Oxazolidinones are small molecule drugs that bind to 23S ribosomal RNA in a specific location and inhibit protein translation. Unlike Zyvox, tedizolid lacks an acetamide group, long assumed to be essential for oxazolidinones to bind to their targets. Strains of MRSA become resistant to oxazolidinones due to mutations at the acetamide site.
“Eliminating the acetamide group minimizes the ability of pathogens to evolve resistance mutations,” says Dr. Stein. Pathogens become resistant to tedizolid 10 times more slowly than to Zyvox, he remarks.
Scientists at Dong-A made tedizolid even better by replacing the acetamide group with a smaller hydroxy methyl group and then adding a phosphate. This makes tedizolid a highly soluble, yet inactive prodrug. The body’s natural serum phosphatases cleave the phosphate ester bond, releasing a highly soluble and active molecule. The highly soluble phosphate group also allows for IV formulation and improves oral bioavailability.
In general, when oxazolidinones are modified to improve potency, they become less soluble and more difficult to formulate as IV drugs. The Korean scientists found “a very clever solution to a problem facing those trying to develop second-generation oxazolidinones,” says Dr. Stein.
Trius Therapeutics announced results of its Phase II trial in June 2009. Patients with complicated skin infections were treated orally with tedizolid for five to seven days. The overall cure rate was 98% for the 200 milligram dose, and patients with MRSA skin infections had a 100% cure rate.
Trius is running two Phase III trials. Top-line data from the first Phase III trial was released in December 2011. The primary endpoint of efficacy noninferiority to Zyvox was met, and noninferiority for safety was also demonstrated, Dr. Stein reports. The second trial is an IV-to-oral transition study, which is still ongoing.