Gene-Altered Antibody May Cut Some Infection Deaths : Medicine: But the drug remains unavailable to those with bloodstream diseases who may benefit from it. The FDA is still reviewing a 1989 marketing application.
In a major advance against a leading cause of death, a national study has found that a genetically engineered medication may significantly reduce the death rate of patients with severe bacterial infections of their bloodstreams.
The experimental drug, known as HA-1A, is a human monoclonal antibody, a man-made form of a specialized immune system molecule designed to protect the body against disease.
However, the medication remains unavailable to most patients who might benefit from it. The U.S. Food and Drug Administration is still reviewing a September, 1989, marketing application submitted by the manufacturer, Centocor Inc. of Malvern, Pa., as well as a December, 1988, application for a related medication submitted by Xoma Corp. of Berkeley.
In the study of hundreds of patients, the group that received a single intravenous dose of the antibody in addition to antibiotics and intensive care had a 30% death rate within 28 days, compared to a 49% death rate for the patients who did not receive the drug, according to a report in today’s New England Journal of Medicine.
“This is a new kind of therapy for a devastating disease,” said Dr. Elizabeth A. Ziegler, an infectious disease specialist at the UC San Diego School of Medicine in La Jolla and the principal author of the study. “It offers the promise of improved survival.”
The impact of HA-1A and similar drugs under development could be vast. About 400,000 cases of sepsis, or bloodstream bacterial infections, occur in the United States annually. Many occur in the elderly, trauma or surgery patients, or those with cancer and other serious diseases. An estimated 30,000 to 100,000 people die each year.
Neither Centocor nor Xoma have asked the FDA to allow wider use of their product before final marketing approval, as companies often do with drugs for life-threatening illnesses, such as AIDS. Centocor has occasionally supplied HA-1A to patients on a “compassionate use basis” and has sent a supply to U.S. military physicians in the Persian Gulf.
FDA officials would not comment on why their reviews of the products are taking so long.
Richard Koenig, Centocor’s director of corporate communications, said “there is no stumbling block which has come up . . . we are looking for approvals in the United States and Europe this year.”
In an editorial for the New England Journal, Dr. Sheldon M. Wolff of New England Medical Center in Boston called for “additional investigations to confirm the results.” Wolff said that clinical trial results with Xoma’s monoclonal antibody product “were only partly confirmatory” of the Centocor study.
If approved, a single dose of HA-1A is likely to cost “in the area of a couple thousand dollars or somewhat more,” according to Koenig. This might create an instant market for the antibody of at least several hundred million dollars a year.
The monoclonal antibody blocks the effects of endotoxin, a part of the cell wall of some bacteria that can invade the bloodstream.
Endotoxin is responsible for many of the symptoms of these bacterial infections, such as fever, lower blood pressure, rapid heartbeat and confusion. Severe cases of bloodstream infection result in shock, which prevents blood from circulating to vital organs.
Antibiotics can kill bacteria and stop them from reproducing. But antibiotics do not counteract the effects of endotoxin released by these bacteria. HA-1A is designed to latch on to a specific, toxic part of endotoxin that is common to many different bacteria.
The new study, conducted at 24 medical centers, included 200 patients who had sepsis caused by endotoxin-containing bacteria. About half of these patients were in shock.
The typical patient was about 60 years old and either had a tumor, diabetes, recent surgery or chronic liver or kidney disease.
All patients with bloodstream infections, including those who were in shock, appeared to benefit from HA-1A. No serious reactions were noted.
Patients with sepsis often deteriorate rapidly. The study recommends prompt treatment with HA-1A when physicians suspect a patient has an endotoxin-related bloodstream infection, and before the diagnosis can be confirmed with blood tests.
Ziegler and other UC San Diego researchers have been researching the use of immunotherapy for serious infections since the early 1970s. They achieved a notable success in 1982, when they showed that an antibody-containing serum obtained from vaccinated human volunteers could reduce mortality from bloodstream infections.
After monoclonal antibody technology became available, UCSD researchers worked with a team at Stanford University to develop the HA-1A antibody. The antibody-producing cell line was then licensed to Centocor, which sponsored the new study.
The FDA has previously approved a monoclonal antibody, OKT3, for use in kidney transplant patients. About 40 of the antibodies are under development as human drugs, primarily for use against various cancers.
