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FDA grants accelerated approval to first drug for Duchenne muscular dystrophy
New therapy addresses unmet medical need
The U.S. Food and Drug Administration today approved Exondys 51 (eteplirsen) injection, the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD.
September 19, 2016
The U.S. Food and Drug Administration today approved Exondys 51 (eteplirsen) injection, the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD.
“Patients with a particular type of Duchenne muscular dystrophy will now have access to an approved treatment for this rare and devastating disease,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “In rare diseases, new drug development is especially challenging due to the small numbers of people affected by each disease and the lack of medical understanding of many disorders. Accelerated approval makes this drug available to patients based on initial data, but we eagerly await learning more about the efficacy of this drug through a confirmatory clinical trial that the company must conduct after approval.”
DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age, and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one out of every 3,600 male infants worldwide.
People with DMD progressively lose the ability to perform activities independently and often require use of a wheelchair by their early teens. As the disease progresses, life-threatening heart and respiratory conditions can occur. Patients typically succumb to the disease in their 20s or 30s; however, disease severity and life expectancy vary.
Exondys 51 was approved under the accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally provide a meaningful advantage over existing treatments. Approval under this pathway can be based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients (how a patient feels or functions or whether they survive). This pathway provides earlier patient access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.
The accelerated approval of Exondys 51 is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. A clinical benefit of Exondys 51, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy.
Under the accelerated approval provisions, the FDA is requiring Sarepta Therapeutics to conduct a clinical trial to confirm the drug’s clinical benefit. The required study is designed to assess whether Exondys 51 improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.
The most common side effects reported by participants taking Exondys 51 in the clinical trials were balance disorder and vomiting.
The FDA granted Exondys 51 fast track designation, which is a designation to facilitate the development and expedite the review of drugs that are intended to treat serious conditions and that demonstrate the potential to address an unmet medical need. It was also granted priority review and orphan drug designation.Priority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as clinical trial tax credits, user fee waiver and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.
The manufacturer received a rare pediatric disease priority review voucher, which comes from a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. This is the seventh rare pediatric disease priority review voucher issued by the FDA since the program began.
Exondys 51 is made by Sarepta Therapeutics of Cambridge, Massachusetts.
|Systematic (IUPAC) name|
Defibrotide sodium is an oligonucleotide mixture with profibrinolytic properties. The chemical name of defibrotide sodium is polydeoxyribonucleotide, sodium salt. Defibrotide sodium is a polydisperse mixture of predominantly single-stranded (ss) polydeoxyribonucleotide sodium salts derived from porcine intestinal tissue having a mean weighted molecular weight of 13-20 kDa, and a potency of 27-39 and 28-38 biological units per mg as determined by two separate assays measuring the release of a product formed by contact between defibrotide sodium, plasmin and a plasmin substrate. The primary structure of defibrotide sodium is shown below.
DEFITELIO (defibrotide sodium) injection is a clear, light yellow to brown, sterile, preservative-free solution in a single-patient-use vial for intravenous use. Each milliliter of the injection contains 80 mg of defibrotide sodium and 10 mg of Sodium Citrate, USP, in Water for Injection, USP. Hydrochloric Acid, NF, and/or Sodium Hydroxide, NF, may have been used to adjust pH to 6.8-7.8.
Defibrotide is the sodium salt of a mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. It has been shown to have antithrombotic, anti-inflammatory and anti-ischemic properties (but without associated significant systemic anticoagulant effects). It is marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries, but is currently not approved in the USA. The manufacturer is Gentium.
Defibrotide is used to treat or prevent a failure of normal blood flow (occlusive venous disease, OVD) in the liver of patients who have had bone marrow transplants or received certain drugs such as oral estrogens, mercaptopurine, and many others.
In 2012, an IND was filed in Japan seeking approval of the compound for the treatment of veno-occlusive disease.
Approved 3/30/3016 US FDA, defibrotide sodium, (NDA) 208114
To treat adults and children who develop hepatic veno-occlusive disease with additional kidney or lung abnormalities after they receive a stem cell transplant from blood or bone marrow called hematopoietic stem cell transplantation
Polydeoxyribonucleotides from bovine lung or other mamalian organs with molecular weight between 15,000 and 30,000 Da
Defibrotide is a polydisperse mixture of oligonucleotides produced by random, chemical cleavage (depolymerisation) of porcine DNA. It is predominantly single stranded, of varying base sequence, lengths and conformations; unfolded, folded or combined. The mean oligonucleotide length is 50 bases with a mean molecular weight of 17 ± 4 kDa. No individually defined component is at more than femtomolar concentration. The only meaningful scientific information that can be obtained about the biochemical nature of defibrotide (aside from determination of percentage of each nucleobase) is a measurement of its average length and its average percentage double stranded character. Therefore, it can be established that this active substance is of highly heterogenic nature.
Jazz Pharmaceuticals plc announced that the FDA has accepted for filing with Priority Review its recently submitted New Drug Application (NDA) for defibrotide. AS ON OCT 2015
Defibrotide is an investigational agent proposed for the treatment of patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with evidence of multi-organ dysfunction (MOD) following hematopoietic stem-cell transplantation (HSCT).
Priority Review status is designated for drugs that may offer major advances in treatment or provide a treatment where no adequate therapy exists. Based on timelines established by the Prescription Drug User Fee Act (PDUFA), FDA review of the NDA is expected to be completed by March 31, 2016.
“The FDA’s acceptance for filing and Priority Review status of the NDA for defibrotide is an important milestone for Jazz and reflects our commitment to bringing meaningful medicines to patients who have significant unmet needs,” said Karen Smith, M.D., Ph.D., Global Head of Research and Development and Chief Medical Officer of Jazz Pharmaceuticals. “We look forward to continuing to work closely with the FDA to obtain approval for defibrotide for patients with hepatic VOD with evidence of MOD in the U.S. as quickly as possible, as there are no other approved therapies for treating this rare, often fatal complication of HSCT.”
The NDA includes safety and efficacy data from three clinical studies of defibrotide for the treatment of hepatic VOD with MOD following HSCT, as well as a retrospective review of registry data from the Center for International Blood and Marrow Transplant Research. The safety database includes over 900 patients exposed to defibrotide in the clinical development program for the treatment of hepatic VOD.
The compound was originally developed under a collaboration between Sanofi and Gentium. In December 2001, Gentium entered into a license and supply agreement with Sigma-Tau Pharmaceuticals, pursuant to which the latter gained exclusive rights to distribute, market and sell the product for the treatment of VOD in the U.S. This agreement was expanded in 2005 to include all of North America, Central America and South America.
Defibrotide was granted orphan drug designations from the FDA in July 1985, May 2003 and January 2007 for the treatment of thrombotic thrombocytopenic purpura (TTP), for the treatment of VOD and for the prevention of VOD, respectively. Orphan drug was also received in the E.U. for the prevention and treatment of hepatic veno-occlusive disease (VOD) in 2004 and for the prevention of graft versus host disease (GvHD) in 2013.
Defibrotide is available as an oral, intravenous, and intramuscular formulation. Its oral bioavailability is in the range of 58-70% of theparenteral forms. T1/2 alpha is in the range of minutes while T1/2 beta is in the range of hours in studies with oral radiolabelleddefibrotide. These data suggest that defibrotide, in spite of its macromolecular nature, is absorbed well after oral administration. Due to the drug’s short half-life, it is necessary to give the daily dose divided in 2 to 4 doses (see below).
In 2014, Jazz Pharmaceuticals (parent of Gentium) acquired the rights of the product in U.S. and in the Americas
Mode of action
The drug appears to prevent the formation of blood clots and to help dissolve blood clots by increasing levels of prostaglandin I2, E2, and prostacyclin, altering platelet activity, increasing tissue plasminogen activator (tPA-)function, and decreasing activity of tissue plasminogen activator inhibitor. Prostaglandin I2 relaxes the smooth muscle of blood vessels and prevents platelets from adhering to each other. Prostaglandin E2 at certain concentrations also inhibits platelet aggregation. Moreover, the drug provides additional beneficial anti-inflammatory and antiischemic activities as recent studies have shown. It is yet unclear, if the latter effects can be utilized clinically (e.g., treatment of ischemic stroke).
Unlike heparin and warfarin, defibrotide appears to have a relatively mild anticoagulant activity, which may be beneficial in the treatment of patients at high risk of bleeding complications. Nevertheless, patients with known bleeding disorders (e.g., hemophilia A) or recent abnormal bleedings should be treated cautiously and under close medical supervision.
The drug was marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries. It is currently not approved in the USA. The manufacturer is Gentium.
Defibrotide also received fast track designation from the FDA for the treatment of severe VOD in recipients of stem cell transplants. In 2011, the compound was licensed to Medison Pharma by Gentium in Israel and Palestine. The license covers the management of named-patient sales program and local registration, authorization, marketing, reimbursement and medical affairs for the treatment of peripheral vascular disease.
Defibrotide is used to treat or prevent a failure of normal blood flow (Veno-occlusive disease, VOD) in the liver of patients having had bone marrow transplants or received certain drugs such as oral estrogens, mercaptopurine, and many others. Without intensive treatment, VOD is often a fatal condition, leading to multiorgan failure. It has repeatedly been reported that defibrotide was able to resolve the condition completely and was well tolerated.
Other indications are: peripheral obliterative arterial disease, thrombophlebitis, and Raynaud’s phenomenon. In very high doses, defibrotide is useful as treatment of acute myocardial infarction. The drug may also be used for the pre- and postoperative prophylaxis of deep venous thrombosis and can replace the heparin use during hemodialytic treatments.
Potential indications in the future
Other recent preclinical studies have demonstrated that defibrotide used in conjunction with Granulocyte Colony-Stimulating Factor (rhG-CSF) significantly increases the number of Peripheral Blood Progenitor Cells (Stem cells). The benefit of this increase in stem cells may be crucial for a variety of clinical indications, including graft engineering procedures and gene therapy programs. This would expand the clinical usefulness of defibrotide to a complete distinct area.
Very recently (since early 2006) combination therapy trials (phase I/II) with defibrotide plus melphalan, prednisone, and thalidomide in patients with multiple myeloma have been conducted. The addition of defibrotide is expected to decrease the myelosuppressive toxicity of melphalan. However, is too early for any definitive results at that stage.
Cautions and contraindications
- The efficacy of the drug has been reported to be poorer in patients with diabetes mellitus.
- Pregnancy: The drug should not be used during pregnancy, because adequate and well controlled human studies do not exist.
- Lactation: No human data is available. In order to avoid damage to the newborn, the nursing mother should discontinue either the drug or breastfeeding, taking into account the importance of treatment to the mother.
- Known Bleeding Disorders or Bleeding Tendencies having occurred recently: Defibrotide should be used cautiously. Before initiation of treatment, the usual coagulation values should be obtained as baseline and regularly controlled under treatment. The patient should be observed regularly regarding local or systemic bleeding events.
Increased bleeding and bruising tendency, irritation at the injection site, nausea, vomiting, heartburn, low blood pressure. Serious allergic reactions have not been observed so far.
Use of heparin with defibrotide may increase the aPTT, reflecting reduced ability of the body to form a clot. Nothing is known about the concomitant application of other anticoagulants than heparin and dextran containing plasma-expanders, but it can be anticipated that the risk of serious bleeding will be increased considerably.
G-CSF (CAS registry number 143011-2-7/Merck Index, 1996, page 4558) is a haematopoietic growth factor which is indispensable in the proliferation and differentiation of the progenitor cells of granulocytes; it is a 18-22 kDa glycoprotein normally produced in response to specific stimulation by a variety of cells, including monocytes, fibroblasts and endothelial cells. The term defibrotide (CAS registry number 83712-60-1) normally identifies a polydeoxyribonucleotide obtained by extraction (US 3,770,720 and US 3,899,481) from animal and/or vegetable tissue; this polydeoxyribonucleotide is normally used in the form of a salt of an alkali metal, generally sodium. Defibrotide is used principally for its anti- thrombotic activity (US 3,829,567) although it may be used in different applications, such as, for example, the treatment of acute renal insufficiency (US 4,694,134) and the treatment of acute myocardial ischaemia (US 4,693,995). United States patents US 4,985,552 and US 5,223,609, finally, describe a process for the production of defibrotide which enables a product to be obtained which has constant and well defined physico-chemical characteristics and is also free from any undesired side-effects
- “Jazz Pharma Acquiring Gentium for $1B”. Gen. Eng. Biotechnol. News (paper) 34 (2). January 15, 2014. p. 10.
- Haussmann U, Fischer J, Eber S, Scherer F, Seger R, Gungor T (June 2006). “Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy”. Haematologica 91 (6): 795–800. PMID 16769582.
- Coccheri S, Andreozzi GM, D’Addato M, Gensini GF (June 2004). “Effects of defibrotide in patients with chronic deep insufficiency. The PROVEDIS study”. Int Angiol 23 (2): 100–7.PMID 15507885.
- Palmer KJ, Goa KL. Defibrotide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs 1993;45:259-94.
- Fisher J, Holland TK, Pescador R, Porta R, Ferro L (January 1996). “Study on pharmacokinetics of radioactive labelled defibrotide after oral or intravenous administration in rats”. Thromb. Res. 81 (1): 55–63. doi:10.1016/0049-3848(95)00213-8. PMID 8747520.
- http://www.gentium.it/Defibrotide.aspx (information provided by manufacturer)
- “Melphalan: profile and news”. Archived from the original on 2007-09-28. (on cytostatic combination therapy)
- Beşişik SK, Oztürk GB, Calişkan Y, Sargin D (March 2005). “Complete resolution of transplantation-associated thrombotic microangiopathy and hepatic veno-occlusive disease by defibrotide and plasma exchange”. Turk J Gastroenterol 16 (1): 34–7. PMID 16252186.
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|EP0416678A1 *||10 Aug 1990||13 Mar 1991||Crinos Industria Farmacobiologica S.p.A.||Topical compositions containing Defibrotide|
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|1||*||CARLO-STELLA, C. (1) ET AL: “Defibrotide significantly enhances peripheral blood progenitor cell mobilization induced by recombinant human granulocyte colony – stimulating factor ( rhG – CSF.” BLOOD, ( NOVEMBER 16, 2000 ) VOL. 96, NO. 11 PART 1, PP. 553A. PRINT. MEETING INFO.: 42ND ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY SAN FRANCISCO, CALIFORNIA, USA DECEMBER 01-05, 2000 AMERICAN SOCIETY OF HEMATOLOGY. , XP002176349|
|2||*||GURSOY A: “PREPARATION, CHARACTERIZATION AND ANTI-INFLAMMATORY EFFECT OF DEFIBROTIDE LIPOSOMES” PHARMAZIE,DD,VEB VERLAG VOLK UND GESUNDHEIT. BERLIN, vol. 48, no. 7, 1 July 1993 (1993-07-01), pages 549-550, XP000372658 ISSN: 0031-7144|
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|WO2009115465A1 *||13 Mar 2009||24 Sep 2009||Gentium Spa||Synthetic phosphodiester oligonucleotides and therapeutical uses thereof|
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|US7915384||5 Jan 2009||29 Mar 2011||Children’s Hospital Medical Center||Chimeric peptides for the regulation of GTPases|
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|US8674075||13 Aug 2012||18 Mar 2014||Children’s Medical Center Corporation||Chimeric peptides for the regulation of GTPases|
|US8980862||12 Nov 2010||17 Mar 2015||Gentium S.P.A.||Defibrotide for use in prophylaxis and/or treatment of Graft versus Host Disease (GVHD)|
|oral, i.m., i.v.|
|Bioavailability||58 – 70% orally (i.v. and i.m. = 100%)|
|Biological half-life||t1/2-alpha = minutes; t1/2-beta = a few hours|
|CAS Registry Number|
///////////Approved, 3/30/3016, US FDA, defibrotide sodium, NDA 208114, FDA 2016
For Immediate Release
March 30, 2016
The U.S. Food and Drug Administration today approved Defitelio (defibrotide sodium) to treat adults and children who develop hepatic veno-occlusive disease (VOD) with additional kidney or lung abnormalities after they receive a stem cell transplant from blood or bone marrow called hematopoietic stem cell transplantation (HSCT). This is the first FDA-approved therapy for treatment of severe hepatic VOD, a rare and life-threatening liver condition.
HSCT is a procedure performed in some patients to treat certain blood or bone marrow cancers. Immediately before an HSCT procedure, a patient receives chemotherapy. Hepatic VOD can occur in patients who receive chemotherapy and HSCT. Hepatic VOD is a condition in which some of the veins in the liver become blocked, causing swelling and a decrease in blood flow inside the liver, which may lead to liver damage. In the most severe form of hepatic VOD, the patient may also develop failure of the kidneys and lungs. Fewer than 2 percent of patients develop severe hepatic VOD after HSCT, but as many as 80 percent of patients who develop severe hepatic VOD do not survive.
“The approval of Defitelio fills a significant need in the transplantation community to treat this rare but frequently fatal complication in patients who receive chemotherapy and HSCT,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
The efficacy of Defitelio was investigated in 528 patients treated in three studies: two prospective clinical trials and an expanded access study. The patients enrolled in all three studies had a diagnosis of hepatic VOD with liver or kidney abnormalities after HSCT. The studies measured the percentage of patients who were still alive 100 days after HSCT (overall survival). In the three studies, 38 to 45 percent of patients treated with Defitelio were alive 100 days after HSCT. Based on published reports and analyses of patient-level data, the expected survival rates 100 days after HSCT would be 21 to 31 percent for patients with severe hepatic VOD who received only supportive care or interventions other than Defitelio.
The most common side effects of Defitelio include abnormally low blood pressure (hypotension), diarrhea, vomiting, nausea and nosebleeds (epistaxis). Serious potential side effects of Defitelio that were identified include bleeding (hemorrhage) and allergic reactions. Defitelio should not be used in patients who are having bleeding complications or who are taking blood thinners or other medicines that reduce the body’s ability to form clots.
The FDA granted the Defitelio application priority review status, which facilitates and expedites the development and review of certain drugs in light of their potential to benefit patients with serious or life-threatening conditions. Defitelio also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.
Defitelio is marketed by Jazz Pharmaceuticals based in Palo Alto, California
An application to use AstraZeneca’s Brilinta to treat patients with a history of heart attack has been placed on a fast track regulatory pathway in the US, meaning that approval could be granted within just six months.
The US Food and Drug Administration has assigned a priority review based on Phase III data showing that Brilinta (ticagrelor), along-side low-dose aspirin, can improve long-term prevention of atherothrombotic cardiovascular events in patients with a history of myocardial infarction. The move signals the regulator’s belief that the drug could offer a benefit over existing approaches.
US priority review for Eisai cancer drug lenvatinib
Eisai has been boosted by news that regulators in the USA have agreed to a quicker review of its anticancer agent lenvatinib.
The US Food and Drug Administration has granted a priority review to Eisai’s New Drug Application for lenvatinib as a treatment for progressive radioiodine-refractory differentiated thyroid cancer. This means that the agency has assigned a Prescription Drug User Fee Act action date of April 14 next year, eight months after the NDA was submitted.
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FDA Approves Ryanodex for the Treatment of Malignant Hyperthermia
WOODCLIFF LAKE, N.J.(BUSINESS WIRE) July 23, 2014 —
Eagle Pharmaceuticals, Inc. (“Eagle” or “the Company”)
(Nasdaq:EGRX) today announced that the U. S. Food and Drug Administration (FDA)
has approved Ryanodex (dantrolene sodium) for injectable
suspension indicated for
the treatment of malignant hyperthermia (MH), along
with the appropriate supportive measures.
MH is an inherited and potentially fatal disorder triggered
by certain anesthesia agents
in genetically susceptible individuals. FDA had designated
Ryanodex as an Orphan Drug in
August 2013. Eagle has been informed by the FDA that it will learn over the next four to
six weeks if it has been granted the seven year Orphan Drug market exclusivity.
READ MORE AT
PATENTS, CAS NO ETC
Hydrocodone bitartrate is morphinan-6-one, 4,5-epoxy-3-methoxy-17-methyl-, (5α)-, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1), hydrate (2:5); also known as 4,5α-Epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5); a fine white crystal or crystalline powder, which is derived from the opium alkaloid, thebaine; and may be represented by the following structural formula:
Molecular weight = 494.5
Purdue’s hydrocodone bitartrate tablets granted priority review designation
Purdue Pharma has been granted priority review designation by the US Food and Drug Administration (FDA) for its hydrocodone bitartrate extended-release tablets for treatment of chronic pain.
The once-daily, single-entity pain medication was formulated to incorporate abuse-deterrent properties designed to make the product more difficult to manipulate for misuse or abuse by various routes of administration.http://www.pharmaceutical-technology.com/news/newspurdues-hydrocodone-bitartrate-tablets-granted-priority-review-designation-4313765?WT.mc_id=DN_News
(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] –
Also known as NDISACC-(4-(4-chlorophenyl)benzyl)A82846B and LY333328,N-(4-(4-chlorophenyl)benzyl)A82846B
The medicines company—
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.
In Dec 2008 the FDA declined to approve it, and an EU application was withdrawn.
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. 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
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.
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.
On February 11, 2008, Targanta submitted a New Drug Application (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.
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.
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.
- LY 333328 diphosphate
- LY333328 diphosphate
- Oritavancin diphosphate
- 192564-14-0 CAS NO
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:
R = B-2-Acetylamido-glucopyraπosyl- Attorney Docket No 33746-704 602
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.
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,
J Antibiot1996, 49, (6) :575-81
(3S,6R,7R,22R,23S,26S,36R,38aR)-3-(Carbamoylmethyl)-10,19-dichloro-7,28,30,32-tetrahydroxy-6-(N-methyl-D-leucylamido)-2,5,24,38,39-pentaoxo-22-(L-vancosaminyloxy)-44-[2-O-(L-vancosaminyl)-beta-D-glucopyranosyloxy]-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,36-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid; A82846B (I)
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.
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:
- Targanta Revives Oritavancin: Next Weapon Against cSSSI? BioWorld Today, November 26, 2007
- “Biotechs pick up slack in antibiotics development”. 17 May 2011.
- 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
- 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.
- 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
- 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
- ASM 2007 Poster: “Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax” / Targanta Press Release May 24, 2007
- 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.
- Zhanel et al. (2012). “Oritavancin: Mechanism of Action”. Clin Infect Dis.doi:10.1093/cid/cir920.
- 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
- ClinicalTrials.gov NCT00514527
- 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.
- “Drugs.com, Targanta Submits Oritavancin New Drug Application”. Retrieved 2008-02-12.
- “FDA News, Targanta to Get FDA Decision by December”. Retrieved 2008-04-10.
- http://www.fiercebiotech.com/press-releases/fda-issues-complete-response-letter-oritavancin Dec 2008.
- “Pharmaceutical Business Review, EMEA accepts Targanta’s oritavancin MAA for review”. Retrieved 2008-06-26.
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The US Food and Drug Administration (FDA) has granted a six-month Priority Review designation to Genzyme’s New Drug Application (NDA) for Cerdelga (eliglustat)
13 dec 2013
Genzyme’s Cerdelga NDA receives US FDA priority review designationpharmabiz.comThe US Food and Drug Administration (FDA) has granted a six-month Priority Review designation to Genzyme’s New Drug Application (NDA) for Cerdelga (eliglustat), an investigational oral therapy for adult patients with Gaucher disease
THERAPEUTIC CLAIM Treatment of lysosomal storage disorders
1. Octanamide, N-[(1R,2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(1-
pyrrolidinylmethyl)ethyl]-, (2R,3R)-2,3-dihydroxybutanedioate (2:1)
MOLECULAR FORMULA C23H36N2O4 . ½ C4H6O6
MOLECULAR WEIGHT 479.6
MANUFACTURER Genzyme Corp.
CODE DESIGNATION Genz-112638
CAS REGISTRY NUMBER 928659-70-5
old article cut paste
Genzyme Announces Positive New Data from Two Phase 3 Studies for Oral Eliglustat Tartrate for Gaucher Disease
Eliglustat tartrate (USAN)
The randomized, double-blind, placebo-controlled study had a primary efficacy endpoint of improvement in spleen size in patients treated with eliglustat tartrate. Patients were stratified at baseline by spleen volume. In the study, a statistically significant improvement in spleen size was observed at nine months in patients treated with eliglustat tartrate compared with placebo. Spleen volume in patients treated with eliglustat tartrate decreased from baseline by a mean of 28 percent compared with a mean increase of two percent in placebo patients, for an absolute difference of 30 percent (p<0.0001).
Eliglustat tartate (Genz-112638)
What is Eliglustat?
- Eliglustat is a new investigational phase 3 compound from Genzyme Corporation that is being studied for type 1 Gaucher Disease.
- Eliglustat works as a substrate reduction therapy by reducing glucocerebroside. formation.
- This product is an oral agent (i.e. a pill) that is taken once or twice a day in contrast to an IV infusion for enzyme replacement therapy. Enzyme replacement therapy focuses on replenishing the enzyme that is deficient in Gaucher Disease and breaks down glucocerebroside that accumulates.
- The clinical trials for eliglustat tartate are sponsored by Genzyme Corporation.
Durata Therapeutics Announces FDA’s Acceptance for Priority Review of NDA for Dalvance (dalbavancin hydrochloride)
CHICAGO, Nov 26, 2013 (GLOBE NEWSWIRE via COMTEX) — Durata Therapeutics, Inc. DRTX +6.48% today announced that the New Drug Application (NDA) for its investigational drug, Dalvance (dalbavancin hydrochloride) for injection, has been accepted for priority review by the U.S. Food and Drug Administration (FDA) with an action date of May 26, 2014. Durata is seeking FDA approval of Dalvance(TM) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive microorganisms, including MRSA (methicillin resistant Staphylococcus aureushttp://www.drugs.com/nda/dalbavancin_131126.html
Dalbavancin is prepared by chemical modification of the natural glycopeptide complex A-40,926 as described in Malabarba and Donadio (1999) Drugs of the Future 24(8):839-846. The predominant component of dalbavancin is Factor Bo, which accounts for >75% of the whole complex.
 The amount of each of the components present in a dalbavancin composition is dictated by a variety of factors, including, for example, the fermentation conditions employed in the preparation of the natural glycopeptide complex A-40926, which is the precursor to dalbavancin (see, e.g., U.S. Pat. No.5,843,679), the conditions employed to recover A-40926 from the fermentation broth, the chemical reactions employed to selectively esterify the caxboxyl group of the sugar moiety of A-40926, the conditions employed to amidate the peptidyl carboxyl group, the conditions employed to saponify the ester of the carboxyl group of the N-acylaminoglucuronic acid function, the conditions employed to recover dalbavancin from the synthetic mixture, and the like.
the semisynthetic glycopeptide dalbavancin was synthesized from the natural antibiotic A 40926, originally isolated from an Actinomadura culture (Malabarba et al., 1998, U.S. Pat. No. 5,750,509). Dalbavancin has shown greater efficacy against various bacterial strains than vancomycin or the antibiotic linezolid and represents a promising new treatment for skin and soft tissue infections (see, e.g., Jabés et al., 2004, Antimicrob. Agents Chemother. 48:1118-1123). According to U.S. Pat. No. 5,750,509, dalbavancin is a glycopeptide antibiotic with a monomethyl moiety at its N15 amino (see FIG. 1 for numbering), and this N15-monomethyl amino could be free (i.e. —NHCH3) or protected with an amino protecting group such as t-butoxycarbonyl, carbobenzyloxy, arylalkyl or benzyl. The method for making certain of the dalbavancin components reported in the ‘509 patent also produced N15,N15-dialkyl analogs of dalbavancin in minor-quantities, but these molecules were not characterized.
Dalbavancin (INN, trade name Zeven) is a novel second-generation lipoglycopeptideantibiotic. It belongs to the same class as vancomycin, the most widely used and one of the few treatments available to patients infected with methicillin-resistant Staphylococcus aureus (MRSA).
It possesses in vitro activity against a variety of Gram-positive pathogens includingMRSA and MRSE. It is a once-weekly, two-dose antibiotic that Pfizer acquired when it bought Vicuron Pharmaceuticals in 2005.
Dalbavancin has undergone a phase III clinical trial for adults with complicated skin infections, but in Dec 2007 the FDA said more data was needed before approval. On September 9, 2008, Pfizer announced that it will withdraw all marketing applications in order to conduct another Phase 3 clinical trial. Durata Therapeutics acquired the rights to dalbavancin in December 2009 and has initiated two new Phase III clinical trials for treatment of acute bacterial skin and skin structure infections. Preliminary results in Dec 2012 looked good.
- Vicuron Pharmaceuticals Submits New Drug Application for Dalbavancin to U.S. Food and Drug Administration
- Scheinfeld NS. (May 2006). “Dalbavancin: A review for dermatologists.”. Dermatology Online Journal 12 (6). Unknown parameter
|numero=ignored (help) PMID 17083861
- Chen AY, Zervos MJ, Vazquez JA (2007). “Dalbavancin: a novel antimicrobial”. Int. J. Clin. Pract. 61 (5): 853–63. doi:10.1111/j.1742-1241.2007.01318.x. PMC 1890846.PMID 17362476.
- Das B, Sarkar C, Biswas R, Pandey S (2008). “Review: dalbavancin-a novel lipoglycopeptide antimicrobial for gram positive pathogens”. Pak J Pharm Sci 21 (1): 78–88. PMID 18166524.
- Dalbavancin: A Novel Lipoglycopeptide Antibacterial
- UPDATE 1-Pfizer says US FDA wants more data on antibiotic. Dec 2007
- “Pfizer Will Withdraw Global Marketing Applications for Dalbavancin to Conduct a New Trial” (Press release). Pfizer Inc. 2008-09-09. Retrieved 2008-09-11.
- Durata Begins Dalbavancin Study Enrollment. Drug Discovery & Development – October 05, 2011.
- Durata Therapeutics Announces Phase 3 Clinical Trial Results for Dalbavancin in the Treatment of ABSSSI