Oritavancin
Encyclopedia
Oritavancin is a novel semi-synthetic glycopeptide antibiotic
being developed for the treatment of serious Gram-positive
infections. Originally discovered and developed by Eli Lilly
, oritavancin was acquired by InterMune in 2001 and then by Targanta Therapeutics
in late 2005.
In Dec 2008 the FDA declined to approve it, and an EU application was withdrawn.
In 2009 the development rights were acquired by The Medicine Co. who are running clinical trials for a possible new FDA application in 2013.
Its structure is similar to vancomycin
It is a lipoglycopeptide
.
, the current standard of care for serious Gram-positive infections in the United States and Europe. Data presented at the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in September 2007 demonstrated that oritavancin possesses potent and rapid bactericidal activity in vitro against a broad spectrum of both resistant and susceptible Gram positive bacteria, including Staphylococcus aureus
, methicillin-resistant Staphylococcus aureus
, Enterococci, and Streptococci. Two posters presented at the meeting also demonstrated that oritavancin was more active than either metronidazole or vancomycin against strains of Clostridium difficile
tested.
Anthrax : Research presented at the American Society for Microbiology (ASM)
107th Annual General Meeting in May 2007, suggested oritavancin’s potential utility as a therapy for exposure to Bacillus anthracis
, the gram-positive bacterium that causes anthrax
, having demonstrated efficacy in a mouse model both pre- and post-exposure to the bacterium
methyl group disrupts the cell membrane of gram positive bacteria.
(cSSSI) caused by Gram-positive bacteria. The primary endpoints of both studies were successfully met, with oritavancin achieving efficacy with fewer days of therapy than the comparator agents (vancomycin
followed by cephalexin). In addition, oritavancin showed a significantly improved safety profile with a 19.2 percent relative reduction in the overall incidence of adverse events versus vancomycin/cephalexin (p<0.001) in the second and larger pivotal trial.
A Phase 2 clinical study was planned to run until May 2008 entitled “Single or Infrequent Doses for the Treatment of Complicated Skin and Skin Structure Infections (SIMPLIFI),” evaluating the efficacy and safety of either a single dose of oritavancin or an infrequent dose of oritavancin compared to the previously studied dosing regimen of 200 mg oritavancin given once daily for 3 to 7 days. Results published May 2011.
(NDA) to the US
FDA
seeking approval of oritavancin; in April 2008, the FDA accepted the NDA submission for standard review. On 9 Dec 2008 the FDA said insufficient data for approval of oritavancin had been provided and they requested a further phase 3 clinical study to include more patients with MRSA.
(MAA) for oritavancin was submitted and accepted for review by the European Medicines Agency
(EMEA), but the company later withdrew the application in Aug 2009.
Glycopeptide antibiotic
Glycopeptide antibiotics are a class of antibiotic drugs. The class is composed of glycosylated cyclic or polycyclic nonribosomal peptides. Significant glycopeptide antibiotics include vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, and decaplanin....
being developed for the treatment of serious Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
infections. Originally discovered and developed by Eli Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
, oritavancin was acquired by InterMune in 2001 and then by Targanta Therapeutics
Targanta Therapeutics Corporation
Targanta Therapeutics Corporation was a biopharmaceutical company headquartered in Cambridge, Massachusetts. The company also had operations in Indianapolis, Montreal and Toronto. Targanta completed its initial public offering on October 9, 2007 and trades on the Nasdaq market under the symbol: TARG...
in late 2005.
In Dec 2008 the FDA declined to approve it, and an EU application was withdrawn.
In 2009 the development rights were acquired by The Medicine Co. who are running clinical trials for a possible new FDA application in 2013.
Its structure is similar to vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
It is a lipoglycopeptide
Lipoglycopeptide
Lipoglycopeptides are a class of antibiotic that have lipophilic side-chains linked to glycopeptides. The class includes oritavancin, telavancin and dalbavancin.Telavancin is the most potent of the 3 against Clostridium spp....
.
In vitro activity
Oritavancin shares certain properties with other members of the glycopeptide class of antibiotics, which includes vancomycinVancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
, the current standard of care for serious Gram-positive infections in the United States and Europe. Data presented at the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in September 2007 demonstrated that oritavancin possesses potent and rapid bactericidal activity in vitro against a broad spectrum of both resistant and susceptible Gram positive bacteria, including Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
, methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus is a bacterium responsible for several difficult-to-treat infections in humans. It is also called multidrug-resistant Staphylococcus aureus and oxacillin-resistant Staphylococcus aureus...
, Enterococci, and Streptococci. Two posters presented at the meeting also demonstrated that oritavancin was more active than either metronidazole or vancomycin against strains of Clostridium difficile
Clostridium difficile
Clostridium difficile , also known as "CDF/cdf", or "C...
tested.
Anthrax : Research presented at the American Society for Microbiology (ASM)
American Society for Microbiology
The American Society for Microbiology is a professional organization for scientists who study viruses, bacteria, fungi, algae, and protozoa as well as other aspects of microbiology. Microbiology is the study of organisms too small to be seen with the naked eye and which must be viewed with a...
107th Annual General Meeting in May 2007, suggested oritavancin’s potential utility as a therapy for exposure to Bacillus anthracis
Bacillus anthracis
Bacillus anthracis is the pathogen of the Anthrax acute disease. It is a Gram-positive, spore-forming, rod-shaped bacterium, with a width of 1-1.2µm and a length of 3-5µm. It can be grown in an ordinary nutrient medium under aerobic or anaerobic conditions.It is one of few bacteria known to...
, the gram-positive bacterium that causes anthrax
Anthrax
Anthrax is an acute disease caused by the bacterium Bacillus anthracis. Most forms of the disease are lethal, and it affects both humans and other animals...
, having demonstrated efficacy in a mouse model both pre- and post-exposure to the bacterium
Mechanism
The 4'-chlorobiphenylBiphenyl
Biphenyl is an organic compound that forms colorless crystals. It has a distinctively pleasant smell. Biphenyl is an aromatic hydrocarbon with a molecular formula 2...
methyl group disrupts the cell membrane of gram positive bacteria.
Clinical progress
Results have been presented (in 2003) but possibly not yet published from two pivotal Phase 3 clinical trials testing the efficacy of daily intravenous oritavancin for the treatment of complicated skin and skin-structure infectionsComplicated skin and skin-structure infections
Complicated skin and skin structure infections also known as cSSSIs are the name for common infections treated in the hospital setting. The main treatment of these infections is antimicrobial therapy along with possible surgery...
(cSSSI) caused by Gram-positive bacteria. The primary endpoints of both studies were successfully met, with oritavancin achieving efficacy with fewer days of therapy than the comparator agents (vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
followed by cephalexin). In addition, oritavancin showed a significantly improved safety profile with a 19.2 percent relative reduction in the overall incidence of adverse events versus vancomycin/cephalexin (p<0.001) in the second and larger pivotal trial.
A Phase 2 clinical study was planned to run until May 2008 entitled “Single or Infrequent Doses for the Treatment of Complicated Skin and Skin Structure Infections (SIMPLIFI),” evaluating the efficacy and safety of either a single dose of oritavancin or an infrequent dose of oritavancin compared to the previously studied dosing regimen of 200 mg oritavancin given once daily for 3 to 7 days. Results published May 2011.
USA
On February 11, 2008, Targanta submitted a New Drug ApplicationNew drug application
The New Drug Application is the vehicle in the United States through which drug sponsors formally propose that the Food and Drug Administration approve a new pharmaceutical for sale and marketing...
(NDA) to the US
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
seeking approval of oritavancin; in April 2008, the FDA accepted the NDA submission for standard review. On 9 Dec 2008 the FDA said insufficient data for approval of oritavancin had been provided and they requested a further phase 3 clinical study to include more patients with MRSA.
Europe
June 2008, Targanta’s Marketing Authorization ApplicationMarketing Authorization Application
Marketing Authorization Application is an application to market a drug or medicine....
(MAA) for oritavancin was submitted and accepted for review by the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
(EMEA), but the company later withdrew the application in Aug 2009.