title: Raxibacumab for the treatment of inhalational anthrax.
abstract: BACKGROUND
  Inhalational anthrax caused by Bacillus anthracis is associated with high mortality primarily due to toxin-mediated injury. Raxibacumab is a human IgG1lambda monoclonal antibody directed against protective antigen, a component of the anthrax toxin.
  
  
  METHODS
  We evaluated the efficacy of raxibacumab as a prophylactic agent and after disease onset in a total of four randomized, placebo-controlled studies conducted in rabbits and monkeys. Animals were exposed to an aerosolized target exposure of B. anthracis spores that was approximately 100 times (in the prophylactic studies) and 200 times (in the therapeutic-intervention studies) the median lethal dose. In the therapeutic-intervention studies, animals were monitored for the onset of symptoms. Animals with detectable protective antigen in serum, a significant increase in temperature, or both received a single intravenous bolus of placebo or raxibacumab at a dose of either 20 mg per kilogram of body weight or 40 mg per kilogram. The primary end point was survival at day 14 (in rabbits) or at day 28 (in monkeys). Safety studies were conducted with intravenous raxibacumab (40 mg per kilogram) in 333 healthy human volunteers.
  
  
  RESULTS
  In both rabbits and monkeys, the time to detection of protective antigen correlated with the time to bacteremia (r=0.9, P<0.001). In the therapeutic-intervention studies, the survival rate was significantly higher among rabbits that received raxibacumab at a dose of 40 mg per kilogram (44% [8 of 18]) than among rabbits that received placebo (0% [0 of 18]; P=0.003). Raxibacumab treatment also significantly increased survival in monkeys (64% [9 of 14], vs. 0% [0 of 12] with placebo; P<0.001). In human subjects, intravenous raxibacumab at a dose of 40 mg per kilogram had a half-life of 20 to 22 days and provided a maximum concentration of the drug in excess of levels that are protective in animals. Concentrations of raxibacumab provide a surrogate end point that should be predictive of clinical benefit.
  
  
  CONCLUSIONS
  A single dose of raxibacumab improved survival in rabbits and monkeys with symptomatic inhalational anthrax. (ClinicalTrials.gov number, NCT00639678.)
authors: Human Genome Sciences, Rockville, MD 20850, USA. thi_migone@hgsi.com
authors: Thi-Sau
authors: TS
authors: Migone
authors: G Mani
authors: GM
authors: Subramanian
authors: John
authors: J
authors: Zhong
authors: Letha M
authors: LM
authors: Healey
authors: Al
authors: A
authors: Corey
authors: Matt
authors: M
authors: Devalaraja
authors: Larry
authors: L
authors: Lo
authors: Stephen
authors: S
authors: Ullrich
authors: Janelle
authors: J
authors: Zimmerman
authors: Andrew
authors: A
authors: Chen
authors: Maggie
authors: M
authors: Lewis
authors: Gabriel
authors: G
authors: Meister
authors: Karen
authors: K
authors: Gillum
authors: Daniel
authors: D
authors: Sanford
authors: Jason
authors: J
authors: Mott
authors: Sally D
authors: SD
authors: Bolmer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000881:Anthrax / Q000188:drug therapy* / Q000276:immunology; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000907:Antibodies, Bacterial / Q000097:blood; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001408:Bacillus anthracis; D016470:Bacteremia; D002939:Ciprofloxacin / Q000009:adverse effects / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D011817:Rabbits; D011897:Random Allocation; D012141:Respiratory Tract Infections / Q000188:drug therapy*; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents; D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D002939:Ciprofloxacin; C542124:raxibacumab