Targanta Therapeutics Corporation has received a Complete Response Letter from the US Food and Drug Administration (FDA) regarding its New Drug Application (NDA) for oritavancin for the treatment of complicated skin and skin structure infections (cSSSI).
The FDA indicated in its letter that they cannot approve the application for oritavancin in its current form and will require Targanta to perform an additional well-controlled clinical study to demonstrate efficacy and safety in order to gain approval. The FDA requested that a sufficient number of patients with methicillin-resistant Staphylococcus aureus (MRSA) as the cause of cSSSI be enrolled in the study to demonstrate the effectiveness of oritavancin in this subset of patients. The FDA further suggested that the clinical study evaluate the effect of oritavancin on macrophage function and monitor for the potential for subsequent infections that could possibly be related to macrophage dysfunction due to the long terminal half-life of oritavancin.
The FDA also requested that the clinical study collect additional information on phlebitis rates. In its letter to Targanta, the FDA stated the company's NDA did not demonstrate the safety and efficacy of oritavancin for treatment of cSSSI. The FDA reasoned that ARRI, the second and larger of two phase-3 clinical studies which met a 10 per cent non-inferiority margin, provided evidence of activity of oritavancin but did not provide substantial evidence alone or in combination with ARRD, the smaller of two phase-3 clinical studies, to support the efficacy and safety of oritavancin.
Regarding ARRD, the FDA determined that the study did not provide sufficient evidence of activity because the 95 per cent confidence interval between oritavancin and vancomycin was not less than 10 per cent. FDA also mentioned that, in ARRI, oritavancin did not appear to perform well in patients with MRSA and, in ARRD, the number of patients with MRSA was insufficient to address the performance of the drug candidate in treating these patients.
The FDA mentioned several safety findings from the two pivotal studies for cSSSI including the higher rate of study discontinuations for lack of efficacy among oritavancin-treated patients, the greater number of oritavancin-treated patients who died or had a serious adverse event of sepsis, septic shock and related events, and more oritavancin-treated patients who experienced adverse events of osteomyelitis and other sepsis.
Oritavancin is a novel, semi-synthetic lipoglycopeptide antibiotic candidate with potent bactericidal (killing) activity against a broad spectrum of gram-positive bacteria. The oritavancin NDA submission included data from 19 clinical trials, including two pivotal phase-3 clinical trials examining the safety and efficacy of oritavancin in the treatment of cSSSI, both of which met their primary endpoints. The NDA dossier also included data from more than 2,100 individuals and in vitro activity data on oritavancin against more than 9,000 clinical bacterial isolates, including a broad range of gram-positive strains resistant to commonly used antibiotics such as oxacillin, methicillin, vancomycin, daptomycin, and linezolid.
Targanta Therapeutics is a biopharmaceutical company focused on developing and commercializing innovative antibiotics to treat serious infections in the hospital and other institutional settings.