Targanta Therapeutics presents preclinical data on Oritavancin against Clostridium difficile infection

Oct 26 2008

Targanta Therapeutics Corporation has released the in vivo data from a preclinical study comparing the activity of its antibiotic drug candidate, oritavancin, to vancomycin in a hamster model of Clostridium difficile infection.

Results are being presented in a poster (B-067) today at 12:15 pm EDT entitled, “Efficacy of Oritavancin against Clostridium difficile (CD) infection in the Hamster Model of CD infection (CDI)” at the combined annual meetings of the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the 46th Infectious Disease Society of America (IDSA), taking place in Washington, DC.

In the study, oritavancin activity at 10, 50 and 100 mg/kg/day and a pegylated (PEG400) formulation of oritavancin at 100 mg/kg/day were compared to vancomycin activity at 50 mg/kg/day against clindamycin-induced C. difficile infection in Golden Syrian hamsters. The Golden Syrian hamster model is widely recognized as the gold standard for C. difficile infection. The hamsters were treated orally for 5 days and their progress measured for a total of 20 days.

Results showed that all doses of oritavancin were highly effective in prolonging survival compared to untreated controls, and prevented relapse longer than treatment with vancomycin at equivalent dose. Oritavancin at 100 mg/kg exhibited superior efficacy to vancomycin at day 12: 100% survival was observed for animals treated with oritavancin compared to 0% survival with vancomycin. The PEG400 formulation of oritavancin protected all hamsters from relapsing, yielding 100% survival out to day 20, compared to vancomycin (0% survival).

These data are consistent with previously presented results from in vitro gut model studies demonstrating that, while both oritavancin and vancomycin were effective in treating clindamycin-induced C. difficile infection, only oritavancin appeared active against the spore forms of the bacteria, suggesting that oritavancin may prevent recurrence of disease.

Targanta plans to continue advancing this program and initiating additional studies that would possibly enable the testing of orally-administered oritavancin for the treatment of C. difficile in the first half of 2009.

C. difficile are anaerobic, gram-positive, spore-forming bacteria that are a major cause of morbidity in the hospitalized elderly. Recent studies estimate that currently there may be as many as 500,000 cases of C. difficile infection occurring annually in the United States, contributing to between 15,000 and 30,000 deaths.1 C. difficile infection is associated with production of toxins in the colon, resulting in disease ranging from uncomplicated diarrhea to severe pseudomembranous colitis. The later more severe disease can be complicated by toxic megacolon, requiring removal of the colon, and sometimes results in death. It is postulated that after the normal gut flora balance is compromised or eradicated by the use of antibiotics, C. difficile spores refractory to current antimicrobial therapies persist, causing recurrent infections.

Oritavancin is a novel semi-synthetic lipoglycopeptide antibiotic candidate with potent bactericidal (killing) activity against a broad spectrum of Gram-positive bacteria. In its intravenous (IV) formulation, the product candidate has been tested in over 2,400 individuals and has completed two Phase 3 studies for the treatment of complicated skin and skin structure infections (cSSSI) in which the primary endpoints were met. Targanta submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in February 2008 seeking to commercialize oritavancin for the treatment of cSSSI; the FDA accepted the NDA submission for standard review, establishing an action date of December 8, 2008. Targanta’s Marketing Authorization Application (MAA) for oritavancin was accepted for review by the European Medicines Agency (EMEA) in June 2008. Targanta is also developing an oral version of oritavancin for the possible treatment of Clostridium difficile.