CENTOCOR's CENTOXIN REDUCES MAJOR COMPLICATIONS OF SEPSIS BY 32%

CENTOCOR's CENTOXIN REDUCES MAJOR COMPLICATIONS OF SEPSIS BY 32% in patients with gram-negative bacteremia, according to a Phase III study published in the Feb. 14 New England Journal of Medicine. The results of the 543-patient placebo controlled Centoxin study, conducted by Elizabeth Ziegler et al., University of California-San Diego, have been submitted to FDA as part of the company's PLA for the product. Preliminary results of the study were reported in abstract form in the American Federation for Clinical Research journal Clinical Research in April 1990 and later at the AFCR annual meeting in May ("The Pink Sheet" April 23, 1990, T&G-11). Of the 543 patients in the trial, a subgroup of 123 gram- negative bacteremic patients experienced at least one major complication from sepsis at the start of the treatment. Among the 61 patients in this group who received Centoxin, complications were resolved in 62% of the patients within seven days of therapy. Only 42% of the 62 patients receiving placebo were free of complications after seven days of treatment. Patients received either a single 100 mg I.V. dose of Centoxin in 3.5 grams of albumin or a placebo (3.5 g of albumin). Centoxin did not significantly benefit the 343 sepsis patients enrolled in the study who did not have gram-negative bacteremia. However, among the 200 sepsis patients with gram-negative bacteremia, the Centoxin group had a 39% improvement in survival versus patients receiving placebo after 28 days. Among the 105 patients with gram-negative bacteremia that received Centoxin therapy, 70% were alive after 28 days versus 51% of the 95 patients with gram-negative bacteremia receiving placebo. Included in the 200-patient gram negative bacteremia subgroup were 101 patients who were in shock at the time treatment was initiated. In that group, there was a 42% reduction in mortality among the 54 patients who received Centoxin compared to the 47 patients receiving placebo. Of the 96 patients who were bacteremic but not in shock, there was a 33% reduction in 28-day mortality associated with Centoxin therapy, 27% compared to 40% for placebo. In a group of 196 bacteremic patients followed through to hospital discharge or death (four patients were lost to followup), the proportion of survivors was 63% in the Centoxin group compared to 48% in the placebo group, a 23% increase in survival. "The results of this clinical trial are similar to the results of a previous clinical trial of human polyclonal J5 antiserum, in which mortality in patients with gram-negative bacteremia was reduced by 37% and in patients with septic shock by 39%," the authors of the article state. The antiserum, developed by immunizing volunteers with heat inactivated cells of the J5 mutant of E. coli 0111:B4, is not commercially available. The researchers caution that "results of this trial should not be extended to infected patients who are not sick enough to meet our criteria for sepsis but should be applied only to patients with sepsis and presumed gram-negative bacteremia." They note that "larger trials will be needed to determine whether HA-1A benefits patients with sepsis and focal gram-negative infections without bacteremia." In an editorial accompanying the NEJM study, Sheldon Wolff, MD, New England Medical Center, suggested that "it would be of interest to study patients who receive a number of doses of the antibody, rather than the single dose employed by Ziegler et al." Wolff noted that "the outcome for the patients treated with the monoclonal antibody was not very different from the results when the polyclonal antiserum was used." Wolff also urged that primary immunization studies with J5 antigen be conducted in patients at risk for gram-negative bacterial infections, such as burn victims, those undergoing elective intra-abdominal surgery and "particularly pertinent as this editorial is being written -- military personnel." Centocor sent an initial 200 doses at $ 2,500 per dose of Centoxin to the Persian Gulf in the fall and received an additional order from the Army in January. "Although the monoclonal antibody has some advantages, such as the availability of large amounts, optimal therapy of this condition in the future will require additional agents," Wolff cautioned. "Studies of the role of cytokines, in particular tumor necrosis factor [TNF] and intereukin-1, in the pathogenesis of bacterial shock offer potentially exciting avenues for future clinical trials." Wolff suggested that soluble receptors of TNF and IL-1 receptor antagonists may prevent endotoxin and E. coli- induced shock.