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SIMPONI® ARIA™ (golimumab),For Infusion Receives FDA Approval For Treatment Of Moderately To Severely Active Rheumatoid Arthritis
July 18, 2013 /PRNewswire/ — Janssen Biotech, Inc. announced today the U.S. Food and Drug Administration (FDA) approval of SIMPONI® ARIATM (golimumab) for infusion for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate. SIMPONI ARIA, the only fully-human anti-tumor necrosis factor (TNF)-alpha infusible therapy, has been shown to significantly improve signs and symptoms and physical function, and inhibit the progression of structural damage. The SIMPONI ARIA dose regimen is 2 mg/kg given as an intravenous infusion at weeks 0 and 4, then every 8 weeks thereafter. The infusion is given over a 30-minute period, providing a short infusion time for patients. Approximately 1.3 million people in the United States are living with RA,[i] a chronic, systemic inflammatory condition that is often characterized by symptoms that include pain, stiffness and inflammation, and in some cases, joint destruction and disability.[ii]
read all at
Golimumab (CNTO 148)is a human monoclonal antibody which is used as an immunosuppressive drug and marketed under the brand name Simponi. Golimumab targets tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory moleculeand hence is a TNF inhibitor.
Golimumab was developed by Centocor and is approved in Canadaand the United Statesas a once monthly subcutaneous treatment for adults with moderately to severely active rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.Golimumab is pending FDA approval for Ulcerative Colitis.
In the same year, Johnson & Johnson, the parent company of Centocor, also received an approval from European Medicines Agency (EMEA) for the use of golimumab as a treatment for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.Golimumab is marketed by Merck & Co, Inc. in Europe, pending final arbitration between J&J and Merck
Recent Progress in the Synthesis of Tamiflu
| ABOVE PICTURE-The synthetic route to tamiflu reported by M. Shibasaki starting from 1,4-cyclohexadiene. See JACS 2006, 128, 6312-6313 |
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| Abstract Tamiflu, one of the most common orally drugs for the treatment and prevention of influenza, has attracted extensive interests of synthetic chemists all over the world.Concise, efficient, and scalable synthetic approaches toward this molecule have been a very active field in recent years, and many diverse synthetic routes have been developed to date.In this review, representative synthetic routes employing chiral starting material or catalytic asymmetric reactions are briefly summarized. |
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| Fund:Project supported by the National Natural Science Foundation of China (Nos.20972059, 21290180), the Program for Changjiang Scholars and Innovative Research Team in University (No.IRT1138) and the Fundamental Research Funds for the Central Universities (No.lzujbky-2013-ct02). | |||||
| Cite this article: |
| Zhang Tiancai,Lu Hui,Zhang Fu-Min et al. Recent Progress in the Synthesis of Tamiflu[J]. Chin. J. Org. Chem., 2013, 33(06): 1235-1243. |
| http://sioc-journal.cn/Jwk_yjhx/EN/abstract/abstract342132.shtml# |
| URL: |
| http://sioc-journal.cn/Jwk_yjhx/EN/10.6023/cjoc201303044 OR http://sioc-journal.cn/Jwk_yjhx/EN/Y2013/V33/I06/1235 |
Oseltamivir total synthesis concerns the total synthesis of the antiinfluenza drug oseltamivirmarketed by Hoffmann-La Roche under the trade name Tamiflu. Its commercial production starts from the biomolecule shikimic acid harvested from Chinese star anise with a limited worldwide supply. Due to its limited supply, searches for alternative synthetic routes preferably not requiring shikimic acid are underway and to date several such routes have been published. Control of stereochemistry is important: the molecule has three stereocenters and the sought-after isomer is only 1 of 8 stereoisomers.
Commercial production
The current production method is based on the first scalable synthesis developed by Gilead Sciences [1] starting from naturally occurring quinic acid or shikimic acid. Due to lower yields and the extra steps required (because of the additional dehydration), the quinic acid route was dropped in favour of the one based on shikimic acid, which received further improvements by Hoffmann-La Roche.[2][3] The current industrial synthesis is summarised below:
Karpf / Trussardi synthesis
The current production method includes two reaction steps with potentially hazardous azides. A reported azide-free Roche synthesis of tamiflu is summarised graphically below:[4]
The synthesis commences from naturally available (−)-shikimic acid. The 3,4-pentylidene acetal mesylate is prepared in three steps: esterification with ethanol and thionyl chloride; ketalization with p-toluenesulfonic acid and 3-pentanone; and mesylation with triethylamine and methanesulfonyl chloride. Reductive opening of the ketal under modified Hunter conditions[5] in dichloromethane yields an inseparable mixture of isomeric mesylates. The corresponding epoxide is formed under basic conditions withpotassium bicarbonate. Using the inexpensive Lewis acid magnesium bromide diethyl etherate (commonly prepared fresh by the addition of magnesium turnings to 1,2-dibromoethane in benzene:diethyl ether), the epoxide is opened with allyl amine to yield the corresponding 1,2-amino alcohol. The water-immiscible solvents methyl tert-butyl ether and acetonitrile are used to simplify the workup procedure, which involved stirring with 1 M aqueous ammonium sulfate. Reduction on palladium, promoted byethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. The aminoalcohol was converted directly to the corresponding allyl-diamine in an interesting cascade sequence that commences with the unselective imination of benzaldehyde with azeotropic water removal in methyl tert-butyl ether. Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Acidic hydrolysis then removed the imine. Selective acylation with acetic anhydride (under buffered conditions, the 5-amino group is protonated owing to a considerable difference in pKa, 4.2 vs 7.9, preventing acetylation) yields the desired N-acetylated product in crystalline form upon extractive workup. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. It is noted that the synthesis avoids the use of potentially explosive azide reagents and intermediates; however, the synthesis actually used by Roche uses azides. Roche has other routes to oseltamivir that do not involve the use of (−)-shikimic acid as a chiral pool starting material, such as a Diels-Alder route involving furan and ethyl acrylate or an isophthalic acid route, which involves catalytic hydrogenation and enzymatic desymmetrization.
Corey synthesis
In 2006 the group of E.J. Corey published a novel route bypassing shikimic acid starting from butadiene and acrylic acid.[6] The inventors chose not to patent this procedure which is described below.
Butadiene 1 reacts in an asymmetric Diels-Alder reaction with the esterfication product of acrylic acid and 2,2,2-Trifluoroethanol 2 catalysed by the CBS catalyst. The ester 3 is converted into an amide in 4 by reaction with ammonia and the next step to lactam 5 is an iodolactamization with iodine initiated by trimethylsilyltriflate. The amide group is fitted with a BOC protective group by reaction with Boc anhydride in 6 and the iodine substituent is removed in an elimination reaction with DBU to the alkene 7. Bromine is introduced in 8 by an allylic bromination with NBS and the amide group is cleaved with ethanol and caesium carbonate accompanied by elimination of bromide to the diene ethyl ester 9. The newly formed double bond is functionalized with N-bromoacetamide 10 catalyzed with Tin(IV) bromide with complete control of stereochemistry. In the next step the bromine atom in 11 is displaced by the nitrogen atom in the amide group with the strong base KHMDS to the aziridine 12 which in turn is opened by reaction with 3-pentanol 13 to the ether 14. In the final step the BOC group is removed with phosphoric acid and the oseltamivir phosphate 15 is formed.
Shibasaki synthesis
Also in 2006 the group of Masakatsu Shibasaki of the University of Tokyo published a synthesis again bypassing shikimic acid.[7][8]
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| Shibasaki Tamiflu synthesis Part I | Part II |
An improved method published in 2007 starts with the enantioselective desymmetrization of aziridine 1 with trimethylsilyl azide (TMSN3) and a chiral catalyst to the azide 2. Theamide group is protected as a BOC group with Boc anhydride and DMAP in 3 and iodolactamization with iodine and potassium carbonate first gives the unstable intermediate 4and then stable cyclic carbamate 5 after elimination of hydrogen iodide with DBU.
The amide group is reprotected as BOC 6 and the azide group converted to the amide 7 by reductive acylation with thioacetic acid and 2,6-lutidine. Caesium carbonateaccomplishes the hydrolysis of the carbamate group to the alcohol 8 which is subsequently oxidized to ketone 9 with Dess-Martin periodinane. Cyanophosphorylation withdiethyl phosphorocyanidate (DEPC) modifies the ketone group to the cyanophosphate 10 paving the way for an intramolecular allylic rearrangement to unstable β-allylphosphate 11 (toluene, sealed tube) which is hydrolyzed to alcohol 12 with ammonium chloride. This hydroxyl group has the wrong stereochemistry and is therefore inverted in a Mitsunobu reaction with p-nitrobenzoic acid followed by hydrolysis of the p-nitrobenzoate to 13.
A second Mitsunobu reaction then forms the aziridine 14 available for ring-opening reaction with 3-pentanol catalyzed by boron trifluoride to ether 15. In the final step the BOC group is removed (HCl) and phosphoric acid added to objective 16.
Fukuyama synthesis
An approach published in 2007 [9] like Corey’s starts by an asymmetric Diels-Alder reaction this time with starting materials pyridine and acrolein.
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| Fukuyama Tamiflu synthesis Part I | Part II |
Pyridine (1) is reduced with sodium borohydride in presence of benzyl chloroformate to the Cbz protected dihydropyridine 2. The asymmetric Diels-Alder reaction with acrolein3 is carried out with the McMillan catalyst to the aldehyde 4 as the endo isomer which is oxidized to the carboxylic acid 5 with sodium chlorite, Monopotassium phosphate and 2-methyl-2-butene. Addition of bromine gives halolactonization product 6 and after replacement of the Cbz protective group by a BOC protective group in 7 (hydrogenolysis in the presence of Di-tert-butyl dicarbonate) a carbonyl group is introduced in intermediate 8 by catalytic ruthenium(IV) oxide and sacrificial catalyst sodium periodate. Addition ofammonia cleaves the ester group to form amide 9 the alcohol group of which is mesylated to compound 10. In the next step iodobenzene diacetate is added, converting the amide in a Hofmann rearrangement to the allyl carbamate 12 after capturing the intermediate isocyanate with allyl alcohol 11. On addition of sodium ethoxide in ethanol three reactions take place simultaneously: cleavage of the amide to form new an ethyl ester group, displacement of the mesyl group by newly formed BOC protected amine to anaziridine group and an elimination reaction forming the alkene group in 13 with liberation of HBr. In the final two steps the aziridine ring is opened by 3-pentanol 14 and boron trifluoride to aminoether 15 with the BOC group replaced by an acyl group and on removal of the other amine protecting group (Pd/C, Ph3P, and 1,3-dimethylbarbituric acid in ethanol) and addition of phosphoric acid oseltamivir 16 is obtained.
Trost synthesis
In 2008 the group of Barry M. Trost of Stanford University published the shortest synthetic route to date.[10]
- Rohloff John C., Kent Kenneth M., Postich Michael J., Becker Mark W., Chapman Harlan H., Kelly Daphne E., Lew Willard, Louie Michael S., McGee Lawrence R. et al. (1998). “Practical Total Synthesis of the Anti-Influenza Drug GS-4104”. J. Org. Chem. 63 (13): 4545–4550. doi:10.1021/jo980330q.
- Federspiel M., Fischer R., Hennig M., Mair H.-J., Oberhauser T., Rimmler G., Albiez T., Bruhin J., Estermann H. et al. (1999). “Industrial Synthesis of the Key Precursor in the Synthesis of the Anti-Influenza Drug Oseltamivir Phosphate (Ro 64-0796/002, GS-4104-02) Ethyl (3R,4S,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate”. Org. Process Res. Dev. 3: 266–274. doi:10.1021/op9900176.
- Abrecht S., Federspiel M. C., Estermann H., Fischer R., Karpf M., Mair H.-J., Oberhauser T., Rimmler G., Trussardi R. et al.. “The Synthetic-Technical Development of Oseltamivir Phosphate Tamiflu™: A Race against Time Chimia”. 2007; 61: 93–99. doi:10.2533/chimia.2007.93.
- New, Azide-Free Transformation of Epoxides into 1,2-Diamino Compounds: Synthesis of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu) Martin Karpf and René Trussardi J. Org. Chem.; 2001; 66(6) pp 2044 – 2051; (Article) doi:10.1021/jo005702l PMID 11300898.
- Birgit Bartels and Roger Hunter (1993). “A selectivity study of activated ketal reduction with borane dimethyl sulfide”. J. Org. Chem. 58 (24): 6756. doi:10.1021/jo00076a041.
- A Short Enantioselective Pathway for the Synthesis of the Anti-Influenza Neuramidase Inhibitor Oseltamivir from 1,3-Butadiene and Acrylic Acid Ying-Yeung Yeung, Sungwoo Hong, and E. J. Corey J. Am. Chem. Soc.; 2006; 128(19) pp 6310 – 6311; (Communication) doi:10.1021/ja0616433
- De Novo Synthesis of Tamiflu via a Catalytic Asymmetric Ring-Opening of meso-Aziridines with TMSN3 Yuhei Fukuta, Tsuyoshi Mita, Nobuhisa Fukuda, Motomu Kanai, and Masakatsu Shibasaki J. Am. Chem. Soc.; 2006; 128(19) pp 6312 – 6313; doi:10.1021/ja061696k
- Second Generation Catalytic Asymmetric Synthesis of Tamiflu: Allylic Substitution Route Tsuyoshi Mita, Nobuhisa Fukuda, Francesc X. Roca, Motomu Kanai, and Masakatsu Shibasaki Org. Lett.; 2007; 9(2) pp 259 – 262; (Letter) doi:10.1021/ol062663c
- A Practical Synthesis of (-)-Oseltamivir Nobuhiro Satoh, Takahiro Akiba, Satoshi Yokoshima, Tohru Fukuyama Angew. Chem. Int. Ed. 2007, 46, 5734 –5736doi:10.1002/anie.200701754
- A Concise Synthesis of (−)-Oseltamivir Barry M.Trost, Ting Zhang Angew. Chem. Int. Ed. 2008, 47, 1-4 doi:10.1002/anie.200800282
Sequella Acquires Exclusive Worldwide Rights To Pfizer’s Sutezolid, Currently In Clinical Development For Tuberculosis
sutezolid
Sequella, a clinical-stage pharmaceutical company commercializing novel antibiotics to treat life-threatening infectious diseases, today announced that it has licensed Pfizer Inc’s exclusive worldwide rights to develop and commercialize sutezolid, a Phase 2 oxazolidinone antibiotic currently in development for the treatment of tuberculosis (TB).
Sutezolid demonstrated potent antibacterial activity against Mycobacterium tuberculosis in the laboratory and in animal models of TB, an aerosol-transmitted infection with a prevalence of over 2 billion people worldwide. It also demonstrated encouraging activity in a Phase 2a Early Bactericidal Activity (EBA) study in TB patients in South Africa. Under the terms of the parties’ exclusive license agreement, Sequella will be solely responsible for completing clinical development and commercializing the product globally. Financial terms of the transaction were not disclosed.http://www.drugdiscoveryonline.com/Doc/sequella-acquires-exclusive-worldwide-rights-pfizer-s-sutezolid-0001
Enbrel (etanercept), Biosimilar innovator drug companies scrambling to copy
Enbrel (etanercept)
http://www.biosimilarnews.com/enbrel-patent-in-the-us
Biosimilars are protein products that are sufficiently similar to a biopharmaceutical already approved by a regulatory agency. Several biotechnology companies and generic drug manufacturers in Asia and Europe are developing biosimilars of tumor necrosis factor inhibitors and rituximab. A biosimilar etanercept is already being marketed in Colombia and China. In the US, several natural source products and recombinant proteins have been approved as generic drugs under Section 505(b)(2) of the Food, Drug, and Cosmetic Act. However, because the complexity of large biopharmaceuticals makes it difficult to demonstrate that a biosimilar is structurally identical to an already approved biopharmaceutical, this Act does not apply to biosimilars of large biopharmaceuticals. Section 7002 of the Patient Protection and Affordable Care Act of 2010, which is referred to as the Biologics Price Competition and Innovation Act of 2009, amends Section 351 of the Public Health Service Act to create an abbreviated pathway that permits a biosimilar to be evaluated by comparing it with only a single reference biological product.
Amgen announced the issuance of U.S. Patent No. 8,063,182 related to Enbrel (etanercept).owned by Hoffmann-la roche and licensed to Amgen (exp2028) VIA immunex
A biosimilar etanercept, manufactured in China by CP Guojian Pharmaceutical Co., Ltd. (Shanghai), is already being marketed in China as Yisaipu [3] and in Colombia as Etanar [4]. Several biotechnology companies in Asia are also developing biosimilar versions of tumor necrosis factor inhibitors. Protalix Biotherapeutics, Inc. (Carmiel, Israel) is developing a biosimilar etanercept that is expressed in plant cells [5]. Mycenax Biotech (Taiwan) has completed early-phase clinical trials of a biosimilar etanercept in Southeast Asia: a phase I trial among 24 healthy subjects in South Korea and a phase I/II trial that enrolled 18 patients with rheumatoid arthritis in Taiwan [6]. Avesthagen (Bangalore, India) has received a patent from the Indian patent office for a biosimilar etanercept [7]. In South Korea, both Celltrion (Yeonsu-gu Incheon City) and Aprogen (Daejeon) are developing a biosimilar of infliximab [8] and LG Life Sciences (Seoul) is developing biosimilars of both etanercept and infliximab to treat rheumatoid arthritis and other inflammatory diseases [9].
Drug developers:
- Avesthagen: Avent™ in clinical studies
read this doc
http://www.avesthagen.com/docs/020910pr.pdf
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- BioXpress Therapeutics: Biosimilar in active development
http://www.bioxpress.com/pipeline/
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- Cipla:Etacept, Launches biosimilar in India on April 17, at a price of Rs. 6,150 ($113.43), 30% less than the innovator product.
- read this
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- Hanwha Chemical: HD203 “scheduled for launch,” company states on its website without including a date, following submission for marketing approval to South Korea’s Korea Ministry of Food and Drug Safety following completion of Phase I and Phase III trials. Hanwha has said it will seek a partner to commercialize HD203 and a biosimilar for Herceptin (trastuzumab).
- http://www.thepharmaletter.com/file/105028/merck-co-links-with-koreas-hanwha-on-biosimilar-of-enbrel.html
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- LG Life Sciences: LBEC0101 completed Phase I trial in South Korea
http://www.lgls.co.kr/rd/pipeline.jsp
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- Mycenax Biotech: TuNEX in Phase III clinical trials in Japan and South Korea
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- Protalix Biotherapeutics: PRX-106 in preclinical studies
http://www.protalix.com/product-development/prx-106.asp
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- Shanghai CP Goujian Pharmaceutical: Etanar®, marketed in Colombia; Yisaipu, marketed in China
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Recently discontinued effort: Merck & Co. and Hanwha Chemical: Hanwha disclosed December 18, 2012, that Merck terminated agreement to develop and manufacture the biosimilar MK-8953, now called HD203, as well as market it in all countries except South Korea and Turkey, an up to $720 million deal signed June 2011.1
Nature and indication: Tumor necrosis factor (TNF) blocker for rheumatoid arthritis, polyarticular Juvenile Idiopathic Arthritis (JIA) in patients aged two years or older; psoriatic arthritis; ankylosing spondylitis; and plaque psoriasis
2012 sales: $7.963 billion (includes $4.236 billion Amgen + $3.737 billion Pfizer). Amgen markets Enbrel in U.S. and Canada under an agreement with Pfizer set to expire October 31, 2013
Patent status: Patents set to expire in EU in 2015; in U.S., 2019, 2023, 2028, and 2029
Etanercept is a fusion protein produced by recombinant DNA, which fuses a soluble human TNF receptor with an IgG1 antibody. This modified protein works by blocking TNF activity, thereby reducing their ability to cause an inflammatory response as well as severe, chronic pain and discomfort to patients. The fusion protein is protected by five different molecule Key patent families (Fig 2) and are all considered to be a constraint to generic entry until expiry. Although the patent families are owned by different patentees, Amgen have entered into licensing agreements with all parties allowing them sole distributing and marketing rights of Enbrel®.
- Public Health Service Act Sec. 262. Regulation of biological products.http://www.fda.gov/RegulatoryInformation/Legislation/ucm149278.htm
- Woodcock J, Griffin J, Behrman R, Cherney B, Crescenzi T, Fraser B, Hixon D, Joneckis C, Kozlowski S, Rosenberg A, Schrager L, Shacter E, Temple R, Webber K, Winkle H. The FDA’s assessment of follow-on protein products: a historical perspective. Nat Rev Drug Discov. 2007;6:437–442. doi: 10.1038/nrd2307. [PubMed] [Cross Ref]
- Yisaipu. http://www.cpgj-pharm.com/en/product_patient.asp?proid=22&action=intro
- Rondon F, Bautista A, Salazar JC, Casas N, Santos P, Vargas F, Marquez J. Etanar therapy in real-life patients with rheumatoid arthritis [abstract]Arthritis Rheum. 2010;62(Suppl 10):1811.
- Pipeline products. http://www.protalix.com/pipeline_products.html
- Biosimilar TuNEX® completes Phase I/II clinical trial in Taiwan, Phase I in Korea. http://www.mycenax.com.tw/webe/html/02news/news_show.aspx?page=1
- Singh K. Avesthagen gets patent for Enbrel biosimilar. Economic Times. 2010.
- Korea’s Celltrion and Aprogen in race to sell biosimilars in Japan.http://sis.windhover.com/buy/abstract.php?id=28101102003
- LG Life Sciences’ Pipeline Overview. http://thinklgls.com/rnd/pipeline
- Dr. Reddy’s Marketed Pharmaceutical Products.http://www.drreddys.com/products/bio_mproducts.html#
- TL011 in severe, active rheumatoid arthritis patients.http://clinicaltrials.gov/ct2/show/NCT01123070
- GP2013 in the treatment of RA patients refractory to or intolerant of standard therapy. http://www.clinicaltrials.gov/ct2/show/NCT01274182
- View Opportunities. http://www.sourcegenerics.com/viewAllListing.asp
- Rudick RA, Simonian NA, Alam JA, Campion M, Scaramucci JO, Jones W, Coats ME, Goodkin DE, Weinstock-Guttman B, Herndon RM, Mass MK, Richert JR, Salazar AM, Munschauer FE, Cookfair DL, Simon JH, Jacobs LD. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG)Neurology. 1998;50:1266–1272. [PubMed]
- Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, Ugo V, Teyssandier I, Varet B, Mayeux P. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346:469–475. doi: 10.1056/NEJMoa011931. [PubMed] [Cross Ref]
- Schellekens H, Jiskoot W. Eprex-associated pure red cell aplasia and leachates. Nat Biotechnol. 2006;24:613–614. doi: 10.1038/nbt0606-613.[PubMed] [Cross Ref]
- Bennett CL, Luminari S, Nissenson AR, Tallman MS, Klinge SA, McWilliams N, McKoy JM, Kim B, Lyons EA, Trifilio SM, Raisch DW, Evens AM, Kuzel TM, Schumock GT, Belknap SM, Locatelli F, Rossert J, Casadevall N. Pure red-cell aplasia and epoetin therapy. N Engl J Med. 2004;351:1403–1408. doi: 10.1056/NEJMoa040528. [PubMed] [Cross Ref]
- Federal Food, Drug, and Cosmetic Act (FD&C Act) SEC. 505. [21 USC §355] New Drugs.http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsandDevices/ucm108125.htm
- Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products. London: European Medicines Agency; 2005.
- Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London: European Medicines Agency; 2006.
- European Medicines Agency. Work plan for the biosimilar medicinal products working party (BMWP) 2011. London: European Medicines Agency; 2010.
- H. R. 3590–686. Patient Protection and Affordable Care Act. Title VII– Improving Access to Innovative Medical Therapies. Subtitle A–Biologics Price Competition and Innovation. Sec. 7002. Approval Pathway for Biosimilar Biological Products.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf
- Implementation of the Biologics Price Competition and Innovation Act of 2009.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm
see details of etanercept
Etanercept
ATC (Anatomical Therapeutic Chemical Classification)
L04AA11,L04AB01
CAS registry number (Chemical Abstracts Service)
0185243-69-0
Chemical Formula
C2224-H3472-N618-O701-S36
Molecular Weight
51238
Therapeutic Categories
Immunosuppressant
Disease-modifying antirheumatic drug, DMARD
Biological response modifier, BRM
Anti-inflammatory agent
Tumor necrosis factor alpha (TNF-α) inhibitor
Chemical Name
Dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1
is made from the combination of two naturally occurring soluble human 75-kilodalton TNF receptors linked to an Fc portion of an IgG1. The effect is an artificially engineered dimeric fusion protein.
• Sandoz continues to advance biosimilar pipeline with seven Phase III trials across five molecules
• Global program underscores Sandoz’s leadership in biosimilarsHolzkirchen, Germany, June 24, 2013 – Sandoz, the global leader in biosimilars, announced it has initiated a major Phase III clinical trial with its biosimilar version of etanercept (Amgen’s Enbrel®).
Read more at
http://www.drugs.com/news/novartis-begins-enbrel-phase-iii-trial-45414.html
| Etanercept (trade name Enbrel) is a biopharmaceutical that treats autoimmune diseases by interfering with tumor necrosis factor (TNF; a soluble inflammatory cytokine) by acting as a TNF inhibitor. It has U.S. F.D.A. approval to treat rheumatoid, juvenile rheumatoid andpsoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF-alpha is the “master regulator” of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha. Etanercept is a fusion protein produced by recombinant DNA. It fuses the TNF receptor to the constant end of the IgG1 antibody. First, the developers isolated the DNA sequence that codes the human gene for soluble TNF receptor 2, which is a receptor that binds to tumor necrosis factor-alpha. Second, they isolated the DNA sequence that codes the human gene for the Fc end of immunoglobulin G1 (IgG1). Third, they linked the DNA for TNF receptor 2 to the DNA for IgG1 Fc. Finally, they expressed the linked DNA to produce a protein that links the protein for TNF receptor 2 to the protein for IgG1 Fc.The prototypic fusion protein was first synthesized and shown to be highly active and unusually stable as a modality for blockade of TNF in vivo in the early 1990s by Bruce A. Beutler, an academic researcher then at the University of Texas Southwestern Medical Center at Dallas, and his colleagues.[2][3][4] These investigators also patented the protein, selling all rights to its use to Immunex, a biotechnology company that was acquired by Amgen in 2002.It is a large molecule, with a molecular weight of 150 kDa., that binds to TNFα and decreases its role in disorders involving excess inflammation in humans and other animals, including autoimmune diseases such as ankylosing spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and, potentially, in a variety of other disorders mediated by excess TNFα.In North America, etanercept is co-marketed by Amgen and Pfizer under the trade name Enbrel in two separate formulations, one in powder form, the other as a pre-mixed liquid. Wyeth is the sole marketer of Enbrel outside North America excluding Japan whereTakeda Pharmaceuticals markets the drug.Etanercept is an example of a protein-based drug created using the tools of biotechnologyand conceived through an understanding afforded by modern cell biology.  |
Figure 2: Molecule Key Patents landscape
International Market
Patents protecting the various technologies of the Etanercept molecule (Fig. 2) across all five families have now expired in Europe, Canada and Australia. In Europe, SPCs and paediatric extensions were granted based on the EP0418014 (1989-09-05) and EP0939121 (1989-09-12) however the last of the paediatric extensions expired in early August, 2015. Finland has been granted a national patent disclosing the Etanercept sequence in the family with priority US40324189A (1989-09-05), which would constrain generic entry until April, 2020. Cyprus has also received a five year patent extension on a national patent set to expire in mid-2016 and would be a constraint for biosimilars entering the market there.
Although the Etanercept molecule is no longer protected in the European, Canadian or Australian markets, no biosimilar has been approved in these major markets suggesting the difficulty of developing a biosimilar which complies with the stringent regulatory pathways in place. Having said that, Merck and Samsung Bioepis (a joint venture from electronics giant Samsung and biotech firm Biogen Idec) has submitted their Etanercept biosimilar candidate SB4 to the EMA, which is currently awaiting review. If approved, it is expected that they will obtain further approval in other territories where Etanercept is no longer protected. With the regulatory approval pathways differing from country to country, Etanercept biosimilars have been approved in smaller markets including India, China and South Korea.
US Market
In the US, the ‘molecule’ patents protecting active ingredient Etanercept have all expired aside from US8,063,182 (‘182) and US8,163,522 (‘522) members from priority CH331989 (1989-09-12) owned by Roche (exclusively licensed to Amgen), which are set to expire in 2028 and 2029, respectively. These patents members disclose a portion of the Etanercept sequence, so are considered to constrain biosimilar entry until expiry. The members are continuation patents filed from US5,610,279 (another member of the same family) and while they were both filed in May, 1995, were not issued until 2011 (‘182) and 2012 (‘522). Under the 35 U.S. Code § 154, these patents received 17 year patent term from the issuing date. Since these patents were applied for in 1995 during the transitional period of the TRIPS agreement, they were not published by the USPTO until they were issued. This situation often gives rise to the term ‘submarine patents’.
Currently there is no system to link relevant patents to biologic drugs in the US as with small molecule drugs (Orange Book) which makes filing biosimilars in the US a convoluted process. While the FDA are currently working on an equivalent to the Orange Book, the ‘Purple book’, companies wishing to develop biosimilars in the US need to do considerable patent landscape searching in order to avoid infringement of any patents potentially protecting the biologic drug. In the case of US member ‘182 and ‘522, upon inspection these patents are clearly relevant to Enbrel®, however without a registry there is no easy way of making this link. The patents have been flagged in the Key Patent module in Ark due to SPCs and paediatric extensions on the equivalent EP0939121 member and litigation in the US (see below).
Currently, biologic drugs approved in the US receive a 12 year data exclusivity period and in Europe, an 8 year data exclusivity period with additional 2 year market exclusivity, starting from the market authorisation date. Enbrel® was approved in 1998 and 2000, in the US and Europe, respectively and data exclusivity protection has therefore now expired.
Development of biosimilars takes considerably longer than generic medicine making it a costly venture for generic pharmaceutical manufacturers. According to Amgen, Enbrel® was protected by US5395760 (‘760) and US5605690 (‘690) members from priority 1989-09-05 which were set to lose patent protection in 2012 and 2014, respectively. In 2004, Sandoz began developing GP2015 a biosimilar equivalent of Etanercept, investing millions of dollars in the hope that they would be ready to launch by the time all the patent protection for Enbrel® expired. Currently, GP2015 is in Phase III study in the US and European Union for patients with moderate to severe chronic plaque-type psoriasis with respect to PASI 75 response rate at Week 12.
In June 2013, Sandoz filed a suit against Amgen and Roche in the US District Court for the Northern District of California seeking declaratory judgment of non-infringement, invalidity and unenforceability of the ‘182 and ‘522 patents. Sandoz claimed a ‘case of controversy’ regarding the patents, as their research and development was based on the understanding that ‘760 and ‘690 patents members were protecting Enbrel®. With the issuing of ‘182 and ‘522 patents this has essentially delayed the prospect of an Etanercept biosimilar from entering the US market until 2029.
Amgen and Roche sought a dismissal of the proceeding due to lack of subject matter jurisdiction, which was granted. Although Sandoz appealed the decision, the Court of Appeals affirmed the dismissal, since there was no real and immediate controversy as Sandoz had not yet filed an FDA application, and they had based their suit on future events and were not able to establish “real and immediate injury or threat of future injury.”
Cabozantinib, Cometriq
Cabozantinib (marketed under the tradename Cometriq, formerly known as XL184) is asmall molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and has been shown to reduce tumor growth, metastasis, and angiogenesis.
It was developed by Exelixis Inc.
Cabozantinib was granted orphan drug status by the U.S. Food and Drug Administration(FDA) in January 2011.
Cabozantinib was approved by the U.S. FDA in November 2012 for the treatment of medullary thyroid cancer.It is currently undergoing clinical trials for the treatment of prostate, ovarian, brain, melanoma, breast, non-small cell lung, pancreatic, hepatocellular and kidney cancers.
In October 2011, cabozantinib met its primary endpoint in a phase 3 clinical trial (EXAM) conducted by Exelixis investigating its effect on progression-free survival in medullary thyroid cancer.A new drug application was submitted in the first half of 2012, and on November 29, 2012 cabozantinib was granted marketing approval by the U.S. FDA under the name Cometriq for treating patients with medullary thyroid cancer.
Grapefruit and grapefruit juice should be avoided as they may increase the concentration of the drug in the blood.
It is not yet known if Cometriq is safe and effective in children.
In 2009 a phase II study for relapsed glioblastoma multiforme reported encouraging interim results.
Positive data from clinical trials in 2011 indicate cabozantinib is beneficial in metastatic advanced prostate cancer (castration-resistant prostate cancer). 97% of patients either had stabilization or improvement in bone malignancies. The median time to disease progression was 29 weeks.
One US trial reported in May 2011: The best results were seen in patients with liver, prostate, and ovarian cancer: 22 of 29 patients with liver cancer, 71 of 100 patients with prostate cancer, and 32 of 51 with ovarian cancer experienced either partial tumor shrinkage or stable disease. Fifty-nine out of 68 patients who had bone metastases had their metastases shrink or disappear during the trial.
A pivotal trial for thyroid cancer should report interim results mid-2011.
It is undergoing clinical trials for the treatment of prostate, ovarian, brain, melanoma, breast, non-small cell lung, hepatocellular and kidney cancers.
The U.S. Food and Drug Administration approved Exelixis Inc’s cabozantinib on November 29, 2012 as a treatment for medullary thyroid cancer (MTC) that has spread to other parts of the body.
Chemical Structure of Cabozantinib L-Malate Salt (Cometriq)
Name:Cabozantinib L-Malate;Cabozantinib S-Malate; XL 184; BMS907351
Chemical Name: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (2S)-2-Hydroxybutanedioic Acid
CAS Number: 1140909-48-3
Brand Name: Cometriq
Developer: Exelixis Inc(South San Francisco, California)
Approval Date: November 29th, 2012(US FDA)
Treatment for: Thyroid Cancer
Chemical Synthesis of Cabozantinib L-Malate Salt (Cometriq)
Reference for the Preparation of Cabozantinib L-Malate
1)St Clair Brown, Adrian; Lamb, Peter; Gallagher, William P.; Preparation of malate salts of N-[4-[[6,7-bis(methyloxy)quinolin-4-yl]oxy]phenyl]-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and crystalline forms thereof for the treatment of cancer; PCT Int. Appl. (2010), WO 2010083414
2)Bannen, Lynne Canne; Chan, Diva Sze-ming; Chen, Jeff; Dalrymple, Lisa Esther; Forsyth, Timothy Patrick; Huynh, Tai Phat; Jammalamadaka, Vasu; Khoury, Richard George; Leahy, James William; Mac, Morrison B.;Preparation of quinolines and quinazolines as inhibitors of c-Met and other tyrosine kinases and therapeutic uses against proliferative diseases; PCT Int. Appl. (2005), WO 2005030140 A2
Synthesis Cabozantinib into two fragments, one clip from the dicarboxylic acid 1 starts, one-pot method carboxylic acid 1 and after conversion to the acid chloride-fluoroaniline ( 2 ) reaction of 3 , 3 with oxalyl chloride into the acid chloride 4 . Another fragment from the 5 and 6 obtained by condensation of 7 , 7 obtained in the reduction of the nitro 8 , 8 and 4 in alkaline conditions condensation Cabozantinib.
Generic Licensing News-SPIRAMYCIN Featured product
SPIRAMYCIN
Spiramycin is a macrolide antibiotic. It is used to treat certain types of infections that are caused by bacteria. It is most commonly used to treat infections of the lung, skin, and mouth.
Spiramycin is sometimes used to treat gonorrhea for people who are allergic to penicillin. Spiramycin is also used as an alternative agent in the treatment of toxoplasmosis during pregnancy.
Spiramycin is a macrolide antibiotic. It is used to treat toxoplasmosisand various other infections of soft tissues. Although used in Europe, Canada and Mexico,[1] spiramycin is still considered an experimental drug in the United States, but can sometimes be obtained by special permission from the FDA for toxoplasmosis in the first trimester of pregnancy.[2]
Spiramycin has been used in Europe since the year 2000 under thetrade name “Rovamycine”, produced by Rhone-Poulenc Rorer and Famar Lyon, France and Eczacibasi Ilae, Turkey. It also goes under the name Rovamycine in Canada (distributed by OdanLaboratories), where it is mostly marketed to dentists for mouth infections.
Spiramycin is a 16-membered ring macrolide (antibiotic). It was discovered in 1952 as a product of Streptomyces ambofaciens. As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice. The antibacterial action involves inhibition of protein synthesis in the bacterial cell during translocation. Resistance to spiramycin can develop by several mechanisms and its prevalence is to a considerable extent proportional to the frequency of prescription in a given area. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium sp., Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action. As compared with erythromycin, it is in vitro weight for weight 5 to 20 less effective, an equipotential therapeutic dose is, however, only double. This difference between the effectiveness in vitro and in vivo is explained above all by the great affinity of spiramycin to tissues where it achieves concentrations many times higher than serum levels. An important part is played also by the slow release of the antibiotic from the tissue compartment, the marked action on microbes in sub-inhibition concentrations and the relatively long persisting post-antibiotic effect. Its great advantage is the exceptionally favourable tolerance-gastrointestinal and general. It is available for parenteral and oral administration
- Spiramycin advanced consumer information | Drugs.com
- Toxoplasmosis at MayoClinic.com
Hypertension- Maybe Your Blood’s too Thick
While watching the documentary Forks Over Knives I heard a physician explain that it was possible that a vegan diet may lower blood pressure by lowering the blood viscosity (thickness). He stated this in passing but to me it was earth-shaking. I have had thousands of patients with high blood pressure and am treating it on a daily basis. I have sat through countless lectures on hypertension and still to this day we do not really know what causes it. The leading explanations include increased sympathetic activity (think high adrenaline, anxiety), decrease kidney function with age, increased hormone called angiotensin II, or complex interaction of genetic factors. However all of these fail to really explain why obesity, inactivity and diet raise blood pressure.
When I heard that it could be the viscosity (thickness) of the blood I was overwhelmed by the simplicity of it. If the blood is thicker it…
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New Drug Approvals 