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Trial Results for Investigational Antibiotic Telavancin Announced

SOUTH SAN FRANCISCO, Calif., Nov. 2 /PRNewswire-FirstCall/ -- Theravance, Inc. announced today that results from a Phase 2 clinical study with the investigational antibiotic telavancin (TD-6424) in patients with complicated Gram-positive skin and skin structure infections were recently presented at the 42nd annual Infectious Disease Society of America (IDSA) meeting in Boston. In addition, pre-clinical in vitro and in vivo studies with telavancin were recently presented at the 44th annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in Washington D.C.

Telavancin, a rapidly bactericidal injectable antibiotic with multiple mechanisms of action, is a novel lipoglycopeptide that was discovered by Theravance through the application of multivalent drug design in a research program dedicated to finding new antibiotics for serious infections due to Staphylococcus aureus (including multi-drug resistant strains) and other Gram-positive pathogens. Telavancin is currently in Phase 3 studies for the treatment of complicated skin and skin structure infections (cSSSI).

Among the highlights of the telavancin studies presented at IDSA and ICAAC were:

1. Results from FAST, an exploratory Phase 2 clinical study, comparing telavancin with standard therapy in 167 patients with complicated Gram-positive skin and skin structure infections. - Efficacy of telavancin was similar to standard therapy. - Among all-treated patients, in the subset with methicillin-resistant S. aureus (MRSA) at baseline, cure rates were 82% for patients treated with telavancin versus 69% for standard therapy. - Minimum inhibitory concentrations (MICs) were lower for telavancin for all tested strains of S. aureus (0.25 mcg/mL or less) compared to vancomycin. - The rate of adverse events (AEs) and discontinuations for AEs were similar in the telavancin-treated and standard therapy groups. 2. Results from a series of in vitro experiments that demonstrated telavancin's bactericidal activity against S. aureus is mediated by multiple mechanisms. This antibacterial activity results from: - interaction with D-Ala-D-Ala-containing peptidoglycan intermediates that leads, at submicromolar concentrations, to inhibition of the transglycosylation step of peptidoglycan synthesis during cell wall synthesis. - at higher concentrations, direct effects on bacterial plasma membrane function, such as potential dissipation and increased permeability, are observed. These results suggest a novel and important additional mechanism and provide a rational basis for the improved pharmacodynamic activity and low potential for resistance observed for telavancin. 3. Results from a series of in vitro experiments with vancomycin-sensitive enterococci (VSE) and vancomycin-resistant enterococci (VRE), showing that the antibacterial activity of telavancin is mediated by multiple mechanisms of action. In VRE, changes in cell permeability and the resulting dissipation of the membrane potential is likely the primary mechanism. In VSE and other vancomycin-sensitive organisms, the combined effects of cell wall synthesis inhibition and membrane permeability changes mediate the antibacterial activity of telavancin and may contribute to its rapid bactericidal effect. 4. In an in vivo model of meningitis using a strain of penicillin-resistant Streptococcus pneumoniae, telavancin was significantly more effective compared to a standard regimen (combination of ceftriaxone and vancomycin). 5. Results from an in vitro study comparing the activity of telavancin and vancomycin against a collection of S. aureus, enriched for isolates tolerant to vancomycin, demonstrated that telavancin produced significantly greater killing than equal concentrations of vancomycin. 6. In an in vitro comparison of telavancin with vancomycin, daptomycin, linezolid and quinupristin/dalfopristin against glycopeptide intermediate susceptible Staphylococcus species (GISS), including hetero-resistant GISS (hGISS), and vancomycin resistant S. aureus (VRSA), telavancin was shown to produce rapid, concentration-dependent bactericidal activity against GISS, hGISS and, to a lesser extent, VRSA. The rate of telavancin killing was diminished in the presence of human serum, however bactericidal activity was maintained. 7. In an in vitro study against Bacillus anthracis, the causative agent of anthrax, telavancin demonstrated potent activity against all 15 B. anthracis strains tested.

Source: Theravance, Inc.

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