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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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FDA Grants Priority Review To New Drug Application For MNK-795
FDA Grants Priority Review To New Drug Application For MNK-795 Submitted By Depomed Licensee Mallinckrodt
Controlled Substance Analgesic Combination Product Uses Depomed’s Proprietary Acuform® Technology
NEWARK, Calif., July 29, 2013 /PRNewswire/ — Depomed, Inc. (NASDAQ:DEPO) announced today that the U. S. Food and Drug Administration (FDA) has accepted for filing a New Drug Application (NDA) from Mallinckrodt (NYSE: MNK) for MNK-795. MNK-795 is a controlled-release oral formulation of oxycodone and acetaminophen that has been studied for the management of moderate to severe acute pain where the use of an opioid analgesic is appropriate. MNK-795 is formulated with Depomed’s Acuform® drug delivery technology.
http://www.pharmalive.com/fda-grants-priority-review-to-new-drug-application-for-mnk-795
Regulatory update: albiglutide US PDUFA date extended by three months
albiglutide,
Friday 2 August 2013, London UK
GlaxoSmithKline plc (LSE:GSK) today announced that the US Prescription Drug User Fee Act (PDUFA) goal date for albiglutide, an investigational once-weekly treatment for adult patients with type 2 diabetes, has been extended by three months to 15 April 2014 to provide time for a full review of information submitted by GSK in response to the Food and Drug Administration’s requests.
http://www.pharmalive.com/fda-delays-approval-decision-for-gsk-s-albiglutide
Albiglutide is a glucagon-like peptide-1 agonist (GLP-1 agonist) drug under investigation by GlaxoSmithKline for treatment oftype 2 diabetes. It is a dipeptidyl peptidase-4-resistant glucagon-like peptide-1 dimer fused to human albumin.
Albiglutide has a half-life of four to seven days, which is considerably longer than the other two GLP-1 analogs approved for market use, exenatide (Byetta) and liraglutide (Victoza). GLP-1 drugs are currently only available for subcutaneous administration on a daily basis, so a GLP-1 drug with a longer half-life is desirable. Such a drug would only need to be injected biweekly or weekly instead of daily, reducing the discomfort and inconvenience of GLP-1 administration considerably.
It has not yet been determined whether albiglutide is as effective an antidiabetic agent as GLP-1 drugs currently on the market, and final data remain to be published regarding the incidence of adverse effects related to the drug. To evaluate the efficacy and safety of the drug, albiglutide is undergoing eight Phase III clinical trials. Four of these trials should report useful data by end 2010
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FDA has granted tentative approval to India-based Strides Arcolab’s HIV drug emtricitabine and tenofovir disoproxil fumarate tablets, 200 mg/300 mg.
chief executive and vice chairman Arun Kumar –Strides arcolab
Deepak Vaidya, chaiman
Headquartered in India, Strides Arcolab is a pharmaceutical company with a key focus on the development and manufacture of IP-led niche products, particularly sterile injectables. It is among the world’s largest manufacturers of soft gelatin capsules. With 14 world-class manufacturing facilities, an innovative R&D hub and a marketing network in 70 countries, Strides is well positioned to meet the demands of the global pharmaceutical industry and has partnered with several of the world’s leading pharmaceutical companies.
2 August 2013
Strides Arcolab’s HIV drug, which is generic version of Gilead Sciences’ Truvada, gets tentative approval from the US FDA.
Tentative approval implies that the drug has met all standards but cannot be marketed in the US due to existing patent protections Good news for HIV AIDS patients
FDA has granted tentative approval to India-based Strides Arcolab’s HIV drug emtricitabine and tenofovir disoproxil fumarate tablets, 200 mg/300 mg. The drug is a generic version of Truvada, 200 mg/300 mg tablets, which is manufactured by Gilead Sciences.
The product is indicated for use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV)-1
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EMTRICITABINE
credit-chemdrug
DONEPEZIL SYNTHESIS
Donepezil, marketed under the trade name Aricept by its developer Eisai and partnerPfizer, is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the palliative treatment of Alzheimer’s disease.Common side effects include gastrointestinal upset. It has an oral bioavailability of 100% and easily crosses the blood–brain barrier. Because it has a biological half-life of about 70 hours, it can be taken once a day.
Currently, no definitive proof shows the use of donepezil or other similar agents alters the course or progression of Alzheimer’s disease (AD). However, 6 to 12-month controlled studies have shown modest benefits in cognition and/or behavior.Pilot studies have reported donepezil therapy may potentially have effects on markers of disease progression, such as hippocampal volume. Therefore, many neurologists, psychiatrists, and primary-care physicians use donepezil in patients with Alzheimer’s disease. In 2005, the UK National Institute for Clinical Excellence (NICE) withdrew its recommendation for use of the drug for mild-to-moderate AD, on the basis of no significant improvement in functional outcome, quality of life, or behavioral symptoms. However, NICE revised its guidelines to suggest donepezil be used in moderate-stage patients for whom the evidence is strongest.
While the drug is currently indicated for mild to moderate Alzheimer’s, evidence from two clinical trials also indicates it may be effective for moderate to severe disease. An example of this is a Karolinska Institute paper published in The Lancet in early 2006, which states donepezil improves cognitive function even in patients with severe AD symptoms. In Oct. 2006 the U.S. Food and Drug Administration also approved Aricept for treatment of severe dementia.
【通用名】 Donepezil hydrochloride, BNAG, E-2020, Eranz, Memorit, Memac, Aricept
【化学名】 (?-1-Benzyl-4-(5,6-dimethoxy-1-oxoindan-2-ylmethyl)piperidine hydrochloride; (?-2-(1-Benzylpiperidin-4-ylmethyl)-5,6-dimethoxyindan-1-one hydrochloride
【CAS登记号】 120011-70-3, 123958-79-2 ([2-14C]-labeled), 142057-77-0 (deleted CAS), 120014-06-4 (free base)
【分子式】 C24-H29-N-O3.Cl-H
【分子量】 415.958
【化学活性】 Alzheimer’s Dementia, Treatment of , Analgesic and Anesthetic Drugs, Antimigraine Drugs, Attention Deficit Hyperactivity Disorder (ADHD), Treatment of, Autism, Treatment of, Cognition Disorders, Treatment of, Immunologic Neuromuscular Disorders, Treatment of, Migraine, Prophylactic Treatment of, Multiple Sclerosis, Agents for, Neurologic Drugs, Psychopharmacologic Drugs, Vascular Dementia, Treatment of, Acetylcholinesterase Inhibitors
【开发阶段】 Launched-1997
【研究机构】 Eisai (Originator), National Institute of Mental Health (Not Determined), Bracco (Licensee), Pfizer (Licensee)
Donepezil inhibiting Torpedo californicaacetylcholinesterase. See Proteopedia1eve.
Research leading to the development of donepezil began in 1983 at Eisai, and the first Phase I clinical trial took place in 1989. In 1996, Eisai received approval from the United States Food and Drug Administration (USFDA) for donepezil under the brand Aricept, which it co-marketed with Pfizer. As of 2011, Aricept was the world’s best-selling Alzheimer’s disease treatment. The first generic donepezil became available in November 2010 with the USFDA approval of a formulation prepared by Ranbaxy Labs. In April 2011 a second generic formulation, from Wockhardt, received tentative USFDA marketing approval
| 标题: | Cyclic amine cpd., its use and pharmaceutical compsns. comprising it |
| 作者: | Sugimoto, H.; Tsuchiya, Y.; Higurashi, K.; Karibe, N.; Iimura, Y.; Sasaki, A.; Yamanashi, Y.; Ogura, H.; Araki, S.; Kosasa, T.; Kusota, A.; Kozasa, M.; Yamatsu, K. (Eisai Co., Ltd.) |
| 来源: | AU 8818216; EP 0296560; EP 0673927; EP 0742207; JP 1989079151; JP 1998067739; US 4895841; US 5100901 |
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| 合成路线图解说明:The condensation of 5,6-dimethoxy-1-indanone (I) with 1-benzylpiperidine-4-carboxaldehyde (II) by means of butyllithium and diisopropylamine in THF gives 1-benzyl-4-(5,6-dimethoxy-1-oxoindan-2-ylidenemethyl)piperidine (III), which is reduced with H2 over Pd/C in THF and treated with HCl in dichloromethane – ethyl acetate. | |
| 标题: | Synthesis of 1-benzyl-4-[(5,6-dimethoxy[2-14C]-1-indanon)-2-yl]methylpiperidine hydrochloride (E-2020-14C) |
| 作者: | Sugimoto, H.; Mishima, M.; Iimura, Y. |
| 来源: | J Label Compd Radiopharm 1989,27(7),835-9 |
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| 合成路线图解说明:The condensation of 5,6-dimethoxy-1-indanone (I) with 1-benzylpiperidine-4-carboxaldehyde (II) by means of butyllithium and diisopropylamine in THF gives 1-benzyl-4-(5,6-dimethoxy-1-oxoindan-2-ylidenemethyl)piperidine (III), which is reduced with H2 over Pd/C in THF and treated with HCl in dichloromethane – ethyl acetate. | |
| 作者: | Casta馿r, J.; Prous, J. |
| 来源: | Drugs Fut 1991,16(1),16 |
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| 合成路线图解说明:The condensation of 5,6-dimethoxy-1-indanone (I) with 1-benzylpiperidine-4-carboxaldehyde (II) by means of butyllithium and diisopropylamine in THF gives 1-benzyl-4-(5,6-dimethoxy-1-oxoindan-2-ylidenemethyl)piperidine (III), which is reduced with H2 over Pd/C in THF and treated with HCl in dichloromethane – ethyl acetate. | |
| 标题: | Synthesis of 1-benzyl-4-[(5,[C-11]6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine: A promising ligand for visualisation of acetylcholine esterase by PET |
| 作者: | Santens, P.; DeReuck, J.; Dierckx, R.A.; Siegers, G.; Vermeirsch, H.; De Vos, F. |
| 来源: | J Label Compd Radiopharm 2000,43(6),595 |
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| 合成路线图解说明:11C-Labeled donepezil was prepared by methylation of 2-(1-benzylpiperidin-4-ylmethyl)-6-hydroxy-5-methoxyindan-1-one (I) with 11CH3I by means of tetrabutylammonium hydroxide in DMF. | |
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Donepezil hydrochloride is a useful memory enhancer introduced by the Japanese pharmaceutical company Eisai. Its preparation was described in patent no. EP 296560. In this patent Donepezil was produced by reaction of 5,6-dimethoxy-1- indanone with 1 -benzyl-4-formylpiperidine in the presence of a strong base, such as lithium diisopropylamide followed by reduction of the double bond. According to this method, Donepezil was obtained (Scheme 1).
Patent application WO 99/36405 describes another process for the synthesis of Donepezil. According to this patent, 2-alkoxycarbonyl-1-indanones are reacted with (4-pyridinyl) methyl halide moiety followed by hydrolysis and decarboxylation to give the 2-(4-pyridinyl)methyl-1-indanone derivative. This is followed by reaction with benzyl halides to obtain the corresponding quaternary ammonium salt, and followed by hydrogenation of the pyridine ring to obtain Donepezil (Scheme 2).
Patent application WO 97/22584 describes the preparation of Donepezil by reaction of pyridine-4-carboxyaldehyde with malonic acid to give 3-(pyridin-4-yl)-2- propenoic acid, followed by hydrogenation of the double bond to give 3-(piperidin-4-yl)-2-propionic acid. Reaction of this intermediate with methyl chloroformate afforded 3-[N-(methyloxycarbonyl) piperidin-4-yl]propionic acid. This was followed by reaction with oxalyl chloride to give methyl 4-(2-chlorocarbonylethyl)piperidin-1-carboxylate. Reaction with 1,2-dimethoxybenzene in the presence of aluminum chloride afforded methyl 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1 -carboxylate. Reaction with tetramethyldiaminomethane afforded 4-[2-(3,4-dimethoxybenzoyl)allyl] piperidin-1-carboxylate. Reaction with sulfuric acid afforded methyl 4-(5,6-dimethoxy-1-oxoindan-2-yl)methylpiperidin-1- carboxylate. This was followed by treatment with base to give 5,6-dimethoxy-2-(piperidin-4-ylmethyl) indan-1-one, then reaction with benzyl bromide afforded Donepezil (Scheme 3).
Patent application EP 711756 describes the preparation of Donepezil by reaction of 5,6-dimethoxy-1- indanone with pyridin-4-aldehyde to give 5,6-dimethoxy-2-(pyridin-4-yl)methylene indan-1-one. Reaction with benzyl bromide afforded 1-benzyl-4-(5,6-dimethoxyindan-1-on-2-ylidene)methylpyridinium bromide. Hydrogenation in the presence of platinum oxide afforded Donepezil (Scheme 4).
United States Patent 6844440
EP 1386607 A1
FDA Grants Priority Review To New Drug Application For MNK-795 Submitted By Depomed Licensee Mallinckrodt
FDA Grants Priority Review To New Drug Application For MNK-795 Submitted By Depomed Licensee Mallinckrodt
Controlled Substance Analgesic Combination Product Uses Depomed’s Proprietary Acuform® Technology
NEWARK, Calif., July 29, 2013 /PRNewswire/ — Depomed, Inc. (NASDAQ:DEPO) announced today that the U. S. Food and Drug Administration (FDA) has accepted for filing a New Drug Application (NDA) from Mallinckrodt (NYSE: MNK) for MNK-795. MNK-795 is a controlled-release oral formulation of oxycodone and acetaminophen that has been studied for the management of moderate to severe acute pain where the use of an opioid analgesic is appropriate. MNK-795 is formulated with Depomed’s Acuform® drug delivery technology.
http://www.pharmalive.com/fda-grants-priority-review-to-new-drug-application-for-mnk-795
British drugmaker AstraZeneca and US biotechnology company FibroGen have formed a strategic partnership to develop and commercialize FG-4592 to treat anemia in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD).
cas no 808118-40-3 FG 4592
FG-4592 oral presentation at ASN 2012
FG-4592 is an orally administered small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity.
As part of the agreement, the deal will focus on US, China and all major markets except the Commonwealth of Independent States, the Middle East, South Africa, Japan and Europe, while both companies can exercise the option to extend their collaboration to other anemia indications.
AstraZeneca will pay FibroGen at least $350 million as part of a strategic collaboration to develop and commercialize FG-4592, a first-in-class oral compound in late stage development for the treatment of anaemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD).
This broad collaboration focuses on the US, China and all major markets excluding Japan, Europe, the Commonwealth of Independent States, the Middle East and South Africa, which are covered by an existing agreement between FibroGen and Astellas Pharma. The AstraZeneca-FibroGen joint effort will be focused on the development of FG-4592 to treat anaemia in CKD and ESRD, and may be extended to other anaemia indications. The companies plan to undertake an extensive FG-4592 Phase III development program for the US, and to initiate Phase III trials in China, with anticipated regulatory filings in China in 2015 and in the US in 2017.
In addition to $350 million in up front and non-contingent payments, AstraZeneca could pay FibroGen potential future development related milestone payments of up to $465 million, and potential future sales related milestone payments in addition to tiered royalty payments on future sales on FG-4592 in the low 20% range. Additional development milestones will be payable for any subsequent indications which the companies choose to pursue. AstraZeneca will be responsible for the US commercialization of FG-4592, with FibroGen undertaking specified promotional activities in the ESRD segment in this market. The companies will also co-commercialize FG-4592 in China where FibroGen will be responsible for clinical trials, regulatory matters, manufacturing and medical affairs, and AstraZeneca will oversee promotional activities and commercial distribution.
FG-4592 is a small molecule inhibitor of hypoxia-inducible factor (HIF), a protein that responds to oxygen changes in the cellular environment and meets the body’s demands for oxygen by inducing erythropoiesis, the process by which red blood cells are produced. The firms claim FG-4592 has the potential to address the considerable unmet medical need for an effective treatment for anaemia that offers the convenience of oral administration and an improved safety profile when compard with current standards of care. At present, treatment options involve a combination of injectable erythropoiesis-stimulating agents (ESAs) and iron supplements.
“Our collaboration with FibroGen on FG-4592 is an important addition to AstraZeneca’s growing late-stage portfolio in cardiovascular and metabolic disease, one of our core therapy areas,” comments Pascal Soriot, AstraZeneca CEO. “We know from our research into complications of renal disease that anaemia continues to be a challenge for patients with chronic kidney disease, due in part to the inconvenience and complexity of existing injectable and intravenous therapies and the safety concerns associated with them. The science behind this compound is compelling. Through our collaboration with FibroGen we aim to offer a first-in-class, convenient treatment option for doctors and patients.”
“FG-4592 has the potential to offer anaemia patients an oral therapy that provides coordinated erythropoiesis, that increases natural erythropoietin within the normal physiological range, and that is effective without intravenous iron supplementation and without an increased risk for hypertension,” adds Thomas B. Neff, FibroGen CEO. “We are especially pleased that AstraZeneca will share our commitment to making China the first-to-launch country for FG-4592 and join our effort to bring important innovation in anaemia therapy to CKD and ESRD patients in the US and other countries. This agreement secures proper development and commercialization resources for FG-4592, and ensures US clinical trial efforts are fully funded.”
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Novavax announces positive preclinical data for vaccine against influenza
Novavax announces positive preclinical data for vaccine against influenza
Novavax has announced positive preclinical results for its virus-like particle (VLP) vaccine candidate against A (H7N9) influenza.
The study examined the immunogenicity, the ability to provoke an immune response, and efficacy of two doses of its A(H7N9) VLP vaccine candidate against a lethal wild-type challenge mouse model.
There were three control groups, including Novavax’ non-homologous A(H7N3) VLP vaccine candidate, its A(H5N1) VLP vaccine candidate, and a placebo. All vaccine candidates were administered with or without Iscomatrix, a saponin-based adjuvant.
read all at
http://www.pharmaceutical-technology.com/news/newsnovavax-announces-positive-preclinical-data-for-vaccine-against-influenza?WT.mc_id=DN_News
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Animal testing failures put drug trial volunteers in danger
© Shutterstock
Poor pre-clinical data and an absence of negative results are pushing candidate molecules into the clinic too soon
The reporting of animal studies is biased, inflating the efficacy of drug candidates and pushing them into the clinic before they are ready. This is the verdict of new research, which finds that more treatments go from pre-clinical to human trials than ought to, wasting valuable resources and potentially putting trial participants in danger.1 It adds to a growing body of evidence pointing to problems in the way animal testing is reported and managed.
READ AT
http://www.rsc.org/chemistryworld/2013/07/failures-animal-testing-put-drug-trial-volunteers-danger
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Gene Therapy for Melanoma: Progress and Perspectives
FIGURE 1.
Schematic representation of the wild type counterpart of the typically used recombinant viral vectors. (A) Gammaretroviruses and (B) lentiviruses share similar structures, but differ greatly in their genomes and their impact on cellular function. Gag, pro, pol and env genes encode structural proteins of the capsid, protease, reverse transcriptase and envelope proteins, respectively. The additional lentiviral genes perform regulatory functions as well as alter cellular function. (C) The serotype 5 adenovirus has a protein capsid (non-enveloped) and a large, complex genome that encodes critical genes for viral replication (E1a, E1b) as well as structural and functional genes that regulate both viral and cellular activities.
Introduction
Gene therapy, the therapeutic transfer of genetic information to a target cell, continues to be a promising alternative in the fight against cancer. In the case of melanoma, the use of an experimental treatment is justified since this disease is incurable in its advanced stages. Is gene therapy a viable option for the treatment of melanoma patients? In this chapter, we will attempt to answer this question by exploring the intersection between the technology of gene therapy and the biology of melanoma, a point at which opportunities for intervention are revealed.
Gene Therapy for Melanoma: Progress and Perspectives
[1] Cancer Institute of Sao Paulo, University of Sao Paulo School of Medicine, Brazil
[2] University of Sao Paulo, Biomedical Sciences Institute, Brazil
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Analysis Of Vical’s Allovectin-7: Best Results Ever In A Melanoma Phase 3 Trial
check this video
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Vical’s (VICL) Allovectin-7 is a pure immune therapy.(1) Which means it does not directly kill cancer cells, but activates the immune system to do so. Vical will soon announce A-7 phase 3 results in Melanoma, but the mechanism of action is not specific to Melanoma, and can be used in any solid tumor cancer.(2) For this reason, I expect that Allovectin-7 will become one of the best selling cancer drugs of all time.
Allovectin-7 is a substance that is being studied as a gene therapy agent in the treatment of cancer, such as malignant melanoma. It is a plasmid/lipid complex containing the DNA sequences encoding HLA-B7 and ß2 microglobulin – two components of major histocompatibility complex (MHC, class I). It increases the ability of the immune system to recognize cancer cells and kill them.
In 1999, FDA granted Allovectin-7 orphan drug designation for the treatment of invasive and metastatic melanoma.
- Allovectin-7 entry in the public domain NCI Dictionary of Cancer Terms
This article incorporates public domain material from the U.S. National Cancer Institute document “Dictionary of Cancer Terms”.
Vical’s Allovectin-7
Allovectin is a first-class DNA-based immunotherapeutic designed to stimulate both innate and adaptive immune responses in local tumors and distal metastases. The goal is to become a first-line treatment for Stage III and IV melanoma, where it is intended to provide improved efficacy, a better safety profile, and simple outpatient administration.
As last reported, the company is approaching completion of a Phase III registration trial versus chemotherapy in patients with metastatic melanoma. The reporting of end results has had numerous delays, but the results are now expected by Q3.
Outside of Allovectin, Vical has ten clinical trials ongoing, three of those independent and the rest in collaboration. Clearly, Vical is not totally dependent on this immunotherapy though it is the most advanced independent program in the company’s pipeline.
Vical has a market cap of $257M, so clearly a homerun therapy could send the stock soaring.
New Drug Approvals 