Oritavancin

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Oritavancin
Oritavancin.svg
Systematic (IUPAC) name
(4R)-22-O-(3-Amino-2,3,6-trideoxy-3-C-methyl-alpha-L-arabinohexopyranosyl)-N3-(p-(p-chlorophenyl)benzyl)vancomycin
Clinical data
Legal status ?
Routes intravenous
Identifiers
CAS number 171099-57-3 YesY
ATC code J01XA05
PubChem CID 16131319
UNII PUG62FRZ2E YesY
Chemical data
Formula C86H97Cl3N10O26 
Mol. mass 1793.1 g/mol
 YesY (what is this?)  (verify)

Oritavancin (INN, also known as LY333328) 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.[1]

In December 2008, the FDA declined to approve it and an EU application was withdrawn.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.[2]

Its chemical structure is similar to vancomycin.[3] It is a lipoglycopeptide.

In vitro activity[edit]

Oritavancin shares certain properties with other members of the glycopeptide class of antibiotics, which includes vancomycin, the current standard of care for serious Gram-positive infections in the United States and Europe.[4] 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.[5] Two posters presented at the meeting also demonstrated that oritavancin was more active than either metronidazole or vancomycin against strains of Clostridium difficile tested.[6]

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[7]

Mechanism[edit]

The 4'-chlorobiphenylmethyl group disrupts the cell membrane of Gram positive bacteria.[8] It also acts by inhibition of transglycosylation and inhibition of transpeptidation.[9]

Clinical progress[edit]

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 infections (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.[10]

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.[11] Results published May 2011.[12]

Regulatory submissions[edit]

USA[edit]

On February 11, 2008, Targanta submitted a New Drug Application (NDA) to the US FDA seeking approval of oritavancin;[13] in April 2008, the FDA accepted the NDA submission for standard review.[14] 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.[15]

Europe[edit]

June 2008, Targanta’s Marketing Authorization Application (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.[16]

References[edit]

  1. ^ Targanta Revives Oritavancin: Next Weapon Against cSSSI? BioWorld Today, November 26, 2007
  2. ^ "Biotechs pick up slack in antibiotics development". 17 May 2011. 
  3. ^ http://www.farm.ucl.ac.be/Full-texts-FARM/Domenech-2009-1.pdf "Interactions of oritavancin, a new lipoglycopeptide derived from vancomycin, with phospholipid bilayers: Effect on membrane permeability and nanoscale lipid membrane organization" 2009
  4. ^ Scheinfeld, N (2007). "A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant Staphylococcus aureus and enterococcus". J Drugs Dermatol. 6 (4): 97–103. PMID 17373167. 
  5. ^ 2007 ICAAC Posters: E-1612 “In Vitro Activity Profile of Oritavancin against a Broad Spectrum of Aerobic and Anaerobic Bacterial Pathogens”/E -1613 “In Vitro Activity Profile of Oritavancin (ORI) Against Organisms Demonstrating Key Resistance Profiles to Other Antimicrobial Agents”/E-1614 “In vitro Time Kill Studies of Oritavancin against Drug-resistant Isolates of Staphylococcus aureus and Enterococci”/E-1615 “Anti-Enterococcal Activity Profile of Oritavancin, a Potent Lipoglycopeptide under Development for Use Against Gram-Positive Infections”/E-1616 “Anti-Streptococcal Activity Profile of Oritavancin, a Potent Lipoglycopeptide under Development for Use Against Gram-Positive Infections”/E-1617 “In Vitro Activity Profile of Oritavancin (ORI) Against Resistant Staphylococcal Populations From a Recent Surveillance Initiative”/E-1620 “Pharmacokinetic Concentrations of Oritavancin Kill Stationary-Phase and Biofilm Staphylococcus aureus In Vitro.” / Targanta Press Release September 19, 2007
  6. ^ ICAAC 2007 Posters: “In Vitro Susceptibility of Genotypically Distinct Clostridium difficile Strains to Oritavancin” and “Activity of Metronidazole, Vancomycin and Oritavancin Against Epidemic Clostridium difficile Spores” / Targanta Press Release September 19, 2007
  7. ^ ASM 2007 Poster: “Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax” / Targanta Press Release May 24, 2007
  8. ^ Belley; McKay, GA; Arhin, FF; Sarmiento, I; Beaulieu, S; Fadhil, I; Parr Jr, TR; Moeck, G (2010). "Oritavancin Disrupts Membrane Integrity of Staphylococcus aureus and Vancomycin-Resistant Enterococci To Effect Rapid Bacterial Killing". Antimicrobial agents and chemotherapy 54 (12): 5369–71. doi:10.1128/AAC.00760-10. PMC 2981232. PMID 20876372. 
  9. ^ Zhanel et al. (2012). "Oritavancin: Mechanism of Action". Clin Infect Dis. doi:10.1093/cid/cir920. 
  10. ^ ICAAC 2003 Late-breaker poster: "Phase III Trial Comparing 3-7 days of Oritavancin vs. 10-14 days of Vancomycin/Cephalexin in the Treatment of Patients with Complicated Skin and Skin Structure Infections (cSSSI)" / InterMune Press Release September 15, 2003
  11. ^ ClinicalTrials.gov NCT00514527
  12. ^ Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: An Analysis of the SIMPLIFI Trial. May 2011. doi:10.1128/AAC.00029-11. 
  13. ^ "Drugs.com, Targanta Submits Oritavancin New Drug Application". Retrieved 2008-02-12. 
  14. ^ "FDA News, Targanta to Get FDA Decision by December". Retrieved 2008-04-10. 
  15. ^ http://www.fiercebiotech.com/press-releases/fda-issues-complete-response-letter-oritavancin Dec 2008.
  16. ^ http://www.nelm.nhs.uk/en/NeLM-Area/News/2009---August/24/European-application-for-investigational-antibiotic-oritavancin-withdrawn-/