin, or EPO, that is the best-selling genetically engineered drug ever, and one of the largest-selling drugs of any kind in the world. EPO is given to patients with conditions that hamper red blood cell production — usually people being treated for kidney problems, like dialysis patients, or for cancer.

Global sales of EPO products exceeded $13 billion last year, with Johnson & Johnson alone accounting for $3.4 billion of that. EPO drugs were the company's best-selling pharmaceutical group, providing more than 10 percent of its revenue.

It was Dr. Casadevall's work in the cloisterlike confines of the Hôtel Dieu, and her publication of the results earlier this year, that alerted doctors and nurses to the problem. That alert contributed in part to increased reporting of red cell aplasia, intensifying the questions about Johnson & Johnson's drug.

Of the 141 cases of red cell aplasia reported in EPO users, most have involved people taking Eprex in Europe, Canada and Australia. Only a handful of cases have appeared in patients using other brands of the drug, including Procrit, Johnson & Johnson's name for the EPO drug it sells in the United States.

Johnson & Johnson makes Eprex at a factory in Puerto Rico. But Procrit is produced for Johnson & Johnson at a factory in Colorado run by a competitor, Amgen, which developed the drug. Regulators and scientists seeking to explain the cases of red cell aplasia have focused on the Puerto Rico plant, and Johnson & Johnson's competitors — mainly Amgen of Thousand Oaks, Calif., and Roche of Switzerland — say the problem is specific to Eprex, not to their EPO drugs.

Those companies cannot help but see opportunity in the tarnishing of Eprex's reputation. Indeed, the problems with Eprex could help Amgen, which now sells a new version of EPO called Aranesp in competition with Johnson & Johnson.

Johnson & Johnson, though, contends that the handful of cases of red cell aplasia in users of its competitors' drugs are evidence that the problem, whatever it is, goes beyond Eprex. Yet J.& J., the third-largest American drug maker, is racing desperately on two fronts: to solve the mystery and to salvage its leading pharmaceutical product.

"Frankly, I'm not sure we realized when we began just how difficult and complex this would become," said Per Peterson, the chairman of pharmaceuticals research at Johnson & Johnson. "But our knowledge is evolving, and we know much more today than we did a year ago."

Dr. Peterson said the company debated whether to take Eprex off the market several times as reports of red cell aplasia multiplied, but decided not to do so, concluding that the drug's benefits far outweighed the risks. Economics, he insisted, were not a deciding factor, noting that Johnson & Johnson did not hesitate to withdraw a popular heartburn drug, Propulsid, when it was linked to dozens of deaths two years ago.

European regulators, loath to withdraw a drug that has proved valuable for hundreds of thousands of patients, have limited their response so far to recommending changes in how Eprex is administered. They have advised doctors to give it intravenously rather than through injections under the skin, noting that most cases of aplasia have been associated with injections. At the same time, they are appealing to doctors to report any new cases.

Dr. Casadevall said she agreed that Eprex should not be taken off the market. When bioengineered EPO reached the market a dozen years ago, she said, "it changed the lives" of patients with kidney disease. Because EPO is naturally produced in the kidneys, when those organs fail people often need to deal with anemia as well as receive dialysis to clean their blood.

"At long last, such patients could live without the risk of anemia," she said. "It was a revolution."

Her belief in that advance was so strong that she was at a loss to explain why her patient in 1998 was acutely anemic, despite being administered Eprex. To try to unwind the riddle, she enlisted the help of Patrick Mayeux, a biochemist at the Cochin Institute of Molecular Genetics in Paris.

Mr. Mayeux used radioactive tracers to study the patient's bone marrow, the soft tissue inside bones that produces red blood cells. He discovered antibodies that not only neutralized the red-cell-producing effect of the Eprex that the woman was taking, but also her own body's ability to replenish its red blood cell supply. Most puzzling, the production of the destructive antibodies seemed to be set in motion by the drug itself.

That unexpected conclusion was soon confirmed by a stream of new, similar cases elsewhere in Europe, Canada and Australia. In virtually all of them, patients on kidney dialysis had been injected with Eprex.

Scientists make Eprex, like other brands of bioengineered erythropoietin, by splicing the human EPO gene into hamster cells. But genetically engineered EPO is subtly different from the natural protein. In the patients with red cell aplasia, Mr. Mayeux found that antibodies treated the drug as a foreign protein — and then did the same to the patient's natural EPO as well.

Early in 1999, after Dr. Casadevall had reviewed three cases of aplasia, she notified the pharmacological centers of Johnson & Johnson and Roche. In the meantime, reports of similar occurrences of red cell aplasia had been coming in to the drug companies from doctors and hospitals. "Perhaps at the beginning they thought it was only one or two cases," she said. "They thought it was chance, not important. But with each new case, they became more and more anxious."

Dr. Casadevall said she knew of two cases in which people who were using erythropoietin had died, though she said she did not know which brand of the protein they were being given and doubted that the deaths were related to the drugs. In most cases, patients who develop red cell aplasia are treated with transfusions or immunosuppressant drugs that neutralize the antibodies. In some cases, she said, patients undergo kidney transplants.

Dr. Peterson praised the work of Dr. Casadevall, calling it "first-rate science," adding that "she has done a tremendous service by calling attention to this problem."

Johnson & Johnson's response has taken several forms: to try to figure out why so many Eprex users have developed aplasia, to seek to shift attention to cases involving its competitors' drugs and to try to hang on to its lead in the European market.

After discovering the pattern that seemed to implicate Eprex, Johnson & Johnson reviewed the way it makes the drug at its factory in Manati, P.R. Among other changes, it reduced the amount of silicone in syringes used to inject Eprex because tiny amounts of the silicone can leak into the drug.

Johnson & Johnson also got a better grip on distribution. Because Eprex prices vary from country to country, independent dealers would buy it in cheaper countries, like Greece and Portugal, and ship it to countries with higher prices in Northern Europe. But did they keep Eprex at temperatures of 36 to 46 degrees, and protect it from light, as required? Johnson & Johnson found that one shipper did not deliver under the right conditions.

The company's troubles with Eprex were compounded last spring when J.& J. learned that the Food and Drug Administration was reviewing accusations by a former employee, Hector Arce, that he had been told to falsify data to conceal manufacturing lapses. The company denies the accusations, which Mr. Arce made in a whistle-blower lawsuit; it says he was a boiler operator not directly involved in making Eprex. The F.D.A. is still investigating.

In the meantime, Johnson & Johnson began to note red cell aplasia in patients taking competing products, including NeoRecormon, which is made by Roche, and Epogen, which is manufactured by Amgen. Dr. Peterson said Johnson & Johnson found that three people taking NeoRecormon exclusively had developed red cell aplasia. If Roche tracked reports of the condition as carefully as Johnson & Johnson did, he added, "they probably would have come in the same ballpark we have been in."

Alexander Klauser, a spokesman for Roche, disputed that. He said his company had not seen evidence to suggest the problem was with combinant EPO in general; rather, that it appears to have something to do with Eprex itself. He acknowledged red cell aplasia in one patient using only NeoRecormon, and said Roche had "no explanation" for it.

At the same time, Johnson & Johnson ordered its sales representatives to knock on doctors' doors throughout Europe to make sure that the drug was being properly stored and administered. It also wrote to doctors telling them of the difficulties that Eprex was encountering.

In an article in February in The New England Journal of Medicine, Dr. Casadevall and Mr. Mayeux professed ignorance of just how the body recognizes Eprex as a foreign protein. Despite continued research since, they can still only speculate. "The trick now is to determine the part of the molecule toward which the antibodies are directed," Dr. Casadevall said. "But it is very difficult technically."

One clue may have been in the sharp rise in reported cases of red cell aplasia in 1999. J.& J. changed the manufacturing process at the Puerto Rico plant in 1998, ending the use of a human blood protein as a stabilizer in Eprex at the request of European health officials concerned about the spread of mad cow disease.

"We clearly speculate that the removal of human serum albumin is a contributing factor to the problem facing patients," said Dr. Peterson, the Johnson & Johnson scientist.

Complicating this theory, Roche never used human blood protein as a stabilizer in its formula for NeoRecormon. Mr. Mayeux, the French scientist, said the problem might be attributable to "something in the patients themselves, some susceptibility in their immune system."

Dr. Casadevall said her first patient still relies on transfusions to survive. "She's a rather older woman with other illnesses, including diabetes," she said. "She received immunosuppressant treatment, though light, because her general health was not good. She is still not cured."

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