[Phase I study of edobacomab (E5) in patients with gram-negative sepsis].

A clinical Phase I study of E5, edobacomab, an anti-endotoxin monoclonal IgM antibody was carried out to evaluate its efficacy, safety and pharmacokinetics and in parallel, explore an optimum dosage in the treatment of patients with gram-negative sepsis (incl. those suspected). A total of 10 patients were administered a dose of 1 mg/kg, 2 mg/kg or 4 mg/kg of E5 by infusion over one hour. 1. Peak blood levels after an intravenous dose of 1 mg/kg, 2 mg/kg and 4 mg/kg of E5 were 9.9, 11.5 and 35.6 micrograms/ml, respectively and the half-lives of elimination were 8.7, 11.7 and 10.8 hours, respectively, about the same at all dose levels. The area under the blood concentration-time curve (AUC) were 129.8, 200.8 and 574.4 micrograms.hr/ml, respectively, showing an increase in proportion with the dosage. 2. Urinary E5 concentration was not detectable in all the patients and renal excretion of unchanged E5 was not observed. 3. Out of the 8 patients with a positive pre-treatment endotoxin level with a value of above 9.8 pg/ml, those who showed its reduction to a level of below 9.8 pg/ml within one hour after dosing of E5 were 0 of 2 patients (0%) at a dose of 1 mg/kg, 3 of 3 (100%) at a dose of 2 mg/kg and 1 of 3 (33.3%) at a dose of 4 mg/kg. 4. The clinical efficacy following a single intravenous dose of E5 was rated as being "good" or "excellent" for 3 of 3 patients (100%) at a dose of 1 mg/kg, 4 of 4 (100%) at a dose of 2 mg/kg and 2 of 3 (66.7%) at a dose of 4 mg/kg. 5. As for antipyretic effect as assessed by the mean value of temperature, a fall in fever to the level of 36 degrees C was noted from 12 hours after administration of E5 in the patients treated with 2 mg/kg. The degree of improvement in WBC, platelet count and CRP was also more evident in this 2 mg/kg group. 6. The safety was rated as "no problem in safety" for all 10 patients. No adverse reaction and clinical laboratory abnormalities suspected of their relation to E5 was observed. 7. Positive antibody (HAMA) response to E5 was observed in 2 of the 10 patients. In one patient (4 mg/kg) of them, response because negative 9 weeks later and in the other patient (1 mg/kg) it tended to decrease.(ABSTRACT TRUNCATED AT 400 WORDS)