Costly Search for a Deadly Killer’s Cure : Health: Sepsis kills thousands of hospital patients a year. It has also ravaged the balance sheets of biotech firms seeking to unlock its secrets.

The potentially lucrative effort to find a cure for sepsis, a syndrome that kills thousands of hospital patients each year, is turning into an expensive nightmare for some biotechnology firms.

The firms have spent hundreds of millions of dollars in what so far has been a spectacularly futile quest for a sepsis cure. The pain of their quest was highlighted again last week by the resignation of two top executives at Synergen, a Boulder, Colo.-based biotech company trying to develop an antisepsis drug.

Sepsis is the overwhelming infection of organs in the human body, usually after surgery. The disease is caused by poisons, called endotoxins, released by bacteria and other organisms.

An effective antisepsis drug would be a blockbuster because the condition is both deadly and expensive. Sepsis kills between 100,000 and 120,000 of the 500,000 hospital patients who are stricken by it each year. Most of the patients who survive wind up in an intensive care unit, where they rack up medical expenses of up to $4,000 a day during stays that can last weeks.

Any drug that could mitigate that cost would be embraced by doctors and insurers, even at the projected treatment cost of $4,000 or more per patient.

But sepsis has proven stubborn, complex and “heterogeneous”--meaning it is caused by a number of factors. And defining the patient population that is likely to benefit from antisepsis drugs has proven a “tremendous problem,” says Dr. Roger C. Bone, dean of Rush Medical College in Chicago, author of numerous sepsis texts and a noted clinical investigator.

These and other problems with finding a cure came into focus again last Thursday when Synergen Chief Executive Jon S. Saxe and clinical trials director Michael A. Catalano resigned less than a month after the company announced disappointing clinical results of its Antril antisepsis drug. The results indicated that the drug did not provide a significant enough therapeutic advantage over a placebo.

Synergen had become the front-runner among firms hoping to produce an antisepsis drug after two competing companies ran aground last year. Last April, the Food and Drug Administration denied approval of Centoxin after its developer, Centocor of Malvern, Pa., failed to demonstrate a significant reduction in patient mortality.

In June, the FDA told Xoma Corp. of Berkeley that its clinical trials generated “insufficient data” for approval of its E5 anti-sepsis drug.

Still, despite the shock waves and investor pessimism, researchers believe the stage may be set for successful antisepsis drugs to be developed. They say biotech companies have added immeasurably to knowledge of sepsis by financing research that, because of federal budget cutbacks, might not otherwise have been performed.

“In general, it’s worth remembering that these companies are pioneers in this area. We should remember that before we judge them too harshly,” says David Webber, biotech analyst with Alex. Brown & Sons.

Such words are of little comfort to shareholders who have watched helplessly as stocks of the three main antisepsis companies have plummeted. Synergen closed Thursday (the last day of trading before the long Easter weekend) at $9.75 per share, down from a 52-week high of $66.25. Xoma closed at $5.875 per share, down from a 52-week high of $23, and Centocor ended at $2.25 per share, down from a 52-week high of $49.

Bone, the medical college dean and author, says Centocor, Xoma and Synergen all made the mistake of trying to treat too broad a range of sepsis patients. They found that the patients most likely to benefit were mixed in with lightly infected patients who would have recovered anyway, and with “irreversibly ill patients” who were beyond help.

Researchers also made the error of designing drugs based on the belief that sepsis was caused exclusively by endotoxin, a poison produced by the body’s resident bacteria, says Dr. Kenneth S. Waxman, associate professor of surgery at UC Irvine and a sepsis expert.

While endotoxins are a major factor, sepsis is also caused by cytokines, a biochemical that regulates blood pressure, inflammation in the body and other functions. Also playing a role in sepsis are other resident bacteria in addition to those that release endotoxins, Waxman says.

It may turn out that sepsis victims are best treated with a “cocktail” of several drugs similar to the variety of medicines administered to heart attack victims, Bone says.

Both Xoma and Synergen say they are not giving up and will resume clinical tests of their drugs this summer--albeit on smaller, more qualified patient populations.

Other biotech companies with antisepsis drugs in advanced stages of development include Chiron, Immunex, Genentech, Coretech and Nova, says Joseph E. Edelman, senior biotech analyst with Prudential Securities in New York.

“There is still a pretty good chance that one or more of these agents will show some benefit,” Edelman says. “However, the benefit is going to be more modest than originally hoped. The mortality reduction in sepsis patients will not be as good as we would have hoped.”