New York Times
July 30, 2002
Rebellious Bodies Dim the Glow of `Natural’ Biotech Drugs

The promise of many biotechnology drugs is that they are the body’s own
solutions. Human proteins like insulin and growth hormones, the same
substances that the body uses every day, are made through genetic
engineering and given to people who do not make enough of the proteins on
their own.

But an outbreak of serious illnesses linked to the anemia drug Eprex shows
that some patients do not react to genetically engineered proteins as if
they were natural. The patients react as if the protein were a germ, and
their immune systems try to destroy it.

In the case of Eprex, which is made by Johnson & Johnson and is sold only
outside the United States, this immune response is widely believed to be
responsible for 141 cases of pure red cell aplasia.

With this condition, the body is unable to produce red blood cells, making
some patients dependent on transfusions to survive.

Although the Eprex case is the most serious, virtually all biotechnology
drugs provoke immune responses in some patients, though usually just tiny
fractions. The reactions are becoming of greater concern as the number of
protein drugs increases.

“Sometimes there are miracle drugs, but they can still have severe side
effects,” said Dr. Huub Schellekens, a professor at Utrecht University in
the Netherlands. “That has come as a surprise to us, really.”

In some cases, patients experience allergic reactions or even potentially

fatal shocks. In many cases, the body makes antibodies that attack the

protein, rendering it less effective as a drug.

Up to one-third of hemophiliacs develop immune reactions to the
blood-clotting protein Factor VIII. In desperation, some undergo yearlong
treatments at a cost of $1 million to try to restore the drug’s usefulness.

>From 5 to 40 percent of multiple sclerosis patients develop resistance to

beta interferon, according to Dr. Richard A. Rudick, director of the Edward
J. and Louise E. Mellen Center for Multiple Sclerosis Treatment and
Research at the Cleveland Clinic. Although there is debate about whether
the presence of the antibodies is important, Dr. Rudick said, many such
patients are unlikely to benefit from the drug.

What makes the illnesses associated with Eprex more alarming is that the
antibodies produced by the patients do more than make the drug ineffective.

They also attack the patient’s equivalent protein. So the patients can no
longer produce any red blood cells, ending up with worse anemia than than

they would have had without the drug.

Amgen saw the same problem a few years ago with patients in a clinical
trial for a drug aimed at increasing the production of blood platelets. The
company halted work on the drug, which never made it to market.

The reasons for the immune responses are not clear. In some cases, the
drugs, which are made by putting the human gene for the protein into
bacteria or animal cells, are subtly different from the natural protein.
One such difference may be in the sugars that coat the protein. In other
cases, the drug may have an impurity, or the proteins may clump together.

In the case of Eprex, the cause remains a mystery. The factory, in Puerto
Rico, is under criminal investigation. Johnson & Johnson says it has done
nothing wrong, and the plant passed two recent inspections.

The same protein, sold in the United States as Procrit by Johnson & Johnson
and as Epogen by Amgen, is linked to just a handful of cases of red cell
aplasia. Amgen, which developed the drug, makes both brands in a factory in

Experts say that because living cells make biotech drugs, the output is not
as predictable as with chemically made drugs. Even slight changes in
manufacturing can affect the product, sometimes in ways that cannot even be

“Despite best efforts to detect product differences and predict the impact
of manufacturing changes, these surprises do continue to occur,” Dr. Chris
Joneckis, an official of the Food and Drug Administration, said in May at a
workshop on the problem. The F.D.A. declined to make officials available
for this article.

Immune responses also occur with protein drugs not made by genetic
engineering like those purified from blood or derived from animals. The
antivenin for rattlesnake bites, from horses’ blood, can be used just once
because after that a person’s immune system is primed to destroy it

“When rattlesnake handlers get just a small bite, they don’t get antivenin
because they want to save it for a large bite,” said Dr. Douglas J.
Ringler, chief executive of TolerRx, a company in Cambridge, Mass., that is
developing techniques to prevent immune reactions to protein drugs.

The 141 suspected cases of red cell aplasia pale in comparison to the three
million people who have been treated with Eprex or its American
counterparts for more than 10 years. Many of those patients are able to
work or lead more normal lives because the drug eliminates the fatigue of

The drug is a form of erythropoietin, a protein produced by the body to
spur the production of red blood cells, which ferry oxygen around the body.
Before the advent of genetic engineering, scientists had tried to isolate
the protein from human urine but could not obtain enough to use it as a

In many cases, the genetically engineered proteins replace those taken from
animals or from human blood or tissues. The biotech drugs are widely
considered safer because they do not carry the risk of viral infection.

Human insulin made by genetic engineering supplanted insulin from animals.
The human version generally provokes far fewer immune reactions and lets
diabetics control their insulin better. Nevertheless, a small percentage of
diabetics say they cannot tolerate the human version and are trying to keep
cow and pig insulin available.

For hemophiliacs, Factor VIII made by genetic engineering is widely seen as
safer than the same protein purified from human blood, which has a small
risk of infections. But up to 35 percent of hemophiliacs develop antibodies
to the genetically engineered factor, said Dr. Louis M. Aledort, a
professor at the Mount Sinai School of Medicine. Fifteen percent developed
antibodies to the blood-derived product, Dr. Aledort said, although the
numbers may not be comparable because of differences in measuring.

Although the Eprex problem is something of a black eye for what has been
the biotechnology industry’s most successful product ? Eprex and its
American cousins exceed $5 billion in combined yearly sales ? it could
actually help in the long run, by eliminating the threat of generic

competition. For drugs made chemically, generic manufacturers do not have

to run expensive clinical trials. They need to show just that their drug is
identical to the brand-name product.

But the biotechnology industry and the F.D.A. have said it is too difficult
to show that two biotech drugs are equivalent without full clinical trials.
Eprex is likely to become Exhibit A in such arguments.