Raxibacumab for the treatment of inhalational anthrax.
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.)
Migone
Thi-Sau
TS
Human Genome Sciences, Rockville, MD 20850, USA. thi_migone@hgsi.com
Subramanian
G Mani
GM
Zhong
John
J
Healey
Letha M
LM
Corey
Al
A
Devalaraja
Matt
M
Lo
Larry
L
Ullrich
Stephen
S
Zimmerman
Janelle
J
Chen
Andrew
A
Lewis
Maggie
M
Meister
Gabriel
G
Gillum
Karen
K
Sanford
Daniel
D
Mott
Jason
J
Bolmer
Sally D
SD
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
D000890:Anti-Infective Agents; D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D002939:Ciprofloxacin; C542124:raxibacumab