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Antibacterial pro-drugs for osteomyelitis

The novel compounds from Targanta's bone-seeking antibiotic development program are intended for the treatment and prevention of osteomyelitis (bacterial infection of the bone), a debilitating, difficult infection. The primary pathogens recovered from bone infections are Gram-positive bacteria: S. aureus and coagulase-negative staphylococci together are responsible for three of every four clinical cases in the U.S. The spread of drug resistance among these and other pathogens is cause for alarm. At present, no antibacterial agent is approved for marketing with an osteomyelitis indication. The current standard-of-care parenteral treatment regimen is long, expensive, and inconvenient and is associated with numerous inherent complications. As such there is an unmet need for osteomyelitis antibiotics with good efficacy and without the need for daily intravenous drug administration.

Targanta's synthetic chemists couple potent, proven antibiotics to bone targeting moieties thereby generating molecules which bring the antibiotics to the bone, where their therapeutic potential will be maximized. In this manner, the toxicity of current standard-of-care high dose therapy will be minimized. Diverse classes of antibiotics that are currently used in the clinic have been coupled to bone seeking moieties, thereby allowing Targanta's chemists to tailor the antibiotic's well-understood potency and pharmacokinetic behaviour to the infecting bacteria.

Targanta applies a comprehensive set of in vitro, cell-based, and in vivo assays to characterize its bone-seeking antibiotic candidates. Established animal models of S. aureus bone infection are used to evaluate Targanta's candidate compounds for further testing. Iterative cycles of synthesis and evaluation are then used to optimize the compound's stability, pharmacokinetic behaviour, and activity. Targanta has already created several proprietary bone-targeting antibacterial pro-drugs that are highly effective at binding to infected bone where they regenerate the antibacterial agent in high concentration to maximize bactericidal effects.

A number of product candidates are currently being tested in various osteomyelitis models. Several candidates (based on generic and proprietary antibacterial agents) will be nominated for development in 2006, with an anticipated Phase II clinical trial start for the first product candidate 24 months thereafter.