Thursday 27 February 2014

Tivorbex (indomethacin); Iroko Pharmaceuticals; For the treatment of acute pain,

Tivorbex (indomethacin); Iroko Pharmaceuticals; For the treatment of acute pain,

Indometacin skeletal.svg
Tivorbex (indomethacin); Iroko Pharmaceuticals; For the treatment of acute pain, Approved February of 2014
2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid
cas 53-86-1
PHILADELPHIA—Iroko Pharmaceuticals, LLC, a global specialty pharmaceutical company dedicated to advancing the science of analgesia, today announced that the U.S. Food and Drug Administration (FDA) has approved TIVORBEX™ (indomethacin) capsules, a nonsteroidal anti-inflammatory drug (NSAID), at 20 mg and 40 mg doses for the treatment of mild to moderate acute pain in adults1.
“TIVORBEX is the second NSAID to be approved from Iroko’s lower dose NSAID pipeline that uses proprietary SoluMatrix Fine Particle Technology™.”
TIVORBEX was approved at dosage strengths that are 20 percent lower than the 25 mg and 50 mg indomethacin products currently on the market2. FDA approval of TIVORBEX was supported by data from two Phase 3 multi-center, placebo-controlled trials that demonstrated significant improvement in pain relief in patients with post-surgical acute pain receiving TIVORBEX compared with patients receiving placebo3.
“The FDA approval of TIVORBEX is another significant milestone for Iroko as it validates our strategic approach towards developing a suite of NSAID products that offer pain management at lower doses,” said John Vavricka, President and CEO of Iroko Pharmaceuticals. “TIVORBEX is the second NSAID to be approved from Iroko’s lower dose NSAID pipeline that uses proprietary SoluMatrix Fine Particle Technology™.”  read at
Indometacin (INN) or indomethacin (USAN and former BAN) is a non-steroidal anti-inflammatory drug (NSAID) commonly used as a prescriptionmedication to reduce feverpain, stiffness, and swelling. It works by inhibiting the production of prostaglandins, molecules known to cause these symptoms. It is marketed under more than seventy different trade names.[1]

Indomethacin was discovered in 1963[8] and it was first approved for use in the U.S. by the Food and Drug Administration in 1965. Its mechanism of action, along with several other NSAIDs that inhibit COX, was described in 1971.[9]

References

  1.  Trade names are listed on DrugBank.ca entry DB00328
  2. Sanders, Lisa (6 January 2012). “Think Like a Doctor: Ice Pick Pain Solved!”The New York Times.
  3.  Garza, I & Schwedt, TJ. “Hemicrania continua.” UpToDate.http://www.uptodate.com/contents/hemicrania-continua. Accessed 8/27/13.
  4.  Smyth JM, Collier PS, Darwish M et al. (September 2004). “Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study”Br J Clin Pharmacol 58 (3): 249–58. doi:10.1111/j.1365-2125.2004.02139.x.PMC 1884560PMID 15327584.
  5.  “INDOMETHACIN”Hazardous Substances Data Bank (HSDB). National Library of Medicine’s TOXNET. Retrieved April 4, 2013.
  6.  Giles W, Bisits A (October 2007). “Preterm labour. The present and future of tocolysis”. Best Pract Res Clin Obstet Gynaecol 21 (5): 857–68. doi:10.1016/j.bpobgyn.2007.03.011.PMID 17459777.
  7.  Akbarpour F, Afrasiabi A, Vaziri N (1985). “Severe hyperkalemia caused by indomethacin and potassium supplementation”. South Med J 78 (6): 756–7. doi:10.1097/00007611-198506000-00039PMID 4002013.
  8.  Hart F, Boardman P (October 1963). “Indomethacin: A New Non-steroid Anti-inflammatory Agent”Br Med J 2 (5363): 965–70. doi:10.1136/bmj.2.5363.965PMC 1873102.PMID 14056924.
  9. Ferreira S, Moncada S, Vane J (Jun 23, 1971). “Indomethacin and aspirin abolish prostaglandin release from the spleen”. Nat New Biol 231 (25): 237–9.doi:10.1038/231237a0PMID 5284362.

Wednesday 26 February 2014

FDA Approves BMS Drug for Rare Fat Disorder

FDA Approves BMS Drug for Rare Fat Disorder

CHEMICAL NAMES
1. Leptin (human), N-methionyl-
2. N-methionylleptin (human)
STRUCTURAL FORMULA
MVPIQKVQDD TKTLIKTIVT RINDISHTQS VSSKQKVTGL DFIPGLHPIL 50
TLSKMDQTLA VYQQILTSMP SRNVIQISND LENLRDLLHV LAFSKSCHLP 100
WASGLETLDS LGGVLEASGY STEVVALSRL QGSLQDMLWQ LDLSPGC 147
Disulfide bridge location
97-147
http://www.ama-assn.org/resources/doc/usan/metreleptin.pdf
MOLECULAR FORMULA C714H1167N191O221S6
MOLECULAR WEIGHT 16.16 kDa
MANUFACTURER Amylin Pharmaceuticals, Inc.
CODE DESIGNATION r-metHuLeptin
An analog of human leptin, metreleptin, has been approved in Japan and is currently under review by the FDA in the US for the treatment of diabetes and/or hypertriglyceridemia, in patients with rare forms of lipodystrophy, syndromes characterized by abnormalities in adipose tissue distribution, and severe metabolic abnormalities. Bristol-Myers Squibb has submitted a New Drug Approval (NDA) for metreleptin to the US Food and Drug Administration (FDA) Office of Orphan Products Development. In a three-year study of metreleptin in patients with lipodystrophy organized by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health, metreleptin treatment was associated with a significant decrease in blood glucose (A1c decreased from 9.4% at baseline to 7.0% at study end) and triglyceride concentration (from 500 mg/dl at baseline to 200 mg/dl at study end). The Juvenile Diabetes Research Foundation has also partnered with Amylin Pharmaceuticals and researchers at the University of Texas Southwestern Medical Center to study whether metreleptin can be used to improve the treatment of type 1 diabetes.
N-Methionylleptin (human)
Recombinant human OB protein, purified to homogenicity as a 16-kDa monomer
Treatment of obesity and related disorders (metabolic homeostasis regulator)
LAUNCHED 2013 IN JAPAN BI SHINOGI
186018-45-1 CAS NO
BLA STN125390
  • Brand name: Myalept
  • Generic name: metreleptin
  • Company: Amylin Pharmaceuticals, Inc.
  • Treatment for: Lipodystrophy
Feb 25, 2014 FDA Approves Myalept to Treat Generalized Lipodystrophy
Dec 12, 2013FDA Advisory Committee Votes on Investigational Medicine Metreleptin
Apr  3, 2012Amylin Completes Biologics License Application for Metreleptin to Treat Diabetes and/or Hypertriglyceridemia in Patients With Rare Forms of Lipodystrophy
Dec 20, 2010Amylin Submits Clinical and Nonclinical Sections of Rolling Biologics License Application for Metreleptin to Treat Rare Forms of Lipodystrophy
LEPTIN
PDB 1ax8 EBI.jpg
Structure of the obese protein leptin-E100.
FDA approves Myalept to treat rare metabolic disease
On Feb. 24, 2014, the U.S. Food and Drug Administration approved Myalept (metreleptin for injection) as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy.Generalized lipodystrophy is a condition associated with a lack of fat tissue. Patients with congenital generalized lipodystrophy are born with little or no fat tissue. Patients with acquired generalized lipodystrophy generally lose fat tissue over time. Because the hormone leptin is made by fat tissue, patients with generalized lipodystrophy have very low leptin levels. Leptin regulates food intake and other hormones, such as insulin.Patients with both types of generalized lipodystrophy often develop severe insulin resistance at a young age and may have diabetes mellitus that is difficult to control or very high levels of triglycerides in the blood (hypertriglyceridemia) that can lead to inflammation of the pancreas.
“Myalept is the first approved therapy indicated for treating the complications associated with congenital or acquired generalized lipodystrophy and provides a needed treatment option for patients with this orphan disease,” said Mary Parks, M.D., deputy director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research.
The safety and effectiveness of Myalept, an analog of leptin made through recombinant DNA technology, were evaluated in an open-label, single-arm study that included 48 patients with congenital or acquired generalized lipodystrophy who also had diabetes mellitus, hypertriglyceridemia, and/or elevated levels of fasting insulin. The trial showed reductions in HbA1c (a measure of blood sugar control), fasting glucose, and triglycerides.
Anti-drug antibodies with neutralizing activity to leptin and/or Myalept may develop, which could result in severe infections or loss of treatment effectiveness. T-cell lymphoma has been reported in patients with acquired generalized lipodystrophy, both treated and not treated with Myalept, so healthcare professionals should carefully consider the benefits and risks of treatment with Myalept in patients with significant hematologic abnormalities and/or acquired generalized lipodystrophy. Myalept is contraindicated in patients with general obesity. Myalept is not approved for use in patients with HIV-related lipodystrophy or in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of generalized lipodystrophy.
Because of the risks associated with the development of neutralizing antibodies and lymphoma, Myalept is available only through the Myalept Risk Evaluation and Mitigation Strategy (REMS) Program. Under this REMS program, prescribers must be certified with the program by enrolling in and completing training. Pharmacies must be certified with the program and only dispense Myalept after receipt of the Myalept REMS Prescription Authorization Form for each new prescription.
Myalept is also approved with a Medication Guide and instructions for use that provides patients with important information about the medication. The guide will be distributed each time a patient fills a prescription.
The FDA is requiring seven studies (post-marketing requirements) for Myalept, including a long-term prospective observational study (product exposure registry) of patients treated with Myalept, a study to assess for the immunogenicity (antibody formation) of Myalept, and an assessment and analysis of spontaneous reports of potential serious risks related to the use of Myalept. Eight additional studies are being requested as post-marketing commitments.
In clinical trials, the most common side effects observed in patients treated with Myalept were low blood sugar (hypoglycemia), headache, decreased weight, and abdominal pain.
Myalept is marketed by San Diego-based Amylin Pharmaceuticals, L.L.C.
For more information:
Metreleptin is an analogue of the human hormone leptin being developed by Amylin Pharmaceuticals (a subsidiary of Bristol-Myers Squibb) for the subcutaneous treatment of metabolic disorders including lipodystrophy. The compound is expected to improve insulin sensitivity, hypertriglyceridaemia and hyperglycaemia in patients with lipodystrophy who are unresponsive to conventional treatment.
Metreleptin has been approved in Japan as a leptin therapy for the treatment of lipodystrophy. Amylin has also completed a submission for regulatory approval to the US FDA for metreleptin in the treatment of diabetes mellitus and/or hypertriglyceridaemia in patients with rare forms of lipodystrophy.
Clinical development of the drug is also underway in the USA for the treatment of type 1 diabetes. Amgen was previously assessing the use of metreleptin as a treatment for amenorrhoea; however, it appears that development in this indication has been discontinued. This article summarizes the milestones in the development of metreleptin leading to this first approval for lipodystrophy.
Metreleptin is a leptin replacement therapy first launched in Japan in 2013 for the treatment of congenital lipodystrophy. Amylin filed for approval in the U.S. in 2010 for the treatment of diabetes and/or hypertriglyceridemia in patients with rare forms of lipodystrophy. In 2013, the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) recommended the approval for the treatment of pediatric and adult patients with generalized lipodystrophy , but not for partial lipodystrophy.
Phase II clinical studies are also under way at Beth Israel Deaconess Medical Center for the treatment of lipodystrophy syndrome associated with AIDS. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is conducting phase II clinical trials for the treatment of nonalcoholic steatohepatitis. Phase II are ongoing at the National Institute for Diabetes and Digestive and Kidney Diseases for the treatment of non-alcoholic fatty liver disease (NAFLD) associated with lipodystropy. Early clinical studies had also been ongoing for the treatment of leptin deficiencies.
The University Texas Southwestern Medical Center at Dallas is evaluating metreleptin for the treatment of type 1 diabetes. Beth Israel Deaconess Medical Center is conducting phase II clinical trials for the treatment of amenorrhea. Amgen had been conducting clinical trials for this indication and for the treatment of type 1 diabetes and depression; however no recent development has been reported for this research.
In 2011, Amylin and Takeda put on hold their clinical trials with metreleptin in combination with pramlintide for the treatment of obesity in order to investigate an antibody-related laboratory finding. Amylin is currently evaluating the compound as monotherapy for the treatment of obesity. The companies had been conducting phase II clinical trials of metreleptin not in combination with pramlintide for the treatment of obesity; however, no recent development has been reported for this research.
Originally developed at the Rockefeller University, an exclusive license to metreleptin was granted to Amgen in 1995. In 2009, the drug candidate was licensed to Takeda by Amylin worldwide for the treatment of obesity. In 2010, orphan drug designation was assigned in the U.S. for the treatment of metabolic disorders secondary to lipodystrophy and for the treatment of leptin deficiency secondary to generalized lipodystrophy and partial familial lipodystrophy.
In 2012, orphan drug designation was assigned in Japan for the treatment of diabetes or hyperlipidemia due to lipoatrophy. In 2012, orphan drug designation was assigned in the E.U. for the treatment of Barraquer-Simons syndrome, Berardinelli-Seip syndrome, familial partial lipodystrophy and Lawrence syndrome. In 2014, AstraZeneca acquired the global rigths for development, manufacture and commercialization of the product.
……………
Other exemplary leptins for use in the methods and compositions described herein include, but are not limited to, the amino acid sequence for mature, recombinant methionyl human leptin (herein called rmetHu-Leptin 1-146 or Metreleptin) having the amino acid sequence:
MVPIQKVQDDTKTLIKTΓVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQTLA VYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASG YSTEWALSRLQGSLQDMLWQLDLSPGC (SEQ ID NO:274).

Friday 21 February 2014

FDA Accepts Filing of NDA for IV Antibiotic Oritavancin with Priority Review

FDA Accepts Filing of NDA for IV Antibiotic Oritavancin with Priority Review

File:Oritavancin.svg
Oritavancin
(4R)-22-O-(3-Amino-2,3,6-trideoxy-3-C-methyl-alpha-L-arabinohexopyranosyl)-N3-(p-(p-chlorophenyl)benzyl)vancomycin
(3S, 6R, 7R, 22R, 23S, 26S, 36R, 38aR) -22 – (3-Amino-2 ,3,6-trideoxy-3-C-methyl-alpha-L-mannopyranosyloxy) -3 – (carbamoylmethyl ) -10,19-dichloro-44-[2-O-[3 - (4'-chlorobiphenyl-4-ylmethylamino) -2,3,6-trideoxy-3-C-methyl-alpha-L-mannopyranosyl] – beta-D-glucopyranosyloxy] -
CAS No.171099-57-3
CBNumber:CB92451283
Molecular Formula:C86H97Cl3N10O26
Formula Weight:1793.12
Also known as NDISACC-(4-(4-chlorophenyl)benzyl)A82846B and LY333328,N-(4-(4-chlorophenyl)benzyl)A82846B
Abbott (Supplier), Lilly (Originator), InterMune (Licensee)
The medicines company—
  1. the Oritavancin Program Results.pdf

    phx.corporate-ir.net/External.File?item…t=1
    Jul 2, 2013 - Inhibits two key steps of cell wall synthesis: – Transglycosylation. – Transpeptidation. • Disrupts bacterial membrane integrity. Differentiated from  

FDA Accepts Filing of NDA for IV Antibiotic Oritavancin with Priority Review
PARSIPPANY, NJ — (Marketwired) — 02/19/14 — The Medicines Company (NASDAQ: MDCO) today announced that the U.S. Food and Drug Administration (FDA) has accepted the filing of a new drug application (NDA) for oritavancin, an investigational intravenous antibiotic, with priority review. The Medicines Company is seeking approval of oritavancin for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), administered as a single dose.
In December 2013, the FDA designated oritavancin as a Qualified Infectious Disease Product (QIDP). The QIDP designation provides oritavancin priority review, and an additional five years of exclusivity upon approval of the product for the treatment of ABSSSI. Priority review means the FDA’s goal is to take action on the application within six months, compared to 10 months under standard review. The FDA action date (PDUFA date) for oritavancin is August 6, 2014.
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 Therapeuticsin late 2005.[1]
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.[2]
Its structure is similar to vancomycin[3] It is a lipoglycopeptide

About Oritavancin

Oritavancin is an investigational intravenous antibiotic for which The Medicines Company is seeking approval in the treatment of ABSSSI caused by susceptible gram-positive bacteria, including MRSA. In clinical trials, the most frequently reported adverse events associated with oritavancin were nausea, headache, vomiting and diarrhea. Hypersensitivity reactions have been reported with the use of antibacterial agents including oritavancin.

 

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 aureusmethicillin-resistant Staphylococcus aureusEnterococci, 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]

oritavancin

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]

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

USA

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

June 2008, Targanta’s Marketing Authorization Application (MAA) for oritavancin was submitted and accepted for review by the European Medicines Agency (EMEA),[16] but the company later withdrew the application in Aug 2009.[17]

About The Medicines Company

The Medicines Company’s purpose is to save lives, alleviate suffering, and contribute to the economics of healthcare by focusing on 3,000 leading acute/intensive care hospitals worldwide. Its vision is to be a leading provider of solutions in three areas: acute cardiovascular care, surgery and perioperative care, and serious infectious disease care. The company operates in the Americas, Europe and the Middle East, and Asia Pacific regions with global centers today in Parsippany, NJ, USA and Zurich, Switzerland.
“We look forward to working with the FDA during the review process, and sharing the knowledge we have gained in our studies of oritavancin,” said Matthew Wikler, MD, Vice President and Medical Director, Infectious Disease Care for The Medicines Company. “We believe that upon approval, oritavancin, administered as a single dose for the treatment of ABSSSI, will offer new options for both physicians and their patients for the treatment of these infections.”
The oritavancin NDA is based on data from two Phase 3 clinical trials, SOLO I and SOLO II, which were conducted under a Special Protocol Assessment (SPA) agreement with the FDA. These Phase 3 trials evaluated the efficacy and safety of a single 1200mg dose of oritavancin compared to 7 to 10 days of twice-daily vancomycin in adults with ABSSSI, including infections caused by MRSA. The combined SOLO studies were conducted in 1,959 patients (modified intent-to -treat population, or mITT), with 405 of the patients suffering from an ABSSSI with a documented MRSA infection.
Figure US20130172237A1-20130704-C00001oritavancin
Drug substance
Oritavancin diphosphate
  • LY 333328 diphosphate
  • LY333328 diphosphate
  • Oritavancin diphosphate
  • UNII-VL1P93MKZN
  • 192564-14-0 CAS NO
INTRODUCTION
Oritavancin
Oritavancin inhibits cell wall synthesis by complexing with the terminal D-Ala-D-Ala of a nascent peptidoglycan chain and also to the pentaglycine bridge, thus inhibiting transglyco- sylation and transpeptidation. Unlike other glycopeptides, oritavancin is able to bind to depsipeptides including D-Ala-D-Lac, which fa- cilitates its inhibition of cell wall synthesis even in organisms exhibiting VanA-type resistance. Oritavancin forms homodimers prior to binding to D-Ala-D-Ala or D-Ala-D-Lac, which increases its binding affinity for the target site.The p-chloro-phenylbenzyl side chain of oritavancin interacts with the cell membrane, exerting two beneficial effects. This binding acts to main- tain the antibacterial in a prime position for peptidoglycan interactions and it also imparts oritavancin with the ability to disrupt the bac- terial membrane potential and thus increase membrane permeability.[22,23] Oritavancin has been shown to dissipate membrane potential in both stationary and exponential phase growing bacteria, which is rare and may carry clinical implications in terms of its activity against slowly growing organisms and biofilms. The dual mechanism of action could also theoretically increase effectiveness and reduce the risk of resist- ance selection. In addition to the aforemen- tioned mechanisms, it has also been hypothesized that oritavancin inhibits RNA synthesis.
vancomycin, desmethylvancomycin, eremomycin, teicoplanin (complex of five compounds), dalbavancin, oritavancin, telavancin, and A82846B (LY264826) having structures A, B, C, D, E, F, G and H:
Figure imgf000002_0001
R = B-2-Acetylamido-glucopyraπosyl- Attorney Docket No 33746-704 602
Figure imgf000003_0001
Figure imgf000003_0002
Dalbavancin, oritavancin and telavancin are semisynthetic lipoglycopeptides that demonstrate promise for the treatment of patients with infections caused by multi-drug-resistant Gram-positive pathogens. Each of these agents contains a heptapeptide core, common to all glycopeptides, which enables them to inhibit transglycosylation and transpeptidation (cell wall synthesis). Modifications to the heptapeptide core result in different in vitro activities for the three semisynthetic lipoglycopeptides. All three lipoglycopeptides contain lipophilic side chains, which prolong their half-life, help to anchor the agents to the cell membrane and increase their activity against Gram-positive cocci. In addition to inhibiting cell wall synthesis, telavancin and oritavancin are also able to disrupt bacterial membrane integrity and increase membrane permeability; oritavancin also inhibits RNA synthesis. Enterococci exhibiting the VanA phenotype (resistance to both vancomycin and teicoplanin) are resistant to both dalbavancin and telavancin, whileoritavancin retains activity. Dalbavancin, oritavancin and telavancin exhibit activity against VanB vancomycin-resistant enterococci.
All three lipoglycopeptides demonstrate potent in vitro activity against Staphylococcus aureus and Staphylococcus epidermidis regardless of their susceptibility to meticillin, as well as Streptococcus spp. Both dalbavancin and telavancin are active against vancomycin-intermediate S. aureus (VISA), but display poor activity versus vancomycin-resistant S. aureus (VRSA). Oritavancin is active against both VISA and VRSA. Telavancin displays greater activity against Clostridium spp. than dalbavancin, oritavancin or vancomycin. The half-life of dalbavancin ranges from 147 to 258 hours, which allows for once-weekly dosing, the half-life of oritavancin of 393 hours may allow for one dose per treatment course, while telavancin requires daily administration. Dalbavancin and telavancin exhibit concentration-dependent activity and AUC/MIC (area under the concentration-time curve to minimum inhibitory concentration ratio) is the pharmacodynamic parameter that best describes their activities.Links
Oritavancin’s activity is also considered concentration-dependent in vitro, while in vivo its activity has been described by both concentration and time-dependent models; however, AUC/MIC is the pharmacodynamic parameter that best describes its activity. Clinical trials involving patients with complicated skin and skin structure infections (cSSSIs) have demonstrated that all three agents are as efficacious as comparators. The most common adverse effects reported with dalbavancin use included nausea, diarrhoea and constipation, while injection site reactions, fever and diarrhoea were commonly observed withoritavancin therapy. Patients administered telavancin frequently reported nausea, taste disturbance and insomnia. To date, no drug-drug interactions have been identified for dalbavancin, oritavancin or telavancin. All three of these agents are promising alternatives for the treatment of cSSSIs in cases where more economical options such as vancomycin have been ineffective, in cases of reduced vancomycin susceptibility or resistance, or where vancomycin use has been associated with adverse events.
Oritavancin diphosphate (oritavancin) is a semi-synthetic lipoglycopeptide derivative of a naturally occurring glycopeptide. Its structure confers potent antibacterial activity against gram-positive bacteria, including vancomycin-resistant enterococci (VRE), methicillin- and vancomycin-resistant staphylococci, and penicillin-resistant streptococci. The rapidity of its bactericidal activity against exponentially-growing S. aureus (≧3-log reduction within 15 minutes to 2 hours against MSSA, MRSA, and VRSA) is one of the features that distinguishes it from the prototypic glycopeptide vancomycin (McKay et al., J Antimicrob Chemother. 63(6):1191-9 (2009), Epub 2009 Apr. 15).
Oritavancin inhibits the synthesis of peptidoglycan, the major structural component of the bacterial cell wall by a mechanism that is shared with glycopeptides, such as vancomycin (Allen et al., Antimicrob Agents Chemother 41(1):66-71 (1997); Cegelski et al., J Mol Biol 357:1253-1262 (2006); Arhin et al., Poster C1-1471: Mechanisms of action of oritavancin in Staphylococcus aureus [poster]. 47th Intersci Conf Antimicro Agents Chemo, Sep. 17-20, 2007; Chicago, Ill.). Oritavancin, like vancomycin, binds to the Acyl-D-Alanyl-D-Alanine terminus of the peptidoglycan precursor, lipid-bound N-acetyl-glucosamine-N-acetyl-muramic acid-pentapeptide (Reynolds, Eur J Clin Microbiol Infect Dis 8(11):943-950 (1989); Nicas and Allen, Resistance and mechanism of action.
In: Nagarajan R, editor. Glycopeptide antibiotics. New York: Marcel Dekker 195-215 (1994); Allen et al., Antimicrob Agents Chemother 40(10):2356-2362 (1996); Allen and Nicas, FEMS Microbiology Reviews 26:511-532 (2003); Kim et al., Biochemistry 45:5235-5250 (2006)). However, oritavancin inhibits cell wall biosynthesis even when the substrate is the altered peptidoglycan precursor that is present in VRE and vancomycin-resistant S. aureus (VRSA). Thus, the spectrum of oritavancin antibacterial activity extends beyond that of vancomycin to include glycopeptide-resistant enterococci and staphylococci (Ward et al., Expert Opin Investig Drugs 15:417-429 (2006); Scheinfeld, J Drugs Dermatol 6:97-103 (2007)). Oritavancin may inhibit resistant bacteria by interacting directly with bacterial proteins in the transglycosylation step of cell wall biosynthesis (Goldman and Gange, Curr Med Chem 7(8):801-820 (2000); Halliday et al., Biochem Pharmacol 71(7):957-967 (2006); Wang et al., Poster C1-1474: Probing the mechanism of inhibition of bacterial peptidoglycan glycotransferases by glycopeptide analogs. 47th Intersci Conf Antimicro Agents Chemo, Sep. 17-20, 2007). Oritavancin also collapses transmembrane potential in gram positive bacteria, leading to rapid killing (McKay et al., Poster C1-682: Oritavancin disrupts transmembrane potential and membrane integrity concomitantly with cell killing in Staphylococcus aureus and vancomycin-resistant Enterococci. 46th Intersci Conf Antimicro Agents Chemo, San Francisco, Calif., Sep. 27-30, 2006). These multiple effects contribute to the rapid bactericidal activity of oritavancin.
Vancomycin (U.S. Patent 3,067,099); A82846A, A82846B, and A82846C (U.S. Patent 5,312,738, European Patent Publication 256,071 A1); PA-42867 factors A, C, and D (U.S. Patent4,946,941 and European Patent Publication 231,111 A2); A83850 (U.S. Patent No. 5,187,082); avoparcm (U.S. Patent 3,338,786 and U.S. Patent 4,322,343); actmoidin, also known as K288 (J. Antibiotics Series A 14:141 (1961); helevecardin (Chem. Abstracts 110:17188 (1989) and Japanese Patent Application 86/157,397); galacardin (Chem. Abstracts 110:17188 (1989) and Japanese Patent Application 89/221,320); and M47767 (European Patent Publication 339,982).
Oritavancin is in clinical development against serious gram-positive infections, where administration of the drug is via intravenous infusion using several dosages administered over a series of days. The development of alternative dosing regimens for the drug could expand treatment options available to physicians. The present invention is directed to novel dosing regimens.
Means for the preparation of the glycopeptide antibiotics, including oritavancin and analogs thereof, may be found, for example, in U.S. Pat. No. 5,840,684,
ORITAVANCIN DIPHOSPHATE

LinksSYNTHESIS

LY-333328 was synthesized by reductocondensation of the glycopeptide antibiotic A82846B (I) with 4′-chlorobiphenyl-4-carboxaldehyde (II) by means of sodium cyanoborohydride in refluxing methanol.
J Antibiot1996, 49, (6) :575-81
LY-333328 was synthesized by reductocondensation of the glycopeptide antibiotic A82846B (I) with 4′-chlorobiphenyl-4-carboxaldehyde (II) by means of sodium cyanoborohydride in refluxing methanol.
…………………..Links
EXAMPLE 4
Preparation of Compound 229
A three liter 3-necked flask was fitted with a
condenser, nitrogen inlet and overhead mechanical stirring apparatus. The flask was charged with pulverized A82846B acetate salt (20.0 g, 1.21 × 10-3 mol) and methanol (1000 mL) under a nitrogen atmosphere. 4′-chlorobiphenylcarboxaldehyde (2.88 g, 1.33 × 10-2 mol, 1.1 eq.) was added to this stirred mixture, followed by methanol (500 mL). Finally, sodium cyanoborohydride (0.84 g, 1.33 × 10-2 mol, 1.1 eq.) was added followed by methanol (500 mL). The resulting mixture was heated to reflux (about 65°C).
After 1 hour at reflux, the reaction mixture attained homogeneity. After 25 hours ac reflux, the heat source was removed and the clear reaction mixture was measured with a pH meter (6.97 at 58.0°C). 1 N NaOH (22.8 mL) was added
dropwise to adjust the pH to 9.0 (at 54.7°C). The flask was equipped with a distillation head and the mixture was concentrated under partial vacuum to a weight of 322.3 grams while maintaining the pot temperature between 40-45°C.
The distillation head was replaced with an addition funnel containing 500 mL of isopropanol (IPA). The IPA was added dropwise to the room temperature solution over 1 hour. After approximately 1/3 of the IPA was added, a granular precipitate formed. The remaining IPA was added at a faster rate after precipitation had commenced. The flask was weighed and found to hold 714.4 grams of the IPA/methanol slurry.
The flask was re-equipped with a still-head and
distilled under partial vacuum to remove the remaining methanol. The resulting slurry (377.8 g) was allowed to chill in the freezer overnight. The crude product was filtered through a polypropylene pad and rinsed twice with 25 mL of cold IPA. After pulling dry on the funnel for 5 minutes, the material was placed in the vacuum oven to dry at 40°C. A light pink solid (22.87 g (theory = 22.43 g) ) was recovered. HPLC analysis versus a standard indicated 68.0% weight percent of Compound 229 (4- [4-chlorophenyl] benzyl-A82846B] in the crude solid, which translated into a
corrected crude yield of 69.3%.
The products of the reaction were analyzed by reverse-phase HPLC utilizing a Zorbax SB-C18 column with ultraviolet light (UV; 230 nm) detection. A 20 minute gradient solvent system consisting of 95% aqueous buffer/5% CH3CN at time=0 minutes to 40% aqueous buffer/60% CH3CN at time=20 minutes was used, where the aqueous buffer was TEAP (5 ml CH3CN, 3 ml phosphoric acid in 1000 ml water).
………………….

Oritavancin (also termed N-(4-(4-chlorophenyl)benzyl)A82846B and LY333328) has the following Formula III:
Figure imgf000029_0001

ReferencesLinks

  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 ofStaphylococcus 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 difficileStrains 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.00760-10PMC 2981232PMID 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.  “Pharmaceutical Business Review, EMEA accepts Targanta’s oritavancin MAA for review”. Retrieved 2008-06-26.
  17.  http://www.nelm.nhs.uk/en/NeLM-Area/News/2009—August/24/European-application-for-investigational-antibiotic-oritavancin-withdrawn-/
  18. http://onlinelibrary.wiley.com/doi/10.1111/j.1574-6976.2003.tb00628.x/pdf
  19. http://www.pjps.pk/wp-content/uploads/pdfs/26/5/Paper-30.pdf
  20. Antimicrobial Agents and Chemotherapy, 2003 ,  vol. 47,   5  p. 1700 – 1706
  21. Antimicrobial Agents and Chemotherapy, 1999 ,  vol. 43,   1  p. 115 – 120
  22. Antimicrobial Agents and Chemotherapy, 1997 ,  vol. 41,   10  p. 2165 – 2172
  23. Tetrahedron, 2004 ,  vol. 60,   47  p. 10611 – 10618………… NMRhttp://www.sciencedirect.com/science/article/pii/S0040402004015108
LinksCooper, R.D.G.; Snyder, N.J.; Zweifel, M.J.; et al.; Reductive alkylation of glycopeptide antibiotics: Synthesis and antibacterial activity. J Antibiot 1996, 49, 6, 575-81.
 Fromtling, R.A.; Castaer, J.; LY-333328. Drugs Fut 1998, 23, 1, 17.
Cooper, R.D.G.; Huff, B.E.; Nicas, T.I.; Quatroche, J.T.; Rodriguez, M.J.; Snyder, N.J.; Staszak, M.A.; Thompson, R.C.; Wilkie, S.C.; Zweifel, M.J. (Eli Lilly and Company); Glycopeptide antibiotic derivs. EP 0817797; JP 1999502534; WO 9630401 .
Cooper, R.D.G.; Huff, B.E.; Nicas, T.I.; Quatroche, J.T.; Rodriguez, M.J.; Snyder, N.J.; Staszak, M.A.; Thompson, R.C.; Wilkie, S.C.; Zweifel, M.J. (Eli Lilly and Company); Glycopeptide antibiotic derivs. EP 0667353; EP 1016670; EP 1031576 .
EP0435503A1 *Dec 11, 1990Jul 3, 1991Eli Lilly And CompanyImprovements in or relating to gylcopeptide derivatives
US4639433 *Aug 14, 1985Jan 27, 1987Eli Lilly And CompanyGlycopeptide derivatives
US4698327 *Apr 18, 1986Oct 6, 1987Eli Lilly And CompanyNovel glycopeptide derivatives
US20040106590 *Aug 29, 2003Jun 3, 2004Barry EisensteinMethods and reagents for treating infections of clostridium difficile and diseases associated therewith
US20050197333Dec 22, 2004Sep 8, 2005Van Duzer John H.Rifamycin analogs and uses thereof
US20070014849Sep 20, 2006Jan 18, 2007Daniela JabesUse of ramoplanin to treat diseases associated with the use of antibiotics
US20030176327 *Oct 18, 2002Sep 18, 2003Cassell Gail HoustonAntibiotics for treating biohazardous bacterial agents
US20040147441Aug 25, 2003Jul 29, 2004Leach Timothy S.Methods and reagents for preventing bacteremias
WO1999010006A1Aug 18, 1998Mar 4, 1999Lilly Co EliTherapy for staphylococcus aureus
WO2000066144A2Apr 19, 2000Nov 9, 2000Lilly Co EliMonthly doses of glycopeptide antibiotics for treatment of streptococcus pneumoniae infections
WO2008097364A2Sep 24, 2007Aug 14, 2008Targanta Therapeutics CorpUse of oritavancin for prevention and treatment of anthrax
WO1998052592A1 *May 5, 1998Nov 26, 1998Lilly Co EliUrea and thiourea derivatives of glycopeptides
WO2002036612A1 *Nov 2, 2001May 10, 2002Univ Cambridge TechAntibacterial agents comprising conjugates of glycopeptides and peptidic membrane-associating elements
WO2007138999A1May 25, 2007Dec 6, 2007Shionogi & CoGlycopeptide antibiotic derivative
WO2009081958A1Dec 25, 2008Jul 2, 2009Shionogi & CoGlycosylated glycopeptide antibiotic derivative
EP2314599A1Nov 24, 2005Apr 27, 2011National University Corporation Nagoya UniversityGlycopeptide antibiotic monomer derivatives
US5919756 *May 1, 1997Jul 6, 1999Eli Lilly And CompanyAmides
US5919771 *Apr 30, 1998Jul 6, 1999Eli Lilly And CompanyUrea and thiourea derivatives of glycopeptides
US7078380Nov 2, 2001Jul 18, 2006Cambridge University Technical Services LimitedAntibacterial agents comprising conjugates of glycopeptides and peptidic membrane associating elements
US8481696Dec 25, 2008Jul 9, 2013Shionogi & Co., Ltd.Glycosylated glycopeptide antibiotic derivatives
Links