Antimicrob Agents Chemother. 2017 Aug 7. pii: AAC.01103-17. doi: 10.1128/AAC.01103-17. [Epub ahead of print]
The fluorocycline TP-271 is efficacious in models of aerosolized Bacillus anthracis infection in BALB/c mice and cynomolgus macaques.
Grossman TH1, Anderson MS2, Drabek L3, Gooldy M4, Heine HS5,6, Henning LN2, Lin W3, Newman JV7, Nevarez R3, Siefkas-Patterson K3, Radcliff AK4, Sutcliffe JA7.
1
Tetraphase Pharmaceuticals, Inc., Watertown, MA tgrossman@yahoo.com.
2
Battelle, Columbus, OH.
3
IIT Research Institute, Chicago, IL.
4
CUBRC, Inc., Buffalo, NY.
5
United States Army Medical Research Institute of Infectious Diseases; Frederick, MD.
6
Institute for Innovative Therapeutics, University of Florida Research and Academic Center, Orlando, FL.
7
Tetraphase Pharmaceuticals, Inc., Watertown, MA.
The fluorocycline TP-271 was evaluated in mouse and non-human (NHP) primate models of inhalational anthrax. BALB/c mice were exposed by nose-only aerosol to 18 - 88 LD50Bacillus anthracis Ames spores. When 21 days of once-daily dosing was initiated at 24 hours post-challenge (post-exposure prophylaxis, PEP), survival for the 3, 6, 12 and 18 mg/kg TP-271 groups was 90%, 95%, 95%, and 84%, respectively. When 21 days of dosing was initiated at 48 hours post-challenge (treatment, Tx) survival for the 6, 12 and 18 mg/kg TP-271 groups was 100%, 91%, and 81%, respectively. No deaths of TP-271-treated mice occurred during the 39-day post-treatment observation period. In the NHP model, cynomolgus macaques received an average dose of 197 LD50B. anthracis Ames spore equivalents using a head-only inhalation exposure chamber and once daily treatment of 1mg/kg TP-271, lasting for 14 or 21 days, was initiated within 3 hours of detection of protective antigen (PA) in the blood. No animals (0/8) survived in the vehicle control group, whereas all 8 infected macaques treated for 21 days, and 4 of 6 in the 14-day treatment group, survived to the end of study (56 days post-challenge). All survivors developed toxin-neutralizing antibody and anti-PA IgG titers, indicating an immunologic response. Based on results in mouse and NHP models, TP-271 shows promise as a countermeasure for the treatment of inhalational anthrax. |
