By David N. Leff

One-fourth of all sick people who check in to a hospital emergency room are in shock. Hypotensive septic shock, that is — the final stage of sepsis.

Sepsis is a blood-borne, multi-organ bacterial infection that afflicts half a million people a year in the U.S. About half of them develop septic shock, from which 40 to 70 percent die.

Most of them expire in hospital intensive-care units, which is where physicians wage unequal combat against the armies of Gram-negative and Gram-positive pathogens, not to mention fungi, that perpetrate the lethal signs and symptoms of septic shock.

In virtually any organ of the body, from skin to brain, the germs and their toxins have wreaked mayhem on tissue, often beyond repair.

One prime target is the liver, which has the job of clearing toxins from the body. When the blood-poisoning micro-organisms reach and damage that organ, its toxin-disposal service shuts down, and circulation carries those poisons to the brain. The consequence: hepato-encephalopathy, causing "alterations in mental status," i.e., "loss of cognitive functions."

The blood itself suffers "intravascular disseminated coagulopathy," or uncontrolled activation of the clotting factors throughout the small blood vessels, resulting in tissue necrosis and bleeding. "So if you draw blood from a vein," explained critical-care specialist Edward Abraham, "the coagulation factors you would expect to find are not there, because they are being consumed elsewhere in the body."

When pathogens invade the bod, and trigger infection, the immune system releases cytokines — hormones that muster the inflammatory process to counterattack. One such molecule that has achieved celebrity status in the 1980s and '90s is tumor necrosis factor (TNF).

Sepsis Challenge Remains Daunting

Originally named for its anticancer properties, TNF, unless held back by another cytokine — interleukin-10 (IL-10) — can and does promote sepsis. "It's a central mediator," Abraham, pointed out, "in terms of organ-system dysfunction and death, in models of endotoxemia and sepsis. It can cause the manifestations of sepsis and septic shock, including hypotension, activation of the clotting cascade, and organ or system dysfunction."

Since the dawn of the 1990s, biotech companies and their pharmaceutical allies have been grooming TNF-targeting monoclonal antibodies as therapeutic agents to reverse sepsis. Hardly a year went by without announcement of yet another failed clinical trial. (See BioWorld Today, May 22, 1997,p. 1, and Jan 14, 1997, p. 1.)

One of the largest such Phase III studies continued that lose-lose tradition this week, in the pages of the latest Lancet, dated March 28, 1998. The study's final report bears the title: "Double-blind randomized controlled trial of monoclonal antibody to human tumor necrosis factor in treatment of septic shock."

That paper's senior author, and the study's principal investigator, is Edward Abraham, who heads critical-care medicine at the University of Colorado, in Denver.

He managed and analyzed participation by 105 hospitals in the U.S. and Canada, which enrolled 1,879 septic-shock patients. Of that cohort, one-half (949 subjects) received infused monoclonal antibodies against TNF-alpha; the other half (930), a placebo consisting of human serum albumin.

By 28 days after treatment, 382 (40.3 percent) of the TNF recipients had died, as had 398 (42.8 percent) of the placebo contingent.

The consortium's finding: "We did not find an improvement in survival after septic shock with TNFa monoclonal antibodies." It concluded that "therapy not solely dependent on TNFa blockade may be required to improve survival."

This clinical trial was sponsored by Bayer Pharmaceutical Corp., in Berkeley, Calif., a subsidiary of Bayer AG, of Leverkusen, Germany.

Despite consistently disappointing results with the TNF blockade against sepsis, the corporate sponsors and their biotech partners haven't given up on the strategy.

"There are still some very large anti-TNF studies ongoing," Abraham said. "Hoffmann-La Roche [of Basel, Switzerland] has just completed, with 1,340 patients in 80 centers, a type I p55-TNF-receptor fusion protein complex. I'm supposed to announce the results within the next month."

He continued: "Then there's the ongoing Knoll [of Ludwigshafen, Germany] study with F(ab)'2 fragments of an anti-TNF antibody."

He noted that Knoll had begun a European study, "which they terminated at the interim analysis for lack of efficacy. Now," he went on, "they are doing a very big, 2,200-patient study in North America, to which they are still adding participating centers.

"Both the Roche and Knoll trials," Abraham pointed out, "are aiming at slightly differing patient populations. Knoll's participating centers have to be very numerous," he observed, "to get so many patients."

Optimistic TNF-Zappers Still In Running

Abraham also cited "a smaller study from Therapeutic Antibodies Inc. [of Nashville, Tenn.] with an anti-TNF polyclonal antibody, and enrolling only several hundred subjects. The theory," he explained, "is that a monoclonal will interact with only one epitope, whereas a polyclonal may be more effective in terms of neutralizing, because it interacts with more sites of interest on the molecule."

Abraham made the point that "the concept of anti-TNF is still kicking around, with different patient populations being focused. But," he added, "to be honest, I wouldn't be overly optimistic, given the results of the present study reported in The Lancet." When the immune system unleashes proinflammatory TNF against an infective pathogen, it also releases an anti-inflammatory cytokine, IL-10, to keep TNF from overacting. IL-10 is being tried against sepsis as an alternative TNF-zapper to antibodies.

"Different therapies will be needed for different categories of sepsis patients," Abraham observed.

"One message of this study is whether to be a lumper in terms of grouping patients, or splitting them into smaller discrete clinical or biochemical groupings."

Despite its no-benefit results, the Lancet-reported trial does carry take-home messages for clinicians, Abraham suggested. "I think one issue is," he reflected, "what would be of use in designing another trial, and looking at new treatment agents.

"You can see from our results," he concluded, "that in the broad group of patients with a clinical diagnosis of sepsis, TNF doesn't appear to have a critical role." *

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